Brainstem

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections result in the temporary loss of smell and taste in about one third of confirmed cases. Methods We used immunohistochemistry to confirm the presence of ACE2, NRP1 and TMPRSS2 in two cranial nerves (IX and X) that mediate taste where they leave/join the medulla. Samples from three (two paraffin embedded and one frozen) postmortem samples were studied (facial (VII) nerve was not available). We also performed immunohistochemistry using the same antibodies in two human cell lines (oligodendrocytes and fibroblasts), and we isolated RNA from one nerve and performed PCR to confirm the presence of the mRNAs that encode the proteins visualized. Findings All three of the proteins (ACE-2, NRP1 and TMPRSS2) required for SARS-CoV-2 infections appear to be present in all cellular components (Schwann cells, axons, vascular endothelium, and connective tissue) of the human IXth and Xth nerves near the medulla. We also found their mRNAs in the nerve and in human oligodendrocytes and fibroblasts which were stained by antibodies directed at the three proteins examined. Interpretation Infection of the IXth and Xth nerves by the SARS-CoV-2 virus is likely to cause the loss of taste experienced by many Covid patients. Migration of the virus from the oral cavity through these nerves to brainstem respiratory centers might contribute to the problems that patients experience.

RESUMEN Los angiomas cavernosos o cavernomas, son una de las malformaciones vasculares descritas originalmente por Mc Cormick. Representan entre un 5-13% de las malformaciones vasculares intracraneales. Antes del advenimiento de la tomografía axial computarizada y la imagen por resonancia magnética se conocían también como malformaciones vasculares ocultas. Aún cuando ocurren en practicamente todas las regiones del sistema nervioso central incluyendo la médula espinal, se frecuencia a nivel del tallo cerebral es de un 15-35% de todos los cavernomas. Los cavernomas del tallo cerebral son lesiones que frecuentemente se han descrito como inoperables y por ende han sido tributarias de tratamientos inefectivos tales como la radiocirugía o la terapia endovascular. En este artículo se presenta una serie de 6 pacientes con cavernomas dee tallo tratados a nivel institucional con diversas localizaciones. En conclusión se puede decir que la selección de un abordaje apropiado de acuerdo a su localización y una disección cuidadosa, asegura la extracción del cavernoma con poco o ningún déficit neurológico agregado. Se discuten las estrategias diagnósticas y de manejo quirúrgico y los abordajes más frecuentemente reportados en la literatura para su tratamiento. El abordaje quirúrgico continúa siendo la mejor opción terapeútica definitiva para los cavernomas de tallo cerebral. Palabras clave: cavernomas, tallo cerebral, tratamiento quirúrgico, malformaciones vasculares cerebrales.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition associated with a high burden of physical disability and an elevated prevalence of cognitive symptoms. Patients show abnormalities in several domains, including systemic and brain metabolism, and the immune system. But the mechanism behind the disease is unknown and there is no cure. Patients with ME/CFS exhibit significant changes in the cingulate cortex, including reduced glucose metabolism, altered resting-state connectivity, increased activation during cognitive tasks, and increased glial activation, all reviewed in this paper. We also show that our analysis of the local spectrum in the cingulate cortex of a patient with ME/CFS confirms the increase of the CHO/CR ratio reported by a previous study. We discuss how a pathology of the cingulate cortex is also confirmed indirectly by cognitive assessment in this patient population. The mechanism behind these abnormalities remains unknown. In this paper, we show that some of these abnormalities are consistent with what is seen in systemic inflammation. We also review some evidence pointing to the hypothesis that they could be secondary to a pathology of the brainstem, including the metabolic shift in the serotoninergic neurons of the Raphe nuclei described by a recent mathematical model of ME/CFS. Alternatively, we propose that the increased CHO/CR ratio in the anterior cingulate cortex may also be a sign of abnormal plasma membrane composition, which is suggested by metabolomic studies and by measures of the electrical properties of PBMCs and plasma, in this patient population.

This paper examines evidence for a disorder of the intrinsic motive processes of the purposeful self in autism spectrum disorder (ASD), which leads to weakening of shared experience in early childhood.  Changed motor and affective regulations that identify autism are traced to faults in neurogenesis in the core brainstem systems of the fetus. These fundamental systems have evolved to serve development of sensory guidance for motor activity and affective regulation of projects of thought and action, including communication of intentions and feelings with other human selves. 
Affective neuroscience describes subcortical organs in mammals that are responsible for the coherence of a primary conscious self-as-agent, with emotions that communicate feelings for selective sociability with other individuals. In humans this affective consciousness is adapted as the foundation for active engagement of an infant with a world of objects and people by expressions under the control of shared rhythms of an ‘intrinsic motive pulse’. We give primary importance to the disorder in autism of the accuracy of timing in this resonant central nervous system, responsible for coordination of movement with companions. We relate this understanding of the disorder to problems in the monitoring of prospective regulation of actions of the conscious Self by a body-related affective valence, which affects the arousal of personal satisfaction of purposes or anxiety at their failure, and engagement in affectionate or antagonistic relations. This leads to evaluation of participation in movements with shared feelings for therapy and teaching to helping the socio-emotional development and learning of children with autism, as well as advice for lifetime care.
In autism, the essential embodiment of early childhood experience for growth of knowledge, skill and collaborative social understanding appears weakened by a sensorimotor deficit in motivation and its affective control. This has life-long developmental consequences, affecting the intersubjective responses of family, and then cooperative attentions of companions and teachers in the community. Mis-coordination of movements leads to frustration, distress, and anxiety, creating social withdrawal and avoidance, or over-compensations expressed as increased arousal and hyper-activity. Indeed, we propose that disabilities in cognitive intelligence and language are secondary to weakness in prospective control of movements with affective appraisal of anticipated experiences.
We identify the origin of these symptoms in disorders of brainstem mechanisms that develop in the late embryo stage and that are essential for motor and affective regulations, as well as autonomic processing.  In particular, data indicate an anatomical and functional disruption of the inferior olive, associated with control of motor timing by the cerebellum, and abnormal development of the neighbouring nucleus ambiguus, involved in expressions of social engagement and speech. These nuclei appear to be critical components of the core neuropsychological system that develops abnormally to produce the varied autistic spectrum disorders.
We draw attention to the limitations of research methods in neuroscience and psychology that seek to identify a primary cognitive, information-processing and neocortically mediated disorder by testing the response of the individual in artificial situations. New research using micro-kinesic descriptive methods clarifies motor deficits that characterize autism. Furthermore, extensive imaging of brain activities supports a philosophical psychology of embodiment that elucidates how confusion in unconscious prospective control of actions from fetal stages impairs the child’s developing subjective agency. Finally, we offer information on movement-based therapies that can help to facilitate learning, self-regulation, and pleasure in social interaction for individuals with ASD.

The young nervous system is primed for sensory learning, facilitating the acquisition of language and communication skills. Social and linguistic impoverishment can limit these learning opportunities, eventually leading to language-related challenges such as poor reading. Music training offers a promising auditory learning strategy by directing attention to meaningful acoustic elements of the soundscape. In light of evidence that music training improves auditory skills and their neural substrates, there are increasing efforts to enact community-based programs to provide music instruction to at-risk children. Harmony Project is a community foundation that has provided free music instruction to over 1000 children from Los Angeles gang-reduction zones over the past decade. We conducted an independent evaluation of biological effects of participating in Harmony Project by following a cohort of children for 1 year. Here we focus on a comparison between students who actively engaged with ...

Background: Stimulation of the vagus nerve via implanted electrodes is currently used to treat refrac-tory epilepsy and depression. Recently, a non-invasive approach to vagal stimulation has demonstrated similar beneficial effects, but it remains unclear whether these effects are mediated via activation of af-ferent vagal fibers. Objective: The present study was designed to ascertain whether afferent vagal projections can be ac-cessed non-invasively by transcutaneous electrical stimulation of the antero-lateral surface of the neck, which overlies the course of the vagus nerve. Methods: Thirteen healthy subjects underwent 2 fMRI scans in one session. Transcutaneous electrical stimulation was applied for 2 min to the right postero-lateral surface of the neck during scan #1 (control condition, sternocleidomastoid stimulation: " SCM ") and to the right antero-lateral surface of the neck during scan #2 (experimental condition, non-invasive vagus nerve stimulation: " nVNS "). Two analyses were conducted using FSL (whole-brain and brainstem; corrected, p < 0.01) to determine whether nVNS activated vagal projections in the brainstem and forebrain, compared to baseline and SCM stimulation. Results: Compared to baseline and control (SCM) stimulation, nVNS significantly activated primary vagal projections including: nucleus of the solitary tract (primary central relay of vagal afferents), parabrachial area, primary sensory cortex, and insula. Regions of the basal ganglia and frontal cortex were also significantly activated. Deactivations were found in the hippocampus, visual cortex, and spinal trigeminal nucleus. Conclusion: The present findings provide evidence in humans that cervical vagal afferents can be ac-cessed non-invasively via transcutaneous electrical stimulation of the antero-lateral surface of the neck, which overlies the course of the nerve, suggesting an alternative and feasible method of stimulating vagal afferents. Published by Elsevier Inc.

Emotions depend upon the integrated activity of neural networks that modulate arousal, autonomic function, motor control, and somatosensation. Brainstem nodes play critical roles in each of these networks, but prior studies of the neuroanatomic basis of emotion, particularly in the human neuropsychological literature, have mostly focused on the contributions of cortical rather than subcortical structures. Given the size and complexity of brainstem circuits, elucidating their structural and functional properties involves technical challenges. However, recent advances in neuroimaging have begun to accelerate research into the brainstem's role in emotion. In this review, we provide a conceptual framework for neuroscience, psychology and behavioral science researchers to study brainstem involvement in human emotions. The "emotional brainstem" is comprised of three major networks-Ascending, Descending and Modulatory. The Ascending network is composed chiefly of the spinothalamic tracts and their projections to brainstem nuclei, which transmit sensory information from the body to rostral structures. The Descending motor network is subdivided into medial projections from the reticular formation that modulate the gain of inputs impacting emotional salience, and lateral projections from the periaqueductal gray, hypothalamus and amygdala that activate characteristic emotional behaviors. Finally, the brainstem is home to a group of modulatory neurotransmitter pathways, such as those arising from the raphe nuclei (serotonergic), ventral tegmental area (dopaminergic) and locus coeruleus (noradrenergic), which form a Modulatory network that coordinates interactions between the Ascending and Descending networks. Integration of signaling within these three networks occurs at all levels of the brainstem, with progressively more complex forms of integration occurring in the hypothalamus and thalamus. These intermediary structures, in turn, provide input for the most complex integrations, which occur in the frontal, insular, cingulate and other regions of the cerebral cortex. Phylogenetically older brainstem networks inform the functioning of evolutionarily newer rostral regions, which in turn regulate and modulate the older structures. Via these bidirectional interactions, the human brainstem contributes to the evaluation of sensory information and triggers fixed-action pattern responses that together constitute the finely differentiated spectrum of possible emotions.

The energy-yielding pathways that provide the large amounts of metabolic energy required by inner ear sensorineural cells are poorly understood. Neuroglobin (Ngb) is a neuron-specific hemoprotein of the globin family, which is suggested to be involved in oxidative energy metabolism. Here, we present quantitative real-time reverse transcription PCR, in situ hybridization, immunohistochemical, and Western blot evidence that neuroglobin is highly expressed in the mouse and rat cochlea. For primary cochlea neurons, Ngb expression is limited to the subpopulation of type I spiral ganglion cells, those which innervate inner hair cells, while the subpopulation of type II spiral ganglion cells which innervate the outer hair cells do not express Ngb.We further investigated Ngb distribution in rat, mouse, and human auditory brainstem centers, and found that the cochlear nuclei and superior
olivary complex (SOC) also express considerable amounts of Ngb. Notably, the majority of olivocochlear neurons, those which provide efferent innervation of outer hair cells as identified by neuronal tract tracing, were Ngb-immunoreactive.
We also observed that neuroglobin in the SOC frequently co-localized with neuronal nitric oxide synthase, the enzyme responsible for nitric oxide production. Our findings suggest that neuroglobin is well positioned to play an important physiologic role in the oxygen homeostasis of the peripheral and central auditory nervous system, and provides the first evidence that Ngb signal differentiates the central projections of the inner and outer hair cells.

Cavernous angiomas,cavernomas or occult vascular malformations, belong to the group of vascular malformations described originally by Mc Cormick. They represent between 5-13% of the total intracranial vascular malformations. Of these, between 15-35% are located at the brainstem from the mesencephalon to the medulla oblongata. Cavernomas of the brainstem are considered frequently out of surgical treatment due to the apparent complexity to reach them safetly. This fact has induced a phenomena of inapropiate alternatives such the radiosurgery or endovascular therapy. The skull base approaches, have demostrated a great advance in exposure and surgical treatment of cavernomas at this location, regardless of their position in the brainstem. In this paper, we report our experience with 6 patients harboring a brainstem cavernoma that underwent surgical treatment at the National Institute of Neurology and Neurosurgery «Manuel Velasco Suarez» – Mexico City. In all cases the excision of the ca...

Ogilvie first described Ogilvie’s syndrome in 1948. This entity is also known as paralytic ileus of the colon, adynamic ileus of the colon,
neurological disease causing damage to the central nervous system was identified as an important independent risk factor we reported a
52-year-old Moroccan man from, without history, one after his admission for hemorrhagic stroke of brain stem. He developed abdominal
discomfort. Plain abdominal radiography showed diffuse bowel loop dilation and computed tomography showed marked bowel loop dilation
and colonic gas. We diagnosed acute pseudo-obstruction of the colon (Ogilvie syndrome) and we decided to use colonoscopic decompression
followed by Intravenous neostigmine was given under cardiac monitorization, with good Results.

Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson’s disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine’s role in locomotion.

Previous studies report prolonged auditory brainstem response (ABR) in children and adults with autism spectrum disorder (ASD). Despite its promise as a biomarker, it is unclear whether healthy newborns who later develop ASD also show ABR abnormalities. In the current study, we extracted ABR data on 139,154 newborns from their Universal Newborn Hearing Screening, including 321 newborns who were later diagnosed with ASD. We found that the ASD newborns had significant prolongations of their ABR phase and V‐negative latency compared with the non‐ASD newborns. Newborns in the ASD group also exhibited greater variance in their latencies compared to previous studies in older ASD samples, likely due in part to the low intensity of the ABR stimulus. These findings suggest that newborns display neurophysiological variation associated with ASD at birth. Future studies with higher‐intensity stimulus ABRs may allow more accurate predictions of ASD risk, which could augment the universal ABR test that currently screens millions of newborns worldwide.

Heme oxygenase has been linked to the oxygen-sensing function of the carotid body, pulmonary vasculature, cerebral vasculature, and airway smooth muscle. We have shown previously that the cardiorespiratory regions of the rostral ventrolateral medulla are excited by local hypoxia and that heme oxygenase-2 (HO-2) is expressed in the hypoxia-chemosensitive regions of the rostral ventrolateral medulla (RVLM), the respiratory pre-Bötzinger complex, and C1 sympathoexcitatory region. To determine whether heme oxygenase is necessary for the hypoxic-excitation of dissociated RVLM neurons (P1) cultured on confluent medullary astrocytes (P5), we examined their electrophysiological responses to hypoxia (NaCN and low Po(2)) using the whole-cell perforated patch clamp technique before and after blocking heme oxygenase with tin protoporphyrin-IX (SnPP-IX). Following the electrophysiological recording, immunocytochemistry was performed on the recorded neuron to correlate the electrophysiological response to hypoxia with the expression of HO-2. We found that the responses to NaCN and hypoxia were similar. RVLM neurons responded to NaCN and low Po(2) with either depolarization or hyperpolarization and SnPP-IX blocked the depolarization response of hypoxia-excited neurons to both NaCN and low Po(2) but had no effect on the hyperpolarization response of hypoxia-depressed neurons. Consistent with this observation, HO-2 expression was present only in the hypoxia-excited neurons. We conclude that RVLM neurons are excited by hypoxia via a heme oxygenase-dependent mechanism.

It is still a matter of debate whether cephalopods can detect sound frequencies above 400 Hz. So far there is no proof for the detection of underwater sound above 400 Hz via a physiological approach. The controversy of whether cephalopods have a sound detection ability above 400 Hz was tested using the auditory brainstem response (ABR) approach, which has been successfully applied in fish, crustaceans, amphibians, reptiles and birds. Using ABR we found that auditory evoked potentials can be obtained in the frequency range 400 to 1500 Hz (Sepiotheutis lessoniana) and 400 to 1000 Hz (Octopus vulgaris), respectively. The thresholds of S. lessoniana were generally lower than those of O. vulgaris.

Objective: Auditory brainstem implants (ABI) in deaf children are gaining momentum in Europe, and protocols for clinical trials are being discussed in the United States. We recently evaluated a young boy with an ABI. In this presentation, we describe the multidisciplinary test protocol and discuss results. Study design: Case study Setting: Tertiary referral center Patients: The child was 3 years, 11 months at time of testing in July, 2006. He was congenitally deaf from Goldenhar Syndrome and presented with auditory nerve agenesis. Intervention: Auditory brainstem implant Main outcome measures: A battery of tests was compiled to assess performance in the domains of speech perception, language, behavior, cognition, quality of life, and parental perceptions. Results: Following 5 weeks of consistent electrical stimulation, the child demonstrated detection of speech sounds, auditory pattern perception with visual cues, and inconsistent auditory-only vowel discrimination. The child was accepting of the ABI, showed awareness to sound and was increasing his vocalizations. Language age using signs was 20 months. The child had normal intelligence but exhibited attention deficits and difficulty completing tasks during a structured activity. The parents were counseled to make sign language a high priority and to increase structure in daily learning activities. Conclusions: Pediatric ABI clinical trials are in the early stages of development in the United States. These trials should encompass a multidisciplinary approach in which children are evaluated in the context of the "whole child" in order to define the relevant variables and to quantify outcomes.

Inflammation-induced release of prostaglandin E2(PGE2) changes breathing patterns and the response to CO2levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspirat...

Neurons in the medullary reticular formation are involved in the control of postural and locomotor behaviors in all vertebrates. Reticulospinal neurons in this brain region provide one of the major descending projections to the spinal cord. Although neurons in the newt medullary reticular formation have been extensively studied using in vivo extracellular recordings, little is known of their intrinsic biophysical properties or of the underlying circuitry of this region. Using whole cell patch-clamp recordings in brain slices containing the rostromedial reticular formation from adult male newts, we observed spontaneous miniature outward currents (SMOCs) in ~2/3 of neurons. Although SMOCs superficially resembled inhibitory postsynaptic currents (IPSCs), they had slower risetimes and decay times than spontaneous IPSCs. SMOCs required intracellular Ca2+ release from ryanodine receptors and were also dependent on the influx of extracellular Ca2+. SMOCs were unaffected by apamin but were ...

(p = 0.006). Lesion size >18 mm (hazards ratio, HR 3.34, 95% CI 1.54-7.26; p = 0.0001) and ventral location or crossing the brain stem's midpoint (HR 2.5, 95% CI 1.14-5.46; p = 0.022) were associated with a major risk of rebleeding in the uni-variate analysis, but only a lesion >18 mm remained statistically significant (HR 2.7, 95% CI 1.2-6.21; p = 0.016) in the multivariate analysis. Conclusion: A lesion size >18 mm was the principal factor associated with hemorrhage recurrence. The overall functional outcome was good. However, significant morbidity was attributable to rebleeding.

Aspiration reflex (AspR) represents a specific inspiratory motor behavior expressed by short, powerful inspiratory activity without subsequent active expiration and characterized by the ability to interrupt strong tonic inspiratory activity, as well as hypoxic apnea and several other functional disorders. Multiresolution analysis-based determination of spectral features arising during AspR has not yet been satisfactorily investigated.
The time–frequency energy distribution of phrenic nerve electrical activity was compared during the AspR, inspiratory phase of tracheobronchial cough and quiet inspiration.
Data obtained from 16 adult cats anesthetized with chloralose or pentobarbital were analyzed using a wavelet transformation, a sensitive method suitable for processing of the non-stationary respiratory output signal.
Phrenic nerve energy was accumulated within lower frequency bands in AspR bursts. In AspR, higher frequencies contributed less to the total power, when compared to cough inspiration. Moreover, AspR indicated a stable time–frequency energy distribution, regardless of which of the two types of anesthesia were used. Chloralose anesthesia induced a decrease of parameters in cough and quiet nspiration related to the quantity of energy.
The results indicate a specific method of information processing during generation of AspR, underlying its powerful ability to influence various severe functional disorders with potential implications for model experiments and clinical practice.

Keywords: Anesthesia, Aspiration reflex, Cat, Inspiration, Wavelet transformation

Freezing of gait is one of the most debilitating symptoms in Parkinson’s disease as it causes falls and reduces mobility and quality of life. The pedunculopontine nucleus is one of the major nuclei of the mesencephalic locomotor region and has neurons related to anticipatory postural adjustments preceding step initiation as well as to the step itself, thus it may be critical for coupling posture and gait to avoid freezing. Because freezing of gait and postural impairments have been related to frontal lesions and frontal dysfunction such as executive function, we hypothesized that freezing is associated with disrupted connectivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural connectivity of the pedunculopontine nucleus in patients with Parkinson’s disease with freezing of gait, without freezing, and healthy age-matched controls. We also included behavioral tasks to gauge severity of freezing of gait, quantify gait metrics, and assess executive cognitive functions to determine whether between-group differences in executive dysfunction were related to pedunculopontine nucleus structural network connectivity. Using seed regions from the pedunculopontine nucleus, we were able to delineate white matter connections between the spinal cord, cerebellum, pedunculopontine nucleus, subcortical and frontal/prefrontal cortical regions. The current study is the first to demonstrate differences in structural connectivity of the identified locomotor pathway in patients with freezing of gait. We report reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus and multiple regions of the frontal cortex. Moreover, these structural differences were observed solely in the right hemisphere of patients with freezing of gait. Finally, we show that the more left hemisphere-lateralized the pedunculopontine nucleus tract volume, the poorer the performance on cognitive tasks requiring the initiation of appropriate actions and/or the inhibition of inappropriate actions, specifically within patients with freezing. These results support the notion that freezing of gait is strongly related to structural deficits in the right hemisphere’s locomotor network involving prefrontal cortical areas involved in executive inhibition function.

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 μg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood-Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.

Background: Measuring hearing functional capabilities by Auditory Brainstem Responses (ABR) may contribute to better treatment, and possible differences in this process may have important clinical implications. Objectives: To measure the validity and reliability of ABR through screening, estimating, and intraoperative monitoring auditory capabilities of Arab infants and children and the degree of their seriousness. Design: Pre-and-posttest was administered to measure the validity and reliability of ABR. Settings: Al Khars hospital in Al Ahsa'a, Kingdom of Saudi Arabia (KSA). Participants: Subjects of the present study are sixty (60) individuals. The study classified them into two groups: Infants (N= 30, ages range between 0-40 weeks) and children (N=30, ages range between 10 months-3 years), diagnosed with auditory problems. Procedures: ABR pre-and-posttest measurement was administered during two weeks. The outcomes of the pre-and-posttest were neuropsycholinguistically and statistically analyzed. Main outcomes & results: The results of the pre-and-posttest for both infants and children did not vary significantly. Also consistent with expectations, higher scores were not registered for the infants' measurements due to age factors. The findings from this study largely indicate that ABR is valid and reliable.

Panic disorder has been associated with altered serotonin metabolism in the brainstem raphe. The aim of study was to evaluate the BR echogenicity on transcranial sonography (TCS) in panic disorder. A total of 96 healthy volunteers were enrolled in the "derivation" cohort, and 26 healthy volunteers and 26 panic disorder patients were enrolled in the "validation" cohort. TCS echogenicity of brainstem raphe and substantia nigra was assessed on anonymized images visually and by means of digitized image analysis. Significantly reduced brainstem raphe echogenicity was detected more frequently in panic disorder patients than in controls using both visual (68% vs. 31%) and digitized image analysis (52% vs. 12%). The optimal cutoff value of digitized brainstem raphe echogenicity indicated the diagnosis of panic disorder with a sensitivity of 64% and a specificity of 73%, and corresponded to the 30th percentile in the derivation cohort. Reduced brainstem raphe echogenicity was associated with shorter treatment duration, and, by trend, lower severity of anxiety. No relationship was found between echogenicity of brainstem raphe or substantia nigra and age, gender, severity of panic disorder, or severity of depression. Patients with panic disorder exhibit changes of brainstem raphe on TCS suggesting an alteration of the central serotonergic system.

Voltage-gated potassium channels play an important role in shaping membrane properties that underlie neurons' discharge patterns and the ways in which they transform their input. In the auditory system, low threshold potassium currents such as those created by Kv1.1 subunits contribute to precise phaselocking and to transient onset responses that provide time markers for temporal features of sounds. The purpose of the present study was to compare information about the distribution of neurons expressing the KV 1.1 in the brainstem auditory nuclei with the distribution of neurons with known functional properties in the auditory system of the big brown bat, Eptesicus fuscus. We used immunocytochemistry and light microscopy to look at the distribution of Kv1.1 subunits in the brainstem auditory nuclei. There was prominent expression in cell types known to contain high levels of Kv1.1 in other species and known to respond to auditory signals with high temporal precision. These included octopus cells and spherical bushy cells of the cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body. In addition, we found high levels of Kv1.1 in neurons of the columnar subdivision of the ventral nucleus of the lateral lemniscus and in ventral periolivary cell groups. Neurons with high levels of Kv1.1 were differentially distributed in the intermediate nucleus of the lateral lemniscus and in the inferior colliculus, suggesting that these structures contain functionally distinct cell populations, some of which may be involved in high-precision temporal processing.

Somatotopic maps in the cortex and the thalamus of adult monkeys and humans reorganize in response to altered inputs. After loss of the sensory afferents from the forelimb in monkeys because of transection of the dorsal columns of the spinal cord, therapeutic amputation of an arm or transection of the dorsal roots of the peripheral nerves, the deprived portions of the hand and arm representations in primary somatosensory cortex (area 3b), become responsive to inputs from the face and any remaining afferents from the arm. Cortical and subcortical mechanisms that underlie this reorganization are uncertain and appear to be manifold. Here we show that the face afferents from the trigeminal nucleus of the brainstem sprout and grow into the cuneate nucleus in adult monkeys after lesions of the dorsal columns of the spinal cord or therapeutic amputation of an arm. This growth may underlie the large-scale expansion of the face representation into the hand region of somatosensory cortex that...

Brainstem is one of the most complex structures of the human body, and has the most complex intracranial anatomy, which makes surgery at this level the most difficult. Due to its hidden position, the brainstem became known later by anatomists, and moreover, brainstem surgery cannot be understood without knowing the evolution of ideas in neuroanatomy, neuropathology, and neuroscience. Starting from the first attempts at identifying brainstem anatomy in prehistory and antiquity, the history of brainstem discoveries and approach may be divided into four periods: macroscopic anatomy, microscopic anatomy and neurophysiology, posterior fossa surgery, and brainstem surgery. From the first trepanning of the posterior fossa and later finger surgery, to the occurrence of safe entry zones, this paper aims to review how neuroanatomy and brainstem surgery were understood historically, and how the surgical technique evolved from Galen of Pergamon up to the twenty-first century.

Diffuse intrinsic pontine glioma (DIPG) is the most common type of brainstem glioma and one of the most deadly brain tumors. DIPG in young adult patients is a rare disease for which treatment options are limited. Radiation therapy remains the standard-of-care for newly-diagnosed DIPG, but no established therapies for recurrent disease are available. This paper describes the results of treatment of a young adult patient diagnosed with DIPG that progressed after radiation therapy. Therapy included sodium phenylbutyrate (PB) in combination with the targeted agents: pazopanib, everolimus, erlotinib, and bevacizumab. The patient achieved a rapid partial response, which persisted over a year and five months. The patient opted to discontinue the therapy and thereafter elected chemotherapy, which resulted in a subsequent rapid progression and death within one month. The targeted treatment was associated with minor toxicity that included a Grade 2 skin rash and Grade 1 elevation of transaminases. In conclusion, a combination of PB and currently available targeted drugs may offer extended survival in patients with recurrent DIPG.

In rough-skinned newts, Taricha granulosa, exposure to an acute stressor results in the rapid release of corticosterone (CORT), which suppresses the ability of vasotocin (VT) to enhance clasping behavior. CORT also suppresses VT-induced spontaneous activity and sensory responsiveness of clasp-controlling neurons in the rostromedial reticular formation (Rf). The cellular mechanisms underlying this interaction remain unclear. We hypothesized that CORT blocks VT-enhanced clasping by interfering with V1a receptor availability and/or VT-induced endocytosis. We administered a physiologically active fluorescent VT conjugated to Oregon Green (VT-OG) to the fourth ventricle 9 min after an intraperitoneal injection of CORT (0, 10, 40 μg/0.1 mL amphibian Ringers). The brains were collected 30 min post-VT-OG, fixed, and imaged with confocal microscopy. CORT diminished the number of endocytosed vesicles, percent area containing VT-OG, sum intensity of VT-OG, and the amount of VT-V1a within each vesicle; indicating that CORT was interfering with V1a receptor availability and VT-V1a receptormediated endocytosis. CORT actions were brain location-specific and season-dependent in a manner that is consistent with the natural and context-dependent expression of clasping behavior. Furthermore, the sensitivity of the Rf to CORT was much higher in animals during the breeding season, arguing for ethologically appropriate seasonal variation in CORT's ability to prevent VT-induced endocytosis. Our data are consistent with the time course and interaction effects of CORT and VT on clasping behavior and neurophysiology. CORT interference with VTinduced endocytosis may be a common mechanism employed by hormones across taxa for mediating rapid context-and season-specific behavioral responses.

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 μg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood-Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.

OBJECTIVE: Brainstem cavernous malformations (BSCMs) account for up to 18% of all intracranial cavernous malformations. Due to their complex anatomic location, they represent a significant challenge for neuro-surgeons. As such, the identification of risk factors associated with negative outcomes is of significant importance. We analyze a series of 50 cases of BSCMs treated surgically in order to identify risk factors for unfavorable outcomes.-METHODS: Patients who underwent surgical resection of BSCM at our institution between 2000 and 2015 were retrospectively reviewed. Univariate and multivariable logistic regression models were used to identify predictors of unfavorable outcomes, defined as those with a modified Rankin score (mRs) of >2.-RESULTS: Fifty Latin American patients, with a mean age of 35.85 AE 13.06 years, consisting of 29 females (58%) and 21 males (42%), underwent surgical resection. Mean modified Rankin Scale (mRs) score at admission was 2.6 AE 1.05, and the mean BCSM size was 18.00 AE 7.19 mm. The rate of gross total resection was 92%. Overall, 80% of patients showed improved or unchanged clinical status at the last follow-up period; however, only 58% of patients had a favorable outcome with a mean mRs of 2.33 AE 1.136. Multivariable logistic binary regression identified hemor-rhagic recurrence (P [ 0.040), lower cranial nerve deficit (P [ 0.019), and BSCMs >15 mm in diameter (P [ 0.006) as predictive factors for unfavorable surgical outcomes.-CONCLUSION: BSCM size, compromise of lower cranial nerves, and hemorrhagic recurrence before surgery were identified as risk factors associated with unfavorable outcomes of surgically treated BSCMs in this cohort.

Neurons in the medullary reticular formation are involved in the control of postural and locomotor behaviors in all vertebrates. Reticulospinal neurons in this brain region provide one of the major descending projections to the spinal cord. Although neurons in the newt medullary reticular formation have been extensively studied using in vivo extracellular recordings, little is known of their intrinsic biophysical properties or of the underlying circuitry of this region. Using whole-cell patch-clamp recordings in brain slices containing the rostromedial reticular formation (rmRF) from adult male newts, we observed spontaneous miniature outward currents (SMOCs) in approximately two-thirds of neurons. Although SMOCs superficially resembled inhibitory postsynaptic currents (IPSCs), they had slower rise-times and decay times than spontaneous IPSCs. SMOCs required intracellular Ca2+ release from ryanodine receptors, and were also dependent upon the influx of extracellular Ca2+. SMOCs were unaffected by apamin but were partially blocked by iberiotoxin and charybdotoxin, indicating that SMOCs were mediated by big conductance Ca2+-activated K+ (BK) channels. Application of the sarco/endoplasmic Ca2+ ATPase inhibitor CPA blocked the generation of SMOCs and also increased neural excitability. Neurons with SMOCs had significantly broader action potentials, slower membrane time constants, and higher input resistance than neurons without SMOCs. Thus, SMOCs may serve as a mechanism to regulate action potential threshold in a majority of neurons within the newt medullary reticular formation.

This paper presents the design of different filtering
techniques for the Neuro-Biomedical signals in single electrode
EEG collected Brainstem Speech Evoked Potentials data of
Audiology for the Signal-to-Noise Ratio performance
evaluations. We have designed Yule-Walk multiband filter,
Cascaded Yule-Walk-Comb-Peak filter; conventional Wavelet
transform filters of Daubechies, Symlet, Coiflet Wavelets for
these Auditory Brainstem Responses. In addition we have
designed a Translation-Invariant (TI) Wavelet estimation
filtering technique which is highly useful. In our research the
idea of Cascaded Yule-Walk-Comb-Peak filter is giving us a
considerable improvement in SNR over Yule-Walk filter; and the
conventional wavelets are performing far better that too
specifically Daubechies wavelets are performing better than all.
The TI wavelets technique is performing exceptionally well and
better than conventional wavelets.

Despite high behavioural similarity, some differences in the central neural control of the cough and sneeze reflexes have been suggested. The main aim of our study was to analyze and compare characteristics of electromyographic (EMG) activities of the respiratory muscles during these two behaviours.
Data were taken from eight adult rabbits under pentobarbital anaesthesia. We compared diaphragm EMG activities in tracheobronchial cough, sneeze, and quiet breathing during inspiration. Electromyograms were read from the abdominal muscles during the expiratory phases of coughing and sneezing. Due to the non-stationary character of electromyographic signals, we used wavelet analysis to determine the time-frequency distribution of energy during the behaviours.
Inspiratory durations of all above mentioned behaviours were similar. The maximum inspiratory power occurred later in sneeze than during quiet inspiration (P < 0.05). The total inspiratory power during sneeze was higher compared to that in cough (P < 0.05) and quiet inspiration (P < 0.01). Lower frequencies contributed to this increase significantly more in sneeze compared to cough (less than 287.5 Hz, P < 0.05; 287.5 Hz up to 575 Hz, P < 0.01). We found similar energy distribution for coughing and quiet inspiration. Its maximum occurred at lower frequency in quiet inspiration compared to sneezing (P < 0.01). The abdominal burst during cough was longer than that in sneezing (P < 0.001). Our results support the concept that both cough and eupnoeic inspiration are generated by similar neuronal structures. A non-specific mechanism producing expiratory activity during tracheobronchial cough and sneeze is suggested.

Key words: defensive respiratory reflexes, neuronal control of breathing and airway reflexes, multiresolution analysis,  EMG