Concept: Medulla oblongata
Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.
Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases.
CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.
Aggregation and neuron-to-neuron transmission are attributes of α-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson’s disease. Intraparenchymal injections of fibrillar α-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous α-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds. Here we describe another paradigm of long-distance brain diffusion of α-synuclein that involves inter-neuronal transfer of monomeric and/or oligomeric species and is independent of recruitment of the endogenous protein. Targeted expression of human α-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal α-synuclein were sufficient to initiate its caudo-rostral diffusion that likely involved at least one synaptic transfer and progressively reached specific brain regions such as the locus coeruleus, dorsal raphae and amygdala in the pons, midbrain and forebrain. Transfer of human α-synuclein was compared in two separate lines of α-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous α-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous α-synuclein. Self-interaction of adjacent molecules of human α-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human α-synuclein with mouse α-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and α-synuclein-deficient mice, accumulation of human α-synuclein within recipient axons in the pons, midbrain and forebrain caused morphological evidence of neuritic pathology. Tissue sections from the medulla oblongata and pons were stained with different antibodies recognizing oligomeric, fibrillar and/or total (monomeric and aggregated) α-synuclein. Following viral vector transduction, monomeric, oligomeric and fibrillar protein was detected within donor neurons in the medulla oblongata. In contrast, recipient axons in the pons were devoid of immunoreactivity for fibrillar α-synuclein, indicating that non-fibrillar forms of α-synuclein were primarily transferred from one neuron to the other, diffused within the brain and led to initial neuronal injury. This study elucidates a paradigm of α-synuclein propagation that may play a particularly important role under pathophysiological conditions associated with enhanced α-synuclein expression. Rapid long-distance diffusion and accumulation of monomeric and oligomeric α-synuclein does not necessarily involve pathological seeding but could still result in a significant neuronal burden during the pathogenesis of neurodegenerative diseases.
Respiratory control entails coordinated activities of peripheral chemoreceptors (mainly the carotid bodies) and central chemosensors within the brain stem respiratory network. Candidates for central chemoreceptors include Phox2b-containing neurons of the retrotrapezoid nucleus, serotonergic neurons of the medullary raphé, and/or multiple sites within the brain stem. Extensive interconnections among respiratory-related nuclei enable central chemosensitive relay. Both peripheral and central respiratory centers are not mature at birth, but undergo considerable development during the first two postnatal weeks in rats. A critical period of respiratory development (∼P12-P13 in the rat) exists when abrupt neurochemical, metabolic, ventilatory, and electrophysiological changes occur. Environmental perturbations, including hypoxia, intermittent hypoxia, hypercapnia, and hyperoxia alter the development of the respiratory system. Carotid body denervation during the first two postnatal weeks in the rat profoundly affects the development and functions of central respiratory-related nuclei. Such denervation delays and prolongs the critical period, but does not eliminate it, suggesting that the critical period may be intrinsically and genetically determined.
INTRODUCTION: Previous reports have suggested that endovascular parent artery occlusion is an effective and safe procedure for the treatment of vertebral artery dissection (VAD). However, the results of long-term outcomes are still unclear. This study reviewed the clinical and imaging outcomes of patients with VAD treated by endovascular internal trapping. METHODS: A total of 73 patients were treated for VAD by endovascular internal trapping between March 1998 and March 2011. Patients were regularly followed up by magnetic resonance imaging, magnetic resonance angiography, and clinical examinations. Clinical outcomes were evaluated using the modified Rankin Scale. RESULTS: Forty-five patients had ruptured VADs, and 28 had unruptured VADs. Clinical follow-up of at least 6 months data was obtained for 61 patients (83.6 %). The follow-up period ranged from 6 to 145 months (mean ± SD, 55.6 ± 8.9 months). Two patients with ruptured VADs had recurrence (2.74 %). Cranial nerve paresis (CNP) was observed in six patients (8.21 %), spinal cord infarction in two patients (2.74 %), and a perforating artery ischemia was diagnosed in seven patients (9.59 %); all patients with CNP and five of the patients with partial Wallenberg syndrome experienced only temporary symptoms; two of the patients with partial Wallenberg syndrome had permanent neurological deficits. Despite their symptoms, most patients were in good general condition, as shown by their clinical scores. CONCLUSIONS: The results of this study have proven that endovascular internal trapping is a stable and durable treatment for closure of VADs. Recanalization is rather rare and occurred only in ruptured cases, both within 3 months after initial treatment without rupture. CNPs were observed in 8.21 %, perforating ischemia in 9.59 %, and spinal cord infarction in 2.74 %. The former two are temporary, while the last can be a factor that affects the modified Rankin Scale. Patients rated their quality of life as good, as corroborated by their posttreatment clinical score. Endovascular internal trapping for VAD is a therapy with a satisfactory long-term outcome.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily involving the corticospinal tract, brainstem, and anterior cells of the spinal cord. Mutations in the profilin 1 gene (PFN1) were recently described in ALS families. To investigate the spectrum and frequency of PFN1 mutations further, we sequenced all 3 exons of the PFN1 gene in 20 familial ALS index cases, 324 sporadic ALS patients, and 355 healthy control subjects. No nonsynonymous coding variants were identified. Our findings suggest that mutations in the PFN1 gene are not a common cause of ALS in the Chinese population.
Lateral medullary infarction (LMI) or Wallenberg syndrome is a type of brain stem stroke, more specifically, a type of crossed brain stem syndrome. LMI is a well-described entity with several documented typical characteristics including pain and temperature impairment in the ipsilateral to the lesion side of the face and the contralateral side of the trunk and limbs. We present a case of LMI which describes a patient who presented with atypical features of analgesia and thermanaesthesia on the contralateral side of the face and absence of sensory deficit on the ipsilateral side. We attributed this pattern of involvement to a lesion that affects the ventral trigeminothalamic tract and spares the dorsolateral part of the medulla where the spinal trigeminal tract and its nucleus lie. This case report highlights the presence of atypical presentations of LMI that may initially challenge the physician’s diagnostic reasoning.
Disruption or embryologic derailment of the normal bony architecture of the craniovertebral junction (CVJ) may result in symptoms. As studies of the embryology and pathology of hypoplasia of the occipital condyles and third occipital condyles are lacking in the literature, the present review was performed. Standard search engines were accessed and queried for publications regarding hypoplastic occipital condyles and third occipital condyles. The literature supports the notion that occipital condyle hypoplasia and a third occipital condyle are due to malformation or persistence of the proatlas, respectively. The Pax-1 gene is most likely involved in this process. Clinically, condylar hypoplasia may narrow the foramen magnum and lead to lateral medullary compression. Additionally, this maldevelopment can result in transient vertebral artery compression secondary to posterior subluxation of the occiput. Third occipital condyles have been associated with cervical canal stenosis, hypoplasia of the dens, transverse ligament laxity, and atlanto-axial instability causing acute and chronic spinal cord compression. Treatment goals are focused on craniovertebral stability. A better understanding of the embryology and pathology related to CVJ anomalies is useful to the clinician treating patients presenting with these entities. Clin. Anat., 2013. © 2013 Wiley Periodicals, Inc.
OBJECTIVE: to review the basic principles and techniques of transcranial magnetic stimulation and provide information and evidence regarding its applications in spinal cord injury clinical rehabilitation. METHODS: A review of the available current and historical literature regarding transcranial magnetic stimulation and a discussion of its potential use in spinal cord injury rehab was conducted. RESULTS: TMS provides reliable information about the functional integrity and conduction properties of the corticospinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. MEPs can be useful in follow-up evaluation of motor function during treatment and rehabilitation, specifically in spinal cord injury and stroke patients. While studies regarding somatomotor functional recovery after spinal cord injury have shown promise, it will require further trials to provide strong and substantial evidence. CONCLUSIONS: TMS is a promising non-invasive tool for the treatment of spasticity, neuropathic pain and somatomotor deficit following SCI. Further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation may induce more pronounced and beneficial clinical effects.