Abnormal beta power is a hallmark of explicit movement control in functional movement disorders.

OBJECTIVE: To determine whether sensorimotor beta-frequency oscillatory power is raised during motor preparation in patients with functional movement disorders (FMD) and could therefore be a marker of abnormal "body-focused" attention. METHODS: We analyzed motor performance and beta-frequency cortical oscillations during a precued choice reaction time (RT) task with varying cue validity (50% or 95% congruence between preparation and go cues). We compared 21 patients with FMD with 13 healthy controls (HCs). RESULTS: In HCs, highly predictive cues were associated with faster RT and beta desynchronization in the contralateral hemisphere (contralateral slope -0.045 [95% confidence interval (CI) -0.057 to -0.033] vs ipsilateral -0.033 [95% CI -0.046 to -0.021], p < 0.001) and with a tendency for reaching lower contralateral end-of-preparation beta power (contralateral -0.482 [95% CI -0.827 to -0.137] vs ipsilateral -0.328 [95% CI -0.673 to 0.016], p = 0.069). In contrast, patients with FMD had no improvement in RTs with highly predictive cues and showed an impairment of beta desynchronization and lateralization before movement. CONCLUSIONS: Persistent beta synchronization during motor preparation could reflect abnormal explicit control of movement in FMD. Excessive attention to movement itself rather than the goal might maintain beta synchronization and impair performance

Pathophysiology of functional (psychogenic) movement disorders

This thesis describes a series of studies involving healthy subjects, carefully selected patients with functional movement disorders and organic movement disorders, in which different aspect of the mechanism underlying functional movement disorders were explored: 1. The presence of physical precipitating factors at onset of functional movement disorder by using semistructured interviews. I found that most patients with functional movement disorder have a clear physical event prior to the onset of functional symptoms. 2. The presence of a “jumping to conclusions” reasoning style that may predispose patients with functional movement disorder to accept new hypothesis on the basis of less evidence. They requested less evidence that healthy controls to make a judgement, which is here suggested to influence the manner in which they process novel sensory data occurring during triggering events. 3. The role of attention in symptoms production by using different motor tasks in which the predictability of movements as well as the effect of explicit and implicit strategies in motor control were manipulated. Motor impairment in patients with functional movement disorder was found to be related to the employment of explicit strategies or when pre-planning movements is possible. 4. The intensity and duration of tremor in patients with functional tremor in a real life situation using accelerometers. They were found to fail to perceive 6 that tremor is not present most of the time compared with patients with organic tremor. 5. Finally, I explored the phenomenon of the sensory attenuation using a force-matching task as a measure of sense of agency for movement in these patients. Patients with functional movement disorders have an abnormal sensory attenuation for movement, which may help to explain the lack of agency for the abnormal movement. These results contribute to the understanding of the mechanisms underlying functional movement disorders and by extension, other functional neurological symptoms, and demonstrate that they are amenable to neuroscientific study

Sensory Attenuation Assessed by Sensory Evoked Potentials in Functional Movement Disorders.

BACKGROUND: Functional (psychogenic) movement disorders (FMD) have features associated with voluntary movement (e.g. distractibility) but patients report movements to be out of their control. One explanation for this phenomenon is that sense of agency for movement is impaired. The phenomenon of reduction in the intensity of sensory experience when movement is self-generated and a reduction in sensory evoked potentials (SEPs) amplitude at the onset of self-paced movement (sensory attenuation) have been linked to sense of agency for movement. METHODS: We compared amplitude of SEPs from median nerve stimulation at rest and at the onset of a self-paced movement of the thumb in 17 patients with FMD and 17 healthy controls. RESULTS: Patients showed lack of attenuation of SEPs at the onset of movement compared to reduction in amplitude of SEPs in controls. FMD patients had significantly different ratios of movement onset to rest SEPs than did healthy controls at each electrode: 0.79 in healthy controls and 1.35 in patients at F3 (t = -4.22, p<0.001), 0.78 in healthy controls and 1.12 at patients C3 (t = -3.15, p = 0.004) and 0.77 in healthy controls and 1.05 at patients P3 (t = -2.88, p = 0.007). CONCLUSIONS: Patients with FMD have reduced sensory attenuation as measured by SEPs at onset of self-paced movement. This finding can be plausibly linked to impairment of sense of agency for movement in these patients

Modulation of Reaction Times and Sense of Agency via Subliminal Priming in Functional Movement Disorders.

Background: In functional movement disorders, explicit movements are impaired, while implicit movements are preserved. Furthermore, there is evidence that the sense of agency is abnormal. Aim: We aimed to investigate how motor responses and sense of agency were affected by subliminal or supraliminal cues in people with functional movement disorders. Methods: Twenty-three people with a functional movement disorder and 26 healthy controls took part in a subliminal and supraliminal priming experiment which investigated reaction times, choice and sense of agency. Participants pressed a left or right arrow key in response to an imperative left or right pointing arrow. Either key could be pressed in response to bidirectional arrows. The imperative arrow was preceded by a small left or right pointing prime arrow, that was non-predictive (50% correct) and was presented in either subliminal or supraliminal conditions. The participant's response caused the appearance of a colored circle and they rated the degree of control they felt over its appearance (sense of agency). The circle's color depended on whether their response was congruent or incongruent with the prime arrow direction. After exclusion, 19 participants remained in each group. Results: Prime-compatible responses led to faster reaction times in both the subliminal and supraliminal condition. Subliminal prime-compatible responses were chosen more frequently in the free choice condition. The sense of agency did not depend on prime-response congruency. There were no significant differences in any of these measures between the two groups. Conclusion: With non-predictive cues, reaction times, choices, and the sense of agency remain normal in people with functional movement disorders, for both subliminal and supraliminal primes. The findings suggest that it is not so much conscious awareness of the movement, but rather conscious motor preparation that is detrimental to motor function in functional movement disorders

Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency

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

Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair.

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society