The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.
SummaryApproximately 10% of subjects thought clinically to have early Parkinson's disease (PD) have normal dopaminergic functional imaging (SWEDDs -Scans Without Evidence of Dopaminergic Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia. Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4) essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical features, the lack of true bradykinesia, occurrence of dystonia, and position-and task-specificity of tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to PAS, and the response of ET patients was no different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adultonset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.
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