Imaging neural circuits in DYT1 Dystonia reveals new insight

Abstract

Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wild-type (WT) controls using resting-state functional magnetic resonance imaging (MRI) and an independent component analysis. In addition, using diffusion MRI we examined how structural integrity across the basal ganglia and cerebellum directly relates to impairments in functional connectivity. Compared to WT mice, Dyt1 KI mice revealed increased functional connectivity across the striatum, thalamus, and somatosensory cortex; and reduced functional connectivity in the motor and cerebellar cortices. Further, Dyt1 KI mice demonstrated elevated free-water (FW) in the striatum and cerebellum compared to WT mice, and increased FW was correlated with impairments in functional connectivity across basal ganglia, cerebellum, and sensorimotor cortex. The current study provides the first in vivo MRI-based evidence in support of the hypothesis that the deletion of a 3-base pair (ΔGAG) sequence in the Dyt1 gene encoding torsinA has network level effects on in vivo functional connectivity and microstructural integrity across the sensorimotor cortex, basal ganglia, and cerebellum.

https://www.ncbi.nlm.nih.gov/pubmed/27404940

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Microstructural properties of premotor pathways predict visuomotor performance in chronic stroke

Hum Brain Mapp. 2016 Feb 27. doi: 10.1002/hbm.23155.
Microstructural properties of premotor pathways predict visuomotor performance in chronic stroke.
Archer DB, Misra G, Patten C, Coombes SA.
http://www.ncbi.nlm.nih.gov/pubmed/26920656

Microstructural properties of the corticospinal tract (CST) descending from the motor cortex predict strength and motor skill in the chronic phase after stroke. Much less is known about the relation between brain microstructure and visuomotor processing after stroke. In this study, individual’s poststroke and age-matched controls performed a unimanual force task separately with each hand at three levels of visual gain. We collected diffusion MRI data and used probabilistic tractography algorithms to identify the primary and premotor CSTs. Fractional anisotropy (FA) within each tract was used to predict changes in force variability across different levels of visual gain. Our observations revealed that individuals poststroke reduced force variability with an increase in visual gain, performed the force task with greater variability as compared with controls across all gain levels, and had lower FA in the primary motor and premotor CSTs. Our results also demonstrated that the CST descending from the premotor cortex, rather than the primary motor cortex, best predicted force variability. Together, these findings demonstrate that the microstructural properties of the premotor CST predict visual gain-related changes in force variability in individuals poststroke.

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Pain-Related Suppression of Beta Oscillations Facilitates Voluntary Movement

Cereb Cortex. 2016 Mar 10. pii: bhw061.
Pain-Related Suppression of Beta Oscillations Facilitates Voluntary Movement.
Misra G, Ofori E, Chung JW, Coombes SA.
http://www.ncbi.nlm.nih.gov/pubmed/26965905

Increased beta oscillations over sensorimotor cortex are antikinetic. Motor- and pain-related processes separately suppress beta oscillations over sensorimotor cortex leading to the prediction that ongoing pain should facilitate movement. In the current study, we used a paradigm in which voluntary movements were executed during an ongoing pain-eliciting stimulus to test the hypothesis that a pain-related suppression of beta oscillations would facilitate the initiation of a subsequent voluntary movement. Using kinematic measures, electromyography, and high-density electroencephalography, we demonstrate that ongoing pain leads to shorter reaction times without affecting the kinematics or accuracy of movement. Reaction time was positively correlated with beta power prior to movement in contralateral premotor areas. Our findings corroborate the view that beta-band oscillations are antikinetic and provide new evidence that pain primes the motor system for action. Our observations provide the first evidence that a pain-related suppression of beta oscillations over contralateral premotor areas leads to shorter reaction times for voluntary movement.

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Nigrostriatal changes with MAO-B Inhibitor in Parkinson’s Disease

Abstract

Rasagiline is a monoamine oxidase type B inhibitor that possesses no amphetamine-like properties, and provides symptomatic relief in early and late stages of Parkinson’s disease (PD). Data in animal models of PD suggest that chronic administration of rasagiline is associated with structural changes in the substantia nigra, and raise the question whether the structure and function of the basal ganglia could be different in PD patients treated chronically with rasagiline as compared with PD patients not treated with rasagiline. Here, we performed a retrospective cross-sectional magnetic resonance imaging (MRI) study at 3 T that investigated nigrostriatal function and structure in PD patients who had taken rasagiline before testing (∼8 months), PD who had not taken rasagiline before testing, and age-matched controls. The two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. We evaluated percent signal change in the posterior putamen during force production using functional MRI, free-water in the posterior substantia nigra using diffusion MRI, and performance on a bimanual coordination task using a pegboard test. All patients were tested after overnight withdrawal from antiparkinsonian medication. The rasagiline group had greater percent signal change in the posterior putamen, less free-water in the posterior substantia nigra, and better performance on the coordination task than the group not taking rasagiline. These findings point to a possible chronic effect of rasagiline on the structure and function of the basal ganglia in PD.

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Free-water diffusion imaging in Parkinson’s disease and Parkinsonism

Link to paper

Abstract

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson’s disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson’s disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson’s disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson’s disease, multiple system atrophy, and progres- sive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional an- isotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson’s disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93–1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson’s disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

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Pain and motor processing in the human cerebellum

Abstract
Pain-related adaptions in movement require a network architecture that allows for integration across pain and motor circuits. Previous studies addressing this issue have focused on cortical areas such as the midcingulate cortex. Here we focus on pain and motor processing in the human cerebellum. The goal in the current study was to identify areas of activation in the cerebellum that are common to pain and motor processing and to determine whether the activation is limited to the superior and inferior cerebellar motor maps, or extends into multimodal areas of the posterior cerebellum. Our observations identified overlapping activity in left and right lobules VI and VIIb during pain and motor processing. Activation in these multimodal regions persisted when pain and motor processes were combined within the same trial, and activation in contralateral left lobule VIIb persisted when stimulation was controlled for. Functional connectivity analyses revealed significant correlations in the BOLD timeseries between multimodal cerebellar regions and sensorimotor regions in the cerebrum including anterior midcingulate cortex, supplementary motor area, and thalamus. The current findings are the first to show multimodal processing in lobules VI and VIIb for motor control and pain processing, and suggest that the posterior cerebellum may be important in understanding pain-related adaptations in motor control.

http://www.ncbi.nlm.nih.gov/pubmed/26307859

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Progression of Parkinson’s Disease and Substantia Nigra

Abstract
There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson’s disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinson’s disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinson’s disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinson’s disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinson’s disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinson's disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinson's disease, increases with progression of Parkinson's disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra. Longitudinal Changes in SN 2015

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Novel technique to estimate cortical rhythms in the cortex during upper limb movement

Abstract

Precise motor control requires the ability to scale the parameters of movement. Theta oscillations across the cortex have been associated with changes in memory, attention, and sensorimotor processing. What has proven more elusive is pinpointing the region-specific frequency band oscillations that are associated with specific parameters of movement during the acceleration and deceleration phases. We report a study using 3D analytic techniques for high density electroencephalography that examines electrocortical dynamics while participants produce upper limb movements to different distances at varying rates. During fast ballistic movements, we observed increased theta band activity in the left motor area contralateral to the moving limb during the acceleration phase of the movement, and theta power correlated with the acceleration of movement. In contrast, beta band activity scaled with the type of movement during the deceleration phase near the end of the movement and correlated with movement time. In the ipsilateral motor and somatosensory area, alpha band activity decreased with the type of movement near the end of the movement, and gamma band activity in visual cortex increased with the type of movement near the end of the movement. Our results suggest that humans use distinct lateralized cortical activity for distance and speed dependent arm movements. We provide new evidence that a temporary increase in theta band power relates to movement acceleration and is important during movement execution. Further, the theta power increase is coupled with desychronization of beta band power and alpha band power which are modulated by the task near the end of movement.

Find article here

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Multiple system atrophy and Parkinson’s disease show different brain patterns

Abstract

Parkinson’s disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1-weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.

Link to article: http://onlinelibrary.wiley.com/doi/10.1002/hbm.22694/abstract

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Bi-tensor model detects increased free-water in the substantia nigra of Parkinson’s disease across MRI sites

Abstract

Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson’s disease. It is the case, however, that partial volume effects from free-water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free-water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free-water is elevated in the substantia nigra for Parkinson’s disease compared with controls. This hypothesis was tested between large cohorts of Parkinson’s disease and control participants in a single-site study, and validated against a multi-site study using multiple scanners. The fractional volume of free-water was increased in the posterior region of the substantia nigra in Parkinson’s disease compared with controls in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water corrected fractional anisotropy or free-water corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson’s disease, and this was evidenced across both single-site and multi-site cohorts.

Link to the paper is at:
http://www.sciencedirect.com/science/article/pii/S0197458014006897

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