ABSTRACT
A low arousal threshold (LAT) is a pathophysiological trait of obstructive sleep apnea (OSA) that may be associated with brainstem ascending reticular activating system-cortical functional connectivity changes. We evaluated resting-state connectivity between the brainstem nuclei and 105 cortical/subcortical regions in OSA patients with or without a LAT and healthy controls. Twenty-five patients with moderate to severe OSA with an apnea-hypopnea index between 20 and 40/hr (15 with and 10 without a LAT) and 15 age- and sex-matched controls were evaluated. Participants underwent functional magnetic resonance imaging after overnight polysomnography. Three brainstem nuclei-the locus coeruleus (LC), laterodorsal tegmental nucleus (LDTg), and ventral tegmental area (VTA)-associated with OSA in our previous study were used as seeds. Functional connectivity values of the two brainstem nuclei (LC and LDTg) significantly differed among the three groups. The connectivity of the LC with the precuneus was stronger in OSA patients than in controls regardless of the concomitant LAT. The connectivity between the LDTg and the posterior cingulate cortex was also stronger in OSA patients regardless of the LAT. Moreover, OSA patients without a LAT showed stronger LDTg-posterior cingulate cortex connectivity than those with a LAT (post hoc p = 0.013), and this connectivity strength was negatively correlated with the minimum oxygen saturation in OSA patients (r = - 0.463, p = 0.023). The LAT in OSA patients was associated with altered LDTg-posterior cingulate cortex connectivity. This result may suggested that cholinergic activity may play a role in the LAT in OSA patients.
Subject(s)
Arousal , Brain Stem , Magnetic Resonance Imaging , Polysomnography , Sleep Apnea, Obstructive , Humans , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/diagnostic imaging , Male , Arousal/physiology , Female , Middle Aged , Adult , Brain Stem/diagnostic imaging , Brain Stem/physiopathology , Case-Control StudiesABSTRACT
Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12â min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating (n = 13) or stable (n = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12â min period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time.
Subject(s)
Magnetic Resonance Imaging , Humans , Male , Female , Middle Aged , Neural Pathways/physiopathology , Adult , Brain Stem/physiopathology , Brain Stem/diagnostic imaging , Trigeminal Nerve Diseases/physiopathology , Aged , Trigeminal Neuralgia/physiopathology , Trigeminal Neuralgia/diagnostic imaging , Pain Measurement , Cerebral Cortex/physiopathology , Cerebral Cortex/diagnostic imagingABSTRACT
BACKGROUND: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism. OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache. METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest. RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79). CONCLUSION: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.
Subject(s)
Brain Stem , Circadian Rhythm , Cluster Headache , Magnetic Resonance Imaging , Pain Threshold , Humans , Cluster Headache/physiopathology , Cluster Headache/diagnostic imaging , Adult , Male , Brain Stem/diagnostic imaging , Brain Stem/physiopathology , Female , Circadian Rhythm/physiology , Middle Aged , Pain Threshold/physiology , Young Adult , AgedABSTRACT
OSA is known to increase the risk for SUDEP in persons with epilepsy, but the relationship between these two factors is not clear. Also, there is no study showing the acute responses to obstructive apnea in a chronic epilepsy model. Therefore, this study aimed to characterize cardiorespiratory responses to obstructive apnea and chemoreceptor stimulation in rats. In addition, we analyzed respiratory centers in the brain stem by immunohistochemistry. Epilepsy was induced with pilocarpine. About 30-60 days after the first spontaneous seizure, tracheal and thoracic balloons, and electrodes for recording the electroencephalogram, electromyogram, and electrocardiogram were implanted. Intermittent apneas were made by inflation of the tracheal balloon during wakefulness, NREM sleep, and REM sleep. During apnea, respiratory effort increased, and heart rate fell, especially with apneas made during wakefulness, both in control rats and rats with epilepsy. Latency to awake from apnea was longer with apneas made during REM than NREM, but rats with epilepsy awoke more rapidly than controls with apneas made during REM sleep. Rats with epilepsy also had less REM sleep. Cardiorespiratory responses to stimulation of carotid chemoreceptors with cyanide were similar in rats with epilepsy and controls. Immunohistochemical analysis of Phox2b, tryptophan hydroxylase, and NK1 in brain stem nuclei involved in breathing and sleep (retrotrapezoid nucleus, pre-Bötzinger complex, Bötzinger complex, and caudal raphe nuclei) revealed no differences between control rats and rats with epilepsy. In conclusion, our study showed that rats with epilepsy had a decrease in the latency to awaken from apneas during REM sleep, which may be related to neuroplasticity in some other brain regions related to respiratory control, awakening mechanisms, and autonomic modulation.
Subject(s)
Disease Models, Animal , Electroencephalography , Epilepsy , Sleep Apnea, Obstructive , Wakefulness , Animals , Wakefulness/physiology , Male , Epilepsy/physiopathology , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/complications , Rats , Chronic Disease , Pilocarpine/toxicity , Brain Stem/physiopathology , Heart Rate/physiology , Electromyography , Rats, Sprague-Dawley , Rats, WistarABSTRACT
Sudden infant death syndrome (SIDS)-the sudden and unexplained death of a seemingly healthy infant, <1 year old-may be associated with abnormalities in the brain regions that underlie breathing and arousal during sleep. While post-mortem studies suggest abnormalities in SIDS infants' brainstems, there are no studies of these infants' brainstem function before death. One way to assess the function of the brainstem is with auditory brainstem response (ABR), a routine hearing-screening method that noninvasively measures the brainstem's response to sound. We hypothesize that anomalies in newborns' ABR measures may predict SIDS. Indeed, previous studies identified abnormalities in ABR characteristics in small samples of near-miss SIDS infants hospitalized for infant apnea syndrome. However, there is a need to examine the ABRs of infants who died of SIDS. Therefore, in the current study, we propose integrating two secondary datasets to examine newborns' ABRs (N = 156,972), including those who later died of SIDS (n = ~42; .27 out of every 1000 infants), using existing archived records of neonatal ABR results from a sample of newborns born in Florida. We hypothesize that infants who die from SIDS are more likely than non-SIDS infants to have abnormal ABRs as newborns. Understanding the association between SIDS and ABR may facilitate more accurate identification of an infant's risk for SIDS at birth, enabling increased monitoring, which may facilitate interventions and improve survivorship.
Subject(s)
Evoked Potentials, Auditory, Brain Stem , Sudden Infant Death , Humans , Evoked Potentials, Auditory, Brain Stem/physiology , Infant, Newborn , Male , Female , Brain Stem/physiopathology , InfantABSTRACT
Background: Spinal cord injuries (SCI) often result in cardiovascular issues, increasing the risk of stroke and cognitive deficits. Objectives: This study assessed cerebrovascular reactivity (CVR) using functional magnetic resonance imaging (fMRI) during a hypercapnic challenge in SCI participants compared to noninjured controls. Methods: Fourteen participants were analyzed (n = 8 with SCI [unless otherwise noted], median age = 44 years; n = 6 controls, median age = 33 years). CVR was calculated through fMRI signal changes. Results: The results showed a longer CVR component (tau) in the grey matter of SCI participants (n = 7) compared to controls (median difference = 3.0 s; p < .05). Time since injury (TSI) correlated negatively with steady-state CVR in the grey matter and brainstem of SCI participants (RS = -0.81, p = .014; RS = -0.84, p = .009, respectively). Lower steady-state CVR in the brainstem of the SCI group (n = 7) correlated with lower diastolic blood pressure (RS = 0.76, p = .046). Higher frequency of hypotensive episodes (n = 7) was linked to lower CVR outcomes in the grey matter (RS = -0.86, p = .014) and brainstem (RS = -0.89, p = .007). Conclusion: Preliminary findings suggest a difference in the dynamic CVR component, tau, between the SCI and noninjured control groups, potentially explaining the higher cerebrovascular health burden in SCI individuals. Exploratory associations indicate that longer TSI, lower diastolic blood pressure, and more hypotensive episodes may lead to poorer CVR outcomes. However, further research is necessary to establish causality and support these observations.
Subject(s)
Cerebrovascular Circulation , Magnetic Resonance Imaging , Spinal Cord Injuries , Humans , Spinal Cord Injuries/physiopathology , Spinal Cord Injuries/complications , Male , Adult , Female , Middle Aged , Cerebrovascular Circulation/physiology , Gray Matter/diagnostic imaging , Gray Matter/physiopathology , Brain Stem/physiopathology , Brain Stem/diagnostic imagingABSTRACT
Background and Aims: The precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation. Methods: This study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined. Results: Participants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (ß = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (ß = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (ß = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (ß = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (ß = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable. Conclusion: We found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.
Subject(s)
Screen Time , Thalamus , Humans , Child , Female , Male , Adolescent , Thalamus/physiopathology , Thalamus/diagnostic imaging , Sleep Wake Disorders/physiopathology , Prefrontal Cortex/physiopathology , Brain Stem/physiopathology , Longitudinal Studies , Magnetic Resonance Imaging , Sleep/physiology , Brain/physiopathologyABSTRACT
BACKGROUND: Lesion occurring in the brainstem may cause a postural tilt and balance disorders, which could be due to an inaccurate perception of the body orientation. The objective of this study was to determine the effects of a brainstem stroke on body representation in horizontal and frontal plane, and links with impaired posture and neuroanatomy. METHODS: Forty patients with stroke in left brainstem (L-BS) or right (R-BS) were compared with 15 matched control subjects (C). The subjective straight-ahead (SSA) was investigated using a method disentangling lateral deviation and tilt components of error. RESULTS: The L-BS patients had contralesional lateral deviation of SSA. In addition, they showed an ipsilesional tilt, more severe for the trunk than for the head. By contrast, in R-BS patients, the representation of the body midline was fairly accurate in both the horizontal and frontal planes and did not differ from that of control subjects. CONCLUSION: This work highlights an asymmetry of representation of body associated with left brainstem lesions extending to the right cerebral hemisphere. This deviation appears only after a left lesion, which may point to a vestibular dominance. These results open a new perspective of neuro-rehabilitation of postural disorders after a stroke, with the correction of the representation of body orientation.
Subject(s)
Brain Stem , Functional Laterality , Humans , Male , Female , Middle Aged , Aged , Brain Stem/physiopathology , Brain Stem/diagnostic imaging , Functional Laterality/physiology , Adult , Stroke/physiopathology , Stroke/complications , Posture/physiology , Brain Stem Infarctions/diagnostic imaging , Brain Stem Infarctions/physiopathology , Brain Stem Infarctions/complications , Body Image/psychologyABSTRACT
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.
Subject(s)
Brain , Cognitive Reserve , Educational Status , Genome-Wide Association Study , Multiple Sclerosis , Protective Factors , Humans , Young Adult , Aging , Brain/immunology , Brain/pathology , Brain/physiopathology , Brain Stem/immunology , Brain Stem/pathology , Brain Stem/physiopathology , Case-Control Studies , Disease Progression , Homozygote , Mobility Limitation , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Multiple Sclerosis/psychology , Time FactorsABSTRACT
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.
Subject(s)
Blood-Brain Barrier , Brain , Dinoprostone , Nasopharynx , Orthomyxoviridae Infections , Sensory Receptor Cells , Animals , Humans , Mice , Behavior, Animal , Blood-Brain Barrier/metabolism , Brain/metabolism , Brain Stem/physiopathology , Dinoprostone/metabolism , Drinking , Eating , Influenza, Human/complications , Influenza, Human/metabolism , Movement , Nasopharynx/innervation , Orthomyxoviridae/pathogenicity , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Sensory Receptor Cells/metabolism , Survival RateABSTRACT
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.
Subject(s)
Amyotrophic Lateral Sclerosis , Speech , Humans , Amyotrophic Lateral Sclerosis/physiopathology , Algorithms , Case-Control Studies , Machine Learning , Tongue/physiology , Lip/physiology , Motor Skills , Brain Stem/physiopathology , Disease Progression , Male , FemaleABSTRACT
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.
Subject(s)
Brain Stem/physiopathology , Cerebral Cortex/physiopathology , Dystonia/physiopathology , Dystonic Disorders/physiopathology , Mandible/physiopathology , HumansABSTRACT
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.
Subject(s)
Parkinson Disease/physiopathology , Pitch Perception/physiology , Speech Perception , Acoustic Stimulation , Aged , Brain Stem/physiopathology , Case-Control Studies , Female , Humans , Male , Middle Aged , Speech/physiologyABSTRACT
OBJECTIVE: Recent studies showed that neonatal necrotizing enterocolitis (NEC) adversely affects the brainstem auditory pathway in babies born at 30-40â¯week gestation. We compared the functional status of the pathway between babies born below 30â¯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 30â¯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 30-34â¯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 30â¯week gestation was longer than in previously reported NEC babies born at 30-34â¯week gestation at all click rates. CONCLUSION: NEC babies born below 30â¯week gestation are associated with delayed brainstem conduction time. Functional status of the brainstem auditory pathway in NEC babies born below 30â¯week gestation is less favorable than that in those with greater gestation.
Subject(s)
Auditory Pathways/physiopathology , Brain Stem/physiopathology , Enterocolitis, Necrotizing/complications , Evoked Potentials, Auditory, Brain Stem/physiology , Female , Functional Status , Humans , Infant, Newborn , Infant, Newborn, Diseases , Infant, Premature , MaleABSTRACT
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.
Subject(s)
Brain Stem , Infant, Newborn, Diseases , Microglia , Opioid-Related Disorders , Substance Withdrawal Syndrome , Tachycardia , Tachypnea , Animals , Animals, Newborn , Brain Stem/immunology , Brain Stem/physiopathology , Disease Models, Animal , Female , Humans , Hypercapnia/immunology , Hypercapnia/physiopathology , Hypoxia/immunology , Hypoxia/physiopathology , Infant, Newborn , Infant, Newborn, Diseases/etiology , Infant, Newborn, Diseases/immunology , Infant, Newborn, Diseases/physiopathology , Microglia/immunology , Opioid-Related Disorders/complications , Opioid-Related Disorders/immunology , Opioid-Related Disorders/physiopathology , Pregnancy , Prenatal Exposure Delayed Effects/immunology , Prenatal Exposure Delayed Effects/physiopathology , Rats , Substance Withdrawal Syndrome/complications , Substance Withdrawal Syndrome/immunology , Substance Withdrawal Syndrome/physiopathology , Tachycardia/etiology , Tachycardia/immunology , Tachycardia/physiopathology , Tachypnea/etiology , Tachypnea/immunology , Tachypnea/physiopathologyABSTRACT
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.
Subject(s)
Anxiety Disorders , Brain Stem , Magnetic Resonance Imaging , Prefrontal Cortex , Adult , Anxiety Disorders/diagnostic imaging , Anxiety Disorders/physiopathology , Brain Stem/diagnostic imaging , Brain Stem/physiopathology , Female , Humans , Male , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/physiopathologyABSTRACT
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.
Subject(s)
Brain Injuries, Traumatic/physiopathology , Brain Stem/physiopathology , Cortical Spreading Depression , Animals , Brain Injuries, Traumatic/metabolism , Brain Stem/metabolism , Male , Oxidative Stress , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Brain Stem/physiopathology , Electric Stimulation/methods , Glaucoma/therapy , Intraocular Pressure/physiology , Lidocaine/administration & dosage , Sclera/blood supply , Venous Pressure/physiology , Administration, Topical , Anesthetics, Local/administration & dosage , Animals , Glaucoma/physiopathology , HumansABSTRACT
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 â¼ 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.
Subject(s)
Brain Stem/physiopathology , Evoked Potentials, Auditory, Brain Stem , Noise , Acoustic Stimulation , Adult , Auditory Perception , Electroencephalography , Female , Hearing/physiology , Humans , Male , Psychomotor Performance , Sensory Thresholds , Speech Perception/physiology , Stochastic Processes , Young AdultABSTRACT
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.