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The mission of the National Institute of Mental Health is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. In consultation with a broad range of experts, the NIMH has identified a set of priorities for stress biology research aimed squarely at creating the basic and clinical knowledge bases for reducing and alleviating mental health burden across the lifespan. Here, we discuss these priority areas in stress biology research, which include: understanding the heterogeneity of stressors and outcomes; refining and expanding the experimental systems used to study stress and its effects; embracing and exploiting the complexity of the stress response; and prioritizing translational studies that seek to test mechanistic hypotheses in human beings. We emphasize the challenge of establishing mechanistic links across levels of analysis to explain how and when specific and diverse stressors lead to enduring changes in neural systems and produce lasting functional deficits in mental health relevant behaviors. An improved understanding of mechanisms underlying stress responses and the functional consequences of stress can and will speed translation from basic research to predictive markers of risk and to improved, personalized interventions for mental illness.
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Transtornos Mentais , Estresse Psicológico , Humanos , Transtornos Mentais/terapia , Saúde Mental , National Institute of Mental Health (U.S.) , Estados Unidos/epidemiologiaRESUMO
Heterogeneity of disorders, comorbidity across diagnoses, and reification of existing disease classifications are some of the challenges facing psychiatry in the twenty-first century. NIMH's Research Domain Criteria (RDoC) Project seeks to address these issues by defining basic dimensions of function that cut across disorders as traditionally defined and can be studied across multiple units of analysis, from genes to neural circuits to behaviors. The intent is to translate rapid progress in basic genetic, neurobiological, and behavioral research to an improved integrative understanding of psychopathology. In so doing, RDoC seeks to facilitate the development of new and/or optimally targeted treatments for mental disorders. The RDoC project would not have been possible without NIMH's long-term investment in basic research. Without the continuation of basic research, both related and unrelated to current RDoC domains and constructs, it will not be possible to sustain the RDoC effort. This article seeks to outline the relationship between RDoC and NIMH's ongoing support for broad-based basic research, from genetics to behavior.
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Pesquisa em Genética , National Institute of Mental Health (U.S.) , Animais , Genômica , Humanos , Modelos Animais , Pesquisa , Pesquisa Translacional Biomédica , Estados UnidosRESUMO
OBJECTIVES: To enhance and evaluate the quality of PubMed search results for Social Determinants of Health (SDoH) through the addition of new SDoH terms to Medical Subject Headings (MeSH). MATERIALS AND METHODS: High priority SDoH terms and definitions were collated from authoritative sources, curated based on publication frequencies, and refined by subject matter experts. Descriptive analyses were used to investigate how PubMed search details and best match results were affected by the addition of SDoH concepts to MeSH. Three information retrieval metrics (Precision, Recall, and F measure) were used to quantitatively assess the accuracy of PubMed search results. Pre- and post-update documents were clustered into topic areas using a Natural Language Processing pipeline, and SDoH relevancy assessed. RESULTS: Addition of 35 SDoH terms to MeSH resulted in more accurate algorithmic translations of search terms and more reliable best match results. The Precision, Recall, and F measures of post-update results were significantly higher than those of pre-update results. The percentage of retrieved publications belonging to SDoH clusters was significantly greater in the post- than pre-update searches. DISCUSSION: This evaluation confirms that inclusion of new SDoH terms in MeSH can lead to qualitative and quantitative enhancements in PubMed search retrievals. It demonstrates the methodology for and impact of suggesting new terms for MeSH indexing. It provides a foundation for future efforts across behavioral and social science research (BSSR) domains. CONCLUSION: Improving the representation of BSSR terminology in MeSH can improve PubMed search results, thereby enhancing the ability of investigators and clinicians to build and utilize a cumulative BSSR knowledge base.
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Dysfunction of the γ-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive-compulsive disorder. The purpose of this study was to identify a possible dysfunction of the γ-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls. Positron emission tomography procedure: after injection of 20 mCi of [(11)C]flumazenil, dynamic emission images of the brain were acquired. Structural magnetic resonance imaging scans were obtained to provide an anatomical framework for the positron emission tomography data analysis. Images of binding potential were created using the two-step version of the simplified reference tissue model. The binding potential images then were spatially normalized, smoothed and compared between groups using statistical parametric mapping. We found decreased binding of GABA(A) receptors in Tourette patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala and right insula. In addition, the GABA(A) receptor binding was increased in the bilateral substantia nigra, left periaqueductal grey, right posterior cingulate cortex and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in Tourette syndrome patients. In addition, the abnormalities in GABA(A) receptor binding in the insula and cerebellum appear particularly noteworthy based upon recent evidence implicating these structures in the generation of tics.
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Encéfalo/metabolismo , Síndrome de Tourette/metabolismo , Síndrome de Tourette/patologia , Ácido gama-Aminobutírico/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Isótopos de Carbono , Estudos de Casos e Controles , Feminino , Flumazenil , Moduladores GABAérgicos , Humanos , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Síndrome de Tourette/diagnóstico por imagem , Adulto JovemRESUMO
The National Institutes of Health (NIH) is increasingly prioritizing research on health-promoting processes. Park et al. (this issue) respond to a call made by NIH to advance the study of emotional well-being (EWB) and to increase understanding of the fundamental constituents of EWB across the lifespan and among diverse subgroups. They propose a definition of EWB that provides an organizing framework for research on 'psychological aspects of well-being' and health. We commend this important first step and urge consideration of three important issues related to operationalization - the process by which an abstract concept is transformed into variables that can be measured - in future research on EWB. We expect that an iterative process of construct refinement and empirical validation will advance the study of EWB, producing scientific discoveries that can be leveraged to enhance health across the lifespan.
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Affective science is a broad and burgeoning field, and the National Institutes of Health (NIH) support research on a similarly broad range of topics. Across NIH, funding is available for basic, translational, and intervention research, including research in non-human animals, healthy populations, and those with or at risk for disease. Multiple NIH Institutes and Centers have specific programs devoted to topics within the affective science umbrella. Here, we introduce the funding priorities of these six: the National Cancer Institute (NCI), National Center for Complementary and Integrative Health (NCCIH), National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Institute on Drug Abuse (NIDA), and National Institute on Minority Health and Health Disparities (NIMHD). We then discuss overlapping themes and offer a perspective on promising research directions.
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The National Institutes of Health established the Science of Behavior Change (SOBC) program to promote basic research on the initiation, personalization, and maintenance of health behavior change. The SOBC Resource and Coordinating Center now leads and supports activities to maximize the creativity, productivity, scientific rigor, and dissemination of the experimental medicine approach and experimental design resources. Here, we highlight those resources, including the Checklist for Investigating Mechanisms in Behavior-change Research (CLIMBR) guidelines introduced in this special section. We describe the ways in which SOBC can be applied across a range of domains and contexts, and end by considering ways to extend SOBC's perspective and reach, so as to best promote behavior change linked with health, quality of life, and well-being.
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Pesquisa Biomédica , Qualidade de Vida , Humanos , Cognição , Comportamentos Relacionados com a Saúde , Projetos de PesquisaRESUMO
Subregions of prefrontal cortex are important for estimating reward values and using these values to guide behavior. The present studies directly tested whether orbital prefrontal cortex (O-PFC) and lateral prefrontal cortex (L-PFC) are necessary for evaluating trial-to-trial changes in the reward values predicted by visual cues. We have compared intact rhesus monkeys, those with bilateral O-PFC lesions (n = 3), and those with bilateral L-PFC lesions (n = 3). We used three versions of a visually cued color discrimination task: we varied reward size, delay to reward, or both. O-PFC lesions altered estimations of predicted reward value in all versions of the task. L-PFC lesions disrupted performance only when both reward size and delay to reward were varied together. Neither lesion directly affected basic internal drive states (satiation curves). Our results suggest that O-PFC is essential for establishing independent, context-specific scales with which predicted reward values are measured. L-PFC appears necessary for integration of predicted reward value across these different scales.
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Percepção de Cores/fisiologia , Córtex Pré-Frontal/fisiologia , Desempenho Psicomotor/fisiologia , Recompensa , Animais , Mapeamento Encefálico/métodos , Macaca mulatta , Masculino , Estimulação Luminosa/métodos , Valor Preditivo dos Testes , Córtex Pré-Frontal/anatomia & histologiaRESUMO
Interoception refers to the representation of the internal states of an organism, and includes the processes by which it senses, interprets, integrates, and regulates signals from within itself. This review presents a unified research framework and attempts to offer definitions for key terms to describe the processes involved in interoception. We elaborate on these definitions through illustrative research findings, and provide brief overviews of central aspects of interoception, including the anatomy and function of neural and non-neural pathways, diseases and disorders, manipulations and interventions, and predictive modeling. We conclude with discussions about major research gaps and challenges.
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Interocepção , HumanosRESUMO
BACKGROUND: Depression exerts a staggering toll that is worsened with co-occurring chronic conditions such as obesity. It is imperative to develop more effective interventions for depression and to identify objective and biological plausible neural mechanisms to understand intervention outcomes. The current study uses functional neuroimaging to determine whether a behavioural intervention changes the negative affect circuit and whether these changes relate to subsequent improvements in both symptom and problem-solving outcomes in depressed patients with co-occurring obesity. METHODS: This study ('ENGAGE') was a pre-planned element of the randomized controlled trial, 'RAINBOW' (ClinicalTrials.gov NCT02246413). 108 depressed patients with obesity were randomized to receive an integrated collaborative care intervention (I-CARE) or usual care. Participants underwent functional neuroimaging using an established facial emotion task at baseline and two months (coinciding with the first two months of intervention focused on problem-solving therapy ('PST')). Amygdala, insula and anterior cingulate cortex activation was extracted using pre-planned definitions and standardized methods. The primary health and behavioural outcomes were depression symptom severity and problem-solving ability respectively, assessed at baseline, the main 6-month outcome point and at 12-month follow up. Mediation analyses used an intent-to-treat approach. FINDINGS: PST, relative to usual care, reduced amygdala activation engaged by threat stimuli at two months. This reduction mediated subsequent improvements in depression severity in an intervention-dependent manner. PST did not change insula activation at two months but did temper the strength of the relationship between insula activation and improvements in problem-solving ability. INTERPRETATION: The negative affect circuit may be an important neural target and potential mediator of PST in patients with comorbid obesity. FUNDING: US National Institutes of Health/National Heart Lung and Blood Institute R01 HL119453 and UH2/UH3 HL132368.
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Terapia Comportamental , Conectoma , Depressão/terapia , Resolução de Problemas , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicaçõesRESUMO
BACKGROUND: Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements. OBJECTIVES: The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors. METHODS: Adults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression. RESULTS: Compared with usual care, PST led to reductions in left amygdala activation (-0.75; 95% CI: -1.49, -0.01) and global scores of the negative affect circuit (-0.43; -0.81, -0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized ß-coefficients were -0.67 in usual care and -0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and -2.02 in usual care and -0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized ß-coefficients were -0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and -1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet. CONCLUSIONS: Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).
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Depressão , Obesidade , Adulto , Tonsila do Cerebelo , Depressão/terapia , Humanos , Estilo de Vida , Obesidade/terapia , Psicoterapia/métodosRESUMO
Despite evidence for effective integrated behavior therapy for treating comorbid obesity and depression, treatment response is highly variable and the underlying neurobiological mechanisms remain unknown. This hampers efforts to identify mechanistic targets in order to optimize treatment precision and potency. Funded within the NIH Science of Behavior Change (SOBC) Research Network, the 2-phased ENGAGE research project applies an experimental precision medicine approach to address this gap. The Phase 1 study focused on demonstrating technical feasibility, target engagement and potential neural mechanisms of responses to an integrated behavior therapy. This therapy combines a video-based behavioral weight loss program and problem-solving therapy for depression, with as-needed intensification of antidepressant medications, and its clinical effectiveness was demonstrated within a parent randomized clinical trial. Here, we describe the ENGAGE Phase 2 (ENGAGE-2) study protocol which builds on Phase 1 in 2 ways: (1) pilot testing of an motivational interviewing-enhanced, integrated behavior therapy in an independent, primarily minority patient sample, and (2) evaluation of a priori defined neural targets, specifically the negative affect (threat and sadness) circuits which demonstrated engagement and malleability in Phase 1, as mediators of therapeutic outcomes. Additionally, the Phase 2 study includes a conceptual and methodological extension to explore the role of microbiome-gut-brain and systemic immunological pathways in integrated behavioral treatment of obesity and depression. This protocol paper documents the conceptualization, design and the transdisciplinary methodologies in ENGAGE-2, which can inform future clinical and translational research in experimental precision medicine for behavior change and chronic disease management. Trial registration: ClinicalTrials.gov #NCT 03,841,682.
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Obesidade , Autocontrole , Afeto , Antidepressivos , Terapia Comportamental , Humanos , Obesidade/terapiaRESUMO
Manganese-enhanced magnetic resonance imaging (MEMRI) provides a powerful tool to study multisynaptic circuits in vivo and thereby to link information about neural structure and function within individual subjects. Making the best use of MEMRI in monkeys requires minimizing manganese-associated neurotoxicity, maintaining sensitivity to manganese-dependent signal changes and mapping transport throughout the brain without a priori anatomical hypotheses. Here, we performed intracortical injections of isotonic MnCl(2), comparisons of preinjection and postinjection scans, and voxelwise statistical mapping. Isotonic MnCl(2) did not cause cell death at the injection site, damage to downstream targets of manganese transport, behavioral deficits, or changes in neuronal responsiveness. We detected and mapped manganese transport throughout cortical-subcortical circuits by using voxelwise statistical comparisons of at least 10 preinjection and two postinjection scans. We were able to differentiate between focal and diffuse projection fields and to distinguish between the topography of striatal projections from orbitofrontal and anterior cingulate cortex in a single animal. This MEMRI approach provides a basis for combining circuit-based anatomical analyses with simultaneous single-unit recordings and/or functional magnetic resonance imaging in individual monkeys. Such studies will enhance our interpretations of functional data and our understanding of how neuronal activity is transformed as it propagates through a circuit.
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Mapeamento Encefálico , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética , Manganês , Córtex Pré-Frontal/anatomia & histologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Condicionamento Clássico/fisiologia , Feminino , Haplorrinos , Processamento de Imagem Assistida por Computador , Masculino , Manganês/farmacologia , Vias Neurais/anatomia & histologia , Vias Neurais/irrigação sanguínea , Vias Neurais/fisiologia , Oxigênio/sangue , Estimulação Luminosa/métodos , Córtex Pré-Frontal/irrigação sanguínea , Córtex Pré-Frontal/fisiologia , Fatores de TempoRESUMO
We investigated how orbitofrontal cortex (OFC) contributes to adaptability in the face of changing reward contingencies by examining how reward representations in monkey orbitofrontal neurons change during a visually cued, multi-trial reward schedule task. A large proportion of orbitofrontal neurons were sensitive to events in this task (69/80 neurons in the valid and 48/58 neurons in the random cue context). Neuronal activity depended upon preceding reward, upcoming reward, reward delivery, and schedule state. Preceding reward-dependent activity occurred in both the valid and random cue contexts, whereas upcoming reward-dependent activity was observed only in the valid context. A greater proportion of neurons encoded preceding reward in the random than the valid cue context. The proportion of neurons with preceding reward-dependent activity declined as each trial progressed, whereas the proportion encoding upcoming reward increased. Reward information was represented by ensembles of neurons, the composition of which changed with task context and time. Overall, neuronal activity in OFC adapted to reflect the importance of different types of reward information in different contexts and time periods. This contextual and temporal adaptability is one hallmark of neurons participating in executive functions.
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Mapeamento Encefálico , Sinais (Psicologia) , Tomada de Decisões/fisiologia , Discriminação Psicológica/fisiologia , Potenciais Evocados/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Animais , Macaca mulatta , MasculinoRESUMO
Precision medicine models for personalizing achieving sustained behavior change are largely outside of current clinical practice. Yet, changing self-regulatory behaviors is fundamental to the self-management of complex lifestyle-related chronic conditions such as depression and obesity - two top contributors to the global burden of disease and disability. To optimize treatments and address these burdens, behavior change and self-regulation must be better understood in relation to their neurobiological underpinnings. Here, we present the conceptual framework and protocol for a novel study, "Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes (ENGAGE)". The ENGAGE study integrates neuroscience with behavioral science to better understand the self-regulation related mechanisms of behavior change for improving mood and weight outcomes among adults with comorbid depression and obesity. We collect assays of three self-regulation targets (emotion, cognition, and self-reflection) in multiple settings: neuroimaging and behavioral lab-based measures, virtual reality, and passive smartphone sampling. By connecting human neuroscience and behavioral science in this manner within the ENGAGE study, we develop a prototype for elucidating the underlying self-regulation mechanisms of behavior change outcomes and their application in optimizing intervention strategies for multiple chronic diseases.
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Controle Comportamental/métodos , Depressão/epidemiologia , Depressão/terapia , Obesidade/epidemiologia , Obesidade/terapia , Medicina de Precisão/métodos , Autocontrole/psicologia , Peso Corporal , Protocolos Clínicos , Comorbidade , Humanos , Imageamento por Ressonância Magnética , Neuroimagem , Smartphone , Realidade VirtualRESUMO
The goal of the NIH Science of Behavior Change (SOBC) Common Fund Program is to provide the basis for an experimental medicine approach to behavior change that focuses on identifying and measuring the mechanisms that underlie behavioral patterns we are trying to change. This paper frames the development of the program within a discussion of the substantial disease burden in the U.S. attributable to behavioral factors, and details our strategies for breaking down the disease- and condition-focused silos in the behavior change field to accelerate discovery and translation. These principles serve as the foundation for our vision for a unified science of behavior change at the NIH and in the broader research community.
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Controle Comportamental , National Institutes of Health (U.S.) , Desenvolvimento de Programas , Pesquisa Biomédica/métodos , Humanos , Estados UnidosRESUMO
We have investigated how neuronal activity in the orbitofrontal-ventral striatal circuit is related to reward-directed behavior by comparing activity in these two regions during a visually guided reward schedule task. When a set of visual cues provides information about reward contingency, that is, about whether or not a trial will be rewarded, significant subpopulations of neurons in both orbitofrontal cortex and ventral striatum encode this information. Orbitofrontal and ventral striatal neurons also differentiate between rewarding and non-rewarding trial outcomes, whether or not those outcomes were predicted. The size of the neuronal subpopulation encoding reward contingency is twice as large in orbitofrontal cortex (50% of neurons) as in ventral striatum (26%). Reward-contingency-dependent activity also appears earlier during a trial in orbitofrontal cortex than in ventral striatum. The peak reward-contingency representation in orbitofrontal cortex (31% of neurons), occurs during the wait period, a period of high anticipation prior to any action. The peak ventral striatal representation of reward contingency (18%) occurs during the go period, a time of action. We speculate that signals from orbitofrontal cortex bias ventral striatal activity, and that a flow of reward-contingency information from orbitofrontal cortex to ventral striatum serves to guide actions toward rewards.