Transcranial magnetic stimulation of the brain: guidelines for pain treatment research

Abstract

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

Figure 1

(A) Schematic of the electrical circuits that underlie transcranial magnetic stimulation (TMS): A capacitor or group of capacitors is charged by a high-voltage power supply (V). They are then discharged by a thyristor trigger switch to send a rapidly changing current through the coil, which produces a transient magnetic field locally. This penetrates through the scalp, skull, meninges, and cerebrospinal fluid to induce a current pulse that transiently changes the polarization across the cell membrane of underlying cells. Specific conditions can depolarize some neurons sufficiently to trigger an action potential that propagates along that neuron's pre-existing anatomical connections. (B) Depiction of TMS administration using a figure-of-8 coil to stimulate the primary (M1) motor cortex.

Figure 2

Pictorial representations of the anatomical targets of neurons within the primary motor cortex located in the precentral gyrus in the brain's frontal lobe. The amount of the cortex devoted to each body region is proportional to how richly innervated that region is, not to its actual size, which creates a distorted representation of the body called a “homunculus.” Neurosurgeon Wilder Graves Penfield (1891-1976), a trainee of Osler, Cushing, and Sherrington, mapped brain functions while developing neurosurgical treatments for epilepsy as the founding director of the Montreal Neurological Institute at McGill University. While operating, he used electrical stimulation to map “eloquent” portions of each patient's exposed brain to minimize surgical damage. (A) A map of the motor cortex published in 1937 by Penfield and Boldrey based on electrical exploration of the cortex of 163 awake, cooperative patients with craniotomies. The lines enclose the areas within which electrical stimulation of the exposed cortex triggered a movement in that part of the body. (B) This anatomical homunculus based on the work of Penfield et al. was drawn for illustrative purposes by medical artist Hortense Cantile. Although oversimplified and criticized, the motor and sensory homunculi continue to be widely reproduced to educate about brain function.

Figure 3

Magnetic resonance imaging (MRI) depicting deep and cortical sites most efficacious to stimulate for treating chronic pain. (A) The periaqueductal gray (PAG), the primary control center for descending pain modulation, and the most effective target for deep brain stimulation for pain (arrows). (B) Mean resting-state functional MRI connectivity mapping of 1000 normal subjects. Spontaneous modulations in the fMRI signal are extracted from the PAG. Fluctuations in the primary sensory and motor cortices (circles) are most correlated with those of the PAG. Modified with permission from.