Over 350 million people worldwide suffer from depression, a third of whom aremedicationresistant. Seizure therapy remains the most effective treatment in depression,even when manytreatments fail. The utility of seizure therapy is limited due to itscognitive side effects andstigma. The biological targets of seizure therapy remain unknown, hinderingdesign of newtreatments with comparable efficacy. Seizures impact the brains temporaldynamicity observedthrough electroencephalography. This dynamicity reflects richness ofinformation processingacross distributed brain networks subserving affective and cognitiveprocesses. We investigatedthe hypothesis that seizure therapy impacts mood (depressive symptoms) andcognition bymodulating brain temporal dynamicity. We obtained resting-state EEG fromthirty-four patients(age = 46.0 + 14.0, 21 females) receiving two types of seizure treatments -electroconvulsivetherapy or magnetic seizure therapy. We employed multi-scale entropy toquantify thecomplexity of brain's temporal dynamics before and after seizure therapy. Wediscovered thatreduction of complexity in fine time scales underlined successful therapeuticresponse to bothseizure treatments. Greater reduction in complexity of fine time scales inparieto-occipital andcentral brain regions was significantly linked with greater improvement indepressive symptoms.Greater increase in complexity of coarse time scales was associated withgreater decline incognition including the autobiographical memory. These findings were region-and time-scalespecific. That is, change in complexity in occipital regions (e.g., O2electrode or right occipitalpole) at fine time-scales was only associated with change in depressivesymptoms, and notchange in cognition, and change in complexity in parieto-central regions(e.g., Pz electrode orintra and transparietal sulcus) at coarser time-scale was only associated withchange in cognition,and not depressive symptoms. Finally, region and time-scale specific changesin complexityclassified both antidepressant and cognitive response to seizure therapy withgood (80%) andexcellent (95%) accuracy, respectively. In this study, we discovered a novelbiological target ofseizure therapy: complexity of the brain resting-state dynamics. Region andtime-scale dependentchanges in complexity of the brain resting-state dynamics is a novelmechanistic marker ofresponse to seizure therapy that explains both the antidepressant response andcognitive changesassociated with this treatment. This marker has tremendous potential to guidedesign of the newgeneration of antidepressant treatments.Keywords: Depression, Seizure Therapy, Complexity, Electroencephalography
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