Individualized theta-burst stimulation modulates hippocampal activity and connectivity in patients with major depressive disorder

Abstract

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.

Resting-State fMRI Functional Connectivity Strength Predicts Local Activity Change in the Dorsal Cingulate Cortex: A Multi-Target Focused rTMS Study

“…It should be noted that although a few multi-target rTMS studies have been reported ( Hendrikse et al. 2020 ; Mielacher et al. 2020 ), these studies involved stimulation of different effective regions.…”

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fibre plasticity in male but not female mice

“…A similar trend is observed in humans, where theta-patterned electrical stimulation of the hippocampus or its inputs promotes memory specificity and paired associates learning (Jun et al, 2020;Titiz et al, 2017). While current TMS protocols cannot directly stimulate the human hippocampus, delivering theta-patterned TMS to parietal regions that are functionally connected to the hippocampus improves associative memory and hippocampal-cortical functional connectivity (Y.-C. Chen et al, 2022;Hermiller et al, 2020;Mielacher et al, 2020;Tambini et al, 2018).…”

“…While current TMS protocols cannot directly stimulate the human hippocampus, delivering theta‐patterned TMS to parietal regions that are functionally connected to the hippocampus improves associative memory and hippocampal–cortical functional connectivity (Y.‐C. Chen et al, 2022; Hermiller et al, 2020; Mielacher et al, 2020; Tambini et al, 2018).…”

Effects of intermittent theta-burst transcranial magnetic stimulation on cognition and hippocampal volumes in bipolar depression

“…Furthermore, patients with major depression who received iTBS to DLPFC in conjunction with parietal stimulation augmentation demonstrated increased functional connectivity between hippocampus and DLPFC, increased hippocampal response, and a stronger correlation between hippocampal response and cognitive function relative to patients receiving DLPFC stimulation only (Mielacher et al. 2020 ). These findings suggest that in order to optimise modulation of hippocampal cognitive/memory functions, future iTBS studies in bipolar disorder should target these parietal cortical regions.…”