With the use of resting-state induced low-frequency BOLD oscillations, we have probed the thalamocortical network and have shown connectivity between the MDN of the thalamus and the prefrontal cortex in healthy controls, validating the use of fcMRI as a tool to examine this network. Using this tool, we have also presented evidence for reduced thalamocortical connectivity in schizophrenia. In addition to these primary results, we found connectivity between the MDN and striatum, which was reduced in the patients. These results have important implications for understanding disturbed network functions in schizophrenia.
Our functional results in healthy subjects parallel the known projections of the MDN to frontal cortex and subcortical structures, with some important exceptions. The MDN contains 3 principal subdivisions (magnocellular, parvocellular, and densocellular nuclei), distinguished by connectivity, myeloarchitecture, and cytoarchitecture.23,55,56
Tract-tracing studies in nonhuman primates have been recently supplemented by MRI tractography in living humans,57,58
also consistent with our functional results. Specifically, the dorsal-most, densocellular region of the MDN has the strongest projections to medial cortex and the striatum,55
where we found functional connectivity. When we displaced our seed ROI in a ventral direction, almost all connectivity disappeared, suggesting that the seed was on the dorsal aspect of the MDN. We also noted connectivity to the lateral cortex, consistent with coverage of the parvocellular nuclei. Although the ROI probably covered the magnocellular nuclei, with projections to orbitofrontal and ventrolateral cortex, we found relatively little connectivity in those regions. This may reflect poor sensitivity of the ROI, which was approximately 15% of the volume of the MDN, to pick up a signal in some subnuclei. Alternatively, different subnuclei of the MDN may exhibit different functional connectivity with cortex. Although these questions await further research, the correspondence of the functional signal with the known thalamocortical projections validates the use of fcMRI as a tool to probe this circuit in schizophrenia.
Because the MDN is a relatively small structure, difficult to localize on an MRI image, and because investigations have reported a reduced size of the MDN,9,11,13
it was important to rule out the possibility of a smaller structure causing reduced connectivity. At the MDN seed ROI, we did not observe gray matter differences between our 2 groups, suggesting that volumetric differences could not account for connectivity differences. It is also not likely that a failure to place the seed ROI in the correct location caused a reduced signal. By moving the seed ROI, we were able to probe the adjacent regions of our central seed location and determine connectivity as a function of displacement. For all of the dorsal displacements, the thalamocortical connectivity signal proved quite robust in the healthy subjects. In none of the subsequently displaced ROIs did we observe an increase in thalamocortical connectivity in schizophrenics. Thus, these analyses show that these methodological issues are unlikely to confound our results.
As mentioned in the “Introduction” section, growing evidence implicates the thalamus in schizophrenia,1–3
and these results provide the first evidence of functional thalamocortical disconnection in chronic schizophrenic patients, to our knowledge. While task-related functional MRI experiments can explicitly probe activity of the thalamus,15
resting-state connectivity probes the relationship of the thalamus with other brain regions. Under the assumption of quiescent communication between nodes along a healthy connection pathway, resting-state fcMRI demonstrates correlations in temporal fluctuations in the BOLD signal between the nodes. This loss of correlation in temporal fluctuations of the BOLD signal can arise either from aberrant functionality in the thalamus, the ACC,59,60
or degradation of the connection between the 2. Thus, while this disconnection is consistent with a dysregulation of excitatory glutamatergic projections from the thalamus to the cortex,1,27,28
other possibilities will require further exploration.
In addition to reduced thalamocortical connectivity to prefrontal cortex, we also found reduced connectivity to subcortical structures—specifically, bilateral caudate nuclei. This finding is not surprising, given the connectivity between MDN and striatum and the cortio-striatal-pallidal-thalamic loop circuits that organize basal ganglia function.24,61
The observation of impaired connectivity of the MDN with the caudate nucleus shows the functional deficit in patients is not confined to thalamocortical circuits, but affects integration in other regions.
Because brain activity was measured during the resting state, when the subjects had no overt engagement in any task, one needs to consider how variability in mental state might affect our results. Although the origin of low-frequency BOLD fluctuations—oscillatory activity in the frequency range of 0.01–0.1 Hz—remains obscure, they appear to reflect neuronal activity that binds together neural nodes, defining functionally meaningful networks.62,63
Connectivity for the M1 seed ROI was not significantly different between the groups, suggesting that reduced connectivity was not a generalized phenomenon of the schizophrenic subjects. While the sensitivity of thalamocortical connectivity to behavior has not been examined, even if it were shown to reflect changes in behavioral state, the demonstration of a difference between patients and healthy subjects would still be meaningful because the subjects received identical instructions about the scan.
Several considerations need to be kept in mind when interpreting our results. The sample size of 11 patients is relatively small, although the positive result in a small sample demonstrates a relatively strong effect. The patients in this study were chronic, with a long duration of illness, raising a question about whether or not these results generalize to a younger, less chronic population. Also the effect of psychotropic medication, which all of the patients were taking, on LFBFs have not yet been sufficiently studied. Of potential relevance for the question of medication, it is notable that LFBFs have been reported to be unaffected by general anesthesia.64
In conclusion, we have conducted the first study, to our knowledge, examining thalamocortical connectivity with LFBF, demonstrated the predicted prefrontal connectivity in healthy controls and the absence of this connectivity in schizophrenic patients. The results provide preliminary evidence demonstrating impairment in the oscillatory dynamics of a neurocircuit believed to be of key importance for schizophrenic pathophysiology.