تغییرات چین سینوسی مغز فرونتال میانی در اسکیزوفرنی؛ رابطه با طول مدت بیماری و اختلال در عملکرد اجرایی

Executive functioning is consistently impaired in schizophrenia, and it has been associated with reduced gray matter volume in prefrontal areas. Abnormalities in prefrontal brain regions have also been related to the illness duration. The aim of the study was to investigate the effect of executive functioning decline and chronicity in prefrontal regions of patients with schizophrenia. Participants comprised 33 schizophrenic patients, 18 with duration of illness (DoI) shorter than 10 years and 15 with duration of illness longer than 10 years. In addition, 24 healthy controls served as a comparison group. Participants performed the Wisconsin Card Sorting Test (WCST) and underwent structural magnetic resonance imaging. Patients with longer DoI showed significant reduction of gray matter volume in the left medial frontal gyrus compared with healthy controls. Moreover, there was a trend for greater gray matter volume decrease in patients with a longer illness duration compared with patients with shorter illness duration. There was no interaction between the volume of the left medial frontal gyrus performance on the WCST. The present study supports the hypothesis that medial frontal gyrus alterations in schizophrenia are sensitive to duration of illness. These alterations were not associated with executive functioning.

During the last two decades, voxel-based morphometry (VBM), a whole-brain automated method used to investigate regional brain functional and structural alterations (Ashburner and Friston, 2000), has been extensively applied to study the neuroanatomy of schizophrenia. The large number of individual studies has been recently reviewed in a voxel-based meta-analysis including 48 VBM studies (Bora et al., 2011). This study found that patients with schizophrenia have significant gray matter reductions compared with healthy controls, in the left and right insula, inferior frontal gyrus, bilateral thalamus and bilateral dorsal medial frontal gyrus/anterior cingulate. These gray matter abnormalities have been associated with the neurobiology of the disorder and they are also thought to underlie its clinical expression, including positive, negative, psychosocial and cognitive symptoms. In particular, there is specific evidence that cognitive dysfunctions are already evident in the early stages of the disorder, during the first episode of psychosis, and also during the prodromal phase (Fusar-Poli et al., 2012a). Recent studies suggest that patients with schizophrenia suffer from a “dysexecutive syndrome”: independent of the executive task, patients with schizophrenia have consistently shown deficits in executive functioning when compared with a healthy control group (Raffard and Bayard, 2012). One of neuropsychological instruments most widely used to assess executive functioning in schizophrenia is the Wisconsin Card Sorting Test (WCST) (Nelson, 1976). The WCST is a multifactorial and complex test that involves different cognitive functions. In particular, capacity of ‘working memory’, along with attentive and executive functions, is considered a relevant factor responsible for the subjects׳ performance. Performance in the WCST is particularly impaired in schizophrenia (Heinrichs and Zakzanis, 1998), and it has been found to be associated with reduced gray matter volume in prefrontal areas (Seidman et al., 1994). A previous study (Rüsch et al., 2007), comparing patients with good versus poor WCST performance, found that prefrontal cortex abnormalities were related to WCST performance. This finding was subsequently confirmed by another study in which gray matter alterations in the prefrontal cortex were associated with poor performance on the WCST (Bonilha et al., 2008). Other studies, however, did not find associations between gray matter alterations and WCST performance in patients with schizophrenia, although they found relations with other neurocognitive tasks (Antonova et al., 2005, Premkumar et al., 2008, Segarra et al., 2008 and Wolf et al., 2008). Considering the above findings, there is not yet consistent evidence indicating that prefrontal alterations in gray matter volume are directly related to WCST performance. The prefrontal cortex is strongly associated with cognitive deterioration in schizophrenia, but the dynamic process underlying such changes is relatively unaddressed (Cahn et al., 2002 and van Haren et al., 2007). Several factors, such as symptom severity and prolonged antipsychotic exposure, are known to influence the progressive brain changes observed in schizophrenia. Among these factors, the duration of illness is well known to play a significant role. Several studies investigated the association between the duration of illness and gray matter alterations, and the most consistent finding is a negative association with the volume of prefrontal (Molina et al., 2004, Premkumar et al., 2006 and Tomelleri et al., 2009) and temporal regions (Hietala et al., 2003 and Tomelleri et al., 2009). The aim of the present study is to investigate the impact of duration of illness on gray matter volume and its relationship with executive functioning. We investigated this by comparing schizophrenia patients with more than 10 years׳ illness duration, schizophrenia patients with less than 10 years׳ illness duration and healthy controls. Our first hypothesis was that duration of illness would be associated with brain volume reductions, mostly in the prefrontal cortex (Molina et al., 2004, Premkumar et al., 2006 and Tomelleri et al., 2009). Our second hypothesis was that there would be a significant interaction between duration of illness and executive dysfunction as measured by the performance on the WCST across our groups (Rüsch et al., 2007 and Bonilha et al., 2008).

Demographic and clinical data of the sample are reported in Table 1. There were no significant differences in gender, level of education, number of admissions, and antipsychotic dose at the time of the scanning and TIV across the three groups. Post-hoc analyses showed the SCZ>10 years group was significantly older than the other two groups (p<0.001). Post-hoc analyses also showed that the SCZ>10 years group had a higher mean PANSS CogF score compared with the SCZ≤10 years group (p=0.03). Table 1. Demographic and clinical characteristics of the sample. Categorical variable HC (N=24) SCZ≤10 years (N=18) SCZ>10 years (N=15) Test statistics N % N % N % χ2 P Gender Male 9 37.5 8 44 9 60 3.409 0.065 Female 15 62.5 10 56 6 40 Continuous variables Mean S.D. Mean S.D. Mean S.D. F P Age 30.3 10.2 29.2 8.6 42.7 7.4 11.209 <0.001 Years of education 15.5 2.3 13.8 3.1 14.8 3.8 1.572 0.217 Tot intracranial Vola 1511.8 155.0 1514.3 159.1 1471.6 199.8 0.331 0.719 WCSTb Completed categories 4 1.7 2.8 2.6 1.7 2.2 4.155 0.022 Perseverative responses 30.1 16.2 36.1 30.3 66.8 35.7 7.405 0.002c Perseverative errors 24.2 13.8 38.5 27.5 45.9 33.3 3.459 0.04 PANSS Positive 7 0 14.9 5.3 15.3 6.2 24.525 <0.001 Negative 7 0 21.1 7.3 24.9 9.4 45.246 <0.001 General 18 1.7 37.4 9.3 40.6 8.9 62.542 <0.001 Total 32 1.9 73.5 19.2 80.8 20.3 63.011 <0.001 Cognitive factor 3.1 0.3 7.2 3.4 9.6 3.3 32.369 <0.001c GAFd 91.4 2.3 52.9 13.6 47.8 12.8 112.072 <0.001 Duration of illness 4.9 3.5 17.2 5.1 −8.197 <0.001 CPZ Eq 302.7 167.9 369 243.3 −0.922 0.363 N admissions 1.5 1.9 1.7 2 −0.247 0.807 SCZ: schizophrenic patients; HC: healthy controls; PANSS: Positive and Negative Syndrome Scale; GAF: Global Assessment of Functioning; CPZ Eq: chlorpromazine equivalents. a Total intracranial volume, mean and S.D. are reported in cc. b SCZ≤10 years N=16; SCZ >10 years N=11. c Bonferroni post-hoc test significant between SCZ groups (see text). d SCZ >10 years N=13. Table options 3.2. Behavioral performance There were significant between-group differences in the three WCST performance measures (Fig. 1). Post-hoc analyses of CAT showed significant differences between the HC and the SCZ>10 years groups (p=0.02, Cohen׳s d=1.21), but not between the HC and the SCZ≤10 years groups. With respect to PR scores, both the HC group and the SCZ≤10 years group performed better than the SCZ>10 years group (respectively, p=0.001, Cohen׳s d=1.56, and p=0.013, Cohen׳s d=0.98). Finally, the HC group performed better on the PE as compared with the SCZ>10 years group (p=0.047, Cohen׳s d=1.01); conversely, there were no PE differences between the SCZ>10 years and the SCZ≤10 years groups. Since there was a baseline group difference in age, age was entered as covariate of no interest with no significant changes on the above results. PANSS Negative scores were positively correlated with PR (r=0.393, p=0.043) and negatively correlated with CAT (r=−0.404, p=0.037) in the patient group, but these results did not survive the correction for multiple comparison. Full-size image (26 K) Fig. 1. Behavioral differences in WCST performance between the three groups: A, difference in completed categories (CAT); B, difference in perseverative responses (PR); C, difference in perseverative errors (PE). The figure shows the mean±1 standard error for each group. CAT: HC=4±0.4, SCZ≤10 years=2.8±0.7, SCZ>10 years=1.7±0.8; PR: HC=30.1±3.5, SCZ≤10 years=36.1±7.6, SCZ>10 years=66.8±10.8; PE: HC=24.2±3, SCZ≤10 years=38.5±6.9, SCZ>10 years=45.9±11.