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A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.

Within the heterogeneity of schizophrenia, apathy constitutes an independent cluster of negative symptoms associated with poor outcomes. Attempts to identify an emotional deficit in patients who have schizophrenia with negative symptoms have yielded mixed results, and studies that focus on the relationship between apathy and emotional disorders are lacking. We set out to remedy this shortcoming using a validated battery of film excerpts to induce positive and negative emotions in patients with chronic schizophrenia with (n = 20) or without (n = 20) apathy, and in controls (n = 20) comparable for age, sex and socioeconomic status. We assessed emotions using an innovative but validated technique to evaluate tonic and phasic electrodermal activity and subjective feelings using a standardized visual analogue scale. Using a qualitative measure of apathy, we did not find a specific decrease in tonic activity during the induction of positive emotions. However, we did observe that patients with apathy showed reduced tonic activity independent of valence (i.e., for both positive and negative emotions) compared with controls and patients without apathy. Moreover, the quantitative measure of apathy (Apathy Evaluation Scale) was the only significant factor, explaining 24% of the variance in tonic activity during induction of positive emotions after controlling for confounding factors. Electrodermal activity was the only physiologic measure we acquired. We induced several emotions sequentially that might have overlapped with each other, but we added an emotional “washout” period and randomized the order of each film excerpt to limit this possibility. Taken together, these results suggest that apathy in schizophrenia could impair tonic activity during positive emotions. Treatments aimed at enhancing positive emotions may help alleviate apathy in schizophrenia.

Apathy and anhedonia are common syndromes of motivation that are associated with a wide range of brain disorders and have no established therapies. Research using animal models suggests that a useful framework for understanding motivated behaviour lies in effort-based decision making for reward. The neurobiological mechanisms underpinning such decisions have now begun to be determined in individuals with apathy or anhedonia, providing an important foundation for developing new treatments. The findings suggest that there might be some shared mechanisms between both syndromes. A transdiagnostic approach that cuts across traditional disease boundaries provides a potentially useful means for understanding these conditions.

Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI), a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people), and then confirmatory analysis (in a different set of 479 individuals), we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains.

There is growing recognition of the importance of changes in behavior as an early clinical marker of the onset of Alzheimer's disease. Behavior symptoms may precede the onset of cognitive symptoms by as many as three years. However, these symptoms are often confused for primary psychiatric pathology and there is an urgent need for markers that can help quantify behaviors with the eventual goal of helping distinguish behavior changes related to psychiatric pathology from behavior changes related to the onset of dementia. This talk will summarize the state of knowledge on mild behavioral impairment, and present data from three studies demonstrating how a range of sensor-derived biomarkers can quantify subtle changes in behavior with precision. The talk will include case presentations around detection of apathy, agitation, pacing. It will also demonstrate how these markers can identify response to medications, which may be one way of distinguishing the presence of psychiatric versus neurodegenerative pathology. Finally, the talk will present data from ongoing clinical trials around how these biomarkers may translate into research and eventually practice.

Background Successful development of agents that improve cognition and behavior in Alzheimer’s disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder. Discussion There have been no recent approvals of cognitive enhancing agents for AD. There are currently 6 cognitive enhancers in Phase 2 trials and 4 in phase 3. They represent a variety of novel mechanisms. There has been progress in developing new treatments for neuropsychiatric symptoms in AD with advances in treatment of insomnia, psychosis, apathy, and agitation in AD. There are currently 4 AD-related psychotropic agents in Phase 2 trials and 7 in Phase 3 trials. Many novel mechanisms are being explored for the treatment of cognitive and behavioral targets. Progress in trial designs, outcomes measures, and population definitions are improving trial conduct for symptomatic treatment of AD. Conclusions Advances in developing new agents for cognitive and behavioral symptoms of AD combined with enhanced trial methods promise to address the unmet needs of patients with AD for improved cognition and amelioration of neuropsychiatric symptoms.

The term “repetitive head impacts” (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the “cumulative head impact index” (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment (p < 0.0001), self-reported executive dysfunction (p < 0.0001), depression (p < 0.0001), apathy (p = 0.0161), and behavioral dysregulation (p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics.

Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19–3.91; MI, 2.10,1.17–3.76; CES-D, 3.08,1.65–5.76; AES, 2.39,1.32–4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76–0.97) and CES-D (OR, 95% CI: 0.85, 0.74–0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.

Apathy is a common symptom in neurological disorders, including dementia, and is associated with a faster rate of cognitive decline, reduced quality of life, and high caregiver burden. There is a lack of effective pharmacological treatments for apathy, and nonpharmacological interventions are a preferred first-line approach to treatment. Virtual reality (VR) using head-mounted displays (HMDs) is being successfully used in exposure- and distraction-based therapies; however, there is limited research on using HMDs for symptoms of neurological disorders. This feasibility study aimed to assess whether VR using HMDs could be used to deliver tailored reminiscence therapy and examine the willingness to participate, response rates to measures, time taken to create tailored content, and technical problems. In addition, this study aimed to explore the immediate effects between verbal fluency and apathy after exposure to VR. A mixed methods study was conducted in a sample of older adults residing in aged care, and 17 participants were recruited. Apathy was measured using the Apathy Evaluation Scale (AES), and verbal fluency was used as a proxy measure of improvements in apathy and debriefing interviews to assess feedback from participants. Side effects that can occur from using HMDs were also measured. We recruited participants from a high socioeconomic status setting with a high education level, and the participation rate was 85% (17/20); most responses to measures were positive. Access to a wide range of freely available content and the absence of technical difficulties made the delivery of a VR reminiscence intervention highly feasible. Participants had improved semantic scores (t =-3.27; P=.006) but not phonemic fluency scores (t =0.55; P=.59) immediately after the intervention. Those with higher levels of apathy demonstrated the greatest cognitive improvements after a VR reminiscence experience, which was indicated by a strong positive relationship between the AES and semantic verbal fluency change scores postminus pre-VR (r=0.719; 95% CI 0.327 to 0.900; P=.003). All participants enjoyed the experience despite 35% (6/17) of participants experiencing temporary side effects. This study provides initial evidence that it is feasible to use VR with HMDs for therapy to treat symptoms of apathy in older adults in residential aged care. However, there is a need to closely monitor the side effects of HMD use in older adults. Further research is needed using an active control group to compare the use of VR with traditional forms of reminiscence therapy.

Apathy and impulsivity are multidimensional constructs that shape goal-directed behavior. Although the motivational dopaminergic spectrum hypothesis frames them as opposing ends of a single continuum, questionnaire-based studies consistently show that they positively co-occur in both healthy and clinical populations. An emerging theoretical resolution of this paradox is that apathy and impulsivity relate to distinct components of goal-directed behavior, with co-occurrence potentially arising from domain-general factors and/or partially overlapping neurophysiological networks. Here, we examined this proposal in the domain of action control using the stop-signal task, which provides separable indices of action inhibition (stop-signal response time, SSRT) and action initiation (go response time, goRT) within the independent race model. Based on prior findings and theoretical considerations, we expected SSRT to covary with urgency-related impulsivity and goRT with action-initiation apathy. A large sample of healthy young adults (N = 144) completed a stop-signal task implemented in accordance with consensus recommendations, alongside validated multidimensional measures of impulsivity (UPPS-P impulsive behavior scale) and apathy (Lille Apathy Rating Scale). Bayesian analyses replicated a positive association between global apathy and impulsivity scores. However, SSRT was not associated with urgency, and goRT was not associated with action-initiation apathy, with moderate evidence for the null. Additional exploratory analyses provided moderate evidence against the majority of correlations between stop-signal indices and the remaining scale dimensions, including global scores. Thus, stop-signal indices did not dissociate apathy and impulsivity in action control, highlighting limits of task-based accounts of their co-occurrence.