Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Structural-functional connectivity bandwidth of the human brain.

BACKGROUND: The human brain is a complex network that seamlessly manifests behaviour and cognition. This network comprises neurons that directly, or indirectly mediate communication between brain regions. Here, we show how multilayer/multiplex network analysis provides a suitable framework to uncover the throughput of structural connectivity (SC) to mediate information transfer-giving rise to functional connectivity (FC). METHOD: We implemented a novel method to reconcile SC and FC using diffusion and resting-state functional MRI connectivity data from 484 subjects (272 females, 212 males; age = 29.15 ± 3.47) from the Human Connectome Project. First, we counted the number of direct and indirect structural paths that mediate FC. FC nodes with indirect SC paths were then weighted according to their least restrictive SC path. We refer to this as SC-FC Bandwidth. We then mapped paths with the highest SC-FC Bandwidth across 7 canonical resting-state networks. FINDINGS: We found that most pairs of FC nodes were connected by SC paths of length two and three (SC paths of length >5 were virtually non-existent). Direct SC-FC connections accounted for only 10% of all SC-FC connections. The majority of FC nodes without a direct SC path were mediated by a proportion of two (44%) or three SC path lengths (39%). Only a small proportion of FC nodes were mediated by SC path lengths of four (5%). We found high-bandwidth direct SC-FC connections show dense intra- and sparse inter-network connectivity, with a bilateral, anteroposterior distribution. High bandwidth SC-FC triangles have a right superomedial distribution within the somatomotor network. High-bandwidth SC-FC quads have a superoposterior distribution within the default mode network. CONCLUSION: Our method allows the measurement of indirect SC-FC using undirected, weighted graphs derived from multimodal MRI data in order to map the location and throughput of SC to mediate FC. An extension of this work may be to explore how SC-FC Bandwidth changes over time, relates to cognition/behavior, and if this measure reflects a marker of neurological injury or psychiatric disorders.

Fixel-based Analysis of Diffusion MRI: Methods, Applications, Challenges and Opportunities.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease.

OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. RESULTS: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. INTERPRETATION: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.

Early white matter pathology in the fornix of the limbic system in Huntington disease.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.

Tracking Huntington's Disease Progression Using Motor, Functional, Cognitive, and Imaging Markers.

BACKGROUND: Potential therapeutic targets and clinical trials for Huntington's disease have grown immensely in the last decade. However, to improve clinical trial outcomes, there is a need to better characterize profiles of signs and symptoms across different epochs of the disease to improve selection of participants. OBJECTIVE: The objective of the present study was to best distinguish longitudinal trajectories across different Huntington's disease progression groups. METHODS: Clinical and morphometric imaging data from 1082 participants across IMAGE-HD, TRACK-HD, and PREDICT-HD studies were combined, with longitudinal times ranging between 1 and 10 years. Participants were classified into 4 groups using CAG and age product. Using multivariate linear mixed modeling, 63 combinations of markers were tested for their sensitivity in differentiating CAG and age product groups. Next, multivariate linear mixed modeling was applied to define the best combination of markers to track progression across individual CAG and age product groups. RESULTS: Putamen and caudate volumes, individually and/or combined, were identified as the best variables to both differentiate CAG and age product groups and track progression within them. The model using only caudate volume best described advanced disease progression in the combined data set. Contrary to expectations, combining clinical markers and volumetric measures did not improve tracking longitudinal progression. CONCLUSIONS: Monitoring volumetric changes throughout a trial (alongside primary and secondary clinical end points) may provide a more comprehensive understanding of improvements in functional outcomes and help to improve the design of clinical trials. Alternatively, our results suggest that imaging deserves consideration as an end point in clinical trials because of the prospect of greater sensitivity. © 2021 International Parkinson and Movement Disorder Society.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Cortical morphometry and neural dysfunction in Huntington's disease: a review.

Numerous neuroimaging techniques have been used to identify biomarkers of disease progression in Huntington's disease (HD). To date, the earliest and most sensitive of these is caudate volume; however, it is becoming increasingly evident that numerous changes to cortical structures, and their interconnected networks, occur throughout the course of the disease. The mechanisms by which atrophy spreads from the caudate to these cortical regions remains unknown. In this review, the neuroimaging literature specific to T1-weighted and diffusion-weighted magnetic resonance imaging is summarized and new strategies for the investigation of cortical morphometry and the network spread of degeneration in HD are proposed. This new avenue of research may enable further characterization of disease pathology and could add to a suite of biomarker/s of disease progression for patient stratification that will help guide future clinical trials.

Brain compensation during response inhibition in premanifest Huntington's disease.

Premanifest Huntington's disease (pre-HD) individuals typically show increased task-related functional magnetic resonance imaging (fMRI), suggested to reflect compensatory strategies. Despite the evidence, no study has attempted to understand the compensatory process in light of 'formal' models of compensation. We used a quantitative model of compensation - the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), to characterise compensation in pre-HD using fMRI. Pre-HD individuals (n = 15) and controls (n = 15) performed a modified stop-signal task that incremented in four levels of stop difficulty. Our results did not support the critical assumption of the CRUNCH model - controls did not show increased fMRI activity with increased level of stop difficulty; however, controls showed decreased fMRI activity with increased stop difficulty in right inferior frontal gyrus and right caudate nucleus. Relative to controls, pre-HD individuals showed increased fMRI activity in right inferior frontal gyrus and in right caudate nucleus at higher levels of stop difficulty, which is the opposite effect to that predicted by the model. Our findings suggest a compensatory process of the response inhibition network in pre-HD; however, the pattern of fMRI activity was not in the manner expected by CRUNCH.

Exploring the brain-body composition relationship in Huntington's disease.

OBJECTIVE: Changes in body composition are a common feature of Huntington's disease (HD) and are associated with disease progression. However, whether these changes in body composition are associated with degeneration of the striatum is unknown. This study aimed to explore the associations between body composition metrics and striatal brain volume in individuals with premanifest HD and healthy controls. METHODS: Twenty-one individuals with premanifest HD and 22 healthy controls participated in this cross-sectional study. Body composition metrics were measured via dual-energy X-ray absorptiometry. Structural magnetic resonance imaging of subcortical structures of the brain was performed to evaluate striatal volume. RESULTS: There were no significant differences in body composition metrics between the premanifest HD and healthy controls group. Striatal volume was significantly reduced in individuals with premanifest HD compared to healthy controls. A significant association between bone mineral density (BMD) and right putamen volume was also observed in individuals with premanifest HD. CONCLUSION: These findings show striatal degeneration is evident during the premanifest stages of HD and associated with BMD. Additional longitudinal studies are nevertheless needed to confirm these findings.

Network spread determines severity of degeneration and disconnection in Huntington's disease.

Trans-neuronal propagation of mutant huntingtin protein contributes to the organised spread of cortico-striatal degeneration and disconnection in Huntington's disease (HD). We investigated whether the network diffusion model, which models transneuronal spread as diffusion of pathological proteins via the brain connectome, can determine the severity of neural degeneration and disconnection in HD. We used structural magnetic resonance imaging (MRI) and high-angular resolution diffusion weighted imaging (DWI) data from symptomatic Huntington's disease (HD) (N = 26) and age-matched healthy controls (N = 26) to measure neural degeneration and disconnection in HD. The network diffusion model was used to test whether disease spread, via the human brain connectome, is a viable mechanism to explain the distribution of pathology across the brain. We found that an eigenmode identified in the healthy human brain connectome Laplacian matrix, accurately predicts the cortico-striatal spatial pattern of degeneration in HD. Furthermore, the spread of neural degeneration from sub-cortical brain regions, including the accumbens and thalamus, generates a spatial pattern which represents the typical neurodegenerative characteristics in HD. The white matter connections connecting the nodes with the highest amount of disease factors, when diffusion based disease spread is initiated from the striatum, were found to be most vulnerable to disconnection in HD. These findings suggest that trans-neuronal diffusion of mutant huntingtin protein across the human brain connectome may explain the pattern of gray matter degeneration and white matter disconnection that are hallmarks of HD.

Temporal evolution of neural activity and connectivity during microsleeps when rested and following sleep restriction.

Even when it is critical to stay awake, such as when driving, sleep deprivation weakens one's ability to do so by substantially increasing the propensity for microsleeps. Microsleeps are complete lapses of consciousness but, paradoxically, are associated with transient increases in cortical activity. But do microsleeps provide a benefit in terms of attenuating the need for sleep? And is the neural response to microsleeps altered by the degree of homeostatic drive to sleep? In this study, we continuously monitored eye-video, visuomotor responsiveness, and brain activity via fMRI in 20 healthy subjects during a 20-min visuomotor tracking task following a normally-rested night and a sleep-restricted (4-h) night. As expected, sleep restriction led to an increased number of microsleeps and an increased variability in tracking error. Microsleeps exhibited transient increases in regional activity in the fronto-parietal and parahippocampal area. Network analyses revealed divergent transient changes in the right fronto-parietal, dorsal-attention, default-mode, and thalamo-cortical functional networks. In all subjects, tracking error immediately following microsleeps was improved compared to before the microsleeps. Importantly, post-microsleep recovery in tracking response speed was associated with hyperactivation in the thalamo-cortical network. The temporal evolution of functional connectivity within the frontal and posterior nodes of the default-mode network and between the right fronto-parietal and default-mode networks was associated with temporal changes in visuomotor responsiveness. These findings demonstrate distinct brain-network-level changes in brain activity during microsleeps and suggest that neural activity in the thalamo-cortical network may facilitate the transient recovery from microsleeps. The temporal pattern of evolution in brain activity and performance is indicative of dynamic changes in vigilance during the struggle to stay awake following sleep loss.

Emotion processing in persons who respond vicariously towards others in pain: Disinhibited left-lateralized neural activity for threatening expressions.

We investigated emotional processing in vicarious pain (VP) responders. VP responders report an explicit sensory and emotional feeling of pain when they witness another in pain, which is greater in magnitude than the empathic processing of pain in the general population. In Study 1, 31 participants completed a chimeric faces task, judging whether emotional chimera in the left, or right, visual field was more intense. VP responders took longer to judge emotionality than non-responders, and fixated more on the angry hemiface in the right visual field, whereas non-responder controls had no lateralized fixation bias. In Study 2, blood-oxygen level-dependent signals were recorded during an emotional face matching task. VP intensity was correlated with increased insula activity and reduced middle frontal gyrus activity for angry faces, and with reduced activity in the inferior and middle frontal gyri for sad faces. Together, these findings suggest that VP responders are more reactive to negative emotional expressions. Specifically, emotional judgements involved altered left-hemisphere activity in VP responders, and reduced engagement of regions involved in emotion regulation.

Time-varying effective connectivity of the cortical neuroelectric activity associated with behavioural microsleeps.

An episode of complete failure to respond during an attentive task accompanied by behavioural signs of sleep is called a behavioural microsleep. We proposed a combination of high-resolution EEG and an advanced method for time-varying effective connectivity estimation for reconstructing the temporal evolution of the causal relations between cortical regions when microsleeps occur during a continuous visuomotor task. We found connectivity patterns involving left-right frontal, left-right parietal, and left-frontal/right-parietal connections commencing in the interval [-500; -250] ms prior to the onset of microsleeps and disappearing at the end of the microsleeps. Our results from global graph indices derived from effective connectivity analysis have revealed EEG-based biomarkers of all stages of microsleeps (preceding, onset, pre-recovery, recovery). In particular, this raises the possibility of being able to predict microsleeps in real-world tasks and initiate a 'wake-up' intervention to avert the microsleeps and, hence, prevent injurious and even multi-fatality accidents.

Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE-FRDA study.

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello-cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n-back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello-cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto-cerebellar networks. These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher-order cognition.

Iron accumulation in the basal ganglia in Huntington's disease: cross-sectional data from the IMAGE-HD study.

OBJECTIVES: To measure iron accumulation in the basal ganglia in Huntington's disease (HD) using quantitative susceptibility mapping (QSM), and to ascertain its relevance in terms of clinical and disease severity. METHODS: In this cross-sectional investigation, T2* weighted imaging was undertaken on 31 premanifest HD, 32 symptomatic HD and 30 control participants as part of the observational IMAGE-HD study. Group differences in iron accumulation were ascertained with QSM. Associations between susceptibility values and disease severity were also investigated. RESULTS: Compared with controls, both premanifest and symptomatic HD groups showed significantly greater iron content in pallidum, putamen and caudate. Additionally, iron accumulation in both putamen and caudate was significantly associated with disease severity. CONCLUSIONS: These findings provide the first evidence that QSM is sensitive to iron deposition in subcortical target areas across premanifest and symptomatic stages of HD. Such findings could open up new avenues for biomarker development and therapeutic intervention.

Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data.

BACKGROUND: The discovery of potential disease-modifying therapies in a neurodegenerative condition like Huntington's disease depends on the availability of sensitive biomarkers that reflect decline across disease stages and that are functionally and clinically relevant. AIMS: To quantify macrostructural and microstructural changes in participants with premanifest and symptomatic Huntington's disease over 30 months, and to establish their functional and clinical relevance. METHOD: Multimodal magnetic resonance imaging study measuring changes in macrostructural (volume) and microstructural (diffusivity) measures in 40 patients with premanifest Huntington's disease, 36 patients with symptomatic Huntington's disease and 36 healthy control participants over three testing sessions spanning 30 months. RESULTS: Relative to controls, there was greater longitudinal atrophy in participants with symptomatic Huntington's disease in whole brain, grey matter, caudate and putamen, as well as increased caudate fractional anisotropy; caudate volume loss was the only measure to differ between premanifest Huntington's disease and control groups. Changes in caudate volume and fractional anisotropy correlated with each other and neurocognitive decline; caudate volume loss also correlated with clinical and disease severity. CONCLUSIONS: Caudate neurodegeneration, especially atrophy, may be the most suitable candidate surrogate biomarker for consideration in the development of upcoming clinical trials.

Longitudinal change in white matter microstructure in Huntington's disease: The IMAGE-HD study.

OBJECTIVE: To quantify 18-month changes in white matter microstructure in premanifest (pre-HD) and symptomatic Huntington's disease (symp-HD). To investigate baseline clinical, cognitive and motor symptoms that are predictive of white matter microstructural change over 18months. METHOD: Diffusion tensor imaging (DTI) data were analyzed for 28 pre-HD, 25 symp-HD, and 27 controls scanned at baseline and after 18months. Unbiased tract-based spatial statistics (TBSS) methods were used to identify longitudinal changes in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) of white matter. Stepwise linear regression models were used to identify baseline clinical, cognitive, and motor measures that are predictive of longitudinal diffusion changes. RESULTS: Symp-HD compared to controls showed 18-month reductions in FA in the corpus callosum and cingulum white matter. Symp-HD compared to pre-HD showed increased RD in the corpus callosum and striatal projection pathways. FA in the body, genu, and splenium of the corpus callosum was significantly associated with a baseline clinical motor measure (Unified Huntington's Disease Rating Scale: total motor scores: UHDRS-TMS) across both HD groups. This measure was also the only independent predictor of longitudinal decline in FA in all parts of the corpus callosum across both HD groups. CONCLUSIONS: We provide direct evidence of longitudinal decline in white matter microstructure in symp-HD. Although pre-HD did not show longitudinal change, clinical symptoms and motor function predicted white matter microstructural changes for all gene positive subjects. These findings suggest that loss of axonal integrity is an early hallmark of neurodegenerative changes which are clinically relevant.

Source-space ICA for EEG source separation, localization, and time-course reconstruction.

We propose source-space independent component analysis (ICA) for separation, tomography, and time-course reconstruction of EEG and MEG source signals. Source-space ICA is based on the application of singular value decomposition and ICA on the neuroelectrical signals from all brain voxels obtained post minimum-variance beamforming of sensor-space EEG or MEG. We describe the theoretical background and equations, then evaluate the performance of this technique in several different situations, including weak sources, bilateral correlated sources, multiple sources, and cluster sources. In this approach, tomographic maps of sources are obtained by back-projection of the ICA mixing coefficients into the source-space (3-D brain template). The advantages of source-space ICA over the popular alternative approaches of sensor-space ICA together with dipole fitting and power mapping via minimum-variance beamforming are demonstrated. Simulated EEG data were produced by forward head modeling to project the simulated sources onto scalp sensors, then superimposed on real EEG background. To illustrate the application of source-space ICA to real EEG source reconstruction, we show the localization and time-course reconstruction of visual evoked potentials. Source-space ICA is superior to the minimum-variance beamforming in the reconstruction of multiple weak and strong sources, as ICA allows weak sources to be identified and reconstructed in the presence of stronger sources. Source-space ICA is also superior to sensor-space ICA on accuracy of localization of sources, as source-space ICA applies ICA to the time-courses of voxels reconstructed from minimum-variance beamforming on a 3D scanning grid and these time-courses are optimally unmixed via the beamformer. Each component identified by source-space ICA has its own tomographic map which shows the extent to which each voxel has contributed to that component.

White matter connectivity reflects clinical and cognitive status in Huntington's disease.

OBJECTIVE: To investigate structural connectivity and the relationship between axonal microstructure and clinical, cognitive, and motor functions in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease. METHOD: Diffusion tensor imaging (DTI) data were acquired from 35 pre-HD, 36 symp-HD, and 35 controls. Structural connectivity was mapped between 40 brain regions of interest using tractography. Between-group differences in structural connectivity were identified using network based statistics. Radial diffusivity (RD) and fractional anisotropy (FA) were compared in the white matter tracts from aberrant networks. RD values in aberrant tracts were correlated with clinical severity, and cognitive and motor performance. RESULTS: A network connecting putamen with prefrontal and motor cortex demonstrated significantly reduced tractography streamlines in pre-HD. Symp-HD individuals showed reduced streamlines in a network connecting prefrontal, motor, and parietal cortices with both caudate and putamen. The symp-HD group, compared to controls and pre-HD, showed both increased RD and decreased FA in the fronto-parietal and caudate-paracentral tracts and increased RD in the putamen-prefrontal and putamen-motor tracts. The pre-HDclose, compared to controls, showed increased RD in the putamen-prefrontal and fronto-parietal tracts. In the pre-HD group, significant negative correlations were observed between SDMT and Stroop performance and RD in the bilateral putamen-prefrontal tract. In the symp-HD group, RD in the fronto-parietal tract was significantly positively correlated with UHDRS motor scores and significantly negatively correlated with performance on SDMT and Stroop tasks. CONCLUSIONS: We have provided evidence of aberrant connectivity and microstructural integrity in white matter networks in HD. Microstructural changes in the cortico-striatal fibers were associated with cognitive and motor performance in pre-HD, suggesting that changes in axonal integrity provide an early marker for clinically relevant impairment in HD.