Tremor pathophysiology:lessons from neuroimaging

Contains fulltext : 226036.pdf (Publisher’s version ) (Closed access)PURPOSE OF REVIEW: We discuss the latest neuroimaging studies investigating the pathophysiology of Parkinson's tremor, essential tremor, dystonic tremor and Holmes tremor. RECENT FINDINGS: Parkinson's tremor is associated with increased activity in the cerebello-thalamo-cortical circuit, with interindividual differences depending on the clinical dopamine response of the tremor. Although dopamine-resistant Parkinson's tremor arises from a larger contribution of the (dopamine-insensitive) cerebellum, dopamine-responsive tremor may be explained by thalamic dopamine depletion. In essential tremor, deep brain stimulation normalizes cerebellar overactivity, which fits with the cerebellar oscillator hypothesis. On the other hand, disconnection of the dentate nucleus and abnormal white matter microstructural integrity support a decoupling of the cerebellum in essential tremor. In dystonic tremor, there is evidence for involvement of both cerebellum and basal ganglia, although this may depend on the clinical phenotype. Finally, in Holmes tremor, different causal lesions map to a common network consisting of the red nucleus, internal globus pallidus, thalamus, cerebellum and pontomedullary junction. SUMMARY: The pathophysiology of all investigated tremors involves the cerebello-thalamo-cortical pathway, and clinical and pathophysiological features overlap among tremor disorders. We draw the outlines of a hypothetical pathophysiological axis, which may be used besides clinical features and cause in future tremor classifications

Increased frontal brain activation during walking while dual tasking: an fNIRS study in healthy young adults

Background: Accumulating evidence suggests that gait is influenced by higher order cognitive and cortical control mechanisms. Recently, several studies used functional near infrared spectroscopy (fNIRS) to examine brain activity during walking, demonstrating increased oxygenated hemoglobin (HbO2) levels in the frontal cortex during walking while subjects completed a verbal cognitive task. It is, however, still unclear whether this increase in activation was related to verbalization, if the response was specific to gait, or if it would also be observed during standing, a different motor control task. The aim of this study was to investigate whether an increase in frontal activation is specific to dual tasking during walking. Methods: Twenty-three healthy young adults (mean 30.9 ± 3.7 yrs, 13 females) were assessed using an electronic walkway. Frontal brain activation was assessed using an fNIRS system consisting of two probes placed on the forehead of the subjects. Assessments included: walking in a self-selected speed; walking while counting forward; walking while serially subtracting 7s (Walking+S7); and standing while serially subtracting 7s (Standing+S7). Data was collected from 5 walks of 30 meters in each condition. Twenty seconds of quiet standing before each walk served as baseline frontal lobe activity. Repeated Measures Analysis of Variance (RM ANOVA) tested for differences between the conditions. Results: Significant differences were observed in HbO2 levels between all conditions (p = 0.007). HbO2 levels appeared to be graded; walking alone demonstrated the lowest levels of HbO2 followed by walking+counting condition (p = 0.03) followed by Walking+S7 condition significantly increased compared to the two other walking conditions (p < 0.01). No significant differences in HbO2 levels were observed between usual walking and the standing condition (p = 0.38) or between standing with or without serial subtraction (p = 0.76). Conclusions: This study provides direct evidence that dual tasking during walking is associated with frontal brain activation in healthy young adults. The observed changes are apparently not a response to the verbalization of words and are related to the cognitive load during gait

The cerebral tremor circuit in a patient with Holmes tremor

The cerebral network associated with Holmes tremor has never been determined directly. A previous study reported a brain network that is functionally connected, in healthy individuals, to different lesions that cause Holmes tremor (lesion connectome). We report a 71-year-old man with severe left-sided tremor caused by a microbleed near the right red nucleus. Using accelerometry-fMRI, we show tremor-related activity in contralateral sensorimotor cortex and cerebellar vermis. This network was distinct from, but functionally coupled to, the Holmes lesion connectome. We propose that Holmes tremor involves three distinct cerebral mechanisms: a structural lesion, an intermediate lesion connectome, and symptom-related activity

Analysis of Free-Living Gait in Older Adults With and Without Parkinson’s Disease and With and Without a History of Falls: Identifying Generic and Disease-Specific Characteristics

Background - Falls are associated with gait impairments in older adults (OA) and Parkinson’s disease (PD). Current approaches for evaluating falls risk are based on self-report or one-time assessment and may be suboptimal. Wearable technology allows gait to be measured continuously in free-living conditions. The aim of this study was to explore generic and specific associations in free-living gait in fallers and nonfallers with and without PD. Methods - Two hundred and seventy-seven fallers (155 PD, 122 OA) who fell twice or more in the previous 6 months and 65 nonfallers (15 PD, 50 OA) were tested. Free-living gait was characterized as the volume, pattern, and variability of ambulatory bouts (Macro), and 14 discrete gait characteristics (Micro). Macro and Micro variables were quantified from free-living data collected using an accelerometer positioned on the low back for one week. Results - Macro variables showed that fallers walked with shorter and less variable ambulatory bouts than nonfallers, independent of pathology. Micro variables within ambulatory bouts showed fallers walked with slower, shorter and less variable steps than nonfallers. Significant interactions showed disease specific differences in variability with PD fallers demonstrating greater variability (step length) and OA fallers less variability (step velocity) than their nonfaller counterparts (p < 0.004). Conclusions - Common and disease-specific changes in free-living Macro and Micro gait highlight generic and selective targets for intervention depending on type of faller (OA-PD). Our findings support free-living monitoring to enhance assessment. Future work is needed to confirm the optimal battery of measures, sensitivity to change and value for fall prediction

Analysis of free-living gait in older adults with and without Parkinson's disease and with and without a history of falls: identifying generic and disease specific characteristics

Falls are associated with gait impairments in older adults (OA) and Parkinson's disease (PD). Current approaches for evaluating falls risk are based on self-report or one-time assessment and may be suboptimal. Wearable technology allows gait to be measured continuously in free-living conditions. The aim of this study was to explore generic and specific associations in free-living gait in fallers and non-fallers with and without PD.status: publishe

Phase-locked transcranial electrical brain stimulation for tremor suppression in dystonic tremor syndromes

Objective: To establish the causal role of the cerebellum and motor cortex in dystonic tremor syndromes, and explore the therapeutic efficacy of phase-locked transcranial alternating current stimulation (TACS). Methods: We applied phase-locked TACS over the ipsilateral cerebellum (N = 14) and contralateral motor cortex (N = 17) in dystonic tremor syndrome patients, while patients assumed a tremor-evoking posture. We measured tremor power using accelerometery during 30 s stimulation periods at 10 different phase-lags (36-degrees increments) between tremor and TACS for each target. Post-hoc, TACS-effects were related to a key clinical feature: the jerkiness (regularity) of tremor. Results: Cerebellar TACS modulated tremor amplitude in a phase-dependent manner, such that tremor amplitude was suppressed or enhanced at opposite sides of the phase-cycle. This effect was specific for patients with non-jerky (sinusoidal) tremor (n = 10), but absent in patients with jerky (irregular) tremor (n = 4). Phase-locked stimulation over the motor cortex did not modulate tremor amplitude. Conclusions: This study indicates that the cerebellum plays a causal role in the generation of (non-jerky) dystonic tremor syndrome. Our findings suggest pathophysiologic heterogeneity between patients with dystonic tremor syndrome, which mirrors clinical variability. Significance: We show tremor phenotype dependent involvement of the cerebellum in dystonic tremor syndrome. Tremor phenotype may thus guide optimal intervention targets

Everyday Stepping Quantity and Quality Among Older Adult Fallers With and Without Mild Cognitive Impairment: Initial Evidence for New Motor Markers of Cognitive Deficits?

Background: Recent work demonstrated that the gait of people with mild cognitive impairment (MCI) differs from that of age-matched controls and, in general, that walking ability, as measured in the clinic, does not necessarily reflect actual, daily performance. We evaluated if the quantity and quality of everyday walking (ie, community ambulation) differs in older adults with MCI, compared to age-matched controls.Methods: Inclusion criteria included: age 65-90 years, able to walk at least 5 minutes unassisted, and &gt;= 2 falls in the past 6 months. Subjects with MCI were included if they scored 0.5 on the Clinical Dementia Rating Scale. To assess stepping quantity and quality, subjects wore a tri-axial accelerometer on the lower-back for 7 days.Results: Age and gender were similar (p &gt; .10) in MCI (n = 36, 77.8 +/- 6.4 years; 27.8% men) and controls (n = 100, 76.0 +/- 6.2 years; 22.0% men). As expected, Montreal Cognitive Assessment scores were lower (p &lt; .001) in MCI (21.31 +/- 4.05), compared to controls (25.81 +/- 2.64). Walking time was lower (p = .016) in MCI (0.74 +/- 0.48 hours/d), compared to controls (1.05 +/- 0.66 hours/d). Within-bout walking (eg, stride regularity) was less consistent (p = .024) in MCI (0.51 +/- 0.14), compared to controls (0.58 +/- 0.14). Changes in stride regularity across bouts were lower (p &lt; .001) in MCI (0.13 +/- 0.04), compared to controls (0.17 +/- 0.01).Conclusions: Older adults with MCI walk less and with a more variable within-bout and less variable across-bout walking pattern, as compared to cognitively-intact subjects matched with respect to age and gender. These findings extend previous clinical work and suggest that MCI affects both the quantity and quality of community ambulation

Barriers and Motivators to Engage in Exercise for Persons with Parkinson's Disease

Exercise is increasingly being recognized as a key element in the overall management of persons living with Parkinson's disease (PD) but various (disease-specific) barriers may impede even motivated patients to participate in regular exercise. We aimed to provide a comprehensive review of the various barriers and motivators for exercise in persons with PD. We scrutinized data on compliance-related factors published in cross-sectional studies, randomized controlled trials and reviews. We classified the barriers and motivators to exercise from a patient perspective according to the International Classification of Functioning, Disability and Health. We present an overview of the large range of potential motivators and barriers for exercise in persons with PD. Healthcare professionals should consider a wide and comprehensive range of factors, in order to identify which specific determinants matter most for each individual. Only when persons with PD are adequately motivated in a way that appeals to them and after all person-specific barriers have been tackled, we can begin to expect their long-term adherence to exercise. Such long-term compliance will be essential if exercise is to live up to its expectations, including the hope that prolonged engagement in regular exercise might help to modify the otherwise relentlessly progressive course of PD.status: publishe

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27). We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power. These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome

Do Patients With Parkinson's Disease With Freezing of Gait Respond Differently Than Those Without to Treadmill Training Augmented by Virtual Reality?

Background. People with Parkinson's disease and freezing of gait (FOG+) have more falls, postural instability and cognitive impairment compared with FOG-. Objective. To conduct a secondary analysis of the V-TIME study, a randomized, controlled investigation showing a greater reduction of falls after virtual reality treadmill training (TT + VR) compared with usual treadmill walking (TT) in a mixed population of fallers. We addressed whether these treadmill interventions led to similar gains in FOG+ as in FOG-. Methods. A total of 77 FOG+ and 44 FOG- were assigned randomly to TT + VR or TT. Participants were assessed pre- and posttraining and at 6 months' follow-up. Main outcome was postural stability assessed by the Mini Balance Evaluation System Test (Mini-BEST) test. Falls were documented using diaries. Other outcomes included the New Freezing of Gait Questionnaire (NFOG-Q) and the Trail Making Test (TMT-B). Results. Mini-BEST scores and the TMT-B improved in both groups after training (P = .001), irrespective of study arm and FOG subgroup. However, gains were not retained at 6 months. Both FOG+ and FOG- had a greater reduction of falls after TT + VR compared with TT (P = .008). NFOG-Q scores did not change after both training modes in the FOG+ group. Conclusions. Treadmill walking (with or without VR) improved postural instability in both FOG+ and FOG-, while controlling for disease severity differences. As found previously, TT + VR reduced falls more than TT alone, even among those with FOG. Interestingly, FOG itself was not helped by training, suggesting that although postural instability, falls and FOG are related, they may be controlled by different mechanisms.status: publishe