By Topic Area

NON-LINEAR DYNAMICS AND COMPLEXITY IN BRAINS AND CIRCUITS
Minati L, Faes L, Frasca M, Oświȩcimka P, Drożdż S.
Apparent remote synchronization of amplitudes: A demodulation and interference effect.
Chaos. 2018; 28:063124

In this paper, we show that novel autonomous chaotic oscillators based on one or two bipolar junction transistors and a limited number of passive components can be obtained via random search with suitable heuristics. Chaos is a pervasive occurrence in these circuits, particularly after manual adjustment of a variable resistor placed in series with the supply voltage source. Following this approach, 49 unique circuits generating chaotic signals when physically realized were designed, representing the largest collection of circuits of this kind to date. These circuits are atypical as they do not trivially map onto known topologies or variations thereof. They feature diverse spectra and predominantly anti-persistent monofractal dynamics. Notably, we recurrently found a circuit comprising one resistor, one transistor, two inductors, and one capacitor, which generates a range of attractors depending on the parameter values. We also found a circuit yielding an irregular quantized spike-train resembling some aspects of neural discharge and another one generating a double-scroll attractor, which represent the smallest known transistor-based embodiments of these behaviors. Through three representative examples, we additionally show that diffusive coupling of heterogeneous oscillators of this kind may give rise to complex entrainment, such as lag synchronization with directed information transfer and generalized synchronization. The replicability and reproducibility of the experimental findings are good.

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Scarpetta S, Apicella I, Minati L, de Candia A.
Hysteresis, neural avalanches, and critical behavior near a first-order transition of a spiking neural network.
Phys. Rev. E 2018; 97:062305

Many experimental results, both in vivo and in vitro, support the idea that the brain cortex operates near a critical point and at the same time works as a reservoir of precise spatiotemporal patterns. However, the mechanism at the basis of these observations is still not clear. In this paper we introduce a model which combines both these features, showing that scale-free avalanches are the signature of a system posed near the spinodal line of a first-order transition, with many spatiotemporal patterns stored as dynamical metastable attractors. Specifically, we studied a network of leaky integrate-and-fire neurons whose connections are the result of the learning of multiple spatiotemporal dynamical patterns, each with a randomly chosen ordering of the neurons. We found that the network shows a first-order transition between a low-spiking-rate disordered state (down), and a high-rate state characterized by the emergence of collective activity and the replay of one of the stored patterns (up). The transition is characterized by hysteresis, or alternation of up and down states, depending on the lifetime of the metastable states. In both cases, critical features and neural avalanches are observed. Notably, critical phenomena occur at the edge of a discontinuous phase transition, as recently observed in a network of glow lamps.

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Minati L, Frasca M, Yoshimura N, Koike Y.
Versatile locomotion control of a hexapod robot using a hierarchical network of non-linear oscillator circuits.
IEEE Access 2018; 99:2799145

A novel hierarchical network based on coupled nonlinear oscillators is proposed for motor pattern generation in hexapod robots. Its architecture consists of a Central Pattern Generator (CPG), producing the global leg coordination pattern, coupled with six Local Pattern Generators (LPGs), each devoted to generating the trajectory of one leg. Every node comprises a simple non-linear oscillator and is well-suited for implementation in a standard Field-Programmable Analog Array (FPAA) device. The network enables versatile locomotion control based on five high-level parameters which determine the inter-oscillator coupling pattern via simple rules. The controller was realized on dedicated hardware, deployed to control an ant-like hexapod robot, and multi-sensory telemetry was performed. As a function of a single parameter, it was able to stably reproduce the canonical gaits observed in six-legged insects, namely the wave, tetrapod and tripod gaits. A second parameter enabled driving the robot in ant-like and cockroach-like postures. Three further parameters enabled inhibiting and resuming walking, steering, and producing uncoordinated movement. Emergent phenomena were observed in the form of a multitude of intermediate gaits, and of hysteresis and metastability close to a point of gait transition. The primary contributions of this work reside in the hierarchical controller architecture and associated approach for collapsing a large set of low-level parameters, stemming from the complex hexapod kinematics, into only five high-level parameters. Such parameters can be changed dynamically, an aspect of broad practical relevance opening new avenues for driving hexapod robots via afferent signals from other circuits representing higher brain areas, or by means of suitable braincomputer interfaces. An additional contribution is the detailed characterization via telemetry of the physical robot, involving the definition of parameters which may aid future comparison with other controllers. The present results renew interest into analog CPG architectures and reinforce the generality of the connectionist approach.

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Minati L, Frasca M, Oświȩcimka P, Faes L, Drożdż S. Atypical transistor-based chaotic oscillators: Design, realization, and diversity.
Chaos. 2017; 27(7):073113

In this paper, we show that novel autonomous chaotic oscillators based on one or two bipolar junction transistors and a limited number of passive components can be obtained via random search with suitable heuristics. Chaos is a pervasive occurrence in these circuits, particularly after manual adjustment of a variable resistor placed in series with the supply voltage source. Following this approach, 49 unique circuits generating chaotic signals when physically realized were designed, representing the largest collection of circuits of this kind to date. These circuits are atypical as they do not trivially map onto known topologies or variations thereof. They feature diverse spectra and predominantly anti-persistent monofractal dynamics. Notably, we recurrently found a circuit comprising one resistor, one transistor, two inductors, and one capacitor, which generates a range of attractors depending on the parameter values. We also found a circuit yielding an irregular quantized spike-train resembling some aspects of neural discharge and another one generating a double-scroll attractor, which represent the smallest known transistor-based embodiments of these behaviors. Through three representative examples, we additionally show that diffusive coupling of heterogeneous oscillators of this kind may give rise to complex entrainment, such as lag synchronization with directed information transfer and generalized synchronization. The replicability and reproducibility of the experimental findings are good.

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Minati L, Winkel J, Bifone A, Oświęcimka P, Jovicich J.
Self-similarity and quasi-idempotence in neural networks and related dynamical systems.
Chaos. 2017; 27(4):043115

Self-similarity across length scales is pervasively observed in natural systems. Here, we investigate topological self-similarity in complex networks representing diverse forms of connectivity in the brain and some related dynamical systems, by considering the correlation between edges directly connecting any two nodes in a network and indirect connection between the same via all triangles spanning the rest of the network. We note that this aspect of self-similarity, which is distinct from hierarchically nested connectivity (coarse-grain similarity), is closely related to idempotence of the matrix representing the graph. We introduce two measures, ι(1) and ι(∞), which represent the element-wise correlation coefficients between the initial matrix and the ones obtained after squaring it once or infinitely many times, and term the matrices which yield large values of these parameters “quasi-idempotent”. These measures delineate qualitatively different forms of “shallow” and “deep” quasi-idempotence, which are influenced by nodal strength heterogeneity. A high degree of quasi-idempotence was observed for partially synchronized mean-field Kuramoto oscillators with noise, electronic chaotic oscillators, and cultures of dissociated neurons, wherein the expression of quasi-idempotence correlated strongly with network maturity. Quasi-idempotence was also detected for macro-scale brain networks representing axonal connectivity, synchronization of slow activity fluctuations during idleness, and co-activation across experimental tasks, and preliminary data indicated that quasi-idempotence of structural connectivity may decrease with ageing. This initial study highlights that the form of network self-similarity indexed by quasi-idempotence is detectable in diverse dynamical systems, and draws attention to it as a possible basis for measures representing network “collectivity” and pattern formation.

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Minati L, de Candia A, Scarpetta S.
Critical phenomena at a first-order phase transition in a lattice of glow lamps: Experimental findings and analogy to neural activity.
Chaos. 2016; 26(7):073103

Networks of non-linear electronic oscillators have shown potential as physical models of neural dynamics. However, two properties of brain activity, namely, criticality and metastability, remain under-investigated with this approach. Here, we present a simple circuit that exhibits both phenomena. The apparatus consists of a two-dimensional square lattice of capacitively coupled glow (neon) lamps. The dynamics of lamp breakdown (flash) events are controlled by a DC voltage globally connected to all nodes via fixed resistors. Depending on this parameter, two phases having distinct event rate and degree of spatiotemporal order are observed. The transition between them is hysteretic, thus a first-order one, and it is possible to enter a metastability region, wherein, approaching a spinodal point, critical phenomena emerge. Avalanches of events occur according to power-law distributions having exponents ≈3/2 for size and ≈2 for duration, and fractal structure is evident as power-law scaling of the Fano factor. These critical exponents overlap observations in biological neural networks; hence, this circuit may have value as building block to realize corresponding physical models.

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Minati L.
Remote synchronization of amplitudes across an experimental ring of non-linear oscillators.
Chaos 2015; 25(12):123107

In this paper, the emergence of remote synchronization in a ring of 32 unidirectionally coupled non-linear oscillators is reported. Each oscillator consists of 3 negative voltage gain stages connected in a loop to which two integrators are superimposed and receives input from its preceding neighbour via a “mixing” stage whose gains form the main system control parameters. Collective behaviour of the network is investigated numerically and experimentally, based on a custom-designed circuit board featuring 32 field-programmable analog arrays. A diverse set of synchronization patterns is observed depending on the control parameters. While phase synchronization ensues globally, albeit imperfectly, for certain control parameter values, amplitudes delineate subsets of non-adjacent but preferentially synchronized nodes; this cannot be trivially explained by synchronization paths along sequences of structurally connected nodes and is therefore interpreted as representing a form of remote synchronization. Complex topology of functional synchronization thus emerges from underlying elementary structural connectivity. In addition to the Kuramoto order parameter and cross-correlation coefficient, other synchronization measures are considered, and preliminary findings suggest that generalized synchronization may identify functional relationships across nodes otherwise not visible. Further work elucidating the mechanism underlying this observation of remote synchronization is necessary, to support which experimental data and board design materials have been made freely downloadable.

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Minati L.
Experimental Implementation of Networked Chaotic Oscillators Based on Cross-Coupled Inverter Rings in a CMOS Integrated Circuit.
J Circuit Syst Comp 2015; 24:1550144

A novel chaotic oscillator based on “cross-coupled” inverter rings is presented. The oscillator consists of a 3-ring to which higher odd n-rings are progressively coupled via diodes and pass gates; it does not contain reactive or resistive elements, and is thus suitable for area-efficient implementation on a CMOS integrated circuit. Numerical simulation based on piece-wise linear approximation predicted the generation of positive spikes having approximately constant periodicity but highly variable cycle amplitude. Simulation Program with Integrated Circuit Emphasis (SPICE) simulations and experimental data from a prototype realized on 0.7 μm technology confirmed this finding, and demonstrated increasing correlation dimension (D2) as 5-, 7- and 9-rings were progressively coupled to the 3-ring. Experimental data from a ring of 24 such oscillator cells showed phase synchronization and partial amplitude synchronization (formation of small clusters), emerging depending on DC gate voltage applied at NMOS transistors implementing diffusive coupling between neighboring cells. Thanks to its small area, simple synchronizability and digital controllability, the proposed circuit enables experimental investigation of dynamical complexity in large networks of coupled chaotic oscillators, and may additionally be suitable for applications such as broadband signal and random number generation.

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Minati L, Chiesa P, Tabarelli D, D'Incerti L, Jovicich J.
Synchronization, non-linear dynamics and low-frequency fluctuations: analogy between spontaneous brain activity and networked single-transistor chaotic oscillators.
Chaos 2015; 25(3):033107

In this paper, the topographical relationship between functional connectivity (intended as inter-regional synchronization), spectral and non-linear dynamical properties across cortical areas of the healthy human brain is considered. Based upon functional MRI acquisitions of spontaneous activity during wakeful idleness, node degree maps are determined by thresholding the temporal correlation coefficient among all voxel pairs. In addition, for individual voxel time-series, the relative amplitude of low-frequency fluctuations and the correlation dimension (D2), determined with respect to Fourier amplitude and value distribution matched surrogate data, are measured. Across cortical areas, high node degree is associated with a shift towards lower frequency activity and, compared to surrogate data, clearer saturation to a lower correlation dimension, suggesting presence of non-linear structure. An attempt to recapitulate this relationship in a network of single-transistor oscillators is made, based on a diffusive ring (n=90) with added long-distance links defining four extended hub regions. Similarly to the brain data, it is found that oscillators in the hub regions generate signals with larger low-frequency cycle amplitude fluctuations and clearer saturation to a lower correlation dimension compared to surrogates. The effect emerges more markedly close to criticality. The homology observed between the two systems despite profound differences in scale, coupling mechanism and dynamics appears noteworthy. These experimental results motivate further investigation into the heterogeneity of cortical non-linear dynamics in relation to connectivity and underline the ability for small networks of single-transistor oscillators to recreate collective phenomena arising in much more complex biological systems, potentially representing a future platform for modelling disease-related changes.

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Minati L.
Experimental synchronization of chaos in a large ring of mutually coupled single-transistor oscillators: phase, amplitude, and clustering effects.
Chaos 2014; 24(4):043108

In this paper, experimental evidence of multiple synchronization phenomena in a large (n = 30) ring of chaotic oscillators is presented. Each node consists of an elementary circuit, generating spikes of irregular amplitude and comprising one bipolar junction transistor, one capacitor, two inductors, and one biasing resistor. The nodes are mutually coupled to their neighbours via additional variable resistors. As coupling resistance is decreased, phase synchronization followed by complete synchronization is observed, and onset of synchronization is associated with partial synchronization, i.e., emergence of communities (clusters). While component tolerances affect community structure, the general synchronization properties are maintained across three prototypes and in numerical simulations. The clusters are destroyed by adding long distance connections with distant notes, but are otherwise relatively stable with respect to structural connectivity changes. The study provides evidence that several fundamental synchronization phenomena can be reliably observed in a network of elementary single-transistor oscillators, demonstrating their generative potential and opening way to potential applications of this undemanding setup in experimental modelling of the relationship between network structure, synchronization, and dynamical properties.

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Minati L.
Experimental dynamical characterization of five autonomous chaotic oscillators with tunable series resistance.
Chaos 2014; 24(3):033110

In this paper, an experimental characterization of the dynamical properties of five autonomous chaotic oscillators, based on bipolar-junction transistors and obtained de-novo through a genetic algorithm in a previous study, is presented. In these circuits, a variable resistor connected in series to the DC voltage source acts as control parameter, for a range of which the largest Lyapunov exponent, correlation dimension, approximate entropy, and amplitude variance asymmetry are calculated, alongside bifurcation diagrams and spectrograms. Numerical simulations are compared to experimental measurements. The oscillators can generate a considerable variety of regular and chaotic sine-like and spike-like signals.

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Minati L.
Emergence of chaos in transistor circuits evolved towards maximization of approximate signal entropy. 8th Intl Symp.
Image and Signal Proc Analysis ISPA2013; 748-753

Chaotic signals have emerging applications which include masking, secure communication and dynamical modeling of biological systems. However, no general methodology for synthesizing chaotic oscillators presently exists. Here, it is shown that chaotic oscillators can be obtained through genetic optimization of the topology of bipolar transistor-based circuits aimed at maximization of approximate signal entropy. A selection of circuits were physically realized and characterized, with features resembling previously-described chaotic oscillators that had been designed by empirical modification of traditional oscillators or implementation of differential equation systems known a-priori to be chaotic. The proposed approach offers a novel means to generate chaotic signal sources without prior topological assumptions, and the emergence of chaos from signal entropy maximization has potential implications for the study of biological neural networks.

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HARDWARE COPROCESSORS FOR FUNCTIONAL MRI ANALYSIS, ROBOTICS, OTHER NEUROTECHNOLOGY
Minati L, Frasca M, Yoshimura N, Koike Y.
Versatile locomotion control of a hexapod robot using a hierarchical network of non-linear oscillator circuits.
IEEE Access 2018; 99:2799145

A novel hierarchical network based on coupled nonlinear oscillators is proposed for motor pattern generation in hexapod robots. Its architecture consists of a Central Pattern Generator (CPG), producing the global leg coordination pattern, coupled with six Local Pattern Generators (LPGs), each devoted to generating the trajectory of one leg. Every node comprises a simple non-linear oscillator and is well-suited for implementation in a standard Field-Programmable Analog Array (FPAA) device. The network enables versatile locomotion control based on five high-level parameters which determine the inter-oscillator coupling pattern via simple rules. The controller was realized on dedicated hardware, deployed to control an ant-like hexapod robot, and multi-sensory telemetry was performed. As a function of a single parameter, it was able to stably reproduce the canonical gaits observed in six-legged insects, namely the wave, tetrapod and tripod gaits. A second parameter enabled driving the robot in ant-like and cockroach-like postures. Three further parameters enabled inhibiting and resuming walking, steering, and producing uncoordinated movement. Emergent phenomena were observed in the form of a multitude of intermediate gaits, and of hysteresis and metastability close to a point of gait transition. The primary contributions of this work reside in the hierarchical controller architecture and associated approach for collapsing a large set of low-level parameters, stemming from the complex hexapod kinematics, into only five high-level parameters. Such parameters can be changed dynamically, an aspect of broad practical relevance opening new avenues for driving hexapod robots via afferent signals from other circuits representing higher brain areas, or by means of suitable braincomputer interfaces. An additional contribution is the detailed characterization via telemetry of the physical robot, involving the definition of parameters which may aid future comparison with other controllers. The present results renew interest into analog CPG architectures and reinforce the generality of the connectionist approach.

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Minati L, Yoshimura N, Koike Y.
Hybrid Control of a Vision-Guided Robot Arm by EOG, EMG, EEG Biosignals and Head Movement Acquired via a Consumer-Grade Wearable Device.
IEEE Access 2016; 4:9528-9541

Simultaneous acquisition of electrooculogram, jaw electromyogram, electroencephalogram, and head movement via consumer-grade wearable devices has become possible. Such devices offer new opportunities to deploy practical biosignal-based interfaces for assistive robots; however, they also pose challenges related to the available signals and their characteristics. In this proof-of-concept study, we demonstrate the possibility of successful control of a 5 + 1 degrees-of-freedom robot arm based on a consumer wireless headband in the form of four control modes predicated on distinct signal combinations. We propose a control approach hybrid at two levels, which seeks a compromise between robot controllability and maintaining the user goal rather than being process-focused. First, robot arm steering combines discrete and proportional aspects. Second, after the robot has been steered toward the approximate target direction, a sparse approach is followed and the user only needs to issue a single command, after which steering adjustment and grasping are performed automatically under stereoscopic vision guidance. We present in detail the associated algorithms, whose implementation is publicly available. Within this framework, we also demonstrate the control of arm posture and grasping force based, respectively, on object visual features and user input. We regard the interface proposed herein as a viable blueprint for future work on controlling wheelchair-mounted and meal-assisting robot arms.

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Minati L, Zacà D, D'Incerti L, Jovicich J.
Fast computation of voxel-level brain connectivity maps from resting-state functional MRI using l1-norm as approximation of Pearson's temporal correlation: proof-of-concept and example vector hardware implementation.
Med Eng Phys 2014, 36(9):1212-7

An outstanding issue in graph-based analysis of resting-state functional MRI is choice of network nodes. Individual consideration of entire brain voxels may represent a less biased approach than parcellating the cortex according to pre-determined atlases, but entails establishing connectedness for 19–111 links, with often prohibitive computational cost. Using a representative Human Connectome Project dataset, we show that, following appropriate time-series normalization, it may be possible to accelerate connectivity determination replacing Pearson correlation with l1-norm. Even though the adjacency matrices derived from correlation coefficients and l1-norms are not identical, their similarity is high. Further, we describe and provide in full an example vector hardware implementation of l1-norm on an array of 4096 zero instruction-set processors. Calculation times

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Minati L, Nigri A, Cercignani M, Chan D.
Detection of scale-freeness in brain connectivity by functional MRI: signal processing aspects and implementation of an open hardware co-processor.
Med Eng Phys 2013; 35(10):1525-1531

An outstanding issue in graph-theoretical studies of brain functional connectivity is the lack of formal criteria for choosing parcellation granularity and correlation threshold. Here, we propose detectability of scale-freeness as a benchmark to evaluate time-series extraction settings. Scale-freeness, i.e., power-law distribution of node connections, is a fundamental topological property that is highly conserved across biological networks, and as such needs to be manifest within plausible reconstructions of brain connectivity. We demonstrate that scale-free network topology only emerges when adequately fine cortical parcellations are adopted alongside an appropriate correlation threshold, and provide the full design of the first open-source hardware platform to accelerate the calculation of large linear regression arrays.

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Minati L, Cercignani M, Chan D.
Rapid geodesic mapping of brain functional connectivity: implementation of a dedicated co-processor in a field-programmable gate array and application to resting state fMRI.
Med Eng Phys 2013; 35(10):1532-1539

Graph theory-based analyses of brain network topology can be used to model the spatiotemporal correlations in neural activity detected through fMRI, and such approaches have wide-ranging potential, from detection of alterations in preclinical Alzheimer’s disease through to command identification in brain–machine interfaces. However, due to prohibitive computational costs, graph-based analyses to date have principally focused on measuring connection density rather than mapping the topological architecture in full by exhaustive shortest-path determination. This paper outlines a solution to this problem through parallel implementation of Dijkstra’s algorithm in programmable logic. The processor design is optimized for large, sparse graphs and provided in full as synthesizable VHDL code. An acceleration factor between 15 and 18 is obtained on a representative resting-state fMRI dataset, and maps of Euclidean path length reveal the anticipated heterogeneous cortical involvement in long-range integrative processing. These results enable high-resolution geodesic connectivity mapping for resting-state fMRI in patient populations and real-time geodesic mapping to support identification of imagined actions for fMRI-based brain–machine interfaces.

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Minati L, Nigri A, Rosazza C, Bruzzone MG.
Thoughts turned into high-level commands: Proof-of-concept study of a vision-guided robot arm driven by functional MRI (fMRI) signals.
Med Eng Phys. 2012; 34(5):650-8

Previous studies have demonstrated the possibility of using functional MRI to control a robot arm through a brain–machine interface by directly coupling haemodynamic activity in the sensory–motor cortex to the position of two axes. Here, we extend this work by implementing interaction at a more abstract level, whereby imagined actions deliver structured commands to a robot arm guided by a machine vision system. Rather than extracting signals from a small number of pre-selected regions, the proposed system adaptively determines at individual level how to map representative brain areas to the input nodes of a classifier network. In this initial study, a median action recognition accuracy of 90% was attained on five volunteers performing a game consisting of collecting randomly positioned coloured pawns and placing them into cups. The “pawn” and “cup” instructions were imparted through four mental imaginery tasks, linked to robot arm actions by a state machine. With the current implementation in MatLab language the median action recognition time was 24.3 s and the robot execution time was 17.7 s. We demonstrate the notion of combining haemodynamic brain–machine interfacing with computer vision to implement interaction at the level of high-level commands rather than individual movements, which may find application in future fMRI approaches relevant to brain-lesioned patients, and provide source code supporting further work on larger command sets and real-time processing.

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Minati L, Rosazza C, Zucca I, D'Incerti L, Scaioli V, Bruzzone MG.
Spatial Correspondence Between Functional MRI (fMRI) Activations and Cortical Current Density Maps of Event-Related Potentials (ERP): A Study with Four Tasks.
Brain Topogr 2008; 21(2):112-27

We investigated the spatial correspondence between functional MRI (fMRI) activations and cortical current density maps of event-related potentials (ERPs) reconstructed without fMRI priors. The presence of a significant spatial correspondence is a prerequisite for direct integration of the two modalities, enabling to combine the high spatial resolution of fMRI with the high temporal resolution of ERPs. Four separate tasks were employed: visual stimulation with a pattern-reversal chequerboard, recognition of images of nameable objects, recognition of written words, and auditory stimulation with a piano note. ERPs were acquired with 19 recording channels, and source localisation was performed using a realistic head model, a standard cortical mesh and the multiple sparse priors method. Spatial correspondence was evaluated at group level over 10 subjects, by means of a voxel-by-voxel test and a test on the distribution of local maxima. Although not complete, it was significant for the visual stimulation task, image and word recognition tasks (P < 0.001 for both types of test), but not for the auditory stimulation task. These findings indicate that partial but significant spatial correspondence between the two modalities can be found even with a small number of channels, for three of the four tasks employed. Absence of correspondence for the auditory stimulation task was caused by the unfavourable situation of the activated cortex being perpendicular to the overlying scalp, whose consequences were exacerbated by the small number of channels. The present study corroborates existing literature in this field, and may be of particular relevance to those interested in combining fMRI with ERPs acquired with the standard 10-20 system.

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Minati L, Ghielmetti F, Ciobanu V, D'Incerti L, Maccagnano C, Bizzi A, Bruzzone MG.
Bio-image warehouse system: concept and implementation of a diagnosis-based data warehouse for advanced imaging modalities in neuroradiology.
J Digit Imaging. 2007; 20(1):32-41

Advanced neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), chemical shift spectroscopy imaging (CSI), diffusion tensor imaging (DTI), and perfusion-weighted imaging (PWI) create novel challenges in terms of data storage and management: huge amounts of raw data are generated, the results of analysis may depend on the software and settings that have been used, and most often intermediate files are inherently not compliant with the current DICOM (digital imaging and communication in medicine) standard, as they contain multidimensional complex and tensor arrays and various other types of data structures. A software architecture, referred to as Bio-Image Warehouse System (BIWS), which can be used alongside a radiology information system/picture archiving and communication system (RIS/PACS) system to store neuroimaging data for research purposes, is presented. The system architecture is conceived with the purpose of enabling to query by diagnosis according to a predefined two-layered classification taxonomy. The operational impact of the system and the time needed to get acquainted with the web-based interface and with the taxonomy are found to be limited. The development of modules enabling automated creation of statistical templates is proposed.

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Minati L, Zorat A.
A tree architecture with hierarchical data processing on a sensor-rich hexapod robot.
Advanced Robotics 2002; 14:595-608

This paper presents the hardware and software architecture of Golem, a hexapod robot designed as a flexible, scalable, general purpose development and experimenting tool targeted to academia, industry, and defense environments. The system is technologically innovative in its architecture, performance, size and integration, and is industrially promising in its filling the gap between low-performance commercial solutions and costly application-specific proprietary solutions.

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RESTING-STATE FUNCTIONAL MRI METHODS AND APPLICATIONS
Marchitelli R, Minati L, Marizzoni M, Bosch B, Bartrés-Faz D, Müller BW, Wiltfang J, Fiedler U, Roccatagliata L, Picco A, Nobili F, Blin O, Bombois S, Lopes R, Bordet R, Sein J, Ranjeva JP, Didic M, Gros-Dagnac H, Payoux P, Zoccatelli G, Alessandrini F, Beltramello A, Bargalló N, Ferretti A, Caulo M, Aiello M, Cavaliere C, Soricelli A, Parnetti L, Tarducci R, Floridi P, Tsolaki M, Constantinidis M, Drevelegas A, Rossini PM, Marra C, Schönknecht P, Hensch T, Hoffmann KT, Kuijer JP, Visser PJ, Barkhof F, Frisoni GB, Jovicich J.
Test-retest reliability of the default mode network in a multi-centric fMRI study of healthy elderly: Effects of data-driven physiological noise correction techniques.
Hum Brain Mapp. 2016; 37(6):2114-32

Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within-site test-retest reliability and the across-site reproducibility consistency of DMN-derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue-based regression, PESTICA and FSL-FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z-scores and, albeit less markedly, the cluster-size in the DMN; in particular, FSL-FIX tended to increase the DMN z-scores compared to others. Within-site test-retest reliability was consistent across sites, with no differences across rPNC methods. The absolute percent errors were in the range of 5-11% for DMN z-scores and cluster-size reliability. DMN pattern overlap was in the range 60-65%. In particular, no rPNC method showed a significant reliability improvement relative to NPC. However, FSL-FIX and Tissue-based physiological correction methods showed both similar and significant improvements of reproducibility consistency across the consortium (ICC = 0.67) for the DMN z-scores relative to NPC. Overall these findings support the use of rPNC methods like tissue-based or FSL-FIX to characterize multisite longitudinal changes of intrinsic functional connectivity.

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Rosazza C, Andronache A, Sattin D, Bruzzone MG, Marotta G, Nigri A, Ferraro S, Sebastiano DR, Porcu L, Bersano A, Benti R, Leonardi M, D'Incerti L, Minati L, Coma Research Centre (CRC) - Besta Institute.
Multimodal study of default-mode network integrity in disorders of consciousness.
Ann Neurol. 2016; 79(5):841-853

OBJECTIVE: Understanding residual brain function in Disorders of Consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default-mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting-state functional MRI (rs-fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment.
METHODS: We enrolled 119 consecutive patients: 72 vegetative state/unresponsive wakefulness state (VS/UWS), 36 minimally-conscious state (MCS) and 11 severe disability. All underwent structural MRI and rs-fMRI, and a subset also performed FDG-PET. Data were analyzed with manual and automatic approaches, in relation to diagnosis and clinical score.
RESULTS: Excluding the quartile with largest head movement, DMN activity was decreased in VS/UWS compared to MCS, and correlated with clinical score. Independent-component and seed-based analyses provided similar results, though the latter and their combination were most informative. Structural MRI and FDG-PET were less sensitive to head movement and had superior diagnostic accuracy than rs-fMRI only when all cases were included. Rs-fMRI indicated relatively preserved DMN activity in a small subset of VS/UWS patients, two of whom evolved to MCS. The integrity of the left hemisphere appears predictive of a better clinical status.
INTERPRETATION: Rs-fMRI of the DMN is sensitive to clinical severity. The effect is consistent across data analysis approaches, but heavily dependent on head movement. Rs-fMRI could be informative to detect residual DMN activity for those patients that remain relatively still during scanning and whose diagnosis is uncertain. This article is protected by copyright. All rights reserved.

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Jovicich J, Minati L, Marizzoni M, Marchitelli R, Sala-Llonch R, Bartrés-Faz D, Arnold J, Benninghoff J, Fiedler U, Roccatagliata L, Picco A, Nobili F, Blin O, Bombois S, Lopes R, Bordet R, Sein J, Ranjeva JP, Didic M, Gros-Dagnac H, Payoux P, Zoccatelli G, Alessandrini F, Beltramello A, Bargalló N, Ferretti A, Caulo M, Aiello M, Cavaliere C, Soricelli A, Parnetti L, Tarducci R, Floridi P, Tsolaki M, Constantinidis M, Drevelegas A, Rossini PM, Marra C, Schönknecht P, Hensch T, Hoffmann KT, Kuijer JP, Visser PJ, Scheltens P, Frisoni GB; PharmaCog Consortium.
Longitudinal reproducibility of default-mode network connectivity in healthy elderly participants: A multicentric resting-state fMRI study.
Neuroimage 2016; 124:442-54

To date, limited data are available regarding the inter-site consistency of test–retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0 T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test–retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test–retest reproducibility in the consortium was high (ICC = 0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test–retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈ 4% test–retest error, ICC = 0.85), the medial frontal cortex the least reliable (≈ 12%, ICC = 0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.

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Minati L, Chiesa P, Tabarelli D, D'Incerti L, Jovicich J.
Synchronization, non-linear dynamics and low-frequency fluctuations: analogy between spontaneous brain activity and networked single-transistor chaotic oscillators.
Chaos 2015; 25(3):033107

In this paper, the topographical relationship between functional connectivity (intended as inter-regional synchronization), spectral and non-linear dynamical properties across cortical areas of the healthy human brain is considered. Based upon functional MRI acquisitions of spontaneous activity during wakeful idleness, node degree maps are determined by thresholding the temporal correlation coefficient among all voxel pairs. In addition, for individual voxel time-series, the relative amplitude of low-frequency fluctuations and the correlation dimension (D2), determined with respect to Fourier amplitude and value distribution matched surrogate data, are measured. Across cortical areas, high node degree is associated with a shift towards lower frequency activity and, compared to surrogate data, clearer saturation to a lower correlation dimension, suggesting presence of non-linear structure. An attempt to recapitulate this relationship in a network of single-transistor oscillators is made, based on a diffusive ring (n=90) with added long-distance links defining four extended hub regions. Similarly to the brain data, it is found that oscillators in the hub regions generate signals with larger low-frequency cycle amplitude fluctuations and clearer saturation to a lower correlation dimension compared to surrogates. The effect emerges more markedly close to criticality. The homology observed between the two systems despite profound differences in scale, coupling mechanism and dynamics appears noteworthy. These experimental results motivate further investigation into the heterogeneity of cortical non-linear dynamics in relation to connectivity and underline the ability for small networks of single-transistor oscillators to recreate collective phenomena arising in much more complex biological systems, potentially representing a future platform for modelling disease-related changes.

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Minati L, Zacà D, D'Incerti L, Jovicich J.
Fast computation of voxel-level brain connectivity maps from resting-state functional MRI using l1-norm as approximation of Pearson's temporal correlation: proof-of-concept and example vector hardware implementation.
Med Eng Phys 2014, 36(9):1212-7

An outstanding issue in graph-based analysis of resting-state functional MRI is choice of network nodes. Individual consideration of entire brain voxels may represent a less biased approach than parcellating the cortex according to pre-determined atlases, but entails establishing connectedness for 19–111 links, with often prohibitive computational cost. Using a representative Human Connectome Project dataset, we show that, following appropriate time-series normalization, it may be possible to accelerate connectivity determination replacing Pearson correlation with l1-norm. Even though the adjacency matrices derived from correlation coefficients and l1-norms are not identical, their similarity is high. Further, we describe and provide in full an example vector hardware implementation of l1-norm on an array of 4096 zero instruction-set processors. Calculation times <1000 s are attainable, removing the major deterrent to voxel-based resting-sate network mapping and revealing fine-grained node degree heterogeneity. L1-norm should be given consideration as a substitute for correlation in very high-density resting-state functional connectivity analyses.

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Rosazza C, Aquino D, D'Incerti L, Cordella R, Andronache A, Zacà D, Bruzzone MG, Tringali G, Minati L
Preoperative mapping of the sensorimotor cortex: comparative assessment of task-based and resting-state FMRI.
PLoS One 2014; 9(6):e98860

Resting state fMRI (rs-fMRI) has recently been considered as a possible complement or alternative to task-based fMRI (tb-fMRI) for presurgical mapping. However, evidence of its usefulness remains scant, because existing studies have investigated relatively small samples and focused primarily on qualitative evaluation. The aim of this study is to investigate the clinical usefulness of rs-fMRI in the context of presurgical mapping of motor functions, and in particular to determine the degree of correspondence with tb-fMRI which, while not a gold-standard, is commonly used in preoperative setting. A group of 13 patients with lesions close to the sensorimotor cortex underwent rs-fMRI and tb-fMRI to localize the hand, foot and mouth motor areas. We assessed quantitatively the degree of correspondence between multiple rs-fMRI analyses (independent-component and seed-based analyses) and tb-fMRI, with reference to sensitivity and specificity of rs-fMRI with respect to tb-fMRI, and centre-of-mass distances. Agreement with electro-cortical stimulation (ECS) was also investigated, and a traditional map thresholding approach based on agreement between two experienced operators was compared to an automatic threshold determination method. Rs-fMRI can localize the sensorimotor cortex successfully, providing anatomical specificity for hand, foot and mouth motor subregions, in particular with seed-based analyses. Agreement with tb-fMRI was only partial and rs-fMRI tended to provide larger patterns of correlated activity. With respect to the ECS data available, rs-fMRI and tb-fMRI performed comparably, even though the shortest distance to stimulation points was observed for the latter. Notably, the results of both were on the whole robust to thresholding procedure. Localization performed by rs-fMRI is not equivalent to tb-fMRI, hence rs-fMRI cannot be considered as an outright replacement for tb-fMRI. Nevertheless, since there is significant agreement between the two techniques, rs-fMRI can be considered with caution as a potential alternative to tb-fMRI when patients are unable to perform the task.

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Minati L, Chan D, Mastropasqua C, Serra L, Spanò B, Marra C, Caltagirone C, Cercignani M, Bozzali M.
Widespread alterations in functional brain network architecture in amnestic mild cognitive impairment.
J Alzheimer Dis 2014; 40(1):213-20

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer’s disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

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Minati L, Nigri A, Cercignani M, Chan D.
Detection of scale-freeness in brain connectivity by functional MRI: signal processing aspects and implementation of an open hardware co-processor.
Med Eng Phys 2013; 35(10):1525-1531

An outstanding issue in graph-theoretical studies of brain functional connectivity is the lack of formal criteria for choosing parcellation granularity and correlation threshold. Here, we propose detectability of scale-freeness as a benchmark to evaluate time-series extraction settings. Scale-freeness, i.e., power-law distribution of node connections, is a fundamental topological property that is highly conserved across biological networks, and as such needs to be manifest within plausible reconstructions of brain connectivity. We demonstrate that scale-free network topology only emerges when adequately fine cortical parcellations are adopted alongside an appropriate correlation threshold, and provide the full design of the first open-source hardware platform to accelerate the calculation of large linear regression arrays.

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Minati L, Cercignani M, Chan D.
Rapid geodesic mapping of brain functional connectivity: implementation of a dedicated co-processor in a field-programmable gate array and application to resting state fMRI.
Med Eng Phys 2013; 35(10):1532-1539

Graph theory-based analyses of brain network topology can be used to model the spatiotemporal correlations in neural activity detected through fMRI, and such approaches have wide-ranging potential, from detection of alterations in preclinical Alzheimer’s disease through to command identification in brain–machine interfaces. However, due to prohibitive computational costs, graph-based analyses to date have principally focused on measuring connection density rather than mapping the topological architecture in full by exhaustive shortest-path determination. This paper outlines a solution to this problem through parallel implementation of Dijkstra’s algorithm in programmable logic. The processor design is optimized for large, sparse graphs and provided in full as synthesizable VHDL code. An acceleration factor between 15 and 18 is obtained on a representative resting-state fMRI dataset, and maps of Euclidean path length reveal the anticipated heterogeneous cortical involvement in long-range integrative processing. These results enable high-resolution geodesic connectivity mapping for resting-state fMRI in patient populations and real-time geodesic mapping to support identification of imagined actions for fMRI-based brain–machine interfaces.

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Andronache A, Rosazza C, Sattin D, Leonardi M, D'Incerti L, Minati L
Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness.
Front NeuroInform 2013; 7:16

An emerging application of resting-state functional MRI (rs-fMRI) is the study of patients with disorders of consciousness (DoC), where integrity of default-mode network (DMN) activity is associated to the clinical level of preservation of consciousness. Due to the inherent inability to follow verbal instructions, arousal induced by scanning noise and postural pain, these patients tend to exhibit substantial levels of movement. This results in spurious, non-neural fluctuations of the rs-fMRI signal, which impair the evaluation of residual functional connectivity. Here, the effect of data preprocessing choices on the detectability of the DMN was systematically evaluated in a representative cohort of 30 clinically and etiologically heterogeneous DoC patients and 33 healthy controls. Starting from a standard preprocessing pipeline, additional steps were gradually inserted, namely band-pass filtering (BPF), removal of co-variance with the movement vectors, removal of co-variance with the global brain parenchyma signal, rejection of realignment outlier volumes and ventricle masking. Both independent-component analysis (ICA) and seed-based analysis (SBA) were performed, and DMN detectability was assessed quantitatively as well as visually. The results of the present study strongly show that the detection of DMN activity in the sub-optimal fMRI series acquired on DoC patients is contingent on the use of adequate filtering steps. ICA and SBA are differently affected but give convergent findings for high-grade preprocessing. We propose that future studies in this area should adopt the described preprocessing procedures as a minimum standard to reduce the probability of wrongly inferring that DMN activity is absent.

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Rosazza C, Minati L, Ghielmetti F, Mandelli ML, Bruzzone MG.
Functional Connectivity during Resting-State Functional MR Imaging: Study of the Correspondence between Independent Component Analysis and Region-of-Interest-Based Methods.
AJNR Am J Neuroradiol 2012; 33(1):180-7

BACKGROUND AND PURPOSE: The connectivity across brain regions can be evaluated through fMRI either by using ICA or by means of correlation analysis of time courses measured in predefined ROIs. The purpose of this study was to investigate quantitatively the correspondence between the connectivity information provided by the 2 techniques.
MATERIALS AND METHODS: In this study, resting-state fMRI data from 40 healthy participants were independently analyzed by using spatial ICA and ROI−based analysis. To assess the correspondence between the results provided by the 2 methods, for all combinations of ROIs, we compared the time course correlation coefficient with the corresponding “ICA coactivation index.”
RESULTS: A strongly significant correspondence of moderate intensity was found for 20 ICA components (r = 0.44, P < .001). Repeating the analysis with 10, 15, 25, 30, 35, and 40 components, we found that the correlation remained but was weaker (r = 0.35–0.41).
CONCLUSIONS: There is a significant but not complete correspondence between the results provided by ICA and ROI−based analysis of resting-state data.

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Rosazza C, Minati L
Resting-state brain networks: literature review and clinical applications.
Neurol Sci 2011; 32(5):773-85

This review focuses on resting-state functional connectivity, a functional MRI technique which allows the study of spontaneous brain activity generated under resting conditions. This approach is useful to explore the brain’s functional organization and to examine if it is altered in neurological or psychiatric diseases. Resting-state functional connectivity has revealed a number of networks which are consistently found in healthy subjects and represent specific patterns of synchronous activity. In this review, we examine the behavioral, physiological and neurological evidences relevant to this coherent brain activity and, in particular, to each network. The investigation of functional connectivity appears promising from a clinical perspective, considering the amount of evidence regarding the importance of spontaneous activity and that resting-state paradigms are inherently simple to implement. We also discuss some examples of existing clinical applications, such as in Alzheimer’s disease, and emerging possibilities such as in pre-operative mapping and disorders of consciousness.

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GRAPH-BASED BRAIN CONNECTIVITY ANALYSIS
Minati L, Winkel J, Bifone A, Oświęcimka P, Jovicich J.
Self-similarity and quasi-idempotence in neural networks and related dynamical systems.
Chaos. 2017; 27(4):043115

Self-similarity across length scales is pervasively observed in natural systems. Here, we investigate topological self-similarity in complex networks representing diverse forms of connectivity in the brain and some related dynamical systems, by considering the correlation between edges directly connecting any two nodes in a network and indirect connection between the same via all triangles spanning the rest of the network. We note that this aspect of self-similarity, which is distinct from hierarchically nested connectivity (coarse-grain similarity), is closely related to idempotence of the matrix representing the graph. We introduce two measures, ι(1) and ι(∞), which represent the element-wise correlation coefficients between the initial matrix and the ones obtained after squaring it once or infinitely many times, and term the matrices which yield large values of these parameters “quasi-idempotent”. These measures delineate qualitatively different forms of “shallow” and “deep” quasi-idempotence, which are influenced by nodal strength heterogeneity. A high degree of quasi-idempotence was observed for partially synchronized mean-field Kuramoto oscillators with noise, electronic chaotic oscillators, and cultures of dissociated neurons, wherein the expression of quasi-idempotence correlated strongly with network maturity. Quasi-idempotence was also detected for macro-scale brain networks representing axonal connectivity, synchronization of slow activity fluctuations during idleness, and co-activation across experimental tasks, and preliminary data indicated that quasi-idempotence of structural connectivity may decrease with ageing. This initial study highlights that the form of network self-similarity indexed by quasi-idempotence is detectable in diverse dynamical systems, and draws attention to it as a possible basis for measures representing network “collectivity” and pattern formation.

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Minati L, Chan D, Mastropasqua C, Serra L, Spanò B, Marra C, Caltagirone C, Cercignani M, Bozzali M.
Widespread alterations in functional brain network architecture in amnestic mild cognitive impairment.
J Alzheimer Dis 2014; 40(1):213-20

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer’s disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

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Minati L, Zacà D, D'Incerti L, Jovicich J.
Fast computation of voxel-level brain connectivity maps from resting-state functional MRI using l1-norm as approximation of Pearson's temporal correlation: proof-of-concept and example vector hardware implementation.
Med Eng Phys 2014, 36(9):1212-7

An outstanding issue in graph-based analysis of resting-state functional MRI is choice of network nodes. Individual consideration of entire brain voxels may represent a less biased approach than parcellating the cortex according to pre-determined atlases, but entails establishing connectedness for 19–111 links, with often prohibitive computational cost. Using a representative Human Connectome Project dataset, we show that, following appropriate time-series normalization, it may be possible to accelerate connectivity determination replacing Pearson correlation with l1-norm. Even though the adjacency matrices derived from correlation coefficients and l1-norms are not identical, their similarity is high. Further, we describe and provide in full an example vector hardware implementation of l1-norm on an array of 4096 zero instruction-set processors. Calculation times <1000 s are attainable, removing the major deterrent to voxel-based resting-sate network mapping and revealing fine-grained node degree heterogeneity. L1-norm should be given consideration as a substitute for correlation in very high-density resting-state functional connectivity analyses.

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Minati L, Sigala N.
Effective connectivity reveals strategy differences in an expert calculator.
PLoS ONE 2013; 8(9):e73746

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material.

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Minati L, Nigri A, Cercignani M, Chan D.
Detection of scale-freeness in brain connectivity by functional MRI: signal processing aspects and implementation of an open hardware co-processor.
Med Eng Phys 2013; 35(10):1525-1531

An outstanding issue in graph-theoretical studies of brain functional connectivity is the lack of formal criteria for choosing parcellation granularity and correlation threshold. Here, we propose detectability of scale-freeness as a benchmark to evaluate time-series extraction settings. Scale-freeness, i.e., power-law distribution of node connections, is a fundamental topological property that is highly conserved across biological networks, and as such needs to be manifest within plausible reconstructions of brain connectivity. We demonstrate that scale-free network topology only emerges when adequately fine cortical parcellations are adopted alongside an appropriate correlation threshold, and provide the full design of the first open-source hardware platform to accelerate the calculation of large linear regression arrays.

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Minati L, Cercignani M, Chan D.
Rapid geodesic mapping of brain functional connectivity: implementation of a dedicated co-processor in a field-programmable gate array and application to resting state fMRI.
Med Eng Phys 2013; 35(10):1532-1539

Graph theory-based analyses of brain network topology can be used to model the spatiotemporal correlations in neural activity detected through fMRI, and such approaches have wide-ranging potential, from detection of alterations in preclinical Alzheimer’s disease through to command identification in brain–machine interfaces. However, due to prohibitive computational costs, graph-based analyses to date have principally focused on measuring connection density rather than mapping the topological architecture in full by exhaustive shortest-path determination. This paper outlines a solution to this problem through parallel implementation of Dijkstra’s algorithm in programmable logic. The processor design is optimized for large, sparse graphs and provided in full as synthesizable VHDL code. An acceleration factor between 15 and 18 is obtained on a representative resting-state fMRI dataset, and maps of Euclidean path length reveal the anticipated heterogeneous cortical involvement in long-range integrative processing. These results enable high-resolution geodesic connectivity mapping for resting-state fMRI in patient populations and real-time geodesic mapping to support identification of imagined actions for fMRI-based brain–machine interfaces.

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Minati L, Varotto G, D’Incerti L, Panzica F, Chan D.
From brain topography to brain topology: relevance of graph theory to functional neuroscience.
NeuroReport 2013; 24(10):536-43

Although several brain regions show significant specialization, higher functions such as cross-modal information integration, abstract reasoning and conscious awareness are viewed as emerging from interactions across distributed functional networks. Analytical approaches capable of capturing the properties of such networks can therefore enhance our ability to make inferences from functional MRI, electroencephalography and magnetoencephalography data. Graph theory is a branch of mathematics that focuses on the formal modelling of networks and offers a wide range of theoretical tools to quantify specific features of network architecture (topology) that can provide information complementing the anatomical localization of areas responding to given stimuli or tasks (topography). Explicit modelling of the architecture of axonal connections and interactions among areas can furthermore reveal peculiar topological properties that are conserved across diverse biological networks, and highly sensitive to disease states. The field is evolving rapidly, partly fuelled by computational developments that enable the study of connectivity at fine anatomical detail and the simultaneous interactions among multiple regions. Recent publications in this area have shown that graph-based modelling can enhance our ability to draw causal inferences from functional MRI experiments, and support the early detection of disconnection and the modelling of pathology spread in neurodegenerative disease, particularly Alzheimer’s disease. Furthermore, neurophysiological studies have shown that network topology has a profound link to epileptogenesis and that connectivity indices derived from graph models aid in modelling the onset and spread of seizures. Graph-based analyses may therefore significantly help understand the bases of a range of neurological conditions. This review is designed to provide an overview of graph-based analyses of brain connectivity and their relevance to disease aimed principally at general neuroscientists and clinicians.

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Nigri A, Ferraro S, D’Incerti L, Critchley HD, Bruzzone MG, Minati L
Connectivity of the amygdala, piriform, and orbitofrontal cortex during olfactory stimulation: a functional MRI study.
NeuroReport 2013; 24(4):171-5

The majority of existing functional MRI studies on olfactory perception have addressed the relationship between stimulus features and the intensity of activity in separate regions considered in isolation. However, anatomical studies as well as neurophysiological recordings in rats and insects suggest that odor features may also be represented in a sparse manner through the simultaneous activity of multiple cortical areas interacting as a network. Here, we aimed to map the interdependence of neural activity among regions of the human brain, representing functional connectivity, during passive smelling. Seventeen healthy participants were scanned while performing a blocked-design task alternating exposure to two unpleasant odorants and breathing fresh air. High efferent connectivity was detected for the piriform cortex and the amygdala bilaterally. By contrast, the medial orbitofrontal cortex was characterized by high afferent connectivity, notably in the absence of an overall change in the intensity of hemodynamic activity during olfactory stimulation. Our results suggest that, even in the context of an elementary task, information on olfactory stimuli is scattered by the amygdala and piriform cortex onto an anatomically sparse representation and then gathered and integrated in the medial orbitofrontal cortex.

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Minati L, Grisoli M, Seth AK, Critchley HD.
Decision-making under risk: a graph-based network analysis using functional MRI.
NeuroImage 2012; 60(4):2191-205

Adaptive behavior requires choosing effectively between options involving risks and potential rewards. Existing studies implicate lateral and medial prefrontal areas, striatum, insula, amygdala and parietal regions in specific aspects of decision-making. However, limited attention is given to how brain networks encode economic parameters in patterns of inter-regional interactions. Here, healthy participants underwent functional MRI while evaluating “mixed” gambles presenting potential gains, losses and associated outcome probabilities. Connectivity graphs were constructed from analyses of psychophysiological interactions across a comprehensive atlas of brain regions. Expected value correlated positively with activity within medial prefrontal and occipital cortices, and modulated effective connectivity across a network that extended substantially beyond these nodes. Value-sensitive effective connections were found to be arranged as a unitary, small world network in which medial and anterior–lateral prefrontal areas featured as hubs, characterized by dense connectivity and high shortest-path centrality. Further analyses revealed that the observed effective connectivity effects were more pertinent to dichotomous gain/loss comparisons than to continuous value determination. Factoring expected value into its constituent components, potential loss modulated connectivity across a subset of the value-sensitive network, whereas potential gain and outcome probability were not significantly embodied in functional interactions. Regional response non-linearity was excluded as an artifactual basis to the observed effects, and directionality inferences were confirmed by comparison of dynamic causal models. Our findings extend current literature demonstrating that the representation of value is dependent on distributed processing taking across a widespread network which feeds information into a limited set of integrative prefrontal nodes. This study also has more general paradigmatic implications for neuroeconomics, demonstrating the value of explicit modeling of inter-regional interactions for understanding the neural substrates of decisional processes.

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DIFFUSION-TENSOR AND OTHER QUANTITATIVE IMAGING TECHNIQUES, MR SPECTROSCOPY AND APPLICATIONS
Marcuzzo S, Bonanno S, Figini M, Scotti A, Zucca I, Minati L, Riva N, Domi T, Fossaghi A, Quattrini A, Galbardi B, D'Alessandro S, Bruzzone MG, García-Verdugo JM, Moreno-Manzano V, Mantegazza R, Bernasconi P.
A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis.
Exp Neurol. 2017; 293:43-52.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron degeneration in the motor cortex, brainstem and spinal cord. It is generally accepted that ALS is caused by death of motor neurons, however the exact temporal cascade of degenerative processes is not yet completely known. To identify the early pathological changes in spinal cord of G93A-SOD1 ALS mice we performed a comprehensive longitudinal analysis employing diffusion-tensor magnetic resonance imaging alongside histology and electron microscopy, in parallel with peripheral nerve histology. We showed the gradient of degeneration appearance in spinal cord white and gray matter, starting earliest in the ventral white matter, due to a cascade of pathological events including axon dysfunction and mitochondrial changes. Notably, we found that even the main sensory regions are affected by the neurodegenerative process at symptomatic disease phase. Overall our results attest the applicability of DTI in determining disease progression in ALS mice. These findings suggest that DTI could be potentially adapted in humans to aid the assessment of ALS progression and eventually the evaluation of treatment efficacy.

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Albi A, Pasternak O, Minati L, Marizzoni M, Bartrés-Faz D, Bargalló N, Bosch B, Rossini PM, Marra C, Müller B, Fiedler U, Wiltfang J, Roccatagliata L, Picco A, Nobili FM, Blin O, Sein J, Ranjeva JP, Didic M, Bombois S, Lopes R, Bordet R, Gros-Dagnac H, Payoux P, Zoccatelli G, Alessandrini F, Beltramello A, Ferretti A, Caulo M, Aiello M, Cavaliere C, Soricelli A, Parnetti L, Tarducci R, Floridi P, Tsolaki M, Constantinidis M, Drevelegas A, Frisoni G, Jovicich J; PharmaCog Consortium.
Free water elimination improves test-retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects.
Hum Brain Mapp. 2017; 38(1):12-26.

Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects.

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Turati L, Moscatelli M, Mastropietro A, Dowell NG, Zucca I, Erbetta A, Cordiglieri C, Brenna G, Bianchi B, Mantegazza R, Cercignani M, Baggi F, Minati L
In vivo quantitative magnetization transfer imaging correlates with histology during de- and remyelination in cuprizone-treated mice.
NMR Biomed. 2015; 28(3):327-37

The pool size ratio measured by quantitative magnetization transfer MRI is hypothesized to closely reflect myelin density, but their relationship has so far been confirmed mostly in ex vivo conditions. We investigate the correspondence between this parameter measured in vivo at 7.0 T, with Black Gold II staining for myelin fibres, and with myelin basic protein and beta-tubulin immunofluorescence in a hybrid longitudinal study of C57BL/6 and SJL/J mice treated with cuprizone, a neurotoxicant causing relatively selective myelin loss followed by spontaneous remyelination upon treatment suspension. Our results confirm that pool size ratio measurements correlate with myelin content, with the correlation coefficient depending on strain and staining method, and demonstrate the in vivo applicability of this MRI technique to experimental mouse models of multiple sclerosis.

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Bertolino N, Marchionni C, Ghielmetti F, Burns B, Finocchiaro G, Anghileri E, Bruzzone MG, Minati L.
Accuracy of 2-hydroxyglutarate quantification by short-echo proton-MRS at 3 T: a phantom study.
Phys Med. 2014; 30(6):702-7.

PURPOSE: We set out to investigate the potential confounding effect of variable concentration of N-acetyl-l-aspartate (NAA) and Glutamate (Glu) on measurement of the brain oncometabolite 2-hydroxyglutarate (2HG) using a standard MRS protocol. This issue may arise due to spectral overlap at clinical magnetic field strengths and thus complicate the usage of 2HG as a putative biomarker of gliomas bearing mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes.
METHODS: Spectra from 25 phantoms (50 mL falcon test tubes) containing a range of known concentrations of 2HG, NAA and Glu were acquired using a clinical 3 T scanner with a quadrature head coil, single-voxel point-resolved spectroscopy sequence with TE = 30 ms. Metabolite concentrations were estimated by linear combination analysis and a simulated basis set.
RESULTS: NAA and Glu concentrations can have a significant confounding effect on 2HG measurements, whereby the negative changes in concentration of these metabolites typically observed in (peri)lesional areas can lead to under-estimation of 2HG concentration with respect to spectra acquired in presence of physiological levels of NAA and Glu.
CONCLUSION: The confounding effect of NAA and Glu concentration changes needs to be considered: in patients, it may mask the presence of 2HG at low concentrations, however it is not expected to lead to false positives. 2HG data acquired using standard short echo-time MRS protocols should be considered with caution.

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Minati L, Aquino D, Bruzzone MG, Erbetta A.
Quantitation of normal metabolite concentrations in six brain regions by in-vivo 1H-MR spectroscopy.
J Med Phys 2010; 35(3):154-63

This study examined the concentrations of brain metabolites visible to in-vivo 1 H-Magnetic Resonance Spectroscopy ( 1 H-MRS) at 1.5 T in a sample of 28 normal subjects. Quantitation was attempted for inositol compounds, choline units, total creatine and N-acetyl moieties, using open-source software. Six brain regions were considered: frontal and parietal white matter, medial temporal lobe, thalamus, pons and cerebellum. Absolute concentrations were derived using tissue water as an internal reference and using an external reference; metabolite signal intensity ratios with respect to creatine were also calculated. The inter-individual variability was smaller for absolute concentrations (internal reference) as compared to that for signal intensity ratios. Significant regional variability in concentration was found for all metabolites, indicating that separate normative values are needed for different brain regions. The values obtained in this study can be used as reference in future studies, provided the same methodology is followed; it is confirmed that despite unsuccessful attempts in the past, smaller coefficients of variation can indeed be obtained through absolute quantification.

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Minati L, Zucca I, Carcassola G, Occhipinti M, Spreafico R, Bruzzone MG.
Effect of diffusion-sensitizing gradient timings on the exponential, biexponential and diffusional kurtosis model parameters: in-vivo measurements in the rat thalamus.
MAGMA 2010; 23(2):115-21

Object: To investigate whether spacing (Δ) and duration (δ) of the diffusion-sensitizing gradient pulses differentially affect exponential (D′), biexponential (Dslow, Dfast and fslow) and diffusional kurtosis (D and K) model parameters.
Methods: Measurements were performed in the rat thalamus for b = 200–3,200 s mm−2, sweeping Δ between 20 and 100 ms at δ = 15 ms, and δ between 15 and 50 ms at Δ = 60 ms. Linear regressions were performed for each model parameter vs. Δ or δ.
Results: Increasing Δ from 20 to 100 ms increases D′ (from 0.64 to 0.70 × 10−3  mm2s−1) and Dslow (from 0.26 to 0.33 × 10−3 mm2s−1), reduces K (from 0.57 to 0.53), and has no effects on Dfast, fslow or D. Increasing δ from 15 to 50 ms increases D (from 0.80 to 0.88 × 10−3  mm2s−1), and has no effects on the other parameters.
Conclusion: The parameters of the biexponential and diffusional kurtosis models are more sensitive than the exponential model to Δ and δ; however, observed effects are too small to account for the discrepancies found in literature.

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Torresin A, Moscato A, Minella M, Cardinale F, Minati L, Aquino D.
Fibre tracking: probabilistic approach and preliminary results.
Pol J Med Phys Eng 2009; 15(4):227-237

The aim of this work is to have a preliminary experience with probabilistic tractography. We performed fibres reconstruction for three tracts of interest with data obtained from two MR imaging units equipped with different gradients system. An acquisition protocol optimization has been necessary in order to obtain a good trade-off between image quality and data collection time. Possible solutions to acquisition and processing problems are discussed. Future developments and possible applications in neurosurgery are also suggested.

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Minati L, Banasik T, Brzezinski J, Mandelli ML, Bizzi A, Bruzzone MG, Konopka M, Jasinski A.
Elevating tensor rank increases anisotropy in brain areas associated with intra-voxel orientational heterogeneity (IVOH): a generalised DTI (GDTI) study.
NMR Biomed 2008; 21(1):2-14

Rank-2 tensors are unable to represent multi-modal diffusion associated with intra-voxel orientational heterogeneity (IVOH), which occurs where axons are incoherently oriented, such as where bundles intersect or diverge. Under this condition, they are oblate or spheroidally shaped, resulting in artefactually low anisotropy, potentially masking reduced axonal density, myelinisation and integrity. Higher rank tensors can represent multi-modal diffusion, and suitable metrics such as generalised anisotropy (GA) and scaled entropy (SE) have been introduced. The effect of tensor rank was studied through simulations, and analysing high angular resolution diffusion imaging (HARDI) data from two volunteers, fit with rank-2, rank-4 and rank-6 tensors. The variation of GA and SE as a function of rank was investigated through difference maps and region of interest (ROI)-based comparisons. Results were correlated with orientation distribution functions (ODF) reconstructed with q-ball, and with colour-maps of the principal and second eigenvectors. Simulations revealed that rank-4 tensors are able to represent multi-modal diffusion, and that increasing rank further has a minor effect on measurements. IVOH was detected in subcortical regions of the corona radiata, along the superior longitudinal fasciculus, in the radiations of the genu of the corpus callosum, in peritrigonal white matter and along the inferior fronto-occipital and longitudinal fascicula. In these regions, elevating tensor rank increased anisotropy. This was also true for the corpus callosum, cingulum and anterior limb of the internal capsule, where increasing tensor rank resulted in patterns that, although mono-modal, were more anisotropic. In these regions the second eigenvector was coherently oriented. As rank-4 tensors have only 15 distinct elements, they can be determined without acquiring a large number of directions. By removing artefactual underestimation of anisotropy, their use may increase the sensitivity to pathological change.

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Minati L
Rapid generation of biexponential and diffusional kurtosis maps using multi-layer perceptrons: a preliminary experience.
MAGMA 2008; 21(4):299-305

Object: To investigate whether multi-layer perceptrons (MLPs) could be used to determine biexponential and diffusional kurtosis model parameters directly from diffusion-weighted images.
Materials and methods: Model parameters were determined with least-squares fitting and with MLPs. The corresponding estimates were compared with linear regressions, t tests and Levene’s tests. Residuals were also compared.
Results: Strong linear correlation was found for all parameters. MLP estimates were unbiased for the biexponential but not for the kurtosis model, and generally had smaller variance. Residuals were smaller for MLP estimates. The maps generated by the two methods were visually very similar.
Conclusion: Multi-layer perceptrons are potentially useful as a curve fitting method for these models.

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Minati L, Węglarz WP.
Physical Foundations, Models and Methods of Diffusion Magnetic Resonance Imaging of the Brain: A Review.
Concepts Magnetic Resonance 2007; 30:278-307

The foundations and characteristics of models and methods used in diffusion magnetic resonance imaging, with particular reference to in vivo brain imaging, are reviewed. The first section introduces Fick’s laws, propagators, and the relationship between tissue microstructure and the statistical properties of diffusion of water molecules. The second section introduces the diffusion-weighted signal in terms of diffusion of magnetization (Bloch–Torrey equation) and of spin-bearing particles (cumulant expansion). The third section is dedicated to the rank-2 tensor model, the bb-matrix, and the derivation of indexes of anisotropy and shape. The fourth section introduces diffusion in multiple compartments: Gaussian mixture models, relationship between fiber layout, displacement probability and diffusivity, and effect of the b-value. The fifth section is devoted to higher-order generalizations of the tensor model: singular value decompositions (SVD), representation of angular diffusivity patterns and derivation of generalized anisotropy (GA) and scaled entropy (SE), and modeling of non-Gaussian diffusion by means of series expansion of Fick’s laws. The sixth section covers spherical harmonic decomposition (SHD) and determination of fiber orientation by means of spherical deconvolution. The seventh section presents the Fourier relationship between signal and displacement probability (Q-space imaging, QSI, or diffusion-spectrum imaging, DSI), and reconstruction of orientation-distribution functions (ODF) by means of the Funk–Radon transform (Q-ball imaging, QBI).

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Minati L, Aquino D, Rampoldi S, Papa S, Grisoli M, Bruzzone MG, Maccagnano E.
Biexponential and diffusional kurtosis imaging, and generalised diffusion-tensor imaging (GDTI) with rank-4 tensors: a study in a group of healthy subjects.
MAGMA 2007; 20(5-6):241-53

Object: Clinical diffusion imaging is based on two assumptions of limited validity: that the radial projections of the diffusion propagator are Gaussian, and that a single directional diffusivity maximum exists in each voxel. The former can be removed using the biexponential and diffusional kurtosis models, the latter using generalised diffusion-tensor imaging. This study provides normative data for these three models.
Materials and methods: Eighteen healthy subjects were imaged. Maps of the biexponential parameters Dfast, Dslow and fslow, of D and K from the diffusional kurtosis model, and of diffusivity D-were obtained. Maps of generalised anisotropy (GA) and scaled entropy(SE) were also generated, for second and fourth rank tensors. Normative values were obtained for 26 regions.
Results: In grey versus white matter, Dslow and D-were higher and Dfast, fslow and K were lower. With respect to maps of D- anatomical contrast was stronger in maps of Dslow and K. Elevating tensor rank increased SE, generally more significantly than GA, in: anterior limb of internal capsule, corpus callosum, deep frontal and subcortical white matter, along superior longitudinal fasciculus and cingulum.
Conclusion: The values reported herein can be used for reference in future studies and in clinical settings.

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Minati L
Aquino D Probing neural connectivity through Diffusion Tensor Imaging (DTI).
Cybernetics and Systems 2006; 263–68

The ability to probe in-vivo the anatomical connections among cortical areas may have considerable relevance in the development of connectionist models of normal and pathological brain function. This article is meant to review the physical principles and capabilities of Diffusion Tensor Imaging (DTI), which is a novel neuroimaging technique enabling to study neural connectivity from the statistical properties of anisotropic water self-diffusion in white matter. The anatomical determinants of anisotropic water diffusion, the measurement process, the tensor model of self-diffusion, the principles of fibre-tracking, and the relevance of the technique are discussed.

NEAR-INFRARED SPECTROSCOPY
Minati L, Visani E, Dowell NG, Medford N, Critchley HD.
Variability comparison of simultaneous brain near-infrared spectroscopy and functional magnetic resonance imaging during visual stimulation.
J Med Eng Technol 2011; 35(6-7):370-6

Brain near-infrared spectroscopy (NIRS) is emerging as a potential alternative to functional magnetic resonance imaging (fMRI). To date, no study has explicitly compared the two techniques in terms of measurement variability, a key parameter dictating attainable statistical power. Here, NIRS and fMRI were simultaneously recorded during event-related visual stimulation. Inter-subject coefficients of variation (CVs) for peak response amplitude were considerably larger for NIRS than fMRI, but inter-subject CVs for response latency and intra-subject CVs for response amplitude were overall comparable. Our results may represent an optimistic estimate of the CVs of NIRS measurements, as optode positioning was guided by structural MRI, which is normally unavailable. We concluded that fMRI may be preferable to NIRS for group comparisons, but NIRS is equally powerful when comparing conditions within participants. The discrepancy between inter- and intra-subject CVs is likely related to variability in head anatomy and tissue properties, which may be better accounted for by emerging NIRS technology.

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Minati L, Kress IU, Visani E, Medford N, Critchley HD.
Intra- and extra-cranial effects of transient blood pressure changes on brain near-infrared spectroscopy (NIRS) measurements.
J Neurosci Met 2011; 197(2):283-8

Brain near-infrared spectroscopy (NIRS) is an emerging neurophysiological tool that combines straightforward activity localization with cost–economy, portability and patient compatibility. NIRS is proving its empirical utility across specific cognitive and emotional paradigms. However, a potential limitation is that it is not only sensitive to haemodynamic changes taking place in the cortex, and task-related cardiovascular responses expressed in the perfusion of extracranial layers may be confounding. Existing literature reports correlations between brain NIRS and systemic blood pressure, yet it falls short of establishing whether in normal participants the blood pressure changes encountered in experimental settings can have confounding effects. Here, we tested this hypothesis by performing two experimental manipulations while recording from superficial occipital cortex, encompassing striate and extrastriate regions. Visual stimulation with reversing chequerboards evoked cortical haemodynamic responses. Simultaneously and independently, transient systemic blood pressure changes were generated through rapid arm-raising. Shallow-penetration NIRS recordings, probing only extra-cerebral tissues, highlighted close haemodynamic coupling with blood pressure. A different coupling pattern was observed in deep-penetration recordings directed at haemodynamic signals from visual cortex. In absence of blood-pressure changes, NIRS signals tracked differences in visual stimulus duration. However when blood pressure was actively manipulated, this effect was absent and replaced by a very large pressure-related response. Our observations demonstrate that blood pressure fluctuations can exert confounding effects on brain NIRS, through expression in extracranial tissues and within the brain itself. We highlight the necessity for continuous blood pressure monitoring alongside brain NIRS, and for further research on methods to correct for physiological confounds.

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Minati L, Jones CL, Gray MA, Medford N, Harrison NA, Critchley HD.
Emotional modulation of visual cortex activity: a functional near-infrared spectroscopy study.
NeuroReport 2009; 20(15):1344-50

Functional neuroimaging and electroencephalography reveal emotional effects in the early visual cortex. Here, we used functional near-infrared spectroscopy to examine haemodynamic responses evoked by neutral, positive and negative emotional pictures, matched for brightness, contrast, hue, saturation, spatial frequency and entropy. Emotion content modulated amplitude and latency of oxy, deoxy and total haemoglobin response peaks, and induced peripheral autonomic reactions. The processing of positive and negative pictures enhanced haemodynamic response amplitude, and this effect was paralleled by blood pressure changes. The processing of positive pictures was reflected in reduced haemodynamic response peak latency. Together these data suggest that the early visual cortex holds amplitude-dependent representation of stimulus salience and latency-dependent information regarding stimulus valence, providing new insight into affective interaction with sensory processing.

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DECISION MAKING
Rêgo GG, Campanhã C, Kassab AP, Romero RL, Minati L, Boggio PS.
Adult-like neuroelectrical response to inequity in children: Evidence from the ultimatum game.
Soc Neurosci. 2016;11(2):193-206

People react aversely when faced with unfair situations, a phenomenon that has been related to an electroencephalographic (EEG) potential known as medial frontal negativity (MFN). To our knowledge, the existence of the MFN in children has not yet been demonstrated. Here, we recorded EEG activity from 15 children playing the ultimatum game (UG) and who afterward performed a recognition task, in order to assess whether they could recognize the unfair and fair (familiar) proposers among unfamiliar faces. During the recognition task, we also acquired pupil dilation data to investigate subconscious recognition processes. A typical (adult-like) MFN component was detected in reaction to unfair proposals. We found a positive correlation between reaction time and empathy, as well as a negative correlation between reaction time and systematic reasoning scores. Finally, we detected a significant difference in pupil dilation in response to unfamiliar faces versus UG proposers. Our data provide the first evidence of MFN in children, which appears to index similar neurophysiological phenomena as in adults. Also, reaction time to fair proposals seems to be related to individual traits, as represented by empathy and systematizing. Our pupil dilation data provide evidence that automatic responses to faces did not index fairness, but familiarity. These findings have implications for our understanding of social development in typically developing children.

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Minati L, Grisoli M, Seth AK, Critchley HD.
Decision-making under risk: a graph-based network analysis using functional MRI.
NeuroImage 2012; 60(4):2191-205

Adaptive behavior requires choosing effectively between options involving risks and potential rewards. Existing studies implicate lateral and medial prefrontal areas, striatum, insula, amygdala and parietal regions in specific aspects of decision-making. However, limited attention is given to how brain networks encode economic parameters in patterns of inter-regional interactions. Here, healthy participants underwent functional MRI while evaluating “mixed” gambles presenting potential gains, losses and associated outcome probabilities. Connectivity graphs were constructed from analyses of psychophysiological interactions across a comprehensive atlas of brain regions. Expected value correlated positively with activity within medial prefrontal and occipital cortices, and modulated effective connectivity across a network that extended substantially beyond these nodes. Value-sensitive effective connections were found to be arranged as a unitary, small world network in which medial and anterior–lateral prefrontal areas featured as hubs, characterized by dense connectivity and high shortest-path centrality. Further analyses revealed that the observed effective connectivity effects were more pertinent to dichotomous gain/loss comparisons than to continuous value determination. Factoring expected value into its constituent components, potential loss modulated connectivity across a subset of the value-sensitive network, whereas potential gain and outcome probability were not significantly embodied in functional interactions. Regional response non-linearity was excluded as an artifactual basis to the observed effects, and directionality inferences were confirmed by comparison of dynamic causal models. Our findings extend current literature demonstrating that the representation of value is dependent on distributed processing taking across a widespread network which feeds information into a limited set of integrative prefrontal nodes. This study also has more general paradigmatic implications for neuroeconomics, demonstrating the value of explicit modeling of inter-regional interactions for understanding the neural substrates of decisional processes.

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Minati L, Campanhã C, Critchley HD, Boggio PS.
Effects of transcranial direct-current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) during a mixed-gambling risky decision-making task.
Cogn. Neurosci 2012; 3(2):80-88

Previous studies have led to hypothesizing that right DLPFC activity is related to risk propensity, but the generality of this relationship remains unclear. Here, we experimentally modulated DLPFC activity in 47 healthy, female volunteers during a risky decision-making task, where monetary gambles defined by potential win, loss, and outcome probability were evaluated in the absence of feedback and uncertainty. Three participant groups, receiving left anodal/right cathodal, right anodal/left cathodal, and sham tDCS, were compared. Overall, participants performed the task well above chance level and were significantly risk averse, but tDCS did not affect task performance or risk propensity. However, right anodal/left cathodal tDCS significantly elevated response confidence, independently of accept/reject response. Our results suggest that the relationship between DLPFC activity and risk propensity may not be universally valid for all task types and requires further characterization. Enhancing right and attenuating left DLPFC activity boosts subjective confidence, with potential implications for understanding pathological gambling.

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Minati L, Grisoli M, Franceschetti S, Epifani F, Granvillano A, Medford N, Harrison NA, Piacentini S, Critchley HD.
Neural signatures of economic parameters during decision-making: a functional MRI (FMRI), electroencephalography (EEG) and autonomic monitoring study.
Brain Topogr 2012; 25(1):73-96

Adaptive behaviour requires an ability to obtain rewards by choosing between different risky options. Financial gambles can be used to study effective decision-making experimentally, and to distinguish processes involved in choice option evaluation from outcome feedback and other contextual factors. Here, we used a paradigm where participants evaluated ‘mixed’ gambles, each presenting a potential gain and a potential loss and an associated variable outcome probability. We recorded neural responses using autonomic monitoring, electroencephalography (EEG) and functional neuroimaging (fMRI), and used a univariate, parametric design to test for correlations with the eleven economic parameters that varied across gambles, including expected value (EV) and amount magnitude. Consistent with behavioural economic theory, participants were risk-averse. Gamble evaluation generated detectable autonomic responses, but only weak correlations with outcome uncertainty were found, suggesting that peripheral autonomic feedback does not play a major role in this task. Long-latency stimulus-evoked EEG potentials were sensitive to expected gain and expected value, while alpha-band power reflected expected loss and amount magnitude, suggesting parallel representations of distinct economic qualities in cortical activation and central arousal. Neural correlates of expected value representation were localized using fMRI to ventromedial prefrontal cortex, while the processing of other economic parameters was associated with distinct patterns across lateral prefrontal, cingulate, insula and occipital cortices including default-mode network and early visual areas. These multimodal data provide complementary evidence for distributed substrates of choice evaluation across multiple, predominantly cortical, brain systems wherein distinct regions are preferentially attuned to specific economic features. Our findings extend biologically-plausible models of risky decision-making while providing potential biomarkers of economic representations that can be applied to the study of deficits in motivational behaviour in neurological and psychiatric patients.

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Campanhã C, Minati L, Fregni F, Boggio PS.
Responding to unfair offers made by a friend: neuroelectrical activity changes in the anterior medial prefrontal cortex.
J Neurosci 2011; 31(43):15569-74

When receiving unfair monetary offers from another person, the most common response is punishment. Existing literature on the Ultimatum Game indicates that individuals frequently refuse unfair offers even when this results in a loss for themselves. Here, we present behavioral and neurophysiological evidence demonstrating that friendship substantially modifies this response. When the proposer was a friend rather than an unknown person, unfair offers were less frequently rejected and the medial frontal negativity (MFN) typically associated with unfair offers was reversed to positive polarity. The underlying generators were located in inferior-mesial and right inferior- and medial-lateral frontal regions (BA10 and BA11). These findings highlight the fundamental role of the anterior prefrontal cortex in interpersonal economic interaction and, particularly, present new evidence on the effects of social distance on the MFN.

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Minati L, Piacentini S, Ferrè F, Nanetti L, Romito L, Mariotti C, Grisoli M, Medford N, Critchley HD, Albanese A.
Choice-option evaluation is preserved in early Huntington and Parkinson's disease.
NeuroReport 2011; 22(15):753-7.

The ability to choose effectively when faced with potential risks and rewards is fundamental for adaptive survival. The striatum has a well-established role supporting learning from the outcomes of decisions, but it remains unclear whether this structure is also necessary for computing expected value (i.e., advantageousness of potential decisions) when all information is explicitly given. We addressed this question presenting simple monetary gambles, where all decisional parameters were given and outcome feedback was absent, to patients with early Huntington’s and Parkinson’s disease, taken as complementary models of striatal dysfunction. Behavioural responses and associated times were found to be unaltered. This negative finding suggests that striatal activity may not be essential for decision-making in situations where all information is provided and learning from outcomes is unnecessary.

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Jones CL, Minati L, Harrison NA, Ward J, Critchley HD
Under pressure: response urgency modulates striatal and insula activity during decision-making under risk.
PLoS One 2011; 6(6):e20942

When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency.

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MUSIC PERCEPTION
Kalda T, Minati L
Detecting Scale Violations in Absence of Mismatch Requires Music-Syntactic Analysis: A Further Look at the Early Right Anterior Negativity (ERAN).
Brain Topogr 2012; 25(3):285-92

The purpose of this study was to determine whether infrequent scale violations in a sequence of in-key notes are detected when the deviants are matched for frequency of occurrence and preceding intervals with the control notes. We further investigated whether the detectability of scale violations is modulated by the presence of melodic context and by the level of musical training. Event related potentials were recorded from 14 musicians and 13 non-musicians. In non-musicians, the out-of-key notes elicited an early right anterior negativity (ERAN), which appeared prominently over right frontal sites only when presented within structured sequences; no effects were found when the out-of-key notes were presented within scrambled sequences. In musicians, the out-of-key notes elicited a similar bilateral ERAN in structured and scrambled sequences. Our findings suggest that scale information is processed at the level of music-syntactic analysis, and that the detection of deviants does not require activation of auditory sensory memory by mismatch effects. Scales are perceived as a broader context, not just as online interval relations. Additional melodic context information appears necessary to support the representation of scale deviants in non-musicians, but not in musically-trained individuals, likely as a consequence of stronger pre-existing representations.

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Minati L, Salvatoni L, Rosazza C, Pietrocini E, Visani E, Panzica F, Scaioli V, Avanzini G, Franceschetti S.
Event-related potential (ERP) markers of melodic processing: The N2 component is modulated by structural complexity, not by melodic 'meaningfulness'.
Brain Res Bull 2010; 83(1-2):23-8

Previous studies have demonstrated that the event-related potential (ERP) evoked by a note shows substantial differences depending on whether the note is part of a melodic context or presented in an unstructured repetition. In particular, the N2 component has been found to have considerably increased latency and a more frontal topography for notes presented in a melody. An open question is whether such effect is related to the ‘meaningfulness’ of a note sequence, that is due to the formation of abstract melodic entities, rather than more simply an indicator of cognitive load associated with processing a structurally-complex sequence as opposed to an unstructured repetition. In this study, we addressed this issue by recording ERPs from 10 healthy non-musicians listening to eight one-part unfamiliar tonal melodies and eight sequences of random notes. The two stimuli were matched for distribution of pitch, intervals and note duration as well as for entropy of the time-series of pitch and duration. While tonal melodies were rated more meaningful (p < 0.001) and pleasant (p < 0.001) by all participants, no effects were found for the N2 component amplitude (p ≥ 0.8) and latency (p = 0.2). Combined with previous findings, this indicates that the N2 evoked by each individual note responds to the structural complexity of the note sequence, i.e., to the presence of pitch and duration changes, but not to higher-level processing related to the formation of abstract melodic entities. In contrast, we found that the amplitude of the P2 component was marginally (p = 0.04) elevated for random notes as compared to tonal melodies. This may be related to attentional modulation, or more specifically to associative components of auditory processing.

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Minati L, Rosazza C, D'Incerti L, Pietrocini E, Valentini L, Scaioli V, Loveday C, Bruzzone MG.
Functional MRI/Event-related potentials study of sensory consonance and dissonance in musicians and non-musicians.
NeuroReport 2009; 20(1):87-92

Pleasurability of individual chords, known as sensory consonance, is widely regarded as physiologically determined and has been shown to be associated with differential activity in the auditory cortex and in several other regions. Here, we present results obtained contrasting isolated four-note chords classified as consonant or dissonant in tonal music. Using event-related functional MRI, consonant chords were found to elicit a larger haemodynamic response in the inferior and middle frontal gyri, premotor cortex and inferior parietal lobule. The effect was right lateralized for nonmusicians and less asymmetric for musicians. Using event-related potentials, the degree of sensory consonance was found to modulate the amplitude of the P1 in both groups and of the N2 in musicians only.

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Minati L, Rosazza C, D'Incerti L, Pietrocini E, Valentini L, Scaioli V, Loveday C, Bruzzone MG.
FMRI/ERP of musical syntax: comparison of melodies and unstructured note sequences.
NeuroReport 2008; 19(14):1381-5

To date, the neural correlates of musical syntax processing have been investigated mainly by means of paradigms in which isolated chords are made incongruent with the harmonic context. Here, we present results obtained contrasting unfamiliar one-part piano melodies with unstructured note sequences, comparable in pitch and rhythm but devoid of any syntactic structure. This paradigm indexes a superset of the cognitive functions involved in processing of harmonic rules. Using functional magnetic resonance imaging, differential activation of a bilateral cortical network comprising the inferior frontal gyrus, superior temporal gyrus and premotor cortex was found. Using event-related potentials, the N2 evoked by each note in melodies was found to have longer latency and a more frontal distribution than that evoked in unstructured sequences.

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IMAGING AND ASSESSEMENT OF NEURODEGENERATIVE DISEASE
Chan D, Gallaher LM, Moodley K, Minati L, Burgess N, Hartley T.
The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease.
J Vis Exp. 2016; 116

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match-to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images. Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimer’s disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI). The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus. 4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of ≤8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55). In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD.

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Wood RA, Moodley KK, Lever C, Minati L, Chan D.
Allocentric Spatial Memory Testing Predicts Conversion from Mild Cognitive Impairment to Dementia: An Initial Proof-of-Concept Study.
Front Neurol. 2016; 7:215

The hippocampus is one of the first regions to exhibit neurodegeneration in Alzheimer’s disease (AD), and knowledge of its role in allocentric spatial memory may therefore aid early diagnosis of AD. The 4 Mountains Test (4MT) is a short and easily administered test of spatial memory based on the cognitive map theory of hippocampal function as derived from rodent single cell and behavioral studies. The 4MT has been shown in previous cross-sectional studies to be sensitive and specific for mild cognitive impairment (MCI) due to AD. This report describes the initial results of a longitudinal study testing the hypothesis that allocentric spatial memory is predictive of conversion from MCI to dementia. Fifteen patients with MCI underwent baseline testing on the 4MT in addition to CSF amyloid/tau biomarker studies, volumetric MRI and neuropsychological assessment including the Rey Auditory Verbal Learning Test (RAVLT) and Trail Making Test “B” (TMT-B). At 24 months, 9/15 patients had converted to AD dementia. The 4MT predicted conversion to AD with 93% accuracy (Cohen’s d = 2.52). The predictive accuracies of the comparator measures were as follows: CSF tau/β-amyloid1-42 ratio 92% (d = 1.81), RAVLT 64% (d = 0.41), TMT-B 78% (d = 1.56), and hippocampal volume 77% (d = 0.65). CSF tau levels were strongly negatively correlated with 4MT scores (r = -0.71). This proof-of-concept study provides initial support for the hypothesis that allocentric spatial memory testing is a predictive cognitive marker of hippocampal neurodegeneration in pre-dementia AD. The 4MT is a brief, non-invasive, straightforward spatial memory test and is therefore ideally suited for use in routine clinical diagnostic practice. This is of particular importance given the current unmet need for simple accurate diagnostic tests for early AD and the ongoing development of potential disease-modifying therapeutic agents, which may be more efficacious when given earlier in the disease course. By applying a test based on studies of hippocampal function in rodents to patient populations, this work represents the first step in the development of translatable biomarkers of hippocampal involvement in early AD for use in both animal models and human subjects.

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Moodley KK, Perani D, Minati L, Della Rosa PA, Pennycook F, Dickson JC, Barnes A, Contarino VE, Michopoulou S, D’Incerti L, Good C, Fallanca F, Vanoli EG, Ell PJ, Chan D.
Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer’s Disease and Frontotemporal Dementia: An Extended Case Series.
J Alzheimer Dis 2015; 46:639-653

Background: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. Objectives: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. Method: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen’s kappa. Results: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0–0.25 for PCA to 0.29–0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. Conclusion: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice

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Moodley K, Minati L, Contarino V, Prioni S, Wood R, Cooper R, D'Incerti L, Tagliavini F, Chan D.
Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory.
Hippocampus 2015; 25(8):939-51

The hippocampus is one of the earliest brain regions affected in Alzheimer’s disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n = 10) and biomarker-negative (MCI–, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI– subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre-dementia due to AD.

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Minati L, Chan D, Mastropasqua C, Serra L, Spanò B, Marra C, Caltagirone C, Cercignani M, Bozzali M.
Widespread alterations in functional brain network architecture in amnestic mild cognitive impairment.
J Alzheimer Dis 2014; 40(1):213-20

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer’s disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

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Aquino D, Contarino V, Albanese A, Minati L, Farina L, Grisoli M, Elia A, Bruzzone MG, Chiapparini L.
Substantia nigra in Parkinson's disease: a multimodal MRI comparison between early and advanced stages of the disease.
Neurol Sci 2014; 35(5):753-8

This study focused on the substantia nigra (SN) in Parkinson’s disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 ± 4.9, 60.5 ± 6.1, and 61 ± 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD (p = 0.04) and control subjects (p < 0.001). In EPD, the SN area was also significantly smaller than in controls (p = 0.006). Similarly, the SN volume significantly differed between LPD and controls (p = 0.001) and between EPD and LPD (p = 0.049), while no significant differences were found between controls and EPD. Both SN area (r = 0.47, p = 0.004) and volume (r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results.

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Moodley KK, Minati L, Barnes A, Dickson JC, Ell PJ, Chan D.
Simultaneous PET-MRI in Frontotemporal Dementia.
Eur Jour Nucl Med 2013; 40(3):468-9
Prodi E, Grisoli M, Panzeri M, Minati L, Fattori F, Erbetta A, Uziel G, D'Arrigo S, Tessa A, Ciano C, Santorelli FM, Savoiardo M, Mariotti C.
Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series.
Eur J Neurol 2013; 20(1):138-46

Background and purpose: The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. The disease, first described in Canadian families from Québec, is characterized by cerebellar ataxia, pyramidal tract involvement and peripheral neuropathy.
Methods: Analysis of SACS gene allowed the identification of 14 patients with ARSACS from 13 unrelated Italian families. Clinical phenotype, gene mutations and magnetic resonance imaging (MRI) findings were analysed.
Results: We found 16 novel SACS gene mutations, including a large in-frame deletion. The age at onset was in infancy, but one patient presented the first symptoms at age 32. Progression of the disease was variable, and increased muscle tone was mostly recognized in later stages. Structural MRI showed atrophy of the superior cerebellar vermis, a bulky pons exhibiting T2-hypointense stripes, identified as the corticospinal tract (CST), thinning of the corpus callosum and a rim of T2-hyperintensity around the thalami in 100% of cases. The presence of iron or other paramagnetic substances was excluded. Diffusion tensor imaging (DTI) revealed grossly over-represented transverse pontine fibres (TPF), which prevented reconstruction of the CST at this level (100% of cases). In all patients, significant microstructural alterations were found in the supratentorial white matter of forceps, cingulum and superior longitudinal fasciculus.
Conclusions: Our findings further enlarge the genetic spectrum of SACS mutations and widen the study of clinical phenotype. MRI characteristics indicate that pontine changes and supratentorial abnormalities are diagnostic. The over-representation of TPF on DTI suggests a developmental component in the pathogenesis of the disease.

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Minati L, Piacentini S, Ferrè F, Nanetti L, Romito L, Mariotti C, Grisoli M, Medford N, Critchley HD, Albanese A.
Choice-option evaluation is preserved in early Huntington and Parkinson's disease.
NeuroReport 2011; 22(15):753-7

The ability to choose effectively when faced with potential risks and rewards is fundamental for adaptive survival. The striatum has a well-established role supporting learning from the outcomes of decisions, but it remains unclear whether this structure is also necessary for computing expected value (i.e., advantageousness of potential decisions) when all information is explicitly given. We addressed this question presenting simple monetary gambles, where all decisional parameters were given and outcome feedback was absent, to patients with early Huntington’s and Parkinson’s disease, taken as complementary models of striatal dysfunction. Behavioural responses and associated times were found to be unaltered. This negative finding suggests that striatal activity may not be essential for decision-making in situations where all information is provided and learning from outcomes is unnecessary.

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Mandelli ML, Savoiardo M, Minati L, Mariotti C, Aquino D, Erbetta A, Genitrini S, Di Donato S, Bruzzone MG, Grisoli M.
Decreased diffusivity in the caudate nucleus of presymptomatic huntington disease gene carriers: which explanation?
AJNR Am J Neuroradiol 2010; 31(4):706-10

BACKGROUND AND PURPOSE: The neostriatum is known to be affected in HD. In this work, our aim was to determine whether microstructural and volumetric alterations occur in the neostriatum of presymptomatic HD gene carriers and in patients with early-stage HD.
MATERIALS AND METHODS: We studied a group of 15 presymptomatic gene carriers who were far from the estimated symptom onset (16% probability of developing the disease within 5 years), a group of 9 patients with early symptomatic HD, and 2 groups of age-matched controls. Volumetric MR imaging and DWIs were acquired, and statistical analyses were performed on the volumes of the caudate nucleus and putamen and on the corresponding MD measurements.
RESULTS: Neostriatal volumes were significantly smaller in both presymptomatic HD gene carriers and symptomatic patients with respect to controls. However, whereas the diffusivity in the caudate nucleus was increased in the symptomatic patients, it was decreased in the presymptomatic gene carriers.
CONCLUSIONS: Altered diffusivity and reduced volume of the caudate nucleus in presymptomatic HD gene carriers indicate that the neostriatum is affected well before the onset of symptoms. The observed initial decrease and subsequent increase of MD might be related to the combined effect of increased oligodendroglial population, putatively a developmental abnormality, and incipient neurodegeneration.

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Gattellaro G, Minati L, Grisoli M, Mariani C, Carella F, Osio M, Ciceri E, Albanese A, Bruzzone MG.
White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study.
AJNR Am J Neuroradiol 2009; 30(6):1222-6

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) offers a unique window on the connectivity changes, extending beyond the basal ganglia, which accompany the cognitive symptoms of Parkinson disease (PD). The primary purpose of this study was to assess the microstructural damage to cerebral white matter occurring in idiopathic PD.
MATERIALS AND METHODS: Our sample included patients with PD without dementia (n = 10; Hoehn and Yahr stages I and II; Unified Parkinson Disease Rating Scale, 20.5 ± 8.3; and Mini-Mental State Examination, 28.3 ± 1.5) and age-matched healthy control subjects (n = 10). DTI was performed on a 1.5T scanner, and mean diffusivity (MD) and fractional anisotropy (FA) maps were obtained. Regions of interest (ROIs) were drawn on the major fiber bundles as well as on gray matter nuclei.
RESULTS: In patients, the MD was increased at borderline significance in the substantia nigra but was unaltered in the thalamus, globus pallidus, putamen, and in the head of the caudate nucleus. The FA and MD were unaltered in the corticospinal tract in the midbrain and at the level of the internal capsule, and in the splenium of the corpus callosum. By contrast, the MD was increased and the FA was decreased in the genu of the corpus callosum and in the superior longitudinal fasciculus; in the cingulum, only the MD was altered. The observed changes were not significantly lateralized.
CONCLUSIONS: Widespread microstructural damage to frontal and parietal white matter occurs already in the early stages of PD.

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Minati L, Edginton T, Bruzzone MG, Giaccone G.
Current concepts in Alzheimer’s disease: a multidisciplinary overview.
Am J Alz Dis & Oth Dem 2009; 24(2):95-121

This comprehensive, pedagogically-oriented review is aimed at a heterogeneous audience representative of the allied disciplines involved in research and patient care. After a foreword on epidemiology, genetics, and risk factors, the amyloid cascade model is introduced and the main neuropathological hallmarks are discussed. The progression of memory, language, visual processing, executive, attentional, and praxis deficits, and of behavioral symptoms is presented. After a summary on neuropsychological assessment, emerging biomarkers from cerebrospinal fluid assays, magnetic resonance imaging, nuclear medicine, and electrophysiology are discussed. Existing treatments are briefly reviewed, followed by an introduction to emerging disease-modifying therapies such as secretase modulators, inhibitors of Abeta aggregation, immunotherapy, inhibitors of tau protein phosphorylation, and delivery of nerve growth factor.

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Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M.
Can MR imaging diagnose adult-onset Alexander disease?
AJNR Am J Neuroradiol 2008; 29(6):1190-6

BACKGROUND AND PURPOSE: In recent years, the discovery that mutations in the glial fibrillary acidic protein gene (GFAP) were responsible for Alexander disease (AD) brought recognition of adult cases. The purpose of this study was to demonstrate that MR imaging allows identification of cases of AD with adult onset (AOAD), which are remarkably different from infantile cases.
MATERIALS AND METHODS: In this retrospective study, brain and spinal cord MR imaging studies of 11 patients with AOAD (7 men, 4 women; age range, 26–64 years; mean age, 43.6 years), all but 1 genetically confirmed, were reviewed. Diffusion and spectroscopic investigations were available in 6 patients each.
RESULTS: Atrophy and changes in signal intensity in the medulla oblongata and upper cervical spinal cord were present in 11 of 11 cases and were the diagnostic features of AOAD. Minimal to moderate supratentorial periventricular abnormalities were seen in 8 patients but were absent in the 3 oldest patients. In these patients, postcontrast enhancement was also absent. Mean diffusivity was not altered except in abnormal white matter (WM). Increase in myo-inositol (mIns) was also restricted to abnormal periventricular WM.
CONCLUSIONS: Awareness of the MR pattern described allows an effective selection of the patients who need genetic investigations for the GFAP gene. This MR pattern even led to identification of asymptomatic cases and should be regarded as highly characteristic of AOAD.

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Mandelli ML, De Simone T, Minati L, Bruzzone MG, Mariotti C, Fancellu R, Savoiardo M, Grisoli M.
Diffusion tensor imaging of spinocerebellar ataxias types 1 and 2.
AJNR Am J Neuroradiol 2007; 28(10):1996-2000

BACKGROUND AND PURPOSE: Structural MR imaging does not enable reliable differentiation of spinocerebellar ataxia (SCA) types 1 and 2 (SCA1 and SCA2), and imaging may be normal during the first years after the onset of symptoms. We aimed at determining whether measurements of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) may enable their differentiation.
MATERIALS AND METHODS: We enrolled 14 patients with SCA1, 11 with SCA2, and 9 age-matched controls. Diffusion tensor imaging (DTI) was performed on a 1.5T scanner, with b = 1000s/mm2 and 12 directions. ADC and FA were measured by means of regions of interest, positioned in the corticospinal tract at the level of the cerebral peduncle and at the level of the pons, in the transverse pontine fibers, in the superior and middle cerebellar peduncle, and in the hemispheric cerebellar white matter.
RESULTS: With respect to controls, the ADC was significantly elevated in the middle cerebellar peduncle and in hemispheric white matter in SCA1, and in all regions under consideration in SCA2. It was significantly higher in SCA2 than in SCA1 in all regions under consideration. With respect to controls, the FA was significantly reduced in all regions under consideration in SCA1 and in SCA2. It was significantly lower in SCA2 than in SCA1 in the transverse pontine fibers and in the corticospinal tract at the level of the cerebral peduncle. Correlations with clinical scores were found.
CONCLUSIONS: DTI did not enable differentiation between SCA1 and SCA2. However, strongly significant differences between the 2 subtypes and with respect to controls and correlations with clinical scores were found.

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Minati L, Grisoli M, Bruzzone MG.
MR spectroscopy, functional MRI, and diffusion-tensor imaging in the aging brain: a conceptual review.
J Geriatr Psychiatry Neurol. 2007; 20(1):3-21

In vivo magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), and diffusion-tensor imaging (DTI) have recently opened new possibilities for noninvasively assessing the metabolic, functional, and connectivity correlates of aging in research and clinical settings. The purpose of this article is to provide a conceptual review intended for a multidisciplinary audience, covering physical principles and main findings related to normal aging and senile cognitive impairment. This article is divided into 3 sections, dedicated to MRS, to fMRI, and to DTI. The spectroscopy section surveys physiological function of the observable metabolites, concentration changes in normal aging and their interpretation, and correlation with cognitive performance. The functional MRI section surveys the hemispheric asymmetry reduction model from compensation and de-differentiation viewpoints, memory encoding, retrieval and consolidation, inhibitory control, perception and action, resting-state networks, and functional deactivations. The DTI section surveys age-related changes, correlation with behavioral scores, and transition to cognitive impairment.

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Minati L, Grisoli M, Carella F, De Simone T, Bruzzone MG, Savoiardo M.
Imaging degeneration of the substantia nigra in Parkinson disease with inversion-recovery MR imaging.
AJNR Am J Neuroradiol. 2007; 28(2):309-13

BACKGROUND AND PURPOSE: Visualizing with MR imaging and obtaining quantitative indexes of degeneration of the substantia nigra in Parkinson disease have been long-sought goals. We investigated the potential role of area and T1 contrast measurements in differentiating patients from controls and their age-related changes.
METHODS: Eight patients with Parkinson disease, 8 age-matched controls, and 8 young controls were imaged. We obtained the pixel-wise difference between 2 sets of inversion-recovery images, acquired parallel to the bicommissural plane, with different inversion times. Pixel-intensity ratios between lateral and medial nigral regions, and nigral area and substantia-nigra/midbrain area ratios were computed.
RESULTS: Compared with that of controls, loss of substantia nigra was evident in patients, its borders taking a smoother and more irregular appearance. Patients were characterized by a lateral-to-medial gradient, due to reduced hypointensity of the lateral portion of the substantia nigra and relative sparing of its medial portion. The visible nigral area was significantly smaller in patients compared with matched controls (P = .04). The substantia nigra/midbrain area ratio enabled considerably better separation (P = .0001). The lateral/medial pixel-intensity ratio was significantly higher in patients compared with matched controls (P = .01) and in young controls compared with age-matched controls (P = .01).
CONCLUSION: Inversion-recovery sequences may provide a convenient way to visualize nigral degeneration. Relative area and pixel-intensity measurements may integrate other techniques (such as diffusion-tensor imaging on nigrostriatal pathways) in the neuroradiologic diagnosis and follow-up of Parkinson disease by quantitatively assessing the degeneration of the substantia nigra.

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Vitali P, Minati L, Chiarenza G, Brugnolo A, Girtler N, Nobili F, De Leo C, Rosati P, Rodriguez G.
The Von Restorff effect in ageing and Alzheimer's disease.
Neurol Sci. 2006; 27(3):166-72

The purpose of the study was to evaluate the Von Restorff effect in normal ageing and in Alzheimer’s disease (AD). A shortened paradigm was administered to three groups of subjects: young volunteers, elderly volunteers and patients with early-stage AD (MMSE>20). Each subject was presented with 25 lists of 10 words each, the target word appearing in double font size. A free recall phase followed the presentation of each list; after completion of the battery, a size recognition test was administered and subjects were inquired regarding the strategy employed and perception of target words. The total number of recalled words differed significantly among the three groups (young volunteers 144.4±38.6, elderly volunteers 86.5±17.6, patients 44.2±14.6). A significant difference in percentage of recall was found between target and non-target words in young (60.0±13.8% vs. 45.7%±15.0%, p<0.001) and in elderly (31.2±11.4% vs. 20.2±6.9%, p<0.001) volunteers, but not in patients (10.7±6.9% vs. 11.8±7.3%). The present study highlights that the Von Restorff effect can be detected in healthy elderly subjects, and that it is significantly reduced in patients in the early stage of AD. On the basis of the findings of the present study it is not possible to disentangle the contribution of visual-perceptual and encoding impairment, both of them potentially contributing to the observed reduction.

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IMAGING AND ASSESSEMENT OF DISORDERS OF CONSCIOUSNESS
Sattin D, Lovaglio P, Brenna G, Covelli V, Rossi Sebastiano D, Duran D, Minati L, Giovannetti AM, Rosazza C, Bersano A, Nigri A, Ferraro S, Leonardi M.
A comparative study on assessment procedures and metric properties of two scoring systems of the Coma Recovery Scale-Revised items: standard and modified scores.
Clin Rehabil. 2017; 31(9):1226-1237

OBJECTIVE: The study compared the metric characteristics (discriminant capacity and factorial structure) of two different methods for scoring the items of the Coma Recovery Scale-Revised and it analysed scale scores collected using the standard assessment procedure and a new proposed method.
DESIGN: Cross sectional design/methodological study.
SETTING: Inpatient, neurological unit.
PARTICIPANTS: A total of 153 patients with disorders of consciousness were consecutively enrolled between 2011 and 2013.
INTERVENTION: All patients were assessed with the Coma Recovery Scale-Revised using standard (rater 1) and inverted (rater 2) procedures.
MAIN OUTCOME MEASURES: Coma Recovery Scale-Revised score, number of cognitive and reflex behaviours and diagnosis.
RESULTS: Regarding patient assessment, rater 1 using standard and rater 2 using inverted procedures obtained the same best scores for each subscale of the Coma Recovery Scale-Revised for all patients, so no clinical (and statistical) difference was found between the two procedures. In 11 patients (7.7%), rater 2 noted that some Coma Recovery Scale-Revised codified behavioural responses were not found during assessment, although higher response categories were present. A total of 51 (36%) patients presented the same Coma Recovery Scale-Revised scores of 7 or 8 using a standard score, whereas no overlap was found using the modified score. Unidimensionality was confirmed for both score systems.
CONCLUSION: The Coma Recovery Scale Modified Score showed a higher discriminant capacity than the standard score and a monofactorial structure was also supported. The inverted assessment procedure could be a useful evaluation method for the assessment of patients with disorder of consciousness diagnosis.

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Rosazza C, Sattin D, Sebastiano DR, Minati L, Leonardi M, Silva S.
Disruption of posteromedial large-scale neural communication predicts recovery from coma.
Neurology. 2016 Jul 5;87(1):120-1.
Rosazza C, Andronache A, Sattin D, Bruzzone MG, Marotta G, Nigri A, Ferraro S, Sebastiano DR, Porcu L, Bersano A, Benti R, Leonardi M, D'Incerti L, Minati L., Coma Research Centre (CRC) - Besta Institute.
Multimodal study of default-mode network integrity in disorders of consciousness.
Ann Neurol. 2016; 79(5):841-853

OBJECTIVE: Understanding residual brain function in Disorders of Consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default-mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting-state functional MRI (rs-fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment.
METHODS: We enrolled 119 consecutive patients: 72 vegetative state/unresponsive wakefulness state (VS/UWS), 36 minimally-conscious state (MCS) and 11 severe disability. All underwent structural MRI and rs-fMRI, and a subset also performed FDG-PET. Data were analyzed with manual and automatic approaches, in relation to diagnosis and clinical score.
RESULTS: Excluding the quartile with largest head movement, DMN activity was decreased in VS/UWS compared to MCS, and correlated with clinical score. Independent-component and seed-based analyses provided similar results, though the latter and their combination were most informative. Structural MRI and FDG-PET were less sensitive to head movement and had superior diagnostic accuracy than rs-fMRI only when all cases were included. Rs-fMRI indicated relatively preserved DMN activity in a small subset of VS/UWS patients, two of whom evolved to MCS. The integrity of the left hemisphere appears predictive of a better clinical status.
INTERPRETATION: Rs-fMRI of the DMN is sensitive to clinical severity. The effect is consistent across data analysis approaches, but heavily dependent on head movement. Rs-fMRI could be informative to detect residual DMN activity for those patients that remain relatively still during scanning and whose diagnosis is uncertain.

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Sattin D, Schnakers C, Pagani M, Arenare F, Devalle G, Giunco F, Guizzetti G, Lanfranchi M, Giovannetti AM, Covelli V, Bersano A, Nigri A, Minati L, Rossi Sebastiano D, Parati E, Bruzzone M, Franceschetti S, Leonardi M.
Evidence of altered pressure pain thresholds in persons with disorders of consciousness as measured by the Nociception Coma Scale-Italian version.
Neuropsychol Rehabil. 2017 Feb 28:1-16.

Pain assessment in patients with disorders of consciousness (DoC) is a controversial issue for clinicians, who require tools and standardised procedures for testing nociception in non-communicative patients. The aims of the present study were, first, to analyse the psychometric properties of the Italian version of the Nociception Coma Scale and, second, to evaluate pressure pain thresholds in a group of patients with DoC. The authors conducted a multi-centre study on 40 healthy participants and 60 DoC patients enrolled from six hospitals in Italy. For each group an electronic algometer was used to apply all nociceptive pressure stimuli. Our results show that the Italian version of the NCS retains the good psychometric properties of the original version and is therefore suitable for standardised pain assessment in clinical practice. In our study, pressure pain thresholds measured in a group of patients in vegetative and minimally conscious state were relatively lower than pain threshold values found in a group of healthy participants. Such findings motivate additional investigation on possible pain sensitisation in patients with severe brain injury and multiple co-morbidities, and on application of tailored therapeutic approaches useful for pain management in patients unable verbally to communicate their feelings.

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Sattin D, Minati L, Rossi D, Covelli V, Giovannetti AM, Rosazza C, Bersano A, Nigri A, Leonardi M.
The Coma Recovery Scale Modified Score: a new scoring system for the Coma Recovery Scale-revised for assessment of patients with disorders of consciousness.
Int J Rehabil Res. 2015; 38(4):350-6

The differential diagnosis between vegetative state and minimally conscious state is still complex and the development of an evaluation systems is one of the challenging tasks for researchers and professionals. The Coma Recovery Scale-revised is considered the gold standard for clinical/behavioral assessment and for the differential diagnosis of patients with disorder of consciousness. However, the scale presents some limitations in that (i) scores may partially overlap between different diagnoses and (ii) there is an underlying assumption that if a patient is able to show higher-level behaviors, he/she is also able to show lower-level responses. In the present study, a procedure to calculate a modified Coma Recovery Scale-revised score is presented that attempts to avoid these problems. To exemplify this new scoring approach, 60 patients with disorder of consciousness were studied and the results showed the usefulness of the Modified Score.

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Sattin D, Giovannetti AM, Ciaraffa F, Covelli V, Bersano A, Nigri A, Ferraro S, Minati L, Rossi D, Duran D, Parati E, Leonardi M.
Assessment of patients with disorder of consciousness: do different Coma Recovery Scale scoring correlate with different settings?
J Neurol 2014; 261(12):2378-86

Differential diagnosis between Vegetative State and Minimally Conscious State is a challenging task that requires specific assessment scales, involvement of expert neuropsychologists or physicians and use of tailored stimuli for eliciting behavioural responses. Although misdiagnosis rate as high as 40 % has been reported, no clear guidelines are available in literature on the optimal setting for assessment. The present study aims to analyse score differences in behavioural assessments of persons with disorders of consciousness (DOC) with or without family members and to determine whether the presence of caregivers could improve clinical accuracy in diagnostic evaluation. The research was conducted on 92 adults with DOC among 153 consecutive patients enrolled in the Coma Research Centre of the Neurological Institute C. Besta of Milan between January 2011 and May 2013. The results indicate that in almost half of the sample the scoring, thus the performance, observed with caregivers was better than without them. Furthermore, in 16 % of the sample, when assessment was performed with caregivers there was a change in diagnosis, from Vegetative to Minimally Conscious State or from that to Severe Disability. Finally, statistical differences were found in relation to diagnosis between mean scores in the “visual function” Coma Recovery Scale revised’s subscale obtained by raters plus caregiver and rates only assessment. This study demonstrates how the presence of caregivers can positively affect behavioural assessments of persons with DOC, thus contributing to the definition of the optimal setting for behavioural evaluation of patients, to decrease misdiagnosis rates.

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Andronache A, Rosazza C, Sattin D, Leonardi M, D'Incerti L, Minati L.
Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness.
Front NeuroInform 2013; 7:16

An emerging application of resting-state functional MRI (rs-fMRI) is the study of patients with disorders of consciousness (DoC), where integrity of default-mode network (DMN) activity is associated to the clinical level of preservation of consciousness. Due to the inherent inability to follow verbal instructions, arousal induced by scanning noise and postural pain, these patients tend to exhibit substantial levels of movement. This results in spurious, non-neural fluctuations of the rs-fMRI signal, which impair the evaluation of residual functional connectivity. Here, the effect of data preprocessing choices on the detectability of the DMN was systematically evaluated in a representative cohort of 30 clinically and etiologically heterogeneous DoC patients and 33 healthy controls. Starting from a standard preprocessing pipeline, additional steps were gradually inserted, namely band-pass filtering (BPF), removal of co-variance with the movement vectors, removal of co-variance with the global brain parenchyma signal, rejection of realignment outlier volumes and ventricle masking. Both independent-component analysis (ICA) and seed-based analysis (SBA) were performed, and DMN detectability was assessed quantitatively as well as visually. The results of the present study strongly show that the detection of DMN activity in the sub-optimal fMRI series acquired on DoC patients is contingent on the use of adequate filtering steps. ICA and SBA are differently affected but give convergent findings for high-grade preprocessing. We propose that future studies in this area should adopt the described preprocessing procedures as a minimum standard to reduce the probability of wrongly inferring that DMN activity is absent.

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Scott RB, Minati L, Dienes Z, Critchley HD, Seth AK.
Detecting conscious awareness from involuntary autonomic responses.
Conscious Cogn 2010; 20(3):936-42

Can conscious awareness be ascertained from physiological responses alone? We evaluate a novel learning-based procedure permitting detection of conscious awareness without reliance on language comprehension or behavioural responses. The method exploits a situation whereby only consciously detected violations of an expectation alter skin conductance responses (SCRs). Thirty participants listened to sequences of piano notes that, without their being told, predicted a pleasant fanfare or an aversive noise according to an abstract rule. Stimuli were presented without distraction (attended), or while distracted by a visual task to remove awareness of the rule (unattended). A test phase included occasional violations of the rule. Only participants attending the sounds reported awareness of violations and only they showed significantly greater SCR for noise occurring in violation, vs. accordance, with the rule. Our results establish theoretically significant dissociations between conscious and unconscious processing and furnish new opportunities for clinical assessment of residual consciousness in patient populations.

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IMAGING AND ASSESSEMENT OF AUTISM SPECTRUM DISORDERS
Radulescu E, Minati L, Ganeshan B, Harrison NA, Gray MA, Beacher FD, Chatwin C, Young RC, Critchley HD.
Abnormalities in fronto-striatal connectivity within language networks relate to differences in grey-matter heterogeneity in Asperger syndrome.
NeuroImage: Clinical 2013; 2:716-726

Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD.

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Ribeiro TC, Valasek CA, Minati L, Boggio PS.
Altered semantic integration in autism beyond language: a cross-modal event-related potentials study.
NeuroReport 2013; 24(8):414-8

Autism spectrum disorders (ASDs) are characterized by impaired communication, particularly pragmatic and semantic language, resulting in verbal comprehension deficits. Semantic processing in these conditions has been studied extensively, but mostly limited only to linguistic material. Emerging evidence, however, suggests that semantic integration deficits may extend beyond the verbal domain. Here, we explored cross-modal semantic integration using visual targets preceded by musical and linguistic cues. Particularly, we have recorded the event-related potentials to evaluate whether the N400 and late positive potential (LPP) components, two widely studied electrophysiological markers of semantic processing, are differently sensitive to congruence with respect to typically developing children. Seven ASD patients and seven neurotypical participants matched by age, education and intelligence quotient provided usable data. Neuroelectric activity was recorded in response to visual targets that were related or unrelated to a preceding spoken sentence or musical excerpt. The N400 was sensitive to semantic congruence in the controls but not the patients, whereas the LPP showed a complementary pattern. These results suggest that semantic processing in ASD children is also altered in the context of musical and visual stimuli, and point to a functional decoupling between the generators of the N400 and LPP, which may indicate delayed semantic processing. These novel findings underline the importance of exploring semantic integration across multiple modalities in ASDs and provide motivation for further investigation in large clinical samples.

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Chiesa P, Minati L
Multimodal imaging of brain connectivity in autism spectrum disorders – an overview. In Riva D (Ed.) Neurobiology, diagnosis and treatment in autism: an update, Fondazione Mariani,
John Libbey Eurotext 2013

While the aetiology of autism spectrum disorders is largely unknown, and clear pathologic hallmarks of disease are lacking, in recent years a remarkable body of literature has accumulated suggesting that anatomic connectivity (i.e., axonal connections) as well as functional connectivity (i.e., spatiotemporal coherencies of intrinsic or task-related neural activity) are significantly altered. There is solid evidence that long-range connectivity is impaired, mildly to severely, and recent data suggest that, on the contrary, short-range connectivity may be enhanced. This altered balance could be closely related to the presence of islands of spared or even excellent cognitive function, in the face of general impairment in associative reasoning, language, and social behaviour. Here, we provide a non exhaustive summary of results obtained in this area, and offer an introduction to two major investigational tools: diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI).

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Beacher FD, Radulescu E, Minati L, Baron-Cohen S, Lombardo MV, Lai MC, Walker A, Howard D, Gray MA, Harrison NA, Critchley HD.
Sex differences and autism: brain function during verbal fluency and mental rotation.
PLoS One 2012; 7(6):e38355

Autism spectrum conditions (ASC) affect more males than females. This suggests that the neurobiology of autism: 1) may overlap with mechanisms underlying typical sex-differentiation or 2) alternately reflect sex-specificity in how autism is expressed in males and females. Here we used functional magnetic resonance imaging (fMRI) to test these alternate hypotheses. Fifteen men and fourteen women with Asperger syndrome (AS), and sixteen typically developing men and sixteen typically developing women underwent fMRI during performance of mental rotation and verbal fluency tasks. All groups performed the tasks equally well. On the verbal fluency task, despite equivalent task-performance, both males and females with AS showed enhanced activation of left occipitoparietal and inferior prefrontal activity compared to controls. During mental rotation, there was a significant diagnosis-by-sex interaction across occipital, temporal, parietal, middle frontal regions, with greater activation in AS males and typical females compared to AS females and typical males. These findings suggest a complex relationship between autism and sex that is differentially expressed in verbal and visuospatial domains.

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Radulescu E, Ganeshan B, Minati L, Beacher FDCC, Gray MA, Chatwin C, Young R, Harrison NA, Critchley HD.
Gray matter textural heterogeneity as a potential in-vivo biomarker of fine structural abnormalities in Asperger syndrome.
Pharmacogenom J 2012; 13(1):70-9

Brain imaging studies contribute to the neurobiological understanding of Autism Spectrum Conditions (ASC). Herein, we tested the prediction that distributed neurodevelopmental abnormalities in brain development impact on the homogeneity of brain tissue measured using texture analysis (TA; a morphological method for surface pattern characterization). TA was applied to structural magnetic resonance brain scans of 54 adult participants (24 with Asperger syndrome (AS) and 30 controls). Measures of mean gray-level intensity, entropy and uniformity were extracted from gray matter images at fine, medium and coarse textures. Comparisons between AS and controls identified higher entropy and lower uniformity across textures in the AS group. Data reduction of texture parameters revealed three orthogonal principal components. These were used as regressors-of-interest in a voxel-based morphometry analysis that explored the relationship between surface texture variations and regional gray matter volume. Across the AS but not control group, measures of entropy and uniformity were related to the volume of the caudate nuclei, whereas mean gray-level was related to the size of the cerebellar vermis. Similar to neuropathological studies, our study provides evidence for distributed abnormalities in the structural integrity of gray matter in adults with ASC, in particular within corticostriatal and corticocerebellar networks. Additionally, this in-vivo technique may be more sensitive to fine microstructural organization than other more traditional magnetic resonance approaches and serves as a future testable biomarker in AS and other neurodevelopmental disorders.

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Beacher FD, Minati L, Baron-Cohen S, Lombardo MV, Lai MC, Gray MA, Harrison NA, Critchley HD.
Autism attenuates sex differences in brain structure: a combined voxel-based morphometry and diffusion tensor imaging study.
AJNR Am J Neuroradiol 2012; 33(1):83-9

BACKGROUND AND PURPOSE: It has been proposed that autism spectrums condition may represent a form of extreme male brain (EMB), a notion supported by psychometric, behavioral, and endocrine evidence. Yet, limited data are presently available evaluating this hypothesis in terms of neuroanatomy. Here, we investigated sex-related anatomic features in adults with AS, a “pure” form of autism not involving major developmental delay.
MATERIALS AND METHODS: Males and females with AS and healthy controls (n = 28 and 30, respectively) were recruited. Structural MR imaging was performed to measure overall gray and white matter volume and to assess regional effects by means of VBM. DTI was used to investigate the integrity of the main white matter tracts.
RESULTS: Significant interactions were found between sex and diagnosis in total white matter volume, regional gray matter volume in the right parietal operculum, and fractional anisotropy (FA) in the body of the CC, cingulum, and CR. Post hoc comparisons indicated that the typical sexual dimorphism found in controls, whereby males have larger FA and total white matter volume, was absent or attenuated in participants with AS.
CONCLUSIONS: Our results point to a fundamental role of the factors that underlie sex-specific brain differentiation in the etiology of autism.

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Beacher FD, Gray MA, Minati L, Whale R, Harrison NA, Critchley HD.
Acute tryptophan depletion attenuates conscious appraisal of social emotional signals in healthy female volunteers.
Psychopharmacology (Berl) 2011; 213(2-3):603-13

Rationale: Acute tryptophan depletion (ATD) decreases levels of central serotonin. ATD thus enables the cognitive effects of serotonin to be studied, with implications for the understanding of psychiatric conditions, including depression.
Objective: To determine the role of serotonin in conscious (explicit) and unconscious/incidental processing of emotional information.
Materials and methods: A randomized, double-blind, cross-over design was used with 15 healthy female participants. Subjective mood was recorded at baseline and after 4 h, when participants performed an explicit emotional face processing task, and a task eliciting unconscious processing of emotionally aversive and neutral images presented subliminally using backward masking.
Results: ATD was associated with a robust reduction in plasma tryptophan at 4 h but had no effect on mood or autonomic physiology. ATD was associated with significantly lower attractiveness ratings for happy faces and attenuation of intensity/arousal ratings of angry faces. ATD also reduced overall reaction times on the unconscious perception task, but there was no interaction with emotional content of masked stimuli. ATD did not affect breakthrough perception (accuracy in identification) of masked images.
Conclusions: ATD attenuates the attractiveness of positive faces and the negative intensity of threatening faces, suggesting that serotonin contributes specifically to the appraisal of the social salience of both positive and negative salient social emotional cues. We found no evidence that serotonin affects unconscious processing of negative emotional stimuli. These novel findings implicate serotonin in conscious aspects of active social and behavioural engagement and extend knowledge regarding the effects of ATD on emotional perception.

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PHYSIOLOGICAL MONITORING TECHNIQUES AND BRAIN-BODY INTERACTION
Garfinkel SN, Zorab E, Navaratnam N, Engels M, Mallorquí-Bagué N, Minati L, Dowell NG, Brosschot JF, Thayer JF, Critchley HD.
Anger in brain and body: the neural and physiological perturbation of decision-making by emotion.
Soc Cogn Affect Neurosci 2016; 11(1):150-8

Emotion and cognition are dynamically coupled to bodily arousal: the induction of anger, even unconsciously, can reprioritise neural and physiological resources toward action states that bias cognitive processes. Here we examine behavioural, neural and bodily effects of covert anger processing and its influence on cognition, indexed by lexical decision-making. While recording beat-to-beat blood pressure, the words ANGER or RELAX were presented subliminally just prior to rapid word/non-word reaction-time judgements of letter-strings. Subliminal ANGER primes delayed the time taken to reach rapid lexical decisions, relative to RELAX primes. However, individuals with high trait anger were speeded up by subliminal anger primes. ANGER primes increased systolic blood pressure and the magnitude of this increase predicted reaction time prolongation. Within the brain, ANGER trials evoked an enhancement of activity within dorsal pons and an attenuation of activity within visual occipitotemporal and attentional parietal cortices. Activity within periaqueductal grey matter, occipital and parietal regions increased linearly with evoked blood pressure changes, indicating neural substrates through which covert anger impairs semantic decisions, putatively through its expression as visceral arousal. The behavioural and physiological impact of anger states compromises the efficiency of cognitive processing through action-ready changes in autonomic response that skew regional neural activity.

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Jones CL, Minati L, Nagai Y, Medford N, Harrison NA, Gray M, Ward J, Critchley HD.
Neuroanatomical substrates for the volitional regulation of heart rate.
Front Psychol 2015; 6:300

The control of physiological arousal can assist in the regulation of emotional state. A subset cortical and subcortical brain regions are implicated in autonomic control of bodily arousal during emotional behaviors. Here, we combined human functional neuroimaging with autonomic monitoring to identify neural mechanisms that support the volitional regulation of heart rate, a process that may be assisted by visual feedback. During functional magnetic resonance imaging (fMRI), 15 healthy adults performed an experimental task in which they were prompted voluntarily to increase or decrease cardiovascular arousal (heart rate) during true, false, or absent visual feedback. Participants achieved appropriate changes in heart rate, without significant modulation of respiratory rate, and were overall not influenced by the presence of visual feedback. Increased activity in right amygdala, striatum and brainstem occurred when participants attempted to increase heart rate. In contrast, activation of ventrolateral prefrontal and parietal cortices occurred when attempting to decrease heart rate. Biofeedback enhanced activity within occipito-temporal cortices, but there was no significant interaction with task conditions. Activity in regions including pregenual anterior cingulate and ventral striatum reflected the magnitude of successful task performance, which was negatively related to subclinical anxiety symptoms. Measured changes in respiration correlated with posterior insula activation and heart rate, at a more lenient threshold, change correlated with insula, caudate, and midbrain activity. Our findings highlight a set of brain regions, notably ventrolateral prefrontal cortex, supporting volitional control of cardiovascular arousal. These data are relevant to understanding neural substrates supporting interaction between intentional and interoceptive states related to anxiety, with implications for biofeedback interventions, e.g., real-time fMRI, that target emotional regulation.

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Critchley HD, Nicotra A, Chiesa PA, Nagai Y, Gray MA, Minati L, Bernardi L.
Slow breathing and hypoxic challenge: cardiorespiratory consequences and their central neural substrates.
PLoS One 2015; 10(5):e0127082

Controlled slow breathing (at 6/min, a rate frequently adopted during yoga practice) can benefit cardiovascular function, including responses to hypoxia. We tested the neural substrates of cardiorespiratory control in humans during volitional controlled breathing and hypoxic challenge using functional magnetic resonance imaging (fMRI). Twenty healthy volunteers were scanned during paced (slow and normal rate) breathing and during spontaneous breathing of normoxic and hypoxic (13% inspired O2) air. Cardiovascular and respiratory measures were acquired concurrently, including beat-to-beat blood pressure from a subset of participants (N = 7). Slow breathing was associated with increased tidal ventilatory volume. Induced hypoxia raised heart rate and suppressed heart rate variability. Within the brain, slow breathing activated dorsal pons, periaqueductal grey matter, cerebellum, hypothalamus, thalamus and lateral and anterior insular cortices. Blocks of hypoxia activated mid pons, bilateral amygdalae, anterior insular and occipitotemporal cortices. Interaction between slow breathing and hypoxia was expressed in ventral striatal and frontal polar activity. Across conditions, within brainstem, dorsal medullary and pontine activity correlated with tidal volume and inversely with heart rate. Activity in rostroventral medulla correlated with beat-to-beat blood pressure and heart rate variability. Widespread insula and striatal activity tracked decreases in heart rate, while subregions of insular cortex correlated with momentary increases in tidal volume. Our findings define slow breathing effects on central and cardiovascular responses to hypoxic challenge. They highlight the recruitment of discrete brainstem nuclei to cardiorespiratory control, and the engagement of corticostriatal circuitry in support of physiological responses that accompany breathing regulation during hypoxic challenge.

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Garfinkel SN, Minati L, Gray MA, Seth AK, Dolan RJ, Critchley HD.
Fear from the heart: sensitivity to fear stimuli depends on individual heartbeats.
J Neurosci 2014; 34(19):6573-82

Cognitions and emotions can be influenced by bodily physiology. Here, we investigated whether the processing of brief fear stimuli is selectively gated by their timing in relation to individual heartbeats. Emotional and neutral faces were presented to human volunteers at cardiac systole, when ejection of blood from the heart causes arterial baroreceptors to signal centrally the strength and timing of each heartbeat, and at diastole, the period between heartbeats when baroreceptors are quiescent. Participants performed behavioral and neuroimaging tasks to determine whether these interoceptive signals influence the detection of emotional stimuli at the threshold of conscious awareness and alter judgments of emotionality of fearful and neutral faces. Our results show that fearful faces were detected more easily and were rated as more intense at systole than at diastole. Correspondingly, amygdala responses were greater to fearful faces presented at systole relative to diastole. These novel findings highlight a major channel by which short-term interoceptive fluctuations enhance perceptual and evaluative processes specifically related to the processing of fear and threat and counter the view that baroreceptor afferent signaling is always inhibitory to sensory perception.

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Garfinkel SN, Barrett AB, Minati L, Dolan RJ, Seth AK, Critchley HD.
What the Heart Forgets: Cardiac Timing Influences Memory for Words and Is Modulated by Metacognition and Interoceptive Sensitivity.
Psychophysiology 2013; 50(6):505-512

Mental functions are influenced by states of physiological arousal. Afferent neural activity from arterial baroreceptors at systole conveys the strength and timing of individual heartbeats to the brain. We presented words under limited attentional resources time-locked to different phases of the cardiac cycle, to test a hypothesis that natural baroreceptor stimulation influences detection and subsequent memory of words. We show memory for words presented around systole was decreased relative to words at diastole. The deleterious memory effect of systole was greater for words detected with low confidence and amplified in individuals with low interoceptive sensitivity, as indexed using a heartbeat counting task. Our observations highlight an important cardiovascular channel through which autonomic arousal impacts a cognitive function, an effect mitigated by metacognition (perceptual confidence) and interoceptive sensitivity.

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Hart N, McGowan J, Minati L, Critchley HD.
Emotional Regulation and Bodily Sensation: Interoceptive Awareness Is Intact in Borderline Personality Disorder.
J Pers Disord 2013; 27(4):506-18

Emotional dysregulation is a core component of borderline personality disorder (BPD). Theoretical models suggest that deficits in labeling physiological sensations of emotion contribute to affective instability in BPD. Interoceptive awareness refers to the ability to perceive changes in internal bodily states, and is linked to the subjective experience and control of emotions. The authors tested whether differences in interoceptive awareness accounted for emotional instability in BPD. Patients diagnosed with BPD (n = 24) were compared to healthy controls (n = 30) on two established measures of interoceptive awareness, a heartbeat perception task and a heartbeat monitoring task. Contrary to their hypothesis, the authors observed no significant differences in objective measures of interoceptive awareness. Their findings provide strong evidence against the notion that difficulties in emotional regulation in BPD are connected to differences in interoceptive awareness.

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Minati L, Grisoli M, Franceschetti S, Epifani F, Granvillano A, Medford N, Harrison NA, Piacentini S, Critchley HD.
Neural signatures of economic parameters during decision-making: a functional MRI (FMRI), electroencephalography (EEG) and autonomic monitoring study.
Brain Topogr 2012; 25(1):73-96

Adaptive behaviour requires an ability to obtain rewards by choosing between different risky options. Financial gambles can be used to study effective decision-making experimentally, and to distinguish processes involved in choice option evaluation from outcome feedback and other contextual factors. Here, we used a paradigm where participants evaluated ‘mixed’ gambles, each presenting a potential gain and a potential loss and an associated variable outcome probability. We recorded neural responses using autonomic monitoring, electroencephalography (EEG) and functional neuroimaging (fMRI), and used a univariate, parametric design to test for correlations with the eleven economic parameters that varied across gambles, including expected value (EV) and amount magnitude. Consistent with behavioural economic theory, participants were risk-averse. Gamble evaluation generated detectable autonomic responses, but only weak correlations with outcome uncertainty were found, suggesting that peripheral autonomic feedback does not play a major role in this task. Long-latency stimulus-evoked EEG potentials were sensitive to expected gain and expected value, while alpha-band power reflected expected loss and amount magnitude, suggesting parallel representations of distinct economic qualities in cortical activation and central arousal. Neural correlates of expected value representation were localized using fMRI to ventromedial prefrontal cortex, while the processing of other economic parameters was associated with distinct patterns across lateral prefrontal, cingulate, insula and occipital cortices including default-mode network and early visual areas. These multimodal data provide complementary evidence for distributed substrates of choice evaluation across multiple, predominantly cortical, brain systems wherein distinct regions are preferentially attuned to specific economic features. Our findings extend biologically-plausible models of risky decision-making while providing potential biomarkers of economic representations that can be applied to the study of deficits in motivational behaviour in neurological and psychiatric patients.

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Eccles JA, Beacher FD, Gray MA, Jones CL, Minati L, Harrison NA, Critchley HD.
Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms.
Br J Psychiatry 2012; 200(6):508-9

Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms.

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Gray MA, Beacher FD, Minati L, Nagai Y, Kemp AH, Harrison NA, Critchley HD.
Emotional appraisal is influenced by cardiac afferent information.
Emotion 2012; 12(1):180-91

Influential models highlight the central integration of bodily arousal with emotion. Some emotions, notably disgust, are more closely coupled to visceral state than others. Cardiac baroreceptors, activated at systole within each cardiac cycle, provide short-term visceral feedback. Here we explored how phasic baroreceptor activation may alter the appraisal of brief emotional stimuli and consequent cardiovascular reactions. We used functional MRI (fMRI) to measure brain responses to emotional face stimuli presented before and during cardiac systole. We observed that the processing of emotional stimuli was altered by concurrent natural baroreceptor activation. Specifically, facial expressions of disgust were judged as more intense when presented at systole, and rebound heart rate increases were attenuated after expressions of disgust and happiness. Neural activity within prefrontal cortex correlated with emotionality ratings. Activity within periaqueductal gray matter reflected both emotional ratings and their interaction with cardiac timing. Activity within regions including prefrontal and visual cortices correlated with increases in heart rate evoked by the face stimuli, while orbitofrontal activity reflected both evoked heart rate change and its interaction with cardiac timing. Our findings demonstrate that momentary physiological fluctuations in cardiovascular afferent information (1) influence specific emotional judgments, mediated through regions including the periaqueductal gray matter, and (2) shape evoked autonomic responses through engagement of orbitofrontal cortex. Together these findings highlight the close coupling of visceral and emotional processes and identify neural regions mediating bodily state influences on affective judgment.

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Jones CL, Gray MA, Minati L, Simner J, Critchley HD, Ward J.
The neural basis of illusory gustatory sensations: two rare cases of lexical-gustatory synaesthesia.
J Neuropsychol 2011; 5(2):243-54

Lexical–gustatory synaesthesia is a rare phenomenon in which the individual experiences flavour sensations when they read, hear, or imagine words. In this study, we provide insight into the neural basis of this form of synaesthesia using functional neuroimaging. Words known to evoke pleasant, neutral, and unpleasant synaesthetic tastes and synaesthetically tasteless words were presented to two lexical–gustatory synaesthetes, during fMRI scanning. Ten non-synaesthetic participants were also scanned on the same list of words. The synaesthetic brain displayed a different pattern of activity to words when compared to the non-synaesthetes, with insula activation related to viewing words that elicited tastes that have an associated emotional valence (i.e., pleasant or unpleasant tastes). The subjective intensity of the synaesthesia was correlated with activity in the medial parietal lobes (precuneus/retrosplenial cortex), which are implicated in polymodal imagery and self-directed thought. This region has also previously been activated in studies of lexical–colour synaesthesia, suggesting its role may not be limited to the type of synaesthesia explored here.

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Visani E, Minati L, Canafoglia L, Gilioli I, Granvillano A, Varotto G, Aquino D, Fazio P, Bruzzone MG, Franceschetti S, Panzica F.
Abnormal ERD/ERS but Unaffected BOLD Response in Patients with Unverricht-Lundborg Disease During Index Extension: A Simultaneous EEG-fMRI Study.
Brain Topogr 2011; 24(1):65-773

Electrophysiological studies indicate that Unverricht–Lundborg’s disease (ULD), the most common form of progressive myoclonus epilepsy in Europe, is characterized by the involvement of multiple cortical regions in degenerative changes that lead to enhanced excitation and deficient inhibition. We searched for the haemodynamic correlates of these effects using functional MRI (fMRI) of self-paced index extensions, a well-accepted task highlighting significant differences. EEG and fMRI were simultaneously acquired in 11 ULD patients and 16 controls, performing the index extensions individually (event-related task) as well as repetitively (block task). ERD/ERS analysis was performed for the EEG data in the alpha and beta bands. fMRI time-series were analyzed using the traditional general linear model, as well as with an assumption-free approach, and by means of cross-region correlations representing functional connectivity. In line with the existing literature, ULD patients had enhanced desynchronization in the alpha band and reduced post-movement synchronization in the beta band. By contrast, fMRI did not reveal any difference between the two groups; there were no activation intensity, latency or extent effects, no significant engagement of additional regions, and no changes to functional connectivity. We conclude that, so long as the patients are executing a task which does not induce obvious action myoclonus, the hypothesized abnormalities in pyramidal neuron and interneuron dynamics are relatively subtle, embodied in processes which are not metabolically-demanding and take place at a time-scale invisible to fMRI.

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Kress IU, Minati L, Ferraro S, Critchley HD.
Direct skin-to-skin versus indirect touch modulates neural responses to stroking versus tapping.
NeuroReport. 2011; 22(13):646-51

It remains unclear whether direct interpersonal contact is processed differently from similar soft touch applied through inanimate objects. We performed a functional MRI experiment in healthy volunteers, whereby activity during gentle stroking or tapping was compared between stimuli delivered using the experimenter’s hand or a velvet stick. Stroking with a hand elicited larger responses than the other three conditions in the contralateral primary and secondary somatosensory areas and in the posterior insula. The observed effects likely originate from a combination of perceptual differences and cognitive and emotional correlates of contact with another person. This empirical observation indicates that, to ensure ecological validity, studies of affective touch processing should be performed with stimuli delivered with direct interpersonal contact rather than inanimate objects.

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Visani E, Minati L, Canafoglia L, Gilioli I, Salvatoni L, Varotto G, Fazio P, Aquino D, Bruzzone MG, Franceschetti S, Panzica F.
Simultaneous EEG-fMRI in patients with Unverricht-Lundborg disease: event-related desynchronization/synchronization and hemodynamic response analysis.
Comput Intell Neurosci 2010; 164278

We performed simultaneous acquisition of EEG-fMRI in seven patients with Unverricht-Lundborg disease (ULD) and in six healthy controls using self-paced finger extension as a motor task. The event-related desynchronization/synchronization (ERD/ERS) analysis showed a greater and more diffuse alpha desynchronization in central regions and a strongly reduced post-movement beta-ERS in patients compared with controls, suggesting a significant dysfunction of the mechanisms regulating active movement and movement end. The event-related hemodynamic response obtained from fMRI showed delayed BOLD peak latency in the contralateral primary motor area suggesting a less efficient activity of the neuronal populations driving fine movements, which are specifically impaired in ULD.

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Gray MA, Minati L, Paoletti G, Critchley HD.
Baroreceptor activation attenuates attentional effects on pain-evoked potentials.
Pain 2010; 151(3):853-61

Focused attention typically enhances neural nociceptive responses, reflected electroencephalographically as increased amplitude of pain‐evoked event‐related potentials (ERPs). Additionally, pain‐evoked ERPs are attenuated by hypertension and baroreceptor activity, through as yet unclear mechanisms. There is indirect evidence that these two effects may interact, suggesting that baroreceptor‐related modulation of nociception is more than a low‐level gating phenomenon. To address this hypothesis, we explored in a group of healthy participants the combined effects of cue‐induced expectancy and baroreceptor activity on the amplitude of pain‐evoked ERPs. Brief nociceptive skin stimuli were delivered during a simple visual task; half were preceded by a visual forewarning cue, and half were unpredictable. Nociceptive stimuli were timed to coincide either with systole (maximum activation of cardiac baroreceptors) or with diastole (minimum baroreceptor activation). We observed a strong interaction between expectancy and cardiac timing for the amplitude of the P2 ERP component; no effects were observed for the N2 component. Cued stimuli were associated with larger P2 amplitude, but this effect was abolished for stimuli presented during baroreceptor activation. No cardiac timing effect was observed for un‐cued stimuli. Taken together, these findings suggest a close integration of cognitive–affective aspects of expectancy and baroreceptor influences on pain, and as such may cast further light on mechanisms underlying mental and physiological contributions to clinical pain.

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Minati L, Jones CL, Gray MA, Medford N, Harrison NA, Critchley HD.
Emotional modulation of visual cortex activity: a functional near-infrared spectroscopy study.
NeuroReport 2009; 20(15):1344-50

Functional neuroimaging and electroencephalography reveal emotional effects in the early visual cortex. Here, we used functional near-infrared spectroscopy to examine haemodynamic responses evoked by neutral, positive and negative emotional pictures, matched for brightness, contrast, hue, saturation, spatial frequency and entropy. Emotion content modulated amplitude and latency of oxy, deoxy and total haemoglobin response peaks, and induced peripheral autonomic reactions. The processing of positive and negative pictures enhanced haemodynamic response amplitude, and this effect was paralleled by blood pressure changes. The processing of positive pictures was reflected in reduced haemodynamic response peak latency. Together these data suggest that the early visual cortex holds amplitude-dependent representation of stimulus salience and latency-dependent information regarding stimulus valence, providing new insight into affective interaction with sensory processing.

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Gray MA, Minati L, Harrison NA, Gianaros PJ, Napadow V, Critchley HD.
Physiological recordings: basic concepts and implementation during functional magnetic resonance imaging.
NeuroImage 2009; 47(3):1105-15

Combining human functional neuroimaging with other forms of psychophysiological measurement, including autonomic monitoring, provides an empirical basis for understanding brain–body interactions. This approach can be applied to characterize unwanted physiological noise, examine the neural control and representation of bodily processes relevant to health and morbidity, and index covert expression of affective and cognitive processes to enhance the interpretation of task-evoked regional brain activity. In recent years, human neuroimaging has been dominated by functional magnetic resonance imaging (fMRI) studies. The spatiotemporal information of fMRI regarding central neural activity is valuably complemented by parallel physiological monitoring, yet such studies still remain in the minority. This review article highlights fMRI studies that employed cardiac, vascular, respiratory, electrodermal, gastrointestinal and pupillary psychophysiological indices to address specific questions regarding interaction between brain and bodily state in the context of experience, cognition, emotion and behaviour. Physiological monitoring within the fMRI environment presents specific technical issues, most importantly related to safety. Mechanical and electrical hazards may present dangers to scanned subjects, operator and/or equipment. Furthermore, physiological monitoring may interfere with the quality of neuroimaging data, or itself be compromised by artefacts induced by the operation of the scanner. We review the sources of these potential problems and the current approaches and advice to enable the combination of fMRI and physiological monitoring in a safe and effective manner.

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Caldiroli D, Minati L.
Early experience with remote pressure sensor respiratory plethysmography monitoring sedation in the MR scanner.
Eur J Anaesthesiol 2007; 24(9):761-9

BACKGROUND AND OBJECTIVE: The importance of monitoring the breathing pattern during sedation of children undergoing magnetic resonance scans is indicated in guidelines, but no appropriate magnetic resonance-compatible devices are available. We report preliminary findings from a technique referred to as remote pressure sensor respiratory plethysmography.
METHODS: A data acquisition system was developed, enabling measurement of respiratory rate, plethysmogram amplitude, proportion of inspiratory time over cycle time, thoraco-abdominal phase shift and sigh rate. Correlation between plethysmogram amplitude and tidal volume was investigated on adult volunteers. Twenty-seven children undergoing sedation were monitored with remote pressure sensor respiratory plethysmography, in addition to SPO2 and PetCO2. Differences in monitoring parameters were searched for among three groups: patients who received chloral hydrate only (chloral succeeded, CS group), those who received a supplementation of sodium thiopental (chloral failed, CF group), and those who were sedated with sodium thiopental directly (no chloral, NC group). Correlations were searched for among monitoring parameters, and with total dose of thiopental. The long-term behaviour of respiratory rate, proportion of inspiratory time over cycle time and phase shift was studied.
RESULTS: Plethysmogram amplitude was found to correlate linearly with tidal volume (r>0.92), with a slope varying up to 22%. While 11% of patients did not tolerate the capnometric probe and readings were discontinuous in 26%, all of them tolerated remote pressure sensor respiratory plethysmography belts. Sighs and non-respiratory movements of the torso could be distinguished on remote pressure sensor respiratory plethysmography waveforms. No significant inter-group differences were found in PetCO2, SPO2, respiratory rate and phase shift. Proportion of inspiratory time over cycle time was higher in the NC group when compared to the CS group (0.497+/-0.03 vs. 0.463+/-0.008; P=0.02), the CF group being characterized by intermediate values (0.480+/-0.008); when compared to the CS group, sigh rate was lower in the CF group (0.04+/-0.04 vs. 0.14+/-0.08; P=0.04) and in the NC group (0.06+/-0.05 vs. 0.14+/-0.08, P=0.03). A positive correlation was found between total dose of thiopental and proportion of inspiratory time over cycle time, with r=0.4 and P=0.04. A large baseline variability in phase shift was found. No long-term trends predictive of patient movement could be identified.
CONCLUSIONS: Breathing pattern monitoring is feasible through pneumatic devices, which are well tolerated. The resulting correlation with changes in tidal volume can be better when compared to visual inspection. Proportion of inspiratory time over cycle time and sigh rate convey information related to the state of the sedated patient. These results are not specific to the technology employed, and large-scale studies on the clinical usefulness of breathing pattern monitoring are motivated.

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OTHER NEUROIMAGING/NEUROPHYSIOLOGY METHODS AND APPLICATIONS
Zacà D, Hasson U, Minati L, Jovicich J.
Method for retrospective estimation of natural head movement during structural MRI.
J Magn Reson Imaging. 2018, epub ahead of print

BACKGROUND: Head motion during brain structural MRI scans biases brain morphometry measurements but quantitative retrospective methods estimating head motion from structural MRI have not been evaluated.
PURPOSE: To verify the hypothesis that two metrics retrospectively computed from MR images: 1) average edge strength (AES, reduced with image blurring) and 2) entropy (ENT, increased with blurring and ringing artifacts) could be sensitive to in-scanner head motion during acquisition of T1 -weighted MR images.
STUDY TYPE: Retrospective.
POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: In all, 83 healthy control (HC) and 120 Parkinson’s disease (PD) patients.
FIELD STRENGTH/SEQUENCE: 3D magnetization-prepared rapid gradient-echo (MPRAGE) images at 3T.
ASSESSMENT: We 1) compared AES and ENT distribution between HC and PD; 2) evaluated the correlation between tremor score (TS) and AES (or ENT) in PD; and 3) investigated cortical regions showing an association between AES (or ENT) and local and network-level covariance measures of cortical thickness (CT), gray to white matter contrast (GWC) and gray matter density maps (GMx).
STATISTICAL TESTS: 1) Student’s t-test. 2) Spearman’s rank correlation. 3) General linear model and partial least square analysis.
RESULTS: AES, but not ENT, differentiated HC and PD (P = 0.02, HC median AES = 39.8, interquartile range = 9.8, PD median AES = 37.6, interquartile range = 8.1). In PD, AES correlated negatively with TS (ρ = -0.21, P = 0.02) and showed a significant relationship (|Z| >3, P < 0.001) with structural covariance of CT and GWC in 54 out of 68 cortical regions.
DATA CONCLUSION: In clinical populations prone to head motion, AES can provide a reliable retrospective index of motion during structural scans, identifying brain areas whose morphometric measures covary with motion

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Canazza A, Minati L, Boffano C, Parati E, Binks S.
Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies.
Front Neurol 2014;5:19

Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment, and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies.

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Rosazza C, Ghielmetti F, Minati L, Vitali P, Giovagnoli A, Deleo F, Didato G, Parente A, Marras C, Bruzzone MG, D'Incerti L, Spreafico R, Villani F.
Preoperative language lateralization in temporal lobe epilepsy (TLE) predicts peri-ictal, pre- and post-operative language performance: an fMRI study.
NeuroImage: Clinical 2013; 3:73-83

In patients with temporal lobe epilepsy (TLE), assessment of language lateralization is important as anterior temporal lobectomy may lead to language impairments. Despite the widespread use of fMRI, evidence of its usefulness in predicting postsurgical language performance is scant. We investigated whether preoperative functional lateralization is related to the preoperative language performance, peri-ictal aphasia, and can predict language outcome one year post-surgery. We studied a total of 72 TLE patients (42 left, 30 right), by using three fMRI tasks: Naming, Verb Generation and Fluency. Functional lateralization indices were analyzed with neuropsychological scores and presence of peri-ictal aphasia.
The key findings are:
1) Both left and right TLE patients show decreased left lateralization compared to controls.
2) Lateralization correlates with language performance before surgery. In left TLE, decreased left lateralization correlates with better fluency performance. In right TLE, increased left lateralization during the Naming task correlates with better naming.
3) Left lateralization correlates with peri-ictal aphasia in left TLE patients.
4) Lateralization correlates with language performance after surgery. In a subgroup of left TLE who underwent surgery (17 left), decreased left lateralization is predictive of better naming performance at 6 and 12 months after surgery.
The present study highlights the clinical relevance of fMRI language lateralization in TLE, especially to predict language outcome one year post-surgery. We also underline the importance of using fMRI tasks eliciting frontal and anterior temporal activations, when studying left and right TLE patients.

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Minati L, Giaccone G, D’Incerti L, Zucca I, Spreafico R, Tagliavini F, Pilleri G.
Severe microcephaly with poly-nodular heterotopia: a high-field MRI and neuropathological case-study.
Eur J Neurol 2013; 20(6):e81-2
Giglio AC, Minati L, Boggio PS.
Throwing the banana away and keeping the peel: Neuroelectric responses to unexpected but physically feasible action endings.
Brain Res 2013; 1532:56-62

Integrative semantic processing and mirror-neuron system activation in response to incongruence detection during action observation have so far been investigated only through paradigms that involve unfeasible action endings, introduction of extraneous objects or synthetic pictures. The ecological validity of the reported effects, particularly modulation of the N400 event-related potential (ERP), therefore remains questionable. To address this shortcoming, we investigated the ERPs evoked by physically feasible and naturalistic but unexpected action endings. We hypothesized that in comparison to existing work our more realistic scenarios would elicit slower processing, due to engagement of deeper analysis as opposed to fast detection based on automatic processes. ERPs were recorded in 14 healthy participants in response to 60 sequences, each containing three pictures, the last of which could be an expected or unexpected action ending. The N400 was larger for the first image compared to the others, and the LPP was enhanced for unexpected endings. Source localization implicated anterior fronto-temporal and temporo-parietal junction regions in generation of these potentials. Our findings challenge the view that the N400 universally indices verbal and action–perception incongruence detection, and point to situation-contingent effects which, in the case of subtle violations, are reflected in later activity components, speculatively reflecting recourse to the “mentalizing” system.

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Lapenta OM, Minati L, Fregni F, Boggio PS.
Je pense donc je fais: transcranial direct current stimulation modulates brain oscillations associated with motor imagery and movement observation.
Front Hum Neurosci. 2013; 7:256

Motor system neural networks are activated during movement imagery, observation and execution, with a neural signature characterized by suppression of the Mu rhythm. In order to investigate the origin of this neurophysiological marker, we tested whether transcranial direct current stimulation (tDCS) modifies Mu rhythm oscillations during tasks involving observation and imagery of biological and non-biological movements. We applied tDCS (anodal, cathodal, and sham) in 21 male participants (mean age 23.8 ± 3.06), over the left M1 with a current of 2 mA for 20 min. Following this, we recorded the EEG at C3, C4, and Cz and surrounding C3 and C4 electrodes. Analyses of C3 and C4 showed significant effects for biological vs. non-biological movement (p = 0.005), and differential hemisphere effects according to the type of stimulation (p = 0.04) and type of movement (p = 0.02). Analyses of surrounding electrodes revealed significant interaction effects considering type of stimulation and imagery or observation of biological or non-biological movement (p = 0.03). The main findings of this study were (1) Mu desynchronization during biological movement of the hand region in the contralateral hemisphere after sham tDCS; (2) polarity-dependent modulation effects of tDCS on the Mu rhythm, i.e., anodal tDCS led to Mu synchronization while cathodal tDCS led to Mu desynchronization during movement observation and imagery (3) specific focal and opposite inter-hemispheric effects, i.e., contrary effects for the surrounding electrodes during imagery condition and also for inter-hemispheric electrodes (C3 vs. C4). These findings provide insights into the cortical oscillations during movement observation and imagery. Furthermore, it shows that tDCS can be highly focal when guided by a behavioral task.

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Garbelli R, Zucca I, Milesi G, Mastropietro A, D'Incerti L, Tassi L, Colombo N, Marras C, Villani F, Minati L, Spreafico R.
Combined 7 T-MRI and histopathological study of normal and dysplastic samples from TLE patients.
Neurology 2011; 76(13):1177-85

OBJECTIVES: The purpose of the study was to investigate the abnormalities of cortical lamination observed in temporal lobe specimens obtained during surgery for intractable temporal lobe epilepsy (TLE) with hippocampal sclerosis. Specifically, we aimed to 1) correlate high-field ex vivo MRI with histopathologic analysis and 2) evaluate the effect of tissue fixation on image contrast.
METHODS: A cohort of 13 specimens was considered. T2-weighted imaging and relaxometry were performed during and after fixation using a 7-T experimental scanner. After imaging, the specimens were studied with histopathologic (Black Gold myelin fiber staining) and immunohistochemical (NeuN neuronal staining) methods in order to explore the correspondence between MRI and histopathologic features.
RESULTS: The principal findings of this study are that 1) superior MRI contrast is obtained among the cortical layers using completely fixed specimens as opposed to recently excised tissue, 2) the intensity of the T2-weighted MRI signal is lowest (hypointensity) at the site of highest fiber concentration and cellular density, and highest (hyperintensity) when the density of fibers and cells is lowest, and 3) the MRI signal is altered in presence of abnormal cortical lamination (focal cortical dysplasia type IA).
CONCLUSIONS: High resolution ex vivo MRI enables the study of intracortical organization in normal and pathologic areas. Comparisons between MRI, NeuN, and Black Gold indicate that the differences apparent in T2-weighted images are mainly related to fiber concentration, although neuronal density might also play a role.

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Rosazza C, Minati L, Ghielmetti F, Maccagnano E, Erbetta A, Villani F, Epifani F, Spreafico R, Bruzzone MG.
Engagement of the medial temporal lobe in verbal and nonverbal memory: assessment with functional MR imaging in healthy subjects.
AJNR Am J Neuroradiol 2009; 30(6):1134-4

BACKGROUND AND PURPOSE: The hippocampus and parahippocampal gyrus have a central role in the acquisition of new memories. Although functional MR imaging (fMRI) can provide information on the functional status of these brain regions, it has not reached widespread use in the presurgical assessment of patients undergoing temporal lobectomy. We aimed to evaluate whether simple memory-encoding paradigms could be used to elicit robust activations in the hippocampus and parahippocampal gyrus and to determine the lateralization of verbal and nonverbal memory. We also studied the relative contribution of the anterior and posterior portions of these structures.
MATERIALS AND METHODS: We conducted this study on 16 healthy subjects by performing event-related fMRI using 3 memory encoding tasks with words, objects, and faces. In addition to a second-level group analysis, region-of-interest (ROI)–based measurements of the signal intensity percent change and of the percentage of activated voxels, determined at 2 thresholds, were performed. ROIs were drawn on the hippocampus and parahippocampal gyrus, divided into anterior and posterior segments.
RESULTS: We found overall left-lateralized activation with words, bilateral activation with objects, and right-lateralized activation with faces. In particular, significant hippocampal activations were observed with all 3 categories of stimuli, and the head of the hippocampus was generally more engaged than its body and tail. Data on the signal intensity percent change and percentage of activated voxels are provided for each ROI and task.
CONCLUSIONS: The combination of these 3 undemanding memory tasks could be considered, following appropriate validation, as a tool to assess the functional status of the medial temporal lobe in clinical settings.

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Rosazza C, Cai Q, Minati L, Paulignan Y, Nazir TA.
Early involvement of dorsal and ventral pathways in visual word recognition: an ERP study.
Brain Res 2009; 1272:32-44

Visual expertise underlying reading is attributed to processes involving the left ventral visual pathway. However, converging evidence suggests that the dorsal visual pathway is also involved in early levels of visual word processing, especially when words are presented in unfamiliar visual formats. In the present study, event-related potentials (ERPs) were used to investigate the time course of the early engagement of the ventral and dorsal pathways during processing of orthographic stimuli (high and low frequency words, pseudowords and consonant strings) by manipulating visual format (familiar horizontal vs. unfamiliar vertical format). While early ERP components (P1 and N1) already distinguished between formats, the effect of stimulus type emerged at the latency of the N2 component (225–275 ms). The N2 scalp topography and sLORETA source localisation for this differentiation showed an occipito-temporal negativity for the horizontal format and a negativity that extended towards the dorsal regions for the vertical format. In a later time window (350–425 ms) ERPs elicited by vertically displayed stimuli distinguished words from pseudowords in the ventral area, as confirmed by source localisation. The sustained contribution of occipito-temporal processes for vertical stimuli suggests that the ventral pathway is essential for lexical access. Parietal regions appear to be involved when a serial mechanism of visual attention is required to shift attention from one letter to another. The two pathways cooperate during visual word recognition and processing in these pathways should not be considered as alternative but as complementary elements of reading.

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Vitali P, Minati L, D'Incerti L, Maccagnano E, Mavilio N, Capello D, Dylgjeri S, Rodriguez G, Franceschetti S, Spreafico R, Villani F.
Functional MRI in malformations of cortical development: activation of dysplastic tissue and functional reorganization.
J Neuroimaging 2008; 18(3):296-305

BACKGROUND AND PURPOSE: Functional neuroimaging and electrophysiological studies suggest that dysplastic neural tissue in malformations of cortical development may participate in task performance, and that functional organization can be altered beyond visible lesion boundaries. The aim of this work was to investigate cortical function in a heterogeneous group of patients with malformations of cortical development.
METHODS: Twelve patients participated in the study, 2 for each of the following categories: subcortical, periventricular, and band heterotopia, unilateral and bilateral polymicrogyria, and focal cortical dysplasia. Functional magnetic resonance imaging was performed with finger tapping, somatosensory and visual stimulation, and language-related tasks.
RESULTS: We found activations within the dysplastic tissue in subcortical heterotopia, band heterotopia, and polymicrogyria, but not in periventricular heterotopic nodules. In one of the patients with focal cortical dysplasia, language-related activation involved part of the lesion. Functional reorganization beyond visible lesion boundaries was seen, with different patterns, in 4 patients.
CONCLUSIONS: In accordance with previous reports, our findings indicate that dysplastic neural tissue can be activated during task performance, and that in some patients, extensive functional reorganization occurs, highlighting the importance of functional magnetic resonance imaging in presurgical planning in those patients for whom epilepsy surgery is considered as an option.

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Cortellazzi P, Minati L, Falcone C, Lamperti M, Caldiroli D.
Predictive value of the El-Ganzouri multivariate risk index for difficult tracheal intubation: a comparison of Glidescope videolaryngoscopy and conventional Macintosh laryngoscopy.
Br J Anaesth 2007; 99(6):906-11

Background: The predictive value of the El-Ganzouri risk index (EGRI) for difficult intubation has been evaluated using Macintosh laryngoscopy as reference standard. The Glidescope® videolaryngoscope provides improved visualization of the glottis. We studied the predictive value of the EGRI using videolaryngoscopy as reference standard.
Methods: Data from two subsequent groups of patients, intubated with Macintosh laryngoscopy (ML, n = 994) and videolaryngoscopy (VL, n = 843), were retrospectively analysed. The EGRI was taken as index test. The two types of laryngoscopy were adopted as reference for the presence of Cormack and Lehane grading III–IV. For both groups, sensitivity, specificity, and positive and negative post-test probabilities (PTP) were calculated for thresholds on the EGRI scale. Receiver operating characteristic curves and corresponding areas (AUC) were obtained.
Results: Sensitivity and specificity were 69.7% and 66.3% at the cut-off value of 2 in the ML group, and 93.3% and 76.6% at the cut-off value of 3 in the VL group. Corresponding positive and negative PTP were 12.81% and 3.15% in the ML group, and 6.73% and 0.16% in the VL group. At the threshold of 4, positive and negative PTP were 31.34% and 4.85% in the ML group. At the threshold of 7, positive and negative PTP were 85.71% and 1.08% in the VL group. The AUC was 0.74 in the ML group and 0.91 in the VL group.
Conclusions: The predictive value of the EGRI may have been underestimated due to limited accuracy of Macintosh laryngoscopy. Using videolaryngoscopy, the EGRI might be reconsidered as a decisional tool.

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Cortellazzi P, Lamperti M, Minati L, Falcone C, Pantaleoni C, Caldiroli D.
Sedation of neurologically impaired children undergoing MRI: a sequential approach.
Paediatr Anaesth 2007; 17(7):630-6

Background:  The purpose of this retrospective study was to determine the efficacy of a sequential approach meant to rescue failed chloral hydrate sedation and to obtain a low rate of adverse events along with predictable timings in neurologically impaired children undergoing magnetic resonance imaging.
Methods:  We retrospectively evaluated 1104 chloral hydrate sedations performed between 2002 and 2004 on 862 children weighing <26 kg. If the desired sedation score (3 on the Skeie Scale) was not reached within 30 min after oral administration of chloral hydrate, sedation was considered as potentially failed, and supplementation with sevoflurane, i.m. or i.v. ketamine, and i.v. pentobarbital and midazolam was started.
Results:  Twenty-seven sessions failed because of excessive movement. Mean induction time was significantly higher for patients who received supplementation (52.2 min vs 39.1 min), while no differences in recovery and total sedation times were found. Supplementation significantly increased the incidence of respiratory obstruction (4.6% vs 2.4%), although the incidence of other adverse events was unaffected.
Conclusions:  Administering up to 1.5 g of chloral hydrate without supplementation was associated with a failure rate of approximately 20%, but the proposed sequential approach enabled us to rescue the majority of failed sedations while maintaining an acceptably low incidence of adverse events.

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Savoiardo M, Minati L, Farina L, De Simone T, Aquino D, Mea E, Filippini G, Bussone G, Chiapparini L.
Spontaneous intracranial hypotension with deep brain swelling.
Brain 2007; 130(7):1884-93

Spontaneous intracranial hypotension (SIH) is caused by leakage of CSF, and characterized on MRI by brain sagging, dilatation of veins and dural sinuses, subdural fluid collections and post-contrast enhancement of the thickened dura. A few cases may present a very severe brain sagging through the tentorial notch and swelling of the diencephalic-mesencephalic structures, with absent or scarce subdural collections and post-contrast enhancement. These patients may have surprisingly few neurological signs or may become drowsy and even lapse into coma due to central herniation. We retrospectively examined the diffusion studies obtained in five patients with these MRI findings, in seven patients with SIH without brain swellings and in ten controls. Mean diffusivity was increased in SIH patients with brain swelling in areas draining into the deep venous system, collected by the vein of Galen (vG) and straight sinus (SS). In the hypothesis that central herniation might be responsible for venous stagnation because of impaired flow of the vG into the SS, the vG/SS angle was measured. The angle formed by the vG entering the SS was not altered in patients without brain swelling (group E, 67.8 degrees +/- 10.3 degrees, mean +/- SD, range 49-80 degrees) when compared to controls (group C, 73.3 degrees +/- 12.3 degrees, mean +/- SD, range 56-95 degrees). It was, however, grossly decreased in patients with brain swelling (group D, 40.7 degrees +/- 12.8 degrees, mean +/- SD, range 22-61 degrees), P < 0.001 for comparison with groups E and C. As suggested by previous studies, downward stretching of the vG and narrowing of the vG/SS angle may cause a functional stenosis at the vG-SS junction. We suggest that in the application of the Monro-Kellie doctrine to SIH, the brain volume should not be considered as always invariable.

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Gladin CR, Salsano E, Menghi F, Grisoli M, Ghielmetti F, Milanesi I, Pollo B, Brock S, Cusin A, Minati L, Finocchiaro G, Bruzzone MG.
Loss of heterozygosity studies in extracranial metastatic meningiomas.
J Neurooncol 2007; 85(1):81-5

Although most meningiomas are slow-growing tumours associated with favourable prognosis, they often present local recurrence after surgical treatment; by contrast, extracranial metastatic meningiomas are rare, occurring in less than 1% of the cases. Risk factors for distal spread remain largely unknown. We report three cases with lung or bone metastases from intracranial recurrent meningiomas. Loss of heterozygosity (LOH) analysis on 1p, 9p, 10q, 14q, and 22q was conducted in available primary, recurrent and metastatic lesions, showing the same LOH pattern in the distal metastases and in the intracranial meningioma. LOH at 1p, 14q and 9p, known to be associated with increased aggressiveness, were found. The results highlight the potential clinical relevance of integrating histopathological studies with molecular genetic analysis in the follow-up of patients with different types of meningiomas.

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Capobianco R, Casalone C, Suardi S, Mangieri M, Miccolo C, Limido L, Catania M, Rossi G, Di Fede G, Giaccone G, Bruzzone MG, Minati L, Corona C, Acutis P, Gelmetti D, Lombardi G, Groschup MH, Buschmann A, Zanusso G, Monaco S, Caramelli M, Tagliavini F.
Conversion of the BASE prion strain into the BSE strain: the origin of BSE?
PLoS Pathog 2007; 3(3):e31-35

Atypical neuropathological and molecular phenotypes of bovine spongiform encephalopathy (BSE) have recently been identified in different countries. One of these phenotypes, named bovine “amyloidotic” spongiform encephalopathy (BASE), differs from classical BSE for the occurrence of a distinct type of the disease-associated prion protein (PrP), termed PrPSc, and the presence of PrP amyloid plaques. Here, we show that the agents responsible for BSE and BASE possess different biological properties upon transmission to transgenic mice expressing bovine PrP and inbred lines of nontransgenic mice. Strikingly, serial passages of the BASE strain to nontransgenic mice induced a neuropathological and molecular disease phenotype indistinguishable from that of BSE-infected mice. The existence of more than one agent associated with prion disease in cattle and the ability of the BASE strain to convert into the BSE strain may have important implications with respect to the origin of BSE and spongiform encephalopathies in other species, including humans.

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Minati L
Neuroimaging Techniques: a Conceptual Overview of Physical Principles, Contribution and History.
AIP Conf. Proc 2006; 839:503-519

This paper is meant to provide a brief overview of the techniques currently used to image the brain and to study non‐invasively its anatomy and function. After a historical summary in the first section, general aspects are outlined in the second section. The subsequent six sections survey, in order, computed tomography (CT), morphological magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), diffusion‐tensor magnetic resonance imaging (DWI/DTI), positron emission tomography (PET), and electro‐ and magneto‐encephalography (EEG/MEG) based imaging. Underlying physical principles, modelling and data processing approaches, as well as clinical and research relevance are briefly outlined for each technique. Given the breadth of the scope, there has been no attempt to be comprehensive. The ninth and final section outlines some aspects of active research in neuroimaging.

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