Caudal Brainstem Research Articles

Postnatal functional integrity of the brainstem auditory pathway in late preterm infants born of small-for-gestation age: how different from those born of appropriate-for-gestation.

It is unclear whether there is any postnatal abnormality in brainstem auditory function in late preterm small-for-gestational-age (SGA) infants. We investigated the functional integrity of the brainstem auditory pathway at 4months after term in late preterm SGA infants and defined differences from appropriate-for-gestational age (AGA) infants. The maximum length sequence brainstem evoked response (MLS BAER) was recorded and analyzed in 24 SGA (birthweight < 3rd centile) infants and 28 AGA infants (birthweight > 10th centile). All infants were born at 33-36-week gestation without major perinatal and postnatal problems. We found that I-V interval in SGA infants was shorter than in AGA infants at higher click rates and significantly shorter at the highest rate of 910/s. Of the two smaller intervals, I-III interval was significantly shorter in SGA infants than in AGA infants at higher click rates of 455 and 910/s clicks, whereas III-V interval was similar in the two groups. The III-V/I-III interval ratio in SGA infants tended to be greater than in AGA infants at all rates and was significantly greater at 455 and 910/s clicks. The slope of I-III interval-rate functions in SGA infants was moderately smaller than in AGA infants. Conclusions: The main and fundamental difference between late preterm SGA and AGA infants was a significant shortening in the MLS BAER I-III interval in SGA infants at higher click rates, suggesting moderately faster neural conduction in the caudal brainstem regions. Postnatal neural maturation in the caudal brainstem regions is moderately accelerated in late preterm SGA infants. What is Known: • At 40weeks of postconceptional age, late preterm SGA infants manifested a mild delay in neural conduction in the auditory brainstem. What is New: • At 56weeks of postconceptional age, late preterm SGA infants manifested moderately faster neural conduction in the caudal brainstem regions. • Postnatal neural maturation is moderately accelerated in the caudal brainstem regions of late preterm SGA infants.

Sequential appetite suppression by oral and visceral feedback to the brainstem

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1–4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.

A new Hoxb8FlpO mouse line for intersectional approaches to dissect developmentally defined adult sensorimotor circuits.

Improvements in the speed and cost of expression profiling of neuronal tissues offer an unprecedented opportunity to define ever finer subgroups of neurons for functional studies. In the spinal cord, single cell RNA sequencing studies support decades of work on spinal cord lineage studies, offering a unique opportunity to probe adult function based on developmental lineage. While Cre/Flp recombinase intersectional strategies remain a powerful tool to manipulate spinal neurons, the field lacks genetic tools and strategies to restrict manipulations to the adult mouse spinal cord at the speed at which new tools develop. This study establishes a new workflow for intersectional mouse-viral strategies to dissect adult spinal function based on developmental lineages in a modular fashion. To restrict manipulations to the spinal cord, we generate a brain-sparing Hoxb8FlpO mouse line restricting Flp recombinase expression to caudal tissue. Recapitulating endogenous Hoxb8 gene expression, Flp-dependent reporter expression is present in the caudal embryo starting day 9.5. This expression restricts Flp activity in the adult to the caudal brainstem and below. Hoxb8FlpO heterozygous and homozygous mice do not develop any of the sensory or locomotor phenotypes evident in Hoxb8 heterozygous or mutant animals, suggesting normal developmental function of the Hoxb8 gene and protein in Hoxb8FlpO mice. Compared to the variability of brain recombination in available caudal Cre and Flp lines, Hoxb8FlpO activity is not present in the brain above the caudal brainstem, independent of mouse genetic background. Lastly, we combine the Hoxb8FlpO mouse line with dorsal horn developmental lineage Cre mouse lines to express GFP in developmentally determined dorsal horn populations. Using GFP-dependent Cre recombinase viruses and Cre recombinase-dependent inhibitory chemogenetics, we target developmentally defined lineages in the adult. We show how developmental knock-out versus transient adult silencing of the same ROR𝛃 lineage neurons affects adult sensorimotor behavior. In summary, this new mouse line and viral approach provides a blueprint to dissect adult somatosensory circuit function using Cre/Flp genetic tools to target spinal cord interneurons based on genetic lineage.

Biopsies of Caudal Brainstem Tumors in Pediatric Patients—A Single-Center Retrospective Case Series

The indication for performing biopsies in patients with diffuse lesions in the brain stem is controversial. Possible risks associated with the technical challenging interventions need to be balanced against clarifying the diagnosis and possible therapeutic options. We reviewed the feasibility, risk profile and diagnostic yield of different biopsy techniques in a pediatric cohort. We retrospectively included all patients under 18 years of age that received a biopsy of the caudal brainstem region (pons, medulla oblongata) at our pediatric neurosurgical center from 2009-2022. We identified 27 children. Biopsies were performed using frameless stereotactic (Varioguide) (n=12), robotic assisted (Autoguide) (n=4), endoscopic (n=3) and open biopsy (n=8) technique. Intervention related mortality was not observed. Three patients experienced transient post-surgical neurological deficit. No patient showed intervention related permanent morbidity. Biopsy yielded histopathological diagnosis in all cases. Molecular analysis was feasible in 97% of cases. Most common diagnosis was H3K27M mutated diffuse midline glioma (60%). Low-grade gliomas were identified in 14%. Overall survival was 62.5% after 24 months of follow up. Biopsies of the caudal brainstem in children were feasible and safe in the presented setup. The amount of acquired tumor material allowing integrated diagnosis and was obtained at reasonable risk. The selection of the surgical technique depends on tumor location and growth pattern. We recommend brainstem tumor biopsies in children being performed at specialized centers to better understand the biology and enable possible novel therapeutic options.

Altered maturation in brainstem neural conduction in very premature babies with fetal growth restriction.

Using maximum length sequence brainstem auditory evoked response (MLS BAER) to study brainstem neural conduction and maturation in fetal growth restriction (FGR) babies born very prematurely and assess the effect of FGR on brainstem neural maturation. MLS BAER was recorded and analyzed at a mean 40 week postmenstrual age in babies born at 27-32 week gestation without other major perinatal conditions or problems. The data were compared between babies with FGR (n = 30) and age-matched babies without FGR (n = 34) to define any differences. A notable difference in MLS BAER was found in interpeak intervals between the babies with FGR and those without FGR. The FGR babies manifested significantly shortened I-III interval, moderately prolonged III-V interval, and significantly decreased III-V/I-III interval ratio. The slope of the I-III interval-rate function in FGR babies was moderately decreased, relative to that in the babies without FGR. FGR babies born very prematurely are associated with accelerated or precocial neural maturation at caudal brainstem regions, but moderately delayed maturation at rostral brainstem regions. The altered brainstem neural maturation is different from previously reported mildly delayed maturation in FGR babies born less prematurely, and may have important implication for neurodevelopmental outcome. This first MLS BAER study in FGR found that brainstem neural maturation in very premature FGR babies differed from age-matched non-FGR babies. Neural maturation in very premature FGR babies is accelerated or precocial at caudal brainstem regions but moderately delayed at rostral brainstem regions. The altered maturation is different from previously reported mild delay in brainstem neural maturation in FGR babies born less prematurely. FGR exerts a major and differential effect on brainstem neural maturation in babies born very prematurely. This alteration in very premature FGR babies may have important implication for their neurodevelopment.

Body Lateropulsion and Pusher Behavior

The relationship between postural disturbance and vertical perception after cerebrovascular disease remains unclear and studies have only recently begun to be conducted. On the other hand, the symptomatic aspect is evident: body lateropulsion is ipsilateral in the case of caudal brainstem lesions and contralateral in the case of rostral brainstem and cerebral hemispheric lesions. In addition, patients with cerebral hemispheric lesions sometimes show“pusher behavior” in which they resist any attempt to correct their posture and push the body back to the paralyzed side using the healthy limbs, as they have a fear of deviation to the healthy side. The pusher behavior is always accompanied by hemiplegia and is detected in about 10% of cases of hemispheric vascular lesions.

Long-term follow-up of surgical intervention pattern in pediatric low-grade gliomas: report from the German SIOP-LGG 2004 cohort.

Neurosurgical treatment is an integral part of the treatment algorithms for pediatric low-grade glioma (LGG), yet patterns of surgical procedures are rarely challenged. The objective of this study was to evaluate surgical treatment patterns in pediatric LGG. The German Societé Internationale d'Oncologie Pédiatrique (SIOP)-LGG 2004 cohort was analyzed to identify relevant patient and tumor characteristics associated with time to death, next surgery, number of resections, and radiological outcome. A total of 1271 patients underwent 1713 neurosurgical interventions (1 intervention in 947, 2 in 230, 3 in 70, and 4-6 in 24). The median age of the study population was 8.57 years at first surgery, and 46.1% were female. Neurofibromatosis type 1 (NF1) was found in 4.4%, and 5.4% had tumor dissemination. Three hundred fifty-four patients (27.9%) had chemotherapy and/or radiotherapy. The cumulative incidence of second surgery at 10 years was 26%, and was higher for infants, those with spinal and supratentorial midline (SML) tumors, and those with pilomyxoid astrocytomas. The hazard ratio for subsequent surgery was higher given dissemination and noncomplete initial resection, and lower for caudal brainstem and SML tumors. Among 1225 patients with fully documented surgical records and radiological outcome, 613 reached complete remission during the observation period, and 50 patients died. Patients with pilocytic astrocytoma had higher chances for a final complete remission, whereas patients with initial partial or subtotal tumor resection, dissemination, NF1, or primary tumor sites in the spinal cord and SML had lower chances. Neurosurgery is a key element of pediatric LGG treatment. In almost 50% of the patients, however, at least some tumor burden will remain during long-term follow-up. This study found that most of these patients reached a stable disease status without further surgeries. Multidisciplinary team decisions must balance the goal of complete resection, risk factors, repeated surgeries, and possible treatment alternatives in a wide range of heterogeneous entities. Procedural details and neurological outcome should be recorded to better assess their impact on long-term outcome.

Diagnostic and prognostic role of magnetic resonance imaging in cases of moderate to severe traumatic brain injury

Moderate to severe traumatic brain injury (TBI) remains a leading cause of death and disability worldwide. Timely diagnosis and accurate prognostication play a key role in informed clinical decision-making. Though magnetic resonance imaging (MRI) is a superior anatomical scan compared to computerized tomography (CT), the latter remains the current investigation of choice in the clinical setting of TBI due to some of the former’s inherent deficiencies in imaging bone/blood, limited access, cost, etc. Nevertheless, the fact that MRI is a valuable adjunct in evaluating the TBI patients with clinical findings disproportionate to the CT scan substantiates its possible complementary/supplementary diagnostic and prognostic role in TBI. MRI scan is ideally placed on demonstrating the shear/diffuse axonal injury (DAI), non-haemorrhagic intraparenchymal lesions, and brain stem lesions poorly delineated by a CT scan. The currently available literature demonstrates that DAI and caudal brainstem lesions are indicators of poorer outcomes. However, the prognostic value of MRI, in addition to that of CT, remains an area of active investigation. We have tried to present the evidence-based use of MRI in moderate to severe TBI. Advances in newer MRI sequences like susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), functional MRI (fMRI), and magnetic encephalography (MEG) have the potential to revolutionize the current role of MRI in TBI.

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed). Moreover, AMPK-α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.

Central NPFF signalling is critical in the regulation of glucose homeostasis

ObjectiveNeuropeptide FF (NPFF) group peptides belong to the evolutionary conserved RF-amide peptide family. While they have been assigned a role as pain modulators, their roles in other aspects of physiology have received much less attention. NPFF peptides and their receptor NPFFR2 have strong and localized expression within the dorsal vagal complex that has emerged as the key centre for regulating glucose homeostasis. Therefore, we investigated the role of the NPFF system in the control of glucose metabolism and the histochemical and molecular identities of NPFF and NPFFR2 neurons. MethodsWe examined glucose metabolism in Npff−/− and wild type (WT) mice using intraperitoneal (i.p.) glucose tolerance and insulin tolerance tests. Body composition and glucose tolerance was further examined in mice after 1-week and 3-week of high-fat diet (HFD). Using RNAScope double ISH, we investigated the neurochemical identity of NPFF and NPFFR2 neurons in the caudal brainstem, and the expression of receptors for peripheral factors in NPFF neurons. ResultsLack of NPFF signalling in mice leads to improved glucose tolerance without significant impact on insulin excursion after the i.p. glucose challenge. In response to an i.p. bolus of insulin, Npff−/− mice have lower glucose excursions than WT mice, indicating an enhanced insulin action. Moreover, while HFD has rapid and potent detrimental effects on glucose tolerance, this diet-induced glucose intolerance is ameliorated in mice lacking NPFF signalling. This occurs in the absence of any significant impact of NPFF deletion on lean or fat masses, suggesting a direct effect of NPFF signalling on glucose metabolism. We further reveal that NPFF neurons in the subpostrema area (SubP) co-express receptors for peripheral factors involved in glucose homeostasis regulation such as insulin and GLP1. Furthermore, Npffr2 is expressed in the glutamatergic NPFF neurons in the SubP, and in cholinergic neurons of the dorsal motor nucleus of the vagus (DMV), indicating that central NPFF signalling is likely modulating vagal output to innervated peripheral tissues including those important for glucose metabolic control. ConclusionsNPFF signalling plays an important role in the regulation of glucose metabolism. NPFF neurons in the SubP are likely to receive peripheral signals and mediate the control of whole-body glucose homeostasis via centrally vagal pathways. Targeting NPFF and NPFFR2 signalling may provide a new avenue for treating type 2 diabetes and obesity.

A red flag for diagnosing brain death: decompressive craniectomy of the posterior fossa

PurposeBrain death/death by neurologic criteria (BD/DNC) may be determined in many countries by a clinical examination that shows coma, brainstem areflexia, and apnea, provided the conditions causing reversible loss of brain function are excluded a priori. To date, accounts of recovery from BD/DNC in adults have been limited to noncompliance with guidelines.Clinical featuresWe report the case of a 72-yr-old man with a combined primary infratentorial (hemorrhagic) and secondary global (anoxic) brain lesion in whom decompressive craniectomy of the posterior fossa and six-hour therapeutic hypothermia (33–34°C) followed by 8-hour rewarming to ≥ 36°C were conducted. Thirteen hours later, clinical findings of brain function loss were documented in addition to guideline-compliant exclusion of reversible causes (arterial hypotension, intoxication, depressant drug effects, relevant metabolic or endocrine disequilibrium, chronic hypercapnia, neuromuscular disorders, and administration of a muscle relaxant). Since a primary infratentorial brain lesion was present, German guidelines required further ancillary testing. Doppler ultrasonography revealed some preserved cerebral circulation, and BD/DNC was not diagnosed. Approximately 24 hr after rewarming to ≥ 36°C, the patient exhibited respiratory efforts. He continued with assisted respiration until final asystole/apnea, without regaining additional brain function other than mild signs of hemispasticity. Follow-up computed tomography showed partial herniation of the cerebellum through the craniectomy gap of the posterior fossa, alleviating caudal brain stem compression.ConclusionsTherapeutic decompressive craniectomy of the posterior fossa may allow for delayed reversal of apnea. In these patients, proof of cerebral circulatory arrest should be mandatory for diagnosing BD/DNC.

Title: P2x7 Receptor Activation and Estrogen Status Drive Neuroinflammatory Mechanisms in a Rat Model for Dry Eye.

Dry eye disease (DED) is recognized as a chronic inflammatory condition with an increase in tear osmolarity and loss of tear film integrity. DED is often accompanied by adverse ocular symptoms which are more prevalent in females than males. The basis for ocular hyperalgesia in DED remains uncertain; however, both peripheral and central neural mechanisms are implicated. A model for aqueous deficient DED, exorbital gland excision, was used to determine if activation of the purinergic receptor subtype 7, P2X7R, expressed by non-neural cells in peripheral and central trigeminal nerve pathways, contributed to persistent ocular hyperalgesia. Densitometry of trigeminal brainstem sections revealed increases in P2X7R, the myeloid cell marker Iba1, and the inflammasome, NLRP3, of estradiol-treated DED females compared to estradiol-treated sham females, while expression in DED males and DED females not given estradiol displayed minor changes. No evidence of immune cell infiltration into the trigeminal brainstem was seen in DED rats; however, markers for microglia activation (Iba1) were increased in all groups. Isolated microglia expressed increased levels of P2X7R and P2X4R, IL-1β (Ιnterleukin-1β), NLRP3, and iNOS (nitric oxide synthase). Further, estradiol-treated DED females displayed greater increases in P2X7R, IL-1β and NLRP3 expression compared to untreated DED females. Orbicularis oculi muscle activity (OOemg) evoked by ocular instillation of hypertonic saline (HS) was recorded as a surrogate measure of ocular hyperalgesia and was markedly enhanced in all DED groups compared to sham rats. Systemic minocycline reduced HS-evoked OOemg in all DED groups compared to sham rats. Local microinjection in the caudal trigeminal brainstem of an antagonist for P2X7R (A804598) greatly reduced HS-evoked OOemg activity in all DE groups, while responses in sham groups were not affected. Intra-trigeminal ganglion injection of siRNA for P2X7R significantly reduced HS-evoked OOemg activity in all DED groups, while evoked responses in sham animals were not affected. These results indicated that activation of P2X7R at central and peripheral sites in trigeminal pain pathways contributed to an increase in ocular hyperalgesia and microglia activation in DED males and females. Estrogen treatment in females further amplified ocular hyperalgesia and neuroimmune responses in this model for aqueous deficient DED.

Stereotaxic Surgical Approach to Microinject the Caudal Brainstem and Upper Cervical Spinal Cord via the Cisterna Magna in Mice.

Stereotaxic surgery to target brain sites in mice is commonly guided by skull landmarks. Access is then obtained via burr holes drilled through the skull. This standard approach can be challenging for targets in the caudal brainstem and upper cervical cord due to specific anatomical challenges as these sites are remote from skull landmarks, leading to imprecision. Here we outline an alternative stereotaxic approach via the cisterna magna that has been used to target discrete regions of interest in the caudal brainstem and upper cervical cord. The cisterna magna extends from the occipital bone to the atlas (i.e., the second vertebral bone), is filled with cerebrospinal fluid, and is covered by dura mater. This approach provides a reproducible route of access to select central nervous system (CNS) structures that are otherwise hard to reach due to anatomical barriers. Furthermore, it allows for direct visualization of brainstem landmarks in close proximity to the target sites, increasing accuracy when delivering small injection volumes to restricted regions of interest in the caudal brainstem and upper cervical cord. Finally, this approach provides an opportunity to avoid the cerebellum, which can be important for motor and sensorimotor studies.

Spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by biallelic mutations in the SMN1 (survival motor neuron1) gene on chromosome 5q13.2, which leads to aprogressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles, although the facial muscles and eye muscles are not affected. The previously purely symptom-oriented treatment has undergone asignificant expansion since 2017 with the approval of three drugs (nusinersen, onasemnogene abeparvovec and risdiplam) that modify the course of the disease at the gene expression level and have led to achange in the natural disease course of SMA. The effect of these new forms of treatment can only be fully assessed in the coming years. New aspects and challenges in this context are discussed in this article.

Degenerate brainstem circuitry after combined physiochemical exposure to jet fuel and noise

ABSTRACT Degenerate neural circuits exhibit “different” circuit properties yet produce similar circuit outcomes (many-to-one) which ensures circuit robustness and complexity. However, neuropathies may hijack degeneracy to yield robust and complex pathological circuits. The aim of the current study was to test the hypothesis that physiochemical exposure to combined jet fuel and noise might induce degeneracy in the brainstem. The auditory brainstem of pigmented rats was used as a model system. The animals were randomized into the following experimental groups: Fuel+Noise, fuel-only, noise-only, and control. Ascending volume conductance from various auditory brainstem regions were evaluated simultaneously with peripheral nervous system (PNS) input to brainstem circuitry. Data demonstrated normal PNS inputs for all groups. However, the Fuel+Noise exposure group produced different caudal brainstem circuit properties while rostral brainstem circuitry initiated outputs that were similar to that of control. This degenerative effect was specific to Fuel+Noise exposure, since neither noise-alone or fuel-alone produced the same result. Degeneracy in the auditory brainstem is consistent with perceptual abnormalities, such as poor speech discrimination (hear but not understand), tinnitus (ringing in the ear), hyperacusis (hypersensitivity to even low-level sound), and loudness intolerance. Therefore, a potential consequence of Fuel+Noise exposure among military and civilian populations may be evidenced as increased rates of super-threshold auditory perceptual abnormalities. This is particularly important because to date, the ototoxic profile of Fuel+Noise exposure has remained unresolved.

Lesion distribution pattern of parenchymal Neuro-Behçet's disease using probability mapping

Background and PurposeBehçet's disease (BD) is an inflammatory disorder with multisystemic involvement. The most disabling aspect of BD is Neuro-Behçet's disease (NBD). In NBD, parenchymal lesions tend to occur in the mesodiencephalic region and brainstem, as reported in large series of NBD. Our study aimed to generate probability maps of parenchymal lesions to compare patient subgroups with different clinical and laboratory features. MethodWe included 66 non-standardized acute relapse MRIs of 55 patients with parenchymal NBD (p-NBD). We used T2-weighted axial images to digitalize the lesions using the CAD software. Boundaries of lesions were determined as polygons and converted into high-definition raster datasets. Then, digitalized lesion maps were transferred into the ICBM-152 brain template to perform spatial analyses. Finally, we created subtraction maps to compare the patient subgroups. ResultsWe used a total of 66 MRIs of 55 patients to generate the probability maps. The most frequently affected parenchymal structures were the rostral pons, mesencephalon, and diencephalic region. Interestingly, the brainstem was more commonly affected in females than males (p<0.01). In the late-onset disease, lesions were localized in the corticospinal tracts and caudal brainstem (p<0.01). Progressive disease and severe disability at the end of the follow-up period were associated with corticospinal tract lesions during relapses (p<0.01). Patients with positive pathergy tests were more likely to present right hemisphere involvement (p<0.01). Additionally, cyclosporine-induced lesions tend to be in atypical locations such as hemispheric white matter. ConclusionsIn the published studies, lesions in NBD were localized according to coarse anatomical regions. Our study uses visual maps to offer accurate lesion localizations using non-standardized brain MRIs, allowing comparisons across different NBD subgroups. By using this technique, we investigated the relationship of the clinical and laboratory features with the lesion locations. We found that the late age of onset was associated with a poor prognosis. Additionally, corticospinal lesions may predict severe and progressive disease course, requiring aggressive treatment. Interestingly, females had more brainstem lesions and lesion lateralization might be influenced by the pathergy test status.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. MethodsWe employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. ResultsWe found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. ConclusionsIn addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment.

Mind affects matter: Hindbrain GLP1 neurons link stress, physiology and behaviour.

What is the topic of this review? This Lecture covers the role of caudal brainstem GLP1 neurons in acute and chronic stress responses. What advances does it highlight? This Lecture focuses on the recent advances in our understanding of GLP1 neurons and their physiological role in many aspects of stress. Particular focus is given to the recent elucidation, in part, of the anatomical basis for recruitment of GLP1 neurons in response to acute stress. Finally, the potential, but at this time somewhat speculative, role of GLP1 neurons in chronic stress is discussed. The brain responds rapidly to stressful stimuli by increasing sympathetic outflow, activating the hypothalamic-pituitary-adrenal axis and eliciting avoidance behaviours to limit risks to safety. Stress responses are adaptive and essential but can become maladaptive when the stress is chronic, causing autonomic imbalance, hypothalamic-pituitary-adrenal axis hyper-reactivity and a state of hypervigilance. Ultimately, this contributes to the development of cardiovascular disease and affective disorders, including major depression and anxiety. Stress responses are often thought to be driven mainly by forebrain areas; however, the brainstem nucleus of the solitary tract (NTS) is ideally located to control both autonomic outflow and behaviour in response to stress. Here, I review the preclinical evidence that the NTS and its resident glucagon-like peptide-1 (GLP1)-expressing neurons are prominent mediators of stress responses. This Lecture introduces the reader to the idea of good and bad stress and outlines the types of stress that engage the NTS and GLP1 neurons. I describe in particular detail the recent studies by myself and others aimed at mapping sources of synaptic inputs to GLP1 neurons and consider the implications for our understanding of the role of GLP1 neurons in stress. This is followed by a discussion of the contribution of brain GLP1 and GLP1 neurons to behavioural and physiological stress responses. The evidence reviewed highlights a potentially prominent role for GLP1 neurons in the response of the brain to acute stress and reveals important unanswered questions regarding their role in chronic stress.

The diverse effects of brain glucagon‐like peptide 1 receptors on ingestive behaviour

Glucagon-like peptide 1 (GLP-1) is well known as a gut hormone and also acts as a neuropeptide, produced in a discrete population of caudal brainstem neurons that project widely throughout the brain. GLP-1 receptors are expressed in many brain areas of relevance to energy balance, and stimulation of these receptors at many of these sites potently suppresses food intake. This review surveys the current evidence for effects mediated by GLP-1 receptors on feeding behaviour at a wide array of brain sites and discusses behavioural and neurophysiological mechanisms for the effects identified thus far. Taken together, it is clear that GLP-1 receptor activity in the brain can influence feeding by diverse means, including mediation of gastrointestinal satiation and/or satiety signalling, suppression of motivation for food reward, induction of nausea and mediation of restraint stress-induced hypophagia, but many questions about the organization of this system remain.

Mapping of the Substrate for Production of Swallow and Cough Within the Rostral Nucleus of the Tractus Solitarius (NTS)/Paramedian Reticular Nucleus by Electrical Stimulation

Swallow and cough are airway protective behaviors which are regulated via overlapping networks in the brainstem. However, it is not known if there are locations in the caudal brainstem which are capable of centrally stimulating both behaviors. To this end, a craniotomy was performed in sodium-pentobarbital anesthetized freely-breathing animals (n = 8). Electromyograms were recorded from upper airway and respiratory muscles to confirm swallow, cough, breathing, and other airway protective behaviors. Using a concentric monopolar electrode, a series of stimulations were performed across the dorsal brainstem. The electrode was systematically placed at points ranging laterally from 0.6 to 3.4 mm, and rostrally from 0 to 2.6 mm away from obex with a depth ranging from 0.5 to 4.0 mm from the surface of the brainstem. We were able to elicit swallow at 63 loci. Visual inspection of the receptive field indicated 2 sub-populations, and a k-means clustering analysis of these points centered them at stereotaxic coordinates (Lateral, Rostral, Depth) of [2.72, 1.82, 1.82] and [1.07, 0.78, 2.46]. In contrast, cough was only elicited in 1 animal at 8 locations in and around the NTS/paramedian reticular nucleus, with a cluster centered around [0.85, 0.53, 2.63]; these locations also elicited swallowing. These results are consistent with and extend early work of Sherrington (1915) and Markwald (1886). The neural substrate responsible for the production of swallow in this region of the medulla appears to be more expansive than that for cough. Our limited success in inducing cough with electrical stimulation in these areas is consistent with: a) a more anatomically distributed cough network relative to that for swallow, and/or b) more complex local synaptic mechanisms for induction of coughing that are resistant to actuation by electrical stimulation. An example of such a mechanism is selective inhibition of some neuron populations that are required to bring cough to threshold. In this case, frank excitation of these populations by electrical stimulation would have a limited effect in eliciting coughing.