Thalamic Directional Deep Brain Stimulation for tremor: Spend less, get more.

BACKGROUND: Directional Deep Brain Stimulation (D-DBS) allows axially asymmetric electrical field shaping, away from structures causing side-effects. However, concerns regarding the impact on device lifespan and complexity of the monopolar survey have contributed to sparing use of these features. OBJECTIVE: To investigate whether chronically implanted D-DBS systems can improve the therapeutic window, without a negative impact on device lifespan, in thalamic deep brain stimulation (DBS). METHODS: We evaluated stable outcomes of initial programming sessions (4-6 weeks post-implantation) retrospectively in 8 patients with drug-resistant disabling tremor syndromes. We assessed the impact of directional stimulation on the Therapeutic Window (TW), Therapeutic Current Strength (TCS), tremor scores, disability scores and total electrical energy delivered. Finally, we performed Volume of Tissue Activation (VTA) modelling, based on a range of parameters. RESULTS: We report significant gains in TW (91%) and reductions in TCS (31%) with stimulation in the best direction compared to best omnidirectional stimulation alternative. Tremor and ADL scores improvements remained unchanged at six months. There was no increase in averaged IPG power consumption (there is a 6% reduction over the omnidirectional-only alternative). Illustrative VTA modelling shows that D-DBS achieves 85% of the total activation volume at just 69% of the stimulation amplitude of non-directional configuration. CONCLUSIONS: D-DBS can improve the therapeutic window over non-directional DBS, leading to significant reduction in disability that may be sustained without additional reprogramming visits. When averaged across the cohort, power output and predicted device lifespan was not impacted by the use of directional stimulation in this study.

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects.

BACKGROUND/OBJECTIVES: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

Transcranial magnetic stimulation: from neurophysiology to pharmacology, molecular biology and genomics.

Noninvasive plasticity paradigms, both physiologically induced and artificially induced, have come into their own in the study of the effects of genetic variation on human cortical plasticity. These techniques have the singular advantage that they enable one to study the effects of genetic variation in its natural and most relevant context, that of the awake intact human cortex, in both health and disease. This review aims to introduce the currently available artificially induced plasticity paradigms, their putative mechanisms-both in the traditional language of the systems neurophysiologist and in the evolving (and perhaps more relevant for the purposes of stimulation genomics) reinterpretation in terms of molecular neurochemistry, and highlights recent studies employing these techniques by way of examples of applications.

Mapping genetic influences on the corticospinal motor system in humans.

It is becoming increasingly clear that genetic variations account for a certain amount of variance in the acquisition and maintenance of different skills. Until now, several levels of genetic influences were examined, ranging from global heritability estimates down to the analysis of the contribution of single nucleotide polymorphisms (SNP) and variable number tandem repeats. In humans, the corticospinal motor system is essential to the acquisition of fine manual motor skills which require a finely tuned coordination of activity in distal forelimb muscles. Here we review recent brain mapping studies that have begun to explore the influence of functional genetic variation as well as mutations on function and structure of the human corticospinal motor system, and also the clinical implications of these studies. Transcranial magnetic stimulation of the primary motor hand area revealed a modulatory role of the common val66met polymorphism in the BDNF gene on corticospinal plasticity. Diffusion-sensitive magnetic resonance imaging has been employed to pinpoint subtle structural changes in corticospinal motor projections in individuals carrying a mutation in genes associated with motor neuron degeneration. These studies underscore the potential of non-invasive brain mapping techniques to characterize the genetic influence on the human corticospinal motor system.

BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease.

BACKGROUND: Levodopa induced dyskinesias (LID) are a common problem which ultimately limit the effective treatment of patients with Parkinson's disease (PD). There is accumulating evidence that LID develop due to abnormal synaptic plasticity, which is in turn influenced by the release of brain derived neurotrophic factor (BDNF). METHODS: The influence of a common functional polymorphism of the BDNF gene on the risk of developing dyskinesias in a large cohort of patients with PD (n = 315), who were independently and variably treated with levodopa and/or other dopaminergic treatments, was investigated. RESULTS: Patients with the met allele of BDNF, associated with lower activity dependent secretion of BDNF, were at significantly higher risk of developing dyskinesias earlier in the course of treatment with dopaminergic agents (hazard ratio for each additional met allele 2.12, p = 0.001), which persisted following adjustment for potential confounding variables. CONCLUSION: This functional polymorphism may help predict which individuals are most at risk of LID and is consistent with the known actions of BDNF on synaptic plasticity in the striatum.

Pattern-specific role of the current orientation used to deliver Theta Burst Stimulation.

OBJECTIVE: To evaluate the role of current direction on the after-effects of Theta Burst Stimulation (TBS) delivered with a biphasic Magstim 200(2) stimulator. METHODS: Inhibitory (cTBS) and excitatory TBS (iTBS) were delivered over the motor cortex of healthy individuals using reversed and standard current orientations (initial current in the antero-posterior direction) at 80% and 100% of their respective active motor thresholds (AMT). The after-effects on the MEP amplitude were measured for 25 min. The effects of the most effective reversed cTBS paradigm on intracortical inhibition (SICI) and facilitation (ICF) were also tested. RESULTS: Reversing the current direction reduced AMT by 26%+/-2%. Compared to standard cTBS, reversed cTBS induced stronger and longer-lasting inhibition of corticospinal excitability when delivered at 100% AMTrev. SICI was reduced after cTBS100%revAMT while ICF was unchanged. The after-effects of reversed iTBS were quite variable regardless of the intensity. CONCLUSIONS: cTBS applied with antero-posterior current is more effective in suppressing subsequent MEPs than conventionally orientated cTBS when the absolute stimulation intensity is similar. On the contrary, posterior current orientation reduces the efficacy of iTBS. SIGNIFICANCE: The current direction may affect the power of inhibitory and excitatory TBS in opposite ways; this should be considered in order to optimise the after-effects of biphasic RTMS.