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    ABSTRACT: Dystonia has historically been considered a disorder of the basal ganglia, however recent clinical and experimental observations promote the hypothesis that the dystonic neuroanatomical network is wider. In particular there is evidence that the cerebellum is a key structure within this network.(1) Eye blink conditioning is a well characterised experimental paradigm that is highly conserved across species and is dependent upon the cerebellum. Previously it has been shown that levels of eye blink conditioning are reduced in cervical and focal hand dystonia, which suggests impaired cerebellar function in these subsets of dystonia.(2) METHOD: In this study we examined eye blink conditioning in 11 patients with genetically confirmed DYT-1 dystonia and five patients with DYT-6 dystonia. 15 healthy age matched controls were also studied. Eye blink conditioning consisted of the pairing of a conditioning stimulus (CS) (salient 2kHz, 400 ms auditory tone via binaural headphones) with a strong unconditioned electrical stimulus (US) (200 µs pulse width, 5×sensory threshold, supraorbital nerve) 400 ms after the conditioning stimulus in order to elicit a blink reflex. After repeated pairings, conditioned responses (consisting of an eye blink starting before the US) are usually seen in healthy subjects. Conditioning consisted of six learning blocks of 11 trials: trials 1-9 were always CS-US pairs, trial 10 was US only and trial 11 was CS only. The main outcome variable was the number of conditioning responses in the final block. In both patient groups eye blink conditioning was observed, but at the group level there was a trend for patients with DYT-1 dystonia to condition less well (Mann-Whitney test, p=.097) compared to patients with DYT-6 dystonia, who conditioned at a comparable amount to aged matched controls. There is now compelling evidence from studies in animal models of dystonia that the cerebellum has a critical role in the pathophysiology of some forms of dystonia. However evidence for cerebellar involvement in humans with the primary form of the disease is less well established. Eye blink conditioning is a unique electrophysiological paradigm in its ability to test associative learning within the cerebellar circuitry. Although the current data do not reveal statistically significant differences between patients with DYT1 and the small group of patients with DYT6 dystonia currently studied, there is an interesting trend towards less conditioning in DYT1 compared with DYT6 mutation carriers, and recruitment of further DYT6 positive patients is ongoing. If confirmed, this trend fits with previous functional imaging and behavioural studies suggesting differences in cerebellar activation patterns during movement in DYT1 and DYT6 dystonia. There may well be important differences in pathophysiology between patients currently grouped within primary dystonia.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2.
  • Journal of Neurology 08/2013;
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    ABSTRACT: This review explores recent developments in understanding the neurobiological mechanism of functional (psychogenic) movement disorders (FMDs). This is particularly relevant given the resurgence of academic and clinical interest in patients with functional neurological symptoms and the clear shift in diagnostic and treatment approaches away from a pure psychological model of functional symptoms. Recent research findings implicate three key processes in the neurobiology of FMD (and by extension other functional neurological symptoms): abnormal attentional focus, abnormal beliefs and expectations, and abnormalities in sense of agency. These three processes have been combined in recent neurobiological models of FMD in which abnormal predictions related to movement are triggered by self-focused attention, and the resulting movement is generated without the normal sense of agency that accompanies voluntary movement. New understanding of the neurobiology of FMD forms an important part of reappraising the way that patients with FMD (and other functional disorders) are characterized and treated. It also provides a testable framework for further exploring the pathophysiology of these common causes of ill health.
    Current opinion in neurology 08/2013; 26(4):442-7.
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    ABSTRACT: We investigated whether clinical improvement observed after deep brain stimulation (DBS) of the globus pallidus internus (GPi) in cervical dystonia (CD) is paralleled by the normalisation of temporal discrimination thresholds (TDTs), a marker of abnormal sensory processing in CD. TDT was tested in 11 patients with CD after they received DBS and was compared with TDT scores from 24 patients with CD and a group of 61 controls. A clear clinical response to GPi-DBS was demonstrated (total Toronto Western Spasmodic Torticollis Rating Scale scores fell from 50 to 18; P < 0.001). In contrast, TDT remained abnormal in the CD-DBS group (P < 0.001) and was not significantly different from the abnormal TDT range observed in CD. Underlying sensory abnormalities in temporal discrimination observed in dystonia do not seem to be corrected by successful GPi-DBS. This adds further data to the ongoing debate regarding which pathophysiological abnormalities observed in dystonia are likely to be causal in the genesis of the disease rather than epiphenomena observed secondary to abnormal motor activity. © 2013 Movement Disorder Society.
    Movement Disorders 07/2013;
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    ABSTRACT: Successive attempts at rebranding may be behind at least some of the proliferation of terms we have at our disposal when describing patients with what are now most often referred to as "psychogenic," "conversion," or "somatoform" symptoms. The most popular term in the movement disorder literature, "psychogenic," provides the aetiology of the disorder within the name, indicating that the symptoms are "born of the mind." Here we argue that it is logical to stop using a term that defines the disorder with regard to a poorly defined aetiology that is not supported by current evidence, and, instead, to use a broad term-functional-not as a "polite eponym" but as a term that is freer from such assumptions and does not reinforce dualistic thinking. The main argument for change is not political or even practical, but scientific. © 2013 Movement Disorder Society.
    Movement Disorders 07/2013;
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    ABSTRACT: Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.
    Brain 06/2013;
  • Article: Commentary.
    Movement Disorders 06/2013; 28(6):739.
  • British Journal of Neurosurgery 05/2013;
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    ABSTRACT: Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioral consequences. This enables causal structure-function inferences, and in combination with neuroimaging, has provided novel insights into the basic mechanisms of action of neurostimulation on distributed networks. For example, more recent work has established the capacity of transcranial magnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neurostimulation with theoretical and biological models of cognition, for example, when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments, including biologically informed computational network analyses for predicting the impact of neurostimulation on brain networks, as well as novel neuroimaging and neurostimulation techniques. Such future developments may offer an expanded set of tools with which to investigate structure-function relationships, and to formulate and reconceptualize testable hypotheses about complex neural network interactions and their causal roles in cognition.
    Annals of the New York Academy of Sciences 04/2013;
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    ABSTRACT: It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.
    Experimental Brain Research 03/2013;
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