Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis

Schizophr Res. 2016 May;173(1-2):1-12. doi: 10.1016/j.schres.2016.02.023. Epub 2016 Mar 7.


Background: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis.

Methods: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n=11). Data were analyzed using SPM8 (2-back>0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined.

Results: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication-naïve CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naïve CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls.

Conclusions: Medication-naïve CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity.

Keywords: Clinical high risk; Prodrome; Psychosis; Working memory; fMRI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Brain Mapping
  • Case-Control Studies
  • Caudate Nucleus / diagnostic imaging*
  • Cognition Disorders / etiology*
  • Female
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term / physiology
  • Neuropsychological Tests
  • Oxygen / blood
  • Parahippocampal Gyrus / diagnostic imaging*
  • Prefrontal Cortex / diagnostic imaging*
  • Psychiatric Status Rating Scales
  • Psychotic Disorders / complications*
  • Psychotic Disorders / diagnostic imaging
  • Psychotic Disorders / pathology*
  • Statistics as Topic
  • Young Adult


  • Oxygen