Rational Electrotherapy in Deep Brain Stimulation

Deep Brain Stimulation (DBS) is often held up as the “poster child” of CNS electrotherapy because of both clinical and market success – including spectacular results in specific patients with Parkinson’s and movement disorders.  Like make electrotherapies, DBS was discovered “by chance” and then developed by adapting existing technologies (spinal chord stimulators) and through empirical optimization of protocols – basic science is still playing “catch up” to the clinical therapy in trying to determine the mechanisms of DBS, a pre-requisite to Rational Electrotherapy.  Though progress has been made, it is our opinion (shared by several of our collaborators) that fundamental and essential questions remain about the mechanisms of DBS.  For example, we proposed that extracellular potassium transients may play a modulatory role in DBS (paper).  In fact the efficacy of intermittent DBS protocols (e.g. 5 min ON, 5 min OFF) as preferred for some indications like epilepsy electrotherapy may directly relate to a primary role for extracellular potassium clearance dynamics (paper).

We also believe that there remain fundamental questions about the safety of DBS; this is indeed a contentious issue given the scale of ongoing DBS implantation.  Evidently, any damage cause by DBS implantation and subsequent electrical activation does not, in most cases, outweigh the benefit of therapy – or at least the potential for benefit (since outcomes are not known until after implantation). But a consensus that DBS technology is currently “safe enough” and a business aversion by companies to change existing FDA approved designs, means that though the “efficacy-mechanisms” of DBS remains an active cottage industry of scientific activity, the “safety mechanisms” of DBS remain, we believe, are an insufficiently addressed topic.   For example, the notion that the densely packed and interconnected neurons and blood-vessels are “gently nudged out of the way’ as a DBS lead is implanted is ludicrous; moreover our colleagues Dr. Schiff and Dr. Gluckman recently suggested that the lesion of axons of passage along the DBS tract (not just neurons directly impaled by the lead) can lead to wide-spread neuronal damage through the brain.  In our own lab we recently addressed the hypothesis that the electric fields induced during DBS (not the mechanical insult from the implantation itself but rather the electrical output could potentially disrupt the blood-brain barrier (paper). We also showed using basic electrochemistry concepts why biphasic voltage control pulses, as used in DBS, may result in undesired electrode potential build-up and damage to both tissue and electrode.  Finally, we have also considered the potential for joule heat (in the extreme case tissue burning) during DBS.  Toward this end we have developed the most sophisticated “physical’ model of DBS leads (link) and, moreover, proposed a simple solution to mitigate temperature increased (patent pending).  All this is not to be alarmist about DBS which is an approved and effective technique – but especially when the mechanisms for efficacy and safety of DBS remain fundamentally unknown, more work in characterizing the safety and efficacy of DBS is warranted. To highlight this point: Recently several patients suffered severe and fatal brain damage undergoing a routine dental procedure, diathermy; Despite suddenly altered MRI guidelines from Medtronic, patients with DBS remain understandably hesitant to enter scanners – in light of such tragedies, more safety analysis is not just warranted but ethically mandated.  Our concerns about DBS safety also motivate our effort to develop non-invasive electrotherapy alternatives.

Rational Electrotherapy in transcranial Direct Current Stimulation

Another application of electrotherapy where our group is applying the concepts of rational electrotherapy is transcranial Direct Current Stimulation (tDCS).  tDCS remains an experimental but highly promising technique to treat a range of neuronal and psychiatric disorders – one thing that make is very attractive compared to technologies such as DBS and VNS is that is it non-invasive, and associated with no or minimal complications.  Also, in contrast to non-invasive technologies such at TMS or ECT, there is no risk/intention to induce seizures and the over-all simplicity of application and low-risk means tDCS can be applied in a wide range of environments (even potentially at home). These factors converge to make tDCS a highly economic and robust therapy, if pivotal clinical studies confirm efficacy.  To remaining challenges to rational tDCS are: 1) understanding the mechanisms by which weak DC fields modulation neuronal function [link to slice] and specifically to lasting (plastic) changes in synaptic function [line to plastic changes]; and understanding how to guide the DC current to the targeted structures.  Our lab is actively innovating in both these areas and developing improved devices for tDCS.

 

Rational Electrotherapy for Epilepsy Control

Another area where our group has been applying the concepts of rational electrotherapy to improve the efficacy and safety of treatment is the electrical control of seizures.  Both general progress and remaining challenges in this field and our own contributions have been reviewed.

For example, we investigated how extracellular potassium transient may play a role on electrical control of seizures (PDF) – the concept that electrical stimulation effects potassium homeostasis is in fact well established, as is the notion that potassium concentration is a pivotal modulator of brain excitability.  Still, the concept that potassium transient may actually play a role in electrotherapies like DBS remains new and unapplied clinically. We went on to propose an “ON-OFF” paradigm for epilepsy electrotherapy, which in interestingly mirrors intermittent protocols developed empirically in clinical epilepsy control. The consideration of the role of extracellular potassium transient in seizure control also links to our interest in non-synaptic communication between cells.

Read our reviews on electrical control of seizures

Sunderam S, Gluckman B, Reato D, Bikson M. Toward rational design of electrical stimulation strategies for epilepsy control. Epilepsy & Behavior . 2010; 17:6-22 PDF

Durand DM, Bikson M. Suppression and control of epileptiform activity by electrical stimulation: a review. Proceedings of the IEEE 2001; 89:1065-1082 PDF

Rational Electrotherapy for Pain

Read our introduction to on an “Overview on electrotherapy technology” in the book Brain Stimulation in the Treatment of Pain. edited by Helena Knotkova, Ricardo Crucianim, and Joav Merrick publihsed by Nova Science, New York 2011 ISBN 978-1-60876-690-1.

Bikson M, Datta A, Elwassif M, Bansal V, Peterchev AV. Introduction to Electrotherapy Technology. Read the chapter here.

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