Parabrachial-insular stimulation does not wake mice.

The parabrachial nucleus (PB) in the upper brainstem receives interoceptive information and sends a massive output projection directly to the cerebral cortex. Its glutamatergic axons primarily target the midinsular cortex, and we have proposed that this PB-insular projection promotes arousal. Here, we test whether stimulating this projection causes wakefulness. We combined optogenetics and video-electroencephalography (vEEG) in mice to test this hypothesis by stimulating PB axons in the insular cortex. Stimulating this projection did not alter the cortical EEG or awaken mice. Also, despite a tendency toward aversion, PB-insular stimulation did not significantly alter real-time place preference (RTPP). These results are not consistent with the hypothesis that the direct PB-insular projection is part of the ascending arousal system.NEW & NOTEWORTHY A brainstem region critical for wakefulness overlaps the medial parabrachial nucleus (PB) and has functional and direct axonal connectivity with the insular cortex. In this study, we hypothesized that this direct projection from the PB to the insular cortex promotes arousal. However, photostimulating PB axons in the insular cortex did not alter the cortical EEG or awaken mice. This information constrains the possible circuit connections through which brainstem neurons may sustain arousal.

Revisiting a Telencephalic Extent of the Ascending Reticular Activating System.

Is the cerebrum involved in its own activation to states of attention or arousal? "Telencephalon" is a term borrowed from embryology to identify not only the cerebral hemispheres of the forebrain, but also the basal forebrain. We review a generally undercited literature that describes nucleus basalis of Meynert, located within the substantia innominata of the ventrobasal forebrain, as a telencephalic extension of the ascending reticular activating formation. Although that formation's precise anatomical definition and localization have proven elusive over more than 70 years, a careful reading of sources reveals that there are histological features common to certain brainstem neurons and those of the nucleus basalis, and that a largely common dendritic architecture may be a morphological aspect that helps to define non-telencephalic structures of the ascending reticular activating formation (e.g., in brainstem) as well as those parts of the formation that are telencephalic and themselves responsible for cortical activation. We draw attention to a pattern of dendritic arborization described as "isodendritic," a uniform (isos-) branching in which distal dendrite branches are significantly longer than proximal ones. Isodendritic neurons also differ from other morphological types based on their heterogeneous, rather than specific afferentation. References reviewed here are consistent in their descriptions of histology, particularly in studies of locales rich in cholinergic neurons. We discuss the therapeutic implications of a basal forebrain site that may activate cortex. Interventions that specifically target nucleus basalis and, especially, the survival of its constituent neurons may benefit afflictions in which higher cortical function is compromised due to disturbed arousal or attentiveness, including not only coma and related syndromes, but also conditions colloquially described as states of cognitive "fog" or of "long-haul" mental compromise.

Sleep apnea pathophysiology.

OBJECTIVE: The purpose of this study is to examine the pathophysiology underlying sleep apnea (SA). BACKGROUND: We consider several critical features of SA including the roles played by the ascending reticular activating system (ARAS) that controls vegetative functions and electroencephalographic findings associated with both SA and normal sleep. We evaluate this knowledge together with our current understanding of the anatomy, histology, and physiology of the mesencephalic trigeminal nucleus (MTN) and mechanisms that contribute directly to normal and disordered sleep. MTN neurons express γ-aminobutyric acid (GABA) receptors which activate them (make chlorine come out of the cells) and that can be activated by GABA released from the hypothalamic preoptic area. METHOD: We reviewed the published literature focused on sleep apnea (SA) reported in Google Scholar, Scopus, and PubMed databases. RESULTS: The MTN neurons respond to the hypothalamic GABA release by releasing glutamate that activates neurons in the ARAS. Based on these findings, we conclude that a dysfunctional MTN may be incapable of activating neurons in the ARAS, notably those in the parabrachial nucleus, and that this will ultimately lead to SA. Despite its name, obstructive sleep apnea (OSA) is not caused by an airway obstruction that prevents breathing. CONCLUSIONS: While obstruction may contribute to the overall pathology, the primary factor involved in this scenario is the lack of neurotransmitters.

The reticular activating system: a narrative review of discovery, evolving understanding, and relevance to current formulations of brain death.

A series of landmark experiments conducted throughout the 20th century progressively localized the regions involved in consciousness to the reticular activating system (RAS) and its ascending projections. The first description of the RAS emerged in 1949 through seminal experiments performed by Moruzzi and Magoun in feline brainstems; additional experiments in the 1950s revealed connections between the RAS and the thalamus and neocortical structures. This knowledge has allowed for the explanation of disorders of consciousness with exquisite anatomic precision. The clinical relevance of the RAS is further apparent in modern definitions of brain death/death by neurologic criteria (BD/DNC), which require demonstration of the complete and permanent loss of capacity for consciousness as one of their core criteria. BD/DNC is currently understood across jurisdictions in terms of "whole brain" and "brainstem" formulations. Although their clinical examination between formulations is indistinguishable, policies for BD/DNC declaration may differ in the rare scenario of patients with isolated infratentorial brain injuries, in which ancillary testing is advised in the whole brain formulation but not the brainstem formulation. Canadian guidelines acknowledge that the distinction between whole brain and brainstem formulations is unclear with respect to clinical implications for patients with isolated infratentorial injuries. This has led to variability in Canadian clinicians' use of ancillary testing when the mechanism of BD/DNC is suspected to be an isolated infratentorial injury. The present narrative review highlights these concepts and explores implications for determination of BD/DNC in Canada, with specific emphasis on the RAS and its relevance to both formulations.

RéSUMé: Une série d'expériences marquantes menées tout au long du 20e siècle a progressivement permis de localiser les régions impliquées dans la conscience dans le système d'activation réticulaire (SAR) et ses projections ascendantes. La première description du SAR a vu le jour en 1949 grâce à des expériences fondatrices réalisées par Moruzzi et Magoun dans des troncs cérébraux félins; d'autres expériences menées au cours des années 1950 ont révélé des liens entre le SAR et le thalamus et les structures néocorticales. Ces connaissances ont permis d'expliquer les troubles de la conscience avec une précision anatomique extraordinaire. La pertinence clinique du SAR est encore plus évidente dans les définitions modernes de la mort cérébrale / du décès déterminé par des critères neurologiques (MC/DCN), qui exigent la démonstration de la perte complète et permanente de la capacité de conscience comme l'un de ses critères de base. La mort cérébrale est actuellement comprise partout en termes de formulations de « cerveau entier ¼ et de « tronc cérébral ¼. Bien que l'examen clinique ne fasse pas de distinction entre ces formulations, les politiques de déclaration de MC/DCN peuvent différer dans le rare cas de patients présentant des lésions cérébrales infratentorielles isolées, pour lesquels des examens auxiliaires sont conseillés lorsqu'on parle de cerveau entier mais pas lorsqu'on utilise la formulation de tronc cérébral. Les lignes directrices canadiennes reconnaissent que la distinction entre les termes de cerveau entier et de tronc cérébral n'est pas claire en ce qui concerne leurs implications cliniques pour les patients présentant des lésions infratentorielles isolées. Cela a entraîné une variabilité dans l'utilisation des examens auxiliaires par les cliniciens canadiens lorsqu'ils soupçonnent que le mécanisme de MC/DCN consiste en une lésion infratentorielle isolée. Ce compte rendu narratif met en lumière ces concepts et explore les implications pour la détermination de la MC/DCN au Canada, en mettant une emphase spécifique sur le SAR et sa pertinence pour les deux formulations.

Memories without Survival: Personal Identity and the Ascending Reticular Activating System.

Lockean views of personal identity maintain that we are essentially persons who persist diachronically by virtue of being psychologically continuous with our former selves. In this article, I present a novel objection to this variant of psychological accounts, which is based on neurophysiological characteristics of the brain. While the mental states that constitute said psychological continuity reside in the cerebral hemispheres, so that for the former to persist only the upper brain must remain intact, being conscious additionally requires that a structure originating in the brainstem-the ascending reticular activating system-be functional. Hence, there can be situations in which even small brainstem lesions render individuals irreversibly comatose and thus forever preclude access to their mental states, while the neural correlates of the states themselves are retained. In these situations, Lockeans are forced to regard as fulfilled their criterion of diachronic persistence since psychological continuity, as they construe it, is not disrupted. Deeming an entity that is never again going to have any mental experiences to be a person, however, is an untenable position for a psychological account to adopt. In their current form, Lockean views of personal identity are therefore incompatible with human neurophysiology.

Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study.

BACKGROUND AND AIMS: Social norms and legality surrounding the use of medical and recreational cannabis are changing rapidly. The prevalence of cannabis use in adolescence is increasing. The aim of this study was to assess any sex-based neurobiological effects of chronically inhaled, vaporised cannabis on adolescent female and male mice. METHODS: Female and male mice were exposed daily to vaporised cannabis (10.3% Δ-9-tetrahydrocannabinol [THC] and 0.05% cannabidiol [CBD]) or placebo from postnatal day 23 to day 51. Following cessation of treatment, mice were examined for changes in brain structure and function using noninvasive multimodal magnetic resonance imaging (MRI). Data from voxel-based morphometry, diffusion weighted imaging and rest state functional connectivity were registered to and analysed with a 3D mouse atlas with 139 brain areas. Following imaging, mice were tested for their preference for a novel object. RESULTS: The effects were sexually dimorphic with females showing a unique distribution and inverse correlation between measures of fractional anisotropy and apparent diffusion coefficient localised to the forebrain and hindbrain. In contrast males displayed significant increased functional coupling with the thalamus, hypothalamus and brainstem reticular activating system as compared with controls. Cannabis males also presented with altered hippocampal coupling and deficits in cognitive function. CONCLUSION: Chronic exposure to inhaled vaporised cannabis had significant effects on brain structure and function in early adulthood corroborating much of the literature. Females presented with changes in grey matter microarchitecture, while males showed altered functional connectivity in hippocampal circuitry and deficits in object recognition.

Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice.

BACKGROUND: The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense. METHODS: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements. RESULTS: CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex. CONCLUSION: The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

Direct Parabrachial-Cortical Connectivity.

The parabrachial nucleus (PB) in the upper brain stem tegmentum includes several neuronal subpopulations with a wide variety of connections and functions. A subpopulation of PB neurons projects axons directly to the cerebral cortex, and limbic areas of the cerebral cortex send a return projection directly to the PB. We used retrograde and Cre-dependent anterograde tracing to identify genetic markers and characterize this PB-cortical interconnectivity in mice. Cortical projections originate from glutamatergic PB neurons that contain Lmx1b (81%), estrogen receptor alpha (26%), and Satb2 (20%), plus mRNA for the neuropeptides cholecystokinin (Cck, 48%) and calcitonin gene-related peptide (Calca, 13%), with minimal contribution from FoxP2+ PB neurons (2%). Axons from the PB produce an extensive terminal field in an unmyelinated region of the insular cortex, extending caudally into the entorhinal cortex, and arcing rostrally through the dorsolateral prefrontal cortex, with a secondary terminal field in the medial prefrontal cortex. In return, layer 5 neurons in the insular cortex and other prefrontal areas, along with a dense cluster of cells dorsal to the claustrum, send a descending projection to subregions of the PB that contain cortically projecting neurons. This information forms the neuroanatomical basis for testing PB-cortical interconnectivity in arousal and interoception.

Neonatal spectral EEG is prognostic of cognitive abilities at school age in premature infants without overt brain damage.

Prematurity is a prototype of biological risk that could affect the late neurocognitive outcome; however, the condition itself remains a non-specific marker. This longitudinal 6-year study aimed to evaluate the prognostic role of neonatal spectral EEG in premature infants without neurological complications. The study cohort was 26 children born 23-34 gestational ages; all neonates underwent multichannel EEG recordings at 35 weeks post-conception. EEG data were transformed into the frequency domain and divided into delta (0.5-4 Hz), theta (5-7 Hz), alpha (8-13 Hz), and beta (14-20 Hz) frequency bands. At 6 years, a neuropsychological and behavioral evaluation was performed. Correlations between spectral bands and neuropsychological assessments were performed with a conservative and robust Bayesian correlation model using weakly informative priors. The correlation of neuropsychological tasks to spectral frequency bands highlighted a significant association with visual and auditory attention tests. The performance on the same tests appears to be mainly impaired.Conclusions: We found that spectral EEG frequencies are independent predictors of performance in attention tasks. We hypothesized that spectral EEG might reflect early circuitries' imbalance in the reticular ascending system and cumulative effect on ongoing development, pointing to the importance of early prognostic instruments. What is Known: • Prematurity is a non-specific marker of late neurocognitive risk. • Precise prognostic instruments are lacking, mostly in patients with low-grade conditions. What is New: • Longitudinal long-term studies are scarce but crucial for the inferential attributive process. • Spectral EEG frequencies are independent predictors of performance in attention tasks.

Association between Excessive Daytime Sleepiness and the Cholinergic Ascending Reticular System in Parkinson's Disease.

BACKGROUND: Excessive daytime sleepiness (EDS) in Parkinson's disease (PD) may occur because of dysfunction on the brain areas in controlling wakefulness; however, the pathophysiology of EDS in PD has not been completely clarified. The Pb component of a middle-latency auditory evoked response (MLR) is generated from the cholinergic ascending reticular activating system (ARAS) projecting to the auditory cortex via the thalamus. We examined the association between EDS and the Pb component in patients with PD. METHODS: Participants were 38 patients with nondemented PD and 18 age-matched controls. EDS was evaluated using the Japanese version of the Epworth Sleepiness Scale (JESS). PD patients were classified into the high sleepiness (HS) group and the low sleepiness (LS) group by the score of JESS. MLRs were recorded from the scalp with each earlobe as a reference under presentation of 1-Hz and 65- to 90-dB click sounds. RESULTS: There was no difference in age, duration, and motor function between the HS PD and the LS PD groups. Peak latencies of Pb were not different between PD group and controls; however, Pb amplitudes were significantly increased in the HS PD group compared with the LS PD group and controls. CONCLUSION: One of the mechanisms of EDS in PD was suggested to be dysregulation of cholinergic neurons from the ARAS projecting to cortical cholinergic neurons.