Radiographic abnormalities and their clinical significance in patients with Parkinson disease who receive deep brain stimulation implants.

OBJECTIVE: Preoperative MR images obtained in patients with Parkinson disease (PD) undergoing deep brain stimulation (DBS) often reveal incidental radiographic abnormalities (RAs). These findings range from small changes to gross pathologies. The effect of these findings on patients' clinical outcomes is unknown. The authors characterized RAs in patients with PD who underwent DBS and assessed clinical outcomes. METHODS: Records of patients at the authors' institution with PD who underwent MRI for DBS electrode implantation from 2010 through 2022 were reviewed. RAs were identified from the official preoperative MRI reports. RAs were grouped into four general categories (ischemic changes, atrophy or degenerative changes [ADCs], structural abnormalities, and tumors) and correlated with clinical outcomes (including subjective clinical response, levodopa equivalent dose [LED], and Unified Parkinson's Disease Rating Scale Part III [UPDRS] score) at the 1-year and last available follow-ups. RESULTS: In this review, 160 patients were identified for initial analysis, with 135 presenting with ≥ 1 RAs. Of these 135 patients, 69.4% (111/160) had ischemic vascular changes, 39.4% (63/160) had ADCs, 16.9% (27/160) had structural changes, and 1.9% (3/160) had tumors. No differences in preoperative LED or UPDRS score were observed between these groups. After DBS, no differences in outcomes were observed between patients with RAs and those without RAs for both the 1-year and last follow-up time points, including mortality rates and times. Structural lesions were associated with lower mortality rates (OR 0.1, p = 0.04). ADCs were associated with a worse subjective clinical response at the 1-year (OR 0.50, p = 0.04) and last (OR 0.49, p = 0.03) follow-ups, but subjectively worse responses were not correlated with worse objective outcome measures. CONCLUSIONS: Most RAs have no significant effect on clinical outcomes in PD patients undergoing DBS. Generalized ADCs may be associated with poorer subjective responses and may warrant further discussion with the patient if diagnosed on preoperative MRI.

Demographics of focused ultrasound thalamotomy for essential tremor and trends in deep brain stimulation surgery after its introduction in the USA.

Background: Essential tremor (ET) is a movement disorder that affects 4%-5% of adults >65 years. For patients with medically refractory ET, neurosurgical interventions such as deep brain stimulation (DBS) and unilateral MR-guided focused ultrasound thalamotomy (MRgFUS) are available. In this retrospective cohort study, we examined the demographics of patients with ET who have received MRgFUS and evaluated trends in DBS usage in the USA after the introduction of MRgFUS in 2016. Methods: We used multiple databases to examine the demographics of patients who received DBS and MRgFUS, and trends in DBS. To assess the demographics, we queried the TriNetX database from 2003 to 2022 to identify patients diagnosed with ET and stratify them by DBS or MRgFUS treatment by using Current Procedural Terminology codes. Patient demographics were reported as frequencies and percentages. To examine the trends in DBS for ET, the yearly frequency of DBS procedures done for ET between 2012 and 2019 was extracted from the National Inpatient Sample (NIS) database, and breakpoint analysis was performed. Additionally, the yearly frequency of MRgFUS procedures for ET was obtained from Insightec Exlabate. Results: Most of the patients (88.69%) in the cohort extracted from TriNetX database self-identified as white, followed by black or African American (2.40%) and Asian (0.52%). A higher percentage of black patients received MRgFUS treatment than DBS (4.10% vs 1.88%). According to the NIS database, from 2012 to 2020, 13 525 patients received DBS for ET. Conclusion: This study provides an overview of the characteristics of patients who undergo DBS or MRgFUS. We found notable differences in sex and race among patients who underwent each treatment type. Additionally, until at least the beginning of 2020, the number of DBS procedures for ET was not negatively affected after the introduction of MRgFUS.

Effect of levodopa on postural blood pressure changes in Parkinson disease: a randomized crossover study.

PURPOSE: We investigated the effect of levodopa on postural blood pressure changes in individuals with Parkinson disease (PD) with (PD+OH) and without neurogenic OH (PD-OH). METHODS: We performed a prospective randomized crossover study with autonomic testing performed ON and OFF levodopa. The primary outcome was the change in systolic blood pressure (SBP) from supine to 70° tilt at 3 min (ΔSBP-3'). Secondary outcomes included indices of baroreflex function and blood pressure and heart rate during tilt. RESULTS: We enrolled 40 individuals with PD (21 PD+OH, 19 PD-OH), mean age (SD) 73.2 years (7.9), 13 women (32.5%)). There was no difference in age, sex, disease duration, and severity between PD+OH and PD-OH. Mean difference in ΔSBP-3' ON versus OFF levodopa in the whole study population was - 3.20 mmHg [- 7.36 to 0.96] (p = 0.14). Mean difference in ΔSBP-3' was - 2.14 mmHg [- 7.55 to 3.28] (p = 0.45) in PD+OH and - 5.14 mmHg [- 11.63 to 1.35] (p = 0.14) in PD-OH. Mean difference in ΔSBP ON versus OFF levodopa was greater at 7 and 10 min (- 7.52 mmHg [- 11.89 to - 3.15], p = 0.002, and - 7.82 mmHg [- 14.02 to - 1.67], p = 0.02 respectively). Levodopa was associated with lower absolute values of blood pressure in both PD+OH and PD-OH and cardiovascular noradrenergic baroreflex impairment. CONCLUSION: Levodopa decreases blood pressure in both PD with and without autonomic failure, but it does not cause a greater fall in blood pressure from supine to standing at 3 min. Levodopa-induced baroreflex sympathetic noradrenergic impairment may contribute to lower blood pressure. Lower standing blood pressure with levodopa may increase the risks of fall and syncope.

Global Perceptions and Utilization of Clinical Neurophysiology in Movement Disorders.

BACKGROUND: Clinical neurophysiology (CNP) involves the use of neurophysiological techniques to make an accurate clinical diagnosis, to quantify the severity, and to measure the treatment response. Despite several studies showing CNP to be a useful diagnostic tool in Movement Disorders (MD), its more widespread utilization in clinical practice has been limited. OBJECTIVES: To better understand the current availability, global perceptions, and challenges for implementation of diagnostic CNP in the clinical practice of MD. METHODS: The International Parkinson and Movement Disorders Society (IPMDS) formed a Task Force on CNP. The Task Force distributed an online survey via email to all the members of the IPMDS between August 5 and 30, 2021. Descriptive statistics were used for analysis of the survey results. Some results are presented by IPMDS geographical sections namely PanAmerican (PAS), European (ES), African (AFR), Asian and Oceanian (AOS). RESULTS: Four hundred and ninety-one IPMDS members (52% males), from 196 countries, responded. The majority of responders from the AFR (65%) and PAS (63%) sections had no formal training in diagnostic CNP (40% for AOS and 37% for ES). The most commonly used techniques are electroencephalography (EEG) (72%) followed by surface EMG (71%). The majority of responders think that CNP is somewhat valuable or very valuable in the assessment of MD. All the sections identified "lack of training" as one of the biggest challenges for diagnostic CNP studies in MD. CONCLUSIONS: CNP is perceived to be a useful diagnostic tool in MD. Several challenges were identified that prevent widespread utilization of CNP in MD.

Noninvasive modulation of essential tremor with focused ultrasonic waves.

Objective: Transcranial focused low-intensity ultrasound has the potential to noninvasively modulate confined regions deep inside the human brain, which could provide a new tool for causal interrogation of circuit function in humans. However, it has been unclear whether the approach is potent enough to modulate behavior.Approach: To test this, we applied low-intensity ultrasound to a deep brain thalamic target, the ventral intermediate nucleus, in three patients with essential tremor.Main results: Brief, 15 s stimulations of the target at 10% duty cycle with low-intensity ultrasound, repeated less than 30 times over a period of 90 min, nearly abolished tremor (98% and 97% tremor amplitude reduction) in 2 out of 3 patients. The effect was observed within seconds of the stimulation onset and increased with ultrasound exposure time. The effect gradually vanished following the stimulation, suggesting that the stimulation was safe with no harmful long-term consequences detected.Significance: This result demonstrates that low-intensity focused ultrasound can robustly modulate deep brain regions in humans with notable effects on overt motor behavior.

Modulation of motor surround inhibition during motor tasks.

Surround inhibition (SI) in the motor system is important in individuation of actions, but is sometimes difficult to demonstrate. It has also not been evaluated in real life tasks. In this study, we use real life tasks and a new method where excitability of the surround muscle is assessed with respect to its current activity level rather than when it is at rest. Motor evoked potential (MEP) amplitudes were measured in the abductor digiti minimi (ADM) muscle while participants performed several motor tasks: "writing" on paper, "holding a pen" precisely and, "holding a water bottle" against gravity. These MEPs were compared to ADM MEPs amplitudes measured during a fifth finger abduction (ADM being the center muscle). SI was also measured in the traditional way, by comparing ADM MEPs during an index finger flexion and at rest. For the "writing" and "holding a pen" tasks, but not the "holding bottle" task, the MEP amplitudes were significantly smaller when compared to MEP amplitudes when the ADM was the center muscle with the same level of activation. The ADM MEP amplitudes were not different between rest and during index finger flexion. The new method employed here shows, that motor SI can be measured during tonic movements. The findings also show motor SI during two real-life motor tasks: "writing" and "holding a pen". The lack of modulation of MEP amplitude during "holding bottle" task seems to indicate that SI is action specific rather than muscle specific.

Recognition subtests of the Repeatable Battery for the Assessment of Neuropsychological Status: evidence for a cortical vs. subcortical distinction.

INTRODUCTION: Within clinical neuropsychology, a classic diagnostic distinction is made between cortical and subcortical disorders, especially based on their memory profiles. Typically, this is based on the comparison of recall and recognition trials, where individuals with cortical conditions do not tend to benefit (i.e., score well) on recognition trials and individuals with subcortical conditions do. Although the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used brief cognitive battery, there is a lack of evidence to support this measure's utility in distinguishing between the memory profiles of these conditions. METHOD: Thirty-six mild Alzheimer's disease (AD), 55 Parkinson's disease (PD), and 105 essential tremor (ET) participants (N = 196) were administered the RBANS with additional Story and Figure Recognition subtests. Group differences on recall and recognition scores (Total Correct, Hits or True Positives, False Positive Errors, and discriminability index) were examined across the three groups, while controlling for the influence of age and gender. RESULTS: As expected, individuals with AD had poorer recognition scores compared to the other clinical groups across tasks (all p-values < .05), while the ET sample largely performed comparably to the PD sample. With the exception of comparable Figure Recognition and Recall in the PD sample, all groups exhibited significantly greater recognition Hit performance compared to Recall (all p-values < .05). CONCLUSIONS: The group differences in performance across RBANS recognition subtests suggest support for traditional "cortical" and "subcortical" profiles. However, all groups, including the mild AD sample, demonstrated a benefit from recognition cues compared to free recall. Overall, these findings support the inclusion of the newly developed Story and Figure Recognition subtests in future clinical practice and research endeavors.

Eye-Closure Rate Modulation in Blepharospasm.

Background: Blepharospasm (BSP) is a type of focal dystonia and a number of patients with BSP have relatives also affected by BSP. The objective of this study was to quantify eye closure rates during activities of daily living in individuals with BSP and individuals without BSP with and without a first-degree relative with BSP. Methods: 37 patients with BSP (BSP group), 10 asymptomatic volunteers with a first-degree relative with BSP (RELATIVES group) and 25 asymptomatic volunteers without relatives with BSP (HV group) were recruited. The number of eye closures for each task were counted per 60 seconds, with a video recording. Within and between groups statistical comparisons of eye-closure rates were performed. Results: The eye-closure rates of the RELATIVES group were not different from the BSP group for the majority of the tasks (except for watching television), and the HV group (for all tasks). The rate of eye closures in the BSP group compared to HV, was significantly increased in two tasks, resting and watching television. Discussion: Eye closure rate varies considerably during activities of daily living in all groups. Individuals with first degree relative with BSP are more likely to have increased eye closure rate at rest.

Physiology of dystonia: Human studies.

In this chapter, we discuss neurophysiological techniques that have been used in the study of dystonia. We examine traditional disease models such as inhibition and excessive plasticity and review the evidence that these play a causal role in pathophysiology. We then review the evidence for sensory and peripheral influences within pathophysiology and look at an emergent literature that tries to probe how oscillatory brain activity may be linked to dystonia pathophysiology.

Laminar VASO fMRI in focal hand dystonia patients.

Focal Hand Dystonia (FHD) is a disabling movement disorder characterized by involuntary movements, cramps and spasms. It is associated with pathological neural microcircuits in the cortical somatosensory system. While invasive preclinical modalities allow researchers to probe specific neural microcircuits of cortical layers and columns, conventional functional magnetic resonance imaging (fMRI) cannot resolve such small neural computational units. In this study, we take advantage of recent developments in ultra-high-field MRI hardware and MR-sequences to capture altered digit representations and laminar processing in FHD patients. We aim to characterize the capability and challenges of layer-specific imaging and analysis tools in resolving laminar and columnar structures in clinical research setups. We scanned N = 4 affected and N = 5 unaffected hemispheres at 7T and found consistent results of altered neural microcircuitry in FHD patients: 1) In affected hemispheres of FHD patients, we found a breakdown of ordered finger representation in the primary somatosensory cortex, as suggested from previous low-resolution fMRI. 2) In affected primary motor cortices of FHD patients, we furthermore found increased fMRI activity in superficial cortico-cortical neural input layers (II/III), compared to relatively weaker activity in the cortico-spinal output layers (Vb/VI). Overall, we show that layer-fMRI acquisition and analysis tools have the potential to address clinically-driven neuroscience research questions about altered computational mechanisms at the spatial scales that were previously only accessible in animal models. We believe that this study paves the way for easier translation of preclinical work into clinical research in focal hand dystonia and beyond.

Inter-Individual Variability in Motor Output Is Driven by Recruitment Gain in the Corticospinal Tract Rather Than Motor Threshold.

Variability in the response of individuals to various non-invasive brain stimulation protocols is a major problem that limits their potential for clinical applications. Baseline motor-evoked potential (MEP) amplitude is the key predictor of an individual's response to transcranial magnetic stimulation protocols. However, the factors that predict MEP amplitude and its variability remain unclear. In this study, we aimed to identify the input-output curve (IOC) parameters that best predict MEP amplitude and its variability. We analysed IOC data from 75 subjects and built a general linear model (GLM) using the IOC parameters as regressors and MEP amplitude at 120% resting motor threshold (RMT) as the response variable. We bootstrapped the data to estimate variability of IOC parameters and included them in a GLM to identify the significant predictors of MEP amplitude variability. Peak slope, motor threshold, and maximum MEP amplitude of the IOC were significant predictors of MEP amplitude at 120% RMT and its variability was primarily driven by the variability of peak slope and maximum MEP amplitude. Recruitment gain and maximum corticospinal excitability are the key predictors of MEP amplitude and its variability. Inter-individual variability in motor output may be reduced by achieving a uniform IOC slope.

Eye Movement Disorders in Movement Disorders.

Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders. Most of the brain is involved in oculomotor control, and thus many neurological conditions present with oculomotor abnormalities. Each of the different classes of eye movements and their features can provide important information that can facilitate differential diagnosis. This educational review presents a clinical approach to eye movement abnormalities that are commonly seen in parkinsonism, ataxia, dystonia, myoclonus, tremor, and chorea. In parkinsonism, subtle signs such as prominent square wave jerks, impaired vertical optokinetic nystagmus, and/or the "round the houses" sign suggest early progressive supranuclear gaze palsy before vertical gaze is restricted. In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia telangiectasia. Opsoclonus myoclonus and oculopalatal myoclonus present with characteristic phenomenology and are usually easy to identify. The oculomotor exam is usually unremarkable in isolated dystonia, but oculogyric crisis is a medical emergency and should be recognized and treated in a timely manner. Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely. Finally, functional eye movements can reinforce the clinical impression of a functional movement disorder.

Management of Anterocapitis and Anterocollis: A Novel Ultrasound Guided Approach Combined with Electromyography for Botulinum Toxin Injection of Longus Colli and Longus Capitis.

Chemodenervation of cervical musculature using botulinum neurotoxin (BoNT) is established as the gold standard or treatment of choice for management of Cervical Dystonia (CD). The success of BoNT procedures is measured by improved symptomology while minimizing side effects and is dependent upon many factors including: clinical pattern recognition, identifying contributory muscles, BoNT dosage, and locating and safely injecting target muscles. In patients with CD, treatment of anterocollis (forward flexion of the neck) and anterocaput (anterocapitis) (forward flexion of the head) are inarguably challenging. The longus Colli (LoCol) and longus capitis (LoCap) muscles, two deep cervical spine and head flexor muscles, frequently contribute to these patterns. Localizing and safely injecting these muscles is particularly challenging owing to their deep location and the complex regional anatomy which includes critical neurovascular and other structures. Ultrasound (US) guidance provides direct visualization of the LoCol, LoCap, other cervical muscles and adjacent structures reducing the risks and side effects while improving the clinical outcome of BoNT for these conditions. The addition of electromyography (EMG) provides confirmation of muscle activity within the target muscle. Within this manuscript, we present a technical description of a novel US guided approach (combined with EMG) for BoNT injection into the LoCol and LoCap muscles for the management of anterocollis and anterocaput in patients with CD.

Self-reported benefit and weakness after botulinum toxin in dystonia.

With this retrospective, single center, chart review study, we investigate the self-reported benefit and weakness after botulinum toxin injections in three different types of dystonia: focal hand dystonia (FHD), blepharospasm and cervical dystonia. We found that the benefit lasts significantly longer in FHD compared to the other two groups.

Parietal conditioning enhances motor surround inhibition.

BACKGROUND: Motor surround inhibition (mSI) is a phenomenon supportive for executing selective finger movements, wherein synergist muscles are selectively facilitated while surround muscles are inhibited. Previous studies of conditioning inputs to several intracortical and cortico-cortical inhibitory networks did not show an influence on mSI. The inhibitory posterior parietal-motor network, which is crucial for executing fine movements, however, has not been studied. OBJECTIVE/HYPOTHESIS: To investigate the role of inhibitory posterior parietal-motor network in mSI. We hypothesized that conditioning this inhibitory network would enhance mSI. METHODS: 11 healthy adults completed study. mSI was elicited by applying a TMS pulse over the motor cortex coupled with or without a conditioning input to an inhibitory spot in the posterior parietal cortex at 2 or 4 ms interval. RESULTS: Conditioning input to the posterior parietal cortex increased mSI by ∼20% CONCLUSION: The inhibitory posterior parietal-motor network appears to contribute to the genesis of mSI.

How to do an electrophysiological study of tremor.

The electrophysiological characterization of hand tremors is a useful method to complement the history and physical exam of tremor patients. Our article describes the methodology (recording, processing and interpretation) used in a diagnostic/phenotypic hand tremor study conducted in our lab at the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke (NINDS), at the National Institutes of Health. The necessary equipment includes two one-axis accelerometers and four-channel electromyography (EMG). The hand tremor is recorded at rest, posture with and without weight loading, and during movement (kinetic). The recorded signals are analyzed in the time and frequency domains. The characterization of the dominant frequencies in the accelerometers and their relationship with the EMG frequencies are essential for the differential diagnosis of different tremor syndromes. We describe the electrophysiological characteristics of several tremor syndromes such as enhanced physiological tremor, essential tremor, Parkinson tremor, pharmacological-induced tremor, orthostatic tremor, and functional (psychogenic) tremor. Simplified guidance for adoption of tremor studies as a clinical tool in a movement disorders subspecialty clinic is provided.

Fatigue induces long-lasting detrimental changes in motor-skill learning.

Fatigue due to physical exertion is a ubiquitous phenomenon in everyday life and especially common in a range of neurological diseases. While the effect of fatigue on limiting skill execution are well known, its influence on learning new skills is unclear. This is of particular interest as it is common practice to train athletes, musicians or perform rehabilitation exercises up to and beyond a point of fatigue. In a series of experiments, we describe how muscle fatigue, defined as degradation of maximum force after exertion, impairs motor-skill learning beyond its effects on task execution. The negative effects on learning are evidenced by impaired task acquisition on subsequent practice days even in the absence of fatigue. Further, we found that this effect is in part mediated centrally and can be alleviated by altering motor cortex function. Thus, the common practice of training while, or beyond, fatigue levels should be carefully reconsidered, since this affects overall long-term skill learning.

Reappraising the role of motor surround inhibition in dystonia.

BACKGROUND: Surround inhibition (SI) in the motor system has been described to be decreased in patients with focal hand dystonia (FHD) but no evidence currently exists for patients with cervical dystonia (CD). OBJECTIVE: To characterise the SI profiles in three groups of participants: healthy volunteers, patients with FHD and patients with CD. To provide sample size calculations for future studies. METHODS: SI was assessed using Transcranial Magnetic Stimulation (TMS) in 31 right-handed healthy participants, 11 patients with CD and 12 patients with FHD. In addition data of SI in patients with FHD were extracted from previously published and analysed for sample size calculations and assessment of SI variability. RESULTS: No statistically significant difference in SI was found amongst the groups (healthy, FHD, CD). Analysis of combined current and previous data suggests that our study and all prior studies were underpowered. At least 26 participants in each group are required for a simple comparison of two groups. Analysis of published data indicated that SI is more variable in FHD patients compared to healthy controls. CONCLUSIONS: The highly variable SI in patients with dystonia can confound statistical comparisons of mean differences. Larger studies are needed to assess SI in dystonia and to explore the origins of its variability.

Cortical inhibitory function in cervical dystonia.

OBJECTIVE: To assess the specificity of cortical inhibitory deficits in cervical dystonia patients. METHODS: A systematic test battery was developed to assess spatial and temporal aspects of cortical inhibition, in motor and somatosensory systems of the hand. We tested 17 cervical dystonia (CD) patients and 19 controls assessing somatosensory spatial inhibition (grating orientation test, interdigital feedforward subliminal inhibition), somatosensory temporal inhibition (temporal discrimination threshold, feedforward subliminal inhibition), motor spatial inhibition (surround inhibition), and motor temporal inhibition (short interval intracortical inhibition). RESULTS: A significant deficit in CD was observed in both measures of somatosensory spatial inhibition, with a trend in the same direction in our measure of motor spatial inhibition. We found no significant group differences in temporal inhibition measures. Importantly, statistical comparison of effect sizes across the different measures showed that deficits in tests of spatial inhibition were greater than those in tests of temporal inhibition. CONCLUSION: Our results suggest that CD is associated with abnormal function of local inhibitory cortical circuits subserving spatial sensory processing. Importantly, this abnormality relates to the somatotopic representation of an unaffected body part. SIGNIFICANCE: These results clarify the nature of deficits in cortical inhibitory function in dystonia.