27 research outputs found
Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors
gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain
Phenotypic variability of GABRA1-related epilepsy in monozygotic twins.
Variants in GABRA1 have been associated with different epilepsies ranging from mild generalized forms to epileptic encephalopathies. Despite the broad clinical spectrum, phenotypes were found to be largely concordant within families. Contrary to this observation, we report monozygotic twin sisters with generalized epilepsy due to the c.541C>T; p.(Pro181Ser) de novo variant in GABRA1. One experienced juvenile absence seizures promptly responding to first-line medication, whereas the second developed severe treatment-refractory epilepsy with febrile, absence, atonic, and tonic-clonic seizures indicating marked intrafamilial variability in GABRA1-related epilepsy. Moreover, we provide a molecular characterization of the novel variant based on recently published structural data
Repeating patterns : Predictive processing suggests an aesthetic learning role of the basal ganglia in repetitive stereotyped behaviors
Recurrent, unvarying, and seemingly purposeless patterns of action and cognition are part of normal development, but also feature prominently in several neuropsychiatric conditions. Repetitive stereotyped behaviors (RSBs) can be viewed as exaggerated forms of learned habits and frequently correlate with alterations in motor, limbic, and associative basal ganglia circuits. However, it is still unclear how altered basal ganglia feedback signals actually relate to the phenomenological variability of RSBs. Why do behaviorally overlapping phenomena sometimes require different treatment approaches−for example, sensory shielding strategies versus exposure therapy for autism and obsessive-compulsive disorder, respectively? Certain clues may be found in recent models of basal ganglia function that extend well beyond action selection and motivational control, and have implications for sensorimotor integration, prediction, learning under uncertainty, as well as aesthetic learning. In this paper, we systematically compare three exemplary conditions with basal ganglia involvement, obsessive-compulsive disorder, Parkinson’s disease, and autism spectrum conditions, to gain a new understanding of RSBs. We integrate clinical observations and neuroanatomical and neurophysiological alterations with accounts employing the predictive processing framework. Based on this review, we suggest that basal ganglia feedback plays a central role in preconditioning cortical networks to anticipate self-generated, movement-related perception. In this way, basal ganglia feedback appears ideally situated to adjust the salience of sensory signals through precision weighting of (external) new sensory information, relative to the precision of (internal) predictions based on prior generated models. Accordingly, behavioral policies may preferentially rely on new data versus existing knowledge, in a spectrum spanning between novelty and stability. RSBs may then represent compensatory or reactive responses, respectively, at the opposite ends of this spectrum. This view places an important role of aesthetic learning on basal ganglia feedback, may account for observed changes in creativity and aesthetic experience in basal ganglia disorders, is empirically testable, and may inform creative art therapies in conditions characterized by stereotyped behaviors.publishe
The Relationship between Training and Mental Health among Caregivers of Individuals with Polytrauma
This was a hypothesis-generating exploration of relationships between caregiver training during TBI/polytrauma rehabilitation and caregiver mental health. In this cross-sectional study, 507 informal caregivers to US service members with TBI who received inpatient rehabilitation care in a Veterans Affairs’ Polytrauma Rehabilitation Center from 2001 to 2009 completed a retrospective, self-report survey. Embedded in the survey were measures of caregiver mental health, including the National Institutes of Health’s Patient Reported Outcome Measurement Information System (PROMIS) Anxiety and Depression Short Forms, the Rosenberg Self-Esteem scale, and the Zarit Burden Short Form. Though no groups endorsed clinical levels, mental health symptoms varied by caregiver training category (Trained, Not Trained, and Did Not Need Training). Caregivers who did not receive training on how to navigate healthcare systems endorsed higher depression and burden and lower self-esteem than those who did. Caregivers who did not receive training in supporting their care recipients’ emotions endorsed higher anxiety, depression, and burden and lower self-esteem than those who did. Analyses also suggested a different association between training and mental health based on caregivers’ relationship to the care recipient and the intensity of care recipient needs. Potential hypotheses for testing in future studies raised by these findings are discussed
The Relationship between Training and Mental Health among Caregivers of Individuals with Polytrauma
This was a hypothesis-generating exploration of relationships between caregiver training during TBI/polytrauma rehabilitation and caregiver mental health. In this cross-sectional study, 507 informal caregivers to US service members with TBI who received inpatient rehabilitation care in a Veterans Affairs’ Polytrauma Rehabilitation Center from 2001 to 2009 completed a retrospective, self-report survey. Embedded in the survey were measures of caregiver mental health, including the National Institutes of Health’s Patient Reported Outcome Measurement Information System (PROMIS) Anxiety and Depression Short Forms, the Rosenberg Self-Esteem scale, and the Zarit Burden Short Form. Though no groups endorsed clinical levels, mental health symptoms varied by caregiver training category (Trained, Not Trained, and Did Not Need Training). Caregivers who did not receive training on how to navigate healthcare systems endorsed higher depression and burden and lower self-esteem than those who did. Caregivers who did not receive training in supporting their care recipients’ emotions endorsed higher anxiety, depression, and burden and lower self-esteem than those who did. Analyses also suggested a different association between training and mental health based on caregivers’ relationship to the care recipient and the intensity of care recipient needs. Potential hypotheses for testing in future studies raised by these findings are discussed
Diversity regained: Precautionary approaches to COVID-19 as a phenomenon of the total environment
As COVID-19 emerged as a phenomenon of the total environment, and despite the intertwined and complex relationships that make humanity an organic part of the Bio- and Geospheres, the majority of our responses to it have been corrective in character, with few or no consideration for unintended consequences which bring about further vulnerability to unanticipated global events. Tackling COVID-19 entails a systemic and precautionary approach to human-nature relations, which we frame as regaining diversity in the Geo-, Bio-, and Anthropospheres. Its implementation requires nothing short of an overhaul in the way we interact with and build knowledge from natural and social environments. Hence, we discuss the urgency of shifting from current to precautionary approaches to COVID-19 and look, through the lens of diversity, at the anticipated benefits in four systems crucially affecting and affected by the pandemic: health, land, knowledge and innovation. Our reflections offer a glimpse of the sort of changes needed, from pursuing planetary health and creating more harmonious forms of land use to providing a multi-level platform for other ways of knowing/understanding and turning innovation into a source of global public goods. These exemplary initiatives introduce and solidify systemic thinking in policymaking and move priorities from reaction-based strategies to precautionary frameworks
Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta
Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators