title: Compensatory frontoparietal activity during working memory: an endophenotype of obsessive-compulsive disorder.
abstract: BACKGROUND
  Subtle deficits in executive functioning are present in patients with obsessive-compulsive disorder (OCD) and their first-degree relatives, suggesting involvement of the frontoparietal circuits. The neural correlates of working memory may be a neurocognitive endophenotype of OCD.
  
  
  METHODS
  Forty-three unmedicated OCD patients, 17 unaffected siblings, and 37 matched comparison subjects performed a visuospatial n-back task, with a baseline condition (N0) and three working memory load levels (N1, N2, N3) during functional magnetic resonance imaging. Task-related brain activity was compared between groups in frontoparietal regions of interest. Generalized psychophysiological interaction analyses were used to study task-related changes in functional connectivity.
  
  
  RESULTS
  Obsessive-compulsive disorder patients, compared with comparison subjects and siblings, showed increased error rates at N3. Compared with comparison subjects, OCD patients showed task-related hyperactivation in left dorsal frontal areas and left precuneus associated with better task performance. Siblings exhibited hyperactivation in a bilateral frontoparietal network. Increased task load was associated with increased task-related brain activity, but in OCD patients and siblings this increase was smaller from load N2 to N3 than in comparison subjects. Obsessive-compulsive disorder patients, compared with siblings and comparison subjects, showed increased task-related functional connectivity between frontal regions and bilateral amygdala.
  
  
  CONCLUSIONS
  These findings indicate that compensatory frontoparietal brain activity in OCD patients and their unaffected relatives preserves task performance at low task loads but is insufficient to maintain performance at high task loads. Frontoparietal dysfunction may constitute a neurocognitive endophenotype for OCD, possibly reflecting limbic interference with and neural inefficiency within the frontoparietal network.
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam. Electronic address: fe.devries@vumc.nl.
authors.forename: Froukje E
authors.initials: FE
authors.lastname: de Vries
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam.
authors.forename: Stella J
authors.initials: SJ
authors.lastname: de Wit
authors.affiliation: Altrecht Academic Anxiety Center (DCC), Utrecht; Department of Clinical and Health Psychology (DCC), Utrecht University, Utrecht.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Cath
authors.affiliation: Department of Anatomy and Neurosciences (YDvdW, OAvdH), VU University Medical Center, Amsterdam; Netherlands Institute for Neuroscience (YDvdW), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam.
authors.forename: Ysbrand D
authors.initials: YD
authors.lastname: van der Werf
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam.
authors.forename: Vionne
authors.initials: V
authors.lastname: van der Borden
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: van Rossum
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam.
authors.forename: Anton J L M
authors.initials: AJ
authors.lastname: van Balkom
authors.affiliation: Department of Psychiatry and Leiden Institute for Brain and Cognition (NJAvdW), Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nic J A
authors.initials: NJ
authors.lastname: van der Wee
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam.
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Veltman
authors.affiliation: Department of Psychiatry (FEdV, SJdW, VvdB, TBvR, AJLMvB, DJV, OAvdH), VU University Medical Center, Amsterdam; Neuroscience Campus Amsterdam (FEdV, SJdW, YDvdW, DJV, OAvdH), VU University, Amsterdam; Department of Anatomy and Neurosciences (YDvdW, OAvdH), VU University Medical Center, Amsterdam.
authors.forename: Odile A
authors.initials: OA
authors.lastname: van den Heuvel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001931:Brain Mapping; D058068:Endophenotypes; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000503:physiopathology*; D010296:Parietal Lobe / Q000503:physiopathology*; D035781:Siblings; D065852:Spatial Memory / Q000502:physiology; D055815:Young Adult
keywords: Endophenotype; fMRI; frontoparietal; n-back; obsessive-compulsive disorder; working memory