Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis

Abstract

Common abnormalities within the schizophrenia spectrum may be essential for the pathogenesis of schizophrenia, but additional pathological changes may be required for the development of full-blown schizophrenia. Clarifying the neurobiological similarities and differences between established schizophrenia and a milder form of schizophrenia spectrum disorder would potentially discriminate the pathophysiological mechanisms underlying the core features of the schizophrenia spectrum from those associated with overt psychosis. High-resolution MRIs were acquired from 25 patients with schizotypal disorder, 53 patients with schizophrenia and 59 healthy volunteers matched for age, gender, handedness and parental education. Volumetric measurements of the medial temporal structures and the prefrontal cortex subcomponents were performed using consecutive 1-mm thick coronal slices. Parcellation of the prefrontal cortex into subcomponents was performed according to the intrinsic anatomical landmarks of the frontal sulci/gyri. Compared with the controls, the bilateral volumes of the amygdala and the hippocampus were reduced comparably in the schizotypal and schizophrenia patients. The parahippocampal gyrus volume did not differ significantly between diagnostic groups. Total prefrontal grey matter volumes were smaller bilaterally in the schizophrenia patients than in the controls and the schizotypal patients, whereas the schizotypal patients had larger prefrontal grey matter than the controls in the right hemisphere. In the schizophrenia patients, grey matter volumes of the bilateral superior frontal gyrus, left middle frontal gyrus, bilateral inferior frontal gyrus and bilateral straight gyrus were smaller than those in the controls. The schizophrenia patients also had reduced grey matter volumes in the right superior frontal gyrus, bilateral middle frontal gyrus and right inferior frontal gyrus relative to the schizotypal patients. Compared with the controls, the schizotypal patients had larger volumes of the bilateral middle frontal gyrus and smaller volumes of the right straight gyrus. There were no significant between-group differences in volumes of the ventral medial prefrontal cortex or the orbitofrontal cortex. These findings suggest that volume reductions in the amygdala and hippocampus are the common morphological substrates for the schizophrenia spectrum, which presumably represent the vulnerability. Additional widespread involvement of the prefrontal cortex in schizophrenia may lead to the loss of inhibitory control in other brain regions and suggests (although it is not specifically be related to) its critical role in the manifestation of overt psychosis.

Cortical gray and white matter volume in unmedicated schizotypal and schizophrenia patients

“…This may result from some variation sparing SPD patients from the full development of schizophrenia, an adaptive response to symptoms of the schizophrenia spectrum, or an associated developmental anomaly among other possibilities. Consistent with our findings, Suzuki et al (2005) demonstrated that the prefrontal volumes were largely preserved in SPD in contrast to widespread prefrontal involvement in schizophrenia. It is of interest that in our prior FDG-PET study (Buchsbaum et al 2002) using a task involving verbal working memory in a subgroup of subjects from this study, metabolic rates in BA10 were distinctly higher in SPD patients compared with healthy controls while schizophrenia patients were lowest and this was determined in the same way as in our present study.…”

“…Thus, for the frontotemporal deficit, the schizophreniaspectrum concept is supported with SPD patients intermediate between healthy controls and schizophrenia patients. This spectrum finding suggests that SPD probably represents a milder form of disease along the schizophrenia continuum which is consistent with the review of Dickey et al (Dickey et al 2002a) and other morphometric studies involving SPD and schizophrenia patients Suzuki et al 2005;Takahashi et al 2006b).…”

“…While SPD and schizophrenia patients appear to show some common temporal lobe abnormalities, SPD patients do not appear to show volumetric decreases in frontal cortex to the same extent as schizophrenia Siever et al 1990;Siever and Davis 2004;Siever et al 2002;Suzuki et al 2005). Reductions in frontal volume are associated with the deficit-like symptoms of SPD, implying that patients with smaller frontal lobe volume are more likely to display traits such as asociality (Diwadkar et al 2006;Raine et al 1992;Siever et al 1993).…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Therefore, a common result in vulnerable individuals could be in a form of contribution to the 'spiraling distress cycle' (Goldstein and McEwen, 2002;Koob and Le Moal, 2001) depicted in Figure 4, whereby excessive palatable food consumption provoked by its enhanced salience and conditioned learning produces additional deterioration in emotional and behavioral problems, leading to further consumption that may eventually produce a transition from excessive eating to food addiction (Tuomisto et al, 1999). Neuroimaging findings 'Hypofrontality', that is, k in cerebral metabolism and blood flow at baseline and when challenged by cognitive tasks (Weinberger and Berman, 1996), correlated with negative symptoms (Wolkin et al, 1992;Andreasen et al, 1992) 'Hypofrontality' (Volkow et al, 1992;) during withdrawal at baseline and when exposed to natural reinforcers (Garavan et al, 2000), correlated with drug craving (Volkow et al, 2001a) Putative mechanisms k In tonic dopaminergic activity leads to k in tonic glutamatergic activity owing to development-related changes Lieberman et al, 1997;Laruelle, 2000), cortical pyramidal cells may be involved in these changes (Sweet et al, 2004;Lewis et al, 2003) k In basal glutamatergic and dopaminergic activity owing to drug-induced dysmorphisms of the cortical pyramidal cells (Kelley and Schiltz, 2004; Motivational correlates k In initiative towards attainment of natural rewards (Tamminga and Buschbaum, 2004); k in inhibitory control (Suzuki et al, 2005) k In initiative towards attainment of natural rewards; k inhibitory control (Goldstein and Volkow, 2002;) mActivity…”

Cingulate gyral reductions are related to low executive functioning and psychotic symptoms in 22q11.2 deletion syndrome

“…As part of the limbic system, the CG is involved in executive function and shares numerous connections with prefrontal cortex and hippocampus (Bush, Luu, & Posner, 2000), two other regions significantly altered in schizophrenia (Gur, Keshavan, & Lawrie, 2007;Suzuki et al, 2005). Moreover, cognitive impairments linked with both of these structures, specifically executive function and working memory, are considered as putative endophenotypes and core features for schizophrenia Mohamed, Paulsen, O'Leary, Arndt, & Andreasen, 1999;Silver, Feldman, Bilker, & Gur, 2003;Snitz, Angus, MacDonald, & Carter, 2006).…”