Dysfunction of thalamocortical networks has been implicated in the pathophysiology of schizophrenia (2
). We used resting-state fMRI to determine the anatomical specificity of thalamocortical network dysfunction in schizophrenia (15
). We found that functional connectivity between the prefrontal cortex and dorsomedial/anterior thalamus is reduced in schizophrenia. In contrast, thalamic functional connectivity with motor and somatosensory cortical areas was markedly increased. The results indicate that functional networks linking cortex to thalamus are abnormal in schizophrenia and that the changes are characterized by both hypo- and hyper-connectivity.
The combination of decreased prefrontal-thalamic and increased thalamic connectivity with motor and somatosensory cortical regions is the most striking aspect of our findings which, at first glance, appear inconsistent with the general notion that neural connectivity is overall reduced in schizophrenia (e.g. 25). However, when interpreted from a developmental perspective, the results provide compelling support for the neurodevelopmental model of schizophrenia. Using the same method, Fair and colleagues (23
) found marked differences in thalamocortical functional connectivity between children, adolescents, and adults. Specifically, prefrontal-thalamic connectivity is largely absent in children and adolescents suggesting that this network develops abruptly during the transition from adolescence to adulthood. Motor and somatosensory connectivity on the other hand appears to follow an inverted U-curve, being maximal in adolescence compared to childhood and adulthood. The changes observed in schizophrenia may result from abnormal late brain maturation, during the transition from adolescence to adulthood, which derails the normal development of prefrontal-thalamic connectivity and refinement of somatomotor-thalamic connectivity. The functional consequences of these changes remain to be characterized; however, reduced structural connectivity between prefrontal cortex and thalamus has been linked to working memory impairment and prefrontal brain activity in schizophrenia (26
). It’s possible that a similar relationship may be observed for resting-state functional connectivity.
While the combination of decreased prefrontal and increased somatomotor connectivity with the thalamus is consistent with atypical brain maturation in schizophrenia, the absence of group differences in temporal-thalamic connectivity potentially argues against a neurodevelopmental basis for thalamocortical dysconnectivity. In contrast to prefrontal-thalamic connectivity, temporal cortex connectivity with the thalamus decreases with age in typically developing individuals (23
). Therefore, patients might be expected to demonstrate increased temporal-thalamic connectivity if thalamocortical network dysfunction is indeed associated with atypical brain maturation. However, the precise timing of developmental changes in thalamocortical functional connectivity is poorly understood. The limited available evidence, which comes from a single cross-sectional study, suggests that much of the reduction in temporal-thalamic connectivity occurs between childhood and adolescence (23
). Consequently, it’s possible that the developmental disruption in schizophrenia occurs after temporal-thalamic connectivity has fully matured, but before prefrontal and somatomotor thalamic networks have reached adult levels. A better understanding of the normal developmental trajectories of thalamocortical connectivity and investigation of thalamocortical connectivity in first episode schizophrenia is required to test this hypothesis. The lack of group differences in temporal-thalamic, and occipital-thalamic connectivity for that matter, is also interesting given strong evidence of sensory processing deficits in schizophrenia (27
). It’s possible that connectivity during tasks, rather than resting-state, may be associated with sensory processing dysfunction. Alternatively, auditory and visual sensory processing deficits in schizophrenia may relate to dysfunction at the level of cortico-cortical interactions, rather thalamocortical connectivity.
Our findings also raise the possibility that thalamocortical dysconnectivity results from selective pathology of one or more nuclei of the thalamus and/or their corresponding cortical targets. Reduced number of neurons in the mediodorsal thalamus has been found by several investigators; although there are also reports of normal numbers of neurons (see 13
for review). Similarly, an array of neuronal and molecular changes have also been found in dorsolateral prefrontal cortex circuitry (see 28
for review). As such, thalamocortical dysconnectivity in schizophrenia may result from selective pathology of specific thalamic nuclei, and/or their corresponding cortical targets. Resting-state connectivity networks are conserved across species suggesting that animal models will be particularly useful in elucidating the effects of focal neuronal, molecular, and genetic manipulations on large-scale brain networks (29
The current results are also informed by considering the physiology of BOLD functional connectivity. There is considerable overlap between functional and structural connectivity in the thalamus suggesting that thalamocortical functional connectivity reflects direct anatomical connections (14
). Results from a recent diffusion tensor imaging investigation showing reduced connectivity between thalamus and lateral prefrontal cortex, and increased connectivity between somatosensory cortex and thalamus in schizophrenia provide a potential anatomical basis for the current findings (26
). However, it is clear from the broader functional connectivity literature that brain regions not directly anatomically connected can still demonstrate robust functional connectivity indicating that resting-state connectivity networks reflect extended, polysynaptic networks (e.g. 34). This interpretation is supported by findings from a recent combined resting-state fMRI/electrocorticography investigation which found that functional connectivity, positive correlations in particular, predicted electrically evoked brain responses (35
). Combined, these findings confirm a neural basis for low frequency BOLD functional connectivity, but raise the possibility that abnormal thalamocortical connectivity in schizophrenia may reflect alterations in direct and/or indirect pathways linking thalamus and cortex. Future work combining functional and structural connectivity will help clarify the nature of thalamocortical dysconnectivity in schizophrenia.
There are several limitations of the current investigation that merit consideration. First, patients were receiving antipsychotic medication. While we did not find any evidence that medication was related to functional connectivity abnormalities observed in patients; it’s possible that antipsychotic treatment effects on connectivity may not be dose-dependent. Second, low frequency BOLD functional connectivity varies to some extent across cognitive states, levels of consciousness (i.e. awake vs. light sleep), and even eyes open vs. closed conditions (36
). Since we instructed subjects to keep their eyes closed during scanning, we can not rule out the possibility that some subjects may have fallen asleep during scanning and that group differences in arousal may have contributed to the results. Studies examining thalamocortical connectivity across cognitive states and levels of arousal will be required to determine if the alterations observed in patients transcend cognitive state and arousal level. Moreover, resting-state connectivity is modified by recent experiences raising the possibility that the abnormalities in thalamocortical connectivity are secondary to negative life experiences associated with illness chronicity, such as long-term reduction in social interaction and cognitive engagement, rather than the pathophysiology of schizophrenia (40
). Third, while we argue that the changes are at least partially consistent with neurodevelopmental hypotheses of schizophrenia, it is premature to exclude a neurodegenerative explanation for the findings. A combination of decreased network connectivity with compensatory increases in other networks has been observed in degenerative illnesses such as Alzheimer’s disease (41
). Replication of the current findings in unmedicated/minimally treated first-episode or early-phase patients will strengthen the case for a neurodevelopmental basis for thalamocortical dysconnectivity. Finally, although we applied a well-established method to examine thalamocortical functional connectivity, there are nonetheless limitations of the technique. The use of large cortical areas as seeds, while useful for functionally segregating the thalamus, does not allow for a more fine-grained analysis at the cortical level. Interestingly, using a voxel located in the mediodorsal thalamus as the seed for functional connectivity analysis, Welsh and colleagues found that mediodorsal thalamic connectivity with bilateral caudate and anterior cingulate gyrus was reduced in schizophrenia (12
). Follow-up investigation using the thalamic clusters identified in the current study as seeds in an independent cohort of patients, or independent components analysis, may help further refine the anatomical specificity of thalamocortical dysconnectivity.
In conclusion, we found altered resting-state functional connectivity between the thalamus and cortex is altered in schizophrenia. The alterations are characterized by decreased prefrontal-thalamic connectivity, and increased thalamic connectivity with motor and somatomotor cortex. Combined, the results implicate abnormal late brain maturation in the neuropathology of schizophrenia. Future studies combining functional connectivity with assessment of phenotypes more closely related to thalamocortical networks than complex, clinical symptoms may help elucidate the functional consequences of thalamocortical dysconnectivity in schizophrenia.