Multilevel assessment of the neurobiological threat system in depressed adolescents: Interplay between the limbic system and hypothalamic–pituitary–adrenal axis

AbstractIntegrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12–19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

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Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyab060 ◽

2021 ◽

Author(s):

Nadine M Melhem ◽

Yongqi Zhong ◽

Jeffrey M Miller ◽

Francesca Zanderigo ◽

R Todd Ogden ◽

...

Keyword(s):

High Risk ◽

Mood Disorder ◽

Receptor Binding ◽

Suicidal Behavior ◽

Social Stress ◽

Familial Risk ◽

Group Differences ◽

Degree Relative ◽

History Of ◽

Cortisol Responses

Abstract Background The serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior. Methods [ 11C]CUMI-101 PET imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high-risk for mood disorder or suicidal behavior on the basis of having a first or second degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk subjects were subdivided into: high-risk resilient having no mood disorder or suicidal behavior (HR-R, n=29); high-risk with mood disorder and no suicidal behavior history (HR-MOOD n=31); and high-risk with mood disorder and suicidal behavior (HR-SA/MOOD, n=25). Groups were compared to healthy volunteers without a family history of mood disorder or suicidal behavior (HV, n=34). Participants underwent the Trier Social Stress Task (TSST). All subjects were free from psychotropic medications at the time of the TSST and PET scanning. Results We observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all subjects and BPp in a subset of the sample), and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within HR-SA/MOOD, lower BPp binding [β=-0.084, Standard Error or SE=0.038, p=0.048] and higher cortisol reactivity to stress [β=9.25, 95% CI (3.27,15.23), p=0.004] were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes. Conclusions 5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how HPA axis function influences such risk.

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Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior

10.31234/osf.io/at7zj ◽

2021 ◽

Author(s):

Nadine Melhem ◽

Yongqi Zhong ◽

Jeffrey Miller ◽

Francesca Zanderigo ◽

R Todd Ogden ◽

...

Keyword(s):

High Risk ◽

Mood Disorder ◽

Receptor Binding ◽

Suicidal Behavior ◽

Social Stress ◽

Familial Risk ◽

Group Differences ◽

Risk And Resilience ◽

Degree Relative ◽

Cortisol Responses

Serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to risk and resilience for suicidal behavior. [11C]CUMI-101 PET imaging to quantify regional brain 5-HT1A receptor binding was conducted in high-risk individuals, having a first or second degree relative(s) with an early onset mood disorder and history of suicidal behavior, and subdivided into: high-risk resilient having no mood disorder or suicidal behavior (HR-R, n=29); high-risk with mood disorder (HR-MOOD n=31); and high-risk with mood disorder and suicidal behavior (HR-SA/MOOD, n=25). Groups were compared to healthy volunteers (HV, n=34). Participants underwent the Trier Social Stress Task (TSST). We observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND and BPp in a subset of the sample), and definitions of regions of interest (ROIs; standard or serotonin-specific ROIs). We also found no group differences on TSST outcomes. Within HR-SA/MOOD, lower BPp binding [=-0.084, Standard Error or SE=0.038, p=0.048] and higher cortisol reactivity to stress [=9.25, 95% CI (3.27,15.23), p=0.004] were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes. In conclusion, 5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how HPA axis function influences such risk.

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The Effects of Visual Displays in Attenuating Discrepancies Between Self-Reported and Physiological Indexes of Stress

European Journal of Psychological Assessment ◽

10.1027/1015-5759/a000587 ◽

2020 ◽

pp. 1-5

Author(s):

Jenny J. W. Liu ◽

Julia Gervasio ◽

Kenneth Fung ◽

Kristin Vickers

Keyword(s):

Social Stress ◽

Visual Display ◽

Physiological Measures ◽

Response Strategies ◽

Subjective Evaluations ◽

Stress Task ◽

Physiological Indexes ◽

Physiological Outcomes ◽

Physiological Markers ◽

The Relationship

Abstract. This study examined whether the relationship between subjective and physiological outcomes of stress, and the responsivity to stressors, are affected by whether participants can see a visual display of their physiological output. Participants were randomly assigned to have a visible view of their physiological output readings, or to a condition in which physiological output readings were out of view. Participants individually completed a 30-min laboratory study including the modified Trier Social Stress Task. Both physiological markers of stress (heart rate and blood pressure) and subjective evaluations of stress (visual analog scale) were measured. Results found little congruency across subjective and physiological measures of stress. The visible visual display condition had elevated physiological arousal, while no group differences were observed in self-reported stress. Findings from the study provide insight into the use of visual physiological displays and hold practical implications for both the measurement of stress in research, and the development of wearable technologies without accompanying response strategies.

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Childhood Adversities and Salivary Cortisol Responses to the Trier Social Stress Test: A Systematic Review of Studies Using the Children Trauma Questionnaire (CTQ)

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010029 ◽

2020 ◽

Vol 18 (1) ◽

pp. 29

Author(s):

Chuk Ling Julian Lai ◽

Daryl Yu Heng Lee ◽

Monique On Yee Leung

Keyword(s):

Salivary Cortisol ◽

Social Stress ◽

Stress Test ◽

Trier Social Stress Test ◽

Future Research ◽

Cortisol Response ◽

Childhood Adversities ◽

Social Stressors ◽

Childhood Trauma Questionnaire ◽

Cortisol Responses

Alteration in cortisol response to acute social stressors has been hypothesized to mediate childhood adversities (CA) and increased morbidity in adulthood. However, the evidence supporting an association between CA and cortisol response to social stressors is inconclusive. The present review addressed this issue by reviewing the literature on CA and cortisol response to acute social stressors, with a focus on studies with adolescents or adults, using the Childhood Trauma Questionnaire (CTQ) to assess CA, and examining salivary cortisol response to the Trier Social Stress Test (TSST). Systematic searches of relevant articles in PsycINFO, PubMed, Web of Science and ScienceDirect in February and March 2020 identified 12 articles including 1196 participants with mean ages ranging from 15.3 to 52.3 yrs. across studies. CTQ scores were significantly associated with cortisol response in 2 studies. In addition, the physical abuse and emotional neglect subscales were associated with cortisol response respectively in 2 separate studies. The lack of association between CA and cortisol response calls for more longitudinal studies, and the use of formal records of maltreatment or informant reports in future research to complement information collected by retrospective measures. In addition, increased attention to biological mechanisms other than that associated with the regulation of cortisol in explaining the connection between CA and psychiatry morbidity is warranted.

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HIV Infection Is Associated with Attenuated Frontostriatal Intrinsic Connectivity: A Preliminary Study

Journal of the International Neuropsychological Society ◽

10.1017/s1355617715000156 ◽

2015 ◽

Vol 21 (3) ◽

pp. 203-213 ◽

Cited By ~ 39

Author(s):

Jonathan C. Ipser ◽

Gregory G. Brown ◽

Amanda Bischoff-Grethe ◽

Colm G. Connolly ◽

Ronald J. Ellis ◽

...

Keyword(s):

Hiv Infection ◽

Brain Regions ◽

Group Differences ◽

Hiv Rna ◽

Functional Connections ◽

Intrinsic Connectivity ◽

Dorsolateral Prefrontal ◽

Independent Replication ◽

Subcortical Regions ◽

The Brain

AbstractHIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV – associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (<50 years, N=9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was also associated with reduced frontostriatal connectivity. In conclusion, our data indicate that HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV-associated dopaminergic abnormalities. These findings warrant independent replication in larger studies. (JINS, 2015, 21, 1–11)

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Comparison of the hypothalamic–pituitary–adrenal axis susceptibility upon single-dose i.m. depot versus long-acting i.v. triamcinolone acetonide therapy: a direct pharmacokinetic correlation

Journal of Endocrinology ◽

10.1677/joe.1.06991 ◽

2006 ◽

Vol 191 (2) ◽

pp. 491-496 ◽

Cited By ~ 8

Author(s):

Getu Abraham ◽

Fioralba Demiraj ◽

Fritz Rupert Ungemach

Keyword(s):

Triamcinolone Acetonide ◽

Plasma Concentrations ◽

Stress Axis ◽

Dihydrogen Phosphate ◽

Maximum Plasma ◽

Acth Challenge ◽

Cortisol Responses ◽

Baseline Values ◽

Cortisol Levels ◽

Long Acting

The effects of single injections of glucocorticoid (GC) depot suspension and of long-acting GC were studied in conscious dogs. Both the depot suspension GC triamcinolone-16,17-α-acetonide (TAA) and the long-acting triamcinolone acetonide-21-dihydrogen phosphate (TAA-DHP) decreased basal and ACTH-stimulated cortisol levels and in a specific time-dependent way. Before treatment, all dogs had normal basal and peak cortisol responses to ACTH challenge (13–15 and > 120 nmol/l at 1 h respectively). Intravenous TAA-DHP reduced cortisol levels for 12 h, i.m. TAA reduced cortisol levels as of 1.5 h and the effect lasted for at least 4 weeks. Both treatments blunted the peak response to ACTH. ACTH elevated cortisol levels to or above baseline values within 10 days following TAA-DHP treatment, but the TAA treatment suppressed an ACTH response for at least 4 weeks. Kinetic analysis of both the preparations demonstrated rapid absorption (tmax, 0.6–1.5 h) and low maximum plasma concentrations (peak Cmax, 2.99–5.51 nmol/l) of the steroids; indeed, the terminal half-life of TAA-DHP (13.9 ± 1.3 h) was very much shorter than that of TAA (125.9 ± 15.8 h). In addition, the mean residence time differed very much (11 vs 160 h for TAA-DHP and TAA respectively), in line with a delayed elimination of the depot compared with the long-acting formulation. Application of these TAA formulations needs careful evaluation for their surprisingly different effects on endocrine stress axis activity.

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Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804412115 ◽

2018 ◽

Vol 115 (43) ◽

pp. E10187-E10196 ◽

Cited By ~ 19

Author(s):

Michael A. van der Kooij ◽

Tanja Jene ◽

Giulia Treccani ◽

Isabelle Miederer ◽

Annika Hasch ◽

...

Keyword(s):

Glucose Metabolism ◽

Spatial Memory ◽

Chronic Stress ◽

High Glucose ◽

Social Stress ◽

Cognitive Impairments ◽

Memory Performance ◽

Dietary Treatment ◽

Metabolic Phenotype ◽

The Brain

Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, ∼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.

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Impaired cognitive performance under psycho-social stress in cannabis-dependent males is mediated by attenuated precuneus activity

10.1101/429951 ◽

2018 ◽

Author(s):

Weihua Zhao ◽

Kaeli Zimmermann ◽

Xinqi Zhou ◽

Feng Zhou ◽

Meina Fu ◽

...

Keyword(s):

Cognitive Performance ◽

Social Stress ◽

Mental Arithmetic ◽

Endocannabinoid System ◽

Impaired Performance ◽

Social Evaluative Threat ◽

Fmri Study ◽

Stress Task ◽

Stress Processing ◽

Stress Responsivity

AbstractBackgroundDeficient regulation of stress plays an important role in the escalation of substance use, addiction and relapse. Accumulating evidence suggests dysregulations in cognitive and reward-related processes and the underlying neural circuitry in cannabis dependence. However, despite the important regulatory role of the endocannabinoid system in the stress response, associations between chronic cannabis use and altered stress processing on the neural level have not been systematically examined.MethodsAgainst this background, the present functional magnetic resonance imaging (fMRI)study examined psycho-social stress processing in cannabis-dependent males (n = 28) and matched controls (n = 23) using an established stress-induction paradigm (Montreal Imaging Stress Task) that combines computerized (adaptive) mental arithmetic challenges with social evaluative threat.ResultsDuring psycho-social stress exposure, but not the no-stress condition, cannabis users demonstrated impaired performance relative to controls. In contrast, levels of experienced stress and cardiovascular stress responsivity did not differ from controls. Functional MRI data revealed that stress-induced performance deteriorations in cannabis users were accompanied by decreased precuneus activity and increased connectivity of this region with the dorsal medial prefrontal cortex.LimitationsOnly male cannabis-dependent users were examined, the generalizability in female users remains to be determined.ConclusionTogether, the present findings provide first evidence for exaggerated stress-induced cognitive performance deteriorations in cannabis users. The neural data suggest that deficient stress-related dynamics of the precuneus may mediate the deterioration of performance on the behavioral level.

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Reduction of Adrenocortiocotropic Hormone (ACTH) and Cortisol in Drug Addicts Treated by Acupuncture and Electrical Stimulation (AES)

The American Journal of Chinese Medicine ◽

10.1142/s0147291778000095 ◽

1978 ◽

Vol 06 (01) ◽

pp. 61-66 ◽

Cited By ~ 6

Author(s):

H. L. WEN ◽

W. K. K. HO ◽

H. K. WONG ◽

Z. D. MEHAL ◽

Y. H. NG ◽

...

Keyword(s):

Electrical Stimulation ◽

Cyclic Amp ◽

Drug Addicts ◽

Plasma Acth ◽

Heroin Addicts ◽

Cortisol Levels ◽

The Brain

Forty-two heroin addicts and 31 normal persons were examined for the effect of acupuncture and electrical stimulation (AES) on plasma ACTH, cortisol and cyclic-AMP levels. Both ACTH and cortisol levels were reduced significantly in the addicts after treatment whereas no such significant reduction was observed in the normals. Plasma cyclic-AMP level was not affected in either group. Taken together, results from the present study suggest that the mechanism of AES in the treatment of addiction may have a neuroendocrinological basis. This hypothesis is particularly attractive in view of the isolation of opiate-like peptides from the brain.

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