Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression

Jonathan Downar; Joseph Geraci; Tim V Salomons; Katharine Dunlop; Sarah Wheeler; Mary Pat McAndrews; Nathan Bakker; Daniel M Blumberger; Zafiris J Daskalakis; Sidney H Kennedy; Alastair J Flint; Peter Giacobbe

doi:10.1016/j.biopsych.2013.10.026

Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression

Biol Psychiatry. 2014 Aug 1;76(3):176-85. doi: 10.1016/j.biopsych.2013.10.026. Epub 2013 Nov 28.

Authors

Affiliations

¹ MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto, Canada; Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada. Electronic address: jonathan.downar@uhn.ca.
² Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
³ MRI-Guided rTMS Clinic, Toronto Western Hospital, Toronto, Canada; Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
⁴ Faculty of Arts and Sciences, University of Toronto, Toronto, Canada.
⁵ Toronto Western Research Institute, University Health Network, Toronto, Canada.
⁶ Toronto Western Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.
⁷ Institute of Medical Sciences, University of Toronto, Toronto, Canada.
⁸ Department of Psychiatry, University of Toronto, Toronto, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.
⁹ Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.
¹⁰ Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.

PMID: 24388670
DOI: 10.1016/j.biopsych.2013.10.026

Abstract

Background: Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes.

Methods: Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode.

Results: Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region.

Conclusions: The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

Keywords: Anhedonia; betweenness; depression; dorsomedial; fMRI; graph theory; prefrontal; rTMS; stimulation; subtype.

MeSH terms

Adult
Anhedonia / physiology*
Brain Mapping
Depressive Disorder, Major / therapy*
Female
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Prefrontal Cortex / physiopathology*
Reward*
Transcranial Magnetic Stimulation*
Treatment Outcome