Monoaminergic and Neurotrophic Gene Variation Associated with Fronto-Limbic Circuitry affect Mood and Cognitive Recovery Post-TBI

Following traumatic brain injury (TBI), ~80% of individuals will experience cognitive deficits, and ~50% will experience post-TBI depression (PTD). Identifying individual risk patterns for these complications is important for preventive treatment and early intervention. In uninjured populations, individuals with depression have distinct accompanying cognitive deficits. Importantly, dysregulation of fronto-limbic regions may, in part, explain the co-occurrence of both depressive and cognitive symptoms. The work presented investigates biological factors that influence survival after severe TBI, and among survivors, the presence and severity of PTD and/or cognitive deficits. The scientific framework under which this work was completed proposes targeted interactions between monoaminergic and neurotrophic gene variation that may lead to cognitive deficits and depressive symptoms. In addition to cognition, serotonergic (5-HT) and dopaminergic (DA) signaling both contribute to depressed mood and anhedonia, suggesting genetic variation in their signaling pathways may modulate PTD risk. Brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin involved in neuronal survival and synaptic plasticity, is implicated in depression and cognitive dysfunction, and BDNF interacts with 5-HT/DA signaling in mood and cognitive processes. The work presented examines monoaminergic-neurotrophic biomarkers for predicting PTD risk and cognitive deficits. Serum and cerebrospinal fluid (CSF) BDNF levels, and fronto-limbic atrophy, were examined as possible biomarkers of PTD and cognitive deficits. A battery of targeted genes were examined for their proposed roles in survival, depression, cognition, and/or modulation of fronto-limbic connectivity. The data show variation within monoaminergic genes was associated with PTD incidence (serotonin transporter, 5-HTTLPR) and cognitive deficits post-TBI (dopamine D2 receptor, DRD2 and COMT). When investigating BDNF associations with PTD, we discovered that variation in BDNF interacts with MONOAMINERGIC AND NEUROTROPHIC GENE VARIATION ASSOCIATED WITH FRONTO-LIMBIC CIRCUITRY AFFECT MOOD AND COGNITIVE RECOVERY POST-TBI Michelle D. Failla, PhD University of Pittsburgh, 2014 v age to influence TBI survival, and acute BDNF levels were consistent biomarkers for TBI survival. Among TBI survivors, acute BDNF levels were associated with chronic cognitive performance and depressive symptoms severity, suggesting early neurotrophic support may facilitate chronic recovery. Investigating fronto-limbic regional brain volumes identified significant relationships to PTD and suggested non-uniform fronto-limbic atrophy patterns that may explain PTD susceptibility. Overall, this work supports that monoaminergic-neurotrophin genetic variability affects individual risk for PTD and related cognitive deficits, possibly through relationships with fronto-limbic circuitry

Pain Processing in Psychiatric Conditions: A systematic review

©American Psychological Association, 2019. This paper is not the copy of record and may not exactly replicate the authoritative document published in the APA journal. Please do not copy or cite without author's permission. The final article is available, upon publication, at: https://doi.org/10.1177/1089268019842771Objective: Pain is a universal, multidimensional experience with sensory emotional, cognitive and social components, which is fundamental to our environmental learning when functioning typically. Understanding pain processing in psychiatric conditions could provide unique insight into the underlying pathophysiology or psychiatric disease, especially given the psychobiological overlap with pain processing pathways. Studying pain in psychiatric conditions is likely to provide important insights, yet, there is a limited understanding beyond the work outside depression and anxiety. This is a missed opportunity to describe psychiatric conditions in terms of neurobiological alterations. In order to examine the research into the pain experiences of these groups and the extent to which a-typicality is present, a systematic review was conducted. Methods: An electronic search strategy was developed and conducted in several databases. Results: The current systematic review included 46 studies covering five DSM-5 disorders: autism, attention deficit hyperactivity disorder, schizophrenia, personality disorder and eating disorders, confirming tentative evidence of altered pain and touch processing. Specifically, hyposensitivity is reported in schizophrenia, personality disorder and eating disorder, hypersensitivity in ADHD and mixed results for autism. Conclusions: Review of the research highlights a degree of methodological inconsistency in the utilisation of comprehensive protocols; the lack of which fails to allow us to understand whether a-typicality is systemic or modality-specific

Promoting successful participation of people living with Alzheimer's disease and related dementias in pain-related neuroimaging research studies

Recruitment and retention of participants for pain-related neuroimaging research is challenging and becomes increasingly so when research participants have a diagnosis of Alzheimer's disease and related dementias (ADRD). This article shares the authors' recommendations from several years of successful recruitment and completion of pain-related neuroimaging studies of people living with ADRD and includes supportive literature. While not an exhaustive list, this review covers several topics related to recruitment and retention of participants living with ADRD, including community engagement, capacity to consent, dementia diagnostic criteria, pain medication and other study exclusion criteria, participant and caregiver burden, communication concerns, and relationships with neuroimaging facilities. Threaded throughout the paper are important cultural considerations. Additionally, we discuss implications of the coronavirus (COVID-19) pandemic for recruitment. Once tailored to specific research study protocols, these proven strategies may assist researchers with successfully recruiting and retaining participants living with ADRD for pain-related neuroimaging research studies toward improving overall health outcomes

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

Examining the Latent Structure and Correlates of Sensory Reactivity in Autism: A Multi-Site Integrative Data Analysis by the Autism Sensory Research Consortium

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these supra-modal traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a general response pattern factor for each supra-modal construct and determine the added value of modality-specific response pattern scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ω LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many real-world sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations

Comportamiento en desgaste deslizante de polietileno de alta densidad entrecruzado con radiacion gamma / Sliding wear behaviour of high density polyethylene cross-linked by gamma radiation

The aim of this study was to determine the sliding wear behavior of &#0947;-irradiated linear polyethylene. The polymers used were two linear polyethylenes that were irradiated by &#0947;- rays at room temperature. Equal total doses of 2, 5, 10 and 20 Mrad were applied. Tribological tests were performed in a Pin On Disc tribometer with normal loads between 2, 5 and 15 N. The results show that the wear rate increases with the applied load in the case of the samples irradiated with the lowest doses, while the wear rate displays a maximum with the applied load in the samples irradiated with the highest dose

Sliding wear behaviour of high density polyethylene cross-linked by gamma radiation

El propósito del trabajo fue evaluar el comportamiento de polietilenos irradiados con rayos gamma sometidos a desgaste deslizante. Para ellos se utilizaron dos polietilenos lineales, que fueron irradiados con radiación gamma a temperatura ambiente, aplicándose a cada grupo dosis de 2, 5, 10 y 20 Mrad. Los estudios tribológicos fueron realizados usando un tribómetro Pin On Disc. Los ensayos se efectuaron aplicando cargas normales entre 2, 5 y 15 N. Se encontró que la velocidad de desgaste se incrementa con la carga aplicada en los materiales irradiados con bajas dosis, mientras que aquellos irradiados con las dosis más altas la velocidad de desgaste atraviesa por un valor máximo con la carga.The aim of this study was to determine the sliding wear behavior of γ-irradiated linear polyethylene. The polymers used were two linear polyethylenes that were irradiated by γ rays at room temperature. Equal total doses of 2, 5, 10 and 20 Mrad were applied. Tribological tests were performed in a Pin On Disc tribometer with normal loads between 2, 5 and 15 N. The results show that the wear rate increases with the applied load in the case of the samples irradiated with the lowest doses, while the wear rate displays a maximum with the applied load in the samples irradiated with the highest dose.Fil: Tuckart, Walter Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Ingeniería; ArgentinaFil: Rosevear, Michelle L.. Swinburne University of Technology; AustraliaFil: Molinari, Erica Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Ingeniería; ArgentinaFil: Gregorio, Marcos Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Ingeniería; ArgentinaFil: Failla, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Ingeniería; Argentin

Intrainsular connectivity and somatosensory responsiveness in young children with ASD

Abstract Background The human somatosensory system comprises dissociable paths for discriminative and affective touch, reflected in separate peripheral afferent populations and distinct cortical targets. Differences in behavioral and neural responses to affective touch may have an important developmental role in early social experiences, which are relevant for autism spectrum disorder (ASD). Methods Using probabilistic tractography, we compared the structural integrity of white matter pathways for discriminative and affective touch in young children with ASD and their typically developing (TD) peers. We examined two tracts: (1) a tract linking the thalamus with the primary somatosensory cortex, which carries discriminative tactile information, and (2) a tract linking the posterior insula—the cortical projection target of unmyelinated tactile afferents mediating affective touch—with the anterior insula, which integrates sensory and visceral inputs to interpret emotional salience of sensory stimuli. We investigated associations between tract integrity and performance on a standardized observational assessment measuring tactile discrimination and affective responses to touch. Results Both the thalamocortical and intrainsular tracts showed reduced integrity (higher mean diffusivity) in the ASD group compared to those in the TD group. Consistent with the previous findings, the ASD group exhibited impaired tactile discriminative ability, more tactile defensiveness, and more sensory seeking (e.g., enthusiastic play or repetitive engagement with a specific tactile stimulus). There was a significant relation between intrainsular tract integrity and tactile seeking. The direction of this relation differed between groups: higher intrainsular mean diffusivity (MD) (reflecting decreased tract integrity) was associated with increased tactile seeking in the TD group but with decreased tactile seeking in the ASD group. In the TD group, decreased tactile defensiveness was also associated with higher intrainsular MD, but there was no relation in the ASD group. Discriminative touch was not significantly associated with integrity of either tract in either group. Conclusions These results support previous findings suggesting a central role for the insula in affective response to touch. While both discriminative and affective touch and both somatosensory tracts are affected in ASD, the restriction of brain–behavior associations to the intrainsular tract and tactile seeking suggests more complex and perhaps higher-order influence on differences in tactile defensiveness and discrimination

Psychometric validation and refinement of the Interoception Sensory Questionnaire (ISQ) in adolescents and adults on the autism spectrum

Abstract Background Individuals on the autism spectrum are reported to display alterations in interoception, the sense of the internal state of the body. The Interoception Sensory Questionnaire (ISQ) is a 20-item self-report measure of interoception specifically intended to measure this construct in autistic people. The psychometrics of the ISQ, however, have not previously been evaluated in a large sample of autistic individuals. Methods Using confirmatory factor analysis, we evaluated the latent structure of the ISQ in a large online sample of adults on the autism spectrum and found that the unidimensional model fit the data poorly. Using misspecification analysis to identify areas of local misfit and item response theory to investigate the appropriateness of the seven-point response scale, we removed redundant items and collapsed the response options to put forth a novel eight-item, five-response choice ISQ. Results The revised, five-response choice ISQ (ISQ-8) showed much improved fit while maintaining high internal reliability. Differential item functioning (DIF) analyses indicated that the items of the ISQ-8 were answered in comparable ways by autistic adolescents and adults and across multiple other sociodemographic groups. Limitations Our results were limited by the fact that we did not collect data for typically developing controls, preventing the analysis of DIF by diagnostic status. Additionally, while this study proposes a new 5-response scale for the ISQ-8, our data were not collected using this method; thus, the psychometric properties for the revised version of this instrument require further investigation. Conclusion The ISQ-8 shows promise as a reliable and valid measure of interoception in adolescents and adults on the autism spectrum, but additional work is needed to examine its psychometrics in this population. A free online score calculator has been created to facilitate the use of ISQ-8 latent trait scores for further studies of autistic adolescents and adults (available at https://asdmeasures.shinyapps.io/ISQ_score/ )