Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation.

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

Quantitative Separation of Tremor and Ataxia in Essential Tremor.

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.

Quality of life in isolated dystonia: non-motor manifestations matter.

OBJECTIVE: To evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition. METHODS: Natural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis. RESULTS: Reduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes. CONCLUSION: HR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health.

Network-level connectivity is a critical feature distinguishing dystonic tremor and essential tremor.

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.

Gait worsening and the microlesion effect following deep brain stimulation for essential tremor.

OBJECTIVE: To investigate the effects of unilateral thalamic deep brain stimulation (DBS) on walking in persons with medication-refractory essential tremor (ET). METHODS: We performed laboratory-based gait analyses on 24 persons with medication-refractory ET before and after unilateral thalamic DBS implantation. Normal and tandem walking parameters were analysed across sessions (PRE-DBS/DBS OFF/DBS ON) by repeated measures analyses of variance. Pearson's correlations assessed whether changes in walking after DBS were global (ie, related across gait parameters). Baseline characteristics, lead locations and stimulation parameters were analysed as possible contributors to gait effects. RESULTS: DBS minimally affected gait at the cohort level. However, 25% of participants experienced clinically meaningful gait worsening. Walking speed decreased by >30% in two participants and by >10% in four others. Decreased walking speed correlated with increased gait variability, indicating global gait worsening in affected participants. The worsening persisted even after the stimulation was turned off. Participants with worse baseline tandem walking performance may be more likely to experience post-DBS gait worsening; the percentage of tandem missteps at baseline was nearly three times higher and tandem walking speeds were approximately 30% slower in participants who experienced gait worsening. However, these differences in tandem walking in persons with gait worsening as compared with those without worsening were not statistically significant. Lead locations and stimulation parameters were similar in participants with and without gait worsening. CONCLUSION: Global gait worsening occurred in 25% of participants with unilateral DBS for medication-refractory ET. The effect was present on and off stimulation, likely indicating a microlesion effect.

Cortical dynamics within and between parietal and motor cortex in essential tremor.

BACKGROUND: Evidence from functional imaging in essential tremor suggests that activity within parietal and motor cortices may be associated with worsening of tremor at increased visual feedback. OBJECTIVES: Examine how cortical oscillations within these regions and the connectivity between these regions is associated with worsening of tremor in essential tremor in response to high visual feedback. METHOD: The study included 24 essential tremor participants and 17 controls. We measured cortical activity and tremor magnitude at low and high feedback conditions. Cortical activity was measured using high-density electroencephalogram and isolated using source localization. RESULTS: Changes in power across feedback in the 4-12 Hz and 12-30 Hz bands were reduced within the contralateral motor cortex of essential tremor patients compared to controls. The 12-30 Hz bidirectional connectivity between the parietal and contralateral motor cortex was decreased in essential tremor patients. Worsening of tremor from low to high visual feedback was associated with 4-12 Hz activity in contralateral motor cortex. The greatest separation between groups was found when using the difference of the contralateral motor cortex activity at high and low feedback, rather than either feedback condition alone. CONCLUSION: Our findings provide new evidence that tremor in essential tremor is associated with reduced power across feedback in the motor cortex and reduced connectivity between the parietal and motor cortices. Combined with previous work on the cerebellar-thalamo-cortical motor circuit, our findings suggest that the network level disturbances associated with essential tremor extend to the cortico-cortical pathway between the parietal cortex and motor cortex. © 2018 International Parkinson and Movement Disorder Society.

A widespread visually-sensitive functional network relates to symptoms in essential tremor.

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4-12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4-12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

Physiological effects of subthalamic nucleus deep brain stimulation surgery in cervical dystonia.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) surgery is clinically effective for treatment of cervical dystonia; however, the underlying physiology has not been examined. We used transcranial magnetic stimulation (TMS) to examine the effects of STN DBS on sensorimotor integration, sensorimotor plasticity and motor cortex excitability, which are identified as the key pathophysiological features underlying dystonia. METHODS: TMS paradigms of short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) were used to examine the sensorimotor integration. Sensorimotor plasticity was measured with paired associative stimulation paradigm, and motor cortex excitability was examined with short interval intracortical inhibition and intracortical facilitation. DBS was turned off and on to record these measures. RESULTS: STN DBS modulated SAI and LAI, which correlated well with the acute clinical improvement. While there were no changes seen in the motor cortex excitability, DBS was found to normalise the sensorimotor plasticity; however, there was no clinical correlation. CONCLUSION: Modulation of sensorimotor integration is a key contributor to clinical improvement with acute stimulation of STN. Since the motor cortex excitability did not change and the change in sensorimotor plasticity did not correlate with clinical improvement, STN DBS demonstrates restricted effects on the underlying physiology. CLINICAL TRIAL REGISTRATION: NCT01671527.

Functional activity of the sensorimotor cortex and cerebellum relates to cervical dystonia symptoms.

Cervical dystonia (CD) is the most common type of focal dystonia, causing abnormal movements of the neck and head. In this study, we used noninvasive imaging to investigate the motor system of patients with CD and uncover the neural correlates of dystonic symptoms. Furthermore, we examined whether a commonly prescribed anticholinergic medication in CD has an effect on the dystonia-related brain abnormalities. Participants included 16 patients with CD and 16 healthy age-matched controls. We collected functional MRI scans during a force task previously shown to extensively engage the motor system, and diffusion and T1-weighted MRI scans from which we calculated free-water and brain tissue densities. The dystonia group was also scanned ca. 2 h after a 2-mg dose of trihexyphenidyl. Severity of dystonia was assessed pre- and post-drug using the Burke-Fahn-Marsden Dystonia Rating Scale. Motor-related activity in CD was altered relative to controls in the primary somatosensory cortex, cerebellum, dorsal premotor and posterior parietal cortices, and occipital cortex. Most importantly, a regression model showed that increased severity of symptoms was associated with decreased functional activity of the somatosensory cortex and increased activity of the cerebellum. Structural imaging measures did not differ between CD and controls. The single dose of trihexyphenidyl altered the fMRI signal in the somatosensory cortex but not in the cerebellum. Symptom severity was not significantly reduced post-treatment. Findings show widespread changes in functional brain activity in CD and most importantly that dystonic symptoms relate to disrupted activity in the somatosensory cortex and cerebellum. Hum Brain Mapp 38:4563-4573, 2017. © 2017 Wiley Periodicals, Inc.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Botulinum Toxin Therapy for Parkinson's Disease.

Botulinum toxin (BoNT) therapy is frequently employed in the treatment of Parkinson's disease (PD) symptoms. It can effectively ameliorate the symptoms of cervical dystonia, blepharospasm, sialorrhea, and hyperactive bladder. It is increasingly being used for additional PD-related indications including limb dystonia, oromandibular dystonia, tremors, constipation, dysphagia, gastroparesis, and sweating dysfunction. Botulinum toxin treatment has mostly local side effects and does not interfere with dopaminergic therapies prescribed for PD. With the exception of dystonia and sialorrhea, most evidence for BoNT efficacy is derived from studies conducted in nonparkinsonian populations. Thus, the data to inform typical response pattern and side-effect profile in PD are still evolving. Nevertheless, BoNT is widely used and is an important tool in the PD-treatment arsenal. In this review, the authors discuss the current literature on the use of BoNT in various PD-related motor and nonmotor disorders.

Functional Brain Activity Relates to 0-3 and 3-8 Hz Force Oscillations in Essential Tremor.

It is well-established that during goal-directed motor tasks, patients with essential tremor have increased oscillations in the 0-3 and 3-8 Hz bands. It remains unclear if these increased oscillations relate to activity in specific brain regions. This study used task-based functional magnetic resonance imaging to compare the brain activity associated with oscillations in grip force output between patients with essential tremor, patients with Parkinson's disease who had clinically evident tremor, and healthy controls. The findings demonstrate that patients with essential tremor have increased brain activity in the motor cortex and supplementary motor area compared with controls, and this activity correlated positively with 3-8 Hz force oscillations. Brain activity in cerebellar lobules I-V was reduced in essential tremor compared with controls and correlated negatively with 0-3 Hz force oscillations. Widespread differences in brain activity were observed between essential tremor and Parkinson's disease. Using functional connectivity analyses during the task evidenced reduced cerebellar-cortical functional connectivity in patients with essential tremor compared with controls and Parkinson's disease. This study provides new evidence that in essential tremor 3-8 Hz force oscillations relate to hyperactivity in motor cortex, 0-3 Hz force oscillations relate to the hypoactivity in the cerebellum, and cerebellar-cortical functional connectivity is impaired.

Variables associated with physical health-related quality of life in Parkinson's disease patients presenting for deep brain stimulation.

Deep brain stimulation (DBS) benefits Parkinson's disease (PD) patient's quality of life specially in domains as mobility, activities of daily living (ADL) and bodily discomfort (BD), but little is known about the variables associated with these HRQOL domains in patients presenting for DBS. The objective is to evaluate variables associated with of HRQOL in a Brazilian sample of PD patients presenting for DBS treatment, specifically in the domains related with motor symptoms. In a cross-sectional study of 59 PD patients evaluated at outpatient Unit for Movement Disorders, multiple linear regression analysis was performed to identify independent variables associated with mobility, ADL and BD domains of the 39-item Parkinson's disease questionnaire (PDQ-39). UPDRS III "on" scores, duration of the disease, age, presence of comorbidities and anxiety and depressive symptoms quantified by hospital anxiety and depression scale (HADS), were the independent variables. In our results, HADS scores were independently associated to mobility domain: ß coefficient 1.36 (95 % CI 0.55-2.15) and BD domain: ß coefficient 1.57 (95 % CI 0.67-2.48). UPDRS III "on" scores were independently associated to mobility domain: 0.42 (95 % CI 0.03-0.81). The model of each multiple linear regression analysis explains 25 % of the mobility domain variability (p < 0.01) and 24 % of the BD domain variability (p < 0.01). Psychiatric symptoms were at least as relevant to quality of life as motor symptoms in PD patients presenting for DBS treatment. The effect of treating these psychiatric symptoms on patients' HRQOL deserves further investigation.

Rate of aspiration pneumonia in hospitalized Parkinson's disease patients: a cross-sectional study.

BACKGROUND: Aspiration pneumonia is an important cause of morbidity and mortality in Parkinson's disease (PD). Clinical characteristics of PD patients in addition to specific alterations in swallowing mechanisms contribute to higher swallowing times and impairment in the effective clearance of the airway. These issues may render patients more prone to dysphagia and aspiration events. We aimed to determine the frequency of aspiration events in a hospitalized PD cohort, and to report the number of in-hospital swallow evaluations. METHODS: A retrospective single center chart review of 212 PD patients who had 339 hospital encounters was performed from January 2011 to March 2013. Demographics, clinical characteristics, and reasons for encounters were documented. The number of in-hospital aspiration events and the number of swallowing evaluations and also the implementation of aspiration precautions were recorded. RESULTS: The cohort had a mean age of 74.1 (SD = 10.1) years with mean disease duration of 6 (SD = 6.3) years. Fifty-two hospital encounters (15.3%) were related to a pulmonary cause. In-hospital aspiration pneumonia events were reported in 8 (2.4%) of the total encounters. Swallow evaluations were performed in 25% of all cases, and aspiration precautions were initiated in 32% of the encounters. The data revealed that 1/8 patient had swallowing evaluations performed prior to an aspiration event. CONCLUSIONS: In-hospital aspiration pneumonia events were reported in 2.4% of the hospitalized PD cohort. Preventive measures and precautions were not routinely performed, however rates of aspiration were relatively low. The results highlight the need for more research into screening and monitoring of swallowing problems in PD patients during hospital encounters.

Global attentional neglect of segmented lines in Parkinson's disease.

Global attention requires disengagement from focal elements of stimuli. Since people with Parkinson's disease (PD) may reveal impaired disengagement, this study attempted to learn if people with PD may be impaired at allocating global attention. Healthy adults and people with PD attempted to bisect lines of uniform thickness and lines composed of two segments of unequal thickness and length. When the longer line segment was to the right of the shorter segment, the group with PD demonstrated an increased deviation toward the longer segment, supporting the postulate that people with PD have an impaired ability to disengage focal attention and engage global spatial attention.

Treatment and physiology in Parkinson's disease and dystonia: using transcranial magnetic stimulation to uncover the mechanisms of action.

Transcranial magnetic stimulation (TMS) has served as an important technological breakthrough in the field of the physiology of movement disorders over the last three decades. TMS has grown popular owing to the ease of application as well as its painless and noninvasive character. The technique has provide important insights into understanding the pathophysiology of movement disorders, particularly Parkinson's disease and dystonia. The basic applications have included the study of motor cortex excitability, functioning of excitatory and inhibitory circuits, study of interactions between sensory and motor systems, and the plasticity response of the brain. TMS has also made important contributions to understanding the response to treatments such as dopaminergic medications, botulinum toxin injections, and deep brain stimulation surgery. This review summarizes the knowledge gained to date with TMS in Parkinson's disease and dystonia, and highlights the current challenges in the use of TMS technology.