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Journal of Clinical EEG & Neuroscience, July, 2008Known, Forgotten and Rediscovered – Electricity and the BrainEditorial: Mark S. GeorgeElectricity is the currency of the brain.1 Our present conceptualization of the brain holds that all behavior, memories, thoughts, movements, or actions derive from the activity of electrically discharging neurons which then pass their electrical information to neighboring neurons.2 It is important to restate and reemphasize this most important idea, which I call here the electricity-as-information-source concept, as many neuroscientists and especially psychiatrists have forgotten this basic electrical dogma. Here are three reasons why this central electrical fact has been underappreciated. 1) One major reason for the “neglect” of the electricity-as-information-source dogma has been the spectacular advance in psychopharmacology over the past 30 years that has transformed our treatment of brain diseases. Because we could administer medications that were clinically effective, at least partially, all eyes shifted away from the entire neuron, working in electrical concert with other neurons, to the synapse, where electrical information from one cell to another is transformed temporarily into chemical messengers that modify the (electrical) information flow. Drugs that modified synapse behavior could treat many major neuropsychiatric diseases like the anxiety disorders, major depression and hallucinations in schizophrenia. But focusing on the synapse and ignoring the overall information flow is incomplete, akin to examining the different types of plugs and wall switches in your house, ignoring the overall wiring diagram. With advances in brain imaging and more neuroscience sophistication, one now has to abandon the “brain as soup” language of the 1990s, and understand that neurotransmitters act within synapses on neurons, which themselves comprise circuits. A neurotransmitter can have quite opposite effects in different brain regions, depending on the role the neurons are playing in the circuits, and the function of the circuit in organizing behavior (e.g., inhibiting, modifying, exciting). “Low serotonin” is no longer a sufficient explanation for anything, particularly a brain activity or disease. Our new level of understanding must use language at least as sophisticated as, for example, “low serotonin in this specific cortex, causes a hypoactivation of an impulse regulating circuit, and electrical information flowing through neurons projecting to orbitofrontal cortex, to…” Oral delivery of synapse-altering medications will soon be considered insufficient delivery systems to focally and discretely interact with the brain in the manners needed for therapy. 2) A second reason that the electricity-as-information-source dogma has been underappreciated has been the complexity of the tools and language used for understanding electrical information. EEG and QEEG are complex methods with an overwhelming language, vocabulary and descriptions that only a few dedicated researchers and clinicians (outside of the readers of this journal) can fully grasp. Newer software and acquisition techniques that allow for simpler display and understanding are gradually opening up the field to others. Some examples of these include MEG, QEEG maps like LORETA and PASCAL, and simple display patterns such as the monitors now used in anesthesia. 3) Perhaps the last, and most important reason that the electrical dogma was lost but is now being rediscovered is that we simply lacked methods for focally interacting with the brain’s electrical patterns. While we could administer oral drugs, we had no way of focally changing electrical activity, short of electroconvulsive therapy (ECT), which incorrectly was viewed as an overall reset of electrical activity rather than a focally precise tool. (We now know that ECT can be focally precise and is not an overall brain “reset.”3,4) Thus, in the absence of any method or technique that could safely and selectively influence focal electrical activity, there was no need to talk about focal electrical information, except perhaps in discussing epilepsy, where aberrant electrical activity could not be ignored. All of this is rapidly changing. We are entering a paradigm shift.5 The articles in this special issue of EEG and Clinical Neuroscience represent the leading advancing edge of a powerful wave, which is sweeping over neuroscience. What is the evidence behind such a radical statement (which risks making me look foolish 10 years from now if these changes do not materialize)? First, there is an explosion of new techniques that can focally electrically stimulate the brain.6-8 At this writing there are at least 12 different techniques. Several are already US FDA approved and on the market (e.g. Deep Brain Stimulation (DBS) for Parkinson’s Disease, Dystonia or Essential Tremor; Vagus Nerve Stimulation (VNS) for epilepsy or depression). Others are working their way through clinical trials. Two of the more promising techniques, because of their relative non-invasiveness, are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). All of these methods deliver electricity in a variety of ways, the effects of which radically differ as a function of the frequency of stimulation, the pulse width or waveform, and other parameters. Thus, in order to effectively use these new techniques, we must refocus on the central electricity-as-information-source dogma, and begin to administer treatments in ways informed by the brain’s underlying firing patterns. With new treatment methods that force the clinician or researcher to make choices concerning electricity (e.g. frequency, pulse width, current direction flow) we can no longer bury our heads in the synaptic sand and ignore the full neuron and the circuits in which they work. Second, we are rediscovering the plastic, reorganizational nature of the brain, and how different stimulation patterns can push the brain to reorganize in new ways. While we have known for almost 40 years that simple circuits can be modified through the processes of long-term potentiation (LTP) or long term depression (LTD),9,10 the delicious new clinical area building on this basic work involves translating this body of work from single cells back up into full circuits, One can then use these basic principles, developed in single cell systems and tested in larger circuits, to refine and perfect the new electrical brain stimulation methods in order to change behavior and treat diseases. For example, using these hypotheses, clinical researchers are investigating whether electrical stimulation treatments, either inhibitory or excitatory, can help sculpt the brain during stroke rehabilitation applied at either the damaged region or other regions attempting to compensate for the stroke. This background provides the context for the articles in this issue. Fitzgerald and colleagues report the very exciting breakthrough of using EEG measures as the dependent variable in TMS excitability research. Much of the advances with TMS have come from studies over the motor cortex, where one can measure the TMS-induced changes in the opposite hand or leg muscle. This large body of electrophysiology work, much of it led by Professor John Rothwell at Queens Square for over 20 years now, has served as the basis for the hypothesis-driven rational use of TMS.11-17 The problem, however, is that it is unclear whether the rules developed in motor cortex apply to other brain regions. Thus, scientists have searched for years to develop a method of using TMS to assess cortical excitability in other brain regions.18-20 The article by Fitzgerald represents a potentially important new method. The two articles by Spronk et al. and Funk and George use EEG as a dependent variable to assess the potential changes induced by a “dose” of prefrontal TMS like those being use currently to treat depression. The case series by Funk holds the promise, if confirmed in the larger sample of the NIMH sponsored OPT-TMS trial, of using EEG changes as a potential biomarker to monitor treatment or even guide dosing. The idea of using EEG to guide TMS dosing brings me to the last, and perhaps most important, area of the electricity-as-information-source dogma. Consider the following: If 1) electrical activity between neurons is the way the brain communicates information (it is), and If this reasoning holds, then the most promising new treatment modalities will be those that couple some measure of focal electrical information (like EEG) with the stimulation tool. The field of cardiology recognized this important concept long ago and now every defibrillator in the public hall, airport or gymnasium has the ability to sense the cardiac rhythm, and then apply electricity (cardiovert) with a precisely timed stimulation. Applying electricity to the heart in the absence of knowing the rhythm is inefficient and even dangerous. It is likely that the same rules apply for the brain. Several brain stimulation device companies have grasped this line of reasoning. To my knowledge, at least one company has developed a DBS device that senses local brain activity and then triggers intermittent stimulation as a function of the EEG pattern.21 The field anxiously awaits their ongoing multisite trial in epilepsy as the “proof of concept” of this new treatment direction. This area is still in its infancy but if the reasoning above is correct, intelligently delivered intermittent brain stimulation designed to cause plastic changes in behavioral circuits could rapidly evolve into one of our most powerful modes of brain treatment, much as intermittent demand-only cardiac pacemakers (defibrillators) are daily saving lives in heart disease patients. Thus, after several decades of being hypnotized by the clinical success of orally administered medications that modify activity in neuronal synapses, we are now slowly reawakening to the most central concept of how the brain functions. Electricity is the currency of the brain and developing better tools to measure this activity, and then to focally and intelligently electrically intervene, is perhaps the hottest new field in neuroscience for the next 20 years. After reading the articles in this issue, be on the lookout for the rest of the wave. Mark S. George, MD Acknowledgments The author would like to thank the following scientists for some of the ideas in this editorial, although listing their name here in no way implies that they agree with this editorial: Dr. Michael Trimble, for recommending the Buzsaki book, and his recent editorials and foreword that set the stage for some of this thinking; Dr. Wayne Goodman for helping to coin the phrase at a recent symposium, ‘electricity is the currency of the brain’; Dr. Philip Devlin at Aspect Medical and Dr. Martha Morrell at Neuropace for their conversations about EEG and stimulation; James Long for helping the author overcome his aversion to EEG; Dr. Harold Sackeim for his pioneering work and discussion about the potential of brain stimulation techniques, and Dr. Ziad Nahas for his years of collaborations and discussions which have moved the field forward. DISCLOSURE AND CONFLICT OF INTEREST Dr. George currently receives funding from 5 R01 MH069887-04, 5 P20 DA022658-02, 1 R21 MH078046-01. Dr. George owns no stock or equity in any device or pharmaceutical company. He is a paid consultant to several device manufacturers, including Neuropace (DBS) and Cyberonics (VNS). He is an unpaid consultant to several TMS manufacturers (Neuronetics, Brainsway), and served as head of the DSMB for Aspect Medical. For the past decade, his entire yearly compensation from all manufacturers and speaking engagements is less than 20% of his university salary. He is the editor-in-chief of a new journal published by Elsevier, entitled Brain Stimulation and has written several books in this area. MUSC holds several patents in his name involving brain stimulation and imaging, one using fMRI (not EEG) to determine the best dose of VNS for a patient. 1. Buzsaki G. Rhythms of the Brain. New York: Oxford University Press; 2006. |
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