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Highlights Mechanisms underlying treatment-resistant schizophrenia are unclear. Effective connectivity within cortico-striatal network differentially disrupted in resistant patients. Resistance associated with lack of top-down control and aberrant glutamate function. We suggest a subtype of schizophrenia with distinct neurobiological mechanism. Results are important for guiding treatment strategies and developing new drugs.

If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Increasing evidence suggests late chronotype individuals are at increased risk of developing depression. However, the underlying neural mechanisms that confer risk are not fully understood. Here, fifty healthy, right-handed individuals without a current or previous diagnosis of depression, family history of depression or sleep disorder underwent functional magnetic resonance imaging (FMRI). Participants completed an implicit emotion processing task (gender discrimination) including happy and fearful facial expressions. Linear effects of chronotype on BOLD response in bilateral amygdala were tested for significance using nonparametric permutation tests. Functional connectivity between amygdala and prefrontal cortex was also investigated using psychophysiological interaction (PPI) analysis. A significant negative correlation between BOLD response and chronotype was observed in bilateral amygdala where later chronotype was associated with an enhanced amygdala response to fearful vs. happy faces. This response remained significant after sleep quality, age, gender, mood, and time of scan were included as covariates in the regression model. Later chronotype was also significantly associated with reduced functional connectivity between amygdala and dorsal anterior cingulate cortex (dACC). The current results appear consistent with theories of impaired emotion regulation of the limbic system (particularly the amygdala) associated with depression and may, in part, explain the increased vulnerability for depression in late chronotype individuals.

Current evidence suggests late chronotype individuals have an increased risk of developing depression. However, the underlying neural mechanisms of this association are not fully understood. Forty-six healthy, right-handed individuals free of current or previous diagnosis of depression, family history of depression or sleep disorder underwent resting-state functional Magnetic Resonance Imaging (rsFMRI). Using an Independent Component Analysis (ICA) approach, the Default Mode Network (DMN) was identified based on a well validated template. Linear effects of chronotype on DMN connectivity were tested for significance using non-parametric permutation tests (applying 5000 permutations). Sleep quality, age, gender, measures of mood and anxiety, time of scan and cortical grey matter volume were included as covariates in the regression model. A significant positive correlation between chronotype and functional connectivity within nodes of the DMN was observed, including; bilateral PCC and precuneus, such that later chronotype (participants with lower rMEQ scores) was associated with decreased connectivity within these regions. The current results appear consistent with altered DMN connectivity in depressed patients and weighted evidence towards reduced DMN connectivity in other at-risk populations which may, in part, explain the increased vulnerability for depression in late chronotype individuals. The effect may be driven by self-critical thoughts associated with late chronotype although future studies are needed to directly investigate this.