Tremor.

INTRODUCTION OR BACKGROUND: Tremor is one of the commonest movement disorders and can be disabling. There are many causes and treatment options include medications, adaptations, botulinum toxin injections and functional neurosurgery. SOURCES OF DATA: Pubmed.gov peer-reviewed journal articles and reviews. AREAS OF AGREEMENT: A new tremor classification has been published. Axis 1 of this classification highlights the clinical characteristics of tremor and axis 2 is dedicated to aetiology. The cerebello-thalamo-cortical network and connections to other brain areas is emerging as pivotal to many types of tremor. AREAS OF CONTROVERSY: There has been ongoing debate around the clinical entity of essential tremor and its pathophysiological basis. GROWING POINTS: Increasing understanding of the pathophysiology underpinning tremor is helping to improve classification and is pushing forward trials of new treatment options, particularly surgical options. AREAS TIMELY FOR DEVELOPING RESEARCH: With deeper phenotyping from the new classification, genetics of common forms of tremor are ripe for discovery. New pharmacological therapeutic options are needed to complement the better understanding of the basis of tremor.

Distinguishing the central drive to tremor in Parkinson's disease and essential tremor.

Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. Both have been associated with similar patterns of network activation leading to the suggestion that they may result from similar network dysfunction, specifically involving the cerebellum. Here, we demonstrate that parkinsonian tremors and ETs result from distinct patterns of interactions between neural oscillators. These patterns are reflected in the tremors' derived frequency tolerance, a novel measure readily attainable from bedside accelerometry. Frequency tolerance characterizes the temporal evolution of tremor by quantifying the range of frequencies over which the tremor may be considered stable. We found that patients with PD (N = 24) and ET (N = 21) were separable based on their frequency tolerance, with PD associated with a broad range of stable frequencies whereas ET displayed characteristics consistent with a more finely tuned oscillatory drive. Furthermore, tremor was selectively entrained by transcranial alternating current stimulation applied over cerebellum. Narrow frequency tolerances predicted stronger entrainment of tremor by stimulation, providing good evidence that the cerebellum plays an important role in pacing those tremors. The different patterns of frequency tolerance could be captured with a simple model based on a broadly coupled set of neural oscillators for PD, but a more finely tuned set of oscillators in ET. Together, these results reveal a potential organizational principle of the human motor system, whose disruption in PD and ET dictates how patients respond to empirical, and potentially therapeutic, interventions that interact with their underlying pathophysiology.

Estimation of the phase response curve from Parkinsonian tremor.

Phase response curves (PRCs), characterizing the response of an oscillator to weak external perturbation, have been estimated from a broad range of biological oscillators, including single neurons in vivo. PRC estimates, in turn, provide an intuitive insight into how oscillatory systems become entrained and how they can be desynchronized. Here, we explore the application of PRC theory to the case of Parkinsonian tremor. Initial attempts to establish a causal effect of subthreshold transcranial magnetic stimulation applied to primary motor cortex on the filtered tremor phase were unsuccessful. We explored the possible explanations of this and demonstrate that assumptions made when estimating the PRC in a traditional setting, such as a single neuron, are not arbitrary when applied to the case of tremor PRC estimation. We go on to extract the PRC of Parkinsonian tremor using an iterative method that requires varying the definition of the tremor cycle and estimating the PRC at multiple peristimulus time samples. Justification for this method is supported by estimates of PRC from simulated single neuron data. We provide an approach to estimating confidence limits for tremor PRC and discuss the interpretational caveats introduced by tremor harmonics and the intrinsic variability of the tremor's period.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

BACKGROUND: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity. OBJECTIVES: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty. METHODS: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor. RESULTS: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%. CONCLUSION: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.

Motor 'surround inhibition' is not correlated with activity in surround muscles.

Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively.

Rest and other types of tremor in adult-onset primary dystonia.

INTRODUCTION: Knowledge regarding tremor prevalence and phenomenology in patients with adult-onset primary dystonia is limited. Dystonic tremor is presumably under-reported, and we aimed to assess the prevalence and the clinical correlates of tremor in patients with adult-onset primary dystonia. METHODS: We enrolled 473 consecutive patients with different types of adult-onset primary dystonia. They were assessed for presence of head tremor and arm tremor (rest, postural and kinetic). RESULTS: A total of 262 patients (55.4%) were tremulous: 196 patients presented head tremor, 140 patients presented arm tremor and 98 of them had a combination of head and arm tremor. Of the 140 patients with arm tremor, all presented postural tremor, 103 patients (73.6%) presented also a kinetic component, whereas 57 patients (40.7%) had rest tremor. Rest tremor was unilateral/asymmetric in up to 92.9% of them. Patients with segmental and multifocal dystonia were more likely tremulous than patients with focal dystonia. Dystonic symptoms involving the neck were more frequently observed in patients with head tremor, whereas dystonic symptoms involving the arms were more frequently observed in patients with arm tremor. DISCUSSION: Here we show that tremor is a common feature of patients with adult-onset primary dystonia. It may involve different body segments, with the head being the most commonly affected site. Arm tremor is also frequent (postural>kinetic>rest), occurring in up to one-third of cases. There is a suggestion of a stronger tendency for spread of dystonic features in patients with associated tremor. Dystonic tremor is under-reported and this underscores the importance of careful clinical examination when assessing tremulous patients without overt dystonia.

Normal motor adaptation in cervical dystonia: a fundamental cerebellar computation is intact.

The potential role of the cerebellum in the pathophysiology of dystonia has become a focus of recent research. However, direct evidence for a cerebellar contribution in humans with dystonia is difficult to obtain. We examined motor adaptation, a test of cerebellar function, in 20 subjects with primary cervical dystonia and an equal number of aged matched controls. Adaptation to both visuomotor (distorting visual feedback by 30°) and forcefield (applying a velocity-dependent force) conditions were tested. Our hypothesis was that cerebellar abnormalities observed in dystonia research would translate into deficits of cerebellar adaptation. We also examined the relationship between adaptation and dystonic head tremor as many primary tremor models implicate the cerebellothalamocortical network which is specifically tested by this motor paradigm. Rates of adaptation (learning) in cervical dystonia were identical to healthy controls in both visuomotor and forcefield tasks. Furthermore, the ability to adapt was not clearly related to clinical features of dystonic head tremor. We have shown that a key motor control function of the cerebellum is intact in the most common form of primary dystonia. These results have important implications for current anatomical models of the pathophysiology of dystonia. It is important to attempt to progress from general statements that implicate the cerebellum to a more specific evidence-based model. The role of the cerebellum in this enigmatic disease perhaps remains to be proven.

Ocular tremor in Parkinson's disease is due to head oscillation.

BACKGROUND: We investigated the origin of a recently reported ocular microtremor in patients with Parkinson's disease (PD). METHODS: Eye movements were recorded in 2 unselected patients with PD. Two recording techniques were used to control for artifacts: infrared video-oculography and infrared scleral reflection techniques. Head movements were also recorded with 2 different accelerometers. RESULTS: We recorded ocular oscillations in both patients (microtremor). Ocular tremor was accompanied by a recordable (but clinically nonvisible) head tremor of equal fundamental frequency and high coherence with both the eye oscillation and a recordable limb tremor. The eye movements were in the opposite direction to the head oscillation (ie, compensatory) and were suppressed by head restraint. There was no subjective oscillopsia, nor ocular tremor on fundoscopy. CONCLUSIONS: The "ocular tremor" observed in patients with PD disease is a compensatory eye movement secondary to transmitted head tremor, in agreement with clinical wisdom that these patients do not report oscillopsia.

Failure of explicit movement control in patients with functional motor symptoms.

Functional neurological symptoms are one of the most common conditions observed in neurological practice, but understanding of their underlying neurobiology is poor. Historic psychological models, based on the concept of conversion of emotional trauma into physical symptoms, have not been implemented neurobiologically, and are not generally supported by epidemiological studies. In contrast, there are robust clinical procedures that positively distinguish between organic and functional motor signs that rely primarily on distracting attention away from movement or accessing it covertly. We aimed to investigate the neurobiological principles underpinning these techniques and implications for understanding functional symptoms. We assessed 11 patients with functional motor symptoms and 11 healthy controls in three experimental set-ups, where voluntary movements were made either with full explicit control or could additionally be influenced automatically by factors of which participants were much less aware (one-back reaching, visuomotor transformation, and precued reaction time with variable predictive value of the precue). Patients specifically failed in those tasks where preplanning of movement could occur and under conditions of increasing certainty regarding the movement to be performed. However, they implicitly learned to adapt to a visuomotor transformation as well as healthy controls. We propose that when the movement to be performed can be preplanned or is highly predicted, patients with functional motor symptoms shift to an explicit attentive mode of processing that impairs kinematics of movement control, but movement becomes normal when such processes cannot be employed (e.g., during unexpected movement or implicit motor adaptation).

Functional movement disorders are not uncommon in the elderly.

BACKGROUND: Functional movement disorders (FMDs) are thought to be rare in the elderly. Clinical characteristics of the elderly people who develop FMDs are rarely reported. The objective of this study was to highlight the clinical characteristics of FMD in the elderly and compared these with a cohort of patients with a younger age of onset. METHODS: The authors performed a retrospective review of the clinical records of patients with FMD who were seen at their center in the last 5 years and had consented to be included in research studies. Patients fulfilling currently accepted diagnostic criteria for FMD as documented, clinically established, or probable were included. RESULTS: Of 151 patients with FMD who were identified and had sufficient information, 21.0% (n=33) had an onset after age 60 years (elderly group). The mean age of onset of FMD was 63.5 years (standard deviation, 5.2 years) in the elderly group and 35.5 years (standard deviation, 12.6 years) in the younger group. Tremor was the most common movement disorder in both groups (elderly group, 33.3%; younger group: 38.9%). Fixed dystonia was not observed in any patient who had an FMD onset after age 60 years. Gait abnormalities were significantly more common in the elderly group (69.7%) than in younger patients (23.5%; P<0.001). Associated psychogenic nonepileptic seizures tended to be more common in elderly patients (18.2%) compared with younger patients (13%; P=0.06). CONCLUSIONS: Contrary to common perceptions, FMDs are not uncommon in the elderly, and 1 in 5 patients in the current cohort, onset of FMD occurred after age 60 years. Gait abnormalities and psychogenic nonepileptic seizures may be more common in older patients.

Functional (psychogenic) symptoms in Parkinson's disease.

It has been reported that patients who have Parkinson's disease have a high prevalence of somatisation (functional neurological symptoms) compared with patients who have other neurodegenerative conditions. Numerous explanations have been advanced for this phenomenon. Here, with illustrative cases, we discuss this topic, including its clinical importance, and suggest a link between the pathophysiology of Parkinson's disease and the proposed propensity to develop functional symptoms.

Believing is perceiving: mismatch between self-report and actigraphy in psychogenic tremor.

We assessed the duration and severity of tremor in a real-life ambulatory setting in patients with psychogenic and organic tremor by actigraphy, and compared this with self-reports of tremor over the same period. Ten participants with psychogenic tremor and eight with organic tremor, diagnosed using standardized clinical criteria, were studied. In an explicit design, participants were asked to wear a small actigraph capable of continuously monitoring tremor duration and intensity for 5 days while keeping a diary of their estimates of tremor duration during the same period. Eight patients with psychogenic tremor and all patients with organic tremor completed the study. Psychogenic patients reported significantly more of the waking day with tremor compared with patients with organic tremor (83.5 ± 14.0% of the waking day versus 58.0 ± 19.0% of the waking day; P < 0.01), despite having almost no tremor recorded by actigraphy (3.9 ± 3.7% of the waking day versus 24.8 ± 7.7% of the waking day; P = 0.001). Patients with organic tremor reported 28% more tremor than actigraphy recordings, whereas patients with psychogenic tremor reported 65% more tremor than actigraphy. These data demonstrate that patients with psychogenic tremor fail to accurately perceive that they do not have tremor most of the day. The explicit study design we employed does not support the hypothesis that these patients are malingering. We discuss how these data can be understood within models of active inference in the brain to provide a neurobiological framework for understanding the mechanism of psychogenic tremor.

Cerebellar transcranial direct current stimulation does not alter motor surround inhibition.

Motor surround inhibition (mSI) is one mechanism by which the central nervous system individuates finger movements, and yet the neuroanatomical substrate of this phenomenon is currently unknown. In this study, we examined the role of the cerebellum in the generation of mSI, using transcranial direct current stimulation of the cerebellum (cDC). We also examined intrasubject and intersubject variability of mSI. Twelve subjects completed a three session cross over study in which mSI was measured before and after (0 and 20 minutes) sham, anodal and cathodal cDC. mSI of the surround muscle (adductor digiti minimi) at the onset of flexion of the index finger was consistently observed. Anodal and cathodal cDC did not modulate the magnitude of mSI. For individual subjects (across the three sessions), the intrasubject coefficient of variation was 27%. Between subjects, the intersubject coefficient of variation was 47%. mSI was a stable effect in individual subjects across multiple sessions. This is an important observation and contrasts with other neurophysiological paradigms such as paired associative stimulation response, which exhibit great variability. In addition, we have quantified intrasubject variability of mSI, which will allow future therapeutic studies that attempt to modulate mSI to be adequately powered. We have not found evidence that the cerebellum contributes to the neuroanatomical network needed for the generation of mSI. Understanding the mechanisms of mSI remains a challenge but is important for disorders in which it is deficient such as Parkinson's disease and focal hand dystonia.

'Jumping to conclusions' bias in functional movement disorders.

BACKGROUND: Patients with functional neurological disorders often report adverse physical events close to the onset of functional symptoms. However, the mechanism via which a triggering event may set off a functional condition is lacking. One possibility is that patients make abnormal inferences about novel information provided by physical triggering events. In this study, the authors aimed to specifically investigate whether patients with functional movement disorders have abnormalities in probabilistic reasoning. METHODS: The authors used a well-studied probabilistic reasoning paradigm, 'the bead task', in 18 patients with functional movement disorders and 18 healthy agematched controls. The authors assessed the number of beads that participants needed to reach a decision and changes in the certainty of their decisions when confronted with confirmatory or contradictory evidence. FINDINGS: Patients with functional movement disorders requested on average significantly fewer beads before reaching a decision than controls (3 vs 6 beads). When confronted with potentially disconfirmatory evidence, patients showed a significantly greater reduction in confidence in their estimates than controls. 40% of patients reached a decision after one or two beads whereas no controls showed this bias. INTERPRETATION: Patients with functional movement disorders requested less information to form a decision and were more likely to change their probability estimates in the direction suggested by the new evidence. These findings may have relevance to the manner with which patients with functional neurological disorders process novel sensory data occurring during physical triggering events commonly reported at onset of symptoms.

Psychogenic palatal tremor may be underrecognized: reappraisal of a large series of cases.

BACKGROUND: Palatal tremor is characterized by rhythmic movements of the soft palate and can be essential or symptomatic. Some patients can have palatal movements as a special skill or due to palatal tics. Psychogenic palatal tremor is recognized but rarely reported in the literature. METHODS: We retrospectively evaluated all patients with palatal tremor seen in our center over a period of 10 years. RESULTS: Of 17 patients with palatal tremor, we identified 10 patients with isolated palatal tremor. In 70% of those the diagnosis of psychogenic palatal tremor could be made. Of the remainder, 2 had palatal tics and 1 essential palatal tremor. CONCLUSIONS: We suggest that psychogenic palatal tremor may be underrecognized and propose that targeted clinical examination of positive signs for psychogenic movement disorders in these patients is essential. The correct identification of such patients has important clinical and scientific implications.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

BACKGROUND: In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. METHODS: We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. RESULTS: Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. CONCLUSIONS: Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

Moving toward "laboratory-supported" criteria for psychogenic tremor.

A confident clinical diagnosis of psychogenic tremor is often possible, but, in some cases, a "laboratory-supported" level of certainty would aid in early positive diagnosis. Various electrophysiological tests have been suggested to identify patients with psychogenic tremor, but their diagnostic reliability has never been assessed "head to head" nor compared to forms of organic tremor other than essential tremor or PD. We compared baseline tremor characteristics (e.g., frequency and amplitude) as well as electrophysiological tests previously reported to distinguish psychogenic and organic tremor in a cohort of 13 patients with psychogenic tremor and 25 patients with organic tremor, the latter including PD, essential-, dystonic-, and neuropathic tremors. We assessed between-group differences and calculated sensitivity and specificity for each test. A number of tests, including entrainment or frequency changes with tapping, pause of tremor during contralateral ballistic movements, increase in tremor amplitude with loading, presence of coherence, and tonic coactivation at tremor onset, revealed significant differences on a group level, but there was no single test with adequate sensitivity and specificity for separating the groups (33%-77% and 84%-100%, respectively). However, a combination of electrophysiological tests was able to distinguish psychogenic and organic tremor with excellent sensitivity and specificity. A laboratory-supported level of diagnostic certainty in psychogenic tremor is likely to require a battery of electrophysiological tests to provide sufficient specificity and sensitivity. Our data suggest such a battery that, if supported in a prospective study, may form the basis of laboratory-supported criteria for the diagnosis of psychogenic tremor.

Cerebellar brain inhibition is decreased in active and surround muscles at the onset of voluntary movement.

Highly selective activation of the desired muscles for each movement and inhibition of adjacent muscles is attributed to surround inhibition (SI) which differentially modulates corticospinal excitability in active and surrounding muscles. Cerebellar brain inhibition (CBI) is another inhibitory neuronal network which is known to be active at rest and during tonic muscle contraction. The way in which CBI may be modulated at movement onset and its relationship with SI has not previously been investigated. We assessed motor evoked potential (MEP) size and CBI in first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles at rest and during a simple motor task where FDI was an active muscle and ADM was not involved in the movement (surround muscle). At onset of movement, MEP size in ADM was significantly suppressed, confirming the existence of SI. In contrast, CBI in both muscles was found to be significantly decreased at the onset of the movement. This was confirmed even after adjustments for changes in MEP size occurring due to onset of muscle activity in FDI and the effects of SI in ADM. Our findings fail to functionally link SI with CBI, but they do indicate a non-topographically specific modulation of CBI in association with initiation of voluntary movement.

Susac syndrome presenting with acute hemibody paraesthesia.

Susac syndrome is an orphan disease characterised by encephalopathy, branch retinal artery occlusion and sensorineural hearing loss. As the clinical triad is rarely present at symptom onset, it is often initially misdiagnosed and appropriate treatment is often delayed. Herewith, we report a case of Susac syndrome in a 47-year-old man presenting with acute hemisensory loss and highlight the challenges of early diagnosis, particularly relevant in the era of hyperacute stroke management.