Neuronal networks showing low frequency BOLD signal fluctuations at rest are involved in important ongoing brain functions. In this study, we focused on the DMN because brain regions within this network may be particularly relevant to the origin and experience of mood and psychotic symptoms (Buckner et al., 2008
; Williamson 2007
; Greicius et al., 2007
). In particular, the pattern of DMN abnormalities in acutely ill subjects is interesting to contrast with previous studies of stable outpatients because acute psychopathology may be associated with more pronounced abnormalities in brain activity. Recent findings indicate that the DMN is active when individuals are attendant to internally-focused tasks, and that each node within the network subserves specific functions related to this general role (Buckner et al., 2008
). Our findings confirm previous reports that the DMN is a robust feature of brain activity identifiable in every subject. They also confirm our hypothesis that the mPFC is a major locus of shared abnormality in the DMN in schizophrenia and bipolar disorder. Broadly speaking, our results suggest that spontaneous oscillations in large-scale neuronal circuits are abnormal in psychiatric conditions, possibly underlying aspects of psychopathology.
In addition, each condition was also characterized by distinct abnormalities. Bipolar disorder was characterized by a reduction of coherence in several nodes within the DMN including the hippocampus, fusiform gyrus and pons, as well as abnormal recruitment of pontine, lateral parietal, and occipital regions into the DMN. Subjects with this condition also showed increased coherence of activity in the primary visual cortex in the V1 component analysis. Since participants were instructed to keep their eyes open during the scan, the V1 component was a particularly relevant control region. On the other hand, the schizophrenia group recruited a node in frontal polar cortex into the DMN, as well as multiple regions within the basal ganglia (caudate, putamen, globus pallidus) bilaterally. For bipolar disorder and schizophrenia, brain regions where DMN was more coherent than the control group were also more coherent than the other patient group (lateral parietal and visual cortices in bipolar disorder, and frontal polar cortex and basal ganglia in schizophrenia). Notable exceptions to this pattern included the insula which emerged in the Bipolar>Schizophrenia but not Bipolar>Control comparison, and temporal regions (fusiform and middle temporal gyri) and superior frontal gyrus which emerged in the Schizophrenia>Bipolar but not Schizophrenia>Control comparison.
In mania, the DMN is characterized by abnormalities in key nodes of the limbic system (mPFC and hippocampus) where abnormalities have been documented in bipolar disorder (Öngür and Price 2000
). At the same time, lateral parietal areas show synchronous activity with the DMN, and a nearby although not identical region is correlated with the level of manic symptomatology (as measured by the YMRS). Reduced coherence in limbic regions and increased coherence in other cortical regions may be consistent with the dysregulated emotional processing and increased goal directed activities seen in mania (Strakowski et al., 2005
; Phillips et al., 2003
). Consistent with the involvement of this brain region in bipolar disorder, manic episodes have been reported following lesions of the parietal cortex (Fenn and George 1999
). The finding of greater than normal coherence within the V1 component in bipolar disorder suggests that the inappropriate recruitment of posterior cortical regions into large-scale neural networks is not restricted to the DMN in this condition. This suggestion is also consistent with previous findings of visual processing abnormalities in bipolar disorder (Chen et al., 2006
; Miller et al., 2003
The only other study of DMN in bipolar disorder and schizophrenia classified these two conditions using the DMN and a temporal lobe network, and did not compare the DMN between groups (Calhoun et al., 2007). A quantitative assessment revealed weaker DMN increases in the posterior cingulate and bilateral parietal cortices in bipolar disorder as compared with controls, but direct comparison with our data is not possible since bipolar disorder subjects in that study were not in a manic episode.
In our study, schizophrenia was associated with deficient recruitment of the anterior cingulate gyrus into the DMN, consistent with a large schizophrenia literature (Benes 1998
). In addition, there was a striking recruitment of multiple basal ganglia regions bilaterally into the DMN in schizophrenia. Circuit-level abnormalities in the basal ganglia have been reported in schizophrenia (Chang et al., 2007
; Menon et al., 2001
) and may be involved in problems of dynamic adjustment of control and cognitive sequencing (Kerns et al., 2008
)(Kerns, et al. 2008
). The abnormal recruitment of basal ganglia regions in schizophrenia is likely coupled with a loss of recruitment of the anterior cingulate cortex because the two are anatomically closely connected. The two findings may relate through a breakdown in executive functioning in schizophrenia. Finally, the frontal polar cortex was strongly recruited into the DMN in schizophrenia. This brain region is implicated in integrating the outcomes of two or more cognitive operations in pursuit of behavioral goals (Ramnani and Owen 2004
), but more work is needed to confirm abnormalities in this process in schizophrenia.
Several previous studies have examined the DMN in schizophrenia. Two studies measuring the temporal homogeneity of BOLD signal reported reductions in coherence of activity in the cerebral cortex and cerebellum (Liang et al., 2006
; Liu et al., 2006
). These studies used region-of-interest based analyses and cannot be compared with the current work. Another study using a functional connectivity approach examined the DMN in schizophrenia, and reported reduced connectivity among dorsomedial PFC, parietal, and temporal regions of the DMN, which was interpreted as “functional disintegration” (Zhou et al., 2007
). Reduced integration of brain activity across areas was also reported by a study of the dorsolateral PFC and striatum (Salvador et al., 2007
), and by a study of posterior cingulate cortex connectivity with prefrontal, temporal, and parietal cortex and the cerebellum (Bluhm et al., 2007
). Finally, another study used ICA to study outpatients with schizophrenia during a simple auditory oddball task (Garrity et al., 2007
). In that study, unlike in ours, ventromedial PFC and anterior cingulate cortex were more coherent with the DMN in schizophrenia than in control subjects. There are many differences among these studies, including those in data acquisition details (TR, TR, voxel size), statistical approaches (seed-based functional connectivity, ICA, other temporal homogeneity approaches), patient population (acute inpatient vs. outpatient), and task instructions (cognitive tasks vs. rest). In addition, many studies do not account for the potential effects of psychotropic medications on BOLD signal oscillations. It is clear that functional integration across nodes of the DMN is deficient in schizophrenia but methodological differences preclude further conclusions.
4.3. Timecourse abnormalities
In an exploratory analysis, we also identified alterations in BOLD signal timecourse within the DMN in bipolar disorder and schizophrenia. Spontaneous neuronal oscillations are a major feature of brain networks, and they support the representation and consolidation of information (Buzsaki and Draguhn 2004
). Low frequency oscillations are dysregulated in bipolar disorder and schizophrenia, suggesting significant abnormalities in underlying brain circuits and increased noise in the network. Bipolar disorder subjects showed a more extreme pattern, where very low frequency power was reduced and high frequency (>0.1 Hz) power was increased. There was no relationship between manic or psychotic symptoms and timecourse abnormalities, perhaps due to small sample size or because timecourse abnormality is a trait-like feature of mania.
This study has a modest sample size because we studied acutely ill patients in 3 groups, which presented logistic difficulties. There was a high attrition rate especially in the mania group, and the patients who could not complete the study were somewhat more symptomatic than those who could. Nonetheless, the YMRS score of our manic patients was over 24, indicating that the completer patients were still highly symptomatic. Also, all patients were medicated at scan time in our study and a role for psychotropic medications in our findings cannot be ruled out. Nonetheless, two factors suggest that medication effects were not prominent in our study: both patient groups were on similar medications, but they showed different DMN abnormalities; and there was no relationship between our findings and CPZ equivalents. Another limitation of our study is the diagnostic heterogeneity in the schizophrenia group, where 7 out of 14 subjects were diagnosed with schizoaffective disorder. We cannot rule out the possibility that schizoaffective disorder patients show a differential pattern of DMN abnormalities which we are confounding with schizophrenia, but we do not think this is the case for two reasons. First, we studied patients who were hospitalized with acute psychosis and not currently in a mood episode, indicating that all patients in this group were phenomenologically similar. Second, a subgroup analysis between schizophrenia and schizoaffective disorder patients did not reveal significant differences, although this was an underpowered analysis.
Another important limitation in this study: psychomotor agitation and autonomic dysregulation (e.g. tachycardia/ tachypnea) are common in bipolar mania and may generate BOLD signal changes which do not reflect oscillations in neuronal activity. Motion parameters did not vary significantly between groups in our study, indicating this is not a likely. On the other hand, we did not collect eye movement data in our scans, and group differences in eye movements may underlie our Brodmann's Area 7 findings in mania, since this region is involved in the planning and modulation of eye movements (Buneo and Andersen 2006
). In addition, we did not collect heart or respiratory rate data. Tachycardia/tachypnea could drive coherent BOLD signal changes in multiple cortical areas and explain some findings. It is unlikely, however, that autonomic differences would lead to both reductions in coherence in the PFC and increases in coherence in posterior cortical areas.
4.5. DMN abnormalities in psychiatric conditions
Abnormalities in the brain system subserving internally focused activity in schizophrenia and bipolar disorder may have important implications for understanding the emergence of aberrant mental states. This approach is promising because most psychopathology is not task-related, but rather arises spontaneously during interactions with the environment. Therefore, networks that modulate these spontaneous interactions are suitable foci of inquiry. For example, these findings may arise from abnormalities in long-tract signaling (Kubicki et al., 2007
) and a breakdown in activity integration among multiple brain areas, ultimately manifesting as disordered processing of emotion, thought, or perception. Our current understanding of large-scale neural networks, however, is not sufficient to make predictions about which DMN abnormalities contribute to which clinical presentations. To this end, we need studies of large-scale neural networks which examine network characteristics under clinically relevant experimental conditions (Greicius 2008
Additional insights may come from the divergence between the previous findings of significantly increased coherence between anterior cingulate cortex and the DMN in schizophrenia during an auditory oddball task (Garrity et al., 2007
) and our findings of significantly reduced coherence in the same region for the same disorder during rest. It is possible that schizophrenia patients recruit the anterior cingulate cortex into the DMN too well during task performance and not enough during rest, i.e. they are unable to “turn it off” during tasks and to “turn it on” at rest. This hypothesis can be tested in studies of the same subjects’ DMN during rest and tasks of varying difficulty.