The present study compared the distribution of OFC sulcogyral patterns in patients with schizophrenia and age-matched control subjects. Similar to a previous study of healthy volunteers, findings from the present study demonstrated substantial stability of the OFC sulcogyral pattern distribution in the current sample of control subjects. That is, controls manifested almost the identical orbitofrontal sulcogyral pattern reported by Chiavaras and Petrides (P = 0.90–0.95), where the distribution was significantly different between the left and right hemisphere (Type I: right>left, Type II, III: left>right, χ2 = 6.41, P = 0.041). This high concordance between two different healthy samples, in their age ranges (mean age: 25 versus 40 years old), suggests the longitudinal stability of the OFC sulcogyral pattern distribution following neurodevelopment.
In contrast, the patient group showed a significantly different distribution of sulcogyral patterns from that of the age-matched control group. First, the patient group did not show the expected asymmetry in the left and right hemispheres that was observed in the healthy control group. That is, whereas healthy controls showed greater right than left asymmetry for Type I expression, and a greater left than right asymmetry for both Type II and Type III expressions, the patients did not. Of further note, the most frequent Type I expression was decreased and the rarest Type III expression was increased in schizophrenia, relative to controls, although the frequency of Type II was almost the same for the two groups. Additionally, within the right hemisphere, subjects with Type III showed a 2.84-fold risk of being categorized in the patient group, compared to those without Type III.
The present study thus provides substantial evidence of altered sulcogyral pattern in orbitofrontal cortex in schizophrenia population. Although longitudinal stability of the sulcogyral pattern should be confirmed in a future study with longitudinal design, the pattern is not likely to change over time following neurodevelopment. Further, while one might argue that longitudinal deterioration in global prefrontal structure might account for changes in the sulcogyral pattern, we think this unlikely as this pattern is set in neurodevelopment and is independent of brain tissue volume changes. We thus interpret findings of altered distribution (increased Type III and decreased Type I) of the sulcogyral pattern in the schizophrenia group as reflecting a possible risk factor or susceptibility to schizophrenia, rather than secondary to the effects of illness. Indeed, in the present cross-sectional dataset, the OFC sulcogyral pattern was not associated with subjects' age at MRI scan, length of the illness, or antipsychotic dosage. Although the sulcogyral pattern of the ‘H-shaped’ sulcus cannot serve as a diagnostic marker of schizophrenia, it could provide a morphological trait marker in the ventral prefrontal cortex, possibly related to a neurodevelopmental variation in the prefrontal paralimbic region.
OFC sulcogyral pattern and outcome
A further question we had is: within the schizophrenia group, does the OFC sulcogyral pattern affect patients' outcomes? We tried to address this question using a categorical regression analysis, which revealed that the least commonly occurring Type III expression in healthy controls was increased in the schizophrenia group was indeed associated with poorer outcome, including poor socioeconomic status, poor cognitive performance and more severe clinical symptoms. In contrast, the most commonly occurring Type I expression in healthy controls, was decreased in the schizophrenia group, and was associated with better outcome, including better cognitive performance and mild clinical symptoms. Even in the control group, Type I expression was associated with better cognitive performance. Type III for the control sample also was associated with perseveration, which is often viewed as indicative of difficulties in switching attentional set. However, the meaning of this association is complicated by other significant correlations with better cognitive performance. Due to the nature of the sulcogyral pattern, which seems to be stable over time following neurodevelopment, observed clinical associations with specific sulco-gyral pattern could reflect the heterogeneity (clinical and biological variability) of schizophrenia, itself, rather than secondary change in the sulcogyral pattern due to environmental factors linked to clinical outcome.
Type III expression in patients with schizophrenia was also strongly associated with poor socioeconomic status, consisting of educational and vocational background. This association is independent of parental socioeconomic status, cognitive function and clinical symptom severity. Therefore, this might suggest that schizophrenic patients with Type III expression have more difficulty in social adjustment than patients without Type III expression. Although the underlying mechanism between brain morphology and social neuroscience should be further investigated, this morphometric marker could be used as a potential clinical marker in the field of psychiatric rehabilitation.
Of further note, within each group, the Type I expression was associated with better cognitive performance, particularly for perceptual organization. In addition, collapsing both groups and covarying full-scale IQ, Type I expression was associated with better performance in working memory index.
For clinical symptoms the results also provided evidence linking Type III expression with poorer outcome and Type I and II expressions with better outcome. Of particular interest, PANSS symptoms that might capture some of the dimensions of the elusive but disabling social disturbance of schizophrenia were more closely associated with Type III expression. These symptoms consisted of passive/apathetic social withdrawal, active social avoidance and emotional withdrawal, which together form a newly introduced ‘withdrawal’ factor (Van den Oord et al., 2006
). This factor seems to reflect social deficit more specifically than an overall negative symptom factor. In contrast, Type I and II expressions were associated with milder symptoms in the positive factor.
For total PANSS score, Type III expression was also associated with higher score (β = 0.45, F = 5.54, P = 0.024), although ANOVA for hypothesis testing of model fitting was only nearly significant (P = 0.067). These clinical associations, especially for the positive factor, might at least partly reflect responsiveness to medication treatment, because all of the present patients were chronically treated patients (duration of illness was 19.5 years on average), except for three first-episode patients who were included in the sample. That is, while speculative, the Type III pattern might be related to more treatment-resistance, and the Type I pattern might be related to more treatment-effectiveness.
Although available data in MPQ were limited, Type III expression in the schizophrenia group was negatively associated with ‘Constraint’ and positively associated with ‘Negative Emotionality’, both of which might reflect impulsivity, as predicted. These associations evoke antisocial and disinhibitory personality changes, commonly observed in patients with ventromedial prefrontal damage or degeneration (Cummings, 1993
), although it is difficult to differentiate intrinsic personality traits from secondary personality changes due to schizophrenic psychosis. Within controls, Type II was positively associated with the ‘Positive Emotionality’ trait.
Among the significant functional–anatomical associations in the patient group, the following three associations of Type III–poor SES (poor social achievement), Type III–severe ‘withdrawal’ PANSS factor (social withdrawal/avoidance), and Type III–less ‘Constraint’ MPQ trait (impulsivity and risk-taking), were found to be more independent and specific than other significant associations, using ordinal regression analyses. Of particular interest, these three variables are specifically related to social functioning, suggesting that the Type III expression may serve as a trait marker for poor social adjustment in schizophrenic population.
Type III expression was also associated with smaller ICC volume in the schizophrenia group, although body sizes of the two subgroups were unknown. This observation may suggest that Type III expression was part of a systematic alteration in the early phase of neurodevelopment. Since adult ICC volume is quite stable over time, this structural association between Type III expression and smaller ICC volume suggests that the increased expression of Type III is not associated with the secondary effects of the illness, but is associated with neurodevelopment (Woods et al., 2005
). Additionally, the lack of normal asymmetric distribution observed in the patient group suggests an alteration in genes that regulate early cortical development, as evidence suggests genetic involvement in human cerebral cortical asymmetry (Sun et al., 2005
). Finally, this pattern may also reflect individual difference in ‘gyrogenesis’ within OFC, involved in regional neurobiological properties such as local connectivity and cytoarchitecture (Armstrong et al., 1995
; Rakic, 1988
Schizophrenic patients with Type III may, therefore, represent a subpopulation of schizophrenia, which might be characterized by an early neurodevelopmental aberration together with a more severe clinical picture including social deficit symptoms and poor treatment response, compared to schizophrenic patients without Type III.
Based on these findings, we view the OFC region, a major part of the social brain, as likely involved in many neuropsychiatric disorders, including, in particular, schizophrenia, affective psychosis, obsessive–compulsive disorder, dementia and a broad range of addiction. The OFC sulcogyral pattern classification could be investigated as a common modulator in social functioning in these different clinical entities.
We note a few limitations in our interpretation of the present results. First, the three categorical sulcogyral patterns were observed across both controls and patients, and we did not include a non-schizophrenic psychosis group to determine the specificity of the findings to schizophrenia. Thus the altered sulcogyral pattern distribution should be regarded as a susceptibility to schizophrenia, but not necessarily as a specific marker for schizophrenia. Second, Type III expression was associated with poorer social functioning in the patient group but not in the control group, suggesting a disease-specific association. We caution, however, that the sample size of controls having Type III is small due to its low expression rate and there is some missing data for the clinical/cognitive measures, thereby inflating the risk of false negatives. For these reasons, we think we should be cautious in concluding group specificity of the poor social functioning–Type III association. Third, interrater reliability of 0.84 for the sulcogyral pattern classification is high, though not a perfect association, thus suggesting perhaps some uncertainty in the classification. In reviewing each case, we note that out of the 50 hemispheres (25 cases), six hemispheres showed a discrepancy between the two raters. More specifically, three out of the six discrepancies were disagreements between Types I and II, and the other three were disagreements between Types I and III. In these controversial hemispheres, the sulcus was disrupted in a few consecutive axial slices and it was connected in a few consecutive axial slices, which made judgement different between the raters. We point out, however, that all of the measures were done by one person (M.N.), and the interrater reliability measures did not change the original determination of Type I, II or III expression. We note that better spatial resolution of MRI data might reduce this kind of ambiguous pattern.
In conclusion, the present study revealed that the orbitofrontal sulcogyral pattern was altered in schizophrenic population, where the most frequently expressed Type I was decreased, and the least frequently expressed Type III was increased in the schizophrenia group, with a lack of normal asymmetrical distribution of the sulcogyral pattern. Furthermore, within the schizophrenia group, Type III expression was associated with poorer socioeconomic status, poorer cognitive function, more severe clinical symptoms (including increased apathy) and impulsivity as reflected in aggressive and reckless personality traits. In contrast, the Type I expression was associated with better cognitive function and milder clinical symptoms. The former was similar to findings in the healthy control group, where the Type I expression was associated with better cognitive function. These findings, taken together, suggest that the orbitofrontal sulcogyral pattern could be used as a morphometric trait marker in the fields of brain research and also clinical neuropsychiatry, and, that for a subset of patients with schizophrenia, Type III expression might also serve as a predictive marker for poorer social ability.