title: Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
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.
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Downar
authors.affiliation: Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Geraci
authors.affiliation: 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.
authors.forename: Tim V
authors.initials: TV
authors.lastname: Salomons
authors.affiliation: Faculty of Arts and Sciences, University of Toronto, Toronto, Canada.
authors.forename: Katharine
authors.initials: K
authors.lastname: Dunlop
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wheeler
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada.
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: McAndrews
authors.affiliation: Institute of Medical Sciences, University of Toronto, Toronto, Canada.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bakker
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Blumberger
authors.affiliation: 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.
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
authors.affiliation: 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.
authors.forename: Sidney H
authors.initials: SH
authors.lastname: Kennedy
authors.affiliation: Department of Psychiatry, University Health Network, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Flint
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Giacobbe
mesh_terms: D000328:Adult; D059445:Anhedonia / Q000502:physiology*; D001931:Brain Mapping; D003865:Major Depressive Disorder / Q000628:therapy*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012201:Reward; D050781:Transcranial Magnetic Stimulation; D016896:Treatment Outcome
keywords: Anhedonia; betweenness; depression; dorsomedial; fMRI; graph theory; prefrontal; rTMS; stimulation; subtype