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There has been a growing interest in resting-state brain alterations in people with social anxiety disorder. However, the evidence has been mixed and contested and further understanding of the neurobiology of this disorder may aid in informing methods to increase diagnostic accuracy and treatment targets. With this systematic review, we aimed to synthesize the findings of the neuroimaging literature on resting-state functional activity and connectivity in social anxiety disorder, and to summarize associations between brain and social anxiety symptoms to further characterize the neurobiology of the disorder. We systematically searched seven databases for empirical research studies. Thirty-five studies met the inclusion criteria, with a total of 1611 participants (795 people with social anxiety disorder and 816 controls). Studies involving resting-state seed-based functional connectivity analyses were the most common. Individuals with social anxiety disorder (vs. controls) displayed both higher and lower connectivity between frontal–amygdala and frontal–parietal regions. Frontal regions were the most consistently implicated across other analysis methods, and most associated with social anxiety symptoms. Small sample sizes and variation in the types of analyses used across studies may have contributed to the inconsistencies in the findings of this review. This review provides novel insights into established neurobiological models of social anxiety disorder and provides an update on what is known about the neurobiology of this disorder in the absence of any overt tasks (i.e., resting state). The knowledge gained from this body of research enabled us to also provide recommendations for a more standardized imaging pre-processing approach to examine resting-state brain activity and connectivity that could help advance knowledge in this field. We believe this is warranted to take the next step toward clinical translation in social anxiety disorder that may lead to better treatment outcomes by informing the identification of neurobiological targets for treatment.

Relative to their young counterparts, older adults are poorer at recognizing facial expressions. A 2008 meta-analysis of 17 facial emotion recognition data sets showed that these age-related difficulties are not uniform. Rather, they are greatest for the emotions of anger, fear, and sadness, comparative with happiness and surprise, with no age-effect found for disgust. Since then, there have been many methodological advances in assessing emotion recognition. The current comprehensive meta-analysis systematically tested the influence of task characteristics (e.g., photographs vs. videos). The meta-analysis included 102 data sets that compared facial emotion recognition in older and young adult samples (N = 10,526). With task type combined, the pattern of age-effects across emotions was mostly consistent with the previous meta-analysis (i.e., largest age-effects for anger, fear, sadness; no effect for disgust). However, the magnitude and direction of age-effects were strongly influenced by elements of task design. Specifically, videos produced relatively moderate age-effects across all emotions, which indicates that older adults may not exhibit a positivity effect for facial emotion recognition. For disgust recognition, older adults demonstrated superior accuracy to young adults for the most common image set (Pictures of Facial Affect). However, they were poorer than young adults at recognizing this emotion for all other stimulus formats and image sets, which suggests that they do not retain disgust recognition. We discuss the implications that such diversity in the age-effects produced by different facial emotion recognition task designs has for understanding real-world deficits and task selection in future emotion recognition studies. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BackgroundSocial anxiety disorder (SAD) is a prevalent and disabling mental health condition, characterized by excessive fear and anxiety in social situations. Resting-state functional magnetic resonance imaging (fMRI) paradigms have been increasingly used to understand the neurobiological underpinnings of SAD in the absence of threat-related stimuli. Previous studies have primarily focused on the role of the amygdala in SAD. However, the amygdala consists of functionally and structurally distinct subregions, and recent studies have highlighted the importance of investigating the role of these subregions independently.MethodUsing multiband fMRI, we analyzed resting-state data from 135 participants (42 SAD, 93 healthy controls). By employing voxel-wise permutation testing, we examined group differences of fMRI connectivity and associations between fMRI connectivity and social anxiety symptoms to further investigate the classification of SAD as a categorical or dimensional construct.ResultsSeed-to-whole brain functional connectivity analysis using multiple ‘seeds’ including the amygdala and its subregions and the precuneus, revealed no statistically significant group differences. However, social anxiety severity was significantly negatively correlated with functional connectivity of the precuneus - perigenual anterior cingulate cortex and positively correlated with functional connectivity of the amygdala (specifically the superficial subregion) - parietal/cerebellar areas.ConclusionOur findings demonstrate clear links between symptomatology and brain connectivity in the absence of diagnostic differences, with evidence of amygdala subregion-specific alterations. The observed brain-symptom associations did not include disturbances in the brain’s fear circuitry (i.e., disturbances in connectivity between amygdala - prefrontal regions) likely due to the absence of threat-related stimuli.

Social anxiety disorder (SAD) is characterised by an excessive fear of negative social evaluation. There is a limited understanding of how individuals with SAD react physiologically and subjectively to social stress.The Trier Social Stress Test (TSST), an acute social stress task, was completed by 40 SAD individuals (50% female) and 41 healthy controls (matched on age, sex, and education) to examine salivary cortisol and self-reported stress reactivity. Salivary cortisol concentrations and self-reported affect (anxiety, sadness, tiredness, withdrawal, and happiness) were assessed at baseline and across nine-time points during the TSST.Bayesian salivary cortisol analyses revealed no group differences in salivary cortisol levels at baseline or during the TSST, with results comparative after the removal of 17 cortisol non-responders (21%). Contrastingly, the groups significantly differed on self-reported affect. At baseline, the SAD group (vs. controls) reported heightened negative affect and diminished happiness. In response to the TSST, the SAD group (vs. controls) displayed greater negative affect reactivity and diminished happiness reactivity, and significantly higher rates of change in their anxiety and sadness over time. After accounting for differences in the temporal resolution of self-reported versus cortisol responses, a moderate positive association was found between salivary cortisol and anxiety reactivity to social stress that was comparable between the groups.Despite elevated subjective anxiety, our findings suggest concordance in psychobiological stress reactivity in SAD and healthy controls. We discuss the possibility of heightened subjective sensitivity to social evaluative stress as a core treatment target for SAD.

The Trier Social Stress Test (TSST) is a reliable biopsychological tool to examine the effects of acute stress on psychological and physiological functioning in humans. While the TSST reliably increases hypothalamic-pituitary-adrenal axis activation, amongst other biomarkers, through a combination of social evaluative threat and uncontrollability, the original protocol is limited in methodological detail that has impacted its reproducibility. Although many studies include a mock job interview and surprise arithmetic task, there are large variations in the timing of events, the number and method of biological (e.g., cortisol) sampling, the administration of a glucose drink, set-up of equipment and rooms, panel composition, and panel interaction with participants. We provide an overview of the potential impact of methodological variations on the stress (cortisol) response. Importantly, we also provide a step-by-step guide as a laboratory manual on how to conduct the TSST. This introductory guide may be a useful and time-saving resource that may also improve the scientific standard and reliability of the reported psychobiological stress effects in future studies.

Background: Age-related declines in many cognitive abilities are common in healthy aging. However, the ability to effectively regulate emotions is preserved, and possibly even enhanced, in late adulthood. This capacity has been examined most commonly in relation to low-intensity emotional stimuli that typically involve static pictures. Evidence is suggesting that older adults may become overwhelmed when exposed to emotional cues of heightened intensity. Objective: In the current study, we assessed whether older adults retain the ability to regulate emotions successfully when exposed to more emotionally evocative (e.g., dynamic) stimuli. Methods: Young and older adults were instructed to regulate, using expressive suppression, their outward behavioral expression of emotions while viewing dynamic stimuli involving amusing and sad films. Facial reactivity, as indexed using electromyography, self-rated emotional experience, and memory for the stimuli were assessed. Results: The results showed that, relative to young adults, older adults were unable to suppress zygomaticus (cheek) activity to amusing films or corrugator (brow) reactivity to sad films, which is likely due to their relatively reduced facial muscle reactivity. Expressive suppression did not affect young or older adults’ subjective feelings or memory for the stimuli. Conclusion: Our findings suggest that there are age differences in facial muscle reactivity to amusing and sad cues of heightened intensity. These findings suggest that older adults’ ability to effectively regulate emotions may be limited, at least with expressive suppression, in the context of high-intensity emotional cues. Further research is needed to investigate possible exceptions the preservation of emotion regulation in older adults.

Functional imaging and behavioural studies have shown that the neuropeptide oxytocin influences processing of emotional faces. However, it is not clear whether these effects reflect modulation at an early or late stage of affective processing. We investigated the effects of oxytocin administration on early and late visual evoked potentials (VEP) in response to faces with neutral, fearful and happy expressions. In addition, we measured multifocal VEP and its associated nonlinearities to ascertain whether any changes observed in electrophysiology were indicative of a generalised effect or of one tied strictly to emotional processing. In a randomized, double-blind, cross-over design, 27 healthy male participants self-administered a nasal spray of either oxytocin (24 IU) or placebo. At very early latencies (40-60ms), oxytocin reduced right-temporal responses to fearful faces (d = .51), and central responses to both fearful (d = .48) and neutral faces (d = .54). For left occipito-temporal electrode sites, oxytocin decreased P100 reactivity to fearful expressions (d = 0.72). Oxytocin also decreased the amplitudes of the vertex positive potential (140-180ms) and late positive potential (400-600ms), regardless of whether the faces had fearful, happy or neutral expressions. The mfVEP showed no signs of selective magno-or parvo-cellular peak modulation comparing OXT with placebo with either low or high contrast stimulation. These results suggest that at early stages of visual processing, nasal oxytocin modulates responses to facial emotions, whereas at later stages of visual processing, it appears to influence more general face processing mechanisms. In addition, the measurable effects of OXT appear to be not a result of generalized brain change, but systematically related to emotional processing.

Rationale Regular cannabis use has been associated with brain functional alterations within frontal, temporal, and striatal pathways assessed during various cognitive tasks. Whether such alterations are consistently reported in the absence of overt task performance needs to be elucidated to uncover the core neurobiological mechanisms of regular cannabis use. Objectives We aim to systematically review findings from studies that examine spontaneous fluctuations of brain function using functional Magnetic Resonance Imaging (fMRI) resting-state functional connectivity (rsFC) in cannabis users versus controls, and the association between rsFC and cannabis use chronicity, mental health symptoms, and cognitive performance. Methods We conducted a PROSPERO registered systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched eight databases. Results Twenty-one studies were included for review. Samples comprised 1396 participants aged 16 to 42 years, of which 737 were cannabis users and 659 were controls. Most studies found greater positive rsFC in cannabis users compared to controls between frontal-frontal, fronto-striatal, and fronto-temporal region pairings. The same region pairings were found to be preliminarily associated with varying measures of cannabis exposure. Conclusions The evidence to date shows that regular cannabis exposure is consistently associated with alteration of spontaneous changes in Blood Oxygenation Level-Dependent signal without any explicit cognitive input or output. These findings have implications for interpreting results from task-based fMRI studies of cannabis users, which may additionally tax overlapping networks. Future longitudinal rsFC fMRI studies are required to determine the clinical relevance of the findings and their link to the chronicity of use, mental health, and cognitive performance.

Supplemental material, sj-pdf-1-anp-10.1177_0004867421998762 for Empirical evidence for cognitive subgroups in body dysmorphic disorder by Amy Malcolm, Sarah N Brennan, Sally A Grace, Toni D Pikoos, Wei Lin Toh, Izelle Labuschagne, Ben Buchanan, Ryan A Kaplan, David J Castle and Susan L Rossell in Australian & New Zealand Journal of Psychiatry

ObjectiveCurrent understanding of cognitive functioning in body dysmorphic disorder (BDD) is limited, owing to few studies, small sample sizes, and assessment across only limited cognitive domains. Existing research has also shown inconsistent findings, with both intact and impaired cognition reported in BDD, which might point toward cognitive heterogeneity in the disorder. This study aimed to examine the cognitive profile of BDD in a large sample across eight cognitive domains, and to explore whether cognitive subgroups might be identified within BDD.MethodsCognitive domains of inhibition/flexibility, working memory, speed of processing, reasoning and problem-solving, visual and verbal learning, attention/vigilance and social cognition were assessed and compared between 65 BDD patients and 70 healthy controls. Then, hierarchical clustering analysis was conducted on the BDD group’s cognitive data.ResultsGroup-average comparisons demonstrated significantly poorer cognitive functioning in BDD than healthy controls in all domains except for attention/vigilance and social cognition. Cluster analysis identified two divergent cognitive subgroups within our BDD cohort characterised by i) broadly intact cognitive function with mild selective impairments (72.3%), and ii) broadly impaired cognitive function (27.7%). However, the clusters did not significantly differ on clinical parameters or most sociodemographic characteristics.ConclusionCognitively diverse subgroups were identified within BDD, yet these were obscured in group-average comparisons. However, subgroup profiles of cognitive functioning seem unrelated to the clinical presentation of BDD. Further research into the underlying mechanisms of cognition in BDD is warranted.Significant OutcomesCognitive function varies widely among people with body dysmorphic disorder (BDD) and includes subgroups characterised by broadly intact or broadly impaired cognitive profiles.However, reduced performances in visual learning and working memory as relative to healthy participants were identified across both BDD cognitive subgroups to differing degrees.Clinical characteristics were not significantly different among the two BDD cognitive subgroups; what role cognitive functioning may play in the aetiology or presentation of BDD remains unclear.LimitationsThe output of clustering analysis is sensitive to the choice of variables entered and requires replication with analogous measures of cognition.Psychiatric comorbidities and medications could have impacted cognitive performances in the BDD group in an unaccounted-for manner.Data availability statementAuthor elects to not share data.

Oxytocin (OXT) is a neuropeptide which has a critical role in human social behaviour and cognition. Research investigating the role of OXT on functional brain changes in humans has often used task paradigms that probe socioemotional processes. Preliminary evidence suggests a central role of the amygdala in the social cognitive effects of intranasal OXT (IN-OXT), however, inconsistencies in task-design and analysis methods have led to inconclusive findings regarding a cohesive model of the neural mechanisms underlying OXT's actions. The aim of this meta-analysis was to systematically investigate these findings. A systematic search of PubMed, PsycINFO, and Scopus databases was conducted for fMRI studies which compared IN-OXT to placebo in humans. First, we systematically reviewed functional magnetic resonance imaging (fMRI) studies of IN-OXT, including studies of healthy humans, those with clinical disorders, and studies examining resting-state fMRI (rsfMRI). Second, we employed a coordinate-based meta-analysis for task-based neuroimaging literature using activation likelihood estimation (ALE), whereby, coordinates were extracted from clusters with significant differences in IN-OXT versus placebo in healthy adults. Data were included for 39 fMRI studies that reported a total of 374 distinct foci. The meta-analysis identified task-related IN-OXT increases in activity within a cluster of the left superior temporal gyrus during tasks of emotion processing. These findings are important as they implicate regions beyond the amygdala in the neural effects of IN-OXT. The outcomes from this meta-analysis can guide a priori predictions for future OXT research, and provide an avenue for targeted treatment interventions.

This study explored the interrelationship between intolerance of uncertainty, sensory hyper-sensitivity and anxiety in Williams syndrome (WS). Thirty-two parents or guardians of individuals with WS (Mage = 24.76 years, SD = 7.55) were included. Associations between anxiety, intolerance of uncertainty, sensory hyper-sensitivity, and ASD symptoms were assessed. Linear regression analysis revealed that intolerance of uncertainty and sensory hyper-sensitivity were unique independent predictors of anxiety, while social communication score was not. There was evidence of a mediating effect of sensory hyper-sensitivity on the relationship between intolerance of uncertainty and anxiety. These findings bear strong resemblance to the pattern seen in ASD and emphasize the need for development of anxiety interventions that attempt to reduce negative beliefs about unpredictable situations in WS.

Background Identity disruption and internalised shame may be important factors in explaining possible psychological mechanisms that underlie body dysmorphic disorder (BDD). These factors have also been linked to obsessive-compulsive disorder (OCD), a condition closely related to BDD. However, these factors have not been specifically examined in BDD, nor contrasted between BDD and OCD. Methods We compared identity functioning and internalised shame among 26 BDD, 22 OCD and 26 healthy control participants, and examined clinical correlates in both disorders. Results Findings demonstrated increased identity disruption and internalised shame in BDD and OCD relative to controls, and increased internalised shame in BDD relative to OCD. In both disorders, shame and identity disruption was correlated with suicidal ideation, depression, stress, and anxiety. In BDD only, increased identity disruption correlated with poorer insight, and increased internalised shame correlated with more severe BDD symptoms and poorer illness insight. Conclusions These data suggest that internalised shame may have important and specific relevance to BDD, and more general relevance to OCD. Moreover, identity disruption may represent an area meriting further research attention in both BDD and OCD. Clinical implications include the potential benefits of addressing internalised shame and identity problems in the treatment of both disorders.

Background. Navigating obstacles whilst walking might be associated with poorer balance and a higher risk of falling in individuals with symptomatic Huntington’s disease (symp-HD). However, this issue has not been investigated within the literature. Objective. A unique obstacle navigation experiment was designed to examine adaptive gait patterns in order to identify spatiotemporal gait characteristics that might be associated with poorer balance and a higher risk of falling in symp-HD. Method. Sixteen diagnosed symp-HD participants and 16 age- and sex-matched healthy controls were included. Gait was examined in 3 experimental conditions: baseline walking, walking while navigating around 1 obstacle, and walking while navigating around 2 obstacles. Navigation around obstacle walks was divided into three step phases (approach, navigation, recovery). Group differences in gait variables were analyzed at baseline and during walking for each obstacle condition respectively. Gait variables were also correlated with the Berg Balance Scale (BBS) and Timed Up and Go (TUG) test. Results. Symp-HD participants, compared with controls, performed significantly poorer on most gait variables during baseline walking. Symp-HD participants significantly decreased their step-length while navigating around 1 obstacle, and increased their step-time while navigating around 1 and 2 obstacles. There were no significant group differences in step-width. Variables associated with navigating around obstacles correlated significantly with BBS and TUG clinical tools, which have been associated in the literature with an increased risk of falling in symp-HD. Conclusion. These findings could aid clinicians in better managing risk of falls in people with Huntington’s disease through targeted and effective strategies.

Background: Family functioning in Huntington’s disease (HD) is known from previous studies to be adversely affected. However, which aspects of family functioning are disrupted is unknown, limiting the empirical basis around which to create supportive interventions. Objective: The aim of the current study was to assess family functioning in HD families. Methods: We assessed family functioning in 61 participants (38 HD gene-expanded participants and 23 family members) using the McMaster Family Assessment Device (FAD; Epstein, Baldwin and Bishop, 1983), which provides scores for seven domains of functioning: Problem Solving; Communication; Affective Involvement; Affective Responsiveness; Behavior Control; Roles; and General Family Functioning. Results: The most commonly reported disrupted domain for HD participants was Affective Involvement, which was reported by 39.5% of HD participants, followed closely by General Family Functioning (36.8%). For family members, the most commonly reported dysfunctional domains were Affective Involvement and Communication (both 52.2%). Furthermore, symptomatic HD participants reported more disruption to Problem Solving than pre-symptomatic HD participants. In terms of agreement between pre-symptomatic and symptomatic HD participants and their family members, all domains showed moderate to very good agreement. However, on average, family members rated Communication as more disrupted than their HD affected family member. Conclusion: These findings highlight the need to target areas of emotional engagement, communication skills and problem solving in family interventions in HD.

The prevailing nosological classification of body dysmorphic disorder (BDD) encompasses an optional specifier “with absent insight/delusional beliefs” for patients who hold high conviction of the veracity of their disorder-specific beliefs. Yet limited research has examined the explicit nature of delusional beliefs in BDD. The current study therefore aimed to compare themes of delusional ideation in BDD relative to schizophrenia (SCZ) and healthy controls (HCs). Participants had a primary diagnosis of BDD (n = 44) or SCZ (n = 55), or were HCs (n = 55) with no personal or immediate family history of a diagnosable mental health disorder. Assessment of multidimensional delusional ideation was based on the Peters Delusional Inventory (PDI). Results showed that BDD and SCZ groups endorsed significantly more items, and had significantly elevated preoccupation and conviction than the HC group. Only the SCZ group exhibited significantly elevated distress relative to HC participants. In addition, BDD (akin to SCZ) participants were more likely to endorse somatic (appearance-related), control and thought alienation themes than the HC group. These findings suggest that delusional beliefs in BDD may not be strictly appearance-related, but rather span broader themes. This conveys therapeutic implications in terms of designing and administering targeted treatments aimed at delusional thinking in BDD.

Opiate use is associated with deficits in decision-making. However, the impact of abstinence and co-morbid factors, like head injury and poly-substance abuse, on this ability, is currently unclear. This meta-analysis aimed to assess 1) the magnitude of decision-making deficits in opiate users; 2) whether co-morbid factors moderate the severity of these deficits; 3) whether ex-opiate users demonstrate smaller decision-making deficits than current users; and 4) whether the length of abstinence is related to the magnitude of decision-making deficits. We analysed 22 studies that compared the performance of current and ex-opiate users to healthy controls on decision-making measures such as the Iowa Gambling Task. Current users demonstrated a moderately strong impairment in decision-making relative to controls, which was not significantly moderated by co-morbid factors. The magnitude of the impairment did not significantly differ between studies assessing current or ex-users, and this impairment was not related to length of abstinence. Thus, it appears that opiate users have relatively severe decision-making deficits that persist at least 1.5 years after cessation of use.

Episodic future thinking (EFT), the ability to imagine experiencing a future event, and prospective memory (PM), the ability to remember and carry out a planned action, are core aspects of future-oriented cognition that have individually been the focus of research attention in the developmental literature. However, the relationship between EFT and PM, including the extent to which it varies with PM task type, remains poorly delineated, particularly in middle childhood. The current study tested this relationship in 62 typically developing children aged 8–12 years. Results indicated that EFT ability was significantly related to performance on three types of PM tasks (regular and irregular event based and regular time based). Age was not found to moderate the relationship. Children’s performance on the retrospective memory component of the PM tasks mediated the relationship between EFT ability and their performance on three types of PM tasks. For irregular event-based tasks, however, EFT made an additional significant contribution. This study adds to the limited empirical literature supporting a relationship between EFT and PM in this age band and supports theoretical models arguing that EFT ability may support PM performance by strengthening the encoding of PM task details in retrospective memory. However, additional mechanisms were also indicated for irregular event-based PM tasks, possibly involving strengthening of cue–context associations. These data show for the first time that the contribution of EFT to children’s PM performance varies across task types. This study provides an important and novel contribution to current understanding of the processes that underlie PM development.

The aetiology of body dysmorphic disorder (BDD) is poorly understood. Recent evidence from functional brain imaging studies suggests that BDD is associated with aberrant task-based functional connectivity and that intranasal oxytocin (OXT) may improve network connectivity in BDD patients. Thus, the aim of this study was to investigate the effect of intranasal OXT on amygdala resting-state functional connectivity (rsFC) in BDD. In a randomized, double-blind, cross-over design, 19 BDD participants and 17 demographically matched healthy control participants received intranasal OXT (24 IU) or placebo prior to resting-state functional magnetic resonance imaging. The left and right amygdala were seeded as regions of interest, and temporal correlations between the amygdalae and all other voxels comprising cortical and subcortical grey matter were investigated. Compared to healthy controls, BDD patients showed greater baseline (placebo) rsFC between the left amygdala and two clusters within the left temporal lobe and one cluster within the superior frontal gyrus which was reversed following OXT administration. The control group also showed significantly greater rsFC between the left amygdala and anterior prefrontal cortex in the OXT session compared to placebo. Whilst preliminary, these findings suggest that BDD patients exhibit abnormal amygdala-temporal connectivity at rest, and OXT might have a role in changing this functional relationship.

Background Previous research has demonstrated an association between emotion recognition and apathy in a number of neurological conditions involving fronto-striatal pathology, including Parkinson’s disease and brain injury. Aims In line with these findings, we aimed to determine whether apathetic participants with early Huntington’s disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. Methods We included 43 HD participants from the TRACK-HD study who had an apathy score >1 on the Problem Behaviours Assessment – short version (PBA-S), 67 HD participants who reported no apathy, and 107 controls matched for age, sex and level of education. During their baseline visit, participants completed a battery of cognitive tests that include an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS), and the PBA-s. Results Compared to the non-apathetic HD group and the control group, the apathetic HD group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology (HADS) and general disease progression (UHDRS total motor score). This was despite no difference between the apathetic and non-apathetic groups on overall cognitive functioning assessed by a cognitive composite score. Conclusions Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on fronto-striatal pathways may broadly explain associations between emotion recognition and apathy found across a number of patient groups, further work is needed to determine what relationships exist between the recognition of specific emotions, distinct subtypes of apathy, and underlying neuropathology.

OBJECTIVE Previous research has consistently shown that the ability to recognize emotions from facial expressions is impaired in Huntington's disease (HD). The aim of this study was to examine whether people with the gene expansion for HD visually scan the most emotionally informative features of human faces less than unaffected individuals, and whether altered visual scanning predicts emotion recognition in HD beyond general disease-related decline. METHOD We recorded eye movements of 25 participants either in the late premanifest or early stage of HD and 25 age-matched healthy control participants during a face-viewing task. The task involved the viewing of pictures depicting human faces with angry, disgusted, fearful, happy, and neutral expressions, and evaluating each face on a valence rating scale. For data analysis, we defined 2 regions of interest (ROIs) on each picture, including an eye-ROI and a nose/mouth-ROI. Emotion recognition abilities were measured using an established emotion-recognition task and general disease-related decline was measured using the UHDRS motor score. RESULTS Compared to the control participants, the HD participants spent less time looking at the ROIs relative to the total time spent looking at the pictures (partial η2 = 0.10), and made fewer fixations on the ROIs (partial η2 = 0.16). Furthermore, visual scanning of the eye-ROI, but not the nose/mouth-ROI, predicted emotion recognition performance in the HD group, over and beyond general disease-related decline. CONCLUSION The emotion recognition deficit in HD may partly be explained by general disease-related decline in cognition and motor functioning and partly by a social-emotional deficit, which is reflected in reduced eye-viewing. (PsycINFO Database Record

Impairments in social cognition and poor social functioning are core features of schizophrenia-spectrum disorders. In recent years, there has been a move towards developing new treatment strategies that specifically target social cognitive and social behavioural deficits. Oxytocin (OXT) is one such strategy that has gained increasing attention. There is a strong rationale for studying OXT in psychosis, from both an evolutionary perspective and neurodevelopmental-cognitive model of schizophrenia. Thus, the aim of this review was to critique and examine the observational and clinical oxytocin trial literature in schizophrenia-spectrum disorders. A handful of clinical trials suggest that OXT treatment may be beneficial for remediating social cognitive impairments, psychiatric symptoms, and improving social outcomes. However, inconsistencies exist in this literature, which may be explained by individual differences in the underlying neural response to OXT treatment and/or variation in the oxytocin and oxytocin receptor genes. Therefore, we additionally reviewed the evidence for structural and functional neural intermediate phenotypes in humans that link genetic variants to social behaviour/thinking, and discuss the implications of such interactions in the context of dysfunctional brain networks in schizophrenia. Factors that pose challenges for future OXT clinical research include the impact of age, sex, and ancestry, task-specific effects, bioavailability and pharmacokinetics, as well as neurotransmitter and drug interactions. While initial findings from OXT single dose/clinical trial studies are promising, more interdisciplinary research in both healthy and psychiatric populations is needed before determining whether OXT is a viable treatment option/adjunct for addressing poor illness outcomes in psychotic disorders.

People with Huntington's disease (HD) exhibit altered processing of emotional information, especially disgust and other negative emotions. These impairments are likely due to the effects of the disease on underlying brain networks. We examined whether oxytocin, when given intranasally, would normalise aberrant brain reactivity to emotional faces in participants with the gene-expansion for HD. In a double-blind placebo-controlled cross-over design, we measured brain activity, using functional magnetic resonance imaging, whilst nine medication-free HD carriers, and ten control participants viewed emotional (disgust, fear, angry, sad, surprise, happy) and neutral faces, following acute intranasal oxytocin (24 IU) and placebo. Subjective mood changes were assessed before and after the neuroimaging on each visit. Permutation-based non-parametric statistical testing for the whole brain, showed significant group × drug interactions (p's < 0.05, TFCE corrected) in areas of the left frontal pole, superior frontal, and middle frontal gyri cortically, and left putamen and thalamus sub-cortically. Parameter estimates extracted from the middle frontal gyrus and putamen showed that, under placebo, the HD group had lower brain activity to disgust stimuli, compared with controls. After intranasal oxytocin, the pattern of activation to disgust stimuli was normalised in the HD group to similar levels as controls; eight of the nine HD carriers showed increased response in the middle frontal gyrus, and seven of the nine HD carriers showed increased response in the putamen. The observed effects of oxytocin occurred in the absence of changes in subjective mood or state anxiety. These findings provide early evidence for a physiological role of oxytocin in the neuropathology of HD. Our findings are the first reported oxytocin effects in a neurodegenerative disease. Further research should examine the therapeutic benefits of oxytocin in alleviating emotional and social cognition deficits in HD and related disorders.

Rationale Opiate use is associated with deficits in decision-making. A possible explanation for these deficits is provided by the somatic marker hypothesis, which suggests that substance users may experience abnormal emotional responses during decision-making involving reward and punishment. This in turn may interfere with the brief physiological arousal, i.e. somatic markers that normally occur in anticipation of risky decisions. To date, the applicability of the somatic marker hypothesis to explain decision-making deficits has not been investigated in opiate users. Objectives This study assessed whether decision-making deficits in opiate users were related to abnormal emotional responses and reduced somatic markers. Methods Opiate users enrolled in an opiate substitute treatment program (n = 28) and healthy controls (n = 32) completed the Iowa Gambling Task (IGT) while their skin conductance responses (SCRs) were recorded. Participants’ emotional responses to emotion-eliciting videos were also recorded using SCRs and subjective ratings. Results Opiate users displayed poorer decision-making on the IGT than did controls. However, there were no differences between the groups in SCRs; both groups displayed stronger SCRs following punishment than following reward, and both groups displayed stronger anticipatory SCRs prior to disadvantageous decisions than advantageous decisions. There were no group differences in objective or subjective measures of emotional responses to the videos. Conclusions The results suggest that deficits in emotional responsiveness are not apparent in opiate users who are receiving pharmacological treatment. Thus, the somatic marker hypothesis does not provide a good explanation for the decision-making deficits in this group.

Huntington's disease (HD) is a neurodegenerative disorder associated with impaired facial emotion recognition and altered subjective experience of emotion. These impairments likely result from the effects of the disease on underlying neurobiological mechanisms. Studies using self-report to examine emotional experiences have been ambiguous regarding whether experiences are diminished or exaggerated, possibly due to cognitive impairment and lack of insight in HD. To infer affective states more objectively and overcome the limitations of self-report, we used facial EMG to measure muscle responses to emotionally-evocative scenes. Further, we examined muscle responses to emotionally-expressive faces, because facial mimicry is thought to facilitate emotion recognition and social affiliation. Twenty-three HD participants (late pre-manifest and early symptomatic) were compared to twenty-five healthy controls in a scene condition and a face condition. EMG activity was measured from facial muscles associated with expressing particular emotions: 1) corrugator supercilii for anger, 2) frontalis for fear, 3) levator labii for disgust, and 4) both zygomaticus major and orbicularis oculi for happiness. Compared to controls, HD participants showed diminished responses to disgusting scenes, and to happy and fearful faces. Our findings provide evidence for a loss of disgust experience in HD. Further, consistent with the alleged affiliative function of facial mimicry, diminished mimicry responses may be relevant to social-emotional changes in HD. Our findings help understand the neural mechanisms underlying emotion processing impairments in HD.

Oxytocin is a neuropeptide that plays a key role in social processing and there are several studies suggesting that intranasally administered oxytocin may enhance social cognitive abilities and visual attention in healthy and clinical groups. However, there are very few studies to date that have investigated the potential benefits of intranasal oxytocin (iOT) on older adults' social cognitive abilities. This is a surprising omission, because relative to their younger counterparts, older adults also exhibit a range of social cognitive difficulties and also show differences in the way they visually attend to social information. Therefore, we tested the effect of iOT (24 IU) versus a placebo spray on 59 older and 61 younger adults' social cognitive abilities and visual attention using a double-blind placebo-controlled within-groups design. While iOT provided no overall age-related benefit on social cognitive abilities, the key finding to emerge was that iOT improved ToM ability in both age-groups when the task had minimal contextual information, but not when the task had enriched contextual information. Interestingly, iOT had gender specific effects during a ToM task with minimal context. For males in both age-groups, iOT reduced gazing to the social aspects of the scenes (i.e., faces & bodies), and for females, iOT eliminated age differences in gaze patterns that were observed in the placebo condition. These effects on eye-gaze were not observed in a very similar ToM task that included more enriched contextual information. Overall, these findings highlight the interactive nature of iOT with task related factors (e.g., context), and are discussed in relation to the social salience hypothesis of oxytocin.

We investigated emotional processing in vicarious pain (VP) responders. VP responders report an explicit sensory and emotional feeling of pain when they witness another in pain, which is greater in magnitude than the empathic processing of pain in the general population. In Study 1, 31 participants completed a chimeric faces task, judging whether emotional chimera in the left, or right, visual field was more intense. VP responders took longer to judge emotionality than non-responders, and fixated more on the angry hemiface in the right visual field, whereas non-responder controls had no lateralized fixation bias. In Study 2, blood-oxygen level-dependent signals were recorded during an emotional face matching task. VP intensity was correlated with increased insula activity and reduced middle frontal gyrus activity for angry faces, and with reduced activity in the inferior and middle frontal gyri for sad faces. Together, these findings suggest that VP responders are more reactive to negative emotional expressions. Specifically, emotional judgements involved altered left-hemisphere activity in VP responders, and reduced engagement of regions involved in emotion regulation.

Heart rate variability (HRV) refers to variation in the interval between successive heart beats. Low HRV is an indicator of potential autonomic nervous system dysfunction. People with chronic pain often display autonomic dysregulation, especially in the parasympathetic nervous system. The hormone oxytocin has been shown to increase HRV in non-clinical samples, but its potential impact on HRV in persons with chronic pain is unknown. This study investigated the impact of intranasal oxytocin on HRV in persons with chronic neck and shoulder pain. Participants included 24 individuals with chronic neck and shoulder pain lasting > 12 months and 24 age- and sex-matched pain-free controls. In a randomised double-blind, placebo-controlled, cross-over study, participants self-administered intranasal oxytocin (24 IU) in one session, and placebo in another, before HRV was recorded at rest and during a mental arithmetic task. Intranasal oxytocin did not influence HRV at rest. However, compared to placebo, intranasal oxytocin elicited small decreases in low-frequency and high-frequency HRV in both groups during the mental arithmetic task. These results suggest that intranasal oxytocin may enhance the salience of the mental arithmetic task, leading to reduced engagement of the parasympathetic nervous system when completing the task. Further investigation and replication of these findings are required to improve our understanding of the effects of intranasal oxytocin on autonomic functioning both at rest and under cognitive stress.

Huntington’s disease (HD) is a neurodegenerative movement disorder associated with deficits in the processing of emotional stimuli, including alterations in the self-reported subjective experience of emotion when presented with pictures of emotional scenes. The aim of this study was to determine whether individuals with HD, compared to unaffected controls, display abnormal visual scanning of emotionally-evocative natural scenes. Using eye-tracking, we recorded eye-movements of 25 HD participants (advanced pre-symptomatic and early symptomatic) and 25 age-matched unaffected control participants during a picture viewing task. Participants viewed pictures of natural scenes associated with different emotions: anger, disgust, happiness, or neutral, and evaluated those pictures on a valence rating scale. Individuals with HD displayed abnormal visual scanning patterns, but did not differ from controls with respect to their valence ratings. Specifically, compared to controls, HD participants spent less time fixating on the pictures and made longer scan paths. This finding highlights the importance of taking visual scanning behavior into account when investigating emotion processing in HD. The visual scanning patterns displayed by HD participants could reflect a heightened, but possibly unfocussed, search for information, and might be linked to attentional deficits or to altered subjective emotional experiences in HD. Another possibility is that HD participants may have found it more difficult than controls to evaluate the emotional valence of the scenes, and the heightened search for information was employed as a compensatory strategy.

Chronic neck and shoulder pain (CNSP) is a common musculoskeletal disorder in adults, which is linked to hypersensitivity to noxious stimuli. The hormone oxytocin has been implicated as a potential therapeutic for the management of chronic pain disorders, and has been suggested to have sex-specific effects on the salience of threatening stimuli. This study investigated the influence of intranasal oxytocin on the perception of noxious thermal stimuli. Participants were 24 individuals with CNSP lasting >12 months (eight women), and 24 age- and sex-matched healthy, pain-free controls. In a randomised double-blind, placebo-controlled, cross-over study, participants attended two sessions, self-administering intranasal oxytocin (24 IU) in one session, and placebo in another. Participants rated intensity and unpleasantness of thermal heat stimuli at three body sites: the cervical spine, deltoid, and tibialis anterior, on 11-point numerical rating scales. Compared with placebo, intranasal oxytocin increased the perceived intensity of noxious heat stimuli in women with CNSP (Cohen’s d = 0.71), but not in men with CNSP, or healthy, pain-free controls. Men and women displayed divergent sensitivity across target sites for ratings of pain intensity (partial eta squared = 0.12) and pain unpleasantness (partial eta squared = 0.24), irrespective of drug condition. Men were more sensitive at the cervical spine and deltoid, whereas women were more sensitive at the tibialis. These findings suggest that oxytocin and endogenous sex hormones may interact to influence the salience of noxious stimuli. The hyperalgesic effects of oxytocin in women suggest that caution should be taken when considering oxytocin in the management of chronic pain. Trial Registration: CT-2016-CTN-01313-1; ACTRN12616000532404

Urgency is the tendency to make impulsive decisions under extreme positive or negative emotional states. Stress, gender and impulsive personality traits are all known to influence decision-making, but no studies have examined the interplay of all of these factors. We exposed 78 men and women to a stress or a non-stress condition, and then administered the Balloon Analogue Risk Task. We found that stress effects varied as a function of gender and urgency traits. Under stress, women low in negative urgency and men high in negative urgency made fewer risky decisions. Positive urgency yielded a similar pattern. Thus, decisions under stress depend on a complex interplay between gender and impulsive personality traits. These findings have implications for clinical disorders, such as substance use disorders, in which there are known deficits in decision-making and high levels of impulsive traits.

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder. The most prominent sign of HD is the presence of involuntary motor movements. However, HD is also characterized by marked cognitive decline, which often precedes the onset of motor symptoms and is generally considered to be more debilitating to the patients and their families, compared to motor symptoms. Cognitive decline is widespread across most faculties of cognition in later stages of the disease, but seems to be selective in preclinical and early stages of the disease, with deficits in the HD patients' ability to multitask, their speed of processing, and executive function. It is now well established that preceding clinical diagnosis there is a preclinical stage, during which HD gene mutation carriers are relatively symptom free, despite disease pathological onset and the presence of neurodegeneration. Evidence from functional brain imaging studies suggests the presence of neural compensation in preclinical stages of HD, whereby the brain undergoes functional reorganization in response to neurodegeneration to preserve motor and cognitive performance. In this review, we will describe the underlying HD pathology with a focus on how it links to the cognitive phenotype. We will also present evidence regarding the presence of neural compensation in HD and the possible mechanisms supporting it. Finally, we will discuss current research in the field of cognitive interventions that aim to support and enhance neural compensation in HD. These research efforts could, one day, prolong the preclinical stage and assist with symptom management of those affected with HD.

Body Dysmorphic Disorder (BDD) is characterised by overvalued or delusional beliefs of 'imagined ugliness'. Delusional beliefs have been explained by a number of cognitive theories, including faulty perceptions, biases in attention, and corruption of semantic memory. Atypical aesthetics may also influence beliefs in BDD. In fourteen BDD patients, compared to controls (n=14), we examined these theories of beliefs in a cognitive test battery consisting of perceptual organisation and visual affect perception tasks, a Stroop task using body words, a sentence verification task, a fluency task, and an attractiveness task. BDD patients performed similar to controls on tasks measuring information (bias) processing and aesthetics. However, BDD showed abnormal abilities on semantic processing involving sentence verification and category fluency. There was only a trend finding of impaired performance on perceptual processing tasks in BDD. The findings suggest that the delusional beliefs in BDD may be explained by impaired semantic processing.

Evidence now suggests executive dysfunction in Body Dysmorphic Disorder (BDD) which may be related to Obsessive-Compulsive Disorder (OCD). However, neurocognitive performance in the two disorders has rarely been compared. This study compared 14 BDD participants on neurocognitive tasks taken from the Cambridge Automated Neuropsychological Test Automated Battery (CANTAB) with previously published data from 23 OCD participants (Purcell, Maruff, Kyrios, & Pantelis, 1998). Effect sizes from three executive function tests (Spatial Span, Spatial Working Memory and Stockings of Cambridge), and one visual memory task (Pattern Recognition) were compared for group differences using difference and equivalence testing. Equivalence testing was used to determine whether BDD and OCD effects sizes were equivalent, non-equivalent or equivocal. Results indicated an equivocal pattern for Spatial Span, Spatial Working Memory, Pattern Recognition and most Stockings of Cambridge measures. However, results for Stockings of Cambridge accuracy measure indicated a non-equivalent pattern, with BDD but not OCD participants performing significantly worse than controls. Results suggest a number of similarities in neurocognitive function in BDD and OCD, although it was not possible to establish statistical equivalence on most study measures. The findings raise the possibility of more severe planning deficits in BDD compared to OCD.

There has been an increase in neuroimaging research in body dysmorphic disorder (BDD), yet little is known about the underlying neurobiological basis of the disorder. We aimed to provide a systematic overview of the literature on the neurobiology of BDD. Two reviewers undertook a search of three electronic research databases: PubMed, PsycINFO, and Google Scholar. The search consisted of synonyms commonly associated with BDD and methods to evaluate brain structure, function, and network organisation. Out of an initial yield of 175 articles, 19 fulfilled inclusion criteria and were reviewed. We identified differences in brain activity, structure, and connectivity in BDD participants in frontostriatal, limbic, and visual system regions when compared to healthy control and other clinical groups. We put forth a neurobiological model of BDD pathophysiology that involves wide-spread disorganisation in neural networks involved in cognitive control and the interpretation of visual and emotional information. This review considers how this model might aid in the development of future research and understanding of BDD.

Deficits in facial emotion recognition in Huntington's disease (HD) have been extensively researched, however, a theory-based integration of these deficits into the broader picture of emotion processing is lacking. To describe the full extent of emotion processing deficits we reviewed the clinical research literature in HD, including a consideration of research in Parkinson's disease, guided by a theoretical model on emotion processing, the Component Process Model. Further, to contribute to understanding the mechanisms underlying deficient emotion recognition, we discussed the literature in light of specific emotion recognition theories. Current evidence from HD studies indicates deficits in the production of emotional facial expressions and alterations in subjective emotional experiences, in addition to emotion recognition deficits. Conceptual understanding of emotions remains relatively intact. Impaired recognition and expression of emotion in HD might be linked, whereas altered emotional experiences appear to be unrelated to emotion recognition. A key implication of this review is the need to take all the components of emotion processing into account to understand specific deficits in neurodegenerative diseases.

The ability to regulate emotions is central to well-being, but healthy emotion regulation may not merely be about using the "right" strategies. According to the strategy-situation-fit hypothesis, emotion-regulation strategies are conducive to well-being only when used in appropriate contexts. This study is the first to test the strategy-situation-fit hypothesis using ecological momentary assessment of cognitive reappraisal-a putatively adaptive strategy. We expected people who used reappraisal more in uncontrollable situations and less in controllable situations to have greater well-being than people with the opposite pattern of reappraisal use. Healthy participants ( n = 74) completed measures of well-being in the lab and used a smartphone app to report their use of reappraisal and perceived controllability of their environment 10 times a day for 1 week. Results supported the strategy-situation-fit hypothesis. Participants with relatively high well-being used reappraisal more in situations they perceived as lower in controllability and less in situations they perceived as higher in controllability. In contrast, we found little evidence for an association between greater well-being and greater mean use of reappraisal across situations.

Generalized social anxiety disorder (GSAD) is associated with heightened limbic and prefrontal activation to negative social cues conveying threat (e.g. fearful faces), but less is known about brain response to negative non-threatening social stimuli. The neuropeptide oxytocin (Oxt) has been shown to attenuate (and normalize) fear-related brain activation and reactivity to emotionally negative cues. Here, we examined the effects of intranasal Oxt on cortical activation to non-threatening sad faces in patients with GSAD and matched controls (Con). In a double-blind placebo-controlled within-subjects design, the cortical activation to sad and happy (vs. neutral) faces was examined using functional magnetic resonance imaging following acute intranasal administration of 24 IU Oxt and placebo. Relative to the Con group, GSAD patients exhibited heightened activity to sad faces in the medial prefrontal cortex (mPFC/BA 10) extending into anterior cingulate cortex (ACC/BA 32). Oxt significantly reduced this heightened activation in the mPFC/ACC regions to levels similar to that of controls. These findings suggest that GSAD is associated with cortical hyperactivity to non-threatening negative but not positive social cues and that Oxt attenuates this exaggerated cortical activity. The modulation of cortical activity by Oxt highlights a broader mechanistic role of this neuropeptide in modulating socially negative cues in GSAD.

Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.

The ability to regulate emotions is central to well-being, but healthy emotion regulation may not merely be about using the "right" strategies. According to the strategy-situation-fit hypothesis, emotion-regulation strategies are conducive to well-being only when used in appropriate contexts. This study is the first to test the strategy-situation-fit hypothesis using ecological momentary assessment of cognitive reappraisal-a putatively adaptive strategy. We expected people who used reappraisal more in uncontrollable situations and less in controllable situations to have greater well-being than people with the opposite pattern of reappraisal use. Healthy participants ( n = 74) completed measures of well-being in the lab and used a smartphone app to report their use of reappraisal and perceived controllability of their environment 10 times a day for 1 week. Results supported the strategy-situation-fit hypothesis. Participants with relatively high well-being used reappraisal more in situations they perceived as lower in controllability and less in situations they perceived as higher in controllability. In contrast, we found little evidence for an association between greater well-being and greater mean use of reappraisal across situations. ispartof: Psychological Science vol:27 issue:12 pages:1651-1659 ispartof: location:United States status: published

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited.

The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.

BACKGROUND: Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. OBJECTIVE: We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. METHODS: Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. RESULTS: In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. CONCLUSIONS: Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder. The most prominent sign of HD is the presence of involuntary motor movements. However, HD is also characterized by marked cognitive decline, which often precedes the onset of motor symptoms and is generally considered to be more debilitating to the patients and their families, compared to motor symptoms. Cognitive decline is widespread across most faculties of cognition in later stages of the disease, but seems to be selective in preclinical and early stages of the disease, with deficits in the HD patients' ability to multitask, their speed of processing, and executive function. It is now well established that preceding clinical diagnosis there is a preclinical stage, during which HD gene mutation carriers are relatively symptom free, despite disease pathological onset and the presence of neurodegeneration. Evidence from functional brain imaging studies suggests the presence of neural compensation in preclinical stages of HD, whereby the brain undergoes functional reorganization in response to neurodegeneration to preserve motor and cognitive performance. In this review, we will describe the underlying HD pathology with a focus on how it links to the cognitive phenotype. We will also present evidence regarding the presence of neural compensation in HD and the possible mechanisms supporting it. Finally, we will discuss current research in the field of cognitive interventions that aim to support and enhance neural compensation in HD. These research efforts could, one day, prolong the preclinical stage and assist with symptom management of those affected with HD.

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT’s effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT’s effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, ‘normalized’) the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.

The neuropeptide oxytocin (OXT) plays an important role in complex socio-affective behaviours such as affiliation, attachment, stress and anxiety. Previous studies have focused on the amygdala as an important target of OXT's effects. However, the effects of OXT on connectivity of the amygdala with cortical regions such as medial frontal cortex, an important mediator of social cognition and emotion regulation, remain unexplored. In a randomized, double-blind, cross-over design, 15 volunteers received intranasal OXT or placebo prior to resting-state functional magnetic resonance imaging. OXT significantly increased connectivity between both amygdalae and rostral medial frontal cortex (rmFC), while having only negligible effects on coupling with other brain regions. These results demonstrate that OXT is a robust and highly selective enhancer of amygdala connectivity with rmFC, a region critical to social cognition and emotion regulation, and add to our understanding of the neural mechanisms by which OXT modulates complex social and cognitive behaviours.

Background Oxytocin (OXT) has shown to play an important role in modulating responses to emotional cues in healthy and clinical populations. Huntington’s disease (HD) is associated with deficits in facial expressions of emotion, particular of disgust, and which have been linked to abnormal neural networks. HD is also associated with a 45% reduction in OXT-expressing neurons in the hypothalamus, the region where OXT is produced. Aims We therefore examined whether administration of OXT intranasally to gene-carriers of HD would have beneficial effects on neural networks involved in emotion processing. Methods We compared 9 gene-carriers of HD and 10 age-matched controls, who were right-handed males, aged between 18–65 years, not medicated, and non-smokers. Using a randomised double-blind placebo-controlled design, each participant administered acute doses of intranasal OXT (24 IU) and placebo sprays over two visits. Participants completed an fMRI task involving matching emotional faces (disgust, happy, anger, fear, sad, surprise and neutral) or geometric shapes. Results Under placebo, and compared to controls, HD gene-carriers showed hypo-activity to disgust (middle/superior prefrontal gyrus) and hyper-activity to surprise (inferior/middle temporal gyrus). Significant Group x Drug interactions was found for five of the seven emotions (angry, disgust, fear, happy and sad). Post-hoc analyses showed significant within-group effects, corrected for multiple comparisons, where OXT significantly increased brain reactivity for happy (middle temporal gyrus) and disgust (precentral/inferior frontal gyrus) in the HD group. Conclusions We found evidence of hypo- and hyper-reactivity to disgust and surprise emotions respectively in HD gene-carriers. OXT increased brain activity in previously hypo-active regions in HD. We provide initial evidence of ‘normalisation’ effects and a broader physiological role of OXT in HD.