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Transcranial Magnetic Stimulation: A Novel Treatment with an Elusive Mechanism





Written by: Shivam Kogar '27

Edited by: Jacqueline Cho '24



To this day, the words ‘electroconvulsive therapy’ evoke horrific images in the collective American memory, hearkening back to the fraught history of brain stimulation technologies. Indeed, the method of using electricity to induce brain seizures has been used in the past in controversial and outright jarring ways, without the informed consent of patients, and as part of pseudoscientific attempts to treat homosexuality [2]. Brain stimulation technologies, however, have been used as early as the sixteenth century, and have progressed tremendously since then. Attitudes surrounding these methods have shifted over time, particularly as research institutions have continued to explore their potential as a novel therapy for treatment-resistant neuropsychiatric disorders. In particular, transcranial magnetic stimulation (TMS), a brain stimulation technology, has sparked significant research interest among scientists and physicians, and has gradually shifted from the fringes of neuropsychiatry and inched toward the mainstream [5].



TMS, a non-invasive brain stimulation device, involves connecting a patient's scalp to a magnetic coil, which is connected to an electric stimulator. The stimulator generates pulses that create a varying current through the coil. Ampère’s law of electromagnetism tells us that this creates a corresponding time-varying magnetic field perpendicular to the coil. As per Faraday’s law of electromagnetic induction, a varying magnetic field induces an electric current [5]. The coil is positioned to target a specific site in the brain, wherein the electric current is induced. For trauma- and mood-related disorders, such as treatment-resistant depression and posttraumatic stress disorder, scientists have identified the dorsolateral prefrontal cortex (dlPFC) as a strong candidate site for stimulation, as neuroimaging studies indicate that abnormalities in the dlPFC are characteristic of these disorders [11].


While researchers across multiple studies have been able to establish the effectiveness of TMS, the exact mechanism remains, to some degree, elusive. In other words, we know that it works but lack a complete picture of why it works. Scientists have proposed various explanations - including the changes in the neurotransmitter systems and brain plasticity induced by TMS. Understanding the exact mechanism is important from both medical and engineering perspectives, as this knowledge can shed light on how varying TMS parameters can optimize the effectiveness of treatment [8].


One possible explanation for the mechanism of TMS relies on the involvement of the dlPFC in monoamine neurotransmission. The monoamine hypothesis argues that a deficit in synaptic levels of monoamines, such as dopamine, serotonin (5-HT), and norepinephrine, is linked to the onset, prognosis, and treatment of depression. This theory, developed in the 1960s, has long been controversial and continues to be contested today. Studies using voltage clamps have verified that the induced electric field of a TMS coil increases the transmembrane voltage of neurons to the threshold voltage, enabling voltage-gated sodium channels to produce action potentials at higher frequencies, thereby inducing neurotransmission [4]. These explanations are controversial in part because scientists have struggled to establish a causal link between synaptic monoamine levels and the onset or course of depression, and many theorists argue that the effectiveness of selective-serotonin reuptake inhibitors (SSRIs) is not indicative of such a causal link. Researchers have gone as far as to argue that there is “no direct evidence about the association between 5-HT and depression”, and that available “indirect evidence is highly inconsistent” [4]. Research on U.S. combat veterans using SPECT brain imaging has shown, however, that TMS induced increased levels of serotonin production in the brain, aligning with positive treatment outcomes. It should be noted, however, that these findings are correlational and fail to establish a causal relationship between TMS-induced serotonin release and positive outcomes [6].


Researchers have also explored the relationship between TMS and neuroplasticity in the brain. The human brain can be theorized as a kind of circuit, with synapses stretching between neurons on a microscopic level, which form broader networks of connectivity between different parts of the brain. Synapses are neuroplastic, which means that they become strengthened when they are repeatedly activated. This strengthening is known as long-term potentiation (LTP), and its inverse, long-term depression (LTD), selectively weakens some synapses to optimize LTP processes [9]. Changes in plasticity are often indicated by the number of neurotransmitter receptors on the synapse. Hence, LTP and LTD are both involved in neurotransmission. Scientists believe that neural plasticity is a candidate mechanism for TMS because of research on neural oscillations. When there appears to be a correspondence (known as cross-frequency coupling) between neural oscillations at different frequencies, this can suggest that distinct neural circuits are interacting with one another, which may be caused by increased functional connectivity due to neuroplasticity. Studies that concurrently administer TMS and also use electroencephalography (EEG) scanning have indicated that TMS induces a type of cross-frequency coupling called alpha-gamma coupling, which is linked to changes in synaptic plasticity [7]. The region stimulated, the dlPFC, is involved in numerous functional pathways involving mood and emotional regulation [1]. It is plausible that the changes in neuroplasticity induced by TMS modulate the connectivity in these functional pathways, leading to advantageous therapeutic outcomes.


These are some of the many potential mechanisms identified by researchers. Other candidates involve the effects of TMS on genetic expression, glial cells, and dendritic branching [8]. The lack of understanding of the exact mechanism of TMS has driven caution and uncertainty surrounding the implementation of TMS treatments. It is widely seen as a last-resort treatment, only to be used in cases where other treatments such as cognitive therapy, SSRIs, and tricyclic antidepressants have been unsuccessful. However, as more studies have continued to demonstrate the effectiveness of TMS, a growing number of regulatory bodies have approved TMS for use in a wider array of cases and beyond simply an experimental setting. As early as 2008, the United States Food & Drug Administration (FDA) cleared the use of rTMS for depression [3]. Similarly, in 2015, the U.K.’s National Institute for Care and Health Excellence (NICE) approved TMS for depression, though prescription of TMS through the National Health Service (NHS) is limited to severe cases [10]. 


TMS and its brethren (deep brain stimulation, transcranial direct current stimulation, etc.) have driven much excitement in the research world due to their potential as novel therapies. The experience of mental illness is incredibly individualized - it is informed by one’s genetic predispositions and influences their environment, culture, relationships, and life events. While theorists may disagree on the exact pathophysiology of mental illnesses, perhaps consensus can be found in the need to research an ever-expanding array of therapeutic approaches. There is no one-size-fits-all, and every new therapy brings the potential to alleviate suffering among patients, families, and communities.















References


1. Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL. Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci. 2007 Dec;2(4):303–12.

2. Sadowsky J. Electroconvulsive Therapy: A History of Controversy, but Also of Help. Scientific American [Internet]. 2017 Jan 13; Available from: https://www.scientificamerican.com/article/electroconvulsive-therapy-a-history-of- controversy-but-also-of-help/

3. U.S. Food & Drug Administration. FDA permits marketing of transcranial magnetic stimulation for treatment of obsessive compulsive disorder. FDA Newsroom [Internet]. 2018 Aug 17; Available from: https://www.fda.gov/news-events/press-announcements/fda-permits- marketing-transcranial-magnetic-stimulation-treatment-obsessive-compulsive-disorder

4. Liu B, Liu J, Wang M, Zhang Y, Li L. From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. Front Cell Neurosci. 2017;11:305.

5. Basil B, Mahmud J, Mathews M, Rodriguez C, Adetunji B. Is there evidence for effectiveness of transcranial magnetic stimulation in the treatment of psychiatric disorders? Psychiatry (Edgmont). 2005 Nov;2(11):64–9.

6. Zubieta JK, Chinitz JA, Lombardi U, Fig LM, Cameron OG, Liberzon I. Medial frontal cortex involvement in PTSD symptoms: a SPECT study. J Psychiatr Res. 1999;33(3):259–64.

7. Glim S, Okazaki YO, Nakagawa Y, Mizuno Y, Hanakawa T, Kitajo K. Phase-Amplitude Coupling of Neural Oscillations Can Be Effectively Probed with Concurrent TMS-EEG. Neural Plast. 2019;2019:6263907.

8. Chervyakov AV, Chernyavsky AY, Sinitsyn DO, Piradov MA. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation. Front Hum Neurosci. 2015;9:303.

9. Castillo PE. Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold Spring Harb Perspect Biol. 2012 Feb 1;4(2):a005728.

10. Statement on Repetitive Transcranial Magnetic Stimulation for Depression. United Kingdom: Royal College of Psychiatrists; 2017 Feb.

11. Yin H. Why is the dorsolatereral prefrontal cortex (DLPFC) the favorite region to stimulate? [Internet]. New Frontiers Psychiatry. 2023. Available from: https://www.newfrontierspsychiatry.com/why-is-the-dorsolatereral-prefrontal-cortex-dlpfc- the-favorite-region-to-stimulate/

     

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