Current Topics in Behavioral Neurosciences

Recent integrative multilevel models offer novel insights into the etiology and course of neurodegenerative conditions. The predictive coding of allostatic-interoception theory posits that the brain adapts to environmental demands by modulating internal bodily signals through the allostatic-interoceptive system. Specifically, a domain-general allostatic-interoceptive network exerts adaptive physiological control by fine-tuning initial top-down predictions and bottom-up peripheral signaling. In this context, adequate adaptation implies the minimization of prediction errors thereby optimizing energy expenditure...

In population neuroscience, three disciplines come together to advance our knowledge of factors that shape the human brain: neuroscience, genetics, and epidemiology (Paus, Human Brain Mapping 31:891-903, 2010). Here, I will come back to some of the background material reviewed in more detail in our previous book (Paus, Population Neuroscience, 2013), followed by a brief overview of current advances and challenges faced by this integrative approach.

In population neuroscience, samples are not often selected with equal or known probability from an underlying population of interest; in other words, samples are not often formally representative of a specified underlying population. This chapter provides an overview of an epidemiological approach to considering the implications of selective participation on the value of our results for population health. We discuss definitions of generalizability and transportability, given the growing recognition that generalizability and transportability are central for interpreting data that are aiming to be population-based...

Neuroimaging has provided important insights into the brain variations related to mental illness. Inconsistencies in prior studies, however, call for methods that lead to more replicable and generalizable brain markers that can reliably predict illness severity, treatment course, and prognosis. A paradigm shift is underway with large-scale international research teams actively pooling data and resources to drive consensus findings and test emerging methods aimed at achieving the goals of precision psychiatry...

Metabolomics technologies enable the quantification of multiple metabolomic measures simultaneously, which provides novel insights into molecular aspects of human health and disease. In large-scale, population-based studies, blood is often the preferred biospecimen. Circulating metabolome may relate to brain health either by affecting or reflecting brain metabolism. Peripheral metabolites may act at or cross the blood-brain barrier and, subsequently, influence brain metabolism, or they may reflect brain metabolism if similar pathways are engaged...

To understand psychiatric and neurological disorders and the structural and functional properties of the human brain, it is essential to consider the roles of sex and gender. In this chapter, I first define sex and gender and describe studies of sex differences in non-human animals. In humans, I describe the sex differences in behavioral and clinical phenotypes and neuroimaging-derived phenotypes, including whole-brain measures, regional subcortical and cortical measures, and structural and functional connectivity...

Population neuroscience aims to advance our understanding of how genetic and environmental factors influence brain development and brain health over the life span, by integrating genomics, epidemiology, and neuroscience at population scale. This big data approach depends on data sharing strategies at both the micro- and macro-level, as well as attention to effective data management and protection of participant privacy. At the micro-level, researchers participate in international consortia that support collaboration, standards, and data sharing...

People's mental health is intertwined with the social environment in which they reside. This chapter explores approaches for quantifying the area-level social environment, focusing specifically on socioeconomic deprivation and social fragmentation. We discuss census data and administrative units, egocentric and ecometric approaches, neighborhood audits, social media data, and street view-based assessments. We close the chapter by discussing possible paths forward from associations between social environments and health to establishing causality, including longitudinal research designs and time-series social environmental indices...

The development of animal models that demonstrate excessive levels of alcohol consumption has played an important role in advancing our knowledge about neurobiological underpinnings and environmental circumstances that engender such maladaptive behavior. The use of these preclinical models has also provided valuable opportunities for discovering new and novel therapeutic targets that may be useful in the treatment of alcohol use disorder (AUD). While no single model can fully capture the complexities of AUD, the goal is to develop animal models that closely approximate characteristics of heavy alcohol drinking in humans to enhance their translational value and utility...

The last two decades have seen a flourishing of research into the immunobiology of psychiatric phenotypes, in particular major depressive disorder. Both preclinical and clinical data have highlighted pathways and possible mechanisms that might link changes in immunobiology, most especially inflammation, to clinically relevant behaviour. From a therapeutics perspective, a major impetus has been the action of Biologics, often monoclonal antibodies, that target specific cytokines acting as "molecular scalpels" helping to uncover the actions of those proteins...

Preclinical studies suggest that physiological learning processes are similar to changes observed in addiction at the molecular, neuronal and structural levels. Based on the importance of classical and instrumental conditioning in the development and maintenance of addictive disorders, many have suggested cue-exposure-based extinction training of conditioned, drug-related responses as a potential treatment of addiction. Recently, the development of virtual reality-assisted cue-exposure treatment has put forward new approaches to extinction training...

Surgically implanted neurostimulation devices for the treatment of depression have been studied for the last three decades. While the surgical risk associated with these treatment approaches clearly limits their use to the most severely impacted depressed patients, they offer a unique opportunity to better understand the impact of relatively localized alteration of neural activity in patient groups. As a result, these approaches provide a strict test of the role of individual neural structures or networks in mechanistic models of depression...

An implicit tenet of the alcohol use disorder (AUD) research field is that knowledge of how alcohol interacts with the brain is critical to the development of an understanding of vulnerability to AUD and treatment approaches. Gaining this understanding requires the mapping of brain function critical to specific components of this heterogeneous disorder. Early approaches in humans and animal models focused on the determination of specific brain regions sensitive to alcohol action and their participation in AUD-relevant behaviors...

Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology...

Animal genetic models have and will continue to provide important new information about the behavioral and physiological adaptations associated with alcohol use disorder (AUD). This chapter focuses on two models, ethanol preference and drinking in the dark (DID), their usefulness in interrogating brain gene expression data and the relevance of the data obtained to interpret AUD-related GWAS and TWAS studies. Both the animal and human data point to the importance for AUD of changes in synaptic transmission (particularly glutamate and GABA transmission), of changes in the extracellular matrix (specifically including collagens, cadherins and protocadherins) and of changes in neuroimmune processes...

Dopaminergic mechanisms are a plausible treatment target for patients with clinical depression but are relatively underexplored in conventional antidepressant medications. There is continuing interest in the potential antidepressant effects of the dopamine receptor agonist, pramipexole, with data from both case series and controlled trials indicating that this agent may produce benefit for patients with difficult-to-treat depression. Pramipexole's therapeutic utility in depression is likely to be expressed through alterations in reward mechanisms which are strongly influenced by dopamine pathways and are known to function abnormally in depressed patients...

In the treatment of depressive disorders, conventional antidepressant therapy has been the mainstay of clinical management, along with well-established nonpharmacological interventions such as various kinds of psychotherapy. Over the last 2 decades, there has been considerable interest in the role of the gastrointestinal system and its microbiota on brain function, behavior, and mental health. Components of what is referred to as the microbiota-gut-brain axis have been uncovered, and further research has elicited functional capabilities such as "gut-brain modules...

Electroconvulsive therapy (ECT) remains the most potent antidepressant treatment available for patients with major depressive disorder (MDD). ECT is highly effective, achieving a response rate of 70-80% and a remission rate of 50-60% even in treatment-resistant patients. The underlying mechanisms of ECT are not fully understood, although several hypotheses have been proposed, including the monoamine hypothesis, anticonvulsive hypothesis, neuroplastic effects, and immunomodulatory properties. In this paper, we provide an overview of magnetic resonance imaging evidence that addresses the neuroplastic changes that occur after ECT at the human systems level and elaborate further on ECTs potent immunomodulatory properties...

Pharmacological treatments that improve mood were first identified serendipitously, but more than half a century later, how these drugs induce their antidepressant effects remains largely unknown. With the help of animal models, a detailed understanding of their pharmacological targets and acute and chronic effects on brain chemistry and neuronal function has been achieved, but it remains to be elucidated how these effects translate to clinical efficacy. Whilst the field has been dominated by the monoamine and neurotrophic hypotheses, the idea that the maladaptive cognitive process plays a critical role in the development and perpetuation of mood disorders has been discussed since the 1950s...

SSRIs are one of the most widely used drug therapies in primary care and psychiatry, and central to the management of the most common mental health problems in today's society. Despite this, SSRIs suffer from a slow onset of therapeutic effect and relatively poor efficacy as well as adverse effects, with recent concerns being focused on a disabling SSRI discontinuation syndrome. The mechanism underpinning their therapeutic effect has long shifted away from thinking that SSRIs act simply by increasing 5-HT in the synapse...