Sleep measures as a predictor of suicidal ideation among high-risk adolescents.

Suicide is the second leading cause of death among youth aged 15-24 years. Identifying modifiable risk factors relevant to adolescents is crucial for suicide prevention. Sleep patterns have been linked to suicidality in adults, but lack sufficient study in youth. This ecological momentary assessment (EMA) study aimed to explore the relationship between objectively and subjectively measured sleep characteristics and next-day suicidal ideation in high-risk youth. We included 29 adolescents (12-18 years old) admitted to the inpatient psychiatric ward post-suicide attempt or due to suicidal intent within the previous month. We conducted objective (actigraphy) and subjective (sleep diary) sleep pattern assessments over ten consecutive days. Daily suicidal ideation was evaluated using a questionnaire based on the validated C-SSRS interview. A significant positive association was observed between sleep onset latency (SOL) and expressing a "death wish" the following day (OR = 1.06, 95% CI [1-1.11], p = .04), with each minute of longer SOL increased the risk for a death wish the following day by 6%. In addition, a marginally significant negative association was observed between total sleep time (TST) and expressing a "death wish" the following day (OR = 0.57, 95% CI [0.3-1.11], p = 0.1), with each one-hour decrease in objectively measured TST increasing the odds of a death wish by 43%. Our study highlights the interplay between sleep patterns and suicidal ideation, with SOL and TST playing a significant role that may function as proximal risk factors for suicidality and as a target for intervention while treating suicidal youth.

Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.

Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.

Aberrant Intrinsic Brain Network Functional Connectivity During a Face-Matching Task in Women Diagnosed With Premenstrual Dysphoric Disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is characterized by affective, cognitive, and physical symptoms, suggesting alterations at the brain network level. Women with PMDD demonstrate aberrant discrimination of facial emotions during the luteal phase of the menstrual cycle and altered reactivity to emotional stimuli. However, previous studies assessing emotional task-related brain reactivity using region-of-interest or whole-brain analysis have reported conflicting findings. Therefore, we utilized both region-of-interest task-reactivity and seed-voxel functional connectivity (FC) approaches to test for differences in the default mode network, salience network, and central executive network between women with PMDD and control participants during an emotional-processing task that yields an optimal setup for investigating brain network changes in PMDD. METHODS: Twenty-four women with PMDD and 27 control participants were classified according to the Daily Record of Severity of Problems. Participants underwent functional magnetic resonance imaging scans while completing the emotional face-matching task during the midfollicular and late-luteal phases of their menstrual cycle. RESULTS: No significant between-group differences in brain reactivity were found using region-of-interest analysis. In the FC analysis, a main effect of diagnosis was found showing decreased default mode network connectivity, increased salience network connectivity, and decreased central executive network connectivity in women with PMDD compared with control participants. A significant interaction between menstrual cycle phase and diagnosis was found in the central executive network for right posterior parietal cortex and left inferior lateral occipital cortex connectivity. A post hoc analysis revealed stronger FC during the midfollicular than the late-luteal phase of PMDD. CONCLUSIONS: Aberrant FC in the 3 brain networks involved in PMDD may indicate vulnerability to experience affective and cognitive symptoms of the disorder.

Examining the synergistic effects of a cognitive control video game and a home-based, self-administered non-invasive brain stimulation on alleviating depression: the DiSCoVeR trial protocol.

Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208.

Resting mononuclear cell NR3C1 and SKA2 expression levels predict blunted cortisol reactivity to combat training stress among elite army cadets exposed to childhood adversity.

Childhood adversity (CA) may alter reactivity to stress throughout life, increasing risk for psychiatric and medical morbidity, yet long-term correlates of milder CA levels among high functioning healthy adolescents are less studied. The current study examined the prevalence and impact of CA exposure among a cohort of healthy motivated elite parachute unit volunteers, prospectively assessed at rest and at the height of an intensive combat-simulation exposure. We found significantly reduced gene expression levels in resting mononuclear cell nuclear receptor, subfamily 3, member 1 (NR3C1), and its transactivator spindle and kinetochore-associated protein 2 (SKA2), that predict blunted cortisol reactivity to combat-simulation stress among CA exposed adolescents. Long-term alterations in endocrine immune indices, subjective distress, and executive functions persist among healthy high functioning adolescents following milder CA exposure, and may promote resilience or vulnerability to later real-life combat exposure.

The imprint of childhood adversity on emotional processing in high functioning young adults.

Adverse childhood experiences (ACEs) have been acknowledged as risk factors for increased mental health complications in adulthood, specifically increasing susceptibility to developing psychopathology upon exposure to trauma. Yet, little is known regarding the impact of mild ACEs on highly functioning population. In this study forty participants were selected from a group of 366 highly selected military parachute trainees using the self-report "childhood trauma questionnaire," and classified into two groups of 20 each, with and without ACEs. Behavioral measurements were obtained before and at the peak of an intensive combat training period, including anxiety, depression and executive function assessment. Functional MRI including a negative emotional face perception task was conducted at the first time point. Psychometric and cognitive measurements revealed higher levels of anxiety and depressive symptoms, and more difficulties in executive functioning in the ACE group at baseline. Slower reaction time to emotional faces presentation was found in the ACE group. Lower activation in response to negative emotional faces stimuli was found in this group in bilateral secondary visual areas, left anterior insula, left parietal cortex and left primary motor and sensory regions. In contrast, higher activation in the ACE group was found in the right ventral lateral prefrontal cortex (Vlpfc). No significant differences between groups were detected in the amygdala. To conclude, mild adverse childhood experiences produce long-term sequela on psychological wellbeing and neurocircuitry even in high functioning population. Brain regions modulated by childhood trauma may instigate avoidance mechanisms dampening the emotional and cognitive effects of intensive stress.

Trait-related changes in brain network topology in premenstrual dysphoric disorder.

The female predominance in the prevalence of depression is partially accounted by reactivity to hormonal fluctuations. Premenstrual dysphoric disorder (PMDD) is a reproductive subtype of depression characterized by cyclic emotional and somatic symptoms that recur before menstruation. Despite the growing understanding that most psychiatric disorders arise from dysfunctions in distributed brain circuits, the brain's functional connectome and its network properties of segregation and integration were not investigated in PMDD. To this end, we examined the brain's functional network organization in PMDD using graph theoretical analysis. 24 drug naïve women with PMDD and 27 controls without premenstrual symptoms underwent 2 resting-state fMRI scans, during the mid-follicular and late-luteal menstrual cycle phases. Functional connectivity MRI, graph theory metrics, and levels of sex hormones were computed during each menstrual phase. Altered network topology was found in PMDD across symptomatic and remitted stages in major graph metrics (characteristic path length, clustering coefficient, transitivity, local and global efficiency, centrality), indicating decreased functional network segregation and increased functional network integration. In addition, PMDD patients exhibited hypoconnectivity of the anterior temporal lobe and hyperconnectivity of the basal ganglia and thalamus, across menstrual phases. Furthermore, the relationship between difficulties in emotion regulation and PMDD was mediated by specific patterns of functional connectivity, including connections of the striatum, thalamus, and prefrontal cortex. The shifts in the functional connectome and its topology in PMDD may suggest trait vulnerability markers of the disorder.

Elevated salivary uric acid levels among adolescents with eating disorders.

OBJECTIVE: Uric acid (UA) is increasingly recognized as having important physiological roles and associated with several peripheral and central pathophysiological outcomes, and might play a role in eating disorders (ED) pathogenesis. We investigated whether UA levels are altered among adolescents with ED. METHODS: Morning salivary UA concentrations were compared between adolescents referred to treatment at the Herman Dana Center receiving a DSM-V diagnosis of an ED and matched healthy controls. RESULTS: Salivary UA was significantly elevated among ED compared with control values (ED mean 3.9 ± 1.2 mg/dl, control mean 2.9 ± 1.9 mg/dl, t = - 3.13 df = 81, p = 0.003). DISCUSSION: Salivary UA is elevated among adolescents with ED. Further studies are required to replicate and extend this finding and evaluate its generalizability as a state or trait marker as regards ED subtypes, other body fluids (plasma and cerebrospinal fluid), and recovery or premorbid stages, as well as its putative mechanistic relevance to ED. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Sex differences during emotion processing are dependent on the menstrual cycle phase.

Sex differences in the neural processing of emotion are of special interest considering that mood and anxiety disorders predominant in females. However, these sex-related differences were typically studied without considering the hormonal status of female subjects, although emotion processing in the brain was shown to differ between phases of the menstrual cycle. In this functional MRI study, we demonstrated the influence of the menstrual cycle phase on sex differences in brain activity and functional connectivity during negative and positive emotions, using two different paradigms: emotion perception and emotion experience. Twenty naturally cycling healthy women without premenstrual symptoms were scanned twice: during the mid-follicular and late-luteal menstrual phases, and compared to a matched group of twenty healthy men. During negative emotion perception, men showed increased neural activity in the right hippocampal formation relative to women in the mid-follicular phase, and increased activity in the right cerebellum relative to women in the late-luteal phase. During experience of amusement, reduced putamen-ventrolateral prefrontal cortex and putamen-dorsomedial prefrontal cortex functional connectivity were observed for women in the late-luteal phase relative to men and associated with levels of sex hormones. These neural and hormonal findings were complemented by behavioral reports of reduced amusement and increased sadness in late-luteal women. Our results demonstrate menstrual phase-dependent sex differences in emotion perception and experience and may suggest a biological tendency for a deficient experience of pleasure and reward during the late-luteal phase. These findings may further shed light on the underlying pathophysiology of premenstrual dysphoric disorder.

Long-Term Immune Alterations Accompanying Chronic Posttraumatic Stress Disorder following Exposure to Suicide Bomb Terror Incidents during Childhood.

BACKGROUND AND AIM: Long-term immune alterations have been proposed to play a mechanistic role in posttraumatic stress disorder (PTSD) as well as in its associated increase in medical morbidity and mortality. Better characterization of altered immune function may help identify diagnostic and prognostic biomarkers and potentially targets for preventive intervention. METHODS: As part of an ongoing study, we conducted a preliminary case-control comparison of resting immune inflammatory profiles between terror victims treated in childhood at the emergency department over the previous decade, who developed chronic PTSD upon long-term follow-up, and healthy controls. RESULTS: Our preliminary results in a subsample of this ongoing study support and extend elevated resting levels of granulocyte colony-stimulating factor, interleukin-4, and regulated on activation, normal T cell expressed and secreted in childhood onset chronic PTSD. CONCLUSION: Chronic immune alterations may participate in inflammatory activation and signal to the CNS through the neurovascular unit, as well as modulate the neuroendocrine axis. Better characterization and understanding of these preliminary findings may point to diagnostic and prognostic biomarkers and potentially elucidate mechanistic involvement of immune activation in PTSD.

Emotional regulation difficulties and premenstrual symptoms among Israeli students.

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) reported to affect 3-8 % of women of reproductive age and resulting in marked emotional and occupational impairment. Despite its prevalence, the etiology of PMDD is largely unknown, and patients remain mostly undiagnosed and poorly treated. It has been suggested that PMDD is a manifestation of underlying depressive disorder which is associated with the inability to regulate emotions in an adaptive manner. Therefore, we hypothesized that women with PMDD would exhibit increased difficulty with emotional regulation. A total of 648 female Israeli college students were assessed by the Premenstrual Symptoms Screening Tool (PSST) and the Difficulties in Emotion Regulation Scale (DERS). Of these women, 166 (25.6 %) met the criteria for PMS. Sixty-four (9.9 %) suffered from PMDD. More emotion regulation deficits were observed in the PMDD and PMS groups compared to the control group. Furthermore, there were more emotional regulation deficits among the predominantly psychological and mixed symptom subtype compared to the predominantly physical symptom subtype group. This is the first study to report an association between emotional dysregulation and PMDD. These findings may lead to development of more individually tailored treatment protocols focused on improving emotional regulation techniques.

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part II: the adrenergic response.

The aim of the study was to prospectively evaluate the association between the occurrence of post-traumatic stress disorder (PTSD) and the adrenergic response to the traumatic event, and additionally, to explore the link between PTSD and the initial norepinephrine:cortisol ratio. Plasma levels and urinary excretion of norepinephrine (NE) were measured in 155 survivors of traumatic events during their admission to a general hospital emergency room (ER) and at 10 d, 1 month and 5 months later. Symptoms of peri-traumatic dissociation, PTSD and depression were assessed in each follow-up session. The Clinician-Administered PTSD Scale (CAPS) conferred a diagnosis of PTSD at 5 months. Trauma survivors with (n=31) and without (n=124) PTSD had similar levels of plasma NE, urinary NE excretion, and NE:cortisol ratio in the ER. Plasma NE levels were lower in subjects with PTSD at 10 d, 1 month, and 5 months. There was a weak but significant positive correlation between plasma levels of NE in the ER and concurrent heart rate, and a negative correlation between NE in the ER and dissociation symptoms. Peripheral levels of NE, shortly after traumatic events, are poor risk indicators of subsequent PTSD among civilian trauma victims. Simplified biological models may not properly capture the complex aetiology of PTSD.

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses.

The aim of the study was to evaluate the association between post-traumatic disorder (PTSD) and hypothalamic-pituitary-adrenal (HPA) axis responses to the triggering trauma. A companion paper evaluates the adrenergic response and interactions between the two. We measured plasma and saliva cortisol, hourly urinary excretion of cortisol, plasma levels of adrenocorticotropin (ACTH), and the leukocyte glucocorticoid receptor (GR) density of 155 non-injured survivors of traumatic events (91 males and 64 females; 125 road traffic accidents, 19 terrorist attacks, 11 others). Measurements were taken during survivors' admissions to an emergency room (ER) of a general hospital, and in the mornings, 10 d, 1 month, and 5 months later. Symptoms of peri-traumatic dissociation, PTSD, and depression were assessed on each follow-up session. The clinician-administered PTSD scale (CAPS) conferred a diagnosis of PTSD at 5 months. Survivors with (n=31) and without (n=124) PTSD at 5 months had similar levels of hormones at all times. Plasma cortisol levels decreased with time in both groups. Female subjects had lower ACTH levels than males. PTSD in females was associated with higher levels of ACTH. In unselected cohorts of trauma survivors, PTSD is not preceded by a detectable abnormality of peripheral HPA axis hormones.

Commentary: biological findings in PTSD -- too much or too little?

Summarizing the contributions in this section of the book, this chapter addresses questions regarding the complex etiology of PTSD, and the relative strength of discernable biological indicators of the disorder. It outlines two major approaches to exploring the biology of the disorder and discusses the reason for the many non-replications of findings. It defines the constructs of multicausality, equifinality, and multifinality, and evaluates their main implication for studies of PTSD, namely that no biological signal can be properly appraised without taking into account its context. Such context, in PTSD, includes both concurring biological systems and regulatory mechanisms, and environmental-psychosocial input. Studies of gene expression of PTSD exemplify one way of studying the context of putative biological signals. The role of biological alterations as templates for responding to psychosocial challenges is discussed.

Basic mechanisms of augmentation of antidepressant effects with thyroid hormone.

The thyroid hormone triiodothyronine (T3) has been used both to augment and accelerate the clinical effects of antidepressants, particularly the tricyclics. More recent work indicates that it may have similar actions with regard to the SSRIs. Two main mechanisms have been put forward to explain its antidepressant actions, (a) an action at the nuclear level involving stimulation of gene transcription, (b) an action at the cell membrane level involving potentiation of neurotransmission. In particular, there is considerable evidence for potentiation by T3 of the actions of the neurotransmitter 5-HT or serotonin. This evidence, which is mainly based on in vivo microdialysis studies, is reviewed, and evidence based on human and animal neuroendocrine studies considered. The effects of T3, alone and together with the SSRI fluoxetine, on mRNA levels for the 5-HT1A and 5-HT1B autoreceptors, which mediate serotonergic neurotransmission by feedback actions at the levels of cell firing(somatodendritic 5-HT1A autoreceptors) and neurotransmitter release (nerve terminal 5-HT1B autoreceptors) were also determined. Administration of a combination of fluoxetine and T3 induced reductions in the transcription of these autoreceptors, which may explain the clinical potentiating effects of this combination, and thus link the nuclear and neurotransmitter hypotheses of T3 action.

Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.

The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been shown that the polymorphic repeat polymorphism in the 5-HTT promotor region (5-HTTLPR) may affect gene-transcription activity. 5-HTT maps to chromosome 17 at position 17q11.17-q12, and the 5-HTTLPR polymorphisms have been extensively investigated in AD with conflicting results. The present study tested the genetic contribution of the 5-HTTLPR polymorphism in a large European multicenter case-control sample, including 539 unipolar (UPAD), 572 bipolar patients (BPAD), and 821 controls (C). Our European collaboration has led to efforts to optimize a methodology that attenuates some of the major limitations of the case-control association approach. No association was found with primary psychiatric diagnosis (UPAD and BPAD) and with phenotypic traits (family history of AD, suicidal attempt, and presence of psychotic features). Our negative findings are not attributable to the lack of statistical power, and may contribute to clarify the role of 5-HTTLPR polymorphism in AD.

[Emotional distress in Israeli medical students].

INTRODUCTION: Increased distress in medical students has been previously documented. However, causal relationship between putative, nh stress factors and emotional state has not yet been determined. Moreover, most data concerning mental health of medical students has been acquired in the USA. METHODS: A list of conceivable stress factors and the Brief Symptom Inventory were used to identify specific loci of stress and examine levels of distress among first, third and fifth year Israeli medical students. RESULTS: Levels of mental distress in all subjects were higher than population norms, with the highest levels in the third (of six) year of Medical Faculty. Predefined stress factors were capable of accounting for most of the variance in medical student distress, although specific factors differed between year and gender. CONCLUSIONS: Considering medical students' reluctance to utilize mental health services, the attempt to modify stress-eliciting elements inherent to the Medical Faculty environment is particularly warranted.

Prospective evaluation of plasma cortisol in recent trauma survivors with posttraumatic stress disorder.

Hypothalamic pituitary adrenal axis abnormalities have been described in posttraumatic stress disorder (PTSD), and among the recently traumatized. Plasma cortisol and continuous measures of PTSD symptoms were obtained from 21 survivors, at 1 week and 6 months after traumatic events. Eight survivors met Clinician Administered PTSD Scale criteria for PTSD at 6 months. Cortisol levels at 1 week did not predict subsequent PTSD. Survivors with and without PTSD had similar mean levels of cortisol at both time points. Cortisol levels at 6 months negatively correlated with self-reported PTSD symptoms within PTSD subjects.