Multimodal Applications of Transcranial Magnetic Stimulation for Circuit Based Psychiatry.
A growing body of research is advancing our understanding of the anatomy and physiology of brain networks and the mechanisms by which they process cognition, behavior, and emotion.1 This "circuit revolution" is changing our conceptualization of psychiatric pathophysiology and calls for technologies to reliably and safely assess the structure and function of brain circuits in humans. Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation technique that applies powerful and rapidly changing magneticfieldsoverthesurfaceoftheskullandgeneratestargetedelectrical currents in the brain, leading to neuronal action potentials. Transcranial magnetic stimulation has a well established safety profile and is able to modulate brain activitywithoutsurgery,anesthesia, or the induction of seizures.2 Transcranial magnetic stimulation is a widely used technique in cognitive and systems neuroscience, and a number of clinical applications, both diagnostic and therapeutic, exist. Diagnostically, it is used by clinical neurophysiologists in conjunction with electromyography to assess pathologies that compromise the motor system.3,4 In addition, the use of neuronavigated TMS for presurgical cortical mapping was recently cleared by the US Food and Drug Administration. Therapeutically, high frequency TMS to the left dorsolateral prefrontal cortex was cleared by the US Food and Drug Administration in 2008 for the treatment of major depressive disorder, and a total of 4 different TMS systems have been cleared since. After 1985, protocols were quickly developed to assess the physiology of the human motor system, including cortical excitability, inhibitory and excitatory mechanisms, conduction time, connectivity, and plasticity. These are the exact same properties that we now need to understand across affective, behavioral, and cognitive circuits, to establish solid circuit based models of neuropsychiatric disease with the potential to affect clinical practice. Therefore, TMS can be a critical tool in psychiatry, with scientific and clinical relevance beyond its current therapeutic applications. To achieve its full potential, though, multimodal combined technologies are needed to measure the neurobiological effects of TMS beyond the motor cortex.Solutionsforthereliablereal timeintegrationofTMSwithelectroencephalography (EEG) positron emission tomography, magnetic resonance imaging, and other neuroimaging methods have been developed and are increasingly available.5 Transcranial magnetic stimulation protocols, while diverse, fall under 3 main categories: singlepulse, paired pulse, and repetitive TMS. Single pulse TMS is used in motor conduction studies to assess the integrity of the corticospinal motor pathway, a measure of connectivity.3,4 One pulse of appropriate intensity is applied over the motor cortex, and the response in the muscle (ie, the motor evoked potential [MEP] is measured by use of electromyography. By assessing the time between the TMS pulse and the beginning of the MEP, one can identify pathological changes in neurons and synapses. Single pulses are also used for motor threshold (MT) determination, a measure of cortical excitability that reflects the state of neuronal membranes, synapses, and their glutamate receptors.6 The MT is defined as the minimum TMS intensity needed to induce a muscle contraction or MEP larger than 50 mV in at least 50% of the trials.3,4 The resting MT is measured with the muscle at rest, and the active MT is measured during isometric contraction (the active MT is typically lower) These measures are stable and reproducible, but can change with factors that modulate cortical excitability, including medications or pathological states. A related protocol is the cortical silent period, a period of electromyographic suppression following a TMS pulse to the motor cortex during active isometric contraction of the contralateral muscle (not during rest) The cortical silent period measures cortical inhibition mediated by g aminobutyric acid receptor class B (GABAB) 6 Thesesimpleprotocols illustrate2fundamentalpropertiesofTMS. First, the physiological effects are circuit wide and not limited to the target brain region; if a single TMS pulse over the motor cortex induces a contralateral muscle contraction, it must change the properties of the primary and secondary motor neurons all the way to the motor unit. The cortical target therefore provides access to an entire functional circuit. Second, the effects of stimulation are state dependent; the fact that the active MT is lower than the resting MT and the fact that the silent period is only observed when the targeted muscle is active demonstratethattheeffectsofTMSdependonthephysiologicalstateofthe brain regions and networks that it is trying to change. These 2 principles applytomotorandnonmotorneurostimulation;complexnetworksthat support affect, behavior, and cognition dynamically fluctuate across different states (in health and in disease) and these physiological oscillations condition the biological and clinical effects of TMS. Paired pulse protocols have been established to study intracortical inhibition and facilitation. They require the application of 2 TMS pulses of different intensities (typically between 80% and 120% of the MT) and interstimulus intervals (usually in the order of a few milliseconds) Combined studies using TMS and pharmacology have identified the neurotransmitters involved in these physiological dynamics.6 The 2 most studied protocols are short interval cortical inhibition and intracortical facilitation.3,4 Short interval cortical inhibition consists in the application of a first (conditioning) subthreshold stimulus (eg, 80% of the MT, but unable to elicit MEPs) followed by a second (test) suprathreshold stimulus (eg, 120%,withashortinterstimulusintervalof1to5milliseconds.TheMEP from the test stimulus is compared with an identical TMS test stimulus that was not preceded by a conditioning pulse. This intervention results in an inhibitory response, characterized by a reduction of the MEP amplitude thought to be mediated by GABAA receptors. 6 Related article page 337 Clinical Review Education
JAMA psychiatry