RESUMEN
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
Asunto(s)
Personal Militar , Trastornos por Estrés Postraumático , Proteínas Adaptadoras Transductoras de Señales/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenoma , Humanos , Sistema Inmunológico , Masculino , Estrés Oxidativo/genética , Trastornos por Estrés Postraumático/genéticaRESUMEN
OBJECTIVES: Data from neurocognitive assessments may not be accurate in the context of factors impacting validity, such as disengagement, unmotivated responding, or intentional underperformance. Performance validity tests (PVTs) were developed to address these phenomena and assess underperformance on neurocognitive tests. However, PVTs can be burdensome, rely on cutoff scores that reduce information, do not examine potential variations in task engagement across a battery, and are typically not well-suited to acquisition of large cognitive datasets. Here we describe the development of novel performance validity measures that could address some of these limitations by leveraging psychometric concepts using data embedded within the Penn Computerized Neurocognitive Battery (PennCNB). METHODS: We first developed these validity measures using simulations of invalid response patterns with parameters drawn from real data. Next, we examined their application in two large, independent samples: 1) children and adolescents from the Philadelphia Neurodevelopmental Cohort (n = 9498); and 2) adult servicemembers from the Marine Resiliency Study-II (n = 1444). RESULTS: Our performance validity metrics detected patterns of invalid responding in simulated data, even at subtle levels. Furthermore, a combination of these metrics significantly predicted previously established validity rules for these tests in both developmental and adult datasets. Moreover, most clinical diagnostic groups did not show reduced validity estimates. CONCLUSIONS: These results provide proof-of-concept evidence for multivariate, data-driven performance validity metrics. These metrics offer a novel method for determining the performance validity for individual neurocognitive tests that is scalable, applicable across different tests, less burdensome, and dimensional. However, more research is needed into their application.
Asunto(s)
Benchmarking , Simulación de Enfermedad , Adulto , Adolescente , Niño , Humanos , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados , Pruebas de Estado Mental y Demencia , Psicometría , Simulación de Enfermedad/diagnósticoRESUMEN
Increasing evidence indicates that inflammation plays a role in PTSD and stress disorder pathophysiology. PTSD is consistently associated with higher circulating inflammatory protein levels. Rodent models demonstrate that inflammation promotes enduring avoidance and arousal behaviors after severe stressors (e.g., predator exposure and social defeat), suggesting that inflammation may play a mechanistic role in trauma disorders. C-reactive protein (CRP) is an innate acute phase reactant produced by the liver after acute infection and chronic disease. A growing number of investigations report associations with PTSD diagnosis and elevated peripheral CRP, CRP gene mutations, and CRP gene expression changes in immune signaling pathways. CRP is reasonably established as a potential marker of PTSD and trauma exposure, but if and how it may play a mechanistic role is unclear. In this review, we discuss the current understanding of immune mechanisms in PTSD with a particular focus on the innate immune signaling factor, CRP. We found that although there is consistent evidence of an association of CRP with PTSD symptoms and risk, there is a paucity of data on how CRP might contribute to CNS inflammation in PTSD, and consequently, PTSD symptoms. We discuss potential mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other innate immune signaling factors in modulating trauma responses. Overall, we found that CRP likely contributes to central inflammation, but how it does so is an area for further study.
Asunto(s)
Proteína C-Reactiva , Trastornos por Estrés Postraumático , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Trastornos por Estrés Postraumático/diagnósticoRESUMEN
BACKGROUND: Recent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early-life adversity. Early-life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self-reported early-life unpredictability is associated with psychiatric symptoms in adult clinical populations. METHODS: Using the newly validated Questionnaire of Unpredictability in Childhood, we assessed early-life unpredictability in 156 trauma-exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early-life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6-month period were determined. RESULTS: Early-life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early-life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms. CONCLUSIONS: Early-life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology.
Asunto(s)
Anhedonia , Trastornos por Estrés Postraumático , Adulto , Animales , Ansiedad , Trastornos de Ansiedad , Emociones , Humanos , Trastornos por Estrés Postraumático/psicologíaRESUMEN
Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained cognitive impairment in military service members and Veterans. However, the mechanism of persistent cognitive deficits including working memory (WM) dysfunction is not fully understood in mTBI. Few studies of WM deficits in mTBI have taken advantage of the temporal and frequency resolution afforded by electromagnetic measurements. Using magnetoencephalography (MEG) and an N-back WM task, we investigated functional abnormalities in combat-related mTBI. Study participants included 25 symptomatic active-duty service members or Veterans with combat-related mTBI and 20 healthy controls with similar combat experiences. MEG source-magnitude images were obtained for alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and low-frequency (1-7 Hz) bands. Compared with healthy combat controls, mTBI participants showed increased MEG signals across frequency bands in frontal pole (FP), ventromedial prefrontal cortex, orbitofrontal cortex (OFC), and anterior dorsolateral prefrontal cortex (dlPFC), but decreased MEG signals in anterior cingulate cortex. Hyperactivations in FP, OFC, and anterior dlPFC were associated with slower reaction times. MEG activations in lateral FP also negatively correlated with performance on tests of letter sequencing, verbal fluency, and digit symbol coding. The profound hyperactivations from FP suggest that FP is particularly vulnerable to combat-related mTBI.
Asunto(s)
Conmoción Encefálica/fisiopatología , Conmoción Encefálica/psicología , Encéfalo/fisiopatología , Trastornos de Combate/patología , Trastornos de Combate/fisiopatología , Memoria a Corto Plazo/fisiología , Adulto , Conmoción Encefálica/etiología , Ondas Encefálicas , Trastornos de Combate/complicaciones , Humanos , Magnetoencefalografía , Masculino , Pruebas Neuropsicológicas , VeteranosRESUMEN
Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity, mortality, and health care costs, and are predicted to reach epidemic proportions with the aging population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-directional. Accordingly, a VA-sponsored conference entitled "Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium" was convened to explore potential relationships and common biological pathways between PTSD and HF. The conference was framed around the hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification of both disease processes. The conference was not intended to identify all independent pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and biological mediators that would be modifiable in both disease processes. The results from this conference identified specific endocrine, autonomic, immune, structural, genetic, and physiological changes that may contribute to shared PTSD-CVD pathophysiology and could represent unique opportunities to develop therapies for both PTSD and HF. Some recommendations from the group for future research opportunities are provided.
Asunto(s)
Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Trastornos por Estrés Postraumático/complicaciones , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Anciano , Encéfalo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos por Estrés Postraumático/psicología , Estados Unidos , United States Department of Veterans Affairs , Veteranos/psicologíaRESUMEN
Contextual threat learning reflects two often competing processes: configural and elemental learning. Configural threat learning is a hippocampal-dependent process of forming a conjunctive representation of a context through binding of several multi-modal elements. In contrast, elemental threat-learning is governed by the amygdala and involves forming associative relationships between individual features within the context. Contextual learning tasks in humans however, rarely probe if a learned fear response is truly due to configural learning vs. simple elemental associations. The aim of the current study was to probe both constructs separately to enable a more refined interpretation of configural vs. elemental threat learning performance and mediating circuits. Subjects (nâ¯=â¯25) performed both a novel feature-identical contextual threat conditioning task and a discrete cue threat acquisition task while undergoing functional magnetic resonance imaging. Results demonstrated increased hippocampus activity for the threat configuration compared to the safe configuration. This pattern was not observed in the amygdala. In contrast, elemental threat learning was associated with increased amygdala, but not hippocampus activity. Whole-brain analyses revealed that both configural and elemental threat acquisition share neural circuitry related to fear expression. These results provide support for the importance of the hippocampus specifically in configural threat acquisition and fear expression.
Asunto(s)
Amígdala del Cerebelo/fisiología , Aprendizaje por Asociación/fisiología , Miedo/fisiología , Hipocampo/fisiología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Femenino , Respuesta Galvánica de la Piel/fisiología , Hipocampo/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma. METHODS: Male Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points. RESULTS: Before deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals. CONCLUSIONS: These findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.
Asunto(s)
Adultos Sobrevivientes de Eventos Adversos Infantiles , Catecol O-Metiltransferasa/genética , Condicionamiento Psicológico/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Interacción Gen-Ambiente , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Humanos , Masculino , Personal Militar , Polimorfismo Genético , Adulto JovenRESUMEN
BACKGROUND: It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change. METHODS: Eight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale. RESULTS: Individuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis. CONCLUSIONS: Deployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.
Asunto(s)
Lesiones Traumáticas del Encéfalo/fisiopatología , Miedo/fisiología , Aprendizaje/fisiología , Personal Militar/estadística & datos numéricos , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Humanos , Masculino , Estudios Prospectivos , Trastornos por Estrés Postraumático/etiología , Adulto JovenRESUMEN
BACKGROUND: Heightened startle response is a symptom of PTSD, but evidence for exaggerated startle in PTSD is inconsistent. This prospective study aimed to clarify whether altered startle reactivity represents a trait risk-factor for developing PTSD or a marker of current PTSD symptoms. METHODS: Marines and Navy Corpsmen were assessed before (n = 2,571) and after (n = 1,632) deployments to Iraq or Afghanistan with the Clinician-Administered PTSD Scale (CAPS). A predeployment startle-threshold task was completed with startle probes presented over 80-114 dB[A] levels. Latent class mixture modeling identified three growth classes of startle performance: "high," "low," and "moderate" threshold classes. Zero-inflated negative binomial regression was used to assess relationships between predeployment startle threshold and pre- and postdeployment psychiatric symptoms. RESULTS: At predeployment, the low-threshold class had higher PTSD symptom scores. Relative to the moderate-threshold class, low-threshold class membership was associated with decreased likelihood of being symptom-free at predeployment, based on CAPS, with particular associations with numbing and hyperarousal subscales, whereas high-threshold class membership was associated with more severe predeployment PTSD symptoms, in particular avoidance. Associations between low-threshold membership and CAPS symptoms were independent from measures of trauma burden, whereas associations between high-threshold membership and CAPS were not. Predeployment startle threshold did not predict postdeployment symptoms. CONCLUSIONS: This study found that both low startle threshold (heightened reactivity) and high startle threshold (blunted reactivity) were associated with greater current PTSD symptomatology, suggesting that startle reactivity is associated with current PTSD rather than a risk marker for developing PTSD.
Asunto(s)
Personal Militar/estadística & datos numéricos , Reflejo de Sobresalto/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Trastornos por Estrés Postraumático/epidemiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Deficits in sensorimotor gating have been hypothesized to underlie the inability to inhibit repetitive thoughts and behaviors. To test this hypothesis, this study assessed prepulse inhibition (PPI), a measure of sensorimotor gating, across three psychiatric disorders (obsessive-compulsive disorder [OCD], social anxiety disorder [SAD], and anorexia nervosa [AN]) whose clinical presentations include repetitive thoughts and behaviors METHODS: We tested acoustic PPI in unmedicated individuals with OCD (n = 45), SAD (n = 37), and AN (n = 26), and compared their results to matched healthy volunteers (n = 62). All participants completed a structured clinical interview and a clinical assessment of psychiatric symptom severity. RESULTS: Percent PPI was significantly diminished in females with OCD compared to healthy female volunteers (P = .039). No other differences between healthy volunteers and participants with disorders (male or female) were observed. Percent PPI was not correlated with severity of obsessions and compulsions, as measured by the Yale-Brown Obsessive Compulsive Scale. CONCLUSIONS: This is the first study to assess PPI in participants with SAD or AN, and the largest study to assess PPI in participants with OCD. We found PPI deficits only in females with OCD, which suggests that the cortico-striato-pallido-thalamic and pontine circuitry (believed to underlie PPI) differs between males and females with OCD. Given that PPI deficits were only present in females with OCD and not related to repetitive thoughts and behaviors, our results do not support the hypothesis that sensorimotor gating deficits, as measured by PPI, underlie the inability to inhibit repetitive thoughts and behaviors in individuals with OCD, SAD, and AN.
Asunto(s)
Anorexia Nerviosa/fisiopatología , Trastorno Obsesivo Compulsivo/fisiopatología , Fobia Social/fisiopatología , Inhibición Prepulso/fisiología , Adulto , Femenino , Humanos , Masculino , Factores Sexuales , Adulto JovenRESUMEN
OBJECTIVE: To examine whether cause, severity, and frequency of traumatic brain injury (TBI) increase risk of postdeployment tinnitus when accounting for comorbid posttraumatic stress disorder. DESIGN: Self-report and clinical assessments were done before and after an "index" deployment to Iraq or Afghanistan. SETTING, PARTICIPANTS, AND MEASURES: Assessments took place on Marine Corps bases in southern California and the VA San Diego Medical Center. Participants were 1647 active-duty enlisted Marine and Navy servicemen who completed pre- and postdeployment assessments of the Marine Resiliency Study. The main outcome was the presence of tinnitus at 3 months postdeployment. RESULTS: Predeployment TBI increased the likelihood of new-onset postdeployment tinnitus (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.28-2.70). Deployment-related TBIs increased the likelihood of postdeployment tinnitus (OR = 2.65; 95% CI, 1.19-5.89). Likelihood of new-onset postdeployment tinnitus was highest for those who were blast-exposed (OR = 2.93; 95% CI, 1.82-6.17), who reported moderate-severe TBI symptoms (OR = 2.22; 95% CI, 1.22-3.40), and who sustained multiple TBIs across study visits (OR = 2.27; 95% CI, 1.44-4.24). Posttraumatic stress disorder had no effect on tinnitus outcome. CONCLUSIONS: Participants who were blast-exposed, sustained multiple TBIs, and reported moderate-severe TBI symptoms were most at risk for new-onset tinnitus.
Asunto(s)
Lesiones Encefálicas/complicaciones , Personal Militar , Acúfeno/etiología , Traumatismos por Explosión/complicaciones , Humanos , Masculino , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Estados Unidos , Guerra , Adulto JovenRESUMEN
Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination.
Asunto(s)
Condicionamiento Clásico/fisiología , Miedo/fisiología , Aprendizaje/fisiología , Sueño REM/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Femenino , Humanos , Masculino , Trastornos por Estrés Postraumático/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. METHODS: In the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice. RESULTS: Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating. CONCLUSIONS: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion.
Asunto(s)
Acatisia Inducida por Medicamentos/fisiopatología , Antagonistas de Aminoácidos Excitadores/toxicidad , Neuronas GABAérgicas/fisiología , Ketamina/toxicidad , Prosencéfalo/fisiopatología , Factor de Transcripción Sp4/metabolismo , Animales , Estudios de Cohortes , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Masculino , Ratones de la Cepa 129 , Ratones Transgénicos , Prosencéfalo/efectos de los fármacos , Filtrado Sensorial/fisiología , Factor de Transcripción Sp4/genéticaRESUMEN
BACKGROUND: Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity. One compound that has generated interest in this regard is oxytocin (OT), a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes. Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance, supporting its potential to augment exposure-based psychotherapy. Here, we tested the hypothesis that OT treatment would facilitate response to exposure therapy in patients with specific phobia. METHODS: We conducted a small proof-of-concept trial investigating the effect of pretreatment intranasal OT administration on a brief, single-session exposure treatment for arachnophobia (fear of spiders). The study was randomized, double-blind, and placebo controlled (n = 13 placebo, 11 females; n = 10 OT, 8 females) with 1-week and 1-month follow-up assessments. Dependent measures attended to arachnophobia symptoms (self-report), phobic behavior (behavioral avoidance of spider task), and treatment credibility/therapeutic alliance. RESULTS: Administration of OT prior to exposure therapy tended to impede treatment response as measured by self-report of symptoms at both follow-up periods. OT treatment did not significantly affect behavioral measures of fear. Immediately after OT administration but before therapy, the OT group trended toward less confidence in the treatment. The OT group also trended toward lower ratings of therapeutic alliance than placebo. CONCLUSIONS: These results suggest that OT administration effects on extinction may vary depending on conditions and population.
Asunto(s)
Terapia Implosiva , Oxitocina/administración & dosificación , Trastornos Fóbicos/terapia , Administración Intranasal , Adulto , Animales , Terapia Combinada , Método Doble Ciego , Miedo/efectos de los fármacos , Femenino , Humanos , Masculino , Procesos Mentales , Persona de Mediana Edad , Premedicación , Arañas , Resultado del TratamientoRESUMEN
Obese individuals develop heightened reactivity to environmental cues associated with hedonic foods through Pavlovian conditioning. This study examined differences between overweight (n = 16) and lean (n = 17) 18-26 year-olds in their acquisition of a swallowing response to visual cues paired with chocolate milk, tasteless water and no taste stimulus. We hypothesized that, compared to lean participants, overweight participants would demonstrate a heightened conditioned swallowing response to the visual cue paired with chocolate milk as well as a resistance to extinction of this response. Results showed that overweight participants swallowed more in response to the visual cue previously paired with chocolate than the cue previously paired with tasteless water (t(15) = -3.057, p = .008) while lean participants showed no cue discrimination (t(16) = -1.027, p = .320). The results evaluating the extinction hypothesis could not be evaluated, as the lean participants did not acquire a conditioned response. In evaluating the conditioned swallow response of overweight participants only, results indicated that there was not a significant decrease in swallowing to cues paired with chocolate milk or water, but overall, overweight participants swallowed more to cues paired with chocolate than cues paired with water. These are the first results to show differential acquisition of Pavlovian conditioned responding in overweight individuals compared to lean individuals, as well as differential conditioning to cues paired with hedonic food stimuli compared to cues paired with neutral stimuli.
Asunto(s)
Condicionamiento Clásico , Señales (Psicología) , Deglución , Obesidad/etiología , Placer , Refuerzo en Psicología , Gusto , Adulto , Cacao , Extinción Psicológica , Femenino , Alimentos , Preferencias Alimentarias/psicología , Humanos , Masculino , Obesidad/psicología , Sobrepeso , Agua , Adulto JovenRESUMEN
OBJECTIVE: Heart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression. METHODS: Four battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively. RESULTS: When adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (ß = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033). CONCLUSIONS: This cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.
Asunto(s)
Lesiones Encefálicas/epidemiología , Trastorno Depresivo/epidemiología , Frecuencia Cardíaca/fisiología , Personal Militar/estadística & datos numéricos , Trastornos por Estrés Postraumático/epidemiología , Análisis de Varianza , Sistema Nervioso Autónomo/fisiopatología , Lesiones Encefálicas/fisiopatología , Cafeína/administración & dosificación , Factores de Confusión Epidemiológicos , Estudios Transversales , Trastorno Depresivo/fisiopatología , Humanos , Masculino , Personal Militar/psicología , Nicotina/administración & dosificación , Fotopletismografía/métodos , Escalas de Valoración Psiquiátrica , Análisis de Regresión , Índice de Severidad de la Enfermedad , Trastornos por Estrés Postraumático/fisiopatología , Adulto JovenRESUMEN
High titers of anti-NMDAR1 autoantibodies in human brain cause anti-NMDAR1 encephalitis, a rare disease that displays a variety of psychiatric symptoms and neurological symptoms. Currently, immunohistochemical staining and cell-based assays are the standard methods for detection and semi-quantification of the anti-NMDAR1 autoantibodies. Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background from less diluted serum/plasma. Development of a new method to quantify these low titers of blood anti-NMDAR1 autoantibodies is necessary to understand their potential impacts on psychiatric symptoms and cognition. Based on our previous One-Step assay, we report the development of a novel simple immunoassay to quantify cross-species blood anti-NMDAR1 autoantibodies, and its validation with immunohistochemistry and cell-based assays in both humans and mice.
RESUMEN
Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 41) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (L1CAM/CD171) biotinylated antibody. The origin of NEEVs was validated with two other neuronal markers - neuronal cell adhesion molecule (NCAM) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3). NEEV specificities were confirmed by flow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation during interoceptive versus exteroceptive attention. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin re-organization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals.
Asunto(s)
Trastorno Depresivo Mayor , Vesículas Extracelulares , Interocepción , MicroARNs , Femenino , Humanos , Masculino , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Estudios de Casos y Controles , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Interocepción/fisiología , Imagen por Resonancia Magnética , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismoRESUMEN
Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.