The present study introduced a new parcellation method of the OFC, one largely based on sulcal information. The parcellation of OFC into three subregions revealed regionally specific patterns of OFC volume deficit in schizophrenia, with a smaller MiOG volume in schizophrenia, one not associated with the OFC sulcogyral pattern, although the pattern differed in the two groups. Additionally, within the smaller MiOG of the schizophrenia group, a VBM analysis of probability maps indicated the left anterior MiOG (area 11) was most robustly decreased compared to control group. We note here that, although left and right MiOG volumes clearly showed marked group differences, these differences were not sufficient to be diagnostic of schizophrenia. Smaller right MiOG volumes within the schizophrenia group were associated with a longer duration of illness, while a smaller left MiOG volume was associated with more severe positive formal thought disorder symptoms. Within the HC group, larger right MiOG volume was associated with better performance in the IGT, as well as higher general intelligence, independently. To our knowledge, this is the first report of a significant association between OFC volume and IGT performance.
Most of the previous OFC volumetry defined the OFC as a single ROI covering the entire ventral prefrontal surface, while some others (Crespo-Facorro et al., 1999
; Lacerda et al., 2003
; Ballmaier et al., 2004
) divided the OFC region into GR and other orbitofrontal region using the olfactory sulcus, the clearest orbitofrontal sulcus, as a boundary sulcus. The present parcellation approach made each OFC ROI less heterogeneous in terms of cytoarchitecture (Ongur et al., 2003
), compared to a single ROI covering the entire ventral prefrontal surface. For example, our LOG ROI exclusively contained a part of area 47 and our MiOG ROI successfully excluded most parts of area 10 including area 11 and area 13. To address the ambiguity of the lateral boundary issue, a highly geometric method has been previously applied in order to evaluate the OFC volume (Lacerda et al., 2003
). Although, this geometric method yielded a very high inter-rater reliability of more than 0.99, intuitively, it seems not to be as sensitive to inter-individual anatomical variation as is our own approach. Furthermore, their OFC ROI definition did not include most of area 47 but did include inferior part of frontopolar gyri (area 10) and part of medial wall area of prefrontal cortex, structures that are considered to be outside of the OFC.
To explore the significance of the MiOG volume deficit observed in the schizophrenia group further, we examined other factors, which might be associated with MiOG volume. We previously reported a sulcogyral pattern alteration in the `H-shaped' sulcus in schizophrenic subjects (Nakamura et al., 2007
). In the present dataset, the alteration in the sulcogyral pattern distribution was replicated in the schizophrenia group, possibly reflecting neurodevelopmental alteration or susceptibility to schizophrenia. However, this sulcogyral pattern was not associated with the MiOG volume, indicating that the regional grey matter volume deficit and its sulcogyral pattern alteration were independent. We did find the least common Type III sulcogyral expression, increased in the schizophrenia group, to be associated with a lack of the normal asymmetry in GR volume and smaller ICC volume, suggesting that the Type III expression may reflect a subgroup of schizophrenia patients characterized by more severe neurodevelopmental aberrations than patients without Type III. Although the smaller right MiOG volume was not associated with the patients' age at MRI scan or chlorpromazine-equivalent antipsychotic dosage, the longer the duration of the illness (starting from first hospitalization for psychosis) the smaller the MiOG. Although a longitudinal study will be needed for definitive conclusions, this finding would be compatible with a post-onset, time-dependent progression of volume loss or medication-related volume loss.
In terms of clinical and cognitive associations with OFC volume in the previous studies on schizophrenia, a smaller OFC volume was associated with more severe negative symptoms (Baare et al., 1999
; Gur et al., 2000
), social dysfunction (Gur et al., 2000
; Chemerinski et al., 2002
) and poor insight (Sapara et al., 2007
). In contrast, a larger OFC volume was associated with a greater level of aggression (Hoptman et al., 2005
) and more severe negative symptom (Lacerda et al., 2007
). Cognitive associations with OFC grey matter volume in schizophrenia have been reported in but a single paper (Hoptman et al., 2005
), with larger right OFC grey matter volume associated with poorer performance in the TMT.
Of particular note, the smaller left MiOG volume observed in the schizophrenia group was strongly associated with more severe positive formal thought disorder as measured by SAPS, especially in `circumstantiality', `tangentiality', `distractive speech' and `incoherence'. We speculate these features associated with left MiOG volume could reflect a milder form of suppression failure of evoked memory traces irrelevant to ongoing reality similar to `spontaneous confabulations' as described in non-psychiatric patients with OFC lesions (Schnider, 2003
). Schizophrenic patients with smaller MiOG volume could have more difficulty in monitoring ongoing reality in speech; in other words, it could be difficult for them to monitor their previous speech and properly adapt the ongoing speech to what had gone before, suppressing irrelevant activations from memory. This might result in enhanced `circumstantiality', `tangentiality', distractive speech' and `incoherence'.
How might this left MiOG association with formal thought disorder be related to our previously reported association between left Superior Temporal Gyrus (STG) volume and the degree of formal thought disorder, as assessed by the Johnston-Holzman measures (Shenton et al., 1992
)? Recent brain stimulation studies in awake individuals during brain tumour surgery showed that left inferior occipitofrontal fasciculus (IOFF) stimulation induced semantic paraphasia while left arcuate fasciculus stimulation induced phonological paraphasia (Duffau et al., 2005
; Mandonnet et al., 2007
). The authors proposed this IOFF-mediated dominant hemisphere neuronal circuit constitutes a `semantic ventral stream', one indispensable for semantic processing and linking language-related temporal cortical regions (including STG) with frontal lobe. Indeed, in schizophrenia, our fiber tractography study has revealed white matter abnormalities in the IOFF (Kubicki et al., 2006
). Combining these findings, we suggest altered neuronal interaction between left OFC and left posterior temporal region via IOFF could be a critical neuronal circuit for formal thought disorder in schizophrenia. Supporting this model, studies in our lab have found schizophrenics showed abnormally enhanced activation of the STG in semantic encoding (Kubicki et al., 2003
) and decreased left inferior prefrontal cortex activation. This abnormally enhanced activation could interact with an OFC failure of suppression of unrelated associations. Clinically, evaluation of patients with IOFF lesions in a dominant hemisphere becomes very interesting in terms of effects of disruption of the proposed neuronal circuit model on formal thought disorder.
On the IGT, the present schizophrenia group demonstrated poorer performance as compared with the HC group. The time course of the gambling score () was markedly contrasting between the groups, and the deficit pattern we found in the schizophrenia group was similar to that reported in patients with ventromedial prefrontal lesions (Bechara et al., 2000
). However, IGT performance in studies of schizophrenic subjects has been inconsistent; some of the previous studies reported poorer performance in schizophrenic subjects (Beninger et al., 2003
; Ritter et al., 2004
; Bark et al., 2005
; Shurman et al., 2005
), consistent with the present results, while some others reported negative findings (Wilder et al., 1998
; Cavallaro et al., 2003
; Rodriguez-Sanchez et al., 2005
The present chronic schizophrenia group had both smaller MiOG volume and poorer IGT performance than the HC group, however, in schizophrenics, the MiOG volume was not associated with IGT performance. Interestingly, the larger MiOG volume was associated with better IGT performance within the HC group, independent of general intelligence. Of note, WCST performance was not associated with OFC volumes or IGT performance. This specific biological association between MiOG volume and IGT performance may reflect normal variability in the decision-making process consequent to OFC structural variability, and is supportive of the validity of our present OFC ROI definitions. Milad et al. (2005)
reported quantitative anatomical–functional association in medial OFC between cortical thickness and fear extinction memory in healthy subjects. The present HC subject finding would add another anatomically based substrate of OFC functional variation among healthy individuals. Within the patient group, disease-related factors such as duration of the illness or the usage of psychotropics might confound the measurement of OFC volume, making it difficult to detect the same association that we observed in the HC group.
Group comparisons in MiOG probability maps suggested that the morphological alteration in MiOG of schizophrenic patients is stronger in anterior heteromodal (neocortical) region than in posterior paralimbic region. This contrast may account for poorer patient group performance of IGT, which is related to abstract reward evaluation. Also, this finding would be compatible with the hypothesis of heteromodal association cortices as a major site of abnormalities in schizophrenia (Ross and Pearlson, 1996
As a methodological limitation of the present study, we note that gender frequency was not matched between the two study groups and the schizophrenia group included only males. Thus, it was impossible to control for gender in volume comparison and also to investigate OFC sexual dimorphism. Future studies with larger samples including both genders are needed.
In conclusion, the present study applied a new anatomically based OFC parcellation and revealed a subregion-specific pattern of OFC volume deficit in schizophrenia, The OFC volume deficit was associated with longer duration of illness and more severe positive formal thought disorder but not with OFC sulcogyral pattern. The schizophrenia group exhibited poorer performance in the IGT, but OFC volume was not correlated with IGT performance. In contrast, the HC group showed a quantitative association between right MiOG volume and IGT performance.