Dorsal Brainstem Research Articles

Neurons in the rat superior colliculus translate visual threat into autonomic responses via a relay in the rostral ventromedial medulla

The superior colliculus (SC) is a sensory integration hub in the dorsal brainstem where multimodal information is combined and, depending on the saliency of the competing sensory inputs, appropriate motor commands and supportive autonomic changes initiated. In rodents, the SC is indispensable for initiating behavioral responses to stereotypical visual stimuli that resemble approaching objects, such as looming (an expanding overhead black circle). Here we report that presentation of overhead looming or naturalistic stimuli drove acute surges in blood pressure in telemetered conscious rats, an effect that was replicated by optogenetic stimulation of the deep SC (dSC). dSC stimulation also evoked increases in respiratory rate and tail vasoconstriction in the absence of detectable anxiety‐like behaviors and continued to exert excitatory effects on heart rate, respiratory rate, and sympathetic nerve activity under urethane anesthesia. The objective of the current study was to identify the central pathways responsible for mediating these physiological effects.Anterograde labeling of dSC neurons revealed a previously uncharacterized axonal projections to brainstem cell groups associated with arousal and autonomic control, including the locus coeruleus, A5 group and, most extensively, neurons within a region that spanned the medullary gigantocellular and raphe cell groups, collectively called the rostral ventromedial medulla (RVMM). Optogenetic stimulation of dSC terminals within the RVMM recapitulated some of the sympathetic and respiratory effects evoked by dSC stimulation, and optogenetic dSC activation evoked powerful excitatory effects on extracellular recordings of putative RVMM sympathetic premotor neurons, suggesting that elements of the physiological response dSC stimulation are mediated by direct activation of medullary autonomic neurons.To investigate the contribution of environmental stimuli to the excitability of this pathway we conducted single‐unit recordings of SC neuronal responses to visual and acoustic stimuli using high‐density silicon probes. In addition to responding to stereotypical audio‐visual looming stimuli, we report the presence of SC neurons with higher‐order visual capabilities relating to object detection that differ by subregion and are several orders of magnitude more complex than previously recognized. These tuning properties were also found in subpopulations of opto‐tagged SC neurons that project to the RVMM. Our data suggest that the SC is not only capable of nuanced object recognition, but can translate naturalistic visual cues into fast‐acting autonomic changes via direct medullary projectionsSupport or Funding InformationResearch was supported by the NHMRC and Hillcrest Foundation

Effect of Superior Cervical Gangionectomy on the Chemoreflex Response to Hypoxia in the Rat Carotid Body

Carotid body (CB) chemosensitive glomus (type I) cells respond to decreases in blood pO2 (hypoxia) by releasing neurotransmitters, which in turn activate adjacent chemosensory afferent fibers within the carotid sinus nerve (CSN). These CSN chemoafferents then signal to the commissural nucleus tractus solitarius (cNTS) within the dorsal brainstem, which leads to a compensatory increase in ventilation in order to restore blood‐gas homeostasis. The CB receives sympathetic innervation via the ganglioglomerular nerve (GGN), whose cell bodies reside in the superior cervical ganglion (SCG). We have found that electrical stimulation of the GGN causes an increase in CB chemosensory afferent discharge. However, it is unknown the effect removing the carotid body’s sympathetic innervation, via superior cervical ganglionectomy, will have on the carotid body’s chemoreflex response to hypoxia. We hypothesize that loss of sympathetic input will decrease the hypoxic ventilatory response (HVR) of the rat, and alter the O2‐sensing mechanism of the CB chemosensitive glomus cells. Sprague Dawley male rats postnatal day 21 were subjected to unilateral or bilateral superior cervical ganglionectomy (SCGX). Four days post surgery (post‐natal day 25), rats either underwent whole body plethysmography recordings or were sacrificed and their carotid bodies removed to either isolate glomus cells and perform whole cell perforated patch clamp, or perform immunohistochemistry on the CB. Our preliminary results show that unilateral (left or right) SCGX appears to decrease the HVR during a 1‐minute exposure to hypoxia (10% O2, 90% N2) compared to bilateral SCGX. Our results also show that following SCGX, isolated glomus cells responded to acute hypoxia (HX) (5–8% O2, 5% CO2, balanced N2) with significant reductions (P<0.05 to P<0.01) in outward K+ current amplitudes over the test potential range +10 to +60 mV. The mean maximal effect, a reduction in K+ amplitude of 64.9 ± 18.5% (mean ± SD, n = 3 cells), occurred at a Vtest of +30mV. In contrast, control carotid body glomus cells responded to acute HX with a significant reduction (P<0.05) in outward K+ current amplitude at a Vtest of +60mV (n = 4 cells). In conclusion, our data suggests that sympathetic innervation to the CB is critical for the ventilatory response to hypoxia, and the O2‐sensing mechanism at the level of the CB glomus cells. Overall this study provides novel evidence for the importance of sympathetic innervation on peripheral chemosensors during exposure to hypoxia.Support or Funding InformationThis work was supported in part by a SPARC NIH award OT2OD023860

Relation of infarction location and volume to vertigo in vertebrobasilar stroke.

ObjectiveVertigo is a common presentation of vertebrobasilar stroke. Anecdotal reports have shown that vertigo occurs more often in multiple than in single brainstem or cerebellar infarctions. We examined the relation between the location and volume of infarction and vertigo in patients with vertebrobasilar stroke.MethodsConsecutive patients with vertebrobasilar stroke were prospectively recruited. The infarction location and volume were assessed in the diffusion‐weighted magnetic resonance imaging.ResultsFifty‐nine patients were included, 32 (54.2%) with vertigo and 27 (45.8%) without vertigo. The infarction volume did not correlate with National Institute of Health Stroke Scale (NIHSS) score on admission (Spearman ρ = .077, p = .56) but correlated with modified Rankin Scale (ρ = .37, p = .004) on discharge. In the vertigo group, the proportion of men was lower (53.1% vs. 77.8%, p = .049), fewer patients had focal neurological deficits (65.6% vs. 96.3%, p = .004), patients tended to present later (median [IQR] was 7.5 [4–46] vs. 4 [2–12] hours, p = .052), numerically fewer patients received intravenous thrombolysis (15.6% vs. 37%, p = .06), and the total infarction volume was larger (5.6 vs. 0.42 cm3, p = .008) than in nonvertigo group. In multivariate logistic regression, infarction location either in the cerebellum or in the dorsal brainstem (odds ratio [OR] 16.97, 95% CI 3.1–92.95, p = .001) and a total infarction volume of >0.48 cm3 (OR 4.4, 95% CI 1.05–18.58, p = .043) were related to vertigo. In another multivariate logistic regression, after adjusting for age, sex, intravenous thrombolysis, serum level of white blood cells, and atrial fibrillation, vertigo independently predicted a total infarction volume of >0.48 cm3 (OR 5.75, 95% CI 1.43–23.08, p = .01).ConclusionInfarction location in the cerebellum and/or dorsal brainstem is an independent predictor of vertigo. Furthermore, larger infarction volume in these structures is associated with vertigo. A considerable proportion of patients with vascular vertigo present without focal neurological deficits posing a diagnostic challenge. National Institute of Health Stroke Scale is not sensitive for vertebrobasilar stroke.

Regional Hyperexcitability and Chronic Neuropathic Pain Following Spinal Cord Injury.

Spinal cord injury (SCI) causes maladaptive changes to nociceptive synaptic circuits within the injured spinal cord. Changes also occur at remote regions including the brain stem, limbic system, cortex, and dorsal root ganglia. These maladaptive nociceptive synaptic circuits frequently cause neuronal hyperexcitability in the entire nervous system and enhance nociceptive transmission, resulting in chronic central neuropathic pain following SCI. The underlying mechanism of chronic neuropathic pain depends on the neuroanatomical structures and electrochemical communication between pre- and postsynaptic neuronal membranes, and propagation of synaptic transmission in the ascending pain pathways. In the nervous system, neurons are the only cell type that transmits nociceptive signals from peripheral receptors to supraspinal systems due to their neuroanatomical and electrophysiological properties. However, the entire range of nociceptive signaling is not mediated by any single neuron. Current literature describes regional studies of electrophysiological or neurochemical mechanisms for enhanced nociceptive transmission post-SCI, but few studies report the electrophysiological, neurochemical, and neuroanatomical changes across the entire nervous system following a regional SCI. We, along with others, have continuously described the enhanced nociceptive transmission in the spinal dorsal horn, brain stem, thalamus, and cortex in SCI-induced chronic central neuropathic pain condition, respectively. Thus, this review summarizes the current understanding of SCI-induced neuronal hyperexcitability and maladaptive nociceptive transmission in the entire nervous system that contributes to chronic central neuropathic pain.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem.

Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma‐specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole‐brain voxel‐wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.

<p>Voxel-Based Morphometry Analysis of Structural MRI for Differentiation Between Dementia with Lewy Bodies and Alzheimer’s Disease [Letter]</p>

Voxel-Based Morphometry Analysis of Structural MRI for Differentiation Between Dementia with Lewy Bodies and Alzheimer's Disease [Letter] Shohei Inui, 1, 2 Keita Sakurai, 1 Yoshio Hashizume 3 1Department of Radiology, Teikyo University School of Medicine, Tokyo, Japan; 2Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3Choju Medical Institute, Fukushimura Hospital, Aichi, JapanCorrespondence: Keita SakuraiDepartment of Radiology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, JapanTel +81-3-3964-1211Email ksak666@yahoo.co.jp We read the article entitled “Differentiation Between Dementia With Lewy Bodies And Alzheimer’s Disease Using Voxel-Based Morphometry Of Structural MRI: A Multicenter Study” by Matsuda et al with great interest.1 The authors recruited 239 patients with dementia with Lewy bodies (DLB) and 385 patients with Alzheimer’s disease (AD), and evaluated the utility of Voxel-Based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD®) for their differentiation. They also emphasized the value of dorsal brainstem (DBS) atrophy in addition to medial temporal lobe (MTL) atrophy. As the authors noted, to differentiate AD from DLB is important in the clinical setting to select appropriate pharmacotherapy. Considering the difficulty of using indicative biomarkers including dopamine transporter SPECT in all patients, it is beneficial to reinforce the supportive feature MRI using voxel-based morphometry for the differential diagnosis.

Development of Genetic Engineering Tools for p75ngfr Methylation and Expression Modulation

Neurotrophic factors, as well as their receptors are key players in the formation and development of the central nervous system. Like the sculptor’s incisor, they form the neural networks and circuits of the future organism. The neurotrophic growth factor receptor p75ngfr interacts with sortilin, serves as a receptor for proform of neurotrophic factors and exhibits a proapoptotic effect in developing neurons—dorsal root ganglia neurons and brainstem norepinephrine neurons. p75ngfr is highly expressed in Locus Coeruleus norepinephrine neurons. Therefore, an important task for developing further methods of CNS gene therapy is the development of tools and molecular methods for suppressing p75ngfr expression in norepinephrine neurons. For this purpose, we’ve developed improved dCas9 vectors with Suntag system to suppress gene expression and enhance methylation of CpG islands. We used 10 times repetitive GCN peptide that were fused to dCas9. Single chain antibody against GCN peptide was fused to KRAB repressor or Dnmt3a catalytic domain. Expression specificity was achieved by using a promoter consisting of 8 repeated phox2a/2b binding sites. In this work, we’ve tested a set of guide RNAs targeting p75ngfr cpg island in the promoter. Usage of Suntag system led us to the conclusion that topological orientation and length of the final complex could influence on p75ngfr antisense transcript expression, and that sequence was established in the rat P3 brainstem.

Differentiation Between Dementia With Lewy Bodies And Alzheimer's Disease Using Voxel-Based Morphometry Of Structural MRI: A Multicenter Study.

BackgroundThe differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is particularly important because DLB patients respond better to cholinesterase inhibitors but sometimes exhibit sensitivity to neuroleptics, which may cause worsening of clinical status. Antemortem voxel-based morphometry (VBM) using structural MRI has previously revealed that patients with DLB have normal hippocampal volume, but atrophy in the dorsal mesopontine area.ObjectivesThe aim of this multicenter study was to determine whether VBM of the brain stem in addition to that of medial temporal lobe structures improves the differential diagnosis of AD and DLB.MethodsWe retrospectively chose 624 patients who were clinically diagnosed with either DLB (239 patients) or AD (385 patients) from 10 institutes using different MR scanners with different magnetic field strengths. In all cases, VBM was performed on 3D T1-weighted images. The degree of local atrophy was calculated using Z-score by comparison with a database of normal volumes of interest (VOIs) in medial temporal lobe (MTL) and the dorsal brain stem (DBS). The discrimination of DLB and AD was evaluated using Z-score values in these two VOIs. MRI data from 414 patients were used as the training data set to determine the classification criteria, with the MRI data from the remaining 210 patients used as the test data set.ResultsThe DLB and AD patients did not differ with respect to mean age or Mini-Mental State Examination scores. Z-index scores showed that there was significantly more atrophy in MTL of AD patients, compared to DLB patients and in DBS of DLB patients, compared to AD patients. The discrimination accuracies of VBM were 63.3% in the test data set and 73.4% in the training data set.ConclusionVBM of DBS in addition to that of MTL improves the differentiation of DLB and AD.

Innervated Properties of Acupuncture Points LI 4 and LR 3 in the Rat: Neural Pathway Tracing with Cholera Toxin Subunit B.

Objective: Increasing evidence from acupuncture research suggests that the nervous system corresponds closely with classical acupuncture points. The aim of this research was to provide neuroanatomical evidence for revealing the innervated properties of different acupuncture points through comparing the sensory and motor pathways associated with Hegu (LI 4) and Taichong (LR 3) in rat extremities. Materials and Methods: Cholera toxin subunit B (CTB) was injected into LI 4 and LR 3 in different rats, and CTB neural labeling was examined using fluorescent immunohistochemistry and observed under fluorescent microscopy in the corresponding areas from the peripheral nervous system to the central nervous system, including the dorsal root ganglia (DRG), spinal cord, and brainstem. Results: When LI 4 was injected with CTB, CTB-labeled sensory neurons ranged from C-5 to T-1 DRG, and their transganglionic axons terminated in the C-5 to C-8 spinal dorsal horn as far as the cuneate nucleus, while labeled motor neurons were located in the C-7 to T-1 spinal ventral horn. In contrast, similar neural labeling was observed for LR 3 CTB injection, with an orderly arrangement in the L-3 to L-5 DRG, L-3 to L-5 spinal dorsal horn, gracile nucleus, and L-4 to L-6 spinal ventral horn. Conclusions: The present results provide further evidence to aid understanding of the differential innervation of acupuncture points LI 4 and LR 3. This innervation establishes its connection with the nervous system in a distinct segmental and regional pattern through the spinal sensory and motor pathways.

MON-430 To B, or Not to B

Background: Wernicke’s encephalopathy (WE) is an acute neuropsychiatric derangement caused by Vitamin-B1 (Thiamine) deficiency. Clinical Case: A 49-year-old Hispanic woman was admitted with abdominal pain, intractable nausea and vomiting, two weeks following a diagnosis of infectious mononucleosis. An upper endoscopy was negative. She was discharged on symptomatic treatment with pantoprazole and sucralfate. Four weeks later, she presented with worsening symptoms and a new complaint of blurry vision. Physical exam revealed decreased visual acuity with dysconjugate gaze. Brain CT and MRI were unremarkable. Outpatient ophthalmology consultation was advised. Four days later, she reported to the ophthalmologist with worsening vision, headaches, distal tingling/numbness, gait instability, mildly impaired cognition. The ocular examination revealed visual acuity restricted to counting fingers, large central scotoma, restricted abduction/adduction, and bilateral horizontal and vertical nystagmus. She was readmitted with a suspicion of Miller-Fischer variant of Guillain-Barre. She denied alcohol consumption, tobacco or recreational drug use. She reported 40lb weight loss in 5 weeks. On physical exam, strength was normal, with decreased distal vibration sensation, absent ankle reflexes and ataxic gait. Anti-GQ1b antibodies and CSF studies were unremarkable. Further testing revealed negative/normal HIV antigen/antibody, vitamin B12 level, glycohemoglobin A1c, Lyme antibodies, angiotensin converting enzyme, ANA and serum protein electrophoresis. Serial brain MRI showed FLAIR hyperintensity in both thalami, dorsal medial brainstem along the mammillary bodies, and the third periventricular white matter. Thiamine deficiency was strongly suspected. A vitamin-B1 level was sent out and she was empirically started on large dose IV thiamine. The thiamine level returned very low at 24nmol/l (70-180nmol/l) confirming WE. Her symptoms began to resolve within 12 hours of thiamine infusion. Given no preceding history of alcoholism, a workup for other causes of thiamine deficiency was pursued. Celiac serology, stool pancreatic elastase, CT chest/abdomen/pelvis, colonoscopy were unremarkable. Thiamine deficiency was attributed to her prolonged history of vomiting, decreased intake, in combination with the recently prescribed pantoprazole and sucralfate which contributed to malabsorption. Discussion: WE is typically related to alcoholism. From 1867-2014, 623 cases of WE were described in non-alcoholics. We should have a high index of suspicion for thiamine deficiency in situations of unbalanced nutrition that has lasted for 2 to 3 weeks to avoid misdiagnosis of the life-threatening WE or irreversible brain damage (Korsakoff syndrome). This should prompt immediate administration of large doses of thiamine parenterally even prior to laboratory confirmation.

Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans

Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation ("urge to cough") accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated ( r2 = 0.47, 0.48) with participants' subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. NEW & NOTEWORTHY Functional brain imaging in humans was optimized for the brain stem. We provide the first detailed description of brain stem sites activated in response to airway irritation. The results are consistent with findings in animal studies and extend our foundational knowledge of brain processing of airway irritation in humans.

Acute flaccid myelitis caused by enterovirus D68: Case definitions for use in clinical practice.

Acute flaccid myelitis (AFM) was increasingly detected in recent years, coinciding with upsurges of enterovirus D68 (EV-D68) infections. We reviewed the evidence for a causal relationship between both. Based on reported cases, we provide case definitions for AFM caused by EV-D68 infections to enable a standard procedure for affected patients. Current case definitions are focussing on epidemiological aspects but clinical case definitions are still missing. We propose the following case definitions to be used in clinical practice in order to mirror clinical realities and facilitate a common systematic approach in case management: A possible case is defined as a person presenting with either acute myelitis/paralysis or Guillain-Barré Syndrome (GBS), particularly during periods of EV-D68 circulation. A probable case is defined as a person presenting with symptoms of either acute myelitis/paralysis or GBS and at least one of the following criteria: i) MRI abnormality representing with T2 hyperintensity in spinal cord grey matter with or without hyperintensity at dorsal brain stem, ii) investigations showing an axonal neuropathy including reduced compound motor action potentials with normal conduction velocities and absence of conduction blocks compatible with anterior horn cell disease or iii) detection of enteroviruses in a respiratory specimen obtained from the lower respiratory tract during periods of EV-D68 circulation. A confirmed case is defined as a person presenting with acute flaccid myelitis/paralysis, MRI abnormality and detection of enterovirus-D68-specific nucleic acids in a respiratory specimen using a validated PCR assay targeting the VP1 gene with subsequent sequencing and typing.

Impaired chemoreflex correlates with decreased c-Fos in respiratory brainstem centers of the streptozotocin-induced Alzheimer's disease rat model

Besides impairment in cognition and memory, patients with Alzheimer's disease (AD) often exhibit marked dysfunction in respiratory control. Sleep-disordered breathing (SDB) is commonly found in cases of AD, resulting in periods of hypoxia during sleep. Early structural changes in brainstem areas controlling respiratory function may account for SDB in the course of AD. However, to date the underlying mechanisms for these complications are not known. The streptozotocin (STZ)-induced rat model of AD exhibits abnormal responses to hypoxia and increased astrogliosis in a key region for respiratory control. In this study we further defined the pathophysiological respiratory response of STZ-AD rats to 10% O2. In addition, we analyzed hypoxia-induced neuronal activation in respiratory and cardiovascular nuclei of the dorsal and ventral brainstem. Two hours of hypoxia induced a transient increase in tidal volume that was followed by a prolonged increase in respiratory rate. Only respiratory rate was significantly blunted in the STZ-AD model, which continued over the entire duration of the hypoxic episode. Analysis of c-Fos expression as a marker for neuronal activation showed abundant labeling throughout the nTS, nuclei of the ventral respiratory column, and A1/C1 cells of cardiovascular centers in the ventral brainstem. STZ-AD rats showed a significant decrease of c-Fos labeling in the caudal/medial nTS, rostral ventral respiratory group, and Bötzinger complex. c-Fos in other respiratory centers and A1/C1 cells was unaltered when compared to control. The results of this study document a region-specific impact of STZ-induced AD in respiratory brainstem nuclei. This decrease in c-Fos expression correlates with the observed blunting of respiration to hypoxia in the STZ-AD rat model.

Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.

Defining mechanisms of neural plasticity after brainstem ischemia in rats.

Neurological recovery after stroke mainly depends on the location of the lesion. A substantial portion of strokes affects the brainstem. However, patterns of neural plasticity following brainstem ischemia are almost unknown. Here, we established a rat brainstem ischemia model that resembles key features of the human disease and investigated mechanisms of neural plasticity, including neurogenesis and axonal sprouting as well as secondary neurodegeneration. Spontaneous functional recovery was accompanied by a distinct pattern of axonal sprouting, for example, an increased bilateral fiber outgrowth from the corticorubral tract to the respective contralesional red nucleus suggesting a compensatory role of extrapyramidal pathways after damage to pyramid tracts within the brainstem. Using different markers for DNA replication, we showed that the brainstem displays a remarkable ability to undergo specific plastic cellular changes after injury, highlighting a yet unknown pattern of neurogenesis. Neural progenitor cells proliferated within the dorsal brainstem and migrated toward the lesion, whereas neurogenesis in classic neurogenic niches, the subventricular zone of the lateral ventricle and the hippocampus, remained, in contrast to what is known from hemispheric stroke, unaffected. These beneficial changes were paralleled by long-term degenerative processes, that is, corticospinal fiber loss superior to the lesion, degeneration of spinal tracts, and a decreased neuron density within the ipsilesional substantia nigra and the contralesional red nucleus that might have limited further functional recovery. Our findings provide knowledge of elementary plastic adaptions after brainstem stroke, which is fundamental for understanding the human disease and for the development of new treatments. Ann Neurol 2018;83:1003-1015.

Superior Cervical Ganglionectomy alters Glomus Cell Potassium‐Channel Properties in Response to Hypoxia

The carotid body (CB) chemosensory glomus (type I) cells respond to changes in blood PO2, PCO2, and pH by releasing neurotransmitters that increase action potential discharge of chemosensory afferent fibers within the carotid sinus nerve (CSN). The CSN then signals to the nucleus tractus solitarius (NTS) within the dorsal brainstem, which leads to a compensatory increase in ventilation in order to restore blood gas levels and pH. Along with the CSN, the ganglioglomerular nerve (GGN) also innervates the carotid body. The GGN consists of post‐ganglionic sympathetic fibers, which originate from the superior cervical ganglion (SCG). Stimulation of the GGN causes an increase in CB chemosensory afferent discharge. However, it is unknown whether loss of sympathetic input to the CB directly alters the chemosensitivity of glomus cells. Our objective was to characterize electrophysiological properties of CB glomus cell potassium (K+) channels in response to acute hypoxia following superior cervical ganglionectomy (SCGx). Sprague Dawley (SD) male rats postnatal (P) 21 were subjected to unilateral (right) SCGx. The left SCG was identified, but not removed. Four days post surgery at P25 the right and left carotid bodies were removed, and primary glomus cells were isolated and plated on coverslips. Glomus cell K+ channel properties were then recorded using the whole‐cell perforated patch‐clamp technique. Our preliminary results reveal that following unilateral (right) SCGx, glomus cells respond to hypoxia with significant reductions (P&lt;0.05 to P&lt;0.01) in outward K+ current amplitudes over the test potential range +10 to +60 mV. The mean maximal effect, a reduction in K+ amplitude of 64.9 ± 18.5% (mean ± SD, n = 3 cells), occurred at a Vtest of +30 mV. In contrast, wild‐type control CB glomus cells respond to hypoxia with a significant reduction (P&lt;0.05) in outward K+ current amplitude at only a Vtest of +60 mV (n = 4 cells). In addition, glomus cells from SCGx rats appear to respond to hypoxia via a different population of K+ channels that do not appear to be presently active in wild‐type glomus cells when exposed to hypoxia. These findings demonstrate that loss of sympathetic input from the SCG increases CB glomus cell sensitivity to hypoxia, and modulates the O2‐sensing capabilities of glomus cell K+ channels.Support or Funding InformationNIH‐SPARC 1OT2OD023860‐02 SJLewisThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Spectrum of MRI brain lesion patterns in neuromyelitis optica spectrum disorder: a pictorial review.

Neuromyelitis optica is a neurotropic autoimmune inflammatory disease of the central nervous system traditionally thought to exclusively involve the optic nerves and spinal cord. With the discovery of the disease-specific aquaporin-4 antibody and the increasing recognition of clinical and characteristic imaging patterns of brain involvement in what is now termed neuromyelitis optica spectrum disorder (NMOSD), MRI now plays a greater role in diagnosis of NMOSD based on the 2015 consensus criteria and in distinguishing it from other inflammatory disorders, particularly multiple sclerosis (MS). Several brain lesion patterns are highly suggestive of NMOSD, whereas others may serve as red flags. Specifically, long corticospinal lesions, hemispheric cerebral white matter lesions and periependymal lesions in the diencephalon, dorsal brainstem and white matter adjacent to lateral ventricles are typical of NMOSD. In contrast, juxtacortical, cortical, or lesions perpendicularly oriented to the surface of the lateral ventricle suggests MS as the diagnosis. Ultimately, a strong recognition of the spectrum of MRI brain findings in NMOSD is essential for accurate diagnosis, and particularly in differentiating from MS. This pictorial review highlights the spectrum of characteristic brain lesion patterns that may be seen in NMOSD and further delineates findings that may help distinguish it from MS.

Focal hyperintensity in the dorsal brain stem of patients with cerebellopontine angle tumor: A high-resolution 3\u2009T MRI study

Focal hyperintensity (FHI) in the dorsal brain stem on T2-weighted images of patients with cerebellopontine angle (CPA) tumor was thought to indicate degeneration of the vestibular nucleus and to be specific to vestibular schwannoma. The purpose of this study was to evaluate FHI by using high-resolution 3 Tesla magnetic resonance imaging (3 T MRI) and the relation to clinical characteristics. We retrospectively reviewed the clinical data and MRI of 45 patients with CPA tumors (34 vestibular schwannomas and 11 other tumors). FHI in the dorsal brain stem was found in 25 (55.6%) patients (20 vestibular schwannomas and 5 other tumors). For the vestibular schwannomas, the factors contributing to positive FHI were age (p = 0.025), max CPA (p = < 0.001), hearing ability (P = 0.005), and canal paresis (p = < 0.001) in the univariate analysis. Multivariate regression analysis showed that max CPA (p = 0.029) was a significant factor of positive FHI. In other CPA tumors, these factors were not significant predictors. With the use of 3 T MRI, FHI was observed more frequently than previously reported. Our results suggest that FHI is not a specific indicator of vestibular schwannoma and is related to not only vestibular function but also other factors.

Cytotoxic edema at onset in West syndrome of unknown etiology: A longitudinal diffusion tensor imaging study.

To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

Morphometric Assesment of the External Anatomy of Fourth Ventricle and Dorsal Brainstem in Fresh Cadavers.

To investigate the external anatomy of the fourth ventricle and dorsal brainstem using morphometric data, which could be useful for preoperative surgical planning. Between January 2017 and December 2017, 42 fresh adult cadavers were investigated for the measurements of the cadaver brainstems and fourth ventricle, and they were recorded by photography. Measurements were evaluated according to body mass indexes (BMIs) of the patients. We also investigate the visualization of facial colliculus and stria medullaris on brainstem. A total of 42 fresh cadavers with a mean age of 45.38 ± 16.41 years old were included in this research. We found no statistically significant difference between measurements and BMIs. Facial colliculus was visualized in 92.9% (n=39), but it could not visualized in 7.1% (n=3) of the subjects. When the right side of the stria medullaris was examined, one bundle was seen in 59.5% (n=25) of the subjects, two bundles were seen in 31% (n=13) of the subjects, and 3 bundles were seen in 9.5% (n=4) of the subjects. When the left side of the stria medullaris was examined, one bundle was seen in 57.1% (n=24) of the subjects, two bundles were seen in 33.3% (n=14) of the subjects, and three bundles were seen in 9.5% (n=4) of the subjects. Knowledge of the normal morphometry of the dorsal brainstem as it has been reported in this study will help one to assess distortions in any preoperative imaging studies and surgical planning.