Transcranial direct current stimulation (tDCS) has been proposed for experimental and therapeutic modulation of regional brain function. Specifically, anodal tDCS of the dorsolateral prefrontal cortex (DLPFC) together with cathodal tDCS of the supraorbital region have been associated with improvement of cognition and mood, and have been suggested for the treatment of several neurological and psychiatric disorders. Although modeled mathematically, the distribution, direction, and extent of tDCS-mediated effects on brain physiology are not well understood. The current study investigates whether tDCS of the human prefrontal cortex modulates resting-state network (RSN) connectivity measured by functional magnetic resonance imaging (fMRI). Thirteen healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. Patterns of resting-state brain connectivity were assessed before and after tDCS with 3 T fMRI, and changes were analyzed for relevant networks related to the stimulation–electrode localizations. At baseline, four RSNs were detected, corresponding to the default mode network (DMN), the left and right frontal-parietal networks (FPNs) and the self-referential network. After real tDCS and compared with sham tDCS, significant changes of regional brain connectivity were found for the DMN and the FPNs both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain.

Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (−36.1%) than after sham tDCS (−0.7%). PANSS sum scores decreased significantly more with active (−23.4%) than with sham stimulation (−2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia.