Stimularea magnetică transcraniană – partea a II-a

 Transcranial magnetic stimulation (TMS) – part II

First published: 20 noiembrie 2021

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Psih.67.4.2021.5713


Transcranial magnetic stimulation (TMS) is a new and effective method of nonpharmacological treatment in psychiatry, with multiple indications. Beyond clinical efficacy, TMS brings a clear benefit in understanding the intracellular mechanisms involved in the pathophysiology of mental disorders. Studies on repetitive transcranial magnetic stimulation (rTMS) have confirmed the role of intracellular signalling pathways involved in mental disorders. rTMS activates the endocannabinoid system, increases the synaptic plasticity and neurogenesis by activating BDNF (which in turn activates the Bcl2 antiapoptotic proteins and inhibits proapoptotic factors Bax), increases monoamine transmission by suppressing the BDNF, activates the cytosolic anti-inflammatory protein Nrf2, and activates the Ras/MAPK/P3K/Akt signaling pathway. Transcranial magnetic stimulation, a noninvasive method with confirmed clinical efficacy, coupled with the identification of parts of the molecular puzzle, constitutes a therapeutic alternative in psychiatry. Transcranial magnetic stimulation is therefore a new and effective method of treatment in psychiatry. In addition to its clinical effectiveness, it gives us a better understanding of synaptic connectivity and the multiple cellular mechanisms involved in the pathophysiology of mental disorders. 

repetitive transcranial magnetic stimulation (rTMS), anti-inflammatory effect, endocannabinoid system, BDNF, protein Nrf2, Sirtuin 1


Stimularea magnetică transcraniană (TMS) este o metodă nouă şi eficientă de tratament nefarmacologic în psihiatrie, cu indicaţii multiple. Dincolo de eficienţa clinică, TMS aduce un beneficiu net privind înţelegerea mecanismelor intracelulare implicate în patofiziologia tulburărilor psihice. Studiile privind stimularea magnetică transcraniană repetitivă (rTMS) au confirmat rolul unor căi de semnalizare intracelulară implicate în tulburările psihice. Prin rTMS este activat sistemul endocanabinoid, cresc plasticitatea sinaptică şi neurogeneza prin activarea BDNF (care, la rândul său, activează proteinele antiapoptotice Bcl2 şi inhibă factorii proapoptotici Bax), creşte transmisia de monoamine prin supresia căii SIRT1/MAO, este activată proteină citozolică Nrf2, cu efect antiinflamator, şi este activată calea de semnalizare Ras/MAPK/P3K/Akt. Stimularea magnetică transcraniană, o metodă neinvazivă cu eficienţă clinică demonstrată, dublată de evidenţierea unor părţi din puzzle-ul molecular, constituie o alternativă terapeutică în psihiatrie. De aceea, stimularea magnetică transcraniană este o metodă eficientă de tratament în psihiatrie. 

Antidepressant mechanism of rTMS

Di Luan et al. (2020) summarize the antidepressant mechanism of rTMS based on preclinical studies. There are discussed:

  • the anti-inflammatory effects mediated by Nrf2 (nuclear factor erythroid 2-related factor) activation;

  • antioxidant effect;

  • increased plasticity and neurogenesis;

  • activation of the endocannabinoid system;

  • activation of BDNF (brain neurotrophic factor)

  • increased monoamine neurotransmission by the inhibition of Sirtuin 1 pathways;

  • decreased activity of the hypothalamic-pituitary-adrenal (HPA) axis.

There are three physical (nonpharmacological) strategies approved by the FDA for the treatment of major depressive disorder (Trapp, 2019): vagus nerve stimulation, ECT and rTMS. Compared to ECT and vagus nerve stimulation, rTMS is more readily accepted by depressed patients because it does not require anaesthesia and is not a minimally invasive procedure.

To understand the antidepressant mechanism of TMS, Di Luan et al. (2020) focused on animal model studies with depressive-like symptoms. Preclinical studies have shown that rTMS has antidepressant effect through a variety of mechanisms with diverse signalling pathways.

rTMS and antioxidative stress effects

In the process of using O2 to generate adenosine triphosphate (ATP), the body produces reactive oxygen species (ROS). Excessive ROS act on lipids, proteins and DNA and produce a wide range of peroxides, generating cellular oxidative stress which is considered an important factor in the development of diseases.

There are two antioxidative stress systems:

  • enzymatic (glutathione peroxidase – GSH-Px);

  • nonenzymatic (glutathione – GSH).

Numerous studies have highlighted the increase of peroxide products and the decrease of antioxidants in major depressive disorder (Block, 2015; Lin, 2015; Mezereew, 2015; Palto, 2014).

O. Durmaz, in 2018, demonstrated an increased level of thiol (an organic sulfur antioxidant) in the serum of patients with major depressive disorder (MDD) after the rTMS treatment (20Hz) compared to pretreatment thiol values. In contrast, E.P. Aydin (2018) found no difference in the serum value of thioredoxin (an antioxidant function protein) between healthy and TRD subjects, nor between TRD patients before and after rTMS. We emphasize that thioredoxin together with glutathione and cysteine constitute the three endogenous thiols antioxidants.

The idea that oxidative stress is one of the causes or characteristics of MDD is not widely accepted in the academic community. In addition, the antidepressant role of rTMS through its antioxidative stress mechanism has been controversial in clinical studies on the grounds that the measurement of oxidative stress markers in peripheral blood does not reflect the actual situation in the brain.

rTMD and anti-inflammatory effects

Inflammation is strongly associated with depression (Roman, 2020; Su, 2019; Lee, 2019; Maydyde, 2019). Patients with autoimmune conditions or acquired infections develop more easily depression (Buesos, 2013). Patients with aseptic brain inflammation (stroke) most often develop depression (Robinson, 2016).

The mechanism by which rTMS exerts its antidepressant effect through the anti-inflammatory process is not fully elucidated. A key factor appears to be the cytosolic protein Nrf2 (nuclear factor erythroid 2-related factor 2). Nrf2 is a transcription factor that regulates both cellular redox status through the antioxidant system and simultaneously has an anti-inflammatory action (Hashimoto, 2018; Yav, 2016; Kensler, 2007). Both ROS and reactive nitrogen species (RNS) are characteristic of inflammatory disorders and pain processes. ROS/RNS induces cytokine release, cell adhesion and inflammasome activation. The signaling pathway is keap 1/Nrf2/ARE and regulates the expression of genes that synthesize anti-inflammatory proteins (Ahmed, 2017) (KEAP1 – kelch-like ECH-associated protein 1; ARE – antioxidant response element).

Under oxidative stress, Nrf2 dissociates from keaps and translocates to the nucleus, forms a heterodimer with the Maj family of proteins and then binds to ARE to transcribe antioxidant genes (Ahmed, 2017). The Nrf2-regulated antioxidant system leads to an increased synthesis of glutathione (GSH) superoxide dismutase (SOD), catalase, heme oxygenase 1 (HO-1) (Joshi, 2012) and to decreased cytokine production. Animal studies (Jaow, 2016; Zhang, 2018) revealed a significant reduction in the Nrf2 expression in both hippocampus and prefrontal cortex in depressive-like mice.

Moreover, postmortem, in patients with MDD, an Nrf2 decrease in the prefrontal cortex was found (Zhang, 2018; Mastin-Hernandez, 2018).

A recent preclinical study (Tian, 2020) showed in rTMS (15 Hz, 1.26 T) and rTMS-suppressed rats increased Nrf2 translocated to the nucleus with decreased expression of TNF-α (tumor necrosis factor), nitric oxide synthase, decreased cytokines IL-1β and IL-6 in the hippocampus. The same author demonstrated that, if the Nrf2 gene is silent (inhibited), the antidepressant effect of rTMS is not observed and cytokine expression is not influenced.

These results suggest that rTMS plays an antidepressant role by enhancing Nrf2-mediated anti-inflammatory action. Moreover, X. Zhito, in 2019, in a clinical study on 58 patients with TRD (resistant depressive disorder) and 30 control subjects (healthy), revealed that IL-1β and peripheral TNF-α increased more in patients than in the control group (before rTMS).

However, the mechanism by which rTMS exerts antidepressant action through anti-inflammatory effect is not yet elucidated.

After four weeks of rTMS (10Hz), IL-1β and TNF-α were found to decrease in TRD patients compared to the non-TMS group.

Endocannabinoid and BNDF system activation through rTMS

Recent studies have suggested the involvement of the endocannabinoid system (ECS) in the pathophysiology of depression (Mechonlam, 2013; Augustin, 2018; Chadwick, 2020).

Receptors of the endocannabinoid system include:

  • type 1 receptors – CB1R;

  • type 2 receptors – CB2R.

The most important ECS donors are:

  • arahydonyl ethanolamide (AEA);

  • arahydonyl glycerol (2-AG).

Endocannabinoids produced in the postsynaptic space activate local endocannabinoid receptors in the presinaptic membrane with the following effects:

  • decreased HHA axis activity;

  • increased hippocampal synaptic plasticity;

  • initiation of neurogenesis in the hippocampus;

  • increased expression of BDNF (brain-derived neurotrophic factor) in the hippocampus (Huang, 2016; Poliszak, 2018; Zhou, 2017; Estrada, 2020).

BDNF – a key factor that activates various signalling pathways in the brain – binds to the TrKB (tyrosine kinase B) receptor on the cell membrane. The Ras/MAPK/P3K/AKE signalling pathway is activated and neurogenesis and increased synaptic plasticity are initiated (Bjorkholm, 2016; Caviedes, 2017; Hing, 2018; Kowianski, 2018; Leal, 2017).

In 2019, J. Jang conducted a study on Wistar rats. The mice had stress-induced depressive-like behavior. They were subjected to rTMS 15 Hz (maximum power). After the administration of this therapy, there were found:

A decreased expression of MAGL (mono-glycerol lipase), a key enzyme in the hydrolysis of 2-AG (2-arachidonyl glycerol endocannabinoid), MAGL being the main enzyme responsible for the inactivation of the most abundant endocannabinoid in the brain – 2AG.

Bax decrease. Bax is a protein found in the cytosol that initiates apoptotic signalling and is then associated with the mitochondrial membrane.

2-AG growth.

CB1R growth.

BDNF increase.

Bcl2 growth. Bcl2 is a protein located in the mitochondrial outer membrane (crista), playing an important role in cell survival and in inhibition of the action of proapoptotic proteins.

Clinically, the improvement of depressive-like behavior was observed in Wistar rats.

CB1R antagonists such as AH25 counteract the biological functions of rTMS mentioned above. BDNF is involved in neurogenesis and synaptic plasticity. Serum BDNF levels in depressed patients are significantly low compared to healthy subjects, and this low value may correlate with the severity of depressive symptoms (Beuzon, 2017; Silverstern, 2015).

In addition, TRD patients monitored with BDNF wave/valley alleles showed increased BDNF levels after rTMS (Beuzon, 2017; Silverstern, 2015). Increased BDNR was also observed in heterozygous TRD after rTMS (Than, 2019; Gedge, 2012; Langue, 2006; Jobinasu, 2006; Zanardini, 2006).

TMS and suppression of Sirtuin-1/MAO signaling pathways

Sirtuins are a family of proteins with a role in cellular energy homeostasis, inhibiting or activating cofactors or metabolic intermediates. Seven isoforms of sirtuins are known, with variable intracellular distribution. Sirtuin 1 and Sirtuin 3 are considered cellular energy sensors. In general, sirtuins use NAD+ (nicotin adenine dinucleotide) to remove acetyl groups from proteins (deacylation) or are involved in ADP ribosylation. Sirtuin-mediated deacylation of critical proteins (SIRT) modulates mitochondrial function (Poulase, 2015).

MAOs are a family of enzymes that catalyse the oxidation of monoamines. Two subtypes of MAO are known:

1. MAO-A

  • increased concentrations in hypothalamus and ­hippocampus;

  • metabolizes serotonin, melatonin, dopamine, tyramine and tryptamine.

2. MAO-B

  • increased concentrations in striatum, blobus pallidus;

  • metabolizes dopamine, tyramine, tryptamine, benzylamine and phenethylamine (Higuch, 2017, 2018; Naoi, 2016).

MAO-A expression is regulated by transcription factors NHLH2 (Nescient Helix Loop Helix 2 Protein), KLF1 and FOXO1 (Forkhead Box Group 0), with an antiapoptotic role.

Of these factors, NHLH2 and FOXO1 must be deactivated by SIRT 1 to be active in the transcription of local factors (Grunewald, 2012; Harris, 2015; Jonhson, 2011; Libat, 2011; Wu, 2011).

In 2015, Harris conducted a study on rats with depressive-like symptoms. He injected the prefrontal cortex with a SIRT1 inhibitor (EX 527). The rats were subjected to rTMS. There were found: clinically – improvement of depressive-like behaviour; biochemically – increase of serotonin concentration and reduction of SIR1 and MAO-A expression. Preclinical studies and clinical trials are needed to address SIRT1/MAO-A signalling in the mechanism of depressive disorder correlated with rTMS.

TMS and the decrease in HHS axis activity

The pathophysiological mechanism of depressive disorder also involves the overactivity of the HPA axis (Juruena, 2018; Merike, 2019; Pariati, 2008). Both preclinical and clinical studies have shown increased HPA axis activity in both depressive-like animals and MDD patients. However, the results of clinical studies are contradictory regarding the level of hormones correlated with circadian rhythm (Lyanarachchi, 2017).

On a depressive-like animal model (rats), rTMS (10 Hz and 15 Hz, respectively) reduced adrenocorticotropic hormone and cortisol levels in peripheral blood (Feng, 2012; Zhov, 2018). There are, however, few clinical and preclinical studies highlighting the antidepressant effect of rTMS by reducing HPA axis activity.

In conclusion, transcranial magnetic stimulation is therefore a new and effective method of treatment in psychiatry. In addition to its clinical effectiveness, it gives us a better understanding of synaptic connectivity and of the multiple cellular mechanisms involved in the pathophysiology of mental disorders. 


Aydin EP, Geng A, Dalkiran H, et al. Thioredoxin is not a marker for treatment-resistance depression but associated with cognitive function: an rTMS study. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 80; 322-328.
Augustin SH, Lovinger DM. Functional relevance of endocannabinoid-dependence synoptic plasticity in the central nervous system. ACS Chem Neurosci. 2018;9:2146- 2161.
Barke AT, Yalinous R. Non-invasive magnetic stimulation of human motor cortex.Lancet. 1985;1:1106-1107.
Benzon G, Tihour Q, Saoud M. Predictors of response repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder. L’Encéphale. 2017;43:3-9.
Black CIN, Bot M, Scheffer PG, et al. Is depression associated with increased oxidative stress? Psychoneuroendocrinology. 2015; 51:164-175.
Bjorkholm C, Monteggia LM. BDNF – a key transducer of antidepressant effects.Neuropharmacology. 2016;102: 72-79.
Carmi L, Alyagon U, Barnea-Ygael N, et al. Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients. Brain Stimulation. 2018;11(1):158-165.
Caviedes A, Lafourcade C, Soto C, et al. BDNI/NF-KB signaling in the neurobiology of depression. Curr Pharma Des. 2017;23:3154-3163.
Chadwick VL, Rohleder C, Koethe D. Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans. Current Opinion in Psychiatry. 2020;33:20-42.
Dunner DL, Aaronson ST, Sackeim HA, et al. A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. J Clin Psychiatry. 2014;75(12):1394-1401.
Durmaz O, Ispir E, Baykan H, et al. The impact of repetitive transcranial magnetic stimulation on oxidative stress in subjects with medication-resistant depression. J ECT. 2018;34:127-131.
Estrada JA, Contreras I. Endocannabinoid receptors in the CNS: potential drug targets for the prevention and treatment of neurologic and psychiatric disorders. Curr Neuropharmacol. 2020;18(8):769-787.
Feng S, Shi T, Fan-Yan GN, et al. Long-lasting effects of chronic rTMS to treat chronic rodent model of depression. Behav Brain Res. 2012; 232: 245-257.
Gedge L, Beaudoin A, Lazowski L, et al. Effects of electroconvulsive therapy and repetitive transcranial magnetic stimulation on serum brain-derived neurotrophic factor levels in patients with depression. Front Psychiatry. 2012 Feb 24;3:12.
Harris S, Johnson S, Duncan JN, et al. Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders. Neuropsychopharmacology. 2015;50:1373-1382.
Hashimoto K. Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective. Front Pharmacol. 2018;8:1182.
Hing B, Sathyaputri L, Potash YB. A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am J Med Genet B Neuropsychiatric Genetics. 2018;177:143-167.
Huang WJ, Chen WW, Zhang X. Endocannabinoid system: Role in depression, reward and pain control. Mol Med Rep. 2016;14:2890-2903.
Johnson S, Stockmeier CA, Meyer J, et al. The reduction of R1, a novel repressor protein for monoamine oxidase A, in major depressive disorder. Neuropsychopharmacology. 2011;36:2139-2148.
Juruena MF, Bocharova M, Augustini B, et al. Atypical depression and non-atypical depression: Is HPA axis function a biomarker? J Affect Disord. 2018;233:45-67.
Kensler TW, Wakabayashi N. Cell Survival Responses to Environmental Stresses via the Keap1-Nrf2-ARE Pathway. Annu Rev Pharmacol Toxicol. 2007;47:89-116.
Kowianski P, Lietzau G, Czuba E, et al. A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol. 2018;33:579-593.
Leal G, Bramham CR, Duarte CB. BDNF and Hippocampal Synaptic Plasticity. Vitamins and Hormones. 2017; 104:153-195.
Lee CH, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696.
Libert S, Pointer K, Bell EL, et al. SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell. 2011;147:1459-1472.
Liyanarachchi K, Ross R, Debono M. Human studies on hypothalamo-pituitary-adrenal (HPA) axis. Best Pract & Res Clin Endocrinol & Metab. 2017;31:459-473.
Líu T, Zhong S, Liao X, Chen J. A meta-analysis of oxidative stress marker in depression. PLoS One. 2015 Oct 7;10(10):e0138904.
Martin-Hernandez D, Caso JR, Javier Meana J, et al. Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants. Journal of Neuroinflammation. 2018,15:251.
Maydych V. The interplay between stress, inflammation and emotional attention: relevance for depression. Front Neurosci. 2019;13:384.
Mazerreeuw G, Hermann N, Andreazza A, et al. CA meta-analysis of lipid peroxidation markers in major depression. Neuropsychiatric Dis Treat. 2015;11:2479-2491.
Mechoulam R, Parker LA. The endocannabinoid systems and the brain. Annu Rev Psychol. 2013;64:21-47.
Menke A. Is the HPA axis as target for depression outdated, or is there a new hope? Front Psychiatry. 2019;10:101.
Naoi M, Riederer P, Maruyama W. Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression. Neural Transm (Vienna). 2016; 123:91-106.
Palta P, Samuel LJ, Miller ER. Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom Med. 2014;76(1):12-19.
Pariante CM, Lightman SL. The HPA axis all Major depression: classical theories and new developments. Trends Neurosci. 2008;31:464-468.
Poleszak E, Wosko S, Stawinska K. Cannabinoids in depressive disorders. Life Sci. 2018;213:18-24.
Poulose N, Raju R. SIRTUIN Regulation in aging and injury. Biochim Biophys Acta. 2015;1852(11):2442-2455.
Rahe C, Khil L, Wellmann J, Baune B. Impact of major depressive disorder, distinct subtypes, and symptom severity on lifestyle in the BiDirect Study. Psychiatry Res. 2016;245:164-171.
Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psychiatry. 2016;173:221-231.
Silverstein WK, Noda Y, Barr MS, et al. Neurobiological predictors of response to dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation in depression: a systematic review. Depress Anxiety. 2015;32:871-891.
Tian L, Sun SS, Cui LB, et al. Repetitive transcranial magnetic stimulation elicits antidepressant and anxiolytic-like effect via Nuclear Factor-E2-related Factor 2-mediated anti-inflammation mechanism in rats. Neuroscience. 2020;429:119-133.
Trebbastoni A, Pichiorri F, Antonio F, et al. Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer’s Disease: Results from a 4-year Prospective Cohort Study. Front Aging Neurosci. 2016;7:1-10.
Roman M, Irwin M. Novel neuroimmunologic therapeutics in depression: A clinical perspective on what we know so far. Brain, Behavior, And Immunity. 2020;83:7-21.
Su WJ, Cao ZY, Jiang CL. Blocking the Trigger: An integrative view on the anti-inflammatory therapy of depression. Brain, Behavior, And Immunity. 2020;82:10-12.
Voigt J, Carpenter L. Cost effectiveness analysis comparing repetitive transcranial magnetic stimulation to antidepressant medications after a first treatment failure for major depressive disorder in newly diagnosed patients – A lifetime analysis. PLoS One. 2017;32:1-15.
Wieczorek T, Kobylko A, Stramecki F, et al. Transcranial magnetic stimulation in treatment of psychiatric disorders-review of current studies. Psychiatr Pol. 2021 Jun 30;55(3):565-583.
Wu JB, Shih JC. Valproic acid induces Monoamine oxidase A ria Akt/Forkhead box O1 activation. Molecular Pharmacology. 2011;80(4):714-723.
Trapp NT, Xiong W, Conway CR. Neurostimulation therapies. Handb Exp Pharmacol. 2019;250:181-224.
Yao W, Zhang JC, Ishima T, et al. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Sci Rep. 2016;6:30659.
Zhang JC, Yao W, Dong C, et al. Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. European Archives of Psychiatry and Clinical Neuroscience. 2018;268:865-870.
Zhou D, Li Y, Tiant T, et al. Role of the endocannabinoid system in the formation and development of depression. Die Pharmazie. 2017;72:435- 439.
Zanardini R, Gazzoli A, Ventriglia M, et al. Effect of rTMS on serum brain derived neurotrophic factor in drug resistant depressed patients. Journal of Affective Disorders. 2006;91:83-86.

Articole din ediţiile anterioare

CASE REPORT | Ediţia 4 75 / 2023

Integrarea datelor farmacogenetice în practica psihiatrică

Andrei G. Mangalagiu, B. Petrescu, Cristian A. Cândea, Octavian Vasiliu

Medicina personalizată este un deziderat care prezintă avantajele unei eficacităţi sporite şi ale unei tolerabilităţi superioare, aspecte care ar î...

29 noiembrie 2023

Canabidiolul – zeci de ani de cercetare şi utilizările clinice actuale

Valentin Rădoi, Gabriel Cicu

Deşi majoritatea cercetărilor referitoare la canabis s-au concentrat asupra delta-9-trans-tetrahidrocanabinolului (THC), recent alte componente ale...

15 noiembrie 2019