Transcranial Magnetic Stimulation (TMS) for Major Depressive Disorder—Modus Operandi!

Abstract

Background

Transcranial magnetic stimulation (TMS) is effective in the management of treatment resistant major depressive disorder (MDD) and has recently become widely available. Our aim was to explore the literature for evidence of the mechanism of action.

Method

We examined our own accumulating TMS library, the reference lists of all available papers and used a search engine to collect information. We collated and examined this information under relevant heading.

Results

TMS produces a large number of physiological changes including site of stimulation neurochemical, brain wave and blood flow effects, and distant structure effects including neurotransmitter effects and volume increase. TMS also corrects generalized and local functional connectivity (FC) abnormalities which are a feature of MDD.

Conclusion

TMS produces a range of physiological changes. It is unclear which of these underpin its antidepressant. It is likely more than one work synergistically to this end—almost certainly the capacity to correct MDD induced FC abnormalities makes a strong antidepressant contribution.

Introduction

The monoamine hypothesis of depression proposes deficits in certain neurochemicals as the cause of depression. While medications which increase serotonin, dopamine and noradrenalin neurotransmitters are effective for some individuals, they are not universally effective and alternative/additional approaches are required. Transcranial magnetic stimulation (TMS) is an effective treatment of major depressive disorder (MDD) and some other mental disorders.¹ It has been available for treatment of MDD in some specialist facilities for twenty years and is now available as routine care in many counties around the world. TMS produces electromagnetic fluctuations in living tissue and is associated a range of biological effects. However, it is unclear which of these (if any) underpin the antidepressant effects. Our aim was to examine the literature and attempt to identify physiological events which contribute to the therapeutic effects of this new MDD treatment.

Method

Our group is acquainted with the field and maintains an accumulating library of papers on the physiological effects of TMS. We examined the reference lists of these publications for additional relevant material. In addition, we used a search engine and sought reports using the words ‘TMS depression’, ‘TMS physiology’, and ‘TMS mechanisms’. A large body of information is available on the topic. There is much repetition and different researchers/authors use slightly different terms for the same brain structures/processes and focus on slightly different areas of the same structure. We chose not to cite every source but to identify leading examples of prominent promising work in the field.

Results

We identified several regions/techniques which described distinct forms of change.

• Local neurochemical effects TMS stimuli cause voltage-gated sodium channels to open and allow neurological depolarization.² Immediate and long-term effects involve both excitatory neurons and inhibitory interneurons.³ Stimulation (10 Hz) of the dorsolateral prefrontal cortex (DLPFC)⁴ can cause a 10% increase in gamma aminobutyric acid (GABA)—the primary brain inhibitory neurotransmitter—in the stimulated tissue. A systematic review of neocortical chemicals in people with MDD treated with TMS⁵ found accounts of increases in GABA, and glutamate—the primary brain excitatory neurotransmitter—along with other chemical changes.

• Local blood flow effects Reduced blood flow to the frontal cortex (termed hypofrontality) is a feature of MDD. A study in which MDD was treated with a course of TMS (10 Hz) applied to the DLPFC⁶ found post-stimulation prefrontal blood flow increased 30-fold. The enabling mechanisms remain unclear.

• Distant structure—neurotransmitter release A study of TMS (10 Hz) stimulation of the left mid-dorsolateral prefrontal cortex of healthy individuals⁷ found dopamine release in the head of the ipsilateral caudate nucleus. It was believed the mechanism probably involved excitatory corticostriatal projection and local release of glutamate. This was an early demonstration of TMS stimulation of the prefrontal cortex (PFC) modifying activity at distant sites. A study of TMS (10 Hz) stimulation of the left DLPFC of depressed individuals⁸ found a significant (13.8%) increase in GABA in the medial PFC. This increase was greater in responders than non-responders.

• Distant structures—volume increase A study compared grey matter volumes (GMV) of patients with MDD and healthy controls⁹—the MDD group revealed lower volumes in six brain regions. TMS (10 Hz) treatment of the MDD group resulted in 3.5–11.2% increases in four of those regions (including the anterior cingulate and the insula). TMS (20 Hz) stimulation of the left DLPFC of MDD patients¹⁰ found a significant (3.4%) increase in the volume of the ipsilateral hippocampus. There was no correlation of the volume increase and depression scores. There was no change in the volume of the right hippocampus or either amygdala–the cellular mechanism remained uncertain. A study of two cohorts of MDD patients treated with TMS (10 Hz) applied to the left DLPFC¹¹ found increased thickness at the left rostral anterior cingulate cortex, which correlated with clinical response. Finally, TMS (10 Hz) applied to the left DLPFC of a group of MDD patients¹² found significant enlargement (P < 0.05) of the thalamus bilaterally.

• Functional connectivity (FC) Functional connectivity (FC) is defined as the temporal coincidence of spatially distant neurophysiological events.¹³ Depression has been described as a brain dysconnectivity disorder.¹⁴ In MDD there is a global reduction of FC, but with certain regions displaying increased FC. Evidence indicates that in MDD there is higher FC between the left DLPFC-striatum¹⁵ and the DLPFC-right insular,¹⁶ with stronger the connectivity the better the TMS treatment outcome. A randomized sham-controlled study of MDD patients provided TMS (10 Hz) to left DLPFC¹⁷ found, compared to the sham group, the actively treated group had significantly greater clinical improvement. In addition, the actively treated group demonstrated significant reduction in the DLPFC-left caudate FC. A study of MDD patients¹⁸ found both reduced global FC and increased FC between particular structures (including the left DLPFC-left amygdala). Amazingly, when TMS (10 Hz) stimulation was applied to the left DLPFC, simultaneously the global FC increased, and the elevated left DLPFC-left amygdala FC reduced. A study which described MDD as featuring “dysfunction in the affective network”¹⁹ compared the FC of MDD patients and healthy controls before and after TMS (10 Hz) applied to the left DLPFC. Compared to healthy controls, preTMS MDD patients demonstrated lower FC between the left insula and several other structures, including the amygdala. Post-TMS the left insula-left amygdala FC increased, and this change positively correlated with the change in depression scores. This was reported as indicating TMS may enhance affective network FC in MDD patients.

• Modification of brain waves A study of MDD using Quantitative (Q)EEG explored the effects of deep (d)TMS applied to the PFC.²⁰ A reduction of slow waves was identified in this area, along with a reduction in depressive symptoms. The authors suggested the slow wave reduction may be a key mechanism underpinning mood improvement.

Discussion

While some basic physiological effects of TMS have been described, various aspects are “still debated”.²¹ Neurochemical/cellular events in the area of stimulation (involving GABA and glutamate among others⁵ are assumed to trigger a cascade of biological events leading to the important antidepressant effects. TMS to induce change, for example, stimulation of the DLPFC can increase in blood flow⁶ and decrease in slow brain waves²⁰ in the immediate area, and release of dopamine in the distant caudate.⁷ The potency of TMS is also illustrated by stimulation of the PFC leading to increased volume of the, insula,⁹ hippocampus,¹⁰ cingulate¹¹ and the thalamus.¹² The circuit-based model of depression acknowledges a large number of independent and interconnected circuits across the brain, and postulates MDD is the consequence of dysfunction in and between them. MDD features reduced global FC which is restored (increased) by TMS treatment.¹⁸ Pathologically increased FC has been restored (reduced) in the DLPFC-caudate,¹⁷ DLPFCamygdala,¹⁸ and left insula-left amygdala¹⁹ circuits. Of patients with treatment resistant depression who complete a course of TMS, about half will achieve remission, which is sustained for some months—thus, a sustained neuroplastic change may be achieved. The optimal site and parameters of stimulation are to be determined and different protocols may be indicated according to yet to be determined biomarkers. TMS has a range of physiological effects. Which are fundamental to the management of MDD remains to be clarified. However, normalization of FC in disparate tracts is associated with reduced depression scores and is most likely central to the TMS antidepressant effect.

Conclusion

TMS is an effective treatment of MDD. In spite of great interest, the fundamental mechanism/s of action remain to be fully elucidated. This examination found reports of local neurochemical, brain wave and blood flow effects. We also found reports of effects on distant structures including neurotransmitter release and volume increase. Consistent with the concept of MDD being a dysconnectivity disorder, MDD features general and localized FC abnormalities. TMS corrects many of these FC abnormalities. We are not able to identify a single TMS induced change which results in MDD remission. It is likely that a number of changes operate synergistically to produce the antidepressant effects. The capacity of TMS to resolve MDD associated FC abnormalities, is very probably a leading contribution to the TMS antidepressant effect.