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;
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:
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:
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.
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:
increased concentrations in hypothalamus and hippocampus;
metabolizes serotonin, melatonin, dopamine, tyramine and tryptamine.
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.