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 progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy 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.

Dystonia is a movement disorder characterized by involuntary muscle co-contractions that give rise to disabling movements and postures. A recent expert consensus labelled the incidence of tremor as a core feature of dystonia that can affect body regions both symptomatic and asymptomatic to dystonic features. We are only beginning to understand the neural network-level signatures that relate to clinical features of dystonic tremor. At the same time, clinical features of dystonic tremor can resemble that of essential tremor and present a diagnostic confound for clinicians. Here, we examined network-level functional activation and connectivity in patients with dystonic tremor and essential tremor. The dystonic tremor group included primarily cervical dystonia patients with dystonic head tremor and the majority had additional upper-limb tremor. The experimental paradigm included a precision grip-force task wherein online visual feedback related to force was manipulated across high and low spatial feedback levels. Prior work using this paradigm in essential tremor patients produced exacerbation of grip-force tremor and associated changes in functional activation. As such, we directly compared the effect of visual feedback on grip-force tremor and associated functional network-level activation and connectivity between dystonic tremor and essential tremor patient cohorts to better understand disease-specific mechanisms. Increased visual feedback similarly exacerbated force tremor during the grip-force task in dystonic tremor and essential tremor cohorts. Patients with dystonic tremor and essential tremor were characterized by distinct functional activation abnormalities in cortical regions but not in the cerebellum. We examined seed-based functional connectivity from the sensorimotor cortex, globus pallidus internus, ventral intermediate thalamic nucleus, and dentate nucleus, and observed abnormal functional connectivity networks in dystonic tremor and essential tremor groups relative to controls. However, the effects were far more widespread in the dystonic tremor group as changes in functional connectivity were revealed across cortical, subcortical, and cerebellar regions independent of the seed location. A unique pattern for dystonic tremor included widespread reductions in functional connectivity compared to essential tremor within higher-level cortical, basal ganglia, and cerebellar regions. Importantly, a receiver operating characteristic determined that functional connectivity z-scores were able to classify dystonic tremor and essential tremor with 89% area under the curve, whereas combining functional connectivity with force tremor yielded 94%. These findings point to network-level connectivity as an important feature that differs substantially between dystonic tremor and essential tremor and should be further explored in implementing appropriate diagnostic and therapeutic strategies.

Antisaccades produce longer reaction times (RT) than their prosaccade counterparts and this latency increase has been linked to an oculomotor 'pre-setting' that prevents the evocation of a stimulus-driven prosaccade. Moreover, a consequence of oculomotor pre-setting is a lengthening of the RTs associated with a subsequent prosaccade. The goal of the present study was to determine whether the constituent elements associated with planning a correct antisaccade (i.e., response suppression and vector inversion) imparts a residual delay that inhibits the planning of a subsequent prosaccade. To that end, participants alternated between pro- and antisaccades in a pseudo-randomized task-switching schedule (e.g., AABBAAB…) and responses were cued via a paradigm that was designed to evoke frequent error antisaccades (i.e., a saccade initially, and incorrectly, planned to the target stimulus). Results showed that RTs for correct antisaccades were longer than error antisaccades and that prosaccades preceded by the former, but not the latter, trial-type were associated with a reliable increase in RT (i.e., prosaccade switch-cost). In other words, error antisaccades were associated with a failure to withhold a stimulus-driven prosaccade and did not delay the planning of a subsequent prosaccade. Based on these findings we propose that the prosaccade switch-cost is not related to an explicit awareness of task goals; rather, our results are consistent with the assertion that a consequence of response suppression and vector inversion is a residual inhibition of stimulus-driven oculomotor planning networks.

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.

In vivo functional and structural brain imaging of synucleinopathies in humans have provided a rich new understanding of the affected networks across the cortex and subcortex. Despite this progress, the temporal relationship between a-synuclein (a-syn) pathology and the functional and structural changes occurring in the brain is not well understood. Here, we examine the temporal relationship between locomotor ability, brain microstructure, functional brain activity, and a-syn pathology by longitudinally conducting rotarod, diffusion magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), and sensory-evoked fMRI on 20 mice injected with a-syn fibrils and 20 PBS-injected mice at three timepoints (10 males and 10 females per group). Intramuscular injection of a-syn fibrils in the hindlimb of M83 1/2 mice leads to progressive a-syn pathology along the spinal cord, brainstem, and midbrain by 16 weeks post-injection. Our results suggest that peripheral injection of a-syn has acute systemic effects on the central nervous system such that structural and resting-state functional activity changes occur in the brain by four weeks post-injection, well before a-syn pathology reaches the brain. At 12 weeks post-injection, a separate and distinct pattern of structural and sensory-evoked functional brain activity changes was observed that are co-localized with previously reported regions of a-syn pathology and immune activation. Microstructural changes in the pons at 12 weeks post-injection were found to predict survival time and preceded measurable locomotor deficits. This study provides preliminary evidence for diffusion and fMRI markers linked to the progression of synuclein pathology and has translational importance for understanding synucleinopathies in humans.

Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABA-ergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to anti-muscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease.

The presentation of a remote – but not proximal – distractor concurrent with target onset increases prosaccade reaction times (RT) (i.e., the remote distractor effect: RDE). The competitive integration model asserts that the RDE represents the time required to resolve the conflict for a common saccade threshold between target- and distractor-related saccade generating commands in the superior colliculus. To our knowledge however, no previous research has examined whether remote and proximal distractors differentially influence antisaccade RTs. This represents a notable question because antisaccades require decoupling of the spatial relations between stimulus and response (SR) and therefore provide a basis for determining whether the sensory- and/or motor-related features of a distractor influence response planning. Participants completed pro- and antisaccades in a target-only condition and conditions wherein the target was concurrently presented with a proximal or remote distractor. As expected, prosaccade RTs elicited a reliable RDE. In contrast, antisaccade RTs were increased independent of the distractor’s spatial location and the magnitude of the effect was comparable across each distractor location. Thus, distractor-related antisaccade RT costs are not accounted for by a competitive integration between conflicting saccade generating commands. Instead, we propose that a visual distractor increases uncertainty related to the evocation of the response-selection rule necessary for decoupling SR relations.

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, "subconcussive" RHIs represent a more frequent and asymptomatic form of exposure. The neural network-level signatures characterizing subconcussive RHIs in youth collision-sport cohorts such as American Football are not known. Here, we used resting-state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8-14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non-collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in-and off-season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network-level FC abnormalities following repetitive, non-concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.