Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia

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Abstract

Rationale

Cognitive deficits are of particular importance in schizophrenia since they are strongly associated with poor prognosis. We investigated the relationship between prefrontal cortical atrophy as measured by MRI and the neuropsychological performance of participants diagnosed with DSM-IV-TR schizophrenia.

Methods

Fourteen unmedicated adult patients and thirteen matched controls were studied. Subjects underwent MRI yielding 1 mm isotropic T1-weighted images. Voxel based morphometry was applied to all images using SPM5. The mean gray level of Brodmann area (BA) 9 was also extracted and evaluated using simple regression along with relative score differences on patients neuropsychological tests compared to controls.

Results

Patients exhibited a poorer performance on the Controlled Word Association Task (COWAT), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Patients also presented a greater level of apathy as indexed by the Apathy Evaluation Scale (AES). There was a significant decrease in gray matter volume in patients with schizophrenia in left supplementary motor area, bilateral superior frontal gyrus, left middle frontal gyrus, right opercular area, left angular gyrus, left superior temporal gyrus and left cerebellar hemisphere. Within the schizophrenia group, decreased BA9 gray matter volume was correlated with poorer performance on the WCST and TMT-B.

Conclusion

Prefrontal gray matter abnormalities in schizophrenia patients may be associated with some symptoms including difficulties with set-shifting and decreased mental flexibility. Further studies evaluating prefrontal connectivity may clarify if such impairment results from abnormalities of the frontal area alone, or are a result of altered networks involving the frontal and extra-frontal areas.

Introduction

Schizophrenia is a devastating neuropsychiatric illness. The overall cost of schizophrenia was estimated to be $62.7 billions in the US in 2002 (Wu et al., 2005). Findings suggest that structural and functional brain abnormalities (Walter et al., 2007, Kuperberg et al., 2007) coexist and are possibly related in the pathological processes underlying the illness.

Structural brain studies employing neuroimaging, particularly Magnetic Resonance Imaging (MRI), have demonstrated that patients with schizophrenia show consistent and reproducible structural brain abnormalities. Cortical loss associated with schizophrenia is progressive (van Haren et al., 2007), more intense in the early course of the disease (Cahn et al., 2002), and related to clinical outcome (Cahn et al., 2002, Cahn et al., 2006).

Even though initial studies reported a general loss of brain volume and subsequent ventricular enlargement (Lawrie and Abukmeil, 1998, Shenton et al., 2001), it is now believed that cortical atrophy preferentially affects a subset of brain regions in schizophrenia. Modern automatic segmentation techniques of structural MRI, combined with whole brain rater independent voxel based analyses, demonstrated that regional gray matter atrophy is more intense in regions such the prefrontal cortex, superior temporal gyrus, caudate and the medial temporal lobe (Anderson et al., 2002, Kwon et al., 1999, van Haren et al., 2007, Chua et al., 2007, Hirayasu et al., 2001). Importantly, such regional atrophy has been related to clusters of clinical symptoms. For instance, progressive prefrontal gray matter atrophy is related to more pronounced negative symptoms (Mathalon et al., 2001) or reduced insight (Sapara et al., 2007). The volume of frontal parietal and temporal regions is linked to reality distortion (Whitford et al., 2005) and finally, abnormalities in the superior temporal gyrus are associated with both psychotic and negative symptoms (Crespo-Facorro et al., 2004a, Crespo-Facorro et al., 2004b) and abnormalities in visual and auditory evoked potentials (Egan et al., 1994).

Of the wide range of clinical symptoms and deficits observed in schizophrenia, higher cognitive deficits are of particular importance since they are strongly associated with poor prognosis (Hofer et al., 2005). Schizophrenic patients show significant deficits in executive function, working memory, and episodic memory (Boeker et al., 2006). These deficits are correlated with well documented patterns of functional neuroimaging (Callicott et al., 2003). It is still unclear if the cognitive profile observed on neuropsychological test performance or the abnormal functional imaging studies implicating in part the dorsolateral prefrontal cortex are a consequence of a specific structural atrophy of the prefrontal cortex, as suspected by some primate (Goldman-Rakic, 1999), and post-partum studies (Selemon et al., 2002) or reflect dysfunctional larger neural networks (Zhou et al., 2007, Wolf et al., 2007).

In the current study, we aimed to investigate the relationship between regional prefrontal atrophy and higher cognitive neuropsychological performance of participants with schizophrenia. Specifically, we hypothesized that gray matter atrophy to the dorsolateral prefrontal cortex, in particular Brodmann area 9 (BA9), will be associated with poor neuropsychological performance on tests that index executive functioning, attention, and word fluency in subjects with schizophrenia compared to matched controls.

Section snippets

Participants

Fourteen participants (11 men, mean age = 40 ± 7 years) and thirteen controls (11 men, mean age = 35 ± 8 years) were enrolled in this study. The majority of participants with schizophrenia came from regional community mental health clinics and a local homeless shelter. Occasionally participants were recruited from the inpatient units operated by the Department of Psychiatry at the Institute of Psychiatry and Ralph H. Johnson Veterans Affairs Medical Center in Charleston, SC. Patients met DSM-IV-TR

Results

There was no significant difference in gender distribution (Pearson's Chi square = 0.008, p = 0.927) or age (t(24) = 1.8, p = 0.1) between controls (n = 13) and patients (n = 14). There were also no differences in the frequency of smokers between groups (Pearson's Chi square = 0.06, p = 0.9), marital status (Pearson's Chi square = 1.081, p = 0.792), handedness (Pearson's Chi square = 1.63, p = 0.65) and race (Pearson's Chi square = 2.3, p = 0.5). There was no difference in time of education in years between groups ((t(24) =

Discussion

To our knowledge this is the first study to demonstrate in unmedicated patients with schizophrenia that the relative impairment in mental flexibility usually seen in schizophrenia is directly related to a relative reduction of gray matter volume in the left dorsolateral prefrontal cortex. We also report regional gray matter atrophy in prefrontal cortex, superior temporal gyrus and cerebellum, consistent with proposed neuronal networks implicated in the pathophysiology of schizophrenia.

It is

Role of funding source

The study was funded by NIMH MH065630-01A1 (ZN).

Contributors

National Institute of Mental Health (NIMH) MH065630-01A1 (ZN).

Conflict of interest

Research grant support: National Institute of Mental Health (NIMH), National Alliance of Research on Schizophrenia and Depression (NARSAD), Hope for Depression Research Foundation (HDRF), Neuronetics Inc, Cyberonics Inc, Medtronic Inc., Eli Lilly, Neuropace, Integra.

Consultant: Neuronetics Inc, Cyberonics Inc., Avanir Pharmaceutical, Aventis Pharmaceutical, Neuro pace.

Speaker Bureau: Cyberonics Inc.Stocks and other funds: None.

All the authors do not have any direct conflict of interest

Acknowledgments

The study was funded by NIMH MH065630-01A1 (ZN). The authors would like to thank Drs Scott Christie and Patricia Nnadi and their clinical teams; Crisis Ministries Homeless Shelter, Charleston, SC; and the South Carolina Department of Mental Health for their assistance in recruiting participants.

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