Brainstem Level Research Articles

Pupillary response to light and tasks in early and late onset essential tremor patients

IntroductionLate-onset essential tremor is characterised by shorter life expectancy and more advanced aging parameters and may therefore be an ‘aging-related’ tremor. Brainstem functions involved in pupillary responses are hypothesized to reflect such earlier aging. The pupillary light response (PLR) and a task evoked pupillary response (TEPR) were used to test this hypothesis in same-aged patients with early onset (EOET) and late onset (LOET) essential tremor and healthy controls. Subjects and methodsAge related changes of the PLR and TEPR during the paced auditory serial addition test (PASAT) were tested in 57 normal subjects. Subsequently, 13 patients with LOET and 16 patients with EOET were compared with 15 age matched healthy controls. Standard parameters of PLR were recorded, amongst others the time to maximum acceleration of the PLR (T1) and the time to maximum velocity (T2). The TEPR was determined during the PASAT as the percentage change in pupil size (PCPS). Data were analysed with ANOVA and post-hoc testing. ResultsIn normal subjects the pupil diameter, latency, maximum acceleration/velocity and percentage amplitude were correlated with age. Latency of the pupillary light response was significantly longer in LOET compared to controls and EOET while no differences were found between EOET and controls. The TEPR showed no significant differences between the three groups. ConclusionLOET showed a prolonged latency of the PLR compared to EOET possibly indicating premature aging or rather pathophysiological differences on brainstem level. This study further supports the hypothesis of abnormal aging in LOET.

REM Sleep without atonia correlates with abnormal vestibular-evoked myogenic potentials in isolated REM sleep behavior disorder.

The neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD). Subjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method. The rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant. Brainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution.

EXPRESS: Products of oxidative stress and TRPA1 expression in the brainstem of rats after lung ischemia-reperfusion injury.

Lung ischemia–reperfusion injury is a common clinical concern. As the injury occurs, the pulmonary afferent nerves play a key role in regulating respiratory functions under pathophysiological conditions. The present study was to examine products of oxidative stress and expression of transient receptor potential A1 in the commissural nucleus of the solitary tract after lung ischemia–reperfusion injury; and further to determine molecular mediators linking to activation of oxidative stress and transient receptor potential ankyrin A1. A rat model of lung ischemia–reperfusion injury was used. Enzyme-linked immunosorbent assay and western blot analysis were employed to examine products of oxidative stress (i.e. 8-isoprostaglandin F2α and 8-hydroxy-2′-deoxyguanosine), and expression of transient receptor potential A1, Nrf2-antioxidant response element, and NADPH oxidase. 8-isoprostaglandin F2α and 8-hydroxy-2′-deoxyguanosine were amplified in the commissural nucleus of the solitary tract of lung ischemia–reperfusion injury rats, accompanied with downregulation of Nrf2-antioxidant response element, and upregulation of NOX4 and transient receptor potential A1. Blocking NADPH oxidase (subtype NOX4) decreased products of oxidative stress in the commissural nucleus of the solitary tract and attenuated upregulation of transient receptor potential A1 induced by lung ischemia–reperfusion injury. Our data revealed specific signaling pathways by which lung ischemia–reperfusion injury impairs Nrf2-antioxidant response and activates oxidative stress in the brainstem thereby leading to amplification of transient receptor potential A1 receptor likely via products of oxidative stress. Data suggest the abnormalities in the pulmonary afferent signals at the brainstem level which is likely to affect respiratory functions as lung ischemia–reperfusion injury occurs.

Brainstem encoding of frequency-modulated sweeps is relevant to Mandarin concurrent-vowels identification for normal-hearing and hearing-impaired listeners

F0 contours convey the primary information of lexical Tones for Mandarin Chinese, and the processing of time-varying F0 contours is important for Mandarin concurrent-vowels identification (MCVI). In this work, we examined the relationship between frequency modulation (FM) detection of auditory system and MCVI in both normal-hearing (NH) and hearing-impaired (HI) listeners. Three experiments were conducted with the same subjects to measure their MCVI, FM detection limen (FMDL), and frequency following responses (FFRs) evoked by FM sweeps, respectively. To ensure that F0 contour was the primary cue utilized, mean F0s and durations were equalized among all test vowels in the MCVI experiment. To simulate the pattern of F0 contours of Mandarin vowels, linearly FM sweeps were used as stimuli in the FMDL and FFRs experiments. The results confirmed that the performance of HI listeners was significantly worse than that of NH listeners in all of the three measurements. Besides, FFRs evoked by FM sweeps had significantly lower tracking accuracy than those evoked by steady tones only for HI listeners. The correlation analysis further revealed that any two of the three measured indices were significantly correlated when the effects of age and absolute threshold were partialed out (|r| ≥ 0.502, p ≤ 0.017). These results suggested an association between the poor performance of HI listeners in the MCVI task and their degraded auditory function on FM detection, and such a behavioral degradation has emerged in the phase-locking activity at the brainstem level.

The value of ABR- and ASSR-based hearing estimation in young children with congenital monaural malformation (atresia)

Background: The electrophysiology of auditory nerve mature is particularly important for unilateral hearing loss.Objectives: To assess the hearing status in young children with congenital monaural malformation and evaluate their potential for practical use in the functional maturation parameters of the auditory pathway.Materials and methods: ABR (auditory brainstem responses) and ASSR (auditory steady-state responses) threshold measurements were performed in 21 young children with congenital monaural atresia.Results: The average electrophysiologic thresholds for the ABR were 65 dB nHL ± 1.20 in malformed ears and 25 dB nHL ± 0.48 in normal ones. All 21 atretic ears presented with typical conductive hearing loss. There was no statistic positive correlation in hearing-impaired ears between the methods of ABR and ASSR responses (r = 0.12, 0.20 and 0.17). The IPL (interpeak latency) of I–III, III–V and I–V of atretic ears in ABR test was decreased relative to normal ears. Furthermore, a shortening of the IPLs I–III, III–V, I–V can be observed with increasing age of the children in malformed ears.Conclusions and significance: The ABR- and ASSR-based hearing evaluation in young children with congenital monaural malformation should be viewed as complementary technologies. Besides, there was no delay of functional maturation at brainstem level although unilateral hearing was deprived during their early years of life.

Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing.

The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention.NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.

Atypical longitudinal development of speech-evoked auditory brainstem response in preschool children with autism spectrum disorders.

Language impairment is common in children with autism spectrum disorders (ASDs). Previous research has shown that this disability may be, in part, due to atypical auditory processing of speech stimuli. However, how speech sounds are processed in children with ASD remains largely unknown. The present study assessed the developmental pattern of auditory information processing at the level of the brainstem in preschool children with ASD using speech-evoked auditory brainstem response (speech-ABR). Children with ASD (N = 15) and of typical developing (TD) (N = 20), both of preschool age, were enrolled. The speech-ABRs recorded at two different time points (T1 and T2; 9.68 months apart on average) were virtually identical in the TD group. However, in the ASD group, the wave V latency of speech-ABR was significantly shortened and the amplitudes of wave A and C were significantly larger at T2, compared to those recorded at T1 (10.78 months apart on average). Compared to the TD group, the wave V and A latencies were prolonged at T1, whereas the wave E amplitude decreased and wave F latency prolonged at T2. There was a positive partial correlation between the language performance and the wave A amplitude in the ASD group. These results indicate that auditory processing at the subcortical level is well-developed in the TD preschool children, but is immature and abnormal in the children with ASD at the same ages. Thus, aberrant speech processing at the brainstem level may contribute significantly to the language impairment in children with ASD at preschool ages. Autism Res 2019, 12: 1022-1031. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Language impairment is common in children with autism spectrum disorders (ASDs). We investigated the developmental pattern of subcortical auditory processing by monitoring changes in the speech-evoked auditory brainstem response (speech-ABR) over a period of 10 months in preschool children. Our results show that subcortical auditory processing is impaired and immature in children with ASD compared with age-matched, typically developing children. The results suggest that speech-ABR may be used as an objective measure in evaluating the language performance of children with ASD. The results also suggest that aberrant speech processing at the level of the brainstem may contribute significantly to the language impairment in preschool children with ASD.

Expression and Function of Transient Receptor Potential Ankyrin 1 Ion Channels in the Caudal Nucleus of the Solitary Tract.

The nucleus of the solitary tract (NTS) receives visceral information via the solitary tract (ST) that comprises the sensory components of the cranial nerves VII, IX and X. The Transient Receptor Potential Ankyrin 1 (TRPA1) ion channels are non-selective cation channels that are expressed primarily in pain-related sensory neurons and nerve fibers. Thus, TRPA1 expressed in the primary sensory afferents may modulate the function of second order NTS neurons. This hypothesis was tested and confirmed in the present study using acute brainstem slices and caudal NTS neurons by RT-PCR, immunostaining and patch-clamp electrophysiology. The expression of TRPA1 was detected in presynaptic locations, but not the somata of caudal NTS neurons that did not express TRPA1 mRNA or proteins. Moreover, caudal NTS neurons did not show somatodendritic responsiveness to TRPA1 agonists, while TRPA1 immunostaining was detected only in the afferent fibers. Electrophysiological recordings detected activation of presynaptic TRPA1 in glutamatergic terminals synapsing on caudal NTS neurons evidenced by the enhanced glutamatergic synaptic neurotransmission in the presence of TRPA1 agonists. The requirement of TRPA1 for modulation of spontaneous synaptic activity was confirmed using TRPA1 knockout mice where TRPA1 agonists failed to alter synaptic efficacy. Thus, this study provides the first evidence of the TRPA1-dependent modulation of the primary afferent inputs to the caudal NTS. These results suggest that the second order caudal NTS neurons act as a TRPA1-dependent interface for visceral noxious-innocuous integration at the level of the caudal brainstem.

Perception of Verticality and Vestibular Disorders of Balance and Falls.

Objective: To review current knowledge of the perception of verticality, its normal function and disorders. This is based on an integrative graviceptive input from the vertical semicircular canals and the otolith organs.Methods: The special focus is on human psychophysics, neurophysiological and imaging data on the adjustments of subjective visual vertical (SVV) and the subjective postural vertical. Furthermore, examples of mathematical modeling of specific vestibular cell functions for orientation in space in rodents and in patients are briefly presented.Results: Pathological tilts of the SVV in the roll plane are most sensitive and frequent clinical vestibular signs of unilateral lesions extending from the labyrinths via the brainstem and thalamus to the parieto-insular vestibular cortex. Due to crossings of ascending graviceptive fibers, peripheral vestibular and pontomedullary lesions cause ipsilateral tilts of the SVV; ponto-mesencephalic lesions cause contralateral tilts. In contrast, SVV tilts, which are measured in unilateral vestibular lesions at thalamic and cortical levels, have two different characteristic features: (i) they may be ipsi- or contralateral, and (ii) they are smaller than those found in lower brainstem or peripheral lesions. Motor signs such as head tilt and body lateropulsion, components of ocular tilt reaction, are typical for vestibular lesions of the peripheral vestibular organ and the pontomedullary brainstem (vestibular nucleus). They are less frequent in midbrain lesions (interstitial nucleus of Cajal) and rare in cortical lesions. Isolated body lateropulsion is chiefly found in caudal lateral medullary brainstem lesions. Vestibular function in the roll plane and its disorders can be mathematically modeled by an attractor model of angular head velocity cell and head direction cell function. Disorders manifesting with misperception of the body vertical are the pusher syndrome, the progressive supranuclear palsy, or the normal pressure hydrocephalus; they may affect roll and/or pitch plane.Conclusion: Clinical determinations of the SVV are easy and reliable. They indicate acute unilateral vestibular dysfunctions, the causative lesion of which extends from labyrinth to cortex. They allow precise topographical diagnosis of side and level in unilateral brainstem or peripheral vestibular disorders. SVV tilts may coincide with or differ from the perception of body vertical, e.g., in isolated body lateropulsion.

5XFAD Mice Show Early Onset Gap Detection Deficits.

Alzheimer's patients show auditory temporal processing deficits very early in disease progression, before the onset of major cognitive impairments. In addition to potentially contributing to speech perception and communication deficits in patients, this also represents a potential early biomarker for Alzheimer's. For this reason, tests of temporal processing such as gap detection have been proposed as an early diagnosis tool. For a biomarker such as gap detection deficits to have maximum clinical value, it is important to understand what underlying neuropathology it reflects. For example, temporal processing deficits could arise from alterations at cortical, midbrain, or brainstem levels. Mouse models of Alzheimer's disease can provide the ability to reveal in detail the molecular and circuit pathology underlying disease symptoms. Here we tested whether 5XFAD mice, a leading Alzheimer's mouse model, exhibit impaired temporal processing. We found that 5XFAD mice showed robust gap detection deficits. Gap detection deficits were first detectable at about 2 months of age and became progressively worse, especially for males and for longer gap durations. We conclude that 5XFAD mice are well-suited to serve as a model for understanding the circuit mechanisms that contribute to Alzheimer's-related gap detection deficits.

Progressive Hemodynamic and Cardiac Autonomic Impairment as a Function of Metabolic State: Local Adipose vs. Systemic Inflammation

Cardiac autonomic neuropathy (CAN) commonly occurs early in the course of diabetes with significant cardiovascular mortality and morbidity. CAN development is linked to hyperglycemia; however, current understanding extends cardiovascular risk to pre‐diabetic patients without glycemic changes. Recent evidence suggests that anti‐diabetic drugs reduce the risk of cardiovascular complications in pre‐diabetes. The mechanism leading to early CAN development, its temporal evolution from pre‐diabetes to diabetes, and the response to therapeutic interventions were not previously described. To address these questions, we developed a rat model of mildly increased caloric intake (HC‐rat) with delayed development of hyperglycemia. Twelve weeks of feeding were not associated with an increase in neither body weight, blood pressure, nor blood glucose levels. These rats only showed an elevated serum insulin level indicative of insulin resistance. Type 2 diabetes was induced by the injection of low‐dose streptozotocin (STZ, 40 mg/kg). Echocadiography and invasive hemodynamic recording were used to assess cardiac autonomic function. Western blotting, PCR, and immunohistochemistry were employed to investigate different changes on the structural and molecular levels. Pre‐diabetic rats showed localized perivascular adipose inflammation together with parasympathetic dysfunction (suppression of baroreflex sensitivity in response to vasopressors), with no signs of cardiac structural or functional impairment. These abnormalities were reversed by non‐hypoglycemic doses of Metformin (Met, 100 mg/Kg) and Pioglitazone (Pio, 2.5 mg/Kg). On the other hand, rats with overt hyperglycemia developed systemic inflammation, with increased IL‐1b levels in serum, brainstem, and heart apex. Augmentation of inflammation in diabetic rats was associated with worsening cardiac autonomic function extending to sympathetic function (suppression of baroreflex sensitivity in response to vasodilators). While control of hyperglycemia through insulin treatment reversed the sympathetic deficit, parasympathetic function was only restored by combined treatment with Insulin+Met or Insulin+Pio producing the highest decrease in systemic inflammation in diabetic rats. As well, diabetic rats showed signs of focal ischemia in ventricular tissues together with an impaired systolic function apparent as >50% decrease in maximal rate of rise of left ventricular pressure. Our present results outline a framework for sequential involvement of disparate detrimental mechanisms in the course of metabolic disease leading to a differential impact on cardiac autonomic control. Furthermore, our findings emphasize the value of early intervention with antidiabetic drugs with potential pleotropic effects.Support or Funding InformationSupported by AUB‐FM MPP grant # 320148This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Novel Approach to Elucidate Human Baroreflex Regulation at the Brainstem Level: Pharmacological Testing During fMRI.

Introduction: Brainstem nuclei govern the arterial baroreflex, which is crucial for heart rate and blood pressure control. Yet, brainstem function is difficult to explore in living humans and is therefore mostly studied using animal models or postmortem human anatomy studies. We developed a methodology to identify brainstem nuclei involved in baroreflex cardiovascular control in humans by combining pharmacological baroreflex testing with functional magnetic resonance imaging.Materials and Methods: In 11 healthy men, we applied eight repeated intravenous phenylephrine bolus doses of 25 and 75 μg followed by a saline flush using a remote-controlled injector during multiband functional magnetic resonance imaging (fMRI) acquisition of the whole brain including the brainstem. Continuous finger arterial blood pressure, respiration, and electrocardiogram (ECG) were monitored. fMRI data were preprocessed with a brainstem-specific pipeline and analyzed with a general linear model (GLM) to identify brainstem nuclei involved in central integration of the baroreceptor input.Results: Phenylephrine elicited a pressor response followed by a baroreflex-mediated lengthening of the RR interval (25 μg: 197 ± 15 ms; 75 μg: 221 ± 33 ms). By combining fMRI responses during both phenylephrine doses, we identified significant signal changes in the nucleus tractus solitarii (t = 5.97), caudal ventrolateral medulla (t = 4.59), rostral ventrolateral medulla (t = 7.11), nucleus ambiguus (t = 5.6), nucleus raphe obscurus (t = 6.45), and several other brainstem nuclei [p < 0.0005 family-wise error (few)-corr.].Conclusion: Pharmacological baroreflex testing during fMRI allows characterizing central baroreflex regulation at the level of the brainstem in humans. Baroreflex-mediated activation and deactivation patterns are consistent with previous investigations in animal models. The methodology has the potential to elucidate human physiology and mechanisms of autonomic cardiovascular disease.

Transcranial direct current stimulation (tDCS) and trigeminal pain: A preclinical study.

Our objective was to evaluate the Transcranial direct current stimulation (tDCS) effect on facial allodynia induced by chronic constriction of the infraorbital nerve (CCI-ION) and on the brainstem levels of TNF-α, NGF, IL-10, and serum LDH in rats. Rats were exposed to the CCI-ION model. Facial allodynia was assessed by von Frey filaments test at baseline, 3, 7, 10, and 14days postsurgery and 24hr and 7days after the bimodal tDCS sessions for 20min/day/8days. Chronic constriction of the infraorbital nerve induced a significant decrease in the mechanical threshold 14days after surgery. This effect was reversed by tDCS treatment, with the mechanical threshold returning to basal levels at 24hr after the end of the treatment and it persisted for 7days after the end of the treatment. tDCS also decreased LDH serum levels compared to those in the control group. There was an interaction between pain and treatment with respect to brainstem levels of NGF, TNF-α, and IL-10. Chronic constriction of the infraorbital nerve model was effective in establishing trigeminal neuropathic pain on 14days after surgery, and tDCS reduced allodynia and LDH serum levels and promoted alterations in NGF, TNF-α, and IL-10 brainstem levels. Thus, we suggest that tDCS may be a potential therapy in the trigeminal pain treatment.

Long-range temporal correlation in Auditory Brainstem Responses to Spoken Syllable/da/

The speech auditory brainstem response (sABR) is an objective clinical tool to diagnose particular impairments along the auditory brainstem pathways. We explore the scaling behavior of the brainstem in response to synthetic /da/ stimuli using a proposed pipeline including Multifractal Detrended Moving Average Analysis (MFDMA) modified by Singular Value Decomposition. The scaling exponent confirms that all normal sABR are classified into the non-stationary process. The average Hurst exponent is H = 0:77 ± 0:12 at 68% confidence interval indicating long-range correlation which shows the first universality behavior of sABR. Our findings exhibit that fluctuations in the sABR series are dictated by a mechanism associated with long-term memory of the dynamic of the auditory system in the brainstem level. The q-dependency of h(q) demonstrates that underlying data sets have multifractal nature revealing the second universality behavior of the normal sABR samples. Comparing Hurst exponent of original sABR with the results of the corresponding shuffled and surrogate series, we conclude that its multifractality is almost due to the long-range temporal correlations which are devoted to the third universality. Finally, the presence of long-range correlation which is related to the slow timescales in the subcortical level and integration of information in the brainstem network is confirmed.

Blast Exposure Impairs Sensory Gating: Evidence from Measures of Acoustic Startle and Auditory Event-Related Potentials.

Many military service members and veterans who have been exposed to high-intensity blast waves experience traumatic brain injury (TBI), resulting in chronic auditory deficits despite normal hearing sensitivity. The current study sought to examine the neurological cause of this chronic dysfunction by testing the hypothesis that blast exposure leads to impaired filtering of sensory information at brainstem and early cortical levels. Groups of blast-exposed and non-blast-exposed participants completed self-report measures of auditory and neurobehavioral status, auditory perceptual tasks involving degraded and competing speech stimuli, and physiological measures of sensory gating, including pre-pulse inhibition and habituation of the acoustic startle reflex and electrophysiological assessment of a paired-click sensory gating paradigm. Blast-exposed participants showed significantly reduced habituation to acoustic startle stimuli and impaired filtering of redundant sensory information at the level the auditory cortex. Multiple linear regression analyses revealed that poorer sensory gating at the cortical level was primarily influenced by a diagnosis of TBI, whereas reduced habituation was primarily influenced by a diagnosis of post-traumatic stress disorder. A statistical model was created including cortical sensory gating and habituation to acoustic startle, which strongly predicted performance on a degraded speech task. These results support the hypothesis that blast exposure impairs central auditory processing via impairment of neural mechanisms underlying habituation and sensory gating.

Interaction between nesfatin-1 and oxytocin in the modulation of the swallowing reflex

Nesfatin-1, an 82-amino acid peptide encoded by the secreted precursor nucleobinin-2 (NUCB2), exerts potent anorexigenic action independently of leptin signaling. This propensity has propelled this peptide and its analogues as potential anti-obesity drug candidates. However, a more extensive comprehension of its biological actions is needed prior to envisaging its potential use in the treatment of metabolic diseases. Swallowing is an essential motor component of ingestive behavior, which induces the propulsion of the alimentary bolus from the mouth to the esophagus. The dorsal swallowing group (DSG) which constitutes a part of the central pattern generator of swallowing (SwCPG) is located within the solitary tract nucleus (STN), a region reported to contain nesfatin-1/NUCB2 expressing neurons. In this context, we investigate here the possible effects of nesfatin-1 on swallowing discharge. Nesfatin-1 dose-dependently inhibited swallowing reflex and activated neurons located in the DSG region. In addition, we provide evidences that strongly suggest that this nesfatin-1 inhibitory effect involved an oxytocinergic relay. Indeed, oxytocin (OT) injection at the brainstem level inhibited swallowing reflex and OT receptor antagonist prevented nesfatin-1 inhibitory action. Altogether, these data constitute the first demonstration that nesfatin-1 modulates swallowing reflex by acting at the brainstem level via an oxytocinergic relay.

Lead Induced Ototoxicity and Neurotoxicity in Adult Guinea Pig.

Lead exposure causes or aggravates hearing damage to human or animal, but the detailed effects of lead exposure on auditory system including injury sites of the cochlea in mammal remain controversy. To investigate the effect of chronic lead exposure on auditory system, 40 adult guinea pigs with normal hearing were randomly divided into five groups. They were fed 2 mmol/L lead acetate in drinking water for 0, 15, 30, 60, and 90 days (n = 8), respectively. Lead concentrations in blood, cochlea, and brainstem were measured. Auditory function was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). The morphology of cochlea and brainstem was observed, and expression of autophagy-related protein in brainstem was also assessed. The blood lead concentration reached a high level at the 15th day and kept stable, but the lead level in brainstem and cochlear tissue increased obviously at the 60th day and 90th day of lead exposure, respectively. There was no significant difference in the morphology of hair cells and stria vascularis (SV) among these five groups, but the number of spiral ganglion neuron (SGN) gradually decreased after 60 days. The differences of ABR thresholds and DPOAE amplitudes were not statistically significant among each group, but I wave latency, III latency, and I-III wave interval of ABR were delayed with the prolonging of time of lead exposure. The expressions of autophagy-related protein ATG5, ATG6, and LC3B in brainstem were increased after 30 days. These results suggest that the key target of lead toxicity was the auditory nerve conduction pathway including SGNs and brainstem, rather than cochlear hair cells and SV. Autophagy may play a very important role in lead toxicity to auditory nervous system.

Juvenile Play Behavior in Neonatally Underfed and Sensory Stimulated Wistar Rats

Play development in juvenile rats depends on specific sensory signals integrated at cortical, limbic and brain stem levels to modulate motoric, metabolic, motivational and social responses. Neonatal undernourishment disrupts the morphological and functional organization of the brain for adaptive responses including play performance. These alterations may be restored by preweaning exposure to sensory-enriched environments. This study was designed to determine in four experimental groups, Control (LC), Underfed (LU), Control Ligated/Stimulated (LCS), and Underfed Ligated/Stimulated (LUS), whether changes in juvenile play of neonatally underfed male rats by the nipple-ligated procedure of F0 dams and/or the handling of F1 rats may restore the deficiencies in juvenile play performance. The pinning frequency values in LC, LCS and LUS groups consistently increased until reaching a significant peak between postnatal days (PDs) 25 and 50 and then gradually declining until PD 60, when the play in pairs was significantly higher compared with the play in groups that follows the same sequence but with lower values in the stimulated groups. The results may reflect poor maternal care and lower somatosensory stimulation; and the sensory massage of LU F1 pups compared with the LC, LUS, and LCS rats. Fewer dorsal body contacts occurred in LU and LUS rats when playing in pairs than in groups. Results suggest that although handling has salutary effects on neuronal play structures, the reduced levels of total pinning and dorsal contacts, mainly in the play of rat pairs in LCS vs. LUS groups, were not fully recovered.

Visibility graph analysis of speech evoked auditory brainstem response in persistent developmental stuttering

In this research, the concept of fractality based on nonlinear science and chaos theory is explored to study and evaluate the complexity of speech-evoked auditory brainstem response (s-ABR) time series in order to capture its intrinsic multiscale dynamics. The visibility graph of the s-ABR series is proposed as a quantitative method to differentiate subjects with persistent developmental stuttering (PDS) from the normal group. Differential complexities between normal and PDS subjects is quantified using Graph index complexity (GIC). The model is applied to 14 individuals with PDS and 15 normal subjects. The results reveal the promising ability of GIC for assessment of abnormal activation of brainstem level in PDS group. It is observed that all s-ABR series have visibility graphs with a power-law topology and fractality in the s-ABR series is dictated by a mechanism associated with long-term memory of the auditory system dynamics at the brainstem level.

Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia.

Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia-telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology.