Clinical, behavioral, and electrophysiological profiles along a continuum of suicide risk: evidence from an implicit association task.

BACKGROUND: An urgent need exists to identify neural correlates associated with differing levels of suicide risk and develop novel, rapid-acting therapeutics to modulate activity within these neural networks. METHODS: Electrophysiological correlates of suicide were evaluated using magnetoencephalography (MEG) in 75 adults with differing levels of suicide risk. During MEG scanning, participants completed a modified Life-Death Implicit Association Task. MEG data were source-localized in the gamma (30-58 Hz) frequency, a proxy measure of excitation-inhibition balance. Dynamic causal modeling was used to evaluate differences in connectivity estimates between risk groups. A proof-of-concept, open-label, pilot study of five high risk participants examined changes in gamma power after administration of ketamine (0.5 mg/kg), an NMDAR antagonist with rapid anti-suicide ideation effects. RESULTS: Implicit self-associations with death were stronger in the highest suicide risk group relative to all other groups, which did not differ from each other. Higher gamma power for self-death compared to self-life associations was found in the orbitofrontal cortex for the highest risk group and the insula and posterior cingulate cortex for the lowest risk group. Connectivity estimates between these regions differentiated the highest risk group from the full sample. Implicit associations with death were not affected by ketamine, but enhanced gamma power was found for self-death associations in the left insula post-ketamine compared to baseline. CONCLUSIONS: Differential implicit cognitive processing of life and death appears to be linked to suicide risk, highlighting the need for objective measures of suicidal states. Pharmacotherapies that modulate gamma activity, particularly in the insula, may help mitigate risk.Clinicaltrials.gov identifier: NCT02543983, NCT00397111.

Limited impacts of biogenetic messaging on neural correlates of cognitive control and beliefs about depression.

During the past 60 years, perceptions about the origins of mental illness have shifted toward a biomedical model, depicting depression as a biological disorder caused by genetic abnormalities and/or chemical imbalances. Despite benevolent intentions to reduce stigma, biogenetic messages promote prognostic pessimism, reduce feelings of agency, and alter treatment preferences, motivations, and expectations. However, no research has examined how these messages influence neural markers of ruminative activity or decision-making, a gap this study sought to fill. In this pre-registered, clinical trial (NCT03998748), 49 participants with current or past depressive experiences completed a sham saliva test and were randomly assigned to receive feedback that they either have (gene-present; n = 24) or do not have (gene-absent; n = 25) a genetic predisposition to depression. Before and after receiving the feedback, resting-state activity and neural correlates of cognitive control (error-related negativity [ERN] and error positivity [Pe]) were measured using high-density electroencephalogram (EEG). Participants also completed self-report measures of beliefs about the malleability and prognosis of depression and treatment motivation. Contrary to hypotheses, biogenetic feedback did not alter perceptions or beliefs about depression, nor did it alter EEG markers of self-directed rumination nor neurophysiological correlates of cognitive control. Explanations of these null findings are discussed in the context of prior studies.

Effects of dopamine modulation on chronic stress-induced deficits in reward learning.

Anhedonia is characteristically preceded by chronic stress, likely involving downstream effects of glucocorticoid alterations on dopamine (DA) function. To elucidate the neural underpinnings of this interaction, we examined whether acute pharmacological modulation of DA alters reward learning after chronic mild stress (CMS). Forty-eight male Wistar rats were exposed to a 21-day CMS regime (n = 48 no stress controls) before completing the probabilistic reward task (PRT), a well-validated cross-species test of reward learning. We first examined whether stress-induced reward dysfunction could be restored by systemic injections of low-dose amisulpride (AMI), which increases DA transmission via D2-like autoreceptor blockade. Then, we investigated region-specific effects through bilateral infusions of quinpirole (QUIN), a D2-like receptor agonist, into either the nucleus accumbens core (NAcc) or medial prefrontal cortex (mPFC). Blunted reward learning in CMS animals was reversed by acute AMI administration, but this treatment did not alter reward learning in the no stress group. Elevated adrenal gland weight, a proxy for stress reactivity, predicted lower reward learning in the untreated CMS group. This effect was extinguished following AMI treatment. These findings might be attributed to significantly higher D2 receptor density in the NAcc of high stress reactive animals. To this end, NAcc QUIN infusions potentiated reward learning relative to mPFC QUIN infusions in CMS rats, but there was no effect in no stress control rats. Collectively, these findings suggest that DA modulation reverses stress-induced reward dysfunction, even among the most stress-reactive animals. The effect might depend on D2-like receptor activation in the mesolimbic system.

Toward objective characterizations of suicide risk: A narrative review of laboratory-based cognitive and behavioral tasks.

Although suicide is a leading cause of preventable death worldwide, current prevention efforts have failed to substantively mitigate suicide risk. Suicide research has traditionally relied on subjective reports that may not accurately differentiate those at high versus minimal risk. This narrative review supports the inclusion of objective task-based measures in suicide research to complement existing subjective batteries. The article: 1) outlines risk factors proposed by contemporary theories of suicide and highlights recent empirical findings supporting these theories; 2) discusses ongoing challenges associated with current risk assessment tools and their ability to accurately evaluate risk factors; and 3) analyzes objective laboratory measures that can be implemented alongside traditional measures to enhance the precision of risk assessment. To illustrate the potential of these methods to improve our understanding of suicide risk, the article reviews how acute stress responses in a laboratory setting can be modeled, given that stress is a major precipitant for suicidal behavior. More precise risk assessment strategies can emerge if objective measures are implemented in conjunction with traditional subjective measures.

Environmental Contributions to Anhedonia.

Anhedonia is a core feature of psychopathological conditions that have recent exposure to stress and trauma as central to their etiology. Indeed, evolutionary accounts of depression suggest that decreased motivation to pursue reward may be an adaptive strategy in the face of social stress, in particular, as it may serve to defuse interpersonal conflict. Through a review of rodent models and research with humans, we show that exposure to stress, particularly when it is chronic, repeated, and/or involves themes of social rejection or defeat, is consistently associated with reduced hedonic capacity ("liking"), motivation to pursue reward ("wanting"), and ability to learn from reward ("reward learning"). Further, across rodent and human research, there is evidence that females show greater stress-induced blunting of reward processing than males. In humans, this sex difference emerges most strongly when examining individual differences in the stress response rather than group differences in stress exposure. We discuss the implications of these findings for understanding the etiology of, and sex differences in, stress-related psychopathology, including depression and addiction.

Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation.

Suicide is a leading cause of death and morbidity worldwide, yet few interventions are available to mitigate its risk. Barriers to effective treatments involve a limited understanding of factors that predict the onset of suicidal thoughts and behaviors. In the context of suicide risk, stress is a precipitating factor that is largely overlooked in the literature. Indeed, the pathophysiology of stress and suicide are heavily interconnected, underscoring the need to target the stress system in suicide prevention. In this review, we integrate findings from the preclinical and clinical literature that links stress and suicide. We focus specifically on the effects of stress on underlying biological functions and processes associated with suicide, allowing for the review of research using animal models. Owing to the rapid anti-suicidal effects of (R,S)-ketamine, we discuss its ability to modulate various stress-related endophenotypes of suicide, as well as its potential role in preventing suicide in those with a history of chronic life stress (e.g., early life adversity). We highlight future research directions that could advance our understanding of stress-related effects on suicide risk, advocating a dimensional, endophenotype approach to suicide research.

Does inflammation link stress to poor COVID-19 outcome?

Coronavirus disease 2019 (COVID-19) continues to ravage communities across the world. Despite its primary effect on the respiratory system, the virus does not solely impact those with underlying lung conditions as initially predicted. Indeed, prognosis is worsened (often fatal) in patients with pre-existing hyperinflammatory responses (e.g., hypertension, obesity and diabetes), yet the mechanisms by which this occurs are unknown. A number of psychological conditions are associated with inflammation, suggesting that these may also be significant risk factors for negative outcomes of COVID-19. In this review, we evaluate preclinical and clinical literature suggesting that chronic stress-induced hyperinflammation interacts synergistically with COVID-19-related inflammation, contributing to a potentially fatal cytokine storm syndrome. In particular, we hypothesize that both chronic stress and COVID-19-related hyperinflammation are a product of glucocorticoid insufficiency. We discuss the devastating effects of SARS-CoV-2 on structural and functional aspects of the biological stress response and how these induce exaggerated inflammatory responses, particularly interleukin (IL)-6 hypersecretion. We postulate that chronic stress should be considered a significant risk factor for adverse COVID-19-related health outcomes, given overlapping peripheral and central immune dysregulation in both conditions. We conclude by discussing how people with a history of chronic stress could mitigate their risk for COVID-19 complications, identifying specific strategies that can be implemented during self-isolation.

Post-acute sequelae of COVID-19: Evidence of mood & cognitive impairment.

Acute health consequences associated with coronavirus disease 2019 (COVID-19) infection have been thoroughly characterized; however, long-term impacts are not yet understood. Post-acute sequelae of COVID-19 (PASC), also known as Long COVID syndrome, is the persistence of COVID-19 symptoms long after viral infection. In addition to physical symptoms, those with PASC experience changes in mental health, but few studies have empirically examined these effects. The current study investigated mood and cognitive functioning in individuals who have recovered from COVID-19 infection. We recruited 100 male and female adults (M â€‹= â€‹30 years old) with no history of mood or cognitive impairment prior to the COVID-19 pandemic (Jan. 2020). Half of the subjects were healthy controls (i.e., no prior COVID-19 infection) and half had received a past COVID-19 diagnosis (ascertained by PCR or antibody test) but were no longer infectious. Participants completed self-reported measures of stress, depression, and anhedonia, as well as the Attention Network Test (ANT), a behavioural measure of attentional alerting, orienting and executive functioning. Relative to controls, depression and anhedonia were significantly higher in the past-COVID group. Selective impairment in attention was observed in the past-COVID group, marked by deficits in executive functioning while alerting and orienting abilities remained intact. Effects were most pronounced among individuals diagnosed 1-4 months prior to assessment. There were no group differences in pandemic-related experiences with respect to social interaction, social distancing, or isolation. The past-COVID group scored significantly higher on perceived stress; however, this did not moderate any effects observed on mood or cognition. These findings implicate a protracted reaction to the virus, possibly via prolonged inflammation, contributing to sustained mood dysregulation and cognitive impairment. Future research should examine the neural and physiological underpinnings of PASC, particularly mechanisms that promote psychiatric sequelae 1-4 months following diagnosis.

Mid-adolescent stress differentially affects binge-like intake of sucrose across estrous cycles in female rats✰.

Binge eating disorder (BED), characterized by excessive food consumption within a discrete period of time, is the most prevalent of all eating disorders, with higher rates in women than men. Chronic stress, particularly during adolescence, is a significant risk factor for BED in women, but the mechanism underlying this relationship remains elusive. We investigated the phenomenon by testing the impact of mid-adolescent intermittent physical stress (IPS) on binge-like intake of sucrose in adult female rats, assessing how the behavior changed across reproductive cycles. One hundred and nineteen Long-Evans rats were exposed to IPS (n = 59) or no stress (NS; n = 60) for 12 days during mid-adolescence (PD35-46). Binge-like eating was induced in adult animals using an intermittent access protocol: animals were provided with 12 h or 24 h access to sucrose, 12 h access to saccharin, or 12 h access to food over 28 days. After 1- or 28-day abstinence, compulsive responding for sucrose was measured using a conditioned suppression paradigm. Rats given 12 h access to sucrose developed binge-like intake, measured as increased consumption during the first hour; the effect was magnified in IPS animals and most pronounced during proestrous. Solution intake in IPS rats was predicted by open arm entries in the elevated plus maze, suggesting that increased risk-taking behavior is associated with greater binge-like eating. IPS blocked conditioned suppression after 28 days of abstinence, pointing to a role of mid-adolescent stress in compulsivity. Collectively, these findings emphasize the impact of stress on the emergence of binge eating in females and suggest that intervention programs for women with a history of adolescent adversity should be investigated as a means to reduce risk for BED.

Comparative cognition and cognitive ecology in the classroom.

The scientific study of animal cognition has roots in both experimental psychology and evolutionary biology, with researchers often working in related disciplines such as neuroscience, computing science, or ecology. The interdisciplinary nature of the endeavor is both a strength and a challenge for the field. We begin this review with a brief history of comparative cognition and cognitive ecology, focusing on cognitive processes as a mechanistic link between ethology and behaviorism. We then present a "snapshot" of modern-day undergraduate courses in Canada, the United States of America, and the United Kingdom that focus on animal cognition, highlighting the various course names and host departments. We emphasize the value of keeping (or adding) this subject material within curricula, either as independent courses or as enhanced material in other courses. We also present pedagogical approaches to teaching animal cognition that include techniques in large lecture-based courses and in smaller courses that emphasize hands-on experiential learning. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Animal models in addiction research: A dimensional approach.

Drug addiction affects approximately 10% of the population and these numbers are rising. Treatment and prevention of addiction are impeded by current diagnostic systems, such as DSM-5, which are based on outcomes rather than processes. Here, we review the importance of adopting a dimensional framework, specifically the Research Domain Criteria (RDoC), to identify protective and vulnerability mechanisms in addiction. We discuss how preclinical researchers should work within this framework to develop animal models based on domains of function. We highlight RDoC paradigms related to addiction and discuss how these can be used to investigate the biological underpinnings of an addiction cycle (i.e., binge/intoxication, negative affect, and craving). Using this information, we then outline the critical role of animal research in ongoing revisions to the RDoC matrix (specifically the functional significance of domains, constructs and subconstructs) and its contribution to the development and refinement of addiction theories. We conclude with an overview of the contribution that animal research has made to the development of pharmacological and behavioural treatments for addiction.

Investigating dopamine and glucocorticoid systems as underlying mechanisms of anhedonia.

RATIONALE: Anhedonia, a deficit in reward processing, is an endophenotype of several neuropsychiatric conditions. Despite its prevalence and debilitating effects, treatments for anhedonia are lacking, primarily because its underlying mechanisms are poorly understood. Dopamine (DA) has been implicated in anhedonia through its role in reward-related learning; glucocorticoid systems may also be involved in that anhedonia is often preceded by chronic stress. OBJECTIVE: This study investigated DA and glucocorticoid systems in anhedonia using a rat version of the probabilistic reward task (PRT). METHODS: Adult male Wistar rats were trained on the PRT and then tested following: (1) activation or inhibition of DA activity induced by amphetamine (AMPH) or pramipexole (PRAMI) injections, (2) chronic mild stress (CMS), or (3) glucocorticoid system activation (dexamethasone (DEX)) or inhibition (mifepristone (MIFE)). RESULTS: AMPH increased and PRAMI decreased response bias, pointing to enhanced and diminished reward responsiveness with DA agonism and antagonism, respectively. CMS reduced response bias but only in a subpopulation of rats. DEX also decreased response bias, suggesting that glucocorticoid processes contribute to anhedonia, although glucocorticoid inhibition (MIFE) had no effect. None of the manipulations altered the ability to detect and respond to reward-paired stimuli. CONCLUSIONS: These results confirm a role of DA in anhedonia and elucidate the contribution of the glucocorticoid system to this effect. In addition, chronic stress may interfere with normal DA functioning, leading to impaired reward-related learning in some animals. These findings may direct future treatment of anhedonia by targeting DA and glucocorticoid systems, as well as a possible interaction between the two.

The lateral septum and anterior hypothalamus act in tandem to regulate burying in the shock-probe test but not open-arm avoidance in the elevated plus-maze.

Both the lateral septum (LS) and anterior hypothalamus (AHA) regulate behavioural defense. We tested whether those two interconnected structures act in serial in that regard. Infusions of the GABAA agonist muscimol into one side of the LS and the contralateral (but not ipsilateral) AHA suppressed rats' burying in the shock-probe test whereas none of our muscimol infusion approaches altered their open-arm avoidance in the elevated plus-maze. These results suggest that the LS-AHA circuit serves a specialized role in defensive responses towards discrete, localizable threat stimuli but not towards potential threats.