Transcranial Direct Current Stimulation: Theory, Treatment of Major Depressive Disorder, and Other Neuropsychiatric Applications

Background and theory

The use of non-invasive brain stimulation for the treatment of various neuropsychiatric disorders, including major depressive disorder (MDD), has rapidly expanded recently. Transcranial direct current electrical stimulation (tDCS), variants of which have been used experimentally for psychiatric (Boggio 2008, Loo 2012, Brunoni 2014, McIntire 2014, Brunoni 2013), neurologic (de 2015, Khedr 2014), and physical rehabilitation (Fregni 2006, Marlow 2013) applications, has garnered a great deal of attention. While it is not yet FDA-approved for any indication, its promise is related to its low cost and wide range of applications; although the breadth of its applicability has been questioned due to heterogeneous data (Horvath 2015), this heterogeneity has been attributed to methodological variability (Antal 2015).

The safety and tolerability of tDCS were outlined by an early study including 567 sessions in 102 patients. The most common adverse effects were mild tingling/itching at the stimulation site and moderate fatigue. Less frequent effects included headaches (11.8%), nausea (2.9%), and insomnia (0.98%), all of which were mild and transient (Poreisz 2007).

The underlying theory is that tDCS modulates the excitability of certain cortical regions (Merzagora 2010, Hampstead 2014, Medeiros 2012) by passage of a small electrical current through conducting pads applied to the scalp in a minimally painful manner. While the precise mechanism is not fully understood, it likely enhances cortical excitability at the anode and depresses it at the cathode (Tremblay 2014, Merzagora 2010, Hampstead 2014).

Proposed mechanisms have been based on data demonstrating relationships between tDCS stimulation and neuropharmacologic effects, cortical electrophysiology, and functional neuroimaging changes. Effects of tDCS on neuroplasticity and cortical excitability have been shown to be differentially modulated by agents affecting neurotransmission via serotonin (citalopram), dopamine (L-dopa), NMDA (dextromethorphan and d-cycloserine), and GABA (lorazepam). Electrophysiologic changes include differential modulation in the presence of agents that modulate sodium channels (carbamazepine) and calcium channels (flunarizine) (Medeiros 2012). Active tDCS shows significant increases in prefrontal cortex activity as measured by functional near infrared spectroscopy (fNIRS), a technique used to measure cortical oxygenation, during and after stimulation – notably, fNIRS measurements may be limited by interference due extracranial blood flow and inability to assess deeper structures, so they merely approximate the functional magnetic resonance imaging (fMRI) signal in superficial structures (Merzagora 2010). Stimulation also increases fMRI activation and connectivity of the underlying cortical regions and hippocampi, though the clinical significance of this is uncertain given that this same study found no behavioral changes (Hampstead 2014).

Use for major depressive disorder

Since the FDA approval of rTMS of the dorsolateral prefrontal cortex (DLPFC) for treatment of MDD, there has been extensive research regarding non-invasive stimulation of the DLPFC. This has led to some literature showing various types of tDCS to have efficacy as standalone treatment for MDD