Blunted brain responses to neutral faces in healthy first-degree relatives of patients with schizophrenia: an image-based fMRI meta-analysis.

Schizophrenia is characterized by the misattribution of emotional significance to neutral faces, accompanied by overactivations of the limbic system. To understand the disorder's genetic and environmental contributors, investigating healthy first-degree relatives is crucial. However, inconsistent findings exist regarding their ability to recognize neutral faces, with limited research exploring the cerebral correlates of neutral face processing in this population. Thus, we here investigated brain responses to neutral face processing in healthy first-degree relatives through an image-based meta-analysis of functional magnetic resonance imaging studies. We included unthresholded group-level T-maps from 5 studies comprising a total of 120 first-degree relatives and 150 healthy controls. In sensitivity analyses, we ran a combined image- and coordinate-based meta-analysis including 7 studies (157 first-degree relatives, 207 healthy controls) aiming at testing the robustness of the results in a larger sample of studies. Our findings revealed a pattern of decreased brain responses to neutral faces in relatives compared with healthy controls, particularly in limbic areas such as the bilateral amygdala, hippocampus, and insula. The same pattern was observed in sensitivity analyses. These results contrast with the overactivations observed in patients, potentially suggesting that this trait could serve as a protective factor in healthy relatives. However, further research is necessary to test this hypothesis.

Detecting bulbar amyotrophic lateral sclerosis (ALS) using automatic acoustic analysis.

Automatic speech assessments have the potential to dramatically improve ALS clinical practice and facilitate patient stratification for ALS clinical trials. Acoustic speech analysis has demonstrated the ability to capture a variety of relevant speech motor impairments, but implementation has been hindered by both the nature of lab-based assessments (requiring travel and time for patients) and also by the opacity of some acoustic feature analysis methods. These challenges and others have obscured the ability to distinguish different ALS disease stages/severities. Validation of automated acoustic analysis tools could enable detection of early signs of ALS, and these tools could be deployed to screen and monitor patients without requiring clinic visits. Here, we sought to determine whether acoustic features gathered using an automated assessment app could detect ALS as well as different levels of speech impairment severity resulting from ALS. Speech samples (readings of a standardized, 99-word passage) from 119 ALS patients with varying degrees of disease severity as well as 22 neurologically healthy participants were analyzed, and 53 acoustic features were extracted. Patients were stratified into early and late stages of disease (ALS-early/ALS-E and ALS-late/ALS-L) based on the ALS Functional Ratings Scale-Revised bulbar score (FRS-bulb) (median [interquartile range] of FRS-bulbar scores: 11[3]). The data were analyzed using a sparse Bayesian logistic regression classifier. It was determined that the current relatively small set of acoustic features could distinguish between ALS and controls well (area under receiver-operating characteristic curve/AUROC = 0.85), that the ALS-E patients could be separated well from control participants (AUROC = 0.78), and that ALS-E and ALS-L patients could be reasonably separated (AUROC = 0.70). These results highlight the potential for automated acoustic analyses to detect and stratify ALS.

Global reward processing deficits predict negative symptoms transdiagnostically and transphasically in a severe mental illness-spectrum sample.

Reward processing impairments are a key factor associated with negative symptoms in those with severe mental illnesses. However, past findings are inconsistent regarding which reward processing components are impaired and most strongly linked to negative symptoms. The current study examined the hypothesis that these mixed findings may be the result of multiple reward processing pathways (i.e., equifinality) to negative symptoms that cut across diagnostic boundaries and phases of illness. Participants included healthy controls (n = 100) who served as a reference sample and a severe mental illness-spectrum sample (n = 92) that included psychotic-like experiences, clinical high-risk for psychosis, bipolar disorder, and schizophrenia participants. All participants completed tasks measuring four RDoC Positive Valence System constructs: value representation, reinforcement learning, effort-cost computation, and hedonic reactivity. A k-means cluster analysis of the severe mental illness-spectrum samples identified three clusters with differential reward processing profiles that were characterized by: (1) global reward processing deficits (22.8%), (2) selective impairments in hedonic reactivity alone (40.2%), and (3) preserved reward processing (37%). Elevated negative symptoms were only observed in the global reward processing cluster. All clusters contained participants from each clinical group, and the distribution of these groups did not significantly differ among the clusters. Findings identified one pathway contributing to negative symptoms that was transdiagnostic and transphasic. Future work further characterizing divergent pathways to negative symptoms may help to improve symptom trajectories and personalized treatments.

Negative Symptom Trajectories in Individuals at Clinical High Risk for Psychosis: Differences Based on Deficit Syndrome, Persistence, and Transition Status.

Background and Hypothesis: Negative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness-deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset-were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution. Study Design: Linear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset (N = 699) and within clinical subgroups. Study Results: Negative symptoms followed a downward curvilinear trend, with marked improvement 0-6 months that subsequently stabilized (6-24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate. Conclusions: Continuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs.

Reinforcement learning profiles and negative symptoms across chronic and clinical high-risk phases of psychotic illness.

Negative symptoms are prominent in individuals with schizophrenia (SZ) and youth at clinical high-risk for psychosis (CHR). In SZ, negative symptoms are linked to reinforcement learning (RL) dysfunction; however, previous research suggests implicit RL remains intact. It is unknown whether implicit RL is preserved in the CHR phase where negative symptom mechanisms are unclear, knowledge of which may assist in developing early identification and prevention methods. Participants from two studies completed an implicit RL task: Study 1 included 53 SZ individuals and 54 healthy controls (HC); Study 2 included 26 CHR youth and 23 HCs. Bias trajectories reflecting implicit RL were compared between groups and correlations with negative symptoms were examined. Cluster analysis investigated RL profiles across the combined samples. Implicit RL was comparable between HC and their corresponding SZ and CHR groups. However, cluster analysis was able to parse performance heterogeneity across diagnostic boundaries into two distinct RL profiles: a Positive/Early Learning cluster (65% of participants) with positive bias scores increasing from the first to second task block, and a Negative/Late Learning cluster (35% of participants) with negative bias scores increasing from the second to third block. Clusters did not differ in the proportion of CHR vs. SZ cases; however, the Negative/Late Learning cluster had more severe negative symptoms. Although implicit RL is intact in CHR similar to SZ, distinct implicit RL phenotypic profiles with elevated negative symptoms were identified trans-phasically, suggesting distinct reward-processing mechanisms can contribute to negative symptoms independent of phases of illness.

Emotion regulation and social knowledge in youth at clinical high-risk for psychosis and outpatients with chronic schizophrenia: Associations with functional outcome and negative symptoms.

AIM: Previous studies indicate that several aspects of social cognition are associated with poor social and vocational outcome in the chronic phase of psychosis. However, it is less clear whether specific aspects of social cognition are impaired in those at clinical high-risk (CHR) for psychosis and associated with functioning. The current study evaluated two understudied components of social cognition, emotion regulation knowledge and social knowledge, to determine whether CHR and chronic schizophrenia (SZ) samples demonstrated comparable magnitudes of impairment and associations with functioning. METHODS: Two studies were conducted. Study 1 included n = 98 outpatients with chronic SZ and n = 88 demographically matched healthy controls (CN). Study 2 included 30 CHR and 30 matched CN participants. In both studies, participants completed the emotion management and social management subtests of the Mayer-Salovey-Caruso Emotional Intelligence Test to assess emotion regulation knowledge and social knowledge, respectively. A battery of clinical interviews was also administered, including measures of: role and social functioning, positive symptoms, negative symptoms, disorganization and general symptoms. RESULTS: Individuals with SZ demonstrated lower emotion management and social management scores than CN participants. CHR demonstrated lower scores in social management than CN but did not display deficits in emotion management. In both studies, reduced social knowledge was associated with worse functioning and negative symptoms. CONCLUSIONS: Findings indicate that deficits in social knowledge are transphasic across the SZ spectrum, and are associated with clinical functioning. Social knowledge may be a novel treatment target for psychosocial interventions.

Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-Based Functional Magnetic Resonance Imaging Meta-analysis.

BACKGROUND: Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia. Functional magnetic resonance imaging studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular, decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the functional magnetic resonance imaging literature. METHODS: Functional magnetic resonance imaging studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy control subjects were identified. Frequentist and Bayesian voxelwise meta-analyses were performed separately, by implementing a random-effect model with unthresholded group-level T-maps from individual studies as input. RESULTS: In total, 17 studies with a cumulative total of 677 at-risk individuals and 805 healthy control subjects were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy control subjects. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. CONCLUSIONS: These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies instead focus on impaired functional connectivity as an alternative and promising endophenotype.

Implicit cognitive effort monitoring impairments are associated with expressive negative symptoms in schizophrenia.

Negative symptoms are a strong predictor of functional impairment in schizophrenia (SZ). Unfortunately, mechanisms underlying negative symptoms are poorly understood and available treatments are minimally effective. The current study evaluated the novel hypothesis that negative symptoms are associated with an implicit cognitive effort monitoring impairment that manifests during tasks requiring sustained allocation of cognitive control. Outpatients with SZ (n = 33) and healthy controls (CN; n = 29) completed an adapted Demand Selection Task (DST) in which subjects made choices between pairs of cognitive tasks that were implicitly and then explicitly made discrepant in effort demands. The SZ group demonstrated a reduced probability of avoiding the high effort cognitive task in the implicit choice condition but were able to become effort avoidant when the demands of the task were made explicit. Implicit cognitive effort monitoring deficits were associated with greater severity of the expressivity dimension of negative symptoms, but not the motivation and pleasure dimension. The association between diminished expressivity and implicit cognitive effort monitoring deficits is interpreted in light of a novel cognitive resource depletion theory, whereby individuals with SZ may become less expressive due to difficulty implicitly monitoring ongoing cognitive effort exertion and dynamically adjusting effort expenditure as task demands fluctuate.

Endogenous oxytocin levels are associated with facial emotion recognition accuracy but not gaze behavior in individuals with schizophrenia.

OBJECTIVE: Difficulties in social cognition are common in individuals with schizophrenia (SZ) and are not ameliorated by antipsychotic treatment. Intranasal oxytocin (OT) administration has been explored as a potential intervention to improve social cognition; however, results are inconsistent, suggesting potential individual difference variables that may influence treatment response. Less is known about the relationship between endogenous OT and social cognition in SZ, knowledge of which may improve the development of OT-focused therapies. We examined plasma OT in relationship to facial emotion recognition and visual attention to salient facial features in SZ and controls. METHODS: Forty-two individuals with SZ and 23 healthy controls viewed photographs of facial expressions of varying emotional intensity and identified the emotional expression displayed. Participants' gaze behavior during the task was recorded via eye tracking. Plasma oxytocin concentrations were determined by radioimmunoassay. RESULTS: SZ were less accurate than controls at identifying high-intensity fearful facial expressions and low-intensity sad expressions. Lower overall and high-intensity facial emotion recognition accuracy was associated with lower plasma OT levels in SZ but not controls. OT was not associated with visual attention to salient facial features; however, SZ had reduced visual attention to the nose region compared to controls. CONCLUSION: Individual differences in endogenous OT predict facial emotion recognition ability in SZ but are not associated with visual attention to salient facial features. Increased understanding of the association between endogenous OT and social cognitive abilities in SZ may help improve the design and interpretation of OT-focused clinical trials in SZ.

"You can't touch this": Delivery of inpatient neuropsychological assessment in the era of COVID-19 and beyond.

Objective: The COVID-19 pandemic is a global health crisis that has created sudden and unique challenges within the field of clinical neuropsychology. Adapting neuropsychology services using teleneuropsychology models (e.g. video or telephone assessments) may not always be a viable option for all providers and settings. Based on the existing teleneuropsychology literature, we propose a "contactless" evidence-based inpatient test battery to be used for in-person assessments amenable to physical distancing. Method: In addition to the proposed test battery, we suggest a decision-making workflow process to help readers determine the appropriateness of the proposed methods given their patients' needs. Considerations for special populations (i.e. seniors, patients with brain injury, psychiatric patients), feedback, limitations of the proposed physical distancing approach, and future directions are also discussed. Conclusions: Our aim is that the suggested teleneuropsychology-informed battery and model may inform safe and practical neuropsychological inpatient assessments during the COVID-19 pandemic and other situations requiring contact precautions for infection prevention and control.

Manipulating visual scanpaths during facial emotion perception modulates functional brain activation in schizophrenia patients and controls.

Individuals with schizophrenia exhibit deficits in facial emotion processing, which have been associated with abnormalities in visual gaze behavior and functional brain activation. However, the relationship between gaze behavior and brain activation in schizophrenia remains unexamined. Studies in healthy individuals and other clinical samples indicate a relationship between gaze behavior and functional activation in brain regions implicated in facial emotion processing deficits in schizophrenia (e.g., fusiform gyrus), prompting the question of whether a similar relationship exists in schizophrenia. This study examined whether manipulating visual scanpaths during facial emotion perception would modulate functional brain activation in a sample of 23 schizophrenia patients and 26 community controls. Participants underwent functional magnetic resonance imaging (MRI) while viewing pictures of emotional faces. During the typical viewing condition, a fixation cue directed participants' gaze primarily to the eyes and mouth, whereas during the atypical viewing condition gaze was directed to peripheral features. Both viewing conditions elicited a robust response throughout face-processing regions. Typical viewing led to greater activation in visual association cortex including the right inferior occipital gyrus/occipital face area, whereas atypical viewing elicited greater activation in primary visual cortex and regions involved in attentional control. There were no between-groups activation differences in response to faces or interaction between group and gaze manipulation. The results indicate that gaze behavior modulates functional activation in early face-processing regions in individuals with and without schizophrenia, suggesting that abnormal gaze behavior in schizophrenia may contribute to activation abnormalities during facial emotion perception. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Task-Related Functional Connectivity Analysis of Emotion Discrimination in a Family Study of Schizophrenia.

Poor emotion recognition is a core deficit in schizophrenia and is associated with poor functional outcome. Functional magnetic resonance imaging (fMRI) multivariate analysis methods were used to elucidate the neural underpinnings of face and emotion processing associated with both genetic liability and disease-specific effects. Schizophrenia patients, relatives, and controls completed a task that included 4 facial emotion discrimination conditions and an age discrimination condition during fMRI. Three functional networks were derived from the data: the first involved in visual attention and response generation, the second a default mode network (DMN), and a third involved in face and emotion processing. No differences in activation were found between groups for the visual attention and response generation network, suggesting that basic processes were intact. Both schizophrenia patients and relatives showed evidence for hyperdeactivation in the DMN compared to controls, with relatives being intermediate, suggesting a genetic liability effect. Both disease-specific and genetic liability effects were found for the face processing network, which included the amygdala. Patients exhibited lower coordinated network activity compared to controls and relatives across all facial discrimination conditions. Additionally, in relation to the other emotion discrimination conditions, a heightened coordinated response during fear and anger discrimination was observed in schizophrenia compared to other conditions, whereas relatives demonstrated heightened coordinated activity for anger discrimination only relative to other emotion conditions. With regards to brain functioning, this study found that schizophrenia is associated with abnormal processing of threat-related information, and that in part may be associated with the genetic risk for the disorder, suggesting that the facial and emotion processing network could be targeted for intervention.

Similar patterns of brain activation abnormalities during emotional and non-emotional judgments of faces in a schizophrenia family study.

Schizophrenia patients have impaired performance and abnormal brain activation during facial emotion recognition, which may represent a marker of genetic liability to schizophrenia. However, it remains unclear whether the impairment is specific to recognizing emotion from faces or is instead attributable to more generalized dysfunction. The current study aimed to distinguish between specific and generalized neural dysfunction underlying impaired facial emotion recognition in schizophrenia and examine associations with genetic liability. Twenty-eight schizophrenia patients, 27 nonpsychotic first-degree relatives, and 27 community controls underwent functional magnetic resonance imaging while making judgments about either the emotion or age of emotional faces. Patients had performance deficits during the emotion and age discrimination conditions compared to relatives and controls, while relatives had intact performance. Patients had hypoactivation compared to controls across conditions, mainly in medial prefrontal cortex. Unlike controls, patients demonstrated a failure to recruit the dorsomedial prefrontal cortex, a region involved in social cognition and decision-making, and relatives had a pattern of recruitment intermediate between patients and controls. Compared to controls, relatives had greater deactivation of regions associated with the default mode network, and patients had similar findings during age discrimination. The common patterns of performance deficits and activation abnormalities during emotion and age discrimination in schizophrenia suggest that generalized cognitive impairment, notably in social cognition and decision-making, contributes to impaired facial emotion recognition. Similar functional activation patterns in relatives, despite intact performance, suggest that brain activation may represent a more sensitive marker of genetic liability than behaviour. Hyperdeactivation of default mode network regions in relatives may represent cognitive inefficiency, or compensatory mechanisms that help maintain intact performance.

A magnetic resonance imaging family study of cortical thickness in schizophrenia.

Schizophrenia is associated with abnormalities in cortical thickness, including both thicker and thinner cortices than controls. Although less reliably than in patients, non-psychotic relatives of schizophrenia patients have also demonstrated both thicker and thinner cortices than controls, suggesting an effect of familial or genetic liability. We investigated cortical thickness in 25 schizophrenia patients, 26 adult non-psychotic first-degree biological relatives, and 23 community controls using the automated program FreeSurfer. Contrary to hypotheses, we found relatives of schizophrenia patients had greater cortical thickness in all lobes compared to patients and controls; however, this finding was not as widespread when compared to controls. In contrast, schizophrenia patients only demonstrated a thinner right fusiform region than controls and relatives. Our finding of greater thickness in adult biological relatives could represent a maladaptive abnormality or alternatively, a compensatory mechanism. Previous literature suggests that the nature of abnormalities in relatives can vary by the age of relatives and change across the developmental period. Abnormalities in patients may depend on lifestyle factors and on current and previous anti-psychotic medication use. Our results speak to the need to study various populations of patients and relatives across the lifespan to better understand different developmental periods and the impact of environmental factors. © 2015 Wiley Periodicals, Inc.

Functional activation abnormalities during facial emotion perception in schizophrenia patients and nonpsychotic relatives.

BACKGROUND: Deficits in facial emotion perception in schizophrenia may be a marker of disorder liability. Previous functional magnetic resonance imaging (fMRI) studies investigating these deficits have been limited by task demands that may recruit other impaired cognitive processes in schizophrenia. METHODS: We used a family study design along with a passive viewing task during fMRI to investigate brain activation abnormalities underlying facial emotion perception in schizophrenia and examine whether such abnormalities are associated with the genetic liability to the disorder. Twenty-eight schizophrenia patients, 27 nonpsychotic relatives, and 27 community controls passively viewed images of facial emotions during an fMRI scan. RESULTS: Analyses revealed hypoactivation in face processing areas for both patients and relatives compared to controls, and hyperactivation in relatives compared to both patients and controls for frontal regions implicated in emotion processing. CONCLUSIONS: Results suggest that activation abnormalities during facial emotion perception are manifestations of the genetic liability to schizophrenia, and may be accompanied by compensatory mechanisms in relatives. Studying mechanisms in nonpsychotic relatives is a valuable way to examine effects of the unexpressed genetic liability to schizophrenia on the brain and behaviour.

Context-updating processes facilitate response reprogramming in younger but not older adults.

The current study used concurrent acquisition of motion capture and event-related potential (ERP) data to test the prediction that response reprogramming relies on context-updating processes, and that age differences in conflicting-response performance are related to context-updating deficits in the elderly. Participants performed a motor sequencing task that included prepotent pairs of key presses, and conflicting pairs that started with the same first key press of the prepotent pair, but ended in an unexpected alternate response. ERP analyses were used to measure the P3b component as an electrophysiological correlate of context updating. The results revealed an age-related reduction in the ability to reprogram a response as younger, but not older, adults exhibited a negative correlation between planning and execution time for conflicting responses, such that shortened execution time led to better performance by the younger group. Both age groups demonstrated a large P3b component following conflicting, but not prepotent stimuli. The peak of this P3b was delayed, and its amplitude reduced in the older, compared with younger, adults. Noteworthy was that conflicting responses with faster execution time were associated with a larger P3b component than responses with slower execution time in younger, but not older, adults, suggesting that better context updating led to more efficient response reprogramming. These findings are novel in showing that context updating is associated with adjustments in response execution, and that older adults were less able to use these context-updating processes to support successful movement reprogramming.

Gesture imitation in musicians and non-musicians.

Imitation plays a crucial role in the learning of many complex motor skills. Recent behavioral and neuroimaging evidence suggests that the ability to imitate is influenced by past experience, such as musical training. To investigate the impact of musical training on motor imitation, musicians and non-musicians were tested on their ability to imitate videoclips of simple and complex two-handed gestures taken from American Sign Language. Participants viewed a set of 30 gestures, one at a time, and imitated them immediately after presentation. Participants' imitations were videotaped and scored off-line by raters blind to participant group. Imitation performance was assessed by a rating of performance accuracy, where the arm, hand, and finger components of the gestures were rated separately on a 5-point scale (1 = unrecognizable; 5 = exact imitation). A global accuracy score (PAglobal) was calculated by summing the three components. Response duration compared to the model (%MTdiff), and reaction time (RT) were also assessed. Results indicated that musicians were able to imitate more accurately than non-musicians, reflected by significantly higher PAglobal and lower %MTdiff scores. Furthermore, the greatest difference in performance was for the fine-motor (finger) gesture component. These findings support the view that the ability to imitate is influenced by experience. This is consistent with generalist theories of motor imitation, which explain imitation in terms of links between perceptual and motor action representations that become strengthened through experience. It is also likely that musical training contributed to the ability to imitate manual gestures by influencing the personal action repertoire of musicians.