Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation

Early life stressors display a high universal prevalence and constitute a major public health problem. Prolonged psychoneurobiological alterations as sequelae of early life stress (ELS) could represent a developmental risk factor and mediate risk for disease, leading to higher physical and mental morbidity rates in later life. ELS could exert a programming effect on sensitive neuronal brain networks related to the stress response during critical periods of development and thus lead to enduring hyper- or hypo-activation of the stress system and altered glucocorticoid signaling. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the ten most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS even decades later (hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system and inflammation, oxidative stress, cardiovascular system, gut microbiome, sleep and circadian system, genetics, epigenetics, structural, and functional brain correlates). Although most findings back a causal relation between ELS and psychobiological maladjustment in later life, the precise developmental trajectories and their temporal coincidence has not been elucidated as yet. Future studies should prospectively investigate putative mediators and their temporal sequence, while considering the potentially delayed time-frame for their phenotypical expression. Better screening strategies for ELS are needed for a better individual prevention and treatment

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Noninvasive vagus nerve stimulation alters neural response and physiological autonomic tone to noxious thermal challenge.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output

High executive functioning is associated with reduced posttraumatic stress after trauma exposure among male U.S. military personnel

IntroductionEvidence suggests that executive function (EF) may play a key role in development of PTSD, possibly influenced by factors such as trauma type and timing. Since EF can be improved through intervention, it may be an important target for promoting resilience to trauma exposure. However, more research is needed to understand the relation between trauma exposure, EF, and PTSD. The goal of this study was to improve understanding of EF as a potential antecedent or protective factor for the development of PTSD among military personnel.MethodIn a cohort of U.S. Marines and Navy personnel (N = 1,373), the current study tested the association between exposure to traumatic events (pre-deployment and during deployment) and PTSD severity, and whether EF moderated these associations. Three types of pre-deployment trauma exposure were examined: cumulative exposure, which included total number of events participants endorsed as having happened to them, witnessed, or learned about; direct exposure, which included total number of events participants endorsed as having happened to them; and interpersonal exposure, which included total number of interpersonally traumatic events participants’ endorsed. EF was measured using the Penn Computerized Neurocognitive Battery.ResultsEF was associated with less PTSD symptom severity at pre-deployment, even when adjusting for trauma exposure, alcohol use, traumatic brain injury, and number of years in the military. EF also moderated the relation between cumulative trauma exposure and interpersonal trauma exposure and PTSD, with higher EF linked to a 20 and 33% reduction in expected point increase in PTSD symptoms with cumulative and interpersonal trauma exposure, respectively. Finally, higher pre-deployment EF was associated with reduced PTSD symptom severity at post-deployment, independent of deployment-related trauma exposure and adjusting for pre-deployment PTSD.ConclusionOur results suggest that EF plays a significant, if small role in the development of PTSD symptoms after trauma exposure among military personnel. These findings provide important considerations for future research and intervention and prevention, specifically, incorporating a focus on improving EF in PTSD treatment

Assessing Neuronal and Astrocyte Derived Exosomes From Individuals With Mild Traumatic Brain Injury for Markers of Neurodegeneration and Cytotoxic Activity.

Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aβ42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aβ40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI

A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease

Measuring Novel Antecedents of Mental Illness: The Questionnaire of Unpredictability in Childhood

Increasing evidence indicates that, in addition to poverty, maternal depression, and other well-established factors, unpredictability of maternal and environmental signals early in life influences trajectories of brain development, determining risk for subsequent mental illness. However, whereas most risk factors for later vulnerability to mental illness are readily measured using existing, clinically available tools, there are no similar measures for assessing early-life unpredictability. Here we validate the Questionnaire of Unpredictability in Childhood (QUIC) and examine its associations with mental health in the context of other indicators of childhood adversity (e.g., traumatic life events, socioeconomic status, and parenting quality). The QUIC was initially validated through administration to a cohort of adult females (N = 116) and then further refined in two additional independent cohorts (male Veterans, N = 95, and male and female adolescents, N = 175). The QUIC demonstrated excellent internal (α = 0.89) and test–retest reliability (r = 92). Scores on the QUIC were positively correlated with other prospective indicators of exposures to unpredictable maternal inputs in infancy and childhood (unpredictable maternal mood and sensory signals), and accuracy of recall also was confirmed with prospective data. Importantly, the QUIC predicted symptoms of anxiety, depression, and anhedonia in the three study cohorts, and these effects persisted after adjusting for other previously established risk factors. The QUIC, a reliable and valid self-report assessment of exposure to unpredictability in the social, emotional, and physical domains during early life, is a brief, comprehensive, and promising instrument for predicting risk for mental illness

Addendum: Exposure to unpredictability and mental health: Validation of the brief version of the Questionnaire of Unpredictability in Childhood (QUIC-5) in English and Spanish

This article is a correction to: Exposure to unpredictability and mental health: Validation of the brief version of the Questionnaire of Unpredictability in Childhood (QUIC-5) in English and Spanish by Lindert, N. G., Maxwell, M. Y., Liu, S. R., Stern, H. S., Baram, T. Z., Poggi Davis, E., Risbrough, V. B., Baker, D. G., Nievergelt, C. M., and Glynn, L. M. (2022). Front. Psychol. 13:971350. doi: 10.3389/fpsyg.2022.97135