Rostral Brainstem Research Articles

Objective information-theoretic algorithm for detecting brainstem-evoked responses to complex stimuli.

The scalp-recorded frequency-following response (FFR), an auditory-evoked potential with putative neural generators in the rostral brainstem, provides a robust representation of the neurophysiologic encoding of complex stimuli. The FFR is rapidly becoming a valuable tool for understanding the neural transcription of speech and music, language-related processing disorders, and brain plasticity at initial stages of the auditory pathway. Despite its potential clinical and empirical utility, determining the presence of a response is still dependent on the subjective interpretation by an experimenter/clinician. The purpose of the present work was to develop and validate a fully objective procedure for the automatic detection of FFRs elicited by complex auditory stimuli, including speech. Mutual information (MI) was computed between the spectrographic representation of neural FFRs and their evoking acoustic stimuli to quantify the amount of shared time-frequency information between electrophysiologic responses and stimulus acoustics. To remove human subjectivity associated with typical response evaluation, FFRs were first simulated at known signal-to-noise ratios using a computational model of the auditory periphery. The MI at which model FFRs contained +3 dB Signal-to-noise ratio was taken as the criterion threshold (θMI) for the presence of a response. θMI was then applied as a binary classifier on actual neurophysiologic responses recorded previously in human participants (n = 35). Sham recordings, in which no stimulus was presented to participants, allowed us to determine the receiver operating characteristics of the MI metric and the capabilities of the algorithm to segregate true evoked responses from sham recordings. RESULTS showed high overall accuracy (93%) in the metric's ability to identify true responses from sham recordings. The metric's overall performance was considerably better than trained human observers who, on average, accurately identified only ∼75% of the true neural responses. Complementary results were found in the metric's receiver operating characteristic test performance characteristics with a sensitivity and specificity of 97% and 85%, respectively. Additionally, MI increased monotonically and was asymptotic with increasing trials (i.e., sweeps) contributing to the averaged FFR and, thus, can be used as a stopping criteria for signal averaging. The present results demonstrate that the mutual information between a complex acoustic stimulus and its corresponding brainstem response can provide a completely objective and robust method for automated FFR detection. Application of the MI metric to evoked potential speech audiometry testing may provide clinicians with a more robust tool to quantitatively evaluate the presence and quality of speech-evoked brainstem responses ultimately minimizing subjective interpretation and human error.

Cerebral Infarction due to Cardiogenic Emboli Originating from Atrial Myxoma: A Case Report

Cardiogenic embolism due to atrial myxoma is a rare cause of cerebral infarction. A 51-year-old woman presented to a hospital elsewhere with sudden onset of vision loss, loss of consciousness and subsequent circulatory collapse. Computed tomography and magnetic resonance imaging of brain revealed a rostral brainstem infarction, cerebral angiography showed evidence of occlusion of the left posterior cerebral artery, and echocardiographic examination revealed the presence of a mass in the left atrium. The patient received palliative care and was discharged. Four months later, she presented with muscle weakness in both legs and was unable to walk. Ultrasonography revealed atherosclerotic plaques in the left and right carotid arteries and multiple segmental emboli in the lower extremities. In addition, physical examination revealed bilateral blepharoptosis, poor pupillary reaction to light, deficient upward and downward eye movements and limited adduction. Anticoagulants and blood-lipid lowering drugs were administered. Auscultation of the precordium revealed systolic murmurs when the patient was in a sitting position. Echocardiographic examination and computed tomography of the chest disclosed a mass in the left atrium. The patient underwent surgical resection of the atrial mass. Histopathological examination of the resected tumor revealed a glandular cardiac myxoma. At four-month follow-up, there was some improvement in neurological symptoms. A cardiac origin of cerebral infarction should be suspected in middleaged patients who present with cardiac myxoma. Early surgical resection of the cardiac myxoma is important to prevent further embolic events.

Sex differences in the expression of estrogen receptor alpha within noradrenergic neurons in the sheep brain stem

In female sheep, high levels of estrogen exert a positive feedback action on gonadotropin releasing hormone (GnRH) secretion to stimulate a surge in luteinizing hormone (LH) secretion. Part of this action appears to be via brain stem noradrenergic neurons. By contrast, estrogen action in male sheep has a negative feedback action to inhibit GnRH and LH secretion. To investigate whether part of this sex difference is due to differences in estrogen action in the brain stem, we tested the hypothesis that the distribution of estrogen receptor α (ERα) within noradrenergic neurons in the brain stem differs between rams and ewes. To determine the distribution of ERα, we used double-label fluorescence immunohistochemistry for dopamine β-Hydroxylase, as a marker for noradrenergic and adrenergic cells, and ERα. In the ventrolateral medulla (A1 region), most ERα-immunoreactive (-ir) cells were located in the caudal part of the nucleus. Overall, there were more ERα-ir cells in rams than ewes, but the proportion of double-labeled cells was did not differ between sexes. Much greater numbers of ERα–ir cells were found in the nucleus of the solitary tract (A2 region), but <10% were double labeled and there were no sex differences. The majority of ERα-labeled cells in this nucleus was located in the more rostral areas. ERα-labeled cells were found in several rostral brain stem regions but none of these were double labeled and so were not quantified. Because there was no sex difference in the number of ERα-ir cells in the brain stem that were noradrenergic, the sex difference in the action of estrogen on gonadotropin secretion in sheep is unlikely to involve actions on brain stem noradrenergic cells.

The temporal coding of pitch: Insights from human electrophysiology

Brian Moore and Roy Patterson have made seminal contributions to our understanding of pitch perception, and in particular the use of temporal pitch information by the auditory brain. The pitch of sounds may be encoded, at least in part, by the tendency of neurons to phase lock to the temporal fine structure and/or envelope of basilar membrane vibration. Direct physiological measures of this mechanism are difficult in humans. However, the gross activity of neurons in the brainstem can be measured using electrophysiological techniques. The frequency-following response (FFR) is an electrophysiological measure of phase locking in the rostral brainstem. The FFR differs between musicians and non-musicians, and across linguistic groups, and is sensitive to short-term pitch discrimination training. These findings suggest that the FFR may reflect neural activity relevant to the encoding of pitch, although other results suggest that it may reflect basic peripheral encoding, rather than the output of a pitch extraction process. Recent results from our laboratory show that combining behavioral and FFR measures can provide insights into the coding of the pitch of pure tones and the coding of musical consonance. The FFR may be a blunt tool, but it provides information that cannot be obtained using other techniques, and this may be particularly useful in investigations of the effects of age and hearing loss on the neural coding of pitch.

Neonatal necrotizing enterocolitis adversely affects neural conduction of the rostral brainstem in preterm babies

ObjectiveNecrotizing enterocolitis (NEC) is a devastating neonatal disease, often leading to long term neurodevelopmental impairment. The effect of NEC on the immature brain remains not fully understood. We test the hypothesis that NEC adversely affects functional integrity, particularly neural conduction, of the preterm brainstem. MethodsThirty-two preterm NEC babies (30–36weeks gestation) were recruited at term age. Maximum length sequence brainstem auditory evoked response was recorded and analysed with click rates 91–910/s at term age. The results were compared with normal term babies and age-matched healthy preterm babies. ResultsWave V latency, I–V and III–V intervals, and III–V/I–III interval ratio differed significantly among the three groups of babies at all click rates 91–910/s. Compared with normal term babies, preterm NEC babies showed significant increase in all these MLS BAER variables at all rates, with no apparent abnormalities in wave I and III latencies and I–III interval. All these abnormalities were more significant at higher than at lower click rates. No notable abnormalities were seen in wave amplitudes. Compared with age-matched healthy preterm babies, NEC babies showed similar abnormalities, although the abnormalities were relatively less significant. ConclusionsMLS BAER components that mainly reflect neural conduction in the more central regions of the auditory brainstem were abnormal in preterm NEC babies, although those components that mainly reflect peripheral function were generally normal. SignificanceNeonatal NEC adversely affects myelination of the more rostral or central regions of the immature brainstem, resulting in delayed or impaired neural conduction, but spares the more peripheral regions.

An animal model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson’s disease

A rostral brainstem structure, the pedunculopontine nucleus (PPN), is severely affected by Parkinson's disease (PD) pathology and is regarded a promising target for therapeutic deep-brain stimulation (DBS). However, understanding the PPN's role in PD and assessing the potential of DBS are hampered by the lack of a suitable model of PPN degeneration. Rats were rendered Parkinsonian through a unilateral substantia nigra pars compacta (SNpc) stereotaxic injection of the proteasome inhibitor Lactacystin, to investigate whether the lesion's pathological effects spread to impact the integrity of PPN cholinergic neurons which are affected in PD. At 5 weeks post-surgery, stereological analysis revealed that the lesion caused a 48 % loss of dopaminergic SNpc neurons and a 61 % loss of PPN cholinergic neurons, accompanied by substantial somatic hypotrophy in the remaining cholinergic neurons. Magnetic resonance imaging revealed T2 signal hyper-/hypointensity in the PPN of the injected hemisphere, respectively at weeks 3 and 5 post-lesion. Moreover, isolated PPN cholinergic neurons revealed no significant alterations in key autophagy mRNA levels, suggesting that autophagy-related mechanisms fail to protect the PPN against Lactacystin-induced cellular changes. Hence, the current results suggest that the Lactacystin PD model offers a suitable model for investigating the role of the PPN in PD.

DOPAMINE TRANSPORTER (DAT) IMAGING CAN BE NORMAL WITH NEUROPATHOLOGICALLY CONFIRMED CORTIOBASAL DEGENERATION

ObjectiveTo report 3 cases of Corticobasal Degeneration with normal DAT scans.BackgroundCorticobasal degeneration (CBD) is a progressive neurodegenerative condition associated with neuronal and glial tau pathology (including astrocytic plaques) in gray...

Loss of rostral brainstem cholinergic activity results in decreased ultrasonic vocalization behavior and altered sensorimotor gating

The parabigeminal (PBG), pedunculopontine (PPTg), and laterodorsal tegmental (LDTg) nuclei located in the rostral brainstem are the primary sources of the neurotransmitter acetylcholine (ACh) for the midbrain and thalamus, and as part of the ascending reticular activating system, these cholinergic signaling pathways regulate mouse behavioral responses to sensory stimuli. Here, I report that mice harboring a conditional deletion of ACh synthesis specifically within these nuclei (ChATEn1 KO) exhibit decreased ultrasonic vocalizations both as pups and adults, consistent with their previously reported hypoactivity when exploring the novel environment of the open field arena. Furthermore, in prepulse inhibition (PPI) tests, ChATEn1 KO animals exhibited increased sensorimotor gating in comparison to control littermates. These data suggest that ACh signaling arising from the rostral brainstem modulates animal behavior in part by tuning the levels of sensorimotor gating. Thus, the net effect of this cholinergic activity is to increase sensitivity to environmental stimuli, and loss of this pathway contributes to the hypoactivity in these mutants by raising the sensory threshold for eliciting exploratory behaviors.

Neuropathology of prolonged unresponsive wakefulness syndrome after blunt head injury: Review of 100 post-mortem cases

Objectives: Recently, ‘unresponsive wakefulness syndrome’ (UWS) was coined for challenging conditions previously termed vegetative state or apallic syndrome.Materials and methods: In a post-mortem series of 630 patients who sustained a blunt traumatic brain injury, 100 (59 men and 41 women, aged 5–86 years; 77% traffic accidents, 23% falls and others) showed various disorders of consciousness which were compared with neuropathology with focus on brainstem lesions.Results: In the total autopsy series (n = 630), the incidence of cortical contusions, diffuse axonal injury (DAI) and intracranial haemorrhages was 41, 55 and 73%, respectively, of diencephalic, hypothalamic and hippocampal lesions 62% each, brainstem lesions 92%. Clinical prognosis was related to the location and extent of brainstem damage. Lesions in central parts of the rostral brainstem, frequently associated with extensive DAI, allowed no recovery from coma or UWS (n = 67), which occurred only with damage to the dorso-lateral brainstem tegmentum or pontine basis (n = 33). Only two of 11 patients with minimally conscious state (MCS), in addition to haemorrhages (n = 4), contusions (n = 10) and DAI (n = 7), showed small lesions in dorsolateral pontine tegmentum or diffuse pontine gliosis.Conclusions: These and other data confirm the importance of the pattern and extent of brainstem damage for the prognosis of UWS, only small peripheral lesions in pontine tegmentum allowing progressive remission.

Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U

BackgroundMultiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions.ResultsThe aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions.ConclusionsThe topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

Evidence for modulation rate specific adaptation in the frequency following response?

We used an adaptation paradigm to investigate whether the frequency following response (FFR) would show evidence for neurons tuned to modulation rate in humans, as has been previously shown in the inferior colliculus of the macaque using fMRI [Baumann et al. Nat. Neurosci. 14, 423–425 (2011)]. The FFR to a 100-ms, 75-dB SPL, target complex tone with an envelope rate of 213 Hz was measured for ten subjects. The target was preceded by a 200-ms, 75-dB SPL, adaptor complex with an envelope rate of 90, 213, or 504 Hz. All complexes contained alternating-phase harmonics from approximately 3.9 to 5.4 kHz. A “vertical” montage (+ Fz, - C7, ground = mid-forehead) was used, for which the FFR is assumed to reflect phase-locked neural activity from generators in the rostral brainstem. The results showed significant adaptation effects in the spectral magnitude of the 213-Hz envelope-related component of the FFR. However, the identical-rate adaptor did not generally produce more adaptation than the different-rate adaptors. Hence, the present results do not provide evidence for neurons tuned to modulation rate in the human brainstem. [Work supported by Wellcome Trust Grant 088263.]

Peduncular hallucinosis in a patient with subclavian steal syndrome: Usefulness of Doppler ultrasonography

The subclavian steal syndrome is characterized by retrograde flow within a vertebral artery ipsilateral to proximal subclavian artery high-grade stenosis or occlusion. It can cause vertebrobasilar insufficiency and hence diverse brainstem symptoms. Peduncular hallucinosis consists of visual images of brief duration that are related to thalamic or rostral brainstem lesions. We describe a patient with peduncular hallucinosis in the setting of subclavian steal syndrome. Inducing a hemodynamic challenge to the vertebrobasilar circulation elicited the patient́s visual symptoms. Thus, careful ultrasonographic evaluation with dynamic testing contributed to explain the physiopathology of the clinical symptoms.

Identification and Characterization of a Sleep-Active Cell Group in the Rostral Medullary Brainstem

Early transection and stimulation studies suggested the existence of sleep-promoting circuitry in the medullary brainstem, yet the location and identity of the neurons comprising this putative hypnogenic circuitry remains unresolved. In the present study, we sought to uncover the location and identity of medullary neurons that might contribute to the regulation of sleep. Here we show the following in rats: (1) a delimited node of medullary neurons located lateral and dorsal to the facial nerve-a region we termed the parafacial zone (PZ)-project to the wake-promoting medial parabrachial nucleus; (2) PZ neurons express c-Fos after sleep but not after wakefulness and hence are sleep active; and (3) cell-body-specific lesions of the PZ result in large and sustained increases (50%) in daily wakefulness at the expense of slow-wave sleep (SWS). Using transgenic reporter mice [vesicular GABA/glycine transporter (Vgat)-GFP], we then show that >50% of PZ sleep-active neurons are inhibitory (GABAergic/glycinergic, VGAT-positive) in nature. Finally, we used a Cre-expressing adeno-associated viral vector and conditional Vgat(lox/lox) mice to selectively and genetically disrupt GABA/glycinergic neurotransmission from PZ neurons. Disruption of PZ GABAergic/glycinergic neurotransmission resulted in sustained increases (40%) in daily wakefulness at the expense of both SWS and rapid eye movement sleep. These results together reveal the location and neurochemical identity of a delimited node of sleep-active neurons within the rostral medullary brainstem.

Organization of the neural switching circuitry underlying reflex micturition

The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain and spinal cord that coordinates the activity of the bladder and urethral outlet. Experimental studies in animals indicate that urine storage is modulated by reflex mechanisms in the spinal cord, whereas voiding is mediated by a spinobulbospinal pathway passing through a coordination centre in the rostral brain stem. Many of the neural circuits controlling micturition exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. This study summarizes the anatomy and physiology of the spinal and supraspinal micturition switching circuitry and describes a computer model of these circuits that mimics the switching functions of the bladder and urethra at the onset of micturition.

Isolated frontalis, corrugator and procerus dystonia: a blepharospasm variant

Blepharospasm (BSM) is a form of cranial dystonia caused by involuntary bilateral eye closure produced by contractions of orbicularis oculi muscles, often accompanied by dystonic movements of the eyebrows, paranasal, facial, masticatory, labial, lingual, oral, pharyngeal, laryngeal and cervical muscles1-3. In most instances, BSM is idiopathic. However, cases associated with lesions in rostral brainstem or other parts of basal ganglia (multiple sclerosis, stroke, thalamotomy and autoimmune disorders) have been described 1,3,4 […] Isolated frontalis, corrugator and procerus dystonia – a blepharospasm [...]

Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.

Cavernous Malformations: A Paradigm for Progress

Cavernous Malformations: A Paradigm for Progress

Wrong-way deviation: Contralateral conjugate eye deviation in acute supratentorial stroke

Supratentorial stroke can cause conjugate eye deviation directed contralateral to the affected side (wrong-way deviation). It is rare and thought to be associated exclusively with hemorrhagic stroke. We prospectively investigated the clinical features and prognostic significance of this wrong-way deviation. Subjects were 12 patients who manifested wrong-way deviation subsequent to supratentorial stroke. These patients were from a group of 968 consecutive patients hospitalized for acute supratentorial stroke during the period April 2007 through March 2010. Clinical features of wrong-way deviation were evaluated. The overall incidence of wrong-way deviation was 1.2%. The causative lesion was a huge intracranial hemorrhage (n=7) or an extensive hemispheric infarction (n=5). Left-sided lesions were most frequent (66.7% of patients). Wrong-way deviation usually appeared a few days after the initial insult and was frequently accompanied by transient downward eye deviation (58.3% of patients). Although the outcomes for patients treated conservatively were generally poor, patients who underwent surgical decompression regained consciousness. Wrong-way deviation can result not only from hemorrhagic but also ischemic stroke if the stroke is extensive. Secondary damage to the adjacent rostral brainstem where oculomotor pathways cross over from the contralateral hemisphere can explain the phenomenon, its temporal evolution, and associated eye signs. Immediate surgical decompression may be necessary to improve the prognosis in such cases.

Corticobasal degeneration: a pathologically distinct 4R tauopathy.

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.

Targeting of the pedunculopontine nucleus by an MRI-guided approach: a cadaver study

Laboratory evidence suggests that the pedunculopontine nucleus (PPN) plays a central role in the initiation and maintenance of gait. Translational research has led to reports on deep brain stimulation (DBS) of the rostral brainstem in parkinsonian patients. However, initial clinical results appear to be rather variable. Possible factors include patient selection and the wide variability in anatomical location of implanted electrodes. Clinical studies on PPN DBS efficacy would, therefore, benefit from an accurate and reproducible method of stereotactic localization of the nucleus. The present study evaluates the anatomical accuracy of a specific protocol for MRI-guided stereotactic targeting of the PPN in a human cadaver. Imaging at 1.5 and 9.4T confirmed electrode location in the intended region as defined anatomically by the surrounding fiber tracts. The spatial relations of each electrode track to the nucleus were explored by subsequent histological examination. This confirmed that the neuropil surrounding each electrode track contained scattered large neurons morphologically consistent with those of the subnucleus dissipatus and compactus of the PPN. The results support the accuracy of the described specific MR imaging protocol.