Professor Greg Murray, PhD, FAPS Sleep and circadian effects on neural reward functioning: Towards a chronobiology of reward for bipolar disorder Professor Greg Murray, PhD, FAPS

Today’s talk Systematic review of circadian and sleep modulation of the neural substrates of reward Next steps: a new dimensional process model linking sleep, reward and circadian function

Ventral Tegmental Area Prefrontal cortex Striatum Suprachiasmatic nucleus Mesocorticolimbic dopaminergic system critical element of reward functioning Only dopamine pathways shown here, also includes GABAergic and glutamatergic loops. Reward system organises behaviour in the context of incentives Dysregulation of reward fundamental to mood disorders (positive affectivity) Ventral Tegmental Area

Systematic review Empirical studies, non-clinical human sample, biological rhythm modulation of reward-related brain structures, English Where imaging stimuli are used, consistent with a reward paradigm fMRI, PET or MEG imaging Search terms: Sleep, SCN, suprachiasmatic, circadian AND reward, arousal, amygdala, MPFC, OFC, striatum, medial prefrontal cortex, orbitofrontal cortex, thalamus, locus coreuleus, anterior cingulate, ventral tegment* Imaging, FMRI, PET, MRI, MEG Cohen’s kappa = .65 for title/abstract screening, = .92 for full-text selection

Constructs and variables in the reviewed 13 studies 27 shortlisted, 14 excluded (9 no reward stimulus, 1 re-analysis, 4 clinical samples) Thirteen studies analysed

Results

Disturbed sleep increases reward activation Reward region Number of studies measuring (ROI) Significant effects Amygdala 10 (2) + Anterior cingulate cortex 10 (1) +, +, + rostral subgenual, - inferior Ventral tegmental area 9 (2) +, decreased correlation with subjective valuation Insula 10 (4) +,+,+,+, decreased activation to monetary loss, decreased activation to loss minimisation choices Striatum 10 (6) +,+,+,+,+,+, increased correlation with valuation signals in ventromedial PFC Prefrontal cortex 10 (5) +,+,+,-,-,-

Circadian vulnerability linked to altered reward activation Circadian misalignment (phase advance from Saturday to Sunday night in adolescents) associated with decreased mPFC, ACC activation (anticipation and receipt), and decreased VS activation to reward anticipation Vulnerable circadian genotype (G allele on rs2304672) associated with decreased activity to reward outcome in dorsal mPFC

Limitations of existing literature Small number, limited range of studies No MEG or PET, only two circadian Heterogeneous designs Reward paradigms Predictor variables fMRI analytic approach Dearth of model-driven research How should we understand the relationship between biological rhythms and reward activation?

The Circadian Reward Rhythm Normative 24-hour biobehavioural rhythm of motivation towards the environment Adapted to optimise reward Abnormalities appear in motivational and sleep dysregulation Novel dynamic endophenotype for bipolar disorder

10 am 2 pm 7 pm Repeated measures fMRI: BOLD gambling task Arterial Spin Labelling Resting state functional connectivity

Conclusions Systematic review adds neuroimaging support to evidence of biological rhythm modulation of reward in humans mPFC and striatum most strongly implicated Future neuroimaging research could be focused by the Circadian Reward Rhythm model Repeated measures fMRI focusing on striatal resting state activity across the waking day

Questions? Nuwan Leitan, Swinburne Charlotte Keating, Swinburne Susan Rossell, Swinburne Sheri Johnson, UC Berkeley Gin Malhi, University of Sydney All but one of 13 studies found biological rhythm changes led to changes in at least one aspect of neural reward activation