Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD.

Valence and arousal influence the late positive potential during central and lateralized presentation of images.

The motivated attention network is believed to be the system that allocates attention toward motivationally relevant, emotional stimuli in order to better prepare an organism for action [Lang, P. J., Bradley, M. M., & Cuthbert, B. N. (1997). Motivated attention: Affect, activation, and action. In P. J. Lang, R. F. Simons, M. Balaban, & R. Simons (Eds.), Attention and orienting: Sensory and motivational processes (pp. 97-135). Psychology Press]. The late positive potential (LPP), an event-related potential (ERP) that is a manifestation of the motivated attention network, has not been found to reliably differentiate the valence of emotionally relevant stimuli. In two studies, we systematically varied epoch, stimulus arousal, stimulus valence, and hemisphere of presentation (Study 2) to investigate valence effects in the LPP. Both central and divided visual field presentations of emotional stimuli found the LPP to be sustained in later windows for high-arousing unpleasant images compared to pleasant images. Further, this effect was driven by sustained LPP responses following left hemisphere presentations of unpleasant stimuli compared to right. Findings are discussed regarding hemispheric processing of emotion and how lateralized emotion processes might contribute to psychopathology.

Do child abuse and maternal care interact to predict military sexual trauma?

OBJECTIVE: The present research tested the hypothesis that maternal care moderates the relationship between childhood sexual abuse and subsequent military sexual trauma (MST). METHOD: Measures of childhood sexual abuse, maternal care, and MST were administered to 197 Iraq and Afghanistan war veterans. RESULTS: After accounting for gender, age, and the main effects of maternal care and childhood sexual abuse, the maternal care x childhood sexual abuse interaction was a significant predictor of MST (odds ratio = .28, ß = -1.26, 95% confidence intervals of .10, .80). As hypothesized, rates of MST were higher among veterans who reported childhood sexual abuse and low levels of maternal care (43%) compared with veterans who reported childhood sexual abuse and high levels of maternal care (11%). CONCLUSION: These findings suggest that high levels of maternal care may act as a protective factor against future revictimization among military service members. These findings have the potential to inform both prevention and intervention efforts.

Considering an aortic arch anomaly in patients with dysphagia.

In patients presenting with a chief complaint of dysphagia, physician assistants should consider anomalous vascularity as a possible cause of esophageal obstruction.

Fluid Optimisation in Emergency Laparotomy (FLO-ELA) Trial: study protocol for a multi-centre randomised trial of cardiac output-guided fluid therapy compared to usual care in patients undergoing major emergency gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. METHODS: The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phase and is ongoing at the time of publication. DISCUSSION: This will be the largest contemporary randomised trial examining the effectiveness of perioperative cardiac output-guided haemodynamic therapy in patients undergoing major emergency gastrointestinal surgery. The multi-centre design and broad inclusion criteria support the external validity of the trial. Although the clinical teams delivering the trial interventions will not be blinded, significant trial outcome measures are objective and not subject to detection bias. TRIAL REGISTRATION: ISRCTN 14729158. Registered on 02 May 2017.

biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.

Common genetic variation impacts stress response in the brain.

To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress, and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery.

The functional connectivity of the human caudate: an application of meta-analytic connectivity modeling with behavioral filtering.

Meta-analysis based techniques are emerging as powerful, robust tools for developing models of connectivity in functional neuroimaging. Here, we apply meta-analytic connectivity modeling to the human caudate to 1) develop a model of functional connectivity, 2) determine if meta-analytic methods are sufficiently sensitive to detect behavioral domain specificity within region-specific functional connectivity networks, and 3) compare meta-analytic driven segmentation to structural connectivity parcellation using diffusion tensor imaging. Results demonstrate strong coherence between meta-analytic and data-driven methods. Specifically, we found that behavioral filtering resulted in cognition and emotion related structures and networks primarily localized to the head of the caudate nucleus, while perceptual and action specific regions localized to the body of the caudate, consistent with early models of nonhuman primate histological studies and postmortem studies in humans. Diffusion tensor imaging (DTI) revealed support for meta-analytic connectivity modeling's (MACM) utility in identifying both direct and indirect connectivity. Our results provide further validation of meta-analytic connectivity modeling, while also highlighting an additional potential, namely the extraction of behavioral domain specific functional connectivity.

Neuropsychological sequelae of PTSD and TBI following war deployment among OEF/OIF veterans.

Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are highly prevalent among Veterans of the conflicts in Iraq and Afghanistan. These conditions are associated with common and unique neuropsychological and neuroanatomical changes. This review synthesizes neuropsychological and neuroimaging studies for both of these disorders and studies examining their co-occurrence. Recommendations for future research, including use of combined neuropsychological and advanced neuroimaging techniques to study these disorders alone and in concert, are presented. It is clear from the dearth of literature that addiitonal studies are required to examine and understand the impact of specific factors on neurocognitive outcome. Of particular relevance are temporal relationships between PTSD and mTBI, risk and resilience factors associated with both disorders and their co-occurrence, and mTBI-specific factors such as time since injury and severity of injury, utilizing comprehensive, yet targeted cognitive tasks.

Depression reduces perceptual sensitivity for positive words and pictures.

There is evidence of maladaptive attentional biases for lexical information (e.g., Atchley, Ilardi, & Enloe, 2003; Atchley, Stringer, Mathias, Ilardi, & Minatrea, 2007) and for pictographic stimuli (e.g., Gotlib, Krasnoperova, Yue, & Joormann, 2004) among patients with depression. The current research looks for depressotypic processing biases among depressed out-patients and non-clinical controls, using both verbal and pictorial stimuli. A d' measure (sensitivity index) was used to examine each participant's perceptual sensitivity threshold. Never-depressed controls evidenced a detection bias for positive picture stimuli, while depressed participants had no such bias. With verbal stimuli, depressed individuals showed specific decrements in the detection of positive person-referent words (WINNER), but not with positive non-person-referent words (SUNSHINE) or with negative words. Never-depressed participants showed no such differences across word types. In the current study, depression is characterised both by an absence of the normal positivistic biases seen in individuals without mood disorders (consistent with McCabe & Gotlib, 1995), and by a specific reduction in sensitivity for person-referent positive information that might be inconsistent with depressotypic self-schemas.

Decoding Shared Versus Divergent Transcriptomic Signatures Across Cortico-Amygdala Circuitry in PTSD and Depressive Disorders.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric disease that is highly comorbid with major depressive disorder (MDD) and bipolar disorder. The overlap in symptoms is hypothesized to stem from partially shared genetics and underlying neurobiological mechanisms. To delineate conservation between transcriptional patterns across PTSD and MDD, the authors examined gene expression in the human cortex and amygdala in these disorders. METHODS: RNA sequencing was performed in the postmortem brain of two prefrontal cortex regions and two amygdala regions from donors diagnosed with PTSD (N=107) or MDD (N=109) as well as from neurotypical donors (N=109). RESULTS: The authors identified a limited number of differentially expressed genes (DEGs) specific to PTSD, with nearly all mapping to cortical versus amygdala regions. PTSD-specific DEGs were enriched in gene sets associated with downregulated immune-related pathways and microglia as well as with subpopulations of GABAergic inhibitory neurons. While a greater number of DEGs associated with MDD were identified, most overlapped with PTSD, and only a few were MDD specific. The authors used weighted gene coexpression network analysis as an orthogonal approach to confirm the observed cellular and molecular associations. CONCLUSIONS: These findings provide supporting evidence for involvement of decreased immune signaling and neuroinflammation in MDD and PTSD pathophysiology, and extend evidence that GABAergic neurons have functional significance in PTSD.

High psychopathic trait females exhibit reduced startle potentiation and increased p3 amplitude.

While there has been steady progress in identifying psychophysiological traits associated with psychopathy, most of the existing research has been carried out using incarcerated male participants, and data that include females are particularly rare. This study examined both affective startle blink modulation and P3 amplitude in a sample of female undergraduates grouped by scores on the Psychopathic Personality Inventory-Revised (PPI-R). Those scoring high for psychopathic traits lacked startle blink potentiation and demonstrated larger P3 amplitudes during auditory and visual oddball tasks. These data support the generalizability of deficient startle potentiation to non-incarcerated females with psychopathic traits, and add to a growing body of literature suggesting that psychopathic traits are associated with distinctive information-processing characteristics as indexed by P3 amplitude.

Amantadine for the treatment of childhood and adolescent psychiatric symptoms.

This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were prescribed amantadine and met study criteria to assess clinical responses and medication outcomes. More than 62% of patients experienced clinically significant symptom control and 83% achieved at least maintenance symptom control, while 11% discontinued amantadine for nonresponse and 6% stopped amantadine because of side effects. Among patients previously receiving other psychotropic medication, 42% and 28% of patients fully discontinued second- or third-generation antipsychotics or antidepressants, respectively. Patients responsive to amantadine who discontinued or reduced antipsychotic dose experienced a significant reduction in body mass index. Amantadine appears be an efficacious and safe alternative for treatment of a broad set of psychiatric symptoms in children and adolescents. Specifically, it may serve as an effective adjunct to stimulants for attention deficit/hyperactivity disorder-related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.

Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD.

Studies evaluating neuroimaging, genetically predicted gene expression, and pre-clinical genetic models of PTSD, have identified PTSD-related abnormalities in the prefrontal cortex (PFC) of the brain, particularly in dorsolateral and ventromedial PFC (dlPFC and vmPFC). In this study, RNA sequencing was used to examine gene expression in the dlPFC and vmPFC using tissue from the VA National PTSD Brain Bank in donors with histories of PTSD with or without depression (dlPFC n = 38, vmPFC n = 35), depression cases without PTSD (n = 32), and psychopathology-free controls (dlPFC n = 24, vmPFC n = 20). Analyses compared PTSD cases to controls. Follow-up analyses contrasted depression cases to controls. Twenty-one genes were differentially expressed in PTSD after strict multiple testing correction. PTSD-associated genes with roles in learning and memory (FOS, NR4A1), immune regulation (CFH, KPNA1) and myelination (MBP, MOBP, ERMN) were identified. PTSD-associated genes partially overlapped depression-associated genes. Co-expression network analyses identified PTSD-associated networks enriched for immune-related genes across the two brain regions. However, the immune-related genes and association patterns were distinct. The immune gene IL1B was significantly associated with PTSD in candidate-gene analysis and was an upstream regulator of PTSD-associated genes in both regions. There was evidence of replication of dlPFC associations in an independent cohort from a recent study, and a strong correlation between the dlPFC PTSD effect sizes for significant genes in the two studies (r = 0.66, p < 2.2 × 10-16). In conclusion, this study identified several novel PTSD-associated genes and brain region specific PTSD-associated immune-related networks.

Transcriptomic organization of the human brain in post-traumatic stress disorder.

Despite extensive study of the neurobiological correlates of post-traumatic stress disorder (PTSD), little is known about its molecular determinants. Here, differential gene expression and network analyses of four prefrontal cortex subregions from postmortem tissue of people with PTSD demonstrate extensive remodeling of the transcriptomic landscape. A highly connected downregulated set of interneuron transcripts is present in the most significant gene network associated with PTSD. Integration of this dataset with genotype data from the largest PTSD genome-wide association study identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked transcriptomic sexual dimorphism that could contribute to higher rates of PTSD in women. Comparison with a matched major depressive disorder cohort revealed significant divergence between the molecular profiles of individuals with PTSD and major depressive disorder despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the prefrontal cortex that contribute to the pathophysiology of PTSD in humans.

PSAPP mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation.

BACKGROUND: Numerous studies have reported that increased expression of S100B, an intracellular Ca2+ receptor protein and secreted neuropeptide, exacerbates Alzheimer's disease (AD) pathology. However, the ability of S100B inhibitors to prevent/reverse AD histopathology remains controversial. This study examines the effect of S100B ablation on in vivo plaque load, gliosis and dystrophic neurons. METHODS: Because S100B-specific inhibitors are not available, genetic ablation was used to inhibit S100B function in the PSAPP AD mouse model. The PSAPP/S100B-/- line was generated by crossing PSAPP double transgenic males with S100B-/- females and maintained as PSAPP/S100B+/- crosses. Congo red staining was used to quantify plaque load, plaque number and plaque size in 6 month old PSAPP and PSAPP/S100B-/- littermates. The microglial marker Iba1 and astrocytic marker glial fibrillary acidic protein (GFAP) were used to quantify gliosis. Dystrophic neurons were detected with the phospho-tau antibody AT8. S100B immunohistochemistry was used to assess the spatial distribution of S100B in the PSAPP line. RESULTS: PSAPP/S100B-/- mice exhibited a regionally selective decrease in cortical but not hippocampal plaque load when compared to PSAPP littermates. This regionally selective reduction in plaque load was accompanied by decreases in plaque number, GFAP-positive astrocytes, Iba1-positive microglia and phospho-tau positive dystrophic neurons. These effects were not attributable to regional variability in the distribution of S100B. Hippocampal and cortical S100B immunoreactivity in PSAPP mice was associated with plaques and co-localized with astrocytes and microglia. CONCLUSIONS: Collectively, these data support S100B inhibition as a novel strategy for reducing cortical plaque load, gliosis and neuronal dysfunction in AD and suggest that both extracellular as well as intracellular S100B contribute to AD histopathology.

Psychiatric Prodrome in Anti-NMDAR-Associated Encephalopathy: Clinical and Pathophysiologic Considerations.

OBJECTIVE: To present a review of the literature on the clinical presentation and pathophysiology of anti-N-methyl-d-aspartate receptor encephalopathy (ANMDARE) with attention to both the more commonly recognized psychotic symptom prodrome and the less well-understood depressive symptom prodrome. DATA SOURCES: The search for clinical neuropsychiatric phenomena and proposed mechanisms involved in ANMDARE pathophysiology was conducted in PubMed. English-language articles published up to September 2019 were identified using a combination of the following search terms: N-methyl-d-aspartate, anti-NMDA receptor encephalitis, schizophrenia, psychosis, depression, major depressive disorder, bipolar I disorder, bipolar II disorder, anxiety, and posttraumatic stress disorder. STUDY SELECTION: From 150 articles identified from the initial search, the 73 most relevant clinical studies, reviews, and case reports related to the study objectives were included. DATA EXTRACTION: Sources were individually analyzed by the 3 authors for the most clinically relevant information. RESULTS: The pathophysiology and mechanisms involved in anti-NMDA receptor antibody delivery to the brain are incompletely characterized, but antibody binding appears to involve the GluN1 subunit in most cases. Psychotic symptoms are the most commonly recognized components of prodromal psychiatric illness in ANMDARE, which may lead to an initial diagnosis of schizophrenia. In addition to psychotic symptoms, there are reports of depressive symptoms occurring before the emergence of, co-occurring with, or instead of psychotic symptoms in ANMDARE. CONCLUSIONS: In addition to the better-known psychotic prodrome, depressive symptomatology can occur in ANMDARE patients. ANMDARE should be considered in patients with initial presentation of either psychotic or atypical depressive illnesses. Early recognition of these psychiatric prodromal states as antecedents to ANMDARE could lead to improved diagnosis and better management of this potentially life-threatening autoimmune disorder.

Utility of oxcarbazepine in the treatment of childhood and adolescent psychiatric symptoms.

The primary aims of this study were to determine if oxcarbazepine is a safely tolerated option for treatment of psychiatric symptoms in children and whether its use facilitates dose modification of other psychotropic medications. A retrospective chart review was completed using data extracted from the electronic medical record of a large outpatient child psychiatry clinic. A total of 507 of 740 children prescribed oxcarbazepine for psychiatric indications for 3 months or more had adequate data to assess clinical responses and medication outcomes. Most patients prescribed oxcarbazepine experienced clinically significant control of irritability/anger, mood stabilization, aggressive outbursts, impulsivity, or anxiety, with over 80% achieving at least maintenance symptom control. In all, 51% and 25% fully discontinued second- or third-generation antipsychotic or antidepressant medication, respectively, after starting oxcarbazepine; 8% discontinued oxcarbazepine for nonresponse, while 9% stopped oxcarbazepine because of emergent side effects. In patients fully discontinuing or reducing the second- or third-generation antipsychotic dose by 50% or more, improvements in body mass index were observed. Oxcarbazepine may prove to be an appropriate alternative to antipsychotic and antidepressant medications for treating psychiatric symptoms in children and adolescents. In particular, it may be a more metabolically neutral psychotropic medication.