Quantifying abnormal emotion processing: A novel computational assessment method and application in schizophrenia.

Abnormal emotion processing is a core feature of schizophrenia spectrum disorders (SSDs) that encompasses multiple operations. While deficits in some areas have been well-characterized, we understand less about abnormalities in the emotion processing that happens through language, which is highly relevant for social life. Here, we introduce a novel method using deep learning to estimate emotion processing rapidly from spoken language, testing this approach in male-identified patients with SSDs (n = 37) and healthy controls (n = 51). Using free responses to evocative stimuli, we derived a measure of appropriateness, or "emotional alignment" (EA). We examined psychometric characteristics of EA and its sensitivity to a single-dose challenge of oxytocin, a neuropeptide shown to enhance the salience of socioemotional information in SSDs. Patients showed impaired EA relative to controls, and impairment correlated with poorer social cognitive skill and more severe motivation and pleasure deficits. Adding EA to a logistic regression model with language-based measures of formal thought disorder (FTD) improved classification of patients versus controls. Lastly, oxytocin administration improved EA but not FTD among patients. While additional validation work is needed, these initial results suggest that an automated assay using spoken language may be a promising approach to assess emotion processing in SSDs.

Effects of Ayahuasca on Gratitude and Relationships with Nature: A Prospective, Naturalistic Study.

Qualitative studies and anecdotal reports suggest that experiences with ayahuasca, a psychedelic brew found in Central and South America, may be followed by individuals enduringly feeling more grateful and connected to nature. Yet, to date, these changes have been understudied. Here, participants (N = 54) completed validated surveys related to gratitude, nature relatedness, and nature appreciation one-week before, one-week after, and one-month after attending an ayahuasca retreat center. Compared to baseline, there was a significant increase in gratitude, nature relatedness, and nature appreciation at the one-week and one-month follow-ups. Ratings of mystical-type experiences and awe, but not ego dissolution, during participants' ayahuasca sessions were weakly-to-moderately correlated with these increases. The number of ayahuasca ceremonies attended at the retreat was not related to change in outcomes, underscoring the importance of the quality rather than the quantity of the experiences in post-acute change. Lastly, participant age was negatively related to the occurrence of mystical-type experiences and awe, supporting literature indicating blunted psychedelic effects with increased age. In the context of study limitations, the results suggest that mystical-type experiences and awe occasioned by ayahuasca may be linked to prosocial changes in gratitude and relationships with nature that may be beneficial to mental health.

Intranasal Oxytocin May Improve High-Level Social Cognition in Schizophrenia, But Not Social Cognition or Neurocognition in General: A Multilevel Bayesian Meta-analysis.

While there is growing interest in the potential for intranasal oxytocin (IN-OT) to improve social cognition and neurocognition (ie, nonsocial cognition) in schizophrenia, the extant literature has been mixed. Here, we perform a Bayesian meta-analysis of the efficacy of IN-OT to improve areas of social and neurocognition in schizophrenia. A systematic search of original research publications identified randomized controlled trials (RCTs) of IN-OT as a treatment for social and neurocognitive deficits in schizophrenia for inclusion. Standardized mean differences (SMD) and corresponding variances were used in multilevel Bayesian models to obtain meta-analytic effect-size estimates. Across a total of 12 studies (N = 273), IN-OT did not improve social cognition (SMD = 0.07, 95% credible interval [CI] = [-0.06, 0.17]) or neurocognition (SMD = 0.12, 95% CI = [-0.12, 0.34]). There was moderate between study heterogeneity for social cognition outcomes (τs= 0.12). Moderator analyses revealed that IN-OT had a significantly larger effect on high-level social cognition (ie, mentalizing and theory of mind) compared to low-level social cognition (ie, social cue perception) (b = 0.19, 95% CI = [0.05, 0.33]). When restricting our analysis to outcomes for high-level social cognition, there was a significant effect of IN-OT (SMD = 0.20, 95 % CI = [0.05, 0.33]) but the effect was not robust to sensitivity analyses. The present analysis indicates that IN-OT may have selective effects on high-level social cognition, which provides a more focused target for future studies of IN-OT.

Intranasal Oxytocin Selectively Modulates Social Perception, Craving, and Approach Behavior in Subjects With Alcohol Use Disorder.

OBJECTIVES: A pharmacotherapy that both improves social abilities and promotes abstinence may be particularly helpful for the treatment of alcohol use disorder. Recent clinical and preclinical evidence suggests that oxytocin has prosocial and antiaddiction effects. We performed a pilot, laboratory-based, preclinical trial of oxytocin in subjects with alcohol abuse (as per Diagnostic and Statistical Manual of Mental Disorders, 4 Edition criteria) to evaluate therapeutic potential and assess tolerability. METHODS: Social perceptual ability, cue-induced craving, and approach bias for alcohol and appetitive imagery were quantified after intranasal oxytocin and placebo administration to 32 nontreatment-seeking individuals with alcohol abuse in a double-blind, crossover study. Because attachment style can moderate the effects of oxytocin, we also explored whether attachment style moderated oxytocin's effects on our behavioral measures. RESULTS: Oxytocin significantly improved recognition of easier items on a social perception task, but had no significant group-level effect on cue-induced craving. However, oxytocin effects on craving were moderated by attachment anxiety, with oxytocin reducing craving in more anxiously attached individuals and increasing craving in less anxiously attached individuals. Subjects did not display an approach bias to alcohol images on the placebo day, preventing meaningful analysis of this measure. Subjects did display an approach bias to appetitive images on the placebo day, which was significantly reduced by oxytocin administration. No adverse reactions were observed. CONCLUSIONS: Intranasal oxytocin has potential to improve social perception, reduce cue-induced alcohol cravings, and reduce appetitive approach bias in subjects with alcohol abuse, and can be safely tolerated in this population. The effects of oxytocin are complex, however, and require further investigation.

The effects of intranasal oxytocin in opioid-dependent individuals and healthy control subjects: a pilot study.

RATIONALE: There has been an explosion of research on the potential benefits of the social neuropeptide oxytocin for a number of mental disorders including substance use disorders. Recent evidence suggests that intranasal oxytocin has both direct anti-addiction effects and pro-social effects that may facilitate engagement in psychosocial treatment for substance use disorders. OBJECTIVES: We aimed to assess the tolerability of intranasal oxytocin and its effects on heroin craving, implicit association with heroin and social perceptual ability in opioid-dependent patients receiving opioid replacement therapy (ORT) and healthy control participants. METHODS: We performed a randomized, double-blind, placebo-controlled, within- and between-subjects, crossover, proof-of-concept trial to examine the effects of oxytocin (40 international units) on a cue-induced craving task (ORT patients only), an Implicit Association Task (IAT), and two social perception tasks: the Reading the Mind in the Eyes Task (RMET) and The Awareness of Social Inference Test (TASIT). RESULTS: Oxytocin was well tolerated by patients receiving ORT but had no significant effects on craving or IAT scores. There was a significant reduction in RMET performance after oxytocin administration versus placebo in the patient group only, and a significant reduction in TASIT performance after oxytocin in both the patient and healthy control groups. CONCLUSIONS: A single dose of intranasal oxytocin is well tolerated by patients receiving ORT, paving the way for future investigations. Despite no significant improvement in craving or IAT scores after a single dose of oxytocin and some evidence that social perception was worsened, further investigation is required to determine the role oxytocin may play in the treatment of opioid use disorder. CLINICAL TRIAL REGISTRATION: Methadone Oxytocin Option. ClinicalTrials.gov identifier: NCT01728909.

Impaired Recognition and Regulation of Disgust Is Associated with Distinct but Partially Overlapping Patterns of Decreased Gray Matter Volume in the Ventroanterior Insula.

BACKGROUND: The ventroanterior insula is implicated in the experience, expression, and recognition of disgust; however, whether this brain region is required for recognizing disgust or regulating disgusting behaviors remains unknown. METHODS: We examined the brain correlates of the presence of disgusting behavior and impaired recognition of disgust using voxel-based morphometry in a sample of 305 patients with heterogeneous patterns of neurodegeneration. Permutation-based analyses were used to determine regions of decreased gray matter volume at a significance level p <= .05 corrected for family-wise error across the whole brain and within the insula. RESULTS: Patients with behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia were most likely to exhibit disgusting behaviors and were, on average, the most impaired at recognizing disgust in others. Imaging analysis revealed that patients who exhibited disgusting behaviors had significantly less gray matter volume bilaterally in the ventral anterior insula. A region of interest analysis restricted to behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia patients alone confirmed this result. Moreover, impaired recognition of disgust was associated with decreased gray matter volume in the bilateral ventroanterior and ventral middle regions of the insula. There was an area of overlap in the bilateral anterior insula where decreased gray matter volume was associated with both the presence of disgusting behavior and impairments in recognizing disgust. CONCLUSIONS: These findings suggest that regulating disgusting behaviors and recognizing disgust in others involve two partially overlapping neural systems within the insula. Moreover, the ventral anterior insula is required for both processes.

Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia.

OBJECTIVE: To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. METHODS: Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions. RESULTS: Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD. CONCLUSIONS: Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD.

BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease.

Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimer's disease (AD). However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with cognitive tests and patterns of brain atrophy using voxelbased morphometry. We found small negative correlations between BDNF serum concentrations and some of the cognitive tests assessing learning, information processing speed and cognitive control in complex situations, however, BDNF did not predict disease group membership despite adequate power. These findings suggest that BDNF serum concentration may not be a reliable diagnostic biomarker to distinguish among neurodegenerative diseases.

The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease.

OBJECTIVE: To identify rates of and risk factors for psychiatric diagnosis preceding the diagnosis of neurodegenerative disease. METHOD: Systematic, retrospective, blinded chart review was performed of 252 patients with a neurodegenerative disease diagnosis seen in our specialty clinic between 1999 and 2008. Neurodegenerative disease diagnoses included behavioral-variant frontotemporal dementia (n = 69), semantic dementia (n = 41), and progressive nonfluent aphasia (n = 17) (all meeting Neary research criteria); Alzheimer's disease (n = 65) (National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association research criteria); corticobasal degeneration (n = 25) (Boxer research criteria); progressive supranuclear palsy (n = 15) (Litvan research criteria); and amyotrophic lateral sclerosis (n = 20) (El Escorial research criteria). Reviewers remained blinded to each patient's final neurodegenerative disease diagnosis while reviewing charts. Extensive caregiver interviews were conducted to ensure accurate and reliable diagnostic histories. For each patient, we recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information. RESULTS: A total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. Behavioral-variant frontotemporal dementia patients received a prior psychiatric diagnosis significantly more often (50.7%; P < .001) than patients with Alzheimer's disease (23.1%), semantic dementia (24.4%), or progressive nonfluent aphasia (11.8%) and were more likely to receive diagnoses of bipolar disorder or schizophrenia than were patients with other neurodegenerative diseases (P < .001). Younger age (P < .001), higher education (P < .05), and a family history of psychiatric illness (P < .05) increased the rate of prior psychiatric diagnosis in patients with behavioral-variant frontotemporal dementia. Cognitive, behavioral, and emotional characteristics did not distinguish patients who did or did not receive a prior psychiatric diagnosis. CONCLUSIONS: Neurodegenerative disease is often misclassified as psychiatric disease, with behavioral-variant frontotemporal dementia patients at highest risk. While this study cannot rule out the possibility that psychiatric disease is an independent risk factor for neurodegenerative disease, when patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress. Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.