Psychosis superspectrum II: neurobiology, treatment, and implications.

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care.

What Is Addiction? History, Terminology, and Core Concepts.

Medicine's acceptance of addiction as a medical concept has waxed and waned over time. Addiction, as a disease, fits with modern disease definitions and scientific advances in elucidating the interactions between neurobiology and environment. Definitions of addiction need to acknowledge the complex interactions of brain circuits, genetics, environmental factors, and individual life experiences. Addiction aligns with diagnostic categories of substance use disorders that do not rely on tolerance and withdrawal as defining characteristics. Shifts in social and political views of addiction continue to propel and mirror changes in addiction treatment approaches and terminology within the medical community.

Tobacco Use Disorder.

Tobacco use disorder is highly prevalent; more than a billion individuals use tobacco worldwide. Popular views on the addictive potential of tobacco often underestimate the complex neural adaptations that underpin continued use. Although sometimes trivialized as a minor substance, effects of nicotine on behavior lead to profound morbidity over a lifetime of exposure. Innovations in processing have led to potent forms of tobacco and delivery devices. Proactive treatment strategies focus on pharmacotherapeutic interventions. Innovations on the horizon hold promise to help clinicians address this problem in a phenotypically tailored manner. Efforts are needed to prevent tobacco use for future generations.

What was learned from studying the effects of early institutional deprivation.

The effect of experiences in infancy on human development is a central question in developmental science. Children raised in orphanage-like institutions for their first year or so of life and then adopted into well-resourced and supportive families provide a lens on the long-term effects of early deprivation and the capacity of children to recover from this type of early adversity. While it is challenging to identify cause-and-effect relations in the study of previously institutionalized individuals, finding results that are consistent with animal experimental studies and the one randomized study of removal from institutional care support the conclusion that many of the outcomes for these children were induced by early institutional deprivation. This review examines the behavioral and neural evidence for altered executive function, declarative memory, affective disorders, reward processing, reactivity to threat, risk-taking and sensation-seeking. We then provide a brief overview of the neurobiological mechanisms that may transduce early institutional experiences into effects on brain and behavior. In addition, we discuss implications for policy and practice.

Employing Multiple New Neurobiological Methods to Investigate Environmental Neurotoxicology in Mice.

The emergence of advanced and powerful neuroscientific technologies has greatly pushed forward the development of neurobiology in the last decade. Although neurotoxicology is an interdisciplinary subject sharing a mass of technologies with neurobiology, the implementation of these advanced technologies in neurotoxicology is merely seen. Here we describe the detailed methods and materials of some emerging neuroscientific technologies, including optogenetics, fiber photometry, in vivo two-photon Imaging, in vivo calcium imaging, and in vivo electrophysiological recording, hoping that the integration of technologies from neurotoxicology and neuroscience can lend weight to the development of neurotoxicology.

Human neural organoids: Models for developmental neurobiology and disease.

Human organoids stand at the forefront of basic and translational research, providing experimentally tractable systems to study human development and disease. These stem cell-derived, in vitro cultures can generate a multitude of tissue and organ types, including distinct brain regions and sensory systems. Neural organoid systems have provided fundamental insights into molecular mechanisms governing cell fate specification and neural circuit assembly and serve as promising tools for drug discovery and understanding disease pathogenesis. In this review, we discuss several human neural organoid systems, how they are generated, advances in 3D imaging and bioengineering, and the impact of organoid studies on our understanding of the human nervous system.

Physician Distress and Burnout: The Neurobiological Perspective.

Physician burnout and other forms of occupational distress are a significant problem in modern medicine, especially during the coronavirus disease pandemic, yet few doctors are familiar with the neurobiology that contributes to these problems. Burnout has been linked to changes that reduce a physician's sense of control over their own practice, undermine connections with patients and colleagues, interfere with work-life integration, and result in uncontrolled stress. Brain research has revealed that uncontrollable stress, but not controllable stress, impairs the functioning of the prefrontal cortex, a recently evolved brain region that provides top-down regulation over thought, action, and emotion. The prefrontal cortex governs many cognitive operations essential to physicians, including abstract reasoning, higher-order decision making, insight, and the ability to persevere through challenges. However, the prefrontal cortex is remarkably reliant on arousal state and is impaired under conditions of fatigue and/or uncontrollable stress when there are inadequate or excessive levels of the arousal modulators (eg, norepinephrine, dopamine, acetylcholine). With chronic stress exposure, prefrontal gray matter connections are lost, but they can be restored by stress relief. Reduced prefrontal cortex self-regulation may explain several challenges associated with burnout in physicians, including reduced motivation, unprofessional behavior, and suboptimal communication with patients. Understanding this neurobiology may help physicians have a more informed perspective to help relieve or prevent symptoms of burnout and may help administrative leaders to optimize the work environment to create more effective organizations. Efforts to restore a sense of control to physicians may be particularly helpful.

Tolerance to alcohol: A critical yet understudied factor in alcohol addiction.

Alcohol tolerance refers to a lower effect of alcohol with repeated exposure. Although alcohol tolerance has been historically included in diagnostic manuals as one of the key criteria for a diagnosis of alcohol use disorder (AUD), understanding its neurobiological mechanisms has been neglected in preclinical studies. In this mini-review, we provide a theoretical framework for alcohol tolerance. We then briefly describe chronic tolerance, followed by a longer discussion of behavioral and neurobiological aspects that underlie rapid tolerance in rodent models. Glutamate/nitric oxide, γ-aminobutyric acid, opioids, serotonin, dopamine, adenosine, cannabinoids, norepinephrine, vasopressin, neuropeptide Y, neurosteroids, and protein kinase C all modulate rapid tolerance. Most studies have evaluated the ability of pharmacological manipulations to block the development of rapid tolerance, but only a few studies have assessed their ability to reverse already established tolerance. Notably, only a few studies analyzed sex differences. Neglected areas of study include the incorporation of a key element of tolerance that involves opponent process-like neuroadaptations. Compared with alcohol drinking models, models of rapid tolerance are relatively shorter in duration and are temporally defined, which make them suitable for combining with a wide range of classic and modern research tools, such as pharmacology, optogenetics, calcium imaging, in vivo electrophysiology, and DREADDs, for in-depth studies of tolerance. We conclude that studies of the neurobiology of alcohol tolerance should be revisited with modern conceptualizations of addiction and modern neurobiological tools. This may contribute to our understanding of AUD and uncover potential targets that can attenuate hazardous alcohol drinking.

The neurobiology of abstinence-induced reward-seeking in males and females.

Drugs of abuse and highly palatable foods (e.g. high fat or sweet foods) have powerful reinforcing effects, which can lead to compulsive and addictive drives to ingest these substances to the point of psychopathology and self-harm--specifically the development of Substance Use Disorder (SUD) and obesity. Both SUD and binge-like overeating can be defined as disorders in which the salience of the reward (food or drug) becomes exaggerated relative to, and at the expense of, other rewards that promote well-being. A major roadblock in the treatment of these disorders is high rates of relapse after periods of abstinence. It is common, although not universal, for cue-induced craving to increase over time with abstinence, often triggered by cues previously paired with the reinforcing substance. Accumulating evidence suggests that similar neural circuits and cellular mechanisms contribute to abstinence-induced and cue-triggered seeking of drugs and palatable food. Although much research has focused on the important role of corticolimbic circuitry in drug-seeking, our goal is to expand focus to the more recently explored hypothalamic-thalamic-striatal circuitry. Specifically, we review how connections, and neurotransmitters therein, among the lateral hypothalamus, paraventricular nucleus of the thalamus, and the nucleus accumbens contribute to abstinence-induced opioid- and (high fat or sweet) food-seeking. Given that biological sex and gonadal hormones have been implicated in addictive behavior across species, another layer to this review is to compare behaviors and neural circuit-based mechanisms of abstinence-induced opioid- or food-seeking between males and females when such data is available.

American racism and the lost legacy of Sir Jagadis Chandra Bose, the father of plant neurobiology.

Sir Jagadis Chandra Bose, India's first modern biologist departed boldly from mainstream botany by claiming that plants possess "nerves" and "pulsating cells" that function respectively much like the nerve and heart cells of animals. These ideas were based on highly sensitive measurements he made of various plant functions by means of assorted ingenious instruments of his own design. Despite being the most internationally celebrated plant biologist of the early 20th century, by the end of his life, Bose had become a scientific pariah whose work was expunged from Western histories of plant biology for nearly a century. In the 21st century, Bose's contributions to biology have begun to be appreciated anew, particularly within the plant neurobiology community. The present contribution examines the motivating factors behind the anti-Bose camp in the United States in the 1920s. It is concluded that the opposition to Bose's ideas during this period had less to do with scientific dialectics than with jealousy over Bose's international acclaim and the prevailing racism of the era.

A Simple and Low-Cost, but Naturalistic Method for Introducing Students to Action Potentials

Abstract Current trends in science education recommend the complementary use of virtual and hands-on methods of teaching. In neurobiology, for instance, there is a plethora of virtual laboratories and simulators that can be readily combined with traditional physical labs. Unfortunately, physical laboratories are almost unaffordable for many institutions due to the high cost of equipment. In this paper, we present a simple and low-cost in vivo method for demonstrating some of the basic biophysical properties of neural action potentials. The method involves the following steps: a) dissection of the ventral nerve cord of earthworm; b) electrical stimulation; c) amplification and visualization of the medial and lateral giant fibers' action potentials; and d) recording. The system showed stability, expected amplification, high signal-to-noise ratio, and an estimated total cost of US$ 5.662. We provide guidelines for assembling the system and discus its utility as a teaching alternative for low budget institutions.

C. elegans: a sensible model for sensory biology.

From Sydney Brenner's backyard to hundreds of labs across the globe, inspiring six Nobel Prize winners along the way, Caenorhabditis elegans research has come far in the past half century. The journey is not over. The virtues of C. elegans research are numerous and have been recounted extensively. Here, we focus on the remarkable progress made in sensory neurobiology research in C. elegans. This nematode continues to amaze researchers as we are still adding new discoveries to the already rich repertoire of sensory capabilities of this deceptively simple animal. Worms possess the sense of taste, smell, touch, light, temperature and proprioception, each of which is being studied in genetic, molecular, cellular and systems-level detail. This impressive organism can even detect less commonly recognized sensory cues such as magnetic fields and humidity.

Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo.

Brain development is an extraordinarily complex process achieved through the spatially and temporally regulated release of key patterning factors. In vitro neurodevelopmental models seek to mimic these processes to recapitulate the steps of tissue fate acquisition and morphogenesis. Classic two-dimensional neural cultures present higher homogeneity but lower complexity compared to the brain. Brain organoids instead have more advanced cell composition, maturation and tissue architecture. They can thus be considered at the interface of in vitro and in vivo neurobiology, and further improvements in organoid techniques are continuing to narrow the gap with in vivo brain development. Here we describe these efforts to recapitulate brain development in neural organoids and focus on their applicability for disease modeling, evolutionary studies and neural network research.

Resilience to Stress and Resilience to Pain: Lessons from Molecular Neurobiology and Genetics.

What biological factors account for resilience to pain or to behavioral stress? Here, we discuss examples of cellular and molecular mechanisms within disparate parts of the nervous system as contributors to such resilience. In some especially well-studied humans, it is possible to identify particular neuronal cell types in the peripheral nervous system (PNS) and pinpoint specific genes that are major contributors to pain resilience. We also discuss more complex factors that operate within the central nervous system (CNS) to confer resilience to behavioral stress. We propose that genetic and neurobiological substrates for resilience are discoverable and suggest more generally that neurology and psychiatry hold lessons for each other as investigators search for actionable, biological underpinnings of disease.

A virtual issue highlighting animal studies of eating disorders as valuable tools for examining neurobiological underpinnings and treatment of eating disorders.

While studies in humans suggest a role for psychosocial factors as well as biological and genetic processes in the development of eating disorders, the specific etiologic mechanisms remain largely unknown. In this virtual issue, we present a collection of 14 archived articles from the International Journal of Eating Disorders to highlight the utility of animal studies of eating disorders to advance our understanding of eating disorder etiology. Selected articles establish animal studies as valid tools to study disordered eating behavior, offer insight into potential neurobiological mechanisms, and highlight novel targets for future pharmacological treatments. Clinical implications of each article's findings are included to demonstrate the translational value of animal studies for the eating disorders field. We hope that the exciting concepts and findings in this issue inspire future animal studies of eating disorders.

The complex neurobiology of resilient functioning after childhood maltreatment.

BACKGROUND: Childhood maltreatment has been associated with significant impairment in social, emotional and behavioural functioning later in life. Nevertheless, some individuals who have experienced childhood maltreatment function better than expected given their circumstances. MAIN BODY: Here, we provide an integrated understanding of the complex, interrelated mechanisms that facilitate such individual resilient functioning after childhood maltreatment. We aim to show that resilient functioning is not facilitated by any single 'resilience biomarker'. Rather, resilient functioning after childhood maltreatment is a product of complex processes and influences across multiple levels, ranging from 'bottom-up' polygenetic influences, to 'top-down' supportive social influences. We highlight the complex nature of resilient functioning and suggest how future studies could embrace a complexity theory approach and investigate multiple levels of biological organisation and their temporal dynamics in a longitudinal or prospective manner. This would involve using methods and tools that allow the characterisation of resilient functioning trajectories, attractor states and multidimensional/multilevel assessments of functioning. Such an approach necessitates large, longitudinal studies on the neurobiological mechanisms of resilient functioning after childhood maltreatment that cut across and integrate multiple levels of explanation (i.e. genetics, endocrine and immune systems, brain structure and function, cognition and environmental factors) and their temporal interconnections. CONCLUSION: We conclude that a turn towards complexity is likely to foster collaboration and integration across fields. It is a promising avenue which may guide future studies aimed to promote resilience in those who have experienced childhood maltreatment.

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Design and structural characterisation of olfactomedin-1 variants as tools for functional studies.

BACKGROUND: Olfactomedin-1 (Olfm1; also known as Noelin or Pancortin) is a highly-expressed secreted brain and retina protein and its four isoforms have different roles in nervous system development and function. Structural studies showed that the long Olfm1 isoform BMZ forms a disulfide-linked tetramer with a V-shaped architecture. The tips of the Olfm1 "V" each consist of two C-terminal ß-propeller domains that enclose a calcium binding site. Functional characterisation of Olfm1 may be aided by new biochemical tools derived from these core structural elements. RESULTS: Here we present the production, purification and structural analysis of three novel monomeric, dimeric and tetrameric forms of mammalian Olfm1 for functional studies. We characterise these constructs structurally by high-resolution X-ray crystallography and small-angle X-ray scattering. The crystal structure of the Olfm1 ß-propeller domain (to 1.25 Å) represents the highest-resolution structure of an olfactomedin family member to date, revealing features such as a hydrophilic tunnel containing water molecules running into the core of the domain where the calcium binding site resides. The shorter Olfactomedin-1 isoform BMY is a disulfide-linked tetramer with a shape similar to the corresponding region in the longer BMZ isoform. CONCLUSIONS: These recombinantly-expressed protein tools should assist future studies, for example of biophysical, electrophysiological or morphological nature, to help elucidate the functions of Olfm1 in the mature mammalian brain. The control over the oligomeric state of Olfm1 provides a firm basis to better understand the role of Olfm1 in the (trans-synaptic) tethering or avidity-mediated clustering of synaptic receptors such as post-synaptic AMPA receptors and pre-synaptic amyloid precursor protein. In addition, the variation in domain composition of these protein tools provides a means to dissect the Olfm1 regions important for receptor binding.

Current understanding of psycho-neurobiology in depressive disorders with suicidal thoughts - translational models.

Epidemiological data confirm the rising incidence of depression associated with suicidal ideation and cardiovascular comorbidities of coronary type. In contradiction with the large number of antidepressant drugs, the therapeutic results are not satisfactory, with numerous existing incomplete remissions characterized by maintained cellular dysfunctionalities that amplify the cognitive deterioration and the risk of several somatic comorbidities. The surprising fact is the relatively high number of deaths in this type of patients due to acute coronary disease (myocardial infarction - MI). The vulnerability of hippocampal and frontal cortex cerebral structures is presented as obtained on animal model consecutive to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and on theoretical model where the hypothalamic disconnectivity determines the activation in the sympathetic autonomic nervous system, leading to heart disorders: high blood pressure, left ventricular hypertrophy and coronary illness. Identifying the association of psychological risk factors, patients fitting in a model of psychosomatic dominant personality traits, where the main risk factors are represented by inflexibility, guilt and self-accusation feelings, associated with increase of biological indicators (proinflammatory factors, endothelial dysfunction and cytokine aggressiveness) and neuroimaging indicators (frontal, temporal, hippocampal atrophy, ventriculomegaly, cerebellum atrophy). Changes identified post-mortem in the arterioles from the frontal cortex were found also in the coronary vessels, suggesting a symmetric evolution The highlighted personality factors are responsible for the decrease of adherence and compliance both in the psychiatric and the cardiologic treatment, the patient being exposed to behavioral risks regarding life style and nutrition, factors that increase the risk for acute coronary accident. The psycho-neurobiological inspired theoretical models argument the importance of a differentiated and customized approach of the patients with depressive disorder and suicidal ideation, and they can be the base for initiating strategies for prevention of unfavorable evolution and risk of death by MI.