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Dystonias are a group of chronic movement–disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.
DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. What is not known is how torsinA dysfunction in these specific cell types contributes to the pathophysiology of DYT1 dystonia. In this study we sought to determine whether torsinA dysfunction in cholinergic neurons alone is sufficient to generate the sensorimotor dysfunction and brain changes associated with dystonia, or if torsinA dysfunction in a broader subset of cell types is needed. We generated two genetically modified mouse models, one with selective Dyt1 knock-out from dopamine-2 receptor expressing neurons (D2KO) and one where only cholinergic neurons are impacted (Ch2KO). We assessed motor deficits and performed in vivo 11.1 T functional MRI to assess sensory-evoked brain activation and connectivity, along with diffusion MRI to assess brain microstructure. We found that D2KO mice showed greater impairment than Ch2KO mice, including reduced sensory-evoked brain activity in key regions of the sensorimotor network, and altered functional connectivity of the striatum that correlated with motor deficits. These findings suggest that (1) the added impact of torsinA dysfunction in medium spiny and dopaminergic neurons of the basal ganglia generate more profound deficits than the dysfunction of cholinergic neurons alone, and (2) that sensory network impairments are linked to motor deficits in DYT1 dystonia.
Wei-En Wang 1 , Rachel L M Ho 1 , Bryan Gatto 2 , Susanne M van der Veen 3 , Matthew K Underation 3 , James S Thomas 3 , Ajay B Antony 4 , Stephen A Coombes 1
Abstract: Although experimental pain alters neural activity in the cortex, evidence of changes in neural activity in individuals with chronic low back pain (cLBP) remains scarce and results are inconsistent. One of the challenges in studying cLBP is that the clinical pain fluctuates over time and often changes during movement. The goal of the present study was to address this challenge by recording high-density electroencephalography (HD-EEG) data during a full-body reaching task to understand neural activity during movement-evoked pain. HD-EEG data were analysed using independent component analyses, source localization and measure projection analyses to compare neural oscillations between individuals with cLBP who experienced movement-evoked pain and pain-free controls. We report two novel findings. First, movement-evoked pain in individuals with cLBP was associated with longer reaction times, delayed peak velocity and greater movement variability. Second, movement-evoked pain was associated with an attenuated reduction in beta power in the premotor cortex and supplementary motor area. Our observations move the field forward by revealing attenuated disinhibition in prefrontal motor areas during movement-evoked pain in cLBP.
Ofori E1, DeKosky ST2, Febo M3, Colon-Perez L4, Chakrabarty P5, Duara R6, Adjouadi M7, Golde TE5, Vaillancourt DE8; Alzheimer’s Disease Neuroimaging Initiative.
Validating sensitive markers of hippocampal degeneration is fundamental for understanding neurodegenerative conditions such as Alzheimer’s disease. In this paper, we test the hypothesis that free-water in the hippocampus will be more sensitive to early stages of cognitive decline than hippocampal volume, and that free-water in hippocampus will increase across distinct clinical stages of Alzheimer’s disease. We examined two separate cohorts (N = 126; N = 112) of cognitively normal controls, early and late mild cognitive impairment (MCI), and Alzheimer’s disease. Demographic, clinical, diffusion-weighted and T1-weighted imaging, and positron emission tomography (PET) imaging were assessed. Results indicated elevated hippocampal free-water in early MCI individuals compared to controls across both cohorts. In contrast, there was no difference in volume of these regions between controls and early MCI. ADNI free-water values in the hippocampus was associated with low CSF AB1-42 levels and high global amyloid PET values. Free-water imaging of the hippocampus can serve as an early stage marker for AD and provides a complementary measure of AD neurodegeneration using non-invasive imaging.
Essential tremor (ET) prominently affects the upper-limbs during voluntary movements, but can also affect the lower-limbs, head, and chin. Although deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of thalamus improves both clinical ratings and quantitative measures of tremor, no study has quantified effects of DBS on tremor across multiple body parts. Our objective was to quantify therapeutic effects of DBS across multiple body parts in ET.
We performed quantitative assessment of tremor in ET patients who had DBS for at least one year. We assessed tremor on and off VIM-stimulation using triaxial accelerometers on the upper-limbs, lower-limbs, head and chin during seated and standing tasks.
VIM-DBS significantly reduced tremor, but there was no statistical difference in degree of tremor reduction across the measured effectors. Compared to healthy controls, ET patients treated with DBS showed significantly greater tremor power (4-8 Hz) across all effectors during seated and standing tasks.
VIM-DBS reduced tremor in ET patients. There was no significant difference in the degree of tremor reduction across the measured effectors.
This study provides new quantitative evidence that VIM-DBS is effective at reducing tremor across multiple parts of the body.
Development of a transcallosal tractography template and its application to dementia.
Archer DB, Coombes SA, McFarland NR, DeKosky ST, Vaillancourt DE
Understanding the architecture of transcallosal connections would allow for more specific assessments of neurodegeneration across many fields of neuroscience, neurology, and psychiatry. To map these connections, we conducted probabilistic tractography in 100 Human Connectome Project subjects in 32 cortical areas using novel post-processing algorithms to create a spatially precise Trancallosal Tract Template (TCATT). We found robust transcallosal tracts in all 32 regions, and a topographical analysis in the corpus callosum largely agreed with well-established subdivisions of the corpus callosum. We then obtained diffusion MRI data from a cohort of patients with Alzheimer’s disease (AD) and another with progressive supranuclear palsy (PSP) and used a two-compartment model to calculate free-water corrected fractional anisotropy (FAT) and free-water (FW) within the TCATT. These metrics were used to determine between-group differences and to determine which subset of tracts was best associated with cognitive function (Montreal Cognitive Assessment (MoCA)). In AD, we found robust between-group differences in FW (31/32 TCATT tracts) in the absence of between-group differences in FAT. FW in the inferior temporal gyrus TCATT tract was most associated with MoCA scores in AD. In PSP, there were widespread differences in both FAT and FW, and MoCA was predicted by FAT in the inferior frontal pars triangularis, preSMA, and medial frontal gyrus TCATT tracts as well as FW in the inferior frontal pars opercularis TCATT tract. The TCATT improves spatial localization of corpus callosum measurements to enhance the evaluation of treatment effects, as well as the monitoring of brain microstructure in relation to cognitive dysfunction and disease progression. Here, we have shown its direct relevance in capturing between-group differences and associating it with the MoCA in AD and PSP.
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Functional brain activity during motor control and pain processing in chronic jaw pain
Roy, Arnaba; Wang, Wei-en; Ho, Rachel L.M.; Ribeiro-Dasilva, Margarete C.; Fillingim, Roger B; Coombes, Stephen A.
Changes in brain function in chronic pain have been studied using paradigms that deliver acute pain-eliciting stimuli or assess the brain at rest. Although motor disability accompanies many chronic pain conditions, few studies have directly assessed brain activity during motor function in individuals with chronic pain. Using chronic jaw pain as a model, we assessed brain activity during a precisely controlled grip force task and during a precisely controlled pain-eliciting stimulus on the forearm. We used multivariate analyses to identify regions across the brain whose activity together best separated the groups. We report 2 novel findings. First, although the parameters of grip force production were similar between the groups, the functional activity in regions including the prefrontal cortex, insula, and thalamus best separated the groups. Second, although stimulus intensity and pain perception were similar between the groups, functional activity in brain regions including the dorsal lateral prefrontal cortex, rostral ventral premotor cortex, and inferior parietal lobule best separated the groups. Our observations suggest that chronic jaw pain is associated with changes in how the brain processes motor and pain-related information even when the effector producing the force or experiencing the pain-eliciting stimulus is distant from the jaw. We also demonstrate that motor tasks and multivariate analyses offer alternative approaches for studying brain function in chronic jaw pain.
Biomarkers Perspective Published in Science Translational Medicine
We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson’s disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that Patients with PD off medication had an exaggerated movement-related beta-band (13–30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement.