The Functional Connectivity Landscape of the Human Brain

Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.</p

The Brain-basis of Large-scale Learning Processes in Schizophrenia

Learning impairments are common in schizophrenia and relate to functional outcome. This thesis explored the brain-basis of learning in schizophrenia in spatial and temporal domains as it unfolded across two fMRI sessions. During fMRI scanning, healthy controls and participants with schizophrenia completed a lexicon-learning task and a comparative reaction-time task. Using multivariate analytic approaches, the thesis used three vantage points on the fMRI-BOLD signal to characterize the brain-learning relationships. Using reaction-time tasks bookending the learning tasks on both scanning days, Study 1 examined task-independent linear changes in the BOLD signal that could potentially interfere with accurate interpretation in fMRI learning studies. It showed that these effects are stronger in schizophrenia in brain areas associated with cognitive control, default mode networks, perceptual and semantic processing. Results suggested that some of the ‘hyperactivation’ attributed to learning processes in the practice-related literature is better attributed to task-independent effects associated with impaired modulation of the BOLD signal during task switching. Study 2 used a brain-behaviour analysis to examine BOLD activity related to learning-success. With practice, controls shifted between early and late learning processes with a switch between early frontotemporal engagement to later subcortically-focused engagement. Persons with schizophrenia failed to show this same pattern; they were differentiated by level of engagement with perceptual processing regions and an overall suggestion of prolonged, early-learning brain processes. Whole-brain functional connectivity patterns related to learning accuracy showed between-groups similarities, differences and a group-by-time interaction in study 3. While again the controls showed two patterns capturing early and late learning, the pattern for the schizophrenia group spanned both days and did not vary with learning stage. Strong differences in schizophrenia included over-connected intra-cerebellar regions, under-connected frontal-cerebellar regions, over-connected sensorimotor-thalamus connection and under-connected prefrontal-thalamus regions. These patterns mirror many resting-state findings in the extant literature, but here we showed how this dysconnectivity pattern impacted directly on learning performance. Together, these three studies showed how learning in schizophrenia is associated with different large-scale interactions that emerge in different spatial and temporal brain-behaviour distributions. The thesis showed how an overall pattern of brain inflexibility underlies learning challenges in schizophrenia.Ph.D

Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia

Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent “time effects” in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group. The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered

Exploring the neural correlates of delusions of reference

Background: Referential delusions are the most common symptom of schizophrenia and offer an opportunity to examine the neural correlates of delusions because they occur in discrete episodes that can be studied in the scanner. The cortical midline structures (CMS) and subcortical regions, including the amygdala and striatum, are linked with self-reference in healthy adults. Less is known about the neural substrates of altered self-reference in schizophrenia. Methods: In this study, patients with schizophrenia experiencing prominent referential delusions (n = 18) and healthy control subjects (n = 17) were presented with ambiguous sentences while in the magnetic resonance imaging scanner and asked to rate whether they felt the sentences had been written specifically about them. The sentences were either generic (nonpersonalized) or individually tailored personalized sentences, designed to induce referential ideation. We hypothesized that both groups would show activity in the CMS, limbic, and striatal regions and that induced referential ideation would be associated with greater activity in striatal areas in patients with schizophrenia. Results: A robust main effect of endorsement (endorsed vs. nonendorsed) was observed in the CMS, as well as subcortical regions, including the nucleus accumbens/ventral striatum, amygdala, insula, and midbrain dopamine regions. A group-by-endorsement interaction was seen in the medial prefrontal cortex, insula and nucleus accumbens/ventral striatum. Activity in insula and ventral striatum also correlated with the strength of the delusions of reference. Conclusions: Referential ideation in persons with delusions is associated with heightened CMS, limbic and striatal activity and reduced differentiation between self- and non-self-relevant information. © 2011 Society of Biological Psychiatry

The Functional Connectivity Landscape of the Human Brain

<div><p>Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.</p></div

Relationship between changes in coherence and Euclidean distance for the MEG dataset (left) and differences in path coefficients from an SEM analysis of the PET dataset (right).

<p>Relationship between changes in coherence and Euclidean distance for the MEG dataset (left) and differences in path coefficients from an SEM analysis of the PET dataset (right).</p

Changes in correlation between conditions of greatest difference in correlation plotted against Euclidean distance.

<p>Changes in correlation between conditions of greatest difference in correlation plotted against Euclidean distance.</p

Details for the neuroimaging studies that were analyzed.

<p>Details for the neuroimaging studies that were analyzed.</p