Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Laminar VASO fMRI in focal hand dystonia patients.

Focal Hand Dystonia (FHD) is a disabling movement disorder characterized by involuntary movements, cramps and spasms. It is associated with pathological neural microcircuits in the cortical somatosensory system. While invasive preclinical modalities allow researchers to probe specific neural microcircuits of cortical layers and columns, conventional functional magnetic resonance imaging (fMRI) cannot resolve such small neural computational units. In this study, we take advantage of recent developments in ultra-high-field MRI hardware and MR-sequences to capture altered digit representations and laminar processing in FHD patients. We aim to characterize the capability and challenges of layer-specific imaging and analysis tools in resolving laminar and columnar structures in clinical research setups. We scanned N = 4 affected and N = 5 unaffected hemispheres at 7T and found consistent results of altered neural microcircuitry in FHD patients: 1) In affected hemispheres of FHD patients, we found a breakdown of ordered finger representation in the primary somatosensory cortex, as suggested from previous low-resolution fMRI. 2) In affected primary motor cortices of FHD patients, we furthermore found increased fMRI activity in superficial cortico-cortical neural input layers (II/III), compared to relatively weaker activity in the cortico-spinal output layers (Vb/VI). Overall, we show that layer-fMRI acquisition and analysis tools have the potential to address clinically-driven neuroscience research questions about altered computational mechanisms at the spatial scales that were previously only accessible in animal models. We believe that this study paves the way for easier translation of preclinical work into clinical research in focal hand dystonia and beyond.

Classification of Functional Movement Disorders with Resting-State Functional Magnetic Resonance Imaging.

Introduction: Functional movement disorder (FMD) is a type of functional neurological disorder characterized by abnormal movements that patients do not perceive as self-generated. Prior imaging studies show a complex pattern of altered activity, linking regions of the brain involved in emotional responses, motor control, and agency. This study aimed to better characterize these relationships by building a classifier using a support vector machine to accurately distinguish between 61 FMD patients and 59 healthy controls using features derived from resting-state functional magnetic resonance imaging. Materials and Methods: First, we selected 66 seed regions based on prior related studies, then we calculated the full correlation matrix between them before performing recursive feature elimination to winnow the feature set to the most predictive features and building the classifier. Results: We identified 29 features of interest that were highly predictive of the FMD condition, classifying patients and controls with 80% accuracy. Several key features included regions in the right sensorimotor cortex, left dorsolateral prefrontal cortex, left cerebellum, and left posterior insula. Conclusions: The features selected by the model highlight the importance of the interconnected relationship between areas associated with emotion, reward, and sensorimotor integration, potentially mediating communication between regions associated with motor function, attention, and executive function. Exploratory machine learning was able to identify this distinctive abnormal pattern, suggesting that alterations in functional linkages between these regions may be a consistent feature of the condition in many FMD patients. Clinical-Trials.gov ID: NCT00500994 Impact statement Our research presents novel results that further elucidate the pathophysiology of functional movement disorder (FMD) with a machine learning model that classifies FMD and healthy controls correctly 80% of the time. Herein, we demonstrate how known differences in resting-state functional magnetic resonance imaging connectivity in FMD patients can be leveraged to better understand the complex pattern of neural changes in these patients. Knowing that there are measurable predictable differences in brain activity in patients with FMD may help both clinicians and patients conceptualize and better understand the illness at the point of diagnosis and during treatment. Our methods demonstrate how an effective combination of machine learning and qualitative approaches to analyzing functional brain connectivity can enhance our understanding of abnormal patterns of brain activity in FMD patients.

Role of supplementary motor area in cervical dystonia and sensory tricks.

Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.

Multimodal imaging of essential tremor and dystonic tremor.

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors. We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine). Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites. Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

Evaluating interhemispheric connectivity during midline object recognition using EEG.

Functional integration between two hemispheres is crucial for perceptual binding to occur when visual stimuli are presented in the midline of the visual field. Mima and colleagues (2001) showed using EEG that midline object recognition was associated with task-related decrease in alpha band power (alpha desynchronisation) and a transient increase in interhemispheric coherence. Our objective in the current study was to replicate the results of Mima et al. and to further evaluate interhemispheric effective connectivity during midline object recognition in source space. We recruited 11 healthy adult volunteers and recorded EEG from 64 channels while they performed a midline object recognition task. Task-related power and coherence were estimated in sensor and source spaces. Further, effective connectivity was evaluated using Granger causality. While we were able to replicate the alpha desynchronisation associated with midline object recognition, we could not replicate the coherence results of Mima et al. The data-driven approach that we employed in our study localised the source of alpha desynchronisation over the left occipito-temporal region. In the alpha band, we further observed significant increase in imaginary part of coherency between bilateral occipito-temporal regions during object recognition. Finally, Granger causality analysis between the left and right occipito-temporal regions provided an insight that even though there is bidirectional interaction, the left occipito-temporal region may be crucial for integrating the information necessary for object recognition. The significance of the current study lies in using high-density EEG and applying more appropriate and robust measures of connectivity as well as statistical analysis to validate and enhance our current knowledge on the neural basis of midline object recognition.

Neural correlates of working memory and compensation at different stages of cognitive impairment in Parkinson's disease.

Working memory (WM) impairment is one of the most frequent cognitive deficits in Parkinson's disease (PD). However, it is not known how neural activity is altered and compensatory responses eventually fail during progression. We aimed to elucidate neural correlates of WM and compensatory mechanisms in PD. Eighteen cognitively normal PD patients (PD-CogNL), 16 with PD with mild cognitive impairment (PD-MCI), 11 with PD with dementia (PDD), and 17 healthy controls (HCs) were evaluated. Subjects performed an n-back task. Functional MRI data were analyzed by event-related analysis for correct responses. Brain activations were evaluated by comparing them to fixation cross or 0-back task, and correlated with n-back task performance. When compared to fixation cross, PD-CogNL patients had more activation in WM areas than HCs for both the 2- and 3-back tasks. PD-MCI and PDD patients had more activation in WM areas than HCs for the 0- and 1-back task. 2-back task performance was correlated with brain activations (vs. 0-back task) in the bilateral dorsolateral prefrontal cortex and frontal eye field (FEF) and left rostral prefrontal cortex, caudate nucleus, inferior/superior parietal lobule (IPL/SPL), and anterior insular cortex as well as anterior cingulate cortex. 3-back task performance was correlated with brain activations (vs. 0-back task) in the left FEF, right caudate nucleus, and bilateral IPL/SPL. Additional activations on top of the 0-back task, rather than fixation cross, are the neural correlates of WM. Our results suggest PD patients have two types of compensatory mechanisms: (1) Hyperactivation for different WM load tasks depending on their cognitive status. PD-CogNL have hyperactivation for moderate and heavy working memory load tasks while maintaining normal working memory performance. In contrast, PD-MCI and PDD have hyperactivation for control task and light working memory load task, leaving less neural resources to further activate for more demanding tasks and resulting in impaired working memory performance. (2) Bilateral recruitment of WM-related areas, in particular the DLPFC, FEF, IPL/SPL and caudate nucleus, to improve WM performance.

Imaging and genetics in Parkinson's disease: assessment of the GBA1 mutation.

INTRODUCTION: Several genetic variants are associated with an increased risk for developing Parkinson's Disease (PD) and limited genotype/phenotype correlation. Specifically, mutations in GBA1, the gene coding for the lysosomal enzyme glucocerebrosidase, are associated with an earlier age of onset and faster disease progression. Given these phenotypic differences associated with GBA1 variants, we explored whether cortical thickness and other biomarkers of neurodegeneration differed in healthy controls and PD patients with and without GBA1 variants. METHODS: To understand how different GBA1 variants influence PD phenotype early in the disease, we retrieved neuroimaging and biospecimen data from the Parkinson's Progression Markers Initiative database. Using FreeSurfer, we compared T1-weighted MRI images from healthy controls (N = 47) to PD patients with heterozygous N370S (N = 21), heterozygous E326K (N = 18) or heterozygous T369M (N = 8) variants, and GBA1 non-mutation carriers (N = 47). RESULTS: Cortical thickness in PD patients differed from controls in the parietal cortex, with E365K, T369M variants, and GBA1 non-mutation carriers showing more cortical thinning than N370S variants. Patients with N370S variants had significantly higher serum neurofilament light levels among all groups. CONCLUSION: Our results demonstrate significant cortical thinning in PD patients independent of genotype in superior parietal and postcentral regions when compared to the controls. They highlight the impact of GBA1 variants on cortical thickness in the parietal cortex. Finally, they suggest that recently diagnosed PD patients with N370S variants have a higher cortical thickness and increased active neurodegeneration when compared to PD patients without GBA1 mutations and PD patients with E326K or T369M variants.

What have we really learned from functional connectivity in clinical populations?

Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts.

Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda.

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart - leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using "rule-in" examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

Dynamics of Top-Down Control and Motor Networks in Parkinson's Disease.

BACKGROUND: Motor symptoms in Parkinson's disease (PD) patients might be related to high-level task-control deficits. We aimed at investigating the dynamics between sensorimotor network and top-down control networks (frontal-parietal, cingulo-opercular, and cerebellar) in PD and at determining the effects of levodopa on the dynamics of these networks. METHODS: We investigated dynamic functional connectivity (dFC), during resting state functional magnetic resonance imaging, between sensorimotor network and top-down control networks in 36 PD patients (OFF medication, PD-OFF) and 36 healthy volunteers. We further assessed the effect of medication on dFC in18 PD patients who were also scanned ON medication. RESULTS: The dFC analyses identified three discrete states: State I (35.68%) characterized by connections between the cerebellum and sensorimotor network, State II (34.17%) with connections between the sensorimotor and frontal-parietal network, and State III (30.15%) with connection between the sensorimotor and cingulo-opercular network. PD patients have significantly fewer occurrences and overall spent less time (shorter dwell time) in State II compared to healthy controls. After levodopa intake, dwell time improved toward normal. The change in dwell time before and after taking levodopa was negatively related to the respective changes in Unified Parkinson's Disease Rating Scale, Part III. PD-OFF showed significantly decreased connectivity between sensorimotor and control networks and increased connectivity within control networks. These changes were partially improved after levodopa intake. CONCLUSIONS: Dopamine depletion in PD is associated with abnormalities in temporal and spatial properties between cognitive control and sensorimotor network, possibly contributing to clinical deficits. Levodopa partially restores the network function toward the values observed in healthy volunteers. © 2021 International Parkinson and Movement Disorder Society.

In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7.

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p < 0.05, FWE corrected; Hedge's g > 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p < 0.05, FWE corrected; Hedge's g > 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = -0.66, p = 0.104, FDR corrected) and global white matter pFA (r = -0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Executive function network's white matter alterations relate to Parkinson's disease motor phenotype.

Parkinson's disease (PD) patients with postural instability and gait disorder phenotype (PIGD) are at high risk of cognitive deficits compared to those with tremor dominant phenotype (TD). Alterations of white matter (WM) integrity can occur in patients with normal cognitive functions (PD-N). However, the alterations of WM integrity related to cognitive functions in PD-N, especially in these two motor phenotypes, remain unclear. Diffusion tensor imaging (DTI) is a non-invasive neuroimaging method to evaluate WM properties and by applying DTI tractography, one can identify WM tracts connecting functional regions. Here, we 1) compared the executive function (EF) in PIGD phenotype with normal cognitive functions (PIGD-N) and TD phenotype with normal cognitive functions (TD-N) phenotypes; 2) used DTI tractography to evaluated differences in WM alterations between these two phenotypes within a task-based functional network; and 3) examined the WM integrity alterations related to EF in a whole brain network for PD-N patients regardless of phenotypes. Thirty-four idiopathic PD-N patients were classified into two groups based on phenotypes: TD-N and PIGD-N, using an algorithm based on UPDRS part III. Neuropsychological tests were used to evaluate patients' EF, including the Trail making test part A and B, the Stroop color naming, the Stroop word naming, the Stroop color-word interference task, as well as the FAS verbal fluency task and the animal category fluency tasks. DTI measures were calculated among WM regions associated with the verbal fluency network defined from previous task fMRI studies and compared between PIGD-N and TD-N groups. In addition, the relationship of DTI measures and verbal fluency scores were evaluated for our full cohort of PD-N patients within the whole brain network. These values were also correlated with the scores of the FAS verbal fluency task. Only the FAS verbal fluency test showed significant group differences, having lower scores in PIGD-N when compared to TD-N phenotype (p < 0.05). Compared to the TD-N, PIGD-N group exhibited significantly higher MD and RD in the tracts connecting the left superior temporal gyrus and left insula, and those connecting the right pars opercularis and right insula. Moreover, compared to TD-N, PIGD-N group had significantly higher RD in the tracts connecting right pars opercularis and right pars triangularis, and the tracts connecting right inferior temporal gyrus and right middle temporal gyrus. For the entire PD-N cohort, FAS verbal fluency scores positively correlated with MD in the superior longitudinal fasciculus (SLF). This study confirmed that PIGD-N phenotype has more deficits in verbal fluency task than TD-N phenotype. Additionally, our findings suggest: (1) PIGD-N shows more microstructural changes related to FAS verbal fluency task when compared to TD-N phenotype; (2) SLF plays an important role in FAS verbal fluency task in PD-N patients regardless of motor phenotypes.

The role of the inferior parietal lobule in writer's cramp.

Humans have a distinguishing ability for fine motor control that is subserved by a highly evolved cortico-motor neuronal network. The acquisition of a particular motor skill involves a long series of practice movements, trial and error, adjustment and refinement. At the cortical level, this acquisition begins in the parieto-temporal sensory regions and is subsequently consolidated and stratified in the premotor-motor cortex. Task-specific dystonia can be viewed as a corruption or loss of motor control confined to a single motor skill. Using a multimodal experimental approach combining neuroimaging and non-invasive brain stimulation, we explored interactions between the principal nodes of the fine motor control network in patients with writer's cramp and healthy matched controls. Patients and healthy volunteers underwent clinical assessment, diffusion-weighted MRI for tractography, and functional MRI during a finger tapping task. Activation maps from the task-functional MRI scans were used for target selection and neuro-navigation of the transcranial magnetic stimulation. Single- and double-pulse TMS evaluation included measurement of the input-output recruitment curve, cortical silent period, and amplitude of the motor evoked potentials conditioned by cortico-cortical interactions between premotor ventral (PMv)-motor cortex (M1), anterior inferior parietal lobule (aIPL)-M1, and dorsal inferior parietal lobule (dIPL)-M1 before and after inducing a long term depression-like plastic change to dIPL node with continuous theta-burst transcranial magnetic stimulation in a randomized, sham-controlled design. Baseline dIPL-M1 and aIPL-M1 cortico-cortical interactions were facilitatory and inhibitory, respectively, in healthy volunteers, whereas the interactions were converse and significantly different in writer's cramp. Baseline PMv-M1 interactions were inhibitory and similar between the groups. The dIPL-PMv resting state functional connectivity was increased in patients compared to controls, but no differences in structural connectivity between the nodes were observed. Cortical silent period was significantly prolonged in writer's cramp. Making a long term depression-like plastic change to dIPL node transformed the aIPL-M1 interaction to inhibitory (similar to healthy volunteers) and cancelled the PMv-M1 inhibition only in the writer's cramp group. These findings suggest that the parietal multimodal sensory association region could have an aberrant downstream influence on the fine motor control network in writer's cramp, which could be artificially restored to its normal function.

Task-specific interhemispheric hypoconnectivity in writer's cramp - An EEG study.

OBJECTIVE: Writer's cramp (WC) is a focal task-specific dystonia characterized by abnormal posturing of the hand muscles during handwriting, but not during other tasks that involve the same set of muscles and objects such as sharpening a pencil. Our objective was to investigate the pathophysiology underlying the task specificity of this disorder using EEG. We hypothesized that premotor-parietal connectivity will be lower in WC patients specifically during handwriting and motor imagery of handwriting. METHODS: We recruited 15 WC patients and 15 healthy controls. EEG was recorded while participants performed 4 tasks - writing with a pencil, sharpening a pencil, imagining writing and imagining sharpening. We determined the connectivity changes between relevant brain regions during these tasks. RESULTS: We found reduced interhemispheric alpha coherence in the sensorimotor areas in WC patients exclusively during handwriting. WC patients also showed less reduction of task-related beta spectral power and a trend for reduced premotor-parietal coherence during motor tasks. CONCLUSION: We could not confirm an abnormality in premotor-parietal connectivity specific to handwriting by this method. However, there was a task-specific reduction in interhemispheric alpha connectivity in WC patients, whose behavioral correlate remains unknown. SIGNIFICANCE: Interhemispheric alpha connectivity can be a potential interventional target in WC.

Gray matter differences in patients with functional movement disorders.

OBJECTIVE: To explore alterations in gray matter volume in patients with functional movement disorders. METHODS: We obtained T1-weighted MRI on 48 patients with clinically definite functional movement disorders, a subset of functional neurologic symptom disorder characterized by abnormal involuntary movements, and on 55 age- and sex-matched healthy controls. We compared between-group differences in gray matter volume using voxel-based morphometry across the whole brain. All participants in addition underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression Scales and the Childhood Trauma Questionnaire. To determine whether confounding factors such as comorbid depression, anxiety, or childhood trauma exposure contributed to the observed structural changes, nonparametric correlation analysis was performed. RESULTS: Patients with functional movement disorders exhibited increased volume of the left amygdala, left striatum, left cerebellum, left fusiform gyrus, and bilateral thalamus, and decreased volume of the left sensorimotor cortex (whole-brain corrected p ≤ 0.05). Volumetric differences did not correlate with measures of disease duration or patient-rated disease severity. CONCLUSION: This study demonstrates that patients with functional movement disorders exhibit structural gray matter abnormalities in critical components of the limbic and sensorimotor circuitry. These abnormalities may represent a premorbid trait rendering patients more susceptible to disease, the disease itself, or a compensatory response to disease.

Pedunculopontine Nucleus Cholinergic Deficiency in Cervical Dystonia.

BACKGROUND: The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. OBJECTIVES: The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. METHODS: Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. RESULTS: Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. CONCLUSIONS: Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

Loss of inhibition in sensorimotor networks in focal hand dystonia.

OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

Changes in functional organization and white matter integrity in the connectome in Parkinson's disease.

Parkinson's disease (PD) leads to dysfunction in multiple cortico-striatal circuits. The neurodegeneration has also been associated with impaired white matter integrity. This structural and functional "disconnection" in PD needs further characterization. We investigated the structural and functional organization of the PD whole brain connectome consisting of 200 nodes using diffusion tensor imaging and resting-state functional MRI, respectively. Data from 20 non-demented PD patients on dopaminergic medication and 20 matched controls were analyzed using graph theory-based methods. We focused on node strength, clustering coefficient, and local efficiency as measures of local network properties; and network modularity as a measure of information flow. PD patients showed reduced white matter connectivity in frontoparietal-striatal nodes compared to controls, but no change in modular organization of the white matter tracts. PD group also showed reduction in functional local network metrics in many nodes distributed across the connectome. There was also decreased functional modularity in the core cognitive networks including the default mode and dorsal attention networks, and sensorimotor network, as well as a lack of modular distinction in the orbitofrontal and basal ganglia nodes in the PD group compared to controls. Our results suggest that despite subtle white matter connectivity changes, the overall structural organization of the PD connectome remains robust at relatively early disease stages. However, there is a breakdown in the functional modular organization of the PD connectome.

Impairment of a parieto-premotor network specialized for handwriting in writer's cramp.

Handwriting with the dominant hand is a highly skilled task singularly acquired in humans. This skill is the isolated deficit in patients with writer's cramp (WC), a form of dystonia with maladaptive plasticity, acquired through intensive and repetitive motor practice. When a skill is highly trained, a motor program is created in the brain to execute the same movement kinematics regardless of the effector used for the task. The task- and effector-specific symptoms in WC suggest that a problem particularly occurs in the brain when the writing motor program is carried out by the dominant hand. In this MRI study involving 12 WC patients (with symptoms only affecting the right dominant hand during writing) and 15 age matched unaffected controls we showed that: (1) the writing program recruited the same network regardless of the effector used to write in both groups; (2) dominant handwriting recruited a segregated parieto-premotor network only in the control group; (3) local structural alteration of the premotor area, the motor component of this network, predicted functional connectivity deficits during dominant handwriting and symptom duration in the patient group. Dysfunctions and structural abnormalities of a segregated parieto-premotor network in WC patients suggest that network specialization in focal brain areas is crucial for well-learned motor skill. Hum Brain Mapp 37:4363-4375, 2016. © 2016 Wiley Periodicals, Inc.