Electric and magnetic stimulation of the human brain can be used to excite or inhibit neurons. Numerous methods have been designed over the years for this purpose with various advantages and disadvantages that are the topic of this review. Deep brain stimulation (DBS) is the most direct and focal application of electric impulses to brain tissue. Electrodes are placed in the brain in order to modulate neural activity and to correct parameters of pathological oscillation in brain circuits such as their amplitude or frequency. Transcranial magnetic stimulation (TMS) is a non-invasive alternative with the stimulator generating a magnetic field in a coil over the scalp that induces an electric field in the brain which, in turn, interacts with ongoing brain activity. Depending upon stimulation parameters, excitation and inhibition can be achieved. Transcranial electric stimulation (tES) applies electric fields to the scalp that spread along the skull in order to reach the brain, thus, limiting current strength to avoid skin sensations and cranial muscle pain. Therefore, tES can only modulate brain activity and is considered subthreshold, i.e., it does not directly elicit neuronal action potentials. In this review, we collect hints for neuroplastic changes such as modulation of behavior, the electric activity of the brain, or the evolution of clinical signs and symptoms in response to stimulation. Possible mechanisms are discussed, and future paradigms are suggested.

SummaryRepetitive transcranial magnetic stimulation (rTMS) has been investigated as treatment for major depressive episodes since the early 1990s. Using data from a recent meta-analysis, we show that most patients included in randomised trials display relatively high degrees of treatment resistance. This might have unfavourably biased the clinical reputation of rTMS.Declaration of interestsM.K. has received a lecture fee from Innomed Medizintechnik in 2017 and 2018.

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Background: While intermittent theta-burst stimulation (iTBS) has been shown to improve symptoms of major depressive disorder (MDD), research has been largely limited to targeting the dorsolateral prefrontal cortex (DLPFC). New approaches utilize patients' individual resting state fMRI data in order to identify superficial cortical stimulation targets functionally connected to deeper brain regions, thus enabling the modulation of previously inaccessible targets for antidepressant therapy. Objective: To improve iTBS treatment of MDD by inducing plasticity in the hippocampus through stimulation of an individually mapped, functionally interconnected site in the parietal cortex. Methods: Fifty-three MDD patients were randomized to three treatment groups and underwent 15 sessions of iTBS to the left DLPFC. This was augmented by adding a second daily session of (i) stimulation over individualized parietal targets functionally connected to the hippocampus, (ii) left DLPFC stimulation, or (iii) sham stimulation. To evaluate the improvement of treatment, we assessed depression severity, neuropsychological performance, functional connectivity and neural activation during an associative memory paradigm pre-vs. post-treatment. Results: Augmentation of left DLPFC stimulation by parieto-hippocampal stimulation increased functional connectivity between hippocampus and DLPFC as well as encoding-related hippocampal activation; the latter was associated with better performance during a spatial planning task dependent on prefrontal and hippocampal contributions. Depressive symptoms improved in all groups after treatment, with best clinical outcomes following twice-daily left DLPFC stimulation. Conclusion: Functional connectivity-guided stimulation of the hippocampus may serve as an adjunct to iTBS in order to target the cognitive symptoms of MDD.

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