tDCS as treatment in neuro-psychiatric disorders : The underlying neuronal mechanisms of tDCS treatment of auditory verbal hallucinations

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation which has gained widespread interest in neurology and psychology, both as a clinical and research tool. While it has been explored as a treatment for numerous disorders and as a potential means to improve function, there is still too little empirical evidence regarding its efficacy. So far, it is only considered effective as a treatment for depression. In schizophrenia, the tDCS montage of anodal stimulation over the dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation over the temporo parietal cortex (TPC) has been proposed as treatment for auditory verbal hallucinations (AVH). This montage is based on the hypofrontal/hypertemporal model in schizophrenia, which says that the DLPFC is hypoactive and therefore has reduced control over the hyperactive TPC, which causes AVH. By placing the anode over the DLPFC, which usually has an excitatory effect, activity in the DLPFC is expected to be boosted; and by placing the usually inhibitory cathode over the TPC activity is expected to be reduced. However, whether the idea that underlies the tDCS treatment is true, namely that tDCS reverses the hypertemporal/hypofrontal activity pattern, has not been studied sufficiently. In general, it is unclear what the underlying mechanisms of tDCS treatment of AVH are. Moreover, since the discovery of the tDCS treatment for AVH, the findings regarding whether it is effective have been inconsistent (Brunelin et al., 2012). Whether the hypofrontal/hypertemporal model and the hypothesized underlying mechanism of the treatment is correct has not been studied sufficiently. Therefore, the main goal of the thesis was to study the underlying mechanisms of tDCS with multimodal neuroimaging, including functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), functional connectivity and structural imaging in both a healthy population (paper II) and a population of people with severe AVH within a randomized controlled trial (paper III). In addition, clinical measures and a behavioral task were included to examine whether the treatment reduces AVH. To study the electric field of tDCS, simulation was performed in the specific montages of the studies. In paper I, the opportunity arose to research, if tDCS works in a specific type of epilepsy caused by mitochondrial disease, specifically a DNA polymerase-gamma (POLG) gene mutation. A previous case study (Ng et al., 2018) raised hopes that tDCS could alleviate symptoms in such POLG patients. Paper I studied the effects of tDCS using electroencephalography and electromyography. The results showed, however, that tDCS treatment at 2mA did not lead to a statistically or clinically significant reduction of myoclonus jerking or epilepsy spikes in the 15-year old POLG patient. In paper II, tDCS did not induce any changes in functional activity in the DLPFC or TPC and there was only a trend for higher glutamate levels (as approximated by Glx = glutamate+glutamine) in both DLPFC and TPC. Neither finding is in line with the hypertemporal/hypofrontal model. Moreover, we found that simulation of tDCS showed peak electric field strength between the electrodes (Broca’s areas), not as hypothesized directly under the electrodes. In paper III, there was a small decrease in AVH after tDCS treatment. However, this decrease only emerged in self-reports from patients but not examinations by professional clinicians and was hard to distinguish from placebo effect. None of the neuroimaging data (rs-fMRI, MRS, structural MRI nor task-related fMRI) showed significant effects for the DLPFC or TPC. Taken together, this thesis gives an overview of tDCS treatment in neurological and psychiatric disorders based on a single case study, a healthy control population and a patient population of schizophrenia/psychosis. It was shown that tDCS does not always relieve epilepsy symptoms in POLG disease cases. With only two case studies on the subject, much more research is needed if and in which cases of POLG disease tDCS can be effective. Paper II tested the hypofrontal/hypertemporal model indirectly and paper III directly tested the notion that underlies the tDCS treatment, namely that this activity pattern could be reversed with tDCS, with multimodal neuroimaging. The results showed that tDCS reduces AVH to a certain degree. In conclusion, the findings from both paper II and III argue against the notion that the tDCS treatment reverses the hypofrontal/hypertemporal activity pattern that is believed to underlie AVH. Our data indicated that the Broca’s area should be investigated, as the peak intensity of the stimulation lies there when DLPFC and TPC are stimulated. In addition, future research should investigate the differences between tDCS responders and non-responders, preferably in a multimodal manner similar to paper II and III, as it is a crucial approach to investigate underlying neuronal mechanisms.Doktorgradsavhandlin