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Auditory sensory over-responsivity (aSOR) is a frequently reported sensory feature of autism spectrum disorders (ASD); however, there is little consensus regarding its prevalence and severity. This cross-sectional study uses secondary data from the Autism Diagnostic Interview-Revised (ADI-R; Item 72: "undue sensitivity to noise") housed in the US National Institute of Mental Health Data Archives to identify prevalence and severity of aSOR. Of the 4104 subjects with ASD ages 2-54 (M = 9, SD = 5.8) who responded to item 72, 60.1% (n = 1876) had aSOR currently (i.e., point prevalence) and 71.1% (n = 2221) reported having aSOR ever (i.e., lifetime prevalence). aSOR prevalence and severity were affected by age, but there were no associations with sex.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been successful in mitigating upper limb tremor, but the effect on gait and balance performance is unclear. Here, we aim to examine the effectiveness of VIM DBS on stride length variability, sway path length, and task-relevant tremor of various body segments in essential tremor (ET). Methods: Seventeen ET individuals treated with DBS (ET DBS) and 17 age-and sexmatched healthy controls (HC) performed a postural balance and overground walking task. In separate and consecutive visits, ET DBS performed gait and balance tasks with DBS ON or OFF. The main outcome measures were sway path length, stride length variability, and tremor quantified from upper limb, lower limb, upper and lower trunk (axial) during the gait and balance tasks. Results: With DBS OFF, ET DBS exhibited significantly greater stride length variability, sway path length, and tremor during gait and balance task relative to HC. Relative to DBS OFF, DBS ON reduced stride length variability and sway path length in ET DBS. The DBS-induced reduction in stride length variability was associated with the reduction in both upper trunk tremor and upper limb tremor. The DBS-induced reduction in sway path length was associated with the reduction in upper trunk tremor. Discussion: The findings of this study revealed that VIM DBS was effective in improving gait and balance in ET DBS and that improvements in gait and postural balance were associated with a reduction of axial tremor during the tasks. [ABSTRACT FROM AUTHOR]

Tackling dystonia with approved drug: Mutations in TOR1A cause a monogenic form of dystonia called DYT1. Patients with DYT1 present chronic movement impairments that persist through life. Effective treatments addressing the cause of the disease are needed. Here, Caffall et al. performed in vitro drug screening and in vivo testing to identify potential approved drugs able to normalize the major hallmarks of DYT1. The HIV protease inhibitor, ritonavir, corrected protein mislocalization in vitro and had therapeutic effects in a mouse model of DYT1, ameliorating the phenotype and restoring brain abnormalities when administered during an early postnatal period. The results suggest that this class of drugs might be effective in treating DYT1 by restoring disease-causing cellular abnormalities. 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. [ABSTRACT FROM AUTHOR]

Objective: This study addresses an important problem in neurology, distinguishing tremor and ataxia using quantitative methods. Specifically, we aimed to quantitatively separate dysmetria, a cardinal sign of ataxia, from tremor in essential tremor (ET).Methods: In Experiment 1, we compared 19 participants diagnosed with ET undergoing thalamic deep brain stimulation (DBS; ETDBS ) to 19 healthy controls (HC). We quantified tremor during postural tasks using accelerometry and dysmetria with fast, reverse-at-target goal-directed movements. To ensure that endpoint accuracy was unaffected by tremor, we quantified dysmetria in selected trials manifesting a smooth trajectory to the endpoint. Finally, we manipulated tremor amplitude by switching DBS ON and OFF to examine its effect on dysmetria. In Experiment 2, we compared 10 ET participants with 10 HC to determine whether we could identify and distinguish dysmetria from tremor in non-DBS ET.Results: Three findings suggest that we can quantify dysmetria independently of tremor in ET. First, ETDBS and ET exhibited greater dysmetria than HC and dysmetria did not correlate with tremor (R2  < 0.01). Second, even for trials with tremor-free trajectories to the target, ET exhibited greater dysmetria than HC (p < 0.01). Third, activating DBS reduced tremor (p < 0.01) but had no effect on dysmetria (p > 0.2).Interpretation: We demonstrate that dysmetria can be quantified independently of tremor using fast, reverse-at-target goal-directed movements. These results have important implications for the understanding of ET and other cerebellar and tremor disorders. Future research should examine the neurophysiological mechanisms underlying each symptom and characterize their independent contribution to disability. ANN NEUROL 2020;88:375-387. [ABSTRACT FROM AUTHOR]

Neurite orientation dispersion and density imaging (NODDI) uses a three‐compartment model to probe brain tissue microstructure, whereas free‐water (FW) imaging models two‐compartments. It is unknown if NODDI detects more disease‐specific effects related to neurodegeneration in Parkinson's disease (PD) and atypical Parkinsonism. We acquired multi‐ and single‐shell diffusion imaging at 3 Tesla across two sites. NODDI (using multi‐shell; isotropic volume [Viso]; intracellular volume [Vic]; orientation dispersion [ODI]) and FW imaging (using single‐shell; FW; free‐water corrected fractional anisotropy [FAt]) were compared with 44 PD, 21 multiple system atrophy Parkinsonian variant (MSAp), 26 progressive supranuclear palsy (PSP), and 24 healthy control subjects in the basal ganglia, midbrain/thalamus, cerebellum, and corpus callosum. There was elevated Viso in posterior substantia nigra across Parkinsonisms, and Viso, Vic, and ODI were altered in MSAp and PSP in the striatum, globus pallidus, midbrain, thalamus, cerebellum, and corpus callosum relative to controls. The mean effect size across regions for Viso was 0.163, ODI 0.131, Vic 0.122, FW 0.359, and FAt 0.125, with extracellular compartments having the greatest effect size. A key question addressed was if these techniques discriminate PD and atypical Parkinsonism. Both NODDI (AUC: 0.945) and FW imaging (AUC: 0.969) had high accuracy, with no significant difference between models. This study provides new evidence that NODDI and FW imaging offer similar discriminability between PD and atypical Parkinsonism, and FW had higher effect sizes for detecting Parkinsonism within regions across the basal ganglia and cerebellum. [ABSTRACT FROM AUTHOR]

Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

• Purkinje cells (PCs) had abnormal spontaneous firing in Dyt1 KI mice. • Increased TEA-sensitive, Ca2+-dependent K+ current in the PCs of Dyt1 KI mice. • Increased paxilline-sensitive current in the PCs of Dyt1 KI mice. • Increased BK protein levels in the cerebellum of Dyt1 KI mice. DYT1 dystonia is an inherited movement disorder caused by a heterozygous trinucleotide (GAG) deletion in DYT1/TOR1A , coding for torsinA. Growing evidence suggests that the cerebellum plays a role in the pathogenesis of dystonia. Brain imaging of both DYT1 dystonia patients and animal models show abnormal activity in the cerebellum. The cerebellum-specific knockdown of torsinA in adult mice leads to dystonia-like behavior. Dyt1 ΔGAG heterozygous knock-in mouse model exhibits impaired corticostriatal long-term depression, abnormal muscle co-contraction, and motor deficits. We and others previously reported altered dendritic structures in Purkinje cells in Dyt1 knock-in mouse models. However, whether there are any electrophysiological alterations of the Purkinje cells in Dyt1 knock-in mice is not known. We used the patch-clamp recording in brain slices and in acutely dissociated Purkinje cells to identify specific alterations of Purkinje cells firing. We found abnormal firing of non-tonic type of Purkinje cells in the Dyt1 knock-in mice. Furthermore, the large-conductance calcium-activated potassium (BK) current and the BK channel protein levels were significantly increased in the Dyt1 knock-in mice. Our results support a role of the cerebellum in the pathogenesis of DYT1 dystonia. Manipulating the Purkinje cell firing and cerebellar output may show great promise for treating DYT1 dystonia. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) has long been recognized as a lifelong condition, but brain aging studies in autistic adults aged >30 years are limited. Free water, a novel brain imaging marker derived from diffusion MRI (dMRI), has shown promise in differentiating typical and pathological aging and monitoring brain degeneration. We aimed to examine free water and free water corrected dMRI measures to assess white and gray matter microstructure and their associations with age in autistic adults. Methods: Forty-three autistic adults ages 30-73 years and 43 age, sex, and IQ matched neurotypical controls participated in this cross-sectional study. We quantified fractional anisotropy (FA), free water, and free water-corrected FA (fwcFA) across 32 transcallosal white matter tracts and 94 gray matter areas in autistic adults and neurotypical controls. Follow-up analyses assessed age effect on dMRI metrics of the whole brain for both groups and the relationship between dMRI metrics and clinical measures of ASD in regions that significantly differentiated autistic adults from controls. Results: We found globally elevated free water in 24 transcallosal tracts in autistic adults. We identified negligible differences in dMRI metrics in gray matter between the two groups. Age-associated FA reductions and free water increases were featured in neurotypical controls; however, this brain aging profile was largely absent in autistic adults. Additionally, greater autism quotient (AQ) total raw score was associated with increased free water in the inferior frontal gyrus pars orbitalis and lateral orbital gyrus in autistic adults. Limitations: All autistic adults were cognitively capable individuals, minimizing the generalizability of the research findings across the spectrum. This study also involved a cross-sectional design, which limited inferences about the longitudinal microstructural changes of white and gray matter in ASD. Conclusions: We identified differential microstructural configurations between white and gray matter in autistic adults and that autistic individuals present more heterogeneous brain aging profiles compared to controls. Our clinical correlation analysis offered new evidence that elevated free water in some localized white matter tracts may critically contribute to autistic traits in ASD. Our findings underscored the importance of quantifying free water in dMRI studies of ASD.

Background: Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been successful in mitigating upper limb tremor, but the effect on gait and balance performance is unclear. Here, we aim to examine the effectiveness of VIM DBS on stride length variability, sway path length, and task-relevant tremor of various body segments in essential tremor (ET)., Methods: Seventeen ET individuals treated with DBS (ET DBS) and 17 age-and sex-matched healthy controls (HC) performed a postural balance and overground walking task. In separate and consecutive visits, ET DBS performed gait and balance tasks with DBS ON or OFF. The main outcome measures were sway path length, stride length variability, and tremor quantified from upper limb, lower limb, upper and lower trunk (axial) during the gait and balance tasks., Results: With DBS OFF, ET DBS exhibited significantly greater stride length variability, sway path length, and tremor during gait and balance task relative to HC. Relative to DBS OFF, DBS ON reduced stride length variability and sway path length in ET DBS. The DBS-induced reduction in stride length variability was associated with the reduction in both upper trunk tremor and upper limb tremor. The DBS-induced reduction in sway path length was associated with the reduction in upper trunk tremor., Discussion: The findings of this study revealed that VIM DBS was effective in improving gait and balance in ET DBS and that improvements in gait and postural balance were associated with a reduction of axial tremor during the tasks., Highlights: ET patients exhibit tremor in various body locations during gait and balance.DBS reduced stride length variability and sway path length.DBS-induced improvements in gait and balance were associated with reduction in axial tremor., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)