Homeostatic feelings and the biology of consciousness
(Source: Brain)
Source: Brain - May 30, 2022 Category: Neurology Source Type: research
Harnessing cortical plasticity via gabapentinoid administration promotes recovery after stroke
AbstractStroke causes devastating sensory-motor deficits and long-term disability due to disruption of descending motor pathways. Restoration of these functions enables independent living and therefore represents a high priority for those afflicted by stroke. Here, we report that daily administration of gabapentin, a clinically approved drug already used to treat various neurological disorders, promotes structural and functional plasticity of the corticospinal pathway after photothrombotic cortical stroke in adult mice. We found that gabapentin administration had no effects on vascular occlusion, haemodynamic changes nor s...
Source: Brain - May 23, 2022 Category: Neurology Source Type: research
Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit
AbstractIn perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice.Through a combination of molecular, tracing and behavioural app...
Source: Brain - May 22, 2022 Category: Neurology Source Type: research
Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer ’s disease
AbstractTo match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation.Much progress has bee...
Source: Brain - May 13, 2022 Category: Neurology Source Type: research
Sex differences in the genetic architecture of cognitive resilience to Alzheimer ’s disease
This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized ba sed on their biological sex and genetic context. (Source: Brain)
Source: Brain - May 13, 2022 Category: Neurology Source Type: research
Pre-symptomatic spinal muscular atrophy: a proposed nosology
Finkel and Benatar highlight the ambiguity of the term ‘pre-symptomatic’ when characterizing infants at genetic risk for spinal muscular atrophy. They propose a conceptual framework that recognizes clinically silent and prodromal stages of pre-symptomatic disease and also accommodates emerging prognostic biomarkers. (Source: Brain)
Source: Brain - April 16, 2022 Category: Neurology Source Type: research
The anatomy of melancholy revisited after 400 years
(Source: Brain)
Source: Brain - April 14, 2022 Category: Neurology Source Type: research
Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy
AbstractPathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown.We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivatingADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previ...
Source: Brain - April 4, 2022 Category: Neurology Source Type: research
Reimagining cholinergic therapy for Alzheimer ’s disease
AbstractCurrently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer ’s disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer’s disease, as four of the six approved therapies are acetylcholinesterase inhibitors.Memantine is anN-methyl-d-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targe...
Source: Brain - March 15, 2022 Category: Neurology Source Type: research
Distinct brainstem to spinal cord noradrenergic pathways inversely regulate spinal neuronal activity
AbstractBrainstem to spinal cord noradrenergic pathways include a locus coeruleus origin projection and diffuse noxious inhibitory controls. While both pathways are traditionally viewed as exerting an inhibitory effect on spinal neuronal activity, the locus coeruleus was previously shown to have a facilitatory influence on thermal nocioception according to the subpopulation of coerulean neurons activated. Coupled with knowledge of its functional modular organisation and the fact that diffuse noxious inhibitory controls are not expressed in varied animal models of chronicity, we hypothesized a regulatory role for the locus ...
Source: Brain - March 4, 2022 Category: Neurology Source Type: research
Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
AbstractDuring the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h.A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found tha...
Source: Brain - February 25, 2022 Category: Neurology Source Type: research
Seizures initiate in zones of relative hyperexcitation in a zebrafish epilepsy model
AbstractSeizures are thought to arise from an imbalance of excitatory and inhibitory neuronal activity. While most classical studies suggest excessive excitatory neural activity plays a generative role, some recent findings challenge this view and instead argue that excessive activity in inhibitory neurons initiates seizures.We investigated this question of imbalance in a zebrafish seizure model with two-photon imaging of excitatory and inhibitory neuronal activity throughout the brain using a nuclear-localized calcium sensor. We found that seizures consistently initiated in circumscribed zones of the midbrain before propa...
Source: Brain - February 23, 2022 Category: Neurology Source Type: research
Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer ’s disease
AbstractMicrotubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions that go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase (TTL).Here we sh...
Source: Brain - February 11, 2022 Category: Neurology Source Type: research
The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target?
AbstractCalcitonin gene-related peptide (CGRP)-antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target.To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity respon...
Source: Brain - February 8, 2022 Category: Neurology Source Type: research
Metabolomic profiling in small vessel disease identifies multiple associations with disease severity
AbstractCerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity.We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-perfor...
Source: Brain - February 8, 2022 Category: Neurology Source Type: research
