In keeping with earlier studies,7,8
healthy volunteers were found to have a correlation between spontaneous low-frequency fluctuations in the BOLD signal in the posterior cingulate and in medial prefrontal cortices, lateral parietal, and cerebellar regions. Regions of negative correlation in healthy controls occurred in bilateral areas in the medial temporal lobe, extending into the temporal pole, and bilateral inferior parietal regions. These findings also replicated those of previous studies,7,8
though these other studies also found negative correlation between the posterior cingulate and the orbital gyrus, supplementary motor areas, and dorsolateral prefrontal cortex. One reason for this may be slight differences between the particular regions of the posterior cingulate used as a seed region in these studies—the present study used a seed region that did not appear to extend as far into the precuneus as did the seed regions used in the other 2 studies. This suggests that further studies may show regional differences in posterior cingulate connectivity, which may in turn help to characterize functional networks, including the default network associated with stimulus-independent thought.
Schizophrenic patients in this study had less correlation between spontaneous slow fluctuations in the BOLD signal in the posterior cingulate and in medial prefrontal, lateral parietal, and cerebellar regions. To our knowledge, this is the first report of anomalies in spontaneous slow fluctuations of the BOLD signal associated with the resting-state default network in schizophrenic patients. These results suggest that connectivity between areas of the default network is reduced in schizophrenic patients.
If the default network reflects self-monitoring and stimulus-independent thought, it should not be surprising that there are anomalies in this network in schizophrenic patients. Frith27
has argued that a failure to recognize internally generated thought as arising endogenously is fundamental to the disorder. (For formal cognitive science analyses of this type of failure of covert cognition in schizophrenia, see Batchhelder and Reifer28
and R. W. J. Neufeld)29
The finding of deficient connectivity between the posterior cingulate and the medial prefrontal cortex fluctuations is also consistent with models of schizophrenia based on limbic basal ganglia-thalamocortical neuronal circuits.16,17
The positive symptom–dependent correlation between posterior cingulate spontaneous low-frequency fluctuations and auditory cortex was not entirely expected. Functional imaging studies of hallucinating patients have found activity in the auditory cortex. The posterior cingulate was not generally associated with hallucinations.30–35
It is possible that previous brain imaging techniques were not able to detect changes in the posterior cingulate by virtue of high levels of activity associated with both hallucinating and nonhallucinating states. If this is the case, spontaneous slow fluctuations may be a better indicator of functional links between the self-monitoring system and activity in the auditory and attentional regions associated with auditory hallucinations. If self-monitoring in the posterior cingulate is not linked with self-monitoring in the anterior cingulate, internally generated verbal thought may be perceived to be produced elsewhere.
The negative symptom–dependent correlation between the spontaneous low-frequency fluctuation in the posterior cingulate and the brain stem is interesting. Dopaminergic projections from the brain stem modulate basal ganglia-thalamocortical neuronal circuits which have been implicated in the pathophysiology of negative symptoms.16,17
It is possible that decreased connectivity between the posterior cingulate and medial prefrontal cortex may lead to compensatory changes in the activity of structures which regulate the medial prefrontal cortex, leading to the association with negative symptoms.
The cerebellum has been previously identified as a node in the default network,7,8
and this study found that it was the area that showed the greatest difference in posterior cingulate connectivity between patients and controls. This finding is inconsistent with earlier work36
which found increased functional connectivity between the cerebellum and a number of other brain regions. This earlier paper, however, did not isolate the posterior cingulate gyrus but rather identified the parietal lobe as a whole as an area showing increased functional connectivity in schizophrenic patients as compared with earlier controls. This discrepancy between the previous work and the current study, together with differences in the results reported in the present work and in other papers investigating connectivity in the default network in healthy adults, suggest that further work is required that can parse out differences in connectivity occurring in different subregions of the nodes of the default network.
It must also be acknowledged that other factors may account for anomalies in the spontaneous slow fluctuations of the BOLD signal in regions associated with the default network in schizophrenic patients. Such a deficiency could be explained by anxiety, which could make it difficult to reach a self-reflective state. This possibility is not likely because an earlier positron emission study found that healthy, anxious subjects had the same activity levels in the medial prefrontal cortex as subjects with their eyes closed at rest.37
However, anxious subjects did not show as much reduction in activity in this region when asked to perform an attention-demanding tasks as nonanxious subjects.37
Another possibility is that the deficit may be explained by antipsychotic medication. Dopamine has been shown to have an inhibitory effect on neural activity in the medial prefrontal cortex.38,39
Consequently, medications which block dopamine are not likely to explain the deficits, but a disease-related anomaly in dopamine might.
There are some limitations in this study. First, the schizophrenic participants in this study showed a wide range of positive and of negative symptoms at the time of scanning and were also at different stages of the disorder. Our patient group spanned younger patients who had been diagnosed fairly recently and older patients with chronic schizophrenia. The possibility that the results of this study are influenced by this heterogeneity of the patient group should be taken into account, and future work should attempt to classify schizophrenic participants into subgroups that may potentially show differences in default network activity. Second, between-group differences in functional anatomy, such as increased ventricle size in patients due to brain atrophy, are always a possible confound in studies that normalize all participants' brains to a single template. Like other neuroimaging studies, the present study did not take account of the possible influence of anatomical differences. This study also examined correlations only with the posterior cingulate; it is likely that there are connectivity deficits involving other regions in these patients.36
Finally, it should be noted that the correlational methods used in this study are able to identify only instantaneous correlation between brain regions and cannot discount the possibility of “time-lagged” correlation between the seed region and other brain areas, in which activity in the posterior cingulate seed region has a delayed effect on activity in other areas of the brain.