Brain Stimulation (BSTIM) Core

The Brain Stimulation (BSTIM) Core, led by an internationally recognized expert in the field, facilitates training and consultation in state-of-the-art brain stimulation methods – used either to measure brain activity/connectivity or as a potential therapy to modify the brain – for the National Center of Neuromodulation for Rehabilitation. Thus, it enables investigators to use advanced BSTIM techniques to obtain neurophysiological measures to study brain plasticity and behavior to guide and individualize rehabilitation, as well as to use current state-of-the-art methods or develop novel tools or methods to perform neuromodulation for rehabilitation applications.

Please email us to explore opportunities to consult or collaborate with NC NM4R faculty in the BSTIM Core.

Training and consultation available for neurophysiological assessments include:

Basic TMS-measured neurophysiology (Motor Threshold, Cortical Silent Period, Paired Pulse, and Recruitment Curves).
Image-guided stimulation
More specialized approaches such as bi-hemispheric paired pulse for transcallosal measurements and paired-associative stimulation for measures of hemispheric plasticity.

Training and consultation available for neuromodulation therapies include repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS) with plans to support additional brain stimulation methods, such as ECT, VNS, DBS, epidural cortical stimulation, transcranial pulsed ultrasound, etc., as research progresses to make them appropriate for applications to rehabilitation.

Leadership, Staff & Expertise

Mark S. George, M.D., Director

Dr. George began using TMS during his first research fellowship (1989) at University College London. He then moved to Washington, DC, working with Dr. Robert Post in the intramural Biological Psychiatry Branch of the National Institute of Mental Health (NIMH). During 4 years at NIMH, Dr. George was among the first to use functional imaging (particularly oxygen PET), discovering that specific brain regions change activity during normal emotions. He then started using imaging to understand brain changes that occur in depression and mania. This imaging work directly led to pioneering use of TMS as a probe of neuronal circuits regulating mood, and to clinical trials using rTMS as an antidepressant.

In 1993 while at NIMH, he discovered that daily prefrontal rTMS over several weeks could treat depression. (TMS was FDA-approved in October 2008 for acute treatment of depression; another manufacturer was approved for depression treatment in January 2013.) In June 1998, he pioneered another new treatment for resistant depression, vagus nerve stimulation (VNS), which was FDA-approved in 2006. He continues to use imaging (particularly functional MRI) and non-invasive stimulation (TMS or VNS), separately or more recently in combination, to understand the brain regions involved in regulating emotion in health and disease. Dr. George is well published (more than 350 publications, H-index 59) and widely recognized as a world expert in the field of brain stimulation. His dual training in neurology and psychiatry foster his interest in using brain stimulation methods pioneered in psychiatry and facilitating their adaption and adoption for NM4R questions.

Core Training & Consultation Opportunities

A common problem in mentoring early career scientists in neuromodulation methods is the steep learning curve to use the methods, which are administrator-sensitive. Our Level 1 and Level 2 workshops provide intensive training. In addition, the BSTIM Core is available for additional hands-on training and consultations in numerous areas. Examples of neurophysiological measures available to support NM4R investigators include TMS measures of cortical excitability and inhibition, transcallosal measures of fiber integrity, and short-term neurophysiological measures of dynamic plasticity in the brain. Training and consultations are available in:

Basic TMS-measured neurophysiology (Motor Threshold, Cortical Silent Period, Paired Pulse, and Recruitment Curves).
Image-guided stimulation.
More specialized approaches such as bi-hemispheric paired pulse for transcallosal measurements and paired-associative stimulation for measures of hemispheric plasticity.
Noninvasive brain stimulation.

Basic TMS-Measured Neurophysiology (Motor Threshold, Cortical Silent Period, Paired Pulse, Recruitment Curves)

TMS involves inducing an electrical current within the brain using pulsating magnetic fields that are generated outside the brain near the scalp. The essential feature is using electricity to generate a rapidly changing electromagnetic field, which in turn produces electrical impulses in the brain. A typical TMS device produces a fairly powerful magnetic field (about 1.5 to 3 Tesla), but only very briefly (a fraction of a millisecond for each pulse). TMS does not simply apply a static or constant magnetic field to the brain and it differs from other brain stimulation techniques that are either invasive (e.g., deep brain stimulation) or require a seizure for therapeutic effect (e.g., electroconvulsive therapy). Conventional TMS coils generate a magnetic field impulse that can reach only the portion of the cerebral cortex that lies on the brain surface. The main effect of the impulse penetrates just 2 to 3 cm below the device.

Motor Threshold (MT)

MT is the minimum amount of energy needed to produce contraction of the thumb (the abductor pollicis brevis muscle). Because this is easy to generate and varies widely across individuals, MT is used as a measure of general cortical excitability and most TMS studies (both research and clinical) report the TMS intensity or dose as a function of individual MT (and not as an absolute physical value). Traditionally, MT was defined through the Mills-Nithi approach, which required laborious measurements above and below the threshold until the border was found. This could sometimes take more than 1 hour

In collaboration with interested mathematicians, Dr. George pioneered a more pragmatic, less time-consuming approach where each successive stimulation intensity follows a logical mathematical sequence to quickly determine the actual MT. This parametric estimation through sequential testing (PEST) technique, which is much more efficient, is now standard in the BSTIM labs. Moreover, by combining the PEST algorithm with EMG measures of the motor evoked potential (MEP), and computer software (SPIKE) that automatically determines if the MEP meets criteria for MT, the BSTIM group has created a wholly automated method for reliably and quickly determining MT. This process is much quicker than traditional methods, with better repeatability and reliability. It also eliminates investigator bias in interpretation.

This system is an example of how the BSTIM Core can help pioneer and test new BSTIM quantitative methods and make them available to SCRCRS researchers, and then the rest of the research community. This automated system was originally created in the main brain simulation lab on the 5^th Fl. of the Psychiatry Institute and is now also at the VA brain stimulation lab. A key function of the Core will be to support the various instantiations of this system across the BSTIM labs, including testing to compare data across the different labs, as many of the QBAR or NI studies will require assessment or treatment of stroke patients with BSTIM methods in the BSTIM satellite laboratories.

Using the MEP, one can determine the motor threshold, cortical silent period, or cortical excitability using paired pulse TMS. These three approaches can be used to understand and measure changes in cortical function and excitability as a function of natural recovery from stroke and to assess for potential therapeutic changes (for review of the basic measures, see Di Lazzaro et al.).

Cortical Silent Period (CSP)

CSP is the amount of time it takes a muscle to return to its resting state after it has been made to discharge with TMS. The cortical silent period (CSP) refers to an interruption of voluntary muscle activity induced via TMS, which can last up to 300 milliseconds (ms) in hand muscles. The early part of CSP is thought to involve spinal inhibition while the later part may involve cortical inhibition via GABA_B receptors. In BSTIM we use a standard squeeze pressure gauge in the hand and record from target muscles.

Paired Pulse TMS

Paired Pulse TMS is where researchers apply two pulses through the same coil in quick succession. By varying the time between pulses or the relative strength of the first pulse compared to the second, one can minimize or enhance the second MEP. Paired-pulse TMS is a simple example of the extended, albeit very brief, effects of a single TMS pulse. Here, two TMS pulses discharge nearly simultaneous, separated by only a few milliseconds. When the separation of the two pulses is short (~1 to 6 ms), the resulting cortical inhibition leads to a reduced MEP. However, when the separation of the two pulses is relatively longer (~10 to 15 ms), the resulting cortical facilitation leads to an increased MEP. With paired-pulse, the first pulse is typically sub-threshold, while the second pulse is typically supra-threshold.

Recruitment Curve

Recruitment Curve is where the motor cortex is systematically stimulated above and below the motor threshold and a dynamic response of the brain to stimulation can be obtained. Again, in BSTIM this has been fully automated. Measuring the MEP amplitudes in a target muscle over a range of TMS intensities creates recruitment curves. As the TMS output is increased, MEPs of increasing amplitude are obtained until a plateau level is reached. Changes in the slope of the RC reflect changes in corticospinal excitability and have been used to detect changes in motor cortex output induced, for example, by ischemia or amputation. To determine a recruitment curve, surface electrodes are placed along the abductor pollicis brevis muscle belly. The peak-to-peak amplitudes of the MEPs are recorded using equipment and software from Cambridge Electronic Design, the signal is converted from analog to digital using the Micro 1401 MK II, and conditioned using the CED1902 signal conditioner. For typical cortical stimulation, a TMS device with a figure-of-eight coil is used (Magstim 200, Whitland, South West Wales, The Magstim Company Limited). The PI or technician determines the optimal location for stimulus induction (the location that gave the maximum MEP amplitude) for the right abductor pollicis brevis muscle and a holder secures the coil in place. The figure-of-eight coil is oriented such that the handle is pointed occipitally (monophasic, posteriorly directed current). This procedure is performed at rest, which is assured by continuous monitoring of the EMG by software control such that no TMS pulse is administered if the EMG amplitude is above 10 µV.

With the automated closed loop system involving SPIKE software and a trained PI or technician, we can acquire the full set of measures described above (Motor Threshold, Cortical Silent Period, Paired Pulse, and Recruitment Curves) in about 20 minutes. BSTIM Core can train investigators to acquire these measures quickly, reliably, with low variance over time, and across different laboratories, in a virtually turnkey fashion. This approach to using TMS measures of cortical function is highly innovative. We also can obtain these basic measures on either upper or lower extremity (using a large butterfly coil).

Image Guided Stimulation (Brainsight)

Knowing where to stimulate is a crucial issue for all BSTIM methods. Our group has a long tradition of using imaging to inform the stimulation protocols and then to evaluate the effects. While we have the ability to perform TMS (and likely tDCS) within the MRI scanner, it is not feasible to perform all studies with real-time image guidance within the scanner. We have thus used Brainsight hardware and software for the past 15 years. Our group was one of the first TMS labs to beta-test Brainsight. Currently, MUSC has 3 Brainsight systems with a 4^th soon to be added for studies performed directly outside the MRI scanner. A key function of BSTIM will be to keep all systems operational, test for variance across the systems, and determine if data can be merged from one system to the other. In addition to using Brainsight for placement on structural MRI scans, BSTIM will work with the NI Core to provide seamless ability to merge functional maps onto the structural scans, and make this composite information available in the TMS labs. This is theoretically possible with BOLD maps, as well as DTI or even spectroscopy regions of interest.

Transcallosal Stimulation (Bi-hemispheric Paired Pulse)

While traditional paired pulse stimulation enables us to assess cortical excitability within a single hemisphere, bi-hemispheric paired pulse enables us to assess the integrity of information flow between the hemispheres, a critical question in stroke rehabilitation research for example. This is achieved using two TMS coils, one over each hemisphere. By placing the conditioning pulse (Pulse 1, less than 100 percent motor) threshold) on one hemisphere, the test pulse (Pulse 2, less than 100 percent motor threshold) on the other hemisphere, and varying the interpulse interval (typically 5 to 30 ms), it is possible to determine transcallosal conduction time, as well as the amplitude of transcallosal inhibition and transcallosal facilitation. The BSTIM Core is one of very few labs that can do Bihemispheric Paired Pulse stimulation, a tool likely to be used by many investigators in the future to examine transcallosal integrity, connectivity and excitability – issues critical to understanding the neural correlates of successful recovery.

TMS Measures of Hemispheric Plasticity (PAS)

Short-term or almost immediate plasticity in the motor cortex can be assessed through a protocol labeled paired-associative stimulation (PAS). In this protocol, TMS stimulation of the motor cortex is done while simultaneously sensory stimulation is applied to the ulnar nerve on the body side opposite the TMS coil. This simultaneous stimulation can rapidly cause either increases or decreases in MEP amplitudes, depending on the relative timing and other factors. It is thought that PAS protocols engage long-term potentiation (LTP). educes neuronal death in remaining motor cortex in rats. These studies laid the foundation for Phase 1 to 3 clinical studies using implantable epidural electrodes. Currently, we have a custom computer program that can simultaneously run up to 8 different wireless stimulators that can be individually programmed for frequency, amplitude, pulse width and timing. Stimulation polarity is controlled via electrode design. This short protocol (~1 hr) provides a snapshot of how ‘plastic’ the motor cortex is at any given time. Researchers will want to use PAS to look at between-group measures of plasticity or how motor plasticity changes over time or with an intervention.

Rehabilitation

The BSTIM Core also provides training and consultations to enable NM4R investigators to use neuromodulation methods, combined with some form of rehabilitation, to potentially induce neuroplastic changes in the brain and theoretically improve neurological recovery. The two major forms to be used are repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), though the science may migrate to any of the other brain stimulation methods (ECT, VNS, DBS, epidural cortical stimulation, transcranial pulsed ultrasound, etc.). The BSTIM Core is ‘aggressively agnostic’ with respect to which brain stimulation methods will be most helpful in NM4R. It will thus be able to move into new technologies as they develop and mature.

Repetitive Transcranial Magnetic Stimulation (rTMS)

Our approaches emphasize the principles of neural plasticity and motor learning and may combine multiple therapeutic interventions to optimize recovery. We will consult with individual investigators to determine the ideal intervention to facilitate exploration of novel collaborative therapies. Each TMS machine has different advantages and disadvantages. The BSTIM Core will work with NM4R investigator to determine the best system for each study. Key factors influencing the final choice will be the total dose of the study (important with respect to heating and cooling of the coils), depth of location and need for special coils (e.g., a large double-coned coil for lower extremity), and ability to use a truly double-blind approach.

Blinding is a crucially important consideration for NM4R studies. The BSTIM Core are expert in addressing true double blinding of clinical studies and can provide consultations and training for investigators. For most truly double-blind studies, MUSC has partnered with industry (Neuronetics) to obtain smart cards that are assigned to patients. Each card allows the TMS system to be operated only in the appropriate (sham or active) mode for the patient. In earlier studies, Dr. George worked with Harold Sackeim to design the first truly active sham system for TMS, where no one who came in contact with the patient knew the randomization status. This involved a complex system of electrical stimulation to the scalp to mimic superficial muscle stimulation and discomfort, a card system to force the appropriate coil for the patient in a manner that kept everyone blind, and active noise-cancelling headphones to mask the noise. This initial system used a modified ECT machine and a complex array. Dr. Borckardt reduced this system to its critical elements, which uses a TENS system and is much less cumbersome and less expensive. The BSTIM Core will continue to innovate and specialize in performing truly double-blind studies.

The BSTIM Core is available for consultation or training with NM4R investigators to achieve specific goals such as determine the best design or beta-test the dose. it can help to develop a user manual for each study, describing the treatment protocol in detail. They will videotape a subject (or staff model) with the treatment; this will be archived and available for consultation or submission with final manuscripts. The BSTIM Core will then work with the PI to apply for IRB (and if needed FDA) approval, and with industry to acquire smart cards if needed.

Transcranial Direct Current Stimulation (tDCS)

tDCS differs from TMS in that it does not require elaborate equipment and has less risk with respect to potentially causing a seizure. It is not simple, however, especially when administering it in a randomized sham controlled trial (RCT). The BSTIM core can provide consultation and training to interested NM4R investigators. The BSTIM Core has many years of experience performing tDCS in laboratory challenge studies and in RCT. Dr. Borckardt has performed more than 15 tDCS studies over the past few years, most in the area of pain management. He has administered tDCS to patients in post-operative suites throughout the MUSC campus. He uniquely designed a computerized system that allows for true double-blind studies. The treater applies the electrodes to the patient, then enters the patient’s research number into the computer. A matching table within the computer sets the machine to administer either an active tDCS session or to stimulate for the first minute and the last minute, ramping on and off and delivering a ‘tingle’ to the scalp. This is done without the treater or patient knowing the randomization status.

The BSTIM Core is available for consultation or training with NM4R investigators to achieve specific goals such as determine the best design or beta-test the dose. It can help to develop a user manual for each study, describing the treatment protocol in detail. They will videotape a subject (or staff model) with the treatment; this will be archived and available for consultation or submission with final manuscripts. The BSTIM Core will then work with the PI to apply for IRB (and if needed FDA) approval, and with industry to acquire smart cards if needed.

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