Locus for severity implicates CNS resilience in progression of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

An airway-to-brain sensory pathway mediates influenza-induced sickness.

Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro-immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis5. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons2. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced prostaglandins and mediates systemic sickness responses to respiratory virus infection.

Measuring Articulatory Patterns in Amyotrophic Lateral Sclerosis Using a Data-Driven Articulatory Consonant Distinctiveness Space Approach.

PURPOSE: The aim of this study was to leverage data-driven approaches, including a novel articulatory consonant distinctiveness space (ACDS) approach, to better understand speech motor control in amyotrophic lateral sclerosis (ALS). METHOD: Electromagnetic articulography was used to record tongue and lip movement data during the production of 10 consonants from healthy controls (n = 15) and individuals with ALS (n = 47). To assess phoneme distinctness, speech data were analyzed using two classification algorithms, Procrustes matching (PM) and support vector machine (SVM), and the area/volume of the ACDS. Pearson's correlation coefficient was used to examine the relationship between bulbar impairment and the ACDS. Analysis of variance was used to examine the effects of bulbar impairment on consonant distinctiveness and consonant classification accuracies in clinical subgroups. RESULTS: There was a significant relationship between the ACDS and intelligible speaking rate (area, p = .003; volume, p = .010), and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) bulbar subscore (area, p = .009; volume, p = .027). Consonant classification performance followed a consistent pattern with bulbar severity, where consonants produced by speakers with more severe ALS were classified less accurately (SVM = 75.27%; PM = 74.54%) than the healthy, asymptomatic, and mild-moderate groups. In severe ALS, area of the ACDS was significantly condensed compared to both asymptomatic (p = .004) and mild-moderate (p = .013) groups. There was no statistically significant difference in area between the severe ALS group and healthy speakers (p = .292). CONCLUSIONS: Our comprehensive approach is sensitive to early oromotor changes in response due to disease progression. The preserved articulatory consonant space may capture the use of compensatory adaptations to counteract influences of neurodegeneration. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22044320.

Pathophysiological mechanisms of oromandibular dystonia.

Oromandibular dystonia (OMD) is a rare form of focal idiopathic dystonia. OMD was clinically identified at the beginning of the 20th century, and the main clinical features have been progressively described over the years. However, OMD has several peculiarities that still remain unexplained, including the high rate of oral trauma, which is often related to the onset of motor symptoms. The purpose of this paper was to formulate a hypothesis regarding the pathophysiology of OMD, starting from the neuroanatomical basis of the masticatory and facial systems and highlighting the features that differentiate this condition from other forms of focal idiopathic dystonia. We provide a brief review of the clinical and etiological features of OMD as well as neurophysiological and neuroimaging findings obtained from studies in patients with OMD. We discuss possible pathophysiological mechanisms underlying OMD and suggest that abnormalities in sensory input processing may play a prominent role in OMD pathophysiology, possibly triggering a cascade of events that results in sensorimotor cortex network dysfunction. Finally, we identify open questions that future studies should address, including the effect of abnormal sensory input processing and oral trauma on the peculiar neurophysiological abnormalities observed in OMD.

Early auditory responses to speech sounds in Parkinson's disease: preliminary data.

Parkinson's disease (PD), as a manifestation of basal ganglia dysfunction, is associated with a number of speech deficits, including reduced voice modulation and vocal output. Interestingly, previous work has shown that participants with PD show an increased feedback-driven motor response to unexpected fundamental frequency perturbations during speech production, and a heightened ability to detect differences in vocal pitch relative to control participants. Here, we explored one possible contributor to these enhanced responses. We recorded the frequency-following auditory brainstem response (FFR) to repetitions of the speech syllable [da] in PD and control participants. Participants with PD displayed a larger amplitude FFR related to the fundamental frequency of speech stimuli relative to the control group. The current preliminary results suggest the dysfunction of the basal ganglia in PD contributes to the early stage of auditory processing and may reflect one component of a broader sensorimotor processing impairment associated with the disease.

Functional status of brainstem auditory pathway in babies born below 30 week gestation with necrotizing enterocolitis.

OBJECTIVE: Recent studies showed that neonatal necrotizing enterocolitis (NEC) adversely affects the brainstem auditory pathway in babies born at 30-40 week gestation. We compared the functional status of the pathway between babies born below 30 week gestation with NEC and those without NEC for any differences to understand whether NEC also affects the pathway in babies born at a smaller gestation. METHOD: Brainstem auditory evoked response was studied at term in NEC babies born below 30 week gestation. The data obtained were compared with age-matched non-NEC babies for any abnormalities, and then compared with previously reported NEC babies born at 30-34 week gestation for any differences. RESULTS: Although the latencies of waves I and III did not differ significantly between NEC and non-NEC babies, wave V latency in NEC babies was longer than in non-NEC babies at all click rates used. In particular, I-V interpeak interval, reflecting brainstem conduction time, in NEC babies was significant longer than in non-NEC babies. Wave V amplitude and the V/I amplitude ratios in NEC babies was smaller than in non-NEC babies at some click rates. The I-V interval in our NEC babies born below 30 week gestation was longer than in previously reported NEC babies born at 30-34 week gestation at all click rates. CONCLUSION: NEC babies born below 30 week gestation are associated with delayed brainstem conduction time. Functional status of the brainstem auditory pathway in NEC babies born below 30 week gestation is less favorable than that in those with greater gestation.

Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome.

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Processing of fMRI-related anxiety and bi-directional information flow between prefrontal cortex and brain stem.

Brain-heart synchronization is fundamental for emotional-well-being and brain-heart desynchronization is characteristic for anxiety disorders including specific phobias. Recording BOLD signals with functional magnetic resonance imaging (fMRI) is an important noninvasive diagnostic tool; however, 1-2% of fMRI examinations have to be aborted due to claustrophobia. In the present study, we investigated the information flow between regions of interest (ROI's) in the cortex and brain stem by using a frequency band close to 0.1 Hz. Causal coupling between signals important in brain-heart interaction (cardiac intervals, respiration, and BOLD signals) was studied by means of Directed Transfer Function based on the Granger causality principle. Compared were initial resting states with elevated anxiety and final resting states with low or no anxiety in a group of fMRI-naïve young subjects. During initial high anxiety the results showed an increased information flow from the middle frontal gyrus (MFG) to the pre-central gyrus (PCG) and to the brainstem. There also was an increased flow from the brainstem to the PCG. While the top-down flow during increased anxiety was predominant, the weaker ascending flow from brainstem structures may characterize a rhythmic pacemaker-like activity that (at least in part) drives respiration. We assume that these changes in information flow reflect successful anxiety processing.

Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model.

Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem.

Enhanced brainstem phase-locking in low-level noise reveals stochastic resonance in the frequency-following response (FFR).

In nonlinear systems, the inclusion of low-level noise can paradoxically improve signal detection, a phenomenon known as stochastic resonance (SR). SR has been observed in human hearing whereby sensory thresholds (e.g., signal detection and discrimination) are enhanced in the presence of noise. Here, we asked whether subcortical auditory processing (neural phase locking) shows evidence of SR. We recorded brainstem frequency-following-responses (FFRs) in young, normal-hearing listeners to near-electrophysiological-threshold (40 dB SPL) complex tones composed of 10 iso-amplitude harmonics of 150 Hz fundamental frequency (F0) presented concurrent with low-level noise (+20 to -20 dB SNRs). Though variable and weak across ears, some listeners showed improvement in auditory detection thresholds with subthreshold noise confirming SR psychophysically. At the neural level, low-level FFRs were initially eradicated by noise (expected masking effect) but were surprisingly reinvigorated at select masker levels (local maximum near âˆ¼ 35 dB SPL). These data suggest brainstem phase-locking to near threshold periodic stimuli is enhanced in optimal levels of noise, the hallmark of SR. Our findings provide novel evidence for stochastic resonance in the human auditory brainstem and suggest that under some circumstances, noise can actually benefit both the behavioral and neural encoding of complex sounds.

Episcleral venous pressure response to brain stem stimulation: Effect of topical lidocaine.

Episcleral venous pressure (EVP) is important for steady state intraocular pressure (IOP), as it has to be overcome by aqueous humor in order to leave the eye. Recent evidence suggests a neuronal tone being present, as topical anesthesia lowered EVP. The superior salivatory nucleus in the brainstem could be identified to elicit increases in EVP during electrical stimulation. In the present study the effect of topical anesthesia on the stimulation effect was investigated. 8 Spraque Dawley rats were anesthetized, artificially ventilated with CO2 monitoring and continuous blood pressure monitoring. Intraocular pressure was measured continuously through a cannula in the vitreous body. Episcleral venous pressure was measured by direct cannulation of an episcleral vein via a custom made glass pipette connected to a servonull micropressure system. Electrical stimulation of the superior salivatory nucleus (9 µA, 200 pulses of 1 ms duration) increased EVP from 8.51 ± 1.82 mmHg to 10.97 ± 1.93 mmHg (p = 0.004). After application of topical lidocaine EVP increased from 7.42 ± 1.59 mmHg to 9.77 ± 1.65 mmHg (p = 0.007). The EVP response to stimulation before and after lidocaine application was not statistically significantly different (2.45 ± 0.5 vs 2.35 ± 0.49 mmHg, p = 0.69), while the decrease in baseline EVP was (8.51 vs. 7.42 mmHg, p = 0.045). The present data suggest that distinct neuronal mechanisms controlling the episcleral circulation of rats exist. This is in keeping with previous reports of two distinct arterio-venous anastomoses, one in the limbal circulation and one in the conjunctival/episcleral circulation.

Spinal cord neural activity of patients with fibromyalgia and healthy controls during temporal summation of pain: an fMRI study.

The cause for the increased sensitivity of patients with fibromyalgia (FM) to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in patients with FM and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Sixteen HC and 14 FM participants received repetitive heat stimuli to the hand at 0.4 Hz to achieve TSSP during functional imaging with a 3 T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neurovascular coil, multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by deactivation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.NEW & NOTEWORTHY "Windup" and its behavioral correlate "temporal-summation-of-second pain" (TSSP) represent spinal cord mechanisms of pain augmentation associated with central sensitization and chronic pain. Fibromyalgia (FM) is a chronic pain disorder, where abnormal TSSP has been demonstrated. We used fMRI to study spinal cord and brainstem activation during TSSP. We characterized the time course of spinal cord and brainstem BOLD activity during TSSP which showed abnormal brainstem activity in patients with FM, possibly due to deficient pain modulation.

On clinical findings of Bickerstaff's brainstem encephalitis in childhood.

A short review on the clinical presentation of pediatrics cases of Bickerstaff brain encephalitis emphasizing the broad clinical spectrum of the disease. Cases of pediatric Bickerstaff's brainstem encephalitis collected on three electronic medical databases (PubMed, Cochrane Library and Scopus Web of Science) are reviewed. The inclusion criteria of the cases were based on the clinical characteristics of the disorder in the pediatric age. We reviewed 20 articles on Bickerstaff's brainstem encephalitis, identifying 40 pediatric cases focused on the clinical symptoms. We saw that the prevalence was higher in male subjects, and the median age at diagnosis was 8 years. The phenotype of pediatrics patients was similar to previously published literature. We identify three cases of overlapping forms between Bickerstaff brain encephalitis and Guillain-Barré Syndrome in patients with lower limbs weakness and typical signs of Bickerstaff brain encephalitis, suggesting a combined involvement of the central and peripheral nervous system. Although there is no defined data on incidence and prevalence in the literature, Bickerstaff's brainstem encephalitis appears to be a rare disorder, especially in children. The incidence of Bickerstaff brain encephalitis and Guillain-Barré Syndrome, and Miller Fisher Syndrome has been underrated in the past, primarily due to an underestimation of the forms with a Peripheral Nervous System involvement. Bickerstaff brain encephalitis usually has a rapid and acute onset within 2-4 weeks, characterized by a typical picture of ophthalmoplegia, hyperreflexia, cerebellar symptoms as ataxia. The subsequent manifestations of hyperreflexia or consciousness disturbances as drowsiness, sleepiness, or coma, indicative of central involvement, suggest a Bickerstaff brain encephalitis clinical diagnosis.

Speech and swallowing deficits in X-Linked Dystonia-Parkinsonism.

INTRODUCTION: X-linked Dystonia-Parkinsonism (XDP) is a progressive, disabling disease characterized by the devastating impairment of bulbar function, including speech and swallowing. Despite these detrimental impacts, bulbar impairments in this population are not well characterized. OBJECTIVES: To identify impairments in the bulbar system measured by oromotor performance in individuals with XDP relative to healthy controls. Secondarily, to detect diagnostic bulbar markers that are sensitive and specific to the initial years of XDP. METHODS: This case-control study included 25 healthy controls and 30 participants with XDP, divided into two subgroups based on the median of their disease length. Multiple clinical and instrumental oromotor tasks and measures were used to evaluate bulbar motor function. RESULTS: Differences were found between both the subgroups with XDP and healthy controls on almost all measures, including maximum performance tasks such as tongue strength, alternating motion rate (AMR), and sequential motion rate (SMR) (p < 0.05). Differences were found between the XDP subgroups and the control group for the percentage of pause time during the speech, a rating of speech severity, and a swallowing task (ps < 0.05). Scores on self-reported questionnaires, tongue strength, the number of repetitions produced during an AMR, percent pause, and speech severity demonstrated good sensitivity and specificity to differentiate the initial years of XDP onset from healthy controls. CONCLUSIONS: Our findings revealed impairments across bulbar functions in participants within the first 7 years of the XDP onset. Highly sensitive and specific bulbar impairment measures were detected in instrumental and self-reported measures that are fundamental for monitoring disease.

Early changes of immunoreactivity to orexin in hypothalamus and to RFamide peptides in brainstem during the development of hypertension.

Baroreflex sensitivity (BRS) is an important function of the nervous system and essential for maintaining blood pressure levels in the physiological range. In hypertension, BRS is decreased both in man and animals. Although increased sympathetic activity is thought to be the main cause of decreased BRS, hence the development of hypertension, the BRS is regulated by both sympathetic (SNS) and parasympathetic (PNS) nervous system. Here, we analyzed neuropeptide changes in the lateral hypothalamus (LH), which favours the SNS activity, as well as in PNS nuclei in the brainstem of spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar Kyoto rats- WKY). The analyses revealed that in the WKY rats the hypothalamic orexin system, known for its role in sympathetic activation, showed a substantial decrease when animals age. At the same time, however, such a decrease was not observed when hypertension developed in the SHR. In contrast, Neuropeptide FF (NPFF) and Prolactin Releasing Peptide (PrRP) expression in the PNS associated Nucleus Tractus Solitarius (NTS) and Dorsal Motor Nucleus of the Vagus (DMV) diminished substantially, not only after the establishment of hypertension but also before its onset. Therefore, the current results indicate early changes in areas of the central nervous system involved in SNS and PNS control of blood pressure and associated with the development of hypertension.

Brainstem Dysfunction in Healthy Aging.

The brainstem controls sub-cortical and cortical activity and influences the processing of incoming information. The goal of this study was to characterize age related alterations of brainstem-brain interactions during different brain states detected by dynamic analysis of task-free fMRI. 79 young (20-40 years) and 51 older adults (55-80 years) were studied. Internal brainstem structures were segmented using a new multi-contrast segmentation approach. Brain and brainstem gray matter segmentations were warped onto a population template. The ICV-corrected Jacobian determinants were converted into z-score maps and the means from 420 cortical/subcortical/brainstem rois extracted. The fMRI was preprocessed in SPM12/Conn18 and the BOLD signal from 420 cortical/subcortical/brainstem rois extracted. A dynamic task-free analysis approach based on hierarchical cluster analysis was used to identify 15 brain states that were characterized using graph analysis (strength, diversity, modularity). Kruskal-Wallis tests and Spearman correlations were used for statistical analysis. One brain state (cluster 21) occurred more often in older adults (p=0.008). It was characterized by a lower mean modular strength and brainstem-cortical strength in older adults compared to younger adults. Global age related gray matter differences were positively correlated with brain state 21's modular strength. Furthermore, brain state 21 duration was negatively correlated with working memory (r = -0.28, p=0.002). The findings suggest an age related weakening of the within and between network synchronization at the brainstem level during brain state 21 in older adults that negatively affects cortical and subcortical synchronization and working memory performance.

Contribution of brainstem circuits in pathophysiology of NREM-sleep parasomnias.

OBJECTIVE: We aimed to investigate the brainstem circuits to reveal if there was any abnormality in these circuits in clinically diagnosed patients with NREM parasomnias during wakefulness. METHODS: Twelve patients with NREM-sleep parasomnia diagnosed according to ICSD-3 criteria and a control group of 16 healthy subjects were enrolled into our study. We analyzed the auditory startle reflex (ASR), blink reflex (BR), prepulse inhibition (PPI) of BR and recovery excitability of BR. RESULTS: There was a trend for longer responses from orbicularis oculi and sternocleidomastoid muscles after auditory stimulation in the patients compared to those in the healthy subjects. The recovery percentages at 200 ms and 300 ms showed a borderline significance in the patients. No significant difference was found in the R2-PPI between the patients and healthy subjects. CONCLUSIONS: Our results suggest a mildly enhanced ASR and relatively early facilitation of BR excitability in patients with NREM-sleep parasomnia during daytime. Although our findings suggest involvement of brainstem networks in NREM-sleep parasomnia during wakefulness, it would be better to study these networks at night and during daytime to see if there is any contribution.

Migraine and Sleep-An Unexplained Association?

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.

Case Studies in Neuroscience: Neuropathology and diaphragm dysfunction in ventilatory failure from late-onset Pompe disease.

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm2) and cervical motoneurons (soma size: 487 ± 189 µm2) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm2) and sacral motoneurons (soma size: 1,411 ± 633 µm2) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle.NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.

Brainstem damage is associated with poorer sleep quality and increased pain in gulf war illness veterans.

AIMS: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. MATERIALS AND METHODS: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. KEY FINDINGS: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. SIGNIFICANCE: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.