Although autism spectrum disorder (ASD) is defined by impaired social communication and restricted and repetitive behaviors and interests, ASD is also characterized by impaired motivational processes. The "social motivation theory of autism" describes how social motivation disruptions in ASD in early childhood may impede the drive to engage in reciprocal social behaviors and ultimately interfere with the development of neural networks critical for social communication (Chevallier et al., Trends Cogn Sci 16:231-239, 2012b). Importantly, clinical studies and preclinical research using model organisms for ASD indicate that motivational impairments in ASD are not constrained to social rewards but are evident in response to a range of nonsocial rewards as well. Additionally, translational studies on certain genetically defined neurodevelopmental disorders associated with ASD indicate that these syndromic forms of ASD are also characterized by motivational deficits and mesolimbicdopamine impairments. In this chapter we summarize clinical and preclinical research relevant to reward processing impairments in ASD and related neurodevelopmental disorders. We also propose a nosology to describe reward processing impairments in these disorders that uses a three-axes model. In this triaxial nosology, the first axis defines the direction of the reward response (i.e., anhedonic, hyperhedonic); the second axis defines the construct of the reward process (e.g., reward liking, reward wanting); and the third axis defines the context of the reward response (e.g., social, nonsocial). A more precise nosology for describing reward processing impairments in ASD and related neurodevelopmental disorders will aid in the translation of preclinical research to clinical investigations which will ultimately help to speed up the development of interventions that target motivational systems for ASD and related neurodevelopmental disorders.

In order to develop effective treatments for anhedonia we need to understand its underlying neurobiological mechanisms. Anhedonia is conceptually strongly linked to reward processing, which involves a variety of cognitive and neural operations. This chapter reviews the evidence for impairments in experiencing hedonic response (pleasure), reward valuation and reward learning based on outcomes (commonly conceptualised in terms of "reward prediction error"). Synthesising behavioural and neuroimaging findings, we examine case-control studies of patients with depression and schizophrenia, including those focusing specifically on anhedonia. Overall, there is reliable evidence that depression and schizophrenia are associated with disrupted reward processing. In contrast to the historical definition of anhedonia, there is surprisingly limited evidence for impairment in the ability to experience pleasure in depression and schizophrenia. There is some evidence that learning about reward and reward prediction error signals are impaired in depression and schizophrenia, but the literature is inconsistent. The strongest evidence is for impairments in the representation of reward value and how this is used to guide action. Future studies would benefit from focusing on impairments in reward processing specifically in anhedonic samples, including transdiagnostically, and from using designs separating different components of reward processing, formulating them in computational terms, and moving beyond cross-sectional designs to provide an assessment of causality.

Sex differences are prominent defining features of neurodevelopmental disorders. Understanding the sex biases in these disorders can shed light on mechanisms leading to relative risk and resilience for the disorders, as well as more broadly advance our understanding of how sex differences may relate to brain development. The prevalence of neurodevelopmental disorders is increasing, and the two most common neurodevelopmental disorders, Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) exhibit male-biases in prevalence rates and sex differences in symptomology. While the causes of neurodevelopmental disorders and their sex differences remain to be fullyunderstood, increasing evidence suggests that the immune system plays a critical role in shaping development. In this chapter we discuss sex differences in prevalence and symptomology of ASD and ADHD, review sexual differentiation and immune regulation of neurodevelopment, and discuss findings from human and rodent studies of immune dysregulation and perinatal immune perturbation as they relate to potential mechanisms underlying neurodevelopmental disorders. This chapter will give an overview of how understanding sex differences in neuroimmune function in the context of neurodevelopmental disorders could lend insight into their etiologies and better treatment strategies.

Herpesviruses alter cognitive functions in humans following acute infections; progressive cognitive decline and dementia have also been suggested. It is important to understand the pathogenic mechanisms of such infections. The complement system - comprising functionally related proteins integral for systemic innate and adaptive immunity - is an important component of host responses. The complement system has specialized functions in the brain. Still, the dynamics of the brain complement system are still poorly understood. Many complement proteins have limited access to the brain from plasma, necessitating synthesis and specific regulation of expression in the brain; thus, complement protein synthesis, activation, regulation, and signaling should be investigated in human brain-relevant cellular models. Cells derived from human-induced pluripotent stem cells (hiPSCs) could enable tractable models. Human-induced pluripotent stem cells were differentiated into neuronal (hi-N) and microglial (hi-M) cells that were cultured with primary culture human astrocyte-like cells (ha-D). Gene expression analyses and complement protein levels were analyzed in mono- and co-cultures. Transcript levels of complement proteins differ by cell type and co-culture conditions, with evidence for cellular crosstalk in co-cultures. Hi-N and hi-M cells have distinct patterns of expression of complement receptors, soluble factors, and regulatory proteins. hi-N cells produce complement factor 4 (C4) and factor B (FB), whereas hi-M cells produce complement factor 2 (C2) and complement factor 3 (C3). Thus, neither hi-N nor hi-M cells can form either of the C3-convertases - C4bC2a and C3bBb. However, when hi-N and hi-M cells are combined in co-cultures, both types of functional C3 convertase are produced, indicated by elevated levels of the cleaved C3 protein, C3a. hiPSC-derived co-culture models can be used to study viral infection in the brain, particularly complement receptor and function in relation to cellular "crosstalk." The models could be refined to further investigate pathogenic mechanisms.

There is now a significant body of literature concerning sex/gender differences in the human brain. This chapter will critically review and synthesise key findings from several studies that have investigated sex/gender differences in structural and functional lateralisation and connectivity. We argue that while small, relative sex/gender differences reliably exist in lateralisation and connectivity, there is considerable overlap between the sexes. Some inconsistencies exist, however, and this is likely due to considerable variability in the methodologies, tasks, measures, and sample compositions between studies. Moreover, research to date is limited in its consideration of sex/gender-related factors, such as sex hormones and gender roles, that can explain inter-and inter-individual differences in brain and behaviour better than sex/gender alone. We conclude that conceptualising the brain as 'sexually dimorphic' is incorrect, and the terms 'male brain' and 'female brain' should be avoided in the neuroscientific literature. However, this does not necessarily mean that sex/gender differences in the brain are trivial. Future research involving sex/gender should adopt a biopsychosocial approach whenever possible, to ensure that non-binary psychological, biological, and environmental/social factors related to sex/gender, and their interactions, are routinely accounted for.

The consequences of cannabis use, especially in the context of schizophrenia, have gained increased importance with the legalization of cannabis in North America and across the globe. Cannabis use has multifaceted impacts on cognition in schizophrenia patients and healthy subjects. Healthy subjects, particularly those who initiated cannabis use at earlier ages and used high-potency cannabis for longer durations, exhibited poorer cognition mainly in working memory and attention. Cannabis use in schizophrenia has been associated with symptom exacerbation, longer and more frequent psychotic episodes, and poorer treatment outcomes. However, cannabis-using patients have better overall cognitive performance compared to patients who were not cannabis users. Interestingly, these effects were only apparent in lifetime cannabis users, but not in current (or within last 6months) users. Moreover, higher frequency and earlier age of cannabis use initiation (i.e., before 17years of age) were associated with better cognitive performance, although they had an earlier illness onset. Three possible hypotheses seem to come forward to explain this paradox. First, some components of cannabis may have antipsychotic or cognitive-enhancing properties. Secondly, chronic cannabis use may alter endocannabinoid signaling in the brain which could be a protective factor for developing psychosis or cognitive impairments. A third explanation could be their representation of a phenotypically distinct patient group with more intact cognitive functioning and less neurodevelopmental pathology. Multiple factors need to be considered to understand the complex relationship between cannabis, cognitive function, and schizophrenia. In short, age at initiation, duration and rate of cannabis use, abstinence duration, co-use of substances and alcohol, prescribed medications, relative cannabinoid composition and potency of cannabis, presence of genetic and environmental vulnerability factors are prominent contributorsto the variability in outcomes. Animal studies support the disruptive effects of Δ9-tetrahydrocannabinol (THC) administration during adolescence on attention and memory performance. They provide insights about interaction of cannabinoid receptors with other neurotransmitter systems, such as GABA and glutamate, and other regulatory molecules, such as PSD95 and synaptophysin. Cannabidiol (CBD), on the other hand, can improve cognitive deficits seen in neurodevelopmental and chemically-induced animal models of schizophrenia. Future studies focusing on bridging the translational gaps between human and animal studies, through the use of translationally relevant methods of exposure (e.g., vaping), consistent behavioral assessments, and congruent circuit interrogations (e.g., imaging) will help to further clarify this complex picture.

Based on core symptoms of inattention and deficient impulse control, and the identification of effective pharmacotherapies such as amphetamine (AMP; Adderall®), methylphenidate (MPH; Ritalin®), and atomoxetine (ATX; Strattera®), ADHD is a clinical condition which provides opportunity for translational research. Neuropsychological tests such as the 5-Choice and Continuous Performance Tasks, which measure aspects of attention and impulse control in animals and humans, provide scope for both forward (animal to human) and reverse (human to animal) translation. Rodent studies support pro-attentive effects of AMP and MPH and effectiveness in controlling some forms of impulsive behavior. In contrast, any pro-attentive effects of ATX appear to be less consistent, the most reliable effects of ATX are recorded in tests of impulsivity. These differences may account for AMP and MPH being recognized as first-line treatments for ADHD with a higher efficacy relative to ATX. DSM-5 classifies three "presentations" of ADHD: predominantly inattentive type (ADHD-I), predominantly hyperactive/impulsive type (ADHD-HI), or combined (ADHD-C). Presently, it is unclear whether AMP, MPH, or ATX has differential levels of efficacy across these presentation types. Nonetheless, these studies encourage confidence for the forward translation of NCEs in efforts to identify newer pharmacotherapies for ADHD.

In the mental health field, the gut-brain axis and associated pathways represent putative mechanisms by which gastrointestinal (GI) microbes and their gene products and metabolites can access and influence the central nervous system (CNS). These GI-centered investigations focus on bacteria, with significant information gaps existing for other microbial community members, such as fungi. Fungi are part of a complex and functionally diverse taxonomic kingdom whose interactions with hosts can be conversely deadly and beneficial. As serious sources of morbidity and mortality, fungal pathogens can quickly turn healthy microbiomes into toxic cycles of inflammation, gut permeability, and dysbiosis. Fungal commensals are also important human symbionts that provide a rich source of physiological functions to the host, such as protection against intestinal injuries, maintenance of epithelial structural integrities, and immune system development and regulation. Promising treatment compounds derived from fungi include antibiotics, probiotics, and antidepressants. Here I aim to illuminate the many attributes of fungi as they are applicable to overall improving our understanding of the mechanisms at work in psychiatric disorders. Healing the gut and its complex ecosystem is currently achievable through diet, probiotics, prebiotics, and other strategies, yet it is critical to recognize that the success of these interventions relies on a more precisely defined role of the fungal and other non-bacterial components of the microbiome.

The development of treatments for impaired cognition in schizophrenia has been characterized as the most important challenge facing psychiatry at the beginning of the twenty-first century. The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) project was designed to build on the potential benefits of using tasks and tools from cognitive neuroscience to better understanding and treat cognitive impairments in psychosis. These benefits include: (1) the use of fine-grained tasks that measure discrete cognitive processes; (2) the ability to design tasks that distinguish between specific cognitive domain deficits and poor performance due to generalized deficits resulting from sedation, low motivation, poor test taking skills, etc.; and (3) the ability to link cognitive deficits to specific neural systems, using animal models, neuropsychology, and functional imaging. CNTRICS convened a series of meetings to identify paradigms from cognitive neuroscience that maximize these benefits and identified the steps need for translation into use in clinical populations. The Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRaCS) Consortium was developed to help carry out these steps. CNTRaCS consists of investigators at five different sites across the country with diverse expertise relevant to a wide range of the cognitive systems identified as critical as part of CNTRICs. This work reports on the progress and current directions in the evaluation and optimization carried out by CNTRaCS of the tasks identified as part of the original CNTRICs process, as well as subsequent extensions into the Positive Valence systems domain of Research Domain Criteria (RDoC). We also describe the current focus of CNTRaCS, which involves taking a computational psychiatry approach to measuring cognitive and motivational function across the spectrum of psychosis. Specifically, the current iteration of CNTRaCS is using computational modeling to isolate parameters reflecting potentially more specific cognitive and visual processes that may provide greater interpretability in understanding shared and distinct impairments across psychiatric disorders.

Anhedonia, a loss of interest or pleasure in activities, is a transdiagnostic symptom that characterizes many individuals suffering from depression and anxiety. Most psychological interventions are designed to decrease negative affect rather than increase positive affect, and are largely ineffective for reducing anhedonia. More recently, affective neuroscience has been leveraged to inform treatments for anhedonia by targeting aspects of the Positive Valence Systems, including impairments in reward anticipation, reward responsiveness, and reward learning. In this chapter, we review the efficacy of treatments and, when possible, highlight links to reward constructs. Augmented behavioral approaches and targeted cognitive interventions designed to target reward anticipation, responsiveness, and learning show preliminary efficacy in reducing anhedonia, while there is a relative lack of treatments that target positive emotion regulation and reward devaluation. In addition to developing treatments that address these targets, the field will benefit from establishing standardized measurement of anhedonia across units of analysis, mapping mechanisms of change onto aspects of reward processing, and examining anhedonia outcomes in the long-term.