Shaping reversibility? Long-term deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms

Abstract

Long-term results show that benefits from chronic deep brain stimulation in dystonia are maintained for many years. Despite this, the neurophysiological long-term consequences of treatment and their relationship to clinical effects are not well understood. Previous studies have shown that transcranial magnetic stimulation measures of abnormal long-term potentiation-like plasticity (paired associative stimulation) and GABAa-ergic inhibition (short-interval intracortical inhibition), which are seen in dystonia, normalize after several months of deep brain stimulation. In the present study, we examine the same measures in a homogenous group of 10 DYT1 gene-positive patients after long-term deep brain stimulation treatment for at least 4.5 years. Recordings were made 'on' deep brain stimulation and after stopping deep brain stimulation for 2 days. The results show that: (i) on average, prior to discontinuing deep brain stimulation, the paired associative stimulation response was almost absent and short-interval intracortical inhibition was reduced compared with normal. This pattern differs from that in both healthy volunteers and from the typical pattern of enhanced plasticity and reduced inhibition seen in deep brain stimulation-naïve dystonia. It is similar to that seen in untreated Parkinson's disease and may relate to thus far unexplained clinical phenomena like parkinsonian symptoms that have sometimes been observed in patients treated with deep brain stimulation. (ii) Overall, there was no change in average physiological or clinical status when deep brain stimulation was turned off for 2 days, suggesting that deep brain stimulation had produced long-term neural reorganization in the motor system. (iii) However, there was considerable variation between patients. Those who had higher levels of plasticity when deep brain stimulation was 'on', had the best retention of clinical benefit when deep brain stimulation was stopped and vice versa. This may indicate that better plasticity is required for longer term retention of normal movement when deep brain stimulation is off. (iv) Patients with the highest plasticity 'on' deep brain stimulation were those who had been receiving stimulation with the least current drain. This suggests that it might be possible to 'shape' deep brain stimulation of an individual patient to maximize beneficial neurophysiological patterns that have an impact on clinical status. The results are relevant for understanding long-term consequences and management of deep brain stimulation in dystonia.

Long-term subthalamic nucleus stimulation improves sensorimotor integration and proprioception

“…LTP-like plasticity in the motor cortex is impaired in PD, particularly in patients with dyskinesias 37. In patients with dystonia treated with globus pallidus pars interna DBS, it has been suggested that changes in LTP-like plasticity in the motor cortex may drive the improvement in dystonia 38 39. Whether restoration of sensorimotor integration by long-term STN DBS is related to LTP-like plasticity mechanisms requires further study.…”

Characterizing the therapeutic response to deep brain stimulation for treatment-resistant depression: a single center long-term perspective

“…The response to DBS for dystonia is more similar to that of depression, as it develops gradually and maximum effect is seen only after months of stimulation (Yianni et al, 2003). In dystonia and depression, neuroplasticity and CNS remodeling may be critical to the long-term treatment response to DBS (Ruge et al, 2011; Gibson et al, 2014). Indeed, changes in serum levels of brain-derived neurotrophic factor are abnormally low and increase with antidepressant treatment (Brunoni et al, 2008, meta-analysis) and in response to chronic DBS in an animal model (Hamani et al, 2012).…”

Deep brain stimulation for dystonia

“…Interindividual differences (endophenotype), such as the levels of cortical plasticity, may play a role in the beneficial effect of DBS 73 74…”