Markers of positive affect and brain state synchrony discriminate melancholic from non-melancholic depression using naturalistic stimuli.

Melancholia has been proposed as a qualitatively distinct depressive subtype associated with a characteristic symptom profile (psychomotor retardation, profound anhedonia) and a better response to biological therapies. Existing work has suggested that individuals with melancholia are blunted in their display of positive emotions and differ in their neural response to emotionally evocative stimuli. Here, we unify these brain and behavioural findings amongst a carefully phenotyped group of seventy depressed participants, drawn from an established Australian database (the Australian Genetics of Depression Study) and further enriched for melancholia (high ratings of psychomotor retardation and anhedonia). Melancholic (n = 30) or non-melancholic status (n = 40) was defined using a semi-structured interview (the Sydney Melancholia Prototype Index). Complex facial expressions were captured whilst participants watched a movie clip of a comedian and classified using a machine learning algorithm. Subsequently, the dynamics of sequential changes in brain activity were modelled during the viewing of an emotionally evocative movie in the MRI scanner. We found a quantitative reduction in positive facial expressivity amongst participants with melancholia, combined with differences in the synchronous expression of brain states during positive epochs of the movie. In non-melancholic depression, the display of positive affect was inversely related to the activity of cerebellar regions implicated in the processing of affect. However, this relationship was reduced in those with a melancholic phenotype. Our multimodal findings show differences in evaluative and motoric domains between melancholic and non-melancholic depression through engagement in ecologically valid tasks that evoke positive emotion. These findings provide new markers to stratify depression and an opportunity to support the development of targeted interventions.

Spurious correlations in surface-based functional brain imaging.

The study of functional MRI data is increasingly performed after mapping from volumetric voxels to surface vertices. Processing pipelines commonly used to achieve this mapping produce meshes with uneven vertex spacing, with closer neighbours in sulci compared to gyri. Consequently, correlations between the fMRI time series of neighbouring sulcal vertices are stronger than expected. However, the causes, extent, and impacts of this bias are not well understood or widely appreciated. We explain the origins of these biases, and using in-silico models of fMRI data, illustrate how they lead to spurious results. The bias leads to leakage of anatomical cortical folding information into fMRI time series. We show that many common analyses can be affected by this "gyral bias", including test-retest reliability, fingerprinting, functional parcellations, regional homogeneity, and brain-behaviour associations. Finally, we provide recommendations to avoid or remedy this spatial bias.

Aberrant Cardiac Interoception in Psychosis.

BACKGROUND AND HYPOTHESIS: There is mounting evidence that cardiac interoception, the perception of one's heartbeat, is central to affective experiences. It has been proposed that symptoms of psychosis could arise from interoceptive dysfunction. Here we hypothesized that people with psychotic disorders would have a specific impairment in cardiac interoception, over and above broader perceptual deficits. STUDY DESIGN: 43 adults with a history of psychosis (31 schizophrenia, 12 schizoaffective disorder) and 41 matched control participants completed a heart rate discrimination task. Participants responded to whether they perceived a sequence of auditory tones to be faster or slower than their heart rate. By trialing a range of auditory tone rates, we estimated a threshold for each participant, the difference between perceived heart rate and actual heart rate. To test whether differences were specific to interoception, participants completed an exteroceptive control condition, testing their discrimination of the rate of 2 sets of audible sounds instead of heart rate. STUDY RESULTS: Participants with a history of psychosis had greater absolute differences between perceived and actual heart rate, indicating over- or under-estimation of heart rate compared to healthy controls. This difference was specific to the interoceptive condition, and not explained by group differences in exteroceptive perception. CONCLUSIONS: Psychotic disorders are associated with misestimation of heart rate. Further research may elucidate whether interoceptive abnormalities contribute to specific symptoms such as somatic delusions or affective features, and whether interoception could be a treatment target in psychotic disorders.

Cognitive Control System Gates Insula Processing of Affective Stimuli in Early Psychosis.

BACKGROUND AND HYPOTHESIS: Impairments in the expression, experience, and recognition of emotion are common in early psychosis (EP). Computational accounts of psychosis suggest disrupted top-down modulation by the cognitive control system (CCS) on perceptual circuits underlies psychotic experiences, but their role in emotional deficits in EP is unknown. STUDY DESIGN: The affective go/no-go task was used to probe inhibitory control during the presentation of calm or fearful faces in young persons with EP and matched controls. Computational modeling of functional magnetic resonance imaging (fMRI) data were performed using dynamic causal modeling (DCM). The influence of the CCS on perceptual and emotional systems was examined using parametric empirical bayes. STUDY RESULTS: When inhibiting motor response to fearful faces, EP participants showed higher brain activity in the right posterior insula (PI). To explain this, we used DCM to model effective connectivity between the PI, regions from the CCS activated during inhibition (dorsolateral prefrontal cortex [DLPFC] and anterior insula [AI]), and a visual input region, the lateral occipital cortex (LOC). EP participants exerted a stronger top-down inhibition from the DLPFC to the LOC than controls. Within the EP cohort, increased top-down connectivity between the LOC and AI was associated with a higher burden of negative symptoms. CONCLUSIONS: Young persons with a recent onset of psychosis show a disturbance in the cognitive control of emotionally salient stimuli and the suppression of irrelevant distractors. These changes are associated with negative symptoms, suggesting new targets for the remediation of emotional deficits in young persons with EP.

Functional re-organization of hippocampal-cortical gradients during naturalistic memory processes.

The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.

Quantifying dynamic facial expressions under naturalistic conditions.

Facial affect is expressed dynamically - a giggle, grimace, or an agitated frown. However, the characterisation of human affect has relied almost exclusively on static images. This approach cannot capture the nuances of human communication or support the naturalistic assessment of affective disorders. Using the latest in machine vision and systems modelling, we studied dynamic facial expressions of people viewing emotionally salient film clips. We found that the apparent complexity of dynamic facial expressions can be captured by a small number of simple spatiotemporal states - composites of distinct facial actions, each expressed with a unique spectral fingerprint. Sequential expression of these states is common across individuals viewing the same film stimuli but varies in those with the melancholic subtype of major depressive disorder. This approach provides a platform for translational research, capturing dynamic facial expressions under naturalistic conditions and enabling new quantitative tools for the study of affective disorders and related mental illnesses.

An active inference perspective on the negative symptoms of schizophrenia.

Predictive coding has played a transformative role in the study of psychosis, casting delusions and hallucinations as statistical inference in a system with abnormal precision. However, the negative symptoms of schizophrenia, such as affective blunting, avolition, and asociality, remain poorly understood. We propose a computational framework for emotional expression based on active inference-namely that affective behaviours such as smiling are driven by predictions about the social consequences of smiling. Similarly to how delusions and hallucinations can be explained by predictive uncertainty in sensory circuits, negative symptoms naturally arise from uncertainty in social prediction circuits. This perspective draws on computational principles to explain blunted facial expressiveness and apathy-anhedonia in schizophrenia. Its phenomenological consequences also shed light on the content of paranoid delusions and indistinctness of self-other boundaries. Close links are highlighted between social prediction, facial affect mirroring, and the fledgling study of interoception. Advances in automated analysis of facial expressions and acoustic speech patterns will allow empirical testing of these computational models of the negative symptoms of schizophrenia.

Fronto-limbic dysconnectivity leads to impaired brain network controllability in young people with bipolar disorder and those at high genetic risk.

Recent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR individuals (n = 84, mean age 22.4), patients with BD (n = 38, mean age 23.9), and age- and gender-matched controls (n = 96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p = 0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p = 0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions.

Inflammatory Bowel Disease Pharmacist Adherence Counseling Improves Medication Adherence in Crohn's Disease and Ulcerative Colitis.

BACKGROUND: While inflammatory bowel diseases (IBD) require long-term medication usage to maintain remission, nonadherence is common and adversely associated with poorer clinical outcomes. Personalized IBD Pharmacist Adherence Counselling, based on the Health Beliefs Model of medication perception, may increase medication adherence. METHODS: This prospective multi-center longitudinal parallel study recruited consecutive IBD subjects that were classified as baseline medication non-adherers and adherers. Non-adherers received a single IBD Pharmacist Adherence Counselling intervention at baseline, while adherers served as controls. Medication Adherence Report Scale and Beliefs about Medicines Questionnaire were administered up to 24 months. Medication acceptance was defined as high perception of medication necessity with low concerns. The primary endpoint was medication adherence at 24 months. RESULTS: Of 114 subjects approached, 100 completed follow-up, with 36 being baseline nonadherers (median Medication Adherence Report Scale = 15.0) and 64 baseline adherers (median Medication Adherence Report Scale = 19.0; P < 0.001). At 24 months, nonadherence in the IBD Pharmacist Adherence Counselling group decreased from 100% to 44.4% (P = 0.001), whereas nonadherence in controls remained unchanged (P = 0.38). Individually, Beliefs about Medicines Questionnaire Necessity and Concern scores showed no significant changes in both groups, but medication acceptance significantly improved in baseline nonadherers at 12 months (P = 0.031) with a trend toward durable improvement at 24 months (P = 0.063). CONCLUSIONS: Medication nonadherence in IBD can be improved through a single personalized counseling session by an IBD pharmacist, and the benefit was durable for 2 years. This benefit was through improving the acceptance of medication.

Pediatric-to-adult Transition and Medication Adherence in Patients with Inflammatory Bowel Disease.

BACKGROUND: Medication nonadherence is common in inflammatory bowel disease and is associated with poor outcomes. There has been no study on pediatric-to-adult transition as a risk factor for nonadherence in inflammatory bowel disease, which has been demonstrated in other diseases. We aimed to assess whether transitioned (TR) patients have higher nonadherence rates than young adults (YAs) diagnosed in adulthood. METHODS: Consecutive ambulatory subjects were prospectively recruited and completed the validated Medication Adherence Reporting Scale (MARS), with the primary outcome being adherence differences between group age-matched TR and YA groups. Pediatric subjects were taken as the control group. Perceptions of medication-related necessity and concerns were assessed with the Beliefs about Medicines Questionnaire (BMQ). Nonadherers (defined as MARS ≤16) received the Inflammatory Bowel Diseases Pharmacist Adherence Counselling (IPAC) intervention and adherence change was reassessed after 6 months as a secondary outcome. RESULTS: Adherence in TR patients (n = 38, mean age 20.4, 13.2% nonadherent) was noninferior to and numerically better than YAs diagnosed in adulthood (n = 41, mean age 21.2, 24.4%). Nonadherence in the pediatric control group (n = 50, mean age 14.7) was 8.0%. YAs had significantly higher medication-related concerns (14.6 versus 11.9, P = 0.02) than the pediatric group. The IPAC intervention reduced nonadherence rates by 60% (P = 0.004). CONCLUSIONS: TR patients did not have worse adherence than YAs diagnosed in adulthood. Protective factors may include previous treatment in pediatric centers and the salient symptomatology of inflammatory bowel disease, whereas increasing concerns over medications contribute to nonadherence in YAs. Pharmacist-led counselling improves adherence in these patients.