Lower Brainstem Research Articles

Basilar invagination presenting as recurrent posterior circulation stroke with locked-in syndrome in a child: a case report

Basilar invagination is a type of craniovertebral junction anomaly which occurs when the tip of odontoid process migrates upward into the intracranial space through foramen magnum and most commonly present as progressive neurological deficit implicating the high cervical cord, lower brainstem and cranial nerves. It can rarely present as vertebro-basilar territory insufficiency and occlusion, leading to stroke. Treatment is typically surgical and continues to centre on varying combinations of anterior or posterior decompression with or without traction or fusion. We present a 13-year-old boy with basilar invagination diagnosed on MRI with angiogram, which was missed on initial presentation, leading to recurrent posterior circulation stroke progressed to Locked-in syndrome. This case report emphasis the need of screening for craniovertebral junction anomalies in young patients presenting with posterior circulation stroke.

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents.

Although genetic factors contribute to almost half of all deafness cases, treatment options for genetic deafness are limited1–5. We developed a genome editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9:guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated in vitro and in primary fibroblasts genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like 1) Beethoven (Bth) mouse model, even though the mutant Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9:guide RNA:lipid complexes targeting the Bth allele into the cochlea of neonatal Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response (ABR) thresholds in injected ears compared with uninjected ears or ears injected with complexes that target an unrelated gene. Enhanced acoustic reflex responses were observed among injected compared to uninjected Bth/+ animals. These findings suggest protein:RNA complex delivery of target gene-disrupting agents in vivo as a potential strategy for the treatment of some autosomal dominant hearing loss diseases.

Neuronal Population Activity in Spinal Motor Circuits: Greater Than the Sum of Its Parts.

The core elements of stereotypical movements such as locomotion, scratching and breathing are generated by networks in the lower brainstem and the spinal cord. Ensemble activities in spinal motor networks had until recently been merely a black box, but with the emergence of ultra-thin Silicon multi-electrode technology it was possible to reveal the spiking activity of larger parts of the network. A series of experiments revealed unexpected features of spinal networks, such as multiple spiking regimes and lognormal firing rate distributions. The lognormality renders the widespread idea of a typical firing rate ± standard deviation an ill-suited description, and therefore these findings define a new arithmetic of motor networks. Focusing on the population activity behind motor pattern generation this review summarizes this advance and discusses its implications.

A clinical-anatomical signature of Parkinson's disease identified with partial least squares and magnetic resonance imaging

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a wide array of motor and non-motor symptoms. It remains unclear whether neurodegeneration in discrete loci gives rise to discrete symptoms, or whether network-wide atrophy gives rise to the unique behavioural and clinical profile associated with PD. Here we apply a data-driven strategy to isolate large-scale, multivariate associations between distributed atrophy patterns and clinical phenotypes in PD. In a sample of N = 229 de novo PD patients, we estimate disease-related atrophy using deformation based morphometry (DBM) of T1 weighted MR images. Using partial least squares (PLS), we identify a network of subcortical and cortical regions whose collective atrophy is associated with a clinical phenotype encompassing motor and non-motor features. Despite the relatively early stage of the disease in the sample, the atrophy pattern encompassed lower brainstem, substantia nigra, basal ganglia and cortical areas, consistent with the Braak hypothesis. In addition, individual variation in this putative atrophy network predicted longitudinal clinical progression in both motor and non-motor symptoms. Altogether, these results demonstrate a pleiotropic mapping between neurodegeneration and the clinical manifestations of PD, and that this mapping can be detected even in de novo patients.

Cervical vestibular-evoked myogenic potentials in patients with multiple sclerosis: sensitive in detecting brainstem involvement?

Cervical vestibular-evoked myogenic potentials (cVEMPs) are accepted to demonstrate the vestibulo-collic reflex. However, the brainstem pathway is still not fully understood. The aim of the study was to evaluate the contribution of cVEMPs to detection of brainstem involvement in multiple sclerosis (MS). Thirty patients fulfilling the criteria for definite MS were included in the study. All were newly diagnosed cases, admitted due to an attack with active lesions on MRI. Thirty-one age- and sex-matched healthy controls constituted the control group. The latencies of peaks p13 and n23 and peak-to-peak amplitude of p13-n23 were measured. Brainstem lesions on MRI were present in 13 of the patients (43.4%). Comparison of the overall results recorded from patients with the healthy controls did not reveal a statistically significant difference in any of the parameters studied (p > 0.05). A significant inter-side difference was not also present between groups (p > 0.05). When p13 and n23 latencies exceeding 2.5 standard deviations (SD) were taken into consideration, it was seen that there were seven patients (23.3%) with prolonged latencies mainly involving the p13 peak. Five of them had brainstem signs on examination and had brainstem lesions on MRI. In the other eight patients with abnormal MRI, normal results were recorded indicating that in only 38% of patients with brainstem lesions, cVEMPs were altered. Absence of a correlation between cVEMPs and brainstem clinical or MRI lesions defies their role in identifying lower brainstem involvement.

Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

Corelease of Inhibitory Neurotransmitters in the Mouse Auditory Midbrain.

The central nucleus of the inferior colliculus (ICC) of the auditory midbrain, which integrates most ascending auditory information from lower brainstem regions, receives prominent long-range inhibitory input from the ventral nucleus of the lateral lemniscus (VNLL), a region thought to be important for temporal pattern discrimination. Histological evidence suggests that neurons in the VNLL release both glycine and GABA in the ICC, but functional evidence for their corelease is lacking. We took advantage of the GlyT2-Cre mouse line (both male and female) to target expression of ChR2 to glycinergic afferents in the ICC and made whole-cell recordings in vitro while exciting glycinergic fibers with light. Using this approach, it was clear that a significant fraction of glycinergic boutons corelease GABA in the ICC. Viral injections were used to target ChR2 expression specifically to glycinergic fibers ascending from the VNLL, allowing for activation of fibers from a single source of ascending input in a way that has not been previously possible in the ICC. We then investigated aspects of the glycinergic versus GABAergic current components to probe functional consequences of corelease. Surprisingly, the time course and short-term plasticity of synaptic signaling were nearly identical for the two transmitters. We therefore conclude that the two neurotransmitters may be functionally interchangeable and that multiple receptor subtypes subserving inhibition may offer diverse mechanisms for maintaining inhibitory homeostasis.SIGNIFICANCE STATEMENT Corelease of neurotransmitters is a common feature of the brain. GABA and glycine corelease is particularly common in the spinal cord and brainstem, but its presence in the midbrain is unknown. We show corelease of GABA and glycine for the first time in the central nucleus of the inferior colliculus of the auditory midbrain. Glycine and GABA are both inhibitory neurotransmitters involved in fast synaptic transmission, so we explored differences between the currents to establish a physiological foundation for functional differences in vivo In contrast to the auditory brainstem, coreleased GABAergic and glycinergic currents in the midbrain are strikingly similar. This apparent redundancy may ensure homeostasis if one neurotransmitter system is compromised.

The 200-year journey of Parkinson disease: Reflecting on the past and looking towards the future

It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967.Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation.At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.

The midline suboccipital subtonsillar approach to the cerebellomedullary cistern: how I do it.

Lesions lateral to the lower brainstem in an area extending from the foraminae of Luschka to the foramen magnum are rare and include different pathologies. There is no consensus on an ideal surgical approach. To gain access to this area, we use the midline suboccipital subtonsillar approach (STA). This midline approach with unilateral retraction of the cerebellar tonsil enables entry into the cerebellomedullary cistern. The STA offers excellent access with a panoramic view of the cerebellomedullary cistern and its structures and therefore can be useful for a number of different pathologies in the lower petroclival area.

Lateral habenula regulation of emotional hyperthermia: mediation via the medullary raph\xe9

The lateral habenula (LHb) has an important role in the behavioural response to salient, usually aversive, events. We previously demonstrated that activation of neurons in the LHb increases brown adipose tissue (BAT) thermogenesis and constricts the cutaneous vascular bed, indicating that the LHb contributes to the central control of sympathetic outflow to thermoregulatory effector organs. We have now investigated whether the LHb mediates BAT thermogenesis elicited by emotional stress, and whether the LHb modulates thermoregulatory sympathetic outflow via the rostral medullary raphé, a key integrative lower brainstem sympathetic control centre. In conscious animals, lesioning the LHb attenuated emotional BAT thermogenesis, suggesting that the LHb is part of the central circuitry mediating emotional hyperthermia. In anesthetized animals, inhibition of neurons in the rostral medullary raphé reversed BAT thermogenesis and cutaneous vasoconstriction elicited by activation of neurons in the LHb, indicating that the LHb-induced autonomic responses are mediated through activation of the rostral medullary raphé neurons. The latency to activate BAT sympathetic discharge from electrical stimulation of the LHb was substantially greater than the corresponding latency after stimulation of the medullary raphé, suggesting that the neuronal pathway connecting those two nuclei is quite indirect.

Speech-in-noise perception in unilateral hearing loss: Relation to pure-tone thresholds and brainstem plasticity.

We investigated speech recognition in noise in subjects with mild to profound levels of unilateral hearing loss. Thirty-five adults were evaluated using an adaptive signal-to-noise ratio (SNR50) sentence recognition threshold test in three spatial configurations. The results revealed a significant correlation between pure-tone average audiometric thresholds in the poorer ear and SNR thresholds in the two conditions where speech and noise were spatially separated: dichotic - with speech presented to the poorer ear and reverse dichotic - with speech presented to the better ear. This first result suggested that standard pure-tone air-conduction thresholds can be a reliable predictor of speech recognition in noise for binaural conditions. However, a subgroup of 14 subjects was found to have poorer-than-expected speech recognition scores, especially in the reverse dichotic listening condition. In this subgroup 9 subjects had been diagnosed with vestibular schwannoma at stage III or IV likely affecting the lower brainstem function. These subjects showed SNR thresholds in the reverse dichotic condition on average 4dB poorer (higher) than for the other 21 normally-performing subjects. For the 7 of 9 subjects whose vestibular schwannoma was removed, the deficit was no longer apparent on average 5 months following the surgical procedure. These results suggest that following unilateral hearing loss the capacity to use monaural spectral information is supported by the lower brainstem.

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

AbstractThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions.

On the existence of a central respiratory oxygen sensor.

A commonly held view that dominates both the scientific and educational literature is that in terrestrial mammals the central nervous system lacks a physiological hypoxia sensor capable of triggering increases in lung ventilation in response to decreases in Po2 of the brain parenchyma. Indeed, a normocapnic hypoxic ventilatory response has never been observed in humans following bilateral resection of the carotid bodies. In contrast, almost complete or partial recovery of the hypoxic ventilatory response after denervation/removal of the peripheral respiratory oxygen chemoreceptors has been demonstrated in many experimental animals when assessed in an awake state. In this essay we review the experimental evidence obtained using in vitro and in vivo animal models, results of human studies, and discuss potential mechanisms underlying the effects of CNS hypoxia on breathing. We consider experimental limitations and discuss potential reasons why the recovery of the hypoxic ventilatory response has not been observed in humans. We review recent experimental evidence suggesting that the lower brain stem contains functional oxygen sensitive elements capable of stimulating respiratory activity independently of peripheral chemoreceptor input.

Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS.

The aim of this study was to evaluate the performance of very high-energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization. Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques. The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS-generated plans in all cases. For the prostate case, the 200MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan. The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing.

Unexpected death after occipital condylar fracture

We present a rare fatal complication of an occipital condylar fracture. The patient was initially neurologically intact, but showed secondary clinical deterioration. Imaging revealed extensive extra-axial hemorrhage at the craniocervical junction and an acute obstructive hydrocephalus. MR imaging demonstrated a T2 hyperintens signal in both the lower brainstem and upper cervical spinal cord, likely caused by the extra-axial hemorrhage. As prognosis was estimated infaust, supportive treatment was discontinued and the patient died soon thereafter. This case report illustrates a rare, delayed complication and unexpected death in a patient having sustained an occipital condylar fracture.

Right-sided dominance of the bilateral vestibular system in the upper brainstem and thalamus.

MRI diffusion tensor imaging tractography was performed on the bilateral vestibular brainstem pathways, which run from the vestibular nuclei via the paramedian and posterolateral thalamic subnuclei to the parieto-insular vestibular cortex. Twenty-one right-handed healthy subjects participated. Quantitative analysis revealed a rope-ladder-like system of vestibular pathways in the brainstem with crossings at pontine and mesencephalic levels. Three structural types of right-left fiber distributions could be delineated: (1) evenly distributed pathways at the lower pontine level from the vestibular nuclei to the pontine crossing, (2) a moderate, pontomesencephalic right-sided lateralization between the pontine and mesencephalic crossings, and (3) a further increase of the right-sided lateralization above the mesencephalic crossing leading to the thalamic vestibular subnuclei. The increasing lateralization along the brainstem was the result of an asymmetric number of pontine and mesencephalic crossing fibers which was higher for left-to-right crossings. The dominance of the right vestibular meso-diencephalic circuitry in right-handers corresponds to the right-hemispheric dominance of the vestibular cortical network. The structural asymmetry apparent in the upper brainstem might be interpreted in relation to the different functions of the vestibular system depending on their anatomical level: a symmetrical sensorimotor reflex control of eye, head, and body mediated by the lower brainstem; a lateralized right-sided upper brainstem-thalamic function as part of the dominant right-sided cortical/subcortical vestibular system that enables a global percept of body motion and orientation in space.

Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system

The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.

Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

Regional volumetric change in Parkinson's disease with cognitive decline

BackgroundParkinson's disease (PD), characterized by motor dysfunction and cognitive decline, may demonstrate specific patterns of brain atrophy. Although cross-sectional magnetic resonance imaging (MRI) studies show correlation between regional brain volume loss and cognitive impairment, there is only scarce evidence from longitudinal studies validating the link between cognition and brain anatomy in PD. ObjectiveTo test the relationship between magnitude and spatial extent of atrophy in PD patients with progressive, significant cognitive decline and dementia (PDD). MethodsWe followed thirty-three initially non-demented patients with prevalent PD for three years while monitoring cognitive function and brain atrophy. Longitudinally acquired T1-weighted magnetic resonance images were analyzed in the voxel-based morphometry framework of SPM. ResultsGroups did not differ significantly with respect to age or gender. More males developed PDD (7 males, 3 females) compared to those remaining intact (12 males, 11 females). Clusters of lower grey matter volume were found in PDD compared to PD in left uncus at baseline and an expanded region that included the left hippocampus and parahippocampal gyrus at 36months. The cognitive status by scan interaction showed differential changes between groups in the right insula. At a more liberal statistical threshold we observed changes in the right insula and bilateral hippocampi as well as the right cuneus additional to the lower brain stem. ConclusionsRegion specific atrophy, consistent with the pattern of cortical Lewy body deposition seen in autopsy studies, can be detected with MRI in PD patients with significant cognitive decline. MRI may be useful for tracking cognitive decline in PD.

Musicianship enhances ipsilateral and contralateral efferent gain control to the cochlea

Human hearing sensitivity is easily compromised with overexposure to excessively loud sounds, leading to permanent hearing damage. Consequently, finding activities and/or experiential factors that distinguish “tender” from “tough” ears (i.e., acoustic vulnerability) would be important for identifying people at higher risk for hearing damage. To regulate sound transmission and protect the inner ear against acoustic trauma, the auditory system modulates gain control to the cochlea via biological feedback of the medial olivocochlear (MOC) efferents, a neuronal pathway linking the lower brainstem and cochlear outer hair cells. We hypothesized that a salient form of auditory experience shown to have pervasive neuroplastic benefits, namely musical training, might act to fortify hearing through tonic engagement of these reflexive pathways. By measuring MOC efferent feedback via otoacoustic emissions (cochlear emitted sounds), we show that dynamic ipsilateral and contralateral cochlear gain control is enhanced in musically-trained individuals. Across all participants, MOC strength was correlated with the years of listeners' training suggested that efferent gain control is experience dependent. Our data provide new evidence that intensive listening experience(s) (e.g., musicianship) can strengthen the ipsi/contralateral MOC efferent system and sound regulation to the inner ear. Implications for reducing acoustic vulnerability to damaging sounds are discussed.