Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia.
OBJECTIVE
Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia.


METHODS
The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic ((1)H-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [(15)O]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with (1)H-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task).


RESULTS
Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships.


CONCLUSIONS
These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder.
Bertolino
A
A
Clinical Brain Disorders Branch, Intramural research Programs, NIMH, NIH, Bethesda, MD 20892, USA.
Esposito
G
G
Callicott
J H
JH
Mattay
V S
VS
Van Horn
J D
JD
Frank
J A
JA
Berman
K F
KF
Weinberger
D R
DR
D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000706:statistics & numerical data; D008297:Male; D008568:Memory / Q000502:physiology*; D008959:Models, Neurological; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009483:Neuropsychological Tests; D010104:Oxygen Radioisotopes; D017397:Prefrontal Cortex / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology*; D012039:Regional Blood Flow; D012559:Schizophrenia / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology*; D014055:Tomography, Emission-Computed / Q000706:statistics & numerical data; D014867:Water
D010104:Oxygen Radioisotopes; D014867:Water; D001224:Aspartic Acid; C000179:N-acetylaspartate