Previous studies have examined the effect of transcranial direct current stimulation (tDCS) on the in-vivo concentrations of neuro-metabolites assessed through magnetic resonance spectroscopy (MRS) in neurological and psychiatry disorders. This review aims to systematically evaluate the data on the effect of tDCS on MRS findings and thereby attempt to understand the potential mechanism of tDCS on neuro-metabolites.

The relevant literature was obtained through PubMed and cross-reference (search till June 2020). Thirty-four studies were reviewed, of which 22 reported results from healthy controls and 12 were from patients with neurological and psychiatric disorders.

The evidence converges to highlight that tDCS modulates the neuro-metabolite levels at the site of stimulation, which, in turn, translates into alterations in the behavioural outcome. It also shows that the baseline level of these neuro-metabolites can, to a certain extent, predict the outcome after tDCS. However, even though tDCS has shown promising effects in alleviating symptoms of various psychiatric disorders, there are limited studies that have reported the effect of tDCS on neuro-metabolite levels.

There is a compelling need for more systematic studies examining patients with psychiatric/neurological disorders with larger samples and harmonised tDCS protocols. More studies will potentially help us to understand the tDCS mechanism of action pertinent to neuro-metabolite levels modulation. Further, studies should be conducted in psychiatric patients to understand the neurological changes in this population and potentially unravel the neuro-metabolite × tDCS interaction effect that can be translated into individualised treatment.

Recent observations demonstrate a significant ameliorative effect of add-on transcranial direct current stimulation (tDCS) on auditory verbal hallucinations (AVHs) in schizophrenia. Of the many SNPs, NRG1 rs35753505 and catechol-o-methyl transferase (COMT) rs4680 polymorphisms have shown to have a strong association with neuroplasticity effect in schizophrenia.

Schizophrenia patients (n=32) with treatment resistant auditory hallucinations were administered with an add-on tDCS. The COMT (rs4680) and NRG1 (rs35753505) genotypes were determined. The COMT genotypes were categorised into Val group (GG; n=15) and Met group (GG/AG; n=17) and NRG1 genotypes were categorised into AA group (n=12) and AG/GG group (n=20).

The reduction in auditory hallucination sub-scale score was significantly affected by COMT-GG genotype [Time×COMT interaction: F(1,28)=10.55, p=0.003, ɳ2=0.27]. Further, COMT-GG effect was epistatically influenced by the co-occurrence of NRG1-AA genotype [Time×COMT×NRG1 interaction: F(1,28)=8.09, p=0.008, ɳ2=0.22]. Irrespective of genotype, females showed better tDCS response than males [Time×Sex interaction: F(1,21)=4.67, p=0.04, ɳ2=0.18].

COMT-GG and NRG1-AA genotypes aid the tDCS-induced improvement in AVHs in schizophrenia patients. Our preliminary observations need replication and further systematic research to understand the neuroplastic gene determinants that modulate the effect of tDCS.

Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders.

A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms.

Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials.

Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.