Median Nerve Stimulation for Treatment of Tics: Randomized, Controlled, Crossover Trial.

A prior study showed that rhythmic, but not arrhythmic, 12 Hz stimulation of the median nerve (MNS) entrained the sensorimotor cortex EEG signal and found that 10 Hz MNS improved tics in Tourette syndrome (TS). However, no control condition was tested, and stimulation blocks lasted only 1 min. We set out to replicate the TS results and to test whether tic improvement occurs by the proposed cortical entrainment mechanism. Preregistration was completed at ClinicalTrials.gov, under number NCT04731714. Thirty-two people with TS, age 15-64, completed two study visits with repeated MNS on and off blocks in random order, one visit for rhythmic and one for arrhythmic MNS. Subjects and staff were blind to order; a video rater was additionally blind to stimulation and to the order of visits and blocks. Rhythmic MNS at 10 Hz improved tics. Both rhythmic and arrhythmic 12 Hz MNS improved tic frequency, intensity, and urges, but the two treatments did not differ significantly. Participant masking was effective, and there was no carryover effect. Several participants described a dramatic benefit. Discomfort was minimal. There was no evidence that the MNS benefit persisted after stimulation ended. These results replicate the tic benefit from MNS but show that the EEG entrainment hypothesis cannot explain that benefit. Another electrophysiological mechanism may explain the benefit; alternatively, these data do not exclude a placebo effect.

Peripheral nerve induction of inhibitory brain circuits to treat Tourette syndrome: A randomized crossover trial.

A prior study showed that rhythmic, but not arrhythmic, 12 Hz stimulation of the median nerve (MNS) entrained sensorimotor cortex EEG signal, and found that 10 Hz MNS improved tics in Tourette syndrome (TS). However, no control condition was tested and stimulation blocks lasted only 1 minute. We set out to replicate the TS results and to test whether tic improvement occurs by the proposed cortical entrainment mechanism. Thirty-two people with TS, age 15-64, completed two study visits with repeated MNS on and off blocks in random order, one visit for rhythmic and one for arrhythmic MNS. Subjects and staff were blind to order; a video rater was additionally blind to stimulation and to order of visits and blocks. Rhythmic MNS at 10 Hz improved tics. Both rhythmic and arrhythmic 12 Hz MNS improved tic frequency, intensity and urges without significant difference. Participant masking was effective and there was no carryover effect. Several participants described dramatic benefit. Discomfort was minimal. MNS benefit did not persist after the end of stimulation. These results replicate the tic benefit from MNS, but show that the EEG entrainment hypothesis cannot explain that benefit. Another electrophysiological mechanism may explain benefit; alternatively, these data do not exclude a placebo effect. Registration: ClinicalTrials.gov , NCT04731714 .

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Real-time motion monitoring improves functional MRI data quality in infants.

Imaging the infant brain with MRI has improved our understanding of early neurodevelopment. However, head motion during MRI acquisition is detrimental to both functional and structural MRI scan quality. Though infants are typically scanned while asleep, they commonly exhibit motion during scanning causing data loss. Our group has shown that providing MRI technicians with real-time motion estimates via Framewise Integrated Real-Time MRI Monitoring (FIRMM) software helps obtain high-quality, low motion fMRI data. By estimating head motion in real time and displaying motion metrics to the MR technician during an fMRI scan, FIRMM can improve scanning efficiency. Here, we compared average framewise displacement (FD), a proxy for head motion, and the amount of usable fMRI data (FD ≤ 0.2 mm) in infants scanned with (n = 407) and without FIRMM (n = 295). Using a mixed-effects model, we found that the addition of FIRMM to current state-of-the-art infant scanning protocols significantly increased the amount of usable fMRI data acquired per infant, demonstrating its value for research and clinical infant neuroimaging.

Functional Connectivity of Vermis Correlates with Future Gait Impairments in Parkinson's Disease.

BACKGROUND: Dysfunction of cerebellar vermis contributes to gait abnormalities in multiple conditions and may play a key role in gait impairment in Parkinson's disease (PD). OBJECTIVE: The purpose of this study was to investigate whether altered resting-state functional connectivity of the vermis relates to subsequent impairment of specific domains of gait in PD. METHODS: We conducted morphometric and resting-state functional connectivity MRI analyses contrasting 45 PD and 32 age-matched healthy participants. Quantitative gait measures were acquired with a GAITRite walkway at varying intervals after functional connectivity data acquisition. RESULTS: At baseline, PD participants had significantly altered functional connectivity between vermis and sensorimotor cortex compared with controls. Altered vermal functional connectivity with bilateral paracentral lobules correlated with subsequent measures of variability in stride length, step time, and single support time after controlling for confounding variables including the interval between imaging and gait measures. Similarly, altered functional connectivity between vermis and left sensorimotor cortex correlated with mean stride length and its variability. Vermis volume did not relate to any gait measure. PD participants did not differ from controls in vermis volume or cortical thickness at the site of significant regional clusters. Only altered lobule V:sensorimotor cortex functional connectivity correlated with subsequent gait measures in exploratory analyses involving all the other cerebellar lobules. CONCLUSIONS: These results demonstrate that abnormal vermal functional connectivity with sensorimotor cortex, in the absence of relevant vermal or cortical atrophy, correlates with subsequent gait impairment in PD. Our data reflect the potential of vermal functional connectivity as a novel imaging biomarker of gait impairment in PD. © 2021 International Parkinson and Movement Disorder Society.

Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant k e was estimated from simulated response data plus Gaussian noise. Predicted time - effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated k e from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa.

Hippocampal Volume in Provisional Tic Disorder Predicts Tic Severity at 12-Month Follow-up.

Previous studies have investigated differences in the volumes of subcortical structures (e.g., caudate nucleus, putamen, thalamus, amygdala, and hippocampus) between individuals with and without Tourette syndrome (TS), as well as the relationships between these volumes and tic symptom severity. These volumes may also predict clinical outcome in Provisional Tic Disorder (PTD), but that hypothesis has never been tested. This study aimed to examine whether the volumes of subcortical structures measured shortly after tic onset can predict tic symptom severity at one-year post-tic onset, when TS can first be diagnosed. We obtained T1-weighted structural MRI scans from 41 children with PTD (25 with prospective motion correction (vNavs)) whose tics had begun less than 9 months (mean 4.04 months) prior to the first study visit (baseline). We re-examined them at the 12-month anniversary of their first tic (follow-up), assessing tic severity using the Yale Global Tic Severity Scale. We quantified the volumes of subcortical structures using volBrain software. Baseline hippocampal volume was correlated with tic severity at the 12-month follow-up, with a larger hippocampus at baseline predicting worse tic severity at follow-up. The volumes of other subcortical structures did not significantly predict tic severity at follow-up. Hippocampal volume may be an important marker in predicting prognosis in Provisional Tic Disorder.

Striatal Dopamine Responses to Feeding are Altered in People with Obesity.

OBJECTIVE: This study determined whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than in the fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after consuming a meal to satiation and after fasting overnight as well as in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight by using positron emission tomography with [11 C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (P < 0.05), but there was no difference in the magnitude of the response between fasting and fed conditions. CONCLUSIONS: People with obesity and prediabetes do not increase striatal DA release after eating a meal to satiation compared with fasting overnight and fail to inhibit DA release in response to high-calorie food stimuli after eating a meal to satiation. These data suggest that impaired DA signaling contributes to greater energy intake during meals in this population.

TicTimer Web: software for measuring tic suppression remotely.

Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. We previously provided a computer program to facilitate recording tic occurrence and to automate reward delivery during the several experimental conditions of the TSP. The present article describes a web-based program that performs the same functions. Implementing this program on the web allows research sessions to be performed remotely, in tandem with a video calling program. Relevant data for each session, such as the timing of tics and dispensed rewards, are stored in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders.

Proteinopathy and longitudinal changes in functional connectivity networks in Parkinson disease.

OBJECTIVE: To evaluate resting-state functional connectivity as a potential prognostic biomarker of Parkinson disease (PD) progression. The study examined longitudinal changes in cortical resting-state functional connectivity networks in participants with PD compared to controls as well as in relation to baseline protein measures and longitudinal clinical progression. METHODS: Individuals with PD without dementia (n = 64) and control participants (n = 27) completed longitudinal resting-state MRI scans and clinical assessments including full neuropsychological testing after overnight withdrawal of PD medications ("off"). A total of 55 participants with PD and 20 control participants also completed baseline ß-amyloid PET scans and lumbar punctures for CSF protein levels of α-synuclein, ß-amyloid, and tau. Longitudinal analyses were conducted with multilevel growth curve modeling, a type of mixed-effects model. RESULTS: Functional connectivity within the sensorimotor network and the interaction between the dorsal attention network with the frontoparietal control network decreased significantly over time in participants with PD compared to controls. Baseline CSF α-synuclein protein levels predicted decline in the sensorimotor network. The longitudinal decline in the dorsal attention-frontoparietal internetwork strength correlated with the decline in cognitive function. CONCLUSIONS: These results indicate that α-synuclein levels may influence longitudinal declines in motor-related functional connectivity networks. Further, the interaction between cortical association networks declines over time in PD prior to dementia onset and may serve as a prognostic marker for the development of dementia.

Cognitive correlates of cerebellar resting-state functional connectivity in Parkinson disease.

OBJECTIVE: To investigate in a cross-sectional study the contributions of altered cerebellar resting-state functional connectivity (FC) to cognitive impairment in Parkinson disease (PD). METHODS: We conducted morphometric and resting-state FC-MRI analyses contrasting 81 participants with PD and 43 age-matched healthy controls using rigorous quality assurance measures. To investigate the relationship of cerebellar FC to cognitive status, we compared participants with PD without cognitive impairment (Clinical Dementia Rating [CDR] scale score 0, n = 47) to participants with PD with impaired cognition (CDR score ≥0.5, n = 34). Comprehensive measures of cognition across the 5 cognitive domains were assessed for behavioral correlations. RESULTS: The participants with PD had significantly weaker FC between the vermis and peristriate visual association cortex compared to controls, and the strength of this FC correlated with visuospatial function and global cognition. In contrast, weaker FC between the vermis and dorsolateral prefrontal cortex was found in the cognitively impaired PD group compared to participants with PD without cognitive impairment. This effect correlated with deficits in attention, executive functions, and global cognition. No group differences in cerebellar lobular volumes or regional cortical thickness of the significant cortical clusters were observed. CONCLUSION: These results demonstrate a correlation between cerebellar vermal FC and cognitive impairment in PD. The absence of significant atrophy in cerebellum or relevant cortical areas suggests that this could be related to local pathophysiology such as neurotransmitter dysfunction.

Correction of respiratory artifacts in MRI head motion estimates.

Head motion represents one of the greatest technical obstacles in magnetic resonance imaging (MRI) of the human brain. Accurate detection of artifacts induced by head motion requires precise estimation of movement. However, head motion estimates may be corrupted by artifacts due to magnetic main field fluctuations generated by body motion. In the current report, we examine head motion estimation in multiband resting state functional connectivity MRI (rs-fcMRI) data from the Adolescent Brain and Cognitive Development (ABCD) Study and comparison 'single-shot' datasets. We show that respirations contaminate movement estimates in functional MRI and that respiration generates apparent head motion not associated with functional MRI quality reductions. We have developed a novel approach using a band-stop filter that accurately removes these respiratory effects from motion estimates. Subsequently, we demonstrate that utilizing a band-stop filter improves post-processing fMRI data quality. Lastly, we demonstrate the real-time implementation of motion estimate filtering in our FIRMM (Framewise Integrated Real-Time MRI Monitoring) software package.

The urge to blink in Tourette syndrome.

Functional neuroimaging studies have attempted to explore brain activity that occurs with tic occurrence in subjects with Tourette syndrome (TS). However, they are limited by the difficulty of disambiguating brain activity required to perform a tic, or activity caused by the tic, from brain activity that generates a tic. Inhibiting ticcing following the urge to tic is important to patients' experience of tics and we hypothesize that inhibition of a compelling motor response to a natural urge will differ in TS subjects compared to controls. This study examines the urge to blink, which shares many similarities to premonitory urges to tic. Previous neuroimaging studies with the same hypothesis have used a one-size-fits-all approach to extract brain signal putatively linked to the urge to blink. We aimed to create a subject-specific and blink-timing-specific pathophysiological model, derived from out-of-scanner blink suppression trials, to eventually better interpret blink suppression fMRI data. Eye closure and continuously self-reported discomfort were reported during five blink suppression trials in 30 adult volunteers, 15 with a chronic tic disorder. For each subject, data from four of the trials were used with an empirical mathematical model to predict discomfort from eye closure observed during the remaining trial. The blink timing model of discomfort during blink suppression predicted observed discomfort much better than previously applied models. Combining this approach with observed eye closure during fMRI blink suppression trials should therefore extract brain signal more tightly linked to the urge to blink. The simple mean of time-discomfort curves from each subject's other trials also outperformed older models. The TS group blinked more than twice as often during the blink suppression block, and reported higher baseline discomfort, smaller excursion from baseline to peak discomfort during the blink suppression block, and slower return of discomfort to baseline during the recovery block.

Tic Suppression in Children With Recent-Onset Tics Predicts 1-Year Tic Outcome.

Successful voluntary tic suppression is a key component of the behavioral interventions that are used to treat tic disorders. This study aimed to examine tic suppression in children with recent-onset tics and determine whether the capacity to suppress tics predicts future tic severity. We tested 45 children (30 male, mean age 7.74 years) with recent-onset tics (mean 3.47 months prior to the first study visit; baseline) and re-examined each child at the 12-month anniversary of the first recognized tic (follow-up). At the baseline visit, children performed a tic suppression task with several conditions: tic freely, inhibit tics given a verbal request, and inhibit tics in the presence of a reward. At the baseline visit, children with tics for only a few months could suppress their tics, and tic suppression was especially successful when they received an immediate and contingent reward. Additionally, the ability to suppress tics in the presence of a reward predicted tic severity at follow-up. These findings suggest that better inhibitory control of tics within months of tic onset may be an important predictor of future tic symptom outcome.

Detection of Pediatric Upper Extremity Motor Activity and Deficits With Accelerometry.

Importance: Affordable, quantitative methods to screen children for developmental delays are needed. Motor milestones can be an indicator of developmental delay and may be used to track developmental progress. Accelerometry offers a way to gather real-world information about pediatric motor behavior. Objective: To develop a referent cohort of pediatric accelerometry from bilateral upper extremities (UEs) and determine whether movement can accurately distinguish those with and without motor deficits. Design, Setting, and Participants: Children aged 0 to 17 years participated in a prospective cohort from December 8, 2014, to December 29, 2017. Children were recruited from Ranken Jordan Pediatric Bridge Hospital, Maryland Heights, Missouri, and Washington University School of Medicine in St Louis, St Louis, Missouri. Typically developing children were included as a referent cohort if they had no history of motor or neurological deficit; consecutive sampling and matching ensured equal representation of sex and age. Children with diagnosed asymmetric motor deficits were included in the motor impaired cohort. Exposures: Bilateral UE motor activity was measured using wrist-worn accelerometers for a total of 100 hours in 25-hour increments. Main Outcomes and Measures: To characterize bilateral UE motor activity in a referent cohort for the purpose of detecting irregularities in the future, total activity and the use ratio between UEs were used to describe typically developing children. Asymmetric impairment was classified using the mono-arm use index (MAUI) and bilateral-arm use index (BAUI) to quantify the acceleration of unilateral movements. Results: A total of 216 children enrolled, and 185 children were included in analysis. Of these, 156 were typically developing, with mean (SD) age 9.1 (5.1) years and 81 boys (52.0%). There were 29 children in the motor impaired cohort, with mean (SD) age 7.4 (4.4) years and 16 boys (55.2%). The combined MAUI and BAUI (mean [SD], 0.86 [0.005] and use ratio (mean [SD], 0.90 [0.008]) had similar F1 values. The area under the curve was also similar between the combined MAUI and BAUI (mean [SD], 0.98 [0.004]) and the use ratio (mean [SD], 0.98 [0.004]). Conclusions and Relevance: Bilateral UE movement as measured with accelerometry may provide a meaningful metric of real-world motor behavior across childhood. Screening in early childhood remains a challenge; MAUI may provide an effective method for clinicians to measure and visualize real-world motor behavior in children at risk for asymmetrical deficits.

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry.

Wolfram syndrome is a rare disease caused by mutations in the WFS1 gene leading to symptoms in early to mid-childhood. Brain structural abnormalities are present even in young children, but it is not known when these abnormalities arise. Such information is critical in determining optimal outcome measures for clinical trials and in understanding the aberrant neurobiological processes in Wolfram syndrome. Using voxel-wise and regional longitudinal analyses, we compared brain volumes in Wolfram patients (n = 29; ages 5-25 at baseline; mean follow-up = 3.6 years), to age and sex-equivalent controls (n = 52; ages 6-26 at baseline; mean follow-up = 2.0 years). Between groups, white and gray matter volumes were affected differentially during development. Controls had uniformly increasing volume in white matter, whereas the Wolfram group had stable (optic radiations) or decreasing (brainstem, ventral pons) white matter volumes. In gray matter, controls had stable (thalamus, cerebellar cortex) or decreasing volumes (cortex), whereas the Wolfram group had decreased volume in thalamus and cerebellar cortex. These patterns suggest that there may be early, stalled white matter development in Wolfram syndrome, with additional degenerative processes in both white and gray matter. Ideally, animal models could be used to identify the underlying mechanisms and develop specific interventions.

Provisional Tic Disorder is not so transient.

Motor and vocal tics are common in childhood. The received wisdom among clinicians is that for most children the tics are temporary, disappearing within a few months. However, that common clinical teaching is based largely on biased and incomplete data. The present study was designed to prospectively assess outcome of children with what the current nomenclature calls Provisional Tic Disorder. We identified 43 children with recent onset tics (mean 3.3 months since tic onset) and re-examined 39 of them on the 12-month anniversary of their first tic. Tic symptoms improved on a group level at the 12-month follow-up, and only two children had more than minimal impairment due to tics. Remarkably, however, tics were present in all children at follow-up, although in several cases tics were apparent only when the child was observed remotely by video. Our results suggest that remission of Provisional Tic Disorder is the exception rather than the rule. We also identified several clinical features present at the first examination that predict one-year outcome; these include baseline tic severity, subsyndromal autism spectrum symptoms, and the presence of an anxiety disorder.

Emergent Functional Network Effects in Parkinson Disease.

The hallmark pathology underlying Parkinson disease (PD) is progressive synucleinopathy, beginning in caudal brainstem that later spreads rostrally. However, the primarily subcortical pathology fails to account for the wide spectrum of clinical manifestations in PD. To reconcile these observations, resting-state functional connectivity (FC) can be used to examine dysfunction across distributed brain networks. We measured FC in a large, single-site study of nondemented PD (N = 107; OFF medications) and healthy controls (N = 46) incorporating rigorous quality control measures and comprehensive sampling of cortical, subcortical and cerebellar regions. We employed novel statistical approaches to determine group differences across the entire connectome, at the network-level, and for select brain regions. Group differences respected well-characterized network delineations producing a striking "block-wise" pattern of network-to-network effects. Surprisingly, these results demonstrate that the greatest FC differences involve sensorimotor, thalamic, and cerebellar networks, with notably smaller striatal effects. Split-half replication demonstrates the robustness of these results. Finally, block-wise FC correlations with behavior suggest that FC disruptions may contribute to clinical manifestations in PD. Overall, these results indicate a concerted breakdown of functional network interactions, remote from primary pathophysiology, and suggest that FC deficits in PD are related to emergent network-level phenomena rather than focal pathology.

Mapping movement, mood, motivation and mentation in the subthalamic nucleus.

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinson's disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patient's clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially.