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1.  Distinguishing the Central Drive to Tremor in Parkinson's Disease and Essential Tremor 
The Journal of Neuroscience  2015;35(2):795-806.
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.
PMCID: PMC4293424  PMID: 25589772
accelerometery; cerebellum; essential tremor; Parkinson's disease; transcranial alternating current stimulation; tremor
2.  Action-effect binding is decreased in motor conversion disorder: implications for sense of agency 
The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of “self-agency.” The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the subject feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder.
Twenty patients with motor conversion disorder and 20 age- and gender-matched healthy volunteers used a rotating clock to judge the time of their own voluntary keypresses (action) and a subsequent auditory tone (effect), after completing conditioning blocks in which high, medium and low tones were coupled to images of happy, fearful and neutral faces.
The results replicate those shown previously: an effect following a voluntary action was reported as occurring earlier, and the preceding action later, compared to trials of only keypresses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores.
We show that motor conversion disorder patients have decreased action-effect binding for normal voluntary movements compared to healthy volunteers, consistent with the greater experience of lack of control.
PMCID: PMC3701023  PMID: 23494975
agency; action-effect binding; conversion disorder; psychogenic movement disorder; forward model
3.  The Selective Influence of Rhythmic Cortical versus Cerebellar Transcranial Stimulation on Human Physiological Tremor 
The Journal of Neuroscience  2014;34(22):7501-7508.
The influence of central neuronal oscillators on human physiological tremor is controversial. To address this, transcranial alternating current stimulation (TACS) was delivered at peak tremor frequency to 12 healthy volunteers in a 2 × 2 crossover study. Two sites were stimulated [contralateral primary motor cortex (M1), vs ipsilateral cerebellum] while participants performed two types of tasks designed to probe the different manifestations of physiological tremor of the hand–kinetic and postural tremor. Tremor was measured by accelerometry. Cortical coherence with the accelerometry signal was also calculated in the absence of stimulation. The phase synchronization index, a measure of the phase entrainment of tremor, was calculated between stimulation and tremor waveforms. The amplitude modulation of tremor was similarly assessed. There was significant phase entrainment that was dependent both on tremor type and site of stimulation: M1 stimulation gave rise to phase entrainment of postural, but not kinetic, tremor, whereas cerebellar stimulation increased entrainment in both cases. There was no effect on tremor amplitude. Tremor accelerometry was shown to be coherent with the cortical EEG recorded during postural, but not kinetic, tremor. TACS modulates physiological tremor, and its effects are dependent both on tremor type and stimulation site. Accordingly, central oscillators play a significant role in two of the major manifestations of tremor in health.
PMCID: PMC4035515  PMID: 24872555
accelerometry; coherence; entrainment; phase synchronization index; physiological tremor; transcranial alternating current stimulation
4.  Imaging Psychogenic Movement Disorders 
The neurobiological basis of psychogenic movement disorders (PMDs) has been elusive, and they remain difficult to treat. In the last few years, functional neuroimaging studies have provided insight into their pathophysiology and neural correlates. Here, we review the various methodological approaches that have been used in both clinical and research practice to address neural correlates of functional disorders. We then review the dominant hypotheses generated from the literature on psychogenic paralysis. Overall, these studies emphasize abnormalities in the prefrontal and anterior cingulate cortices. Recently, functional neuroimaging has been used to specifically examine PMDs. These studies have addressed a major point of controversy: whether higher frontal brain areas are directly responsible for inhibiting motor areas or whether they reflect modulation by attentional and/or emotional processes. In addition to elucidating the mechanism and cause, recent work has also explored the lack of agency that characterizes PMDs. We describe the results and implications of the results of these imaging studies and discuss possible interpretations.
PMCID: PMC3825153  PMID: 24057974
Psychogenic movement disorder; Functional disorder; Motor conversion; Somatoform disorder; Dissociative disorder; Medically unexplained; Neurological symptom; Functional imaging; Functional magnetic resonance imaging; Positron emission tomography; Single photon emission computed tomography; Motor; Cerebellum; Striatum; Basal ganglia; Prefrontal cortex; Attention; Emotion; Agency
5.  The functional neuroimaging correlates of psychogenic versus organic dystonia 
Brain  2013;136(3):770-781.
The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical–subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.
PMCID: PMC3580272  PMID: 23436503
psychogenic movement disorder; fixed dystonia; DYT1 gene; functional imaging; motor; cerebellum; basal ganglia; dorsolateral prefrontal cortex; attention
6.  Impulse control disorders in Parkinson’s disease: recent advances 
Current opinion in neurology  2011;24(4):324-330.
Purpose of review
To review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICD) in Parkinson’s disease (PD).
Recent findings
Large cross-sectional and case-control multicentre studies show that ICDs in PD are common with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between the behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data points towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possibly inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation.
Recent large scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in PD which can guide prevention of these behaviours and optimize therapeutic approaches.
PMCID: PMC3154756  PMID: 21725242
Impulse control disorders; Parkinson’s disease; dopamine agonists; pathological gambling; impulsivity
7.  Extracellular Charge Adsorption Influences Intracellular Electrochemical Homeostasis in Amphibian Skeletal Muscle 
Biophysical Journal  2008;94(11):4549-4560.
The membrane potential measured by intracellular electrodes, Em, is the sum of the transmembrane potential difference (E1) between inner and outer cell membrane surfaces and a smaller potential difference (E2) between a volume containing fixed charges on or near the outer membrane surface and the bulk extracellular space. This study investigates the influence of E2 upon transmembrane ion fluxes, and hence cellular electrochemical homeostasis, using an integrative approach that combines computational and experimental methods. First, analytic equations were developed to calculate the influence of charges constrained within a three-dimensional glycocalyceal matrix enveloping the cell membrane outer surface upon local electrical potentials and ion concentrations. Electron microscopy confirmed predictions of these equations that extracellular charge adsorption influences glycocalyceal volume. Second, the novel analytic glycocalyx formulation was incorporated into the charge-difference cellular model of Fraser and Huang to simulate the influence of extracellular fixed charges upon intracellular ionic homeostasis. Experimental measurements of Em supported the resulting predictions that an increased magnitude of extracellular fixed charge increases net transmembrane ionic leak currents, resulting in either a compensatory increase in Na+/K+-ATPase activity, or, in cells with reduced Na+/K+-ATPase activity, a partial dissipation of transmembrane ionic gradients and depolarization of Em.
PMCID: PMC2480687  PMID: 18310253

Results 1-7 (7)