Anhedonia in Semantic Dementia-Exploring Right Hemispheric Contributions to the Loss of Pleasure.

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith-Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer's disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer's patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer's disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.This study was supported in part by funding to ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases, from the National Health and Medical Research Council (NHMRC) Program grant (#1132524) and Dementia Research Team Grant (#1095127), as well as the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (CE11000102) and an NHMRC Project grant (#1121791). The authors acknowledge the technical assistance provided by the Sydney Informatics Hub, a Core Research Facility of the University of Sydney. M.I. is supported by an ARC Future Fellowship (FT160100096). A.E.W. is supported by an NHMRC Fellowship (#1110773). O.P. is supported by an NHMRC Senior Research Fellowship (GNT1103258). These funding sources were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the manuscript for publication

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target—the KCNQ-type potassium channel—for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of ten weeks. Resting state functional magnetic resonance imaging data were collected at baseline and post-treatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: −13.7±9.7,

Impact of a mobile phone and web program on symptom and functional outcomes for people with mild-to-moderate depression, anxiety and stress: a randomised controlled trial.

Background Mobile phone-based psychological interventions enable real time self-monitoring and self-management, and large-scale dissemination. However, few studies have focused on mild-to-moderate symptoms where public health need is greatest, and none have targeted work and social functioning. This study reports outcomes of a CONSORT-compliant randomised controlled trial (RCT) to evaluate the efficacy of myCompass, a self-guided psychological treatment delivered via mobile phone and computer, designed to reduce mild-to-moderate depression, anxiety and stress, and improve work and social functioning. Method Community-based volunteers with mild-to-moderate depression, anxiety and/or stress (N= 720) were randomly assigned to the myCompass program, an attention control intervention, or to a waitlist condition for seven weeks. The interventions were fully automated, without any human input or guidance. Participants’ symptoms and functioning were assessed at baseline, post-intervention and 3-month follow-up, using the Depression, Anxiety and Stress Scale and the Work and Social Adjustment Scale. Results Retention rates at post-intervention and follow-up for the study sample were 72.1% (n= 449) and 48.6% (n= 350) respectively. The myCompass group showed significantly greater improvement in symptoms of depression, anxiety and stress and in work and social functioning relative to both control conditions at the end of the 7-week intervention phase (between-group effect sizes ranged from d= .22 to d= .55 based on the observed means). Symptom scores remained at near normal levels at 3-month follow-up. Participants in the attention control condition showed gradual symptom improvement during the post-intervention phase and their scores did not differ from the myCompass group at 3-month follow-up. Conclusions The myCompass program is an effective public health program, facilitating rapid improvements in symptoms and in work and social functioning for individuals with mild-to-moderate mental health problems

Effects of mental health self-efficacy on outcomes of a mobile phone and web intervention for mild-to-moderate depression, anxiety and stress: secondary analysis of a randomised controlled trial.

Background: Online psychotherapy is clinically effective yet why, how, and for whom the effects are greatest remain largely unknown. In the present study, we examined whether mental health self-efficacy (MHSE), a construct derived from Bandura’s Social Learning Theory (SLT), influenced symptom and functional outcomes of a new mobile phone and web-based psychotherapy intervention for people with mild-to-moderate depression, anxiety and stress. Methods: STUDY I: Data from 49 people with symptoms of depression, anxiety and/or stress in the mild-to-moderate range were used to examine the reliability and construct validity of a new measure of MHSE, the Mental Health Self-efficacy Scale (MHSES). STUDY II: We conducted a secondary analysis of data from a recently completed randomised controlled trial (N = 720) to evaluate whether MHSE effected post-intervention outcomes, as measured by the Depression, Anxiety and Stress Scales (DASS) and Work and Social Adjustment Scale (WSAS), for people with symptoms in the mild-to-moderate range. Results: STUDY I: The data established that the MHSES comprised a unitary factor, with acceptable internal reliability (Cronbach’s alpha = .89) and construct validity. STUDY II: The intervention group showed significantly greater improvement in MHSE at post-intervention relative to the control conditions (p’s < = .000). MHSE mediated the effects of the intervention on anxiety and stress symptoms. Furthermore, people with low pre-treatment MHSE reported the greatest post-intervention gains in depression, anxiety and overall distress. No effects were found for MHSE on work and social functioning. Conclusion: Mental health self-efficacy influences symptom outcomes of a self-guided mobile phone and web-based psychotherapeutic intervention and may itself be a worthwhile target to increase the effectiveness and efficiency of online treatment programs

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

From deontology to disorder: an examination of moral and pathological disgust

Disgust is expressed in response to sources of contamination and disease, and alsoarises in response to violations of moral norms. The overlap in these two functions hadled some theorists to suggest that moral disgust may be an example of exaptation – theevolutionary process whereby the function of a trait shifts to serve a secondary purpose.This has important implications for our understanding of moral reasoning as it suggeststhat moral judgments may be driven by early affective processes, rather than by morerecently evolved higher order cognitive functions. However, critics argue that disgustexpressed in a moral context may simply be used either metaphorically to convey angeror to draw similarities with acts that are prototypically offensive. Therefore, the firstaim of the current research was to examine whether disgust was uniquely implicated inmoral judgment, over and above the emotion of anger. Using a variety of assessmenttools, including facial electromyography, the first study in this thesis examined thespecificity of the link between disgust and morality. Results showed that physicaldisgust at the trait, state and physiological level was more closely associated with moraltransgressions than anger, indicating that expression of disgust in moral contexts is notsimply metaphorical. Building on this, the next two studies provided a furtherexamination of the link between disgust and morality within the context of obsessivecompulsivedisorder (OCD) - a psychological disorder that is often characterised byheightened disgust and moral rigidity. Results showed that individuals with OCDexperience stronger disgust than those with other forms of anxiety, and that trait disgusthas a distinct impact on moral reasoning in individuals with OCD compared toindividuals with other anxiety disorders. In the final two studies a clinical approach wasadopted, providing the first investigation into the effects of a novel cognitive biasmodification paradigm on disgust responding. The findings outlined in the five studiesof this thesis provide novel evidence in support of an exaptation model of moral disgust,as well as a crucial first step in investigating novel adjuncts to the treatment ofpathological disgust

Smoking as a Common Modulator of Sensory Gating and Reward Learning in Individuals with Psychotic Disorders

Motivational and perceptual disturbances co-occur in psychosis and have been linked to aberrations in reward learning and sensory gating, respectively. Although traditionally studied independently, when viewed through a predictive coding framework, these processes can both be linked to dysfunction in striatal dopaminergic prediction error signaling. This study examined whether reward learning and sensory gating are correlated in individuals with psychotic disorders, and whether nicotine—a psychostimulant that amplifies phasic striatal dopamine firing—is a common modulator of these two processes. We recruited 183 patients with psychotic disorders (79 schizophrenia, 104 psychotic bipolar disorder) and 129 controls and assessed reward learning (behavioral probabilistic reward task), sensory gating (P50 event-related potential), and smoking history. Reward learning and sensory gating were correlated across the sample. Smoking influenced reward learning and sensory gating in both patient groups; however, the effects were in opposite directions. Specifically, smoking was associated with improved performance in individuals with schizophrenia but impaired performance in individuals with psychotic bipolar disorder. These findings suggest that reward learning and sensory gating are linked and modulated by smoking. However, disorder-specific associations with smoking suggest that nicotine may expose pathophysiological differences in the architecture and function of prediction error circuitry in these overlapping yet distinct psychotic disorders

Cognitive and psychophysiological correlates of disgust in obsessive-compulsive disorder

Objectives Evidence suggests that obsessive-compulsive disorder (OCD) is characterized by heightened self-reported disgust, however, it is unclear if this extends to physiology. The relationship between obsessive beliefs and disgust also remains poorly understood. Therefore, we examined whether the heightened trait and self-reported disgust observed in individuals with OCD is reflected in heightened physiological disgust responses. We also examined whether obsessive beliefs are associated with disgust responding. Design A 3 (group) × 6 (stimulus) repeated measures design was used to examine disgust responses in individuals with OCD to six categories of image stimuli: body waste, contamination, injury, sociomoral, neutral, negative non-disgust. Methods Individuals with OCD (n = 25) were compared to individuals with non-OCD anxiety disorders (n = 21) and healthy participants (n = 25) with respect to trait, self-reported, facial electromyographic and electrodermal disgust responses. Results Individuals with OCD showed greater disgust propensity and self-reported disgust to images of body waste compared to healthy and anxious participants, however, there were no group differences in physiological responses. After controlling for trait disgust, obsessive beliefs positively correlated with increased self-reported disgust to neutral images and increased levator labii activity to negative non-disgusting images. Conclusions Although individuals with OCD showed elevated disgust propensity and self-reported ratings of body waste stimuli, there was little evidence that OCD is characterized by an abnormal physiological disgust response. The intensity of obsessive beliefs was associated with a tendency to respond with disgust in contexts that are non-disgusting, indicating that obsessive beliefs may be implicated in pathological disgust. Practitioner points Individuals with OCD display greater levels of disgust propensity and self-reported disgust to images of body waste compared to healthy control participants and individuals with non-OCD anxiety disorders. The abnormalities in self-reported disgust observed in those with OCD do not extend to abnormalities in electrodermal activity or facial electromyographic responses. Maladaptive obsessive beliefs commonly associated with OCD predict heightened disgust in contexts where objective sources of disgust are absent, even after controlling for trait disgust. Maladaptive obsessive beliefs may therefore be implicated in pathological disgust. This study used a heterogeneous OCD sample and future research is needed to determine whether the observed effects are greater for those with primarily washing and contamination symptoms. Although group differences emerged in self-reported disgust, further replications using measures of state anxiety are needed to rule out the possibility that heightened self-reported disgust was confounded with co-occurring fear or general negative affect

Reward Learning, Neurocognition, Social Cognition, and Symptomatology in Psychosis

Background: Patients with psychosis spectrum disorders exhibit deficits in social and neurocognition, as well as hallmark abnormalities in motivation and reward processing. Aspects of reward processing may overlap behaviorally and neurobiologically with some elements of cognitive functioning, and abnormalities in these processes may share partially overlapping etiologies in patients. However, whether reward processing and cognition are associated across the psychoses and linked to state and trait clinical symptomatology is unclear. Method The present study examined associations between cognitive functioning, reward learning, and clinical symptomatology in a cross-diagnostic sample. Patients with schizophrenia (SZ; n = 37), bipolar I disorder with psychosis (BD; n = 42), and healthy controls (n = 29) were assessed for clinical symptoms (patients only), neurocognitive functioning using the MATRICS Battery (MCCB) and reward learning using the probabilistic reward task (PRT). Groups were compared on neurocognition and PRT response bias, and associations between PRT response bias and neurocognition or clinical symptoms were examined controlling for demographic variables and PRT task difficulty (discriminability). Results: Patients with SZ performed worse than controls on most measures of neurocognition; patients with BD exhibited deficits in some domains between the level of patients with SZ and controls. The SZ – but not BD – group exhibited deficits in social cognition compared to controls. Patients and controls did not differ on PRT response bias, but did differ on PRT discriminability. Better response bias across the sample was associated with poorer social cognition, but not neurocognition; conversely, discriminability was associated with neurocognition but not social cognition. Symptoms of psychosis, particularly negative symptoms, were associated with poorer response bias across patient groups. Discussion Reward learning was associated with symptoms of psychosis – in particular negative symptoms – across diagnoses, and was predictive of worse social cognition. Reward learning was not associated with neurocognitive performance, suggesting that, across patient groups, social cognition but not neurocognition may share common pathways with this aspect of reinforcement learning. Better understanding of how cognitive dysfunction and reward processing deficits relate to one another, to other key symptom dimensions (e.g., psychosis), and to diagnostic categories, may help clarify shared etiological pathways and guide efforts toward targeted treatment approaches

Age invariance in rapid facial affective reactions to emotionally valenced stimuli

It has been suggested that an age-related positivity effect may only occur in the context of explicit information processing, but it is unclear whether this bias extends to the processing of rapid facial reactions. In addition, most studies that have looked for evidence of age-related implicit positivity have used attentional (as opposed to sensory) unawareness paradigms, or used broad-based indicators of attentional awareness that do not speak to the nature of the affective response. In the present study, younger and older adults were therefore asked to view non-facial images presented supraliminally (i.e., consciously) as well as outside of sensory awareness (i.e., subliminally) while their facial reactions were indexed using electromyography. The results indicated that both younger and older adults exhibited rapid facial reactions congruent with the emotional valence of non-facial images in both supraliminal and subliminal conditions. Relative to young, older adults did not respond with greater zygomaticus (cheek) activity to positive stimuli or reduced corrugator (brow) activity to negative stimuli in either condition. These data show that rapid facial reactions to emotional stimuli are intact in late adulthood, even in response to stimuli that activate more automatic and implicit forms of emotion processing. However, there is no evidence for any age-related positivity bias in these behavioral responses