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SfN 2011—Connectomics and Schizophrenia (Part 2)

3 Apr 2012

Editor's Note: As the final installment in our coverage of the 2011 Society for Neuroscience meeting, held 12-16 November 2011 in Washington, DC, we bring you an illuminating two-part survey of connectomics studies, written by volunteer meeting reporter Scott Bolkan of Columbia University. See also Part 1.

4 April 2012. Resting-state fMRI is an increasingly popular fMRI technique that measures spontaneous, low-frequency fluctuations in blood oxygen level dependent (BOLD) signals while subjects lie at rest in an MRI scanner. As no overt task is performed during imaging, this signal is thought to reflect intrinsic properties of strength and connectivity between local and distributed brain areas.

As with diffusion tensor imaging, a growing number of research groups have used resting-state fMRI to map brain networks in schizophrenia (see Lynall et al., 2010; reviewed in Libby and Ragland, 2011). Some of the latest findings were shared at poster sessions during the SfN meeting. A Dutch group from the University Medical Centre in Utrecht used resting-state fMRI to analyze the functional connectivity of the cerebellum in 62 schizophrenia patients, 67 healthy relatives, and 41 healthy controls (Collin et al. SfN 2011, 680.13). Although abnormalities in structural and functional connections within the cerebellum and various cortical areas have been previously reported in schizophrenia patients, if these disconnectivity profiles represent genetic risk for schizophrenia, they should also be present in the functional connectivity profile of healthy family members of schizophrenia patients. Adding support to this idea, first author Guusje Collin and colleagues found reduced functional connectivity between cerebellum and a range of cortical structures—including left anterior hippocampus, thalamus, and left insula—in patients and their healthy family members, but not healthy controls.

A cross-the-pond collaborative group between the National Institute of Mental Health in Bethesda, Maryland, and the University of Cambridge, U.K., analyzed brainwide network connectivity using resting-state fMRI in 20 healthy volunteers and 19 patients with childhood-onset schizophrenia (Alexander-Bloch et al. SfN 2011, 680.24). Influenced by neurodevelopmental theories of schizophrenia that hypothesize developmental over-pruning as a mechanism of brain network dysfunction, first author Aaron Alexander-Bloch and colleagues analyzed functional connectivity and brainwide network topology based on the anatomical distance between connected brain regions. Consistent with previous findings, they found that brain networks in healthy controls form clusters of highly interconnected nodes that are anatomically spaced close together. A single node within a particular cluster had relatively few, if any, long-range connections between nodes in clusters anatomically distant from it. In contrast, in the brain networks of childhood-onset schizophrenia patients, they found fewer local connections within clusters, thus leading to greater average distances in inter-node connections within clusters and across the whole brain. The researchers propose that excessive “pruning” of local brain connections during development could play a causal role in the observed brainwide network disturbances seen in childhood-onset schizophrenia.

Building on findings of structural and functional disconnectivity between medial temporal lobe and prefrontal cortex, University of California, Davis, researchers measured resting-state and task-active fMRI from several anatomically established regions of interest in the medial temporal lobe of schizophrenia patients and healthy controls (Libby et al. SfN 2011, 752.08). In previous studies, they found a dissociation in the functional connectivity profiles of parahippocampal cortex and perirhinal cortex, the former connecting more strongly to medial prefrontal cortex and anterior thalamus, among other regions. While they observed these same connectivity profiles in both patients and controls at rest, during an active word-pairing task first author Laura Libby and colleagues observed a shift in parahippocampal functional connectivity to dorsolateral prefrontal cortex in healthy controls, and a disintegration of parahippocampal-prefrontal connectivity in patients. This functional connectivity finding complements structural findings of impaired white matter tracts in medial temporal lobe, and suggests the parahippocampal cortex may be a particularly affected brain region.

The road ahead

As with diffusion-weighted imaging techniques, it is important to note limits on the resolution of resting-state fMRI functional connectivity maps. First, the precise spatial and temporal relationship between neural activity and the BOLD is still a hotly debated topic (see Logothetis 2003). Second, many resting-state fMRI studies rely on the a priori establishment of brain nodes based on gross MRI-derived images of brain tissue. Subtle differences in the locations researchers establish for brain nodes can alter the resulting resting-state connectivity profile. The development of improved analytic tools for establishing nodes that reliably reflect functional anatomical brain areas should provide one solution to this problem (Wig GS et al. SfN 20011, 290.01). Comparing functional resting-state fMRI functional connectivity maps with DTI-derived structural maps could also provide another form of verification for both connectivity profiles.

Together, structural studies using diffusion-weighted imaging techniques and functional studies using resting-state fMRI provide powerful new tools for dissecting the nature of disconnectivity in schizophrenia. As momentum builds in the field of human connectomics, there is sure to be continued refinement of these techniques, as well as an increase in their application towards structural and functional analyses of disconnectivity in schizophrenia. Both these trends could be observed at the 2011 SfN meeting. As more findings are added to the literature, future studies that integrate structural and functional connectivity measurements in individuals may be of particular importance for elucidating our understanding of disconnectivity in schizophrenia (see Stephan et al., 2009). Such approaches can provide within-subject coherence between structural and functional deficits that may better correlate with cognitive measures, traits, or symptoms.—Scott Bolkan.

See also Part 1.