Specific Relationship Between Prefrontal Neuronal N -Acetylaspartate and Activation of the Working Memory Cortical Network in Schizophrenia

Clinical Brain Disorders Branch, Intramural research Programs, NIMH, NIH, Bethesda, MD 20892, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 01/2000; 157(1):26-33. DOI: 10.1176/ajp.157.1.26
Source: PubMed


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.
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).
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.
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.

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    • "Other correlations of proton spectroscopy measures examined in schizophrenia are connections with cognitive function disorders. Bertolino et al. observed a strong correlation between NAA level in the dorsolateral prefrontal cortex and activation of working memory, including prefrontal, temporal and lower parietal cortex [22]. Delamillieure et al. found a correlation between NAA level in the medial prefrontal cortex on the right side and outcomes of Stroop test in deficit schizophrenia patients (poorer outcomes were connected with lower NAA level) [23]. "
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    ABSTRACT: Proton magnetic resonance spectroscopy (1H MRS) allows for examining brain functions in vivo in schizophrenic patients. Correlations between N-acetylaspartate (NAA) level in the frontal lobe and cognitive functions and clinical symptoms have been observed. The aim of the present study was evaluation of relationship between clinical symptoms, cognitive outcomes and brain function in 1H MRS measures in schizophrenic patients. The study included a group of 47 patients with chronic schizophrenia. Patients were assessed by means of PANSS, CGI, and a battery of cognitive tests: WCST, TMT, and verbal fluency test. MRI and MRS procedures were performed. Regions of interest were located in the left frontal lobe, temporal lobe and thalamus. Metabolite (NAA, choline, myoinositol and Glx complex) ratios to creatine were calculated. We observed a significant negative correlation between myoinositol level in the frontal lobe and WSCT test performance. These data were confirmed by further analysis, which showed a significant correlation between WCST outcome, negative symptoms score, education level and myoinositol ratio in the frontal lobe. When analyzing negative symptoms as independent variables, the analysis of regression revealed a significant relationship between negative symptoms score and verbal fluency score, together with choline level in the thalamus. The above data seem to confirm a significant role of the thalamus--a "transmission station" involved in connections with the prefrontal cortex--for psychopathology development (especially negative) in schizophrenia. Moreover, our results suggest that a neurodegenerative process may be involved in schizophrenia pathogenesis.
    Medical science monitor: international medical journal of experimental and clinical research 06/2012; 18(6):CR390-8. DOI:10.12659/MSM.882909 · 1.43 Impact Factor
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    • "Prefrontal function and metabolism is altered in patients with severe psychiatric disorders (Andreasen et al., 1997; Drevets, 2001; Weinberger et al., 1994). For instance, cognitive deficits in schizophrenia patients are mediated by derangements in brain circuits involving the prefrontal cortex (Bertolino et al., 2000; Elvevag & Goldberg, 2000), and an imbalance in glucose metabolism between prefrontal cortex and several anatomically related areas has been described (Andreasen et al., 1997). Similarly, abnormal glucose utilization has been consistently found in prefrontal cortex of patients with major depression (decrease) and post-traumatic stress disorder (increase). "

    Psychiatric Disorders - Worldwide Advances, 10/2011; , ISBN: 978-953-307-833-5
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    • "In patients, the finding of an association between greater NAA concentration and better working memory supports evidence for the role of frontal lobe function in working memory using functional MRI and proton MRS in schizophrenia (Bertolino et al., 2000; Callicott et al., 2000; Ohrmann et al., 2007), although this association explained only a very small amount (3%) of the variance in NAA concentration that was additional to that explained by positive symptoms. "
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    ABSTRACT: This study investigated the clinical and neuropsychological correlates of N-acetyl aspartate (NAA) concentration in the anterior cingulate cortex (ACC) in schizophrenia, and explored whether ACC NAA concentration is sensitive to symptom change following cognitive behaviour therapy for psychosis (CBTp). Participants comprised 30 patients and 15 healthy controls who underwent magnetic resonance spectroscopy of the ACC and were assessed on frontal lobe based neuropsychological tasks. Twenty-four (of 30) patients were followed-up; 11 subsequently received 8-9 months of CBTp in addition to standard care (CBTp+SC) and 13 received SC only. At baseline (i) NAA and Cr concentrations were lower in patients compared to controls, (ii) in patients, NAA concentration correlated inversely with positive symptoms and general psychopathology (positive symptoms explained 21% of the variance; total variance explained=25%) and Cho concentration correlated inversely with positive symptoms, and (iii) in controls, NAA concentration correlated positively with working and short-term memory and Cr concentration inversely with executive function. NAA concentration tended to increase in CBTp+SC patients at follow-up (n=7 with usable data) concomitant with improvement in positive symptoms. NAA concentration may be more closely associated with symptoms and symptom change than frontal lobe based neuropsychological function in schizophrenia, perhaps because the latter is relatively stable during the long-term illness course.
    Psychiatry Research 06/2010; 182(3):251-60. DOI:10.1016/j.pscychresns.2010.02.008 · 2.47 Impact Factor
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