Mechanisms of Working Memory Impairment in Schizophrenia

Biol Psychiatry. 2016 Oct 15;80(8):617-26. doi: 10.1016/j.biopsych.2016.02.017. Epub 2016 Feb 23.


Background: The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population.

Methods: Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance.

Results: A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity.

Conclusions: These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.

Keywords: Cognitive impairment; Functional magnetic resonance imaging; Inverted-U; Schizophrenia; Short-term memory; Working memory.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Brain Mapping
  • Case-Control Studies
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory Disorders / physiopathology*
  • Memory Disorders / psychology*
  • Memory, Short-Term*
  • Neural Pathways / physiopathology
  • Neuropsychological Tests
  • Occipital Lobe / physiopathology
  • Prefrontal Cortex / physiopathology
  • Schizophrenia / physiopathology*
  • Schizophrenic Psychology*
  • Young Adult