Circuit-based neuromodulation
The use of external neuromodulation devices, a less invasive circuit-based treatment approach than DBS has also become an alternative treatment option for refractory schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) has been the method most investigated. In rTMS time-varying currents are generated in an induction coil and are held over the scalp and applied to stimulate and improve the functioning and synchrony of the GBO networks and GABA inhibitory mechanisms within the brain circuits beneath it. There have been several randomized studies conducted to show that stimulation targeted over the left TPJ, a critical hub involved in the pathophysiology of AVH, can reduce these symptoms (209–215).
Transcranial direct current stimulation (tDCS) is an alternative non-invasive form of neuromodulation that has been used to target specific circuits of the brain to improve treatment-refractory symptom domains of schizophrenia. It is a smaller, lightweight, portable and less expensive option than TMS and could be easily used at home to reduce the burden of having to receive daily treatments within a clinical setting (216). In this approach, two sponge electrodes are positioned on the scalp to facilitate a low-intensity electrical current (1–2 mA) that is passed between them. The transcranial current that is generated is continuous and flows in a direct current from an anode (current that enters the body) to induce prolonged depolarization to a cathode (a current that exits the body) to induce hyperpolarization under the cathode (217–220). It is thought that the mechanisms involved in the longer-lasting effects of tDCS are protein synthesis-dependent and in the modification of intracellular cascades beyond the membrane potential to influence cellular features associated with NMDA receptor functioning (216, 217). tDCS is increasingly being investigated by more independent schizophrenia researchers and primarily for improvement of positive (AVH) and negative symptom domain refractory symptoms.
Based on observations of the dysconnectivity of fronto-temporal circuits from functional neuroimaging studies of patients experiencing AVH (60–62), clinical studies have used tDCS to improve the dysconnectivity of these circuits to decrease AVH in patients with schizophrenia. In these studies, the anode electrode is applied over the left DLPFC (abnormally hypoactive) with the cathode electrode applied over the TPJ (abnormally hyperactive) to modulate the circuit and alleviate the severity of the AVH in schizophrenia (218, 221, 222). Results have been mixed in the ability of tDCS to reduce severity and frequency of AVH. For reviews see Li et al. (223), Ponde et al. (224), and Agarwal et al. (225). Studies that have reported a stronger and longer lasting response have had a higher number of treatment sessions and/or shorter time interval between sessions within their design (221, 226).
Open-label and randomized clinical trials that have examined the effects of tDCS to target negative symptoms of schizophrenia have placed the anode over the left DLPFC and the cathode over the right DLPFC or the right supraorbital region or placed it extra-cephalically (221, 227–229). A meta-analysis concluded that tDCS treatment is beneficial for improving negative symptom domain indications (211). There has been direct support for the safety of tDCS in human clinical trials with the most often reported side-effect of mild skin erythema, itching, tingling and burning under the electrode placement as well as temporary headache and dizziness which resolves after stimulation (218, 220).