Groups of familial and sporadic schizophrenia patients demonstrated different resting rCBF patterns. The sporadic patients showed hypofrontality (left frontal gyrus at the principal sulcus, orbitofrontal cortex, anterior cingulate, and paracingulate cortices), whereas familial patients had left temporoparietal hypoperfusion (posterior Sylvian fissure at the superior and inferior parietal lobules, angular and supramarginal gyri). Both schizophrenia subgroups had increased rCBF in the parahippocampal gyrus, which has been strongly associated with positive schizophrenia symptoms (Bogerts 1997
) and in cerebellum and pons. The hypofrontal sporadic patients showed increased perfusion in the fusiform area, whereas the parietotemporal hypoperfusion in familial patients was accompanied by widespread subcortical hyperperfusion, including in the brainstem, amygdala, hippocampus, dentate gyrus, uncus, thalamus, and striatum. Comparisons between the two schizophrenia groups also showed significantly lower anterior cingulate and paracingulate rCBF for sporadic patients and increased sublobar claustrum and putamen rCBF for familial patients.
Negative schizophrenia symptoms have previously been associated with both left dorsolateral prefrontal and with left superior parietal association areas hypoperfusion, although they are more frequently associated with hypofrontality (Lahti et al 2001
; Liddle et al 1990
). The greater negative symptoms in the familial cases bolster a role for parietal dysfunction as a source of negative symptoms (Lahti et al 2001
). Resting and behavioral activation conditions engage different neural circuitry and cannot be readily compared. It is worth noting that resting hypofrontality may paradoxically produce greater task-related increases in rCBF, such that lower resting activity may translate into apparently greater activation for behavioral conditions. Perhaps this may contribute to the association between increased task related perfusion and poor performance observed in some schizophrenia studies that has been attributed to inefficiency (Callicott et al 2000
; Siegel et al 1995
The results of this study are unlikely to follow from methodologic limitations of SPECT imaging technology, and the groups were well matched for medication treatment and chronicity. The hypofrontal sporadic cases had significantly more years of education and lower negative symptoms ratings, showing that their hypofrontality was not explained by negative symptom severity. Similar educational and symptom differences between familial and sporadic groups have been observed in larger patient samples (Malaspina et al 2001
). Although SPM96 software carries with it some downside risk in terms of spatial localization of regions, similar widespread dysfunction in cortico-striato-thalamo-cortical and limbic circuitry as in the familial group was reported from a PET study of resting neuroleptic-naive schizophrenia patients (Andreasen et al 1997
). In addition to having decreased left parietal and increased thalamic and cerebellar rCBF, those patients also had lower rCBF in lateral, orbital, and medial prefrontal regions, similar to our sporadic group, as might happen if the groups in our study were combined. Andreasen proposed a “Unitary Model” for schizophrenia in which all of its phenomena resulted from such cortical-cerebellar disconnectivity (mediated by the thalamus), which interfered with the processes linking thought and action (Andreasen et al 1999
). A widespread disruption in cortical–subcortical circuitry, as seen in the familial cases, could arise from diverse factors affecting excitatory or inhibitory neuroregulation, including neuroreceptor abnormalities or neurodevelopmental pathology. Familial schizophrenia is a polygenic disorder, and individual relevant loci may each have only a minor effect on neurocircuitry function. A pattern of hypofrontality accompanied by increased medial temporal lobe (limbic) rCBF, as observed in these sporadic patients, is also commonly observed in schizophrenia imaging studies. A recent PET study of medication-free schizophrenia patients found that increased parahippocampal and cerebellar and decreased dorsolateral prefrontal and anterior cingulate rCBF accounted for the significant differences between schizophrenia patients and comparison subjects (Meyer-Lindenberg et al 2001
These results further suggest that subgroup differences in default neural activity may contribute to the conflicting findings concerning resting metabolism in patients with schizophrenia. The variable inclusion of subjects with disparate default metabolic profiles may explain such diverse prior imaging results as relative hyperfrontality, global hypoperfusion, only lateralized abnormalities and absent hypofrontality. These discrepant results have not been explained by age, gender, medication status, illness state, chronicity, or other methodologic differences and were largely attributed to the use of “resting” baseline conditions that did not adequately control cognitive activity. The prefrontal hypometabolism for cognitive tasks found in most studies may reflect a final common pathway related to the schizophrenia syndrome but be less indicative of heterogeneous subgroups than default neural activity. There are many analogous situations in medicine, such as congestive heart failure. Just as decreased cardiac output, particularly with a physical challenge, may define the congestive heart failure syndrome without indicating etiology, low prefrontal perfusion, particularly with mental challenge, may comparably characterize the schizophrenia syndrome without differentiating between the subgroups.
Three of the four general regions that are normally active in the default state were hypoperfused by the schizophrenia groups: the ventral medial prefrontal cortex (VMPFC) and dorsal medial prefrontal cortex (DMPFC) by the sporadic group and the posterior lateral cortices by the familial group. Neither group differed from the comparison group in posterior cingulate rCBF, a region that shows the highest default activity because it monitors the environment and allocates attention to relevant stimuli. Because default processing supports self-generated mental operations, including goal formation and conscious self-awareness (Binder et al 1999
; Frith 1996
; McGuire et al 1996
), this study bolsters the hypotheses that these processes are important in explaining schizophrenia (Raichle et al 2001
). The VMPFC is densely interconnected to the limbic system and participates in monitoring the environment and the internal milieu with respect to stimuli with emotional salience. The DMPFC includes the anterior cingulate and paracingulate cortices, whose activity accompanies monitoring or reporting one’s own mental state, such as self-generated thoughts, intended speech, and emotions, and which may represent the multifaceted self (Frith and Frith 1999
). The posterior lateral region, which includes the inferior parietal lobe and temporal and occipital areas at the posterior end of the Sylvain fissure and superior temporal sulcus, is involved in the intentional or unintentional recall of episodic memories and its relationship to language areas, consistent with providing language and thought concerning these representations. The region is active when the actions of others are imitated, which may be related to the development of empathy (Decety et al 2002
Although the presence of underlying regional structural abnormalities cannot be concluded from this functional imaging data, it is of interest that prominent volume reductions are reported in frontomedial and frontoorbital (paralimbic) cortices, middle frontal gyrus, anterior cingulate and paracingulate gyri, insula, and supramarginal gyrus for schizophrenia patients (Goldstein et al 1999
). Volume reductions in the inferior parietal cortex and prefrontal cortex are each found in about 60% of relevant morphometric studies (Shenton et al 2001
). Neuropathologic studies show increased neuronal density, consistent with volume loss, in the medial prefrontal and paracingulate cortices (Selemon et al 1995
), the principal sulcus (Selemon et al 1998
), and the anterior cingulate (Benes et al 2001
), although none of these have discriminated among subgroups of patients. The lateralized hypoperfusion we observed in the familial patients is congruent with the results of other studies that have categorized schizophrenia patients by family history. Some familial cases may derive from processes that disrupt lateralized neural functioning. In fact, genes controlling human brain asymmetries in language centers are purported to underlie genetic schizophrenia susceptibility (Crow et al 1998
Our findings are particularly striking given that these familial and sporadic subgroups are also likely to be heterogeneous, in part due to misclassification biases from family history methods. We minimized this problem by requiring the presence of chronic nonaffective psychoses in first- or second-degree relatives to define a case as familial. Such family history methods are vulnerable to underreporting of affective illness, substance abuse and personality disorders but are sensitive to the presence of broadly defined psychotic illness in relatives. Defined in this way, the familial and sporadic subgroups are expected to contain, respectively, greater proportions of cases with penetrable genes for psychosis versus de novo etiologies.
Resting neural activity may better indicate homogeneous subgroups within the schizophrenia syndrome that provide clues to disparate pathways than do activation studies. These resting neuroimaging results suggest that a significant portion of familial schizophrenia patients have a lateralized parietotemporal dysfunction and that a significant portion of sporadic patients have greater prefrontal and cingulate dysfunction. If these findings are replicated, particularly using other neuroimaging techniques, they may have indications for stratifying schizophrenia patients to yield more homogeneous subgroups for neuropathologic, genetic, and pharmaceutical studies.