In Neural Imaging, Dr. Parra is collaborating with Memorial-Sloan Kettering Cancer Center to develop tools for the analysis of Magnetic Resonance Spectroscopic Imaging (MRSI). The goal is to identify markers of metabolic function that are indicative of brain tumors. Dr Bikson is concurrently developing technology to facilitate drug delivery to the brain, including for the treatment of identified tumors. Dr. Bikson is developing devices for Electrochemotherapy and drug delivery as well as intra-operative assist tools.

Safety Validation

Evidently, safety is paramount when deploying an clinical device.  In addition to exhaustively considering risks associated with the devices we develop, our group has also provided expert advice of medical device and electrical safety to a range of companies and institutes including the counties leading medical device corporations.  Pre-clinical (animal) work is also conducted by our group.

Clinical Testing

The final and pivotal stage of medical device validation is clinical testing.  The clinical network facilitated throughThe New York Center for Biomedical Engineering facilitates tremendous access to the nation leading clinical center and practitioners. The NYCBE also provides a range of logistical support services (notably CCNY BME Senior Design program), sub-consortiums (like the MSKCC-CCNY partnership), seed-grants, and student placement (namely CCNY engineering MS and PhD engineering candidates working in clinical centers).  Outside the NYCBE, we are fortunate to have tremendously active and accomplished colleagues in hospital along the north-east corridor, from Harvard Medical to The National Institute of Health to the Medical University of South Carolina.

Devices developed by the CCNY Neural Engineering team and Prof. Marom Bikson’s lab are in clinical trials in over 18 national medical centers.

Reflective Pulse Oximeter

For proto-typing medical devices, we leverage the tremendous infrastructure at the CUNY campuses, as well as expertise within our own group. Tools such as 3-D rendering, circuit and PCB design and fabrication, 3-D printing and laser-cutting are standard tools we employ to rapidly develop prototypes for clinical testing.  Devices are designed to address IRB and regulatory concerns as appropriate (e.g. FDA NSR).

We have successfully designed and developed both diagnostic and therapeutic devices ranging from reflective intra-operative pulse oximeters for cancer durgery to non-Invasive brain stimulation devices for depression treatment.  We work closely with our clinical partners as well as provide support for several leading medical technology companies.

Additional details on developed devices (Products) and ongoing work (Projects) can be found in this website.  Our work has been recognized through numerous grants (NIH, DoD, Andy Grove Foundation…) and awards (Wallace H Coulter Translational Research, NYC Bioaccelerate Award Finalist…).  And we welcome all further inquiries.

http://www.youtube.com/v/saCX4uwInLc

Our work in Neural Signal Processing focuses on developing signal analysis tools for imaging the central nervous system. We emphasize multivariate signal analysis and probabilistic modeling, drawing heavily on advanced machine learning techniques. Projects on functional imaging are based on Electro-Encephalography (EEG). Experiments in Parra’s high-density EEG recording lab study processes involved in human auditory and visual perception and attention. The latest perceptual modeling work in this laboratory seeks to explain the origin of tinnitus, and develop potential treatment options.

062513_slice01_gamma_acute_line_picfull

 

Precisely how electricity changes nervous system function can be fully characterized, understood, and then leveraged to design electrical therapies. To understand the biophysics of electric-nervous tissue interactions, we have developed a research program structures along three “tiers” of characterization.   The tiers are evidently not independent (the nervous system is not ‘divided’ along these lines), but they provide a rational basis for understanding electric field effects and they lend themselves to specific experimental questions.

This page is intended as a rather technical and historical overview of Quantiative Neurophysiology with Applied Electric Fields as developed in the CCNY Neural Engineering Lab based on innovative work by other groups.

3 Tiers by CCNY

These tiers also provide a basis for designing rational electrotherapies based on “Functional Targeting”.  Our premise for functional targeting is that the same brain structures that are responsible for disease (and hence should be changed by stimulation) are also responsible for some normal functions (and so should be spared by stimulation).  So while it is important to improve “spatial targeting” namely by guiding current only to specific structures – we propose that a concurrent scheme for functional targeting –namely changing the abnormal process while sparing the normal functions within a specific structure – is also necessary.

You can watch Dr. Bikson discuss Rational Electrotherapy and Functional Targeting at three tiers at the 2008 Neural Interface Conference here as well as follow recent presentations by our group (news). You can also find additional background information on the CCNY Neural Engineering Course page.

Functional Targeting of Electrical Stimulation

1st Tier: Single Cell     CellCCNY

In this section we introduce our Single Cell tier (1st tier) for Rational Electrotherapy and Functional Targeting. This introduction is put in a broader historical and technical context, and links with our ongoing projects.

Transmembrane Potential: The starting point for understanding how electrical stimulation effects cells is considering how the electric fields generated by stimulation (e.g. the current flowing around the cells) leads to changes in transmembane potential.  These changes in transmembane potential then determine what the outcome of stimulation is: understanding how transmembrane potential changes lead to functional outcomes is complex; none-the-less determining induced transmembrane potential is a necessary first step.  There are other potential mechanisms by which stimulation might change neuronal function, such as joule heating, but transmembrane potential is largely the focus of rational electrotherapy.  Electroporation results from large change in transmembrane potential so is a sub-phenomenon (e.g. endothelial cells).  If transmembrane potential exceeds a threshold value, it may lead to action potential generation [link AP firiing] – but even small “sub-threshold” polarization may profoundly change function [link sub].

Biphasic Polarization and the ‘somatic doctrine’: It’s important to understand that there is no such thing as simply “all depolarizing” or “all hyper-polarizing” stimulation.  As shown in the pictures below [add figure], for any stimulation and any cell, a current that cross into the membrane must also cross out – so there is always regions of depolarization and hyperpolarization.  Sometimes people focus on just the soma compartment, in which case it is possible to discuss a “somatic depolarizing” of “somatic hyper-polarizing” field.  The ‘somatic doctrine’ was useful to explain early animal results with CNS stimulation [link to early in vivo] but ignores the potentially profound effect of dendrite depolarization of cellular functions including synaptic integrations and plasticity [link synapse].

CellPolarizationCCNY

Single Neuron Stimulation Models: There is a significant history of using computational approaches to model the effects of electrical current on neuronal membrane polarization The consensus of these reports is that the magnitude of neuronal polarization is highly sensitive to detailed neuronal geometry, distributed (active) membrane properties, and the profile of the induced extracellular potentials (Ranck 1975; Yim 1986; Tranchina and Nicholson 1986; Vigmond 1997; Holt and Koch 1999; McIntyre and Grill, 1999; Bokil 2001; McIntyre and Grill, 2002; McIntyre 2004).

Computational neuroscientists have employed both analytical approaches using simplified cellular geometries such as spheres and numerical approaches which have recently evolved to include neurons with hundreds of compartments; each compartment loads with a range of voltage gated channels, each channel control by multiple gating kinetics.   Whereas the former is limited by simplicity (mathematical tractability), the later can result in such complexity that results are phenomenological.

On our General approach to computational modeling: We believe strongly in the usefulness of models to make testable predictions, equally important is that models are precisely parameterized based on experimental data, including experiments where fully controlled (e.g. uniform [link]) is applied to reduced systems [link].  This emphasis has lead us to define and focus on specific metrics of electrical activation, such as “coupling constant” (see below) which facilitates a tight dialogue between specific models (with no more complexity then needed), quantitative predications, and experiments.  We are determining and exploring similar metrics at the network level.  This approach is of course not unique to our group, but we have developed an integration of expertise around our own efforts toward computational modeling in support of rational electrotherapy.

Early Animal Studies of Electrical Stimulation:  In vivo animal experiments in the 60’s established qualitative relationships between electrical stimulation and CNS neuronal function including showing polarity dependent changes (see somatic doctrine below) and also changes that outlasted the duration of stimulation.  However, in our view, significant steps forward in determining the quantitative relationship between electric fields and changes in neuronal function, largely initiated only with the use of isolated preparations: in these isolated preparations is was possible to 1) precisely and reproducibly control the applied currents (including uniform fields); and 2) directly link specific responses to electric fields.

Isolated Preparations:  We believe that the majority of insight into how electrical stimulation affects CNS structures has come from experiments using isolated preparations: Indeed, our group continues to rely heavily on in vitro brain slices to test specific hypothesis about electrical modulation.   As indicated above, there are two core features of isolated preparation necessary to draw quantitative insight on electric field effects.  First, the electrical environment of the cells is precisely and fully controlled, so that we can always indicated and reproduce what we are applying.  This is in contrast to in vivo or human stimulation, where even under the best controls, the induced electric fields will depend on subject specific anatomy.  Second, isolated preparations allow direst quantification and isolation of stimulation effects.  Through a range of electrophysiological (e.g. intracellular, extracellular), imaging (e.g. optical imaging), pharmacological, and other approaches, well worked out in isolated preparations, it is possible to determine in detail the specific pathways by which electric field modulated neurons – such detailed biophysical understanding is a necessary step toward rational electrotherapy.  The limitation of isolated preparations will always be just that-the tissue is isolated for the animal, so things like behavior is evidently absent.  But in our work, we aim to design experiments to take advantage of this isolation, allowing us to determine precise mechanisms of action, rather then make phenomenological observations.

“Sub-threshold” and “Supra-threshold” electrical stimulation:  Sub-threshold (also call neuro-modulation) and supra-threshold fields are terms that have been applied widely, including by our group, to distinguish between a perceived fundamental division between how weak currents verse strong current affect brain function – and hence how distinct electrotherapies should be interpreted and designed.  But, especially our work cortical neurons and network oscillations has made us increasingly wary of these popular terms.

These terms are generally interpreted at the single cell (1st tier) level.  Supra-threshold stimulation, which is typically applied in (repetitive) pulses, results in action potential generation in the target neurons; in the simplest case in a one-pulse to one-action potential volley fashion. Sub-threshold stimulation nominally indicated stimulation that is applied to an isolated and quiescent neuron will not trigger action potential. [my video]. But neurons in the brain are hardly uncoupled and quiescent.  For example during oscillation neurons are constantly near and crossing action potential threshold, in this case a very weak field can cause a neuron to fire; it is not straightforward to the say if this is a sub or supra threshold stimulation.  Instead of “sub-threshold” we propose using “weak current” stimulation.

Uniform Fields and ‘Quasi-Uniform’ Assumption: A uniform field indicated an electric field that has only one direction and magnitude in a tissue region of interest; the latter emphasis is important because in reality there is not globally uniform field.  Following the ‘quasi-uniform’ assumption, we have proposed that for many stimulation modalities, such as tDCS, the induced electric fields are largely uniform on the scale of each single neuron – for example in one cortical column.  Though the electric field will vary across the brain, we can speak of the single electric field magnitude and direction in each region of interest.  Though an abstraction, there are several advantages to the ‘quasi-uniform’ assumption in the understanding and design of electrotherapy.  One advantage is the use of uniform field in isolated preparations.

Our work on modeling transcranial electrical stimulation is addressing how valid the quasi-uniform assumption is for specific electrotherapies like tDCS.

Adapting a technique applied by John Jefferys in 1981 (pubmed), in 1986, Steven Schiff and Bruce Gluckmanapplied uniform fields in the control of experimental seizures (pubmed), and approach that we and others followed.

The “Coupling Constant” Theory: The coupling constant, also called the ‘coupling strength’ or ‘polarization length’, is a key substrate of our efforts to quantify the effects of stimulation on neurons, relying on experimentally verified hypothesis.    The concept is straightforward:  We assume that for weak electric fields (stimulation intensities too weak to activation significant voltage gated membrane channels and below action potential threshold, that the membrane potential polarization at any given compartment is a linear of stimulation intensity.  Moreover, for a uniform electric fields, the membrane potential polarization can be expressed as:

Equation Vtm = G * E

CouplingConstantCCNY

Weak current “Coupling Constant” Data: Coupling constant quantification for various neuron types have been done using isolated stimulation preparations.  Some of the initial work quantifying uniform field coupling constants was done by Christopher Chan around 1986 and 1988, then in the lab of Charles Nicholson.  Dr. Chan used very low frequency field and intracellular recording from multiple compartments in turtle cerebellum neurons.   This pioneering work was then develoed into an analytical model.

Dr. Marom Bikson, working on the lab of John Jefferys determined coupling constants for rat CA1 neurons (PDF).  John Jefferys group went on to determine these values for CA3 cells [pubmed]; values that were used our later CA3 network models (project). Working with Dr. Bikson, Dr. Radman then led our effort to determine coupling constants in morphological reconstructed cortical neurons (project).

Firing Thresholds: For supra-threshold stimulation the traditional focus at the 1st tier is “recruitment order”: or which cell fires first (as stimulation intensity is gradually increased).  For example in DBS there has been significant modeling effort to model the first cellular responders.   Dr. Radman characterized firing threshold in cortical neurons (project) – one important finding of his work is that neurons that are ‘down-stream’ from first activated neurons will also fire but indirectly due to synaptic input.  Evidently in the brain, the synaptic connections are intact and wide-spread such that the concept of firing threshold could be considered in the context of the single neuron and all its afferents.

Small Polarization Big Effects I-Single Neurons: One of the fundamental challenges in rational electrotherapy with weak electric fields is understanding how relatively small polarization (e.g. 1 mV/mm field leading to a 0.1 mV somatic polarization) could have functional effects on CNS function and hence be used in therapy.   In addition to quantification of coupling constants, this challenges if understanding how weak current are “transduced” the by CNS has been a focus of our research efforts at the 1st tier.  For example, we showed how when responding to depolarizing ‘ramps’ (e.g. a gradual EPSP), the weak polarization induced in fields can be dramatically amplified through a change in firing time– this led us to propose that weak electric field that may be too weak to trigger action potentials or even change action potential threshold, may exert a powerful effect on CNS function through spike timing.

We have investigated additional ‘amplification’ mechanisms at the synapse and network levels, as well as through clinical collaborations.

Beyond Neurons: Glia and Endothelial Cells.  In 2006, Dr. Bikson argued that any Rational Electrotherapyparadigm must consider non-neuronal cells in the brain.   Indeed, this concept is hardly new, but essentially ignored in most studies of electrical stimulation and medical device design.  Work on electrical stimulation on non-neuronal cells also links with our general studies of non-synaptic mechanisms in the CNS.

Glia represent the majority of cell in the CNS – the concept that they are just passive support cells is being increasingly outdated.  As such, one might ask could electric fields modulate CNS function, in part, through direct action on glia (indirect modulation of glia following intense neuronal activation is more of a given).   One of the original investigations in the role of glia in response to DC stimulation was Dr. Gardner-Medwin (who incidentally was John Jefferys’ PhD mentor).

Endothelial cells form the Blood-Brain Barrier (BBB), which tightly regulate the neuronal environment.  Any electrical action on the BBB may thus profoundly impact brain function.  We have been collaborating with Dr. John Tarbell (CCNY), and world expert on endothelial barriers, to directly evaluate this hypothesis (project).

Functional Targeting 2nd Tier: Synapses                 SynapseCCNY

Our group has developed the concept of “Functional Targeting” [link] at three “tiers” as a neurophysiological substrate for Rational Electrotherapy.   Our 2nd tier is direct action of electricity on Synaptic Function.  Synapses evidently underlie CNS function and changes in synaptic function (e.g. LTP, LTD) are though to underpin normal (e.g. learning) as well as abnormal (e.g. epilepsy) function.    Understanding how applied current change synaptic function is therefore necessary for Rational Electrotherapy.  We separately consider the acute (immediate and short lasting) and plastic (long lasting) changes in synaptic function.  The latter is particularly relevant for therapies using non-invasive electrotherapy technologies where, because a subject cannot walk around forever with the stimulator, changes should outlast the treatment-period of stimulation.

Micro-Tetanic Stimulation LTP and LTD: The general concept that electrical stimulation can change synaptic function is well born out in the areas of experimental tetanic (high-frequency pulse) supra-threshold stimulation in animal LTP studies – these studies have elegantly characterized the pre- and post-synaptic molecular cascades leading to changes in synaptic efficacy.  However, these studies have some key limitations in the context of Rational Electrotherapy namely 1) Electrical stimulation used by many neurophysiologist as an almost ‘mystical’ force that is little understood so applied in a poorly controlled (‘irrational’) manner – essentially the details of stimulation (e.g. monopolar or bipolar) are either ignored or considered irrelevant to outcome; 2) the nature of stimulation applied (e.g. using micro-electrodes) is often not translatable to a clinical setting, nor is that a consideration in these basic science studies.

Uniform currents on acute synaptic function: The use of uniform field in isolated preparations allows precise and reproducible characterization of how applied currents changes synaptic function.  Perhaps the first systematic characterization along these lines was by Dr. Jefferys who illustrated that synaptic efficacy in the dentate gyrus (pubmed) could be modulated by weak fields.  Dr. Marom Bikson worked with Dr. Jefferys to extend this analysis to the CA1 region of the hippocampus (pdf), some of the most important findings from this work were 1) that the different afferent bundles will be modulated in different ways by the same electric field (e.g. one bundle could be potentiated even as another was depressed); and 2) field were equally effective in modulating synaptic terminals and post-synaptic neurons – so that uniform fields applied perpendicular to the main post-synaptic neuron axis (and hence not significantly polarizing the post-synaptic neuron) but parallel to synaptic fibers (and hence polarizing pre-synaptic terminals) are effective in modulating synaptic function.

Uniform fields of plastic synaptic function:  Having established acute effects on synaptic efficacy for electric fields, our attention has recently focused on plastic (lasting) changes following electrical stimulation.   We are particularly interested in induction of plasticity by weak current stimulation, which is relatable to non-invasive electrotherapy technologies like tDCS – plastic changes induced by “blasting” the system with supra-threshold pulse trains are investigated elsewhere in the context of LTP.   We have ongoing projects in this area focusing on the cortex, an important target for non-invasive stimulation, and the hippocampus, and important target for memory and disease treatment.  We believe plastic changes my represent a new level of weak current amplification at our 2nd tier.

Small Currents Big Changes 2: Synapses.  One concept we have been developing is that the effects of weak current, when applied over several minutes, is cumulative.  Simply put the idea is that a particular current applied for only a short period, and then stopped, will not lead to any lasting changes in synaptic function.  But a weak current applied for a long duration (e.g. minutes, hours) will interact with the CNS in such a manner that its effects are “amplified” through changes in synaptic plasticity.

On clinical translation area of this work is tDCS.  Clinical studies with tDCS have in fact shows that DC stimulation needs to be applied for several minutes to have lasting effects.  We are now directly investigating the mechanisms of action of this in cortical slices [link Asif work].  We already showed in hippocampal slices that application of even high-intensity DC current for short periods does not induce plastic changes (only acute changes) – a reasonable question is then what would happen is the field we applied and “left on” for several minutes.

We are also investigating the induction of plastic synaptic changes by long duration application of AC currents.  This is relevant for clinical tACS (ref Paulus) but also in concerns about environmental exposure to AC fields (e.g. power-lines).   Though there was an initial suggestion that short duration application of relatively weak AC currents could induce plastic changes (Bawin papers) – this result has not been reproduced (Jefferys paper).  Preliminary data from our group suggest that weak AC fields induce cumulative changes in synaptic function over time-scales of 10’s of minutes [link Je Hi project].

Functional Targeting of Electrical Stimulation 3rd tier: Network        Network CCNY

Our group has developed the concept of “Functional Targeting” at three “tier” as a neurophysiological substrate for Rational Electrotherapy.   Our 3nd tier is actions of electricity that are only manifest at the network level, generally as modulation of coherent endogenous network activity such as oscillations.

This is a very interesting and active area of research (example project on gamma) for several reasons.  Changes in network function and oscillations may be closely linked to several normal brain functions (e.g. slow-wave oscillations in sleep and memory consolidation).   Moreover, was have observed phenomena under stimulation of coherent (oscillating networks) that are not predicted based solely on single neuron/synapse function, but rather seem to reflect the active and dynamic response of the coupled neuronal network.

Small Fields Big Changes 3: Networks: We have proposed several mechanisms by which new networks may functionally “amplify” the effects of field that appear too weak to modulate single neuron function, especially in the presence on normal brain noise.

Comming soon-

Bridging Tiers: From Networks back to Synaptic Plasticity

Bridging Tiers: From Network back to Single Cell Responses

Learn more about Medical Device Development [link] at CCNY BME.

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.

For example, our group has identified “spike-timing” as a mechanism for field effect modulation of neuronal function and developed/validated basic quantitative models of field modulation of spike-timing.  Despite extensive theoretical studies of neuronal network oscillations and coherent activity, scarce studies analyze this potentially unique and pivotal role of field effects on spike timing during normal CNS function.

In the past, many neuroscientists have dismissed field effects as having a function role in the CNS because they were too “weak” to trigger action potentials.  So while classical synaptic transmission is taught extensively in basic neuroscience and medical textbooks, field effects are often wholly omitted from the discussion, or like gap junction coupling [link to non-synaptic] are briefly presented as secondary and ambiguous phenomena.  Through our research we have become increasingly convinced that field effects in fact play a unique and defined role in CNS function – specifically we have considered how the fact that endogenous fields both reflect aggregate population activity and simultaneously coherently effect a neuronal aggregate may result in field effects playing a pivotal role in coherent activity and timing-dependant information processing.

As indicated above, field effects may play a critical role in modulating network spike timing as a result of several unique features of field effect interactions.  Field effects are uniquely both rapid, like synaptic chemical transmission or gap junctions, and also global and cumulative, like chemical neuro-modulators.  The magnitude of induced extracellular fields are additive reflecting the cumulative activity of neurons, and they have the potential to simultaneously polarize a large number of neurons exposed to generated electric fields.  This stands in contrast to synaptic coupling, which involves only localized and salutary interactions between pairs of neurons. Moreover, field effect coupling is not affected by axonal propagation or synaptic transmission delays.  Because they are cumulative, with the potential for feed-back unto the same population generated them, the system dynamics of field effects are unique.  Finally, field potentials are generally localized, and so it is only regional spike timing that may be affected.  Thus, for coherent firing, or oscillations of local populations, field effects could play a distinctive and unique role.

Additional work is evidently required before field effects can be established as a pivotal mechanism for information transfer and integration in the brain (and so essential neuroscience learning!) and we expect to continue to contribute to in this area – this type of analysis require leveraging of traditional neural engineering skill sets.

Despite only “weakly” polarizing membranes, we have continually emphasized that 1) weak signal can profoundly modulate CNS function; and 2) the non-linear nature of the CNS means that small field effect may be “amplified”.  Working closely with colleagues, our efforts have therefore focused on developing a precise and quantitative framework to address this modulation and amplification.

Field effects (also called ‘ephaptic interaction’) refer to neuronal interactions mediated by electrical current flowing through the extracellular space. Simply put: When current is generated across a cell membrane, for example as during an action potential, a current will also be generated in the extracellular space around that cell; this extracellular current may then effect a neighboring cell by passing through its membrane. Dr. Faber previously demonstrated functional field effects between small groups of CNS neurons including goldfish Mauthner/inter-neurons and rat cerebellar cortex (Faber and Korn 1973; Faber and Korn 1983). Despite advances in our understanding of the basic mechanisms of field effects, their functional role in modulating spike timing in large central neuronal networks remains largely unknown and strongly debated (Faber and Korn 1989; Bullock 1997; Dudek 1998).

A significant amount of our work on applied weak electrical stimulation [link Writing-Brain] is in fact directly relevant to this topic, in particular our consideration of how apparently “weak” electric fields, whether endogenous of applied, are functionally “amplified” by the nervous system as the single cell and network levels. Therefore concepts we have developed in characterizing “applied” fields are also referenced within the following endogenous section.

It is well established, in humans and animal models, that application of exogenous fields (by passing current between two stimulating electrodes) can profoundly affect nervous system function. These findings have lead to speculation that endogenous fields (fields generated by the nervous system) would also modulate CNS function. Though the effects of uniform fields have been characterized extensively in brain slice (link to uniform), the effects of physiologically-relevant non-uniform extracellular fields on neuronal membranes have so far not been systematically quantified. Dr. Bikson and Dr. Parra have received funding from NIH precisely to address this fundamental question for endogenous fields. Knowledge of field-effect coupling-strength and time-constant (i.e. how much neuronal polarization is induced for a given extracellular potential profile (link to coupling) is a prerequisite to understanding how field-effect induced polarization will affect the behavior of a neuronal network. We predict that non-uniform fields will be more effective than uniform field in polarizing cell membranes (and specifically cell somatic compartments) and that quantifying this issue is a necessary first step toward a rational understanding of the role of endogenous fields.

Non-synaptic mechanisms exert a powerful influence on seizure threshold. Dr. Jefferys among others established that non-synaptic mechanisms are actually sufficient in themselves to induce seizures and illustrated by epileptiform activity induced in hippocampal slices by reducing extracellular Ca2+ concentration. We showed that non-synaptic epileptiform activity can also be readily induced in-vitro in normal (2 mM) Ca2+ levels. Though of-course in the brain synaptic and non-synaptic mechanisms of both present, given that non-synaptic mechanisms are sufficiently powerful to start, propagate, and terminate electrographic seizures in themselves, it would seem that any comprehensive approach to understanding and treating epilepsy should not ignore non-synaptic mechanisms.