Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action.
Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.
Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland. scheidegger@biomed.ee.ethz.ch
Milan
M
Scheidegger
Martin
M
Walter
Mick
M
Lehmann
Coraline
C
Metzger
Simone
S
Grimm
Heinz
H
Boeker
Peter
P
Boesiger
Anke
A
Henning
Erich
E
Seifritz
D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology*; D001931:Brain Mapping; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006179:Gyrus Cinguli / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D010919:Placebos; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D012686:Septal Nuclei / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology
D000928:Antidepressive Agents; D010919:Placebos; D007649:Ketamine