Michael D. Staudt

A Pivotal Role of Lumbar Spinothalamic Cells in the Regulation of Ejaculation via Intraspinal Connections

INTRODUCTION A population of lumbar spinothalamic cells (LSt cells) has been demonstrated to play a pivotal role in ejaculatory behavior and comprise a critical component of the spinal ejaculation generator. LSt cells are hypothesized to regulate ejaculation via their projections to autonomic and motor neurons in the lumbosacral spinal cord. AIM The current study tested the hypothesis that ejaculatory reflexes are dependent on LSt cells via projections within the lumbosacral spinal cord. METHODS Male rats received intraspinal injections of neurotoxin saporin conjugated to substance P analog, previously shown to selectively lesion LSt cells. Two weeks later, males were anesthetized and spinal cords were transected. Subsequently, males were subjected to ejaculatory reflex paradigms, including stimulation of the dorsal penile nerve (DPN), urethrogenital stimulation or administration of D3 agonist 7-OH-DPAT. Electromyographic recordings of the bulbocavernosus muscle (BCM) were analyzed for rhythmic bursting characteristic of the expulsion phase of ejaculation. In addition, a fourth commonly used paradigm for ejaculation and erections in unanesthetized, spinal-intact male rats was utilized: the ex copula reflex paradigm. MAIN OUTCOME MEASURES LSt cell lesions were predicted to prevent rhythmic bursting of BCM following DPN, urethral, or pharmacological stimulation, and emissions in the ex copula paradigm. In contrast, LSt cell lesions were not expected to abolish erectile function as measured in the ex copula paradigm. RESULTS LSt cell lesions prevented rhythmic contractions of the BCM induced by any of the ejaculatory reflex paradigms in spinalized rats. However, LSt cell lesions did not affect erectile function nor emissions determined in the ex copula reflex paradigm. CONCLUSIONS These data demonstrate that LSt cells are essential for ejaculatory, but not erectile reflexes, as previously reported for mating animals. Moreover, LSt cells mediate ejaculation via projections within the spinal cord, presumably to autonomic and motor neurons.

Activation of NMDA Receptors in Lumbar Spinothalamic Cells is Required for Ejaculation

INTRODUCTION The sexual reflex ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord. A population of spinothalamic (LSt) neurons forms a key component of this generator, as manipulations of LSt cells either block or trigger ejaculation. However, it is currently unknown which afferent signals contribute to the activation of LSt cells and ejaculation. AIM The current study tested the hypothesis that glutamate, via activation of N-Methyl-D-aspartic acid (NMDA) receptors in LSt cells, is a key regulator of ejaculation. METHODS Expression of phosphorylated NMDA receptor subunit 1 (NR1) was investigated following mating, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intraspinal delivery of NMDA receptor antagonist AP-5 on DPN stimulation-induced ejaculation were examined. Moreover, the ability of intraspinal delivery of NMDA to trigger ejaculation was examined. Finally, the site of action of NMDA was determined by studying effects of NMDA in male rats with LSt cell-specific lesions. MAIN OUTCOME MEASURES Expression of NR1 and phosphorylated NR1 in LSt cells was analyzed. Electromyographic recordings of the bulbocavernosus muscle (BCM) were recorded in anesthetized, spinalized rats following stimulation of the DPN and delivery of AP-5 or NMDA. RESULTS Results indicate that the NR1 receptors are activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, NR1 activation in LSt cells is an essential trigger for rhythmic BCM bursting, as DPN stimulation-induced reflexes were absent following administration of NMDA receptor antagonist in the L3-L4 spinal area, and were triggered by NMDA. NMDA effects were dependent on intact LSt cells and were absent in LSt-lesioned males. CONCLUSION These results demonstrate that glutamate, via activation of NMDA receptors in LSt cells, is a key afferent signal for ejaculation.

Activation of MAP Kinase in Lumbar Spinothalamic Cells Is Required for Ejaculation

INTRODUCTION Ejaculation is a reflex controlled by a spinal ejaculation generator located in the lumbosacral spinal cord responsible for the coordination of genital sensory with autonomic and motor outputs that regulate ejaculation. In the male rat, a population of lumbar spinothalamic cells (LSt cells) comprises an essential component of the spinal ejaculation generator. LSt cells are activated with ejaculation, but the nature of the signal transduction pathways involved in this activation is unknown. Moreover, it is unknown if LSt cell activation is required for expression of ejaculation. AIM The current study tested the hypothesis that ejaculatory reflexes are triggered via activation of the mitogen-activated protein (MAP) kinase signaling pathway in the LSt cells. METHODS Expression of phosphorylated extracellular signal-related kinases 1 and 2 (pERK) was investigated following mating behavior, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intrathecal or intraspinal delivery of Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor U0126 on DPN stimulation-induced ejaculation was examined. MAIN OUTCOME MEASURES Expression of pERK in LSt cells and associated areas was analyzed. Electromyographic recordings of the bulbocavernosus muscle were recorded in anesthetized, spinalized rats. RESULTS Results indicate that the MAP kinase signaling pathway is activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, ERK activation in LSt cells is an essential trigger for ejaculation, as DPN stimulation-induced reflexes were absent following administration of MEK inhibitor in the L3-L4 spinal area. CONCLUSION These data provide insight into the nature of the signal transduction pathways involved in the activation of ejaculation through LSt cells. The data demonstrate that ERK activation in LSt cells is essential for ejaculation and contribute to a more detailed understanding of the spinal generation of ejaculation.

Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report.

The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previously, her mother revealed similar features. Cerebellar liponeurocytoma is a poorly understood entity. This report provides novel evidence of an inheritable predisposition for tumor development. Accurate diagnosis and reporting of clinical outcomes and associated genetic and histopathological changes are necessary for guiding prognosis and developing recommendations for patient care.

Advances in Neurotrophic Factor and Cell-Based Therapies for Parkinson's Disease: A Mini-Review

Parkinsons disease (PD) affects an estimated 7-10 million people worldwide and remains without definitive or disease-modifying treatment. There have been many recent developments in cell-based therapy (CBT) to replace lost circuitry and provide chronic biological sources of therapeutic agents to the PD-affected brain. Early neural transplantation studies underscored the challenges of immune compatibility, graft integration and the need for renewable, autologous graft sources. Neurotrophic factors (NTFs) offer a potential class of cytoprotective pharmacotherapeutics that may complement dopamine (DA) replacement and CBT strategies in PD. Chronic NTF delivery may be an integral goal of CBT, with grafts consisting of autologous drug-producing (e.g., DA, NTF) cells that are capable of integration and function in the host brain. In this mini-review, we outline the past experience and recent advances in NTF technology and CBT as promising and integrated approaches for the treatment of PD.

Advances in HSP27 and HSP90-targeting strategies for glioblastoma

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. There is a critical need for novel strategies to abolish the molecular mechanisms that support GBM growth, invasion and treatment resistance. The heat shock proteins, HSP27 and HSP90, serve these pivotal roles in tumor cells and have been identified as effective targets for developing therapeutics. Natural and synthetic inhibitors have been evaluated in clinical trials for several forms of systemic cancer but none as yet for GBM. This topic review summarizes the current preclinical evidence and rationale to define the potential of HSP27 and HSP90 inhibitors in GBM management.

Multilevel, ultra-large-volume epidural blood patch for the treatment of neurocognitive decline associated with spontaneous intracranial hypotension: case report

Spontaneous intracranial hypotension (SIH) is a progressive clinical syndrome characterized by orthostatic headaches, nausea, emesis, and occasionally focal neurological deficits. Rarely, SIH is associated with neurocognitive changes. An epidural blood patch (EBP) is commonly used to treat SIH when conservative measures are inadequate, although some patients require multiple EBP procedures or do not respond at all. Recently, the use of a large-volume (LV) EBP has been described to treat occult leak sites in treatment-refractory SIH. This article describes the management of a patient with profound neurocognitive decline associated with SIH, who was refractory to conservative management and multiple interventions. The authors describe the successful use of an ultra-LV-EBP of 120 ml across multiple levels, the largest volume reported in the literature, and describe the technical aspects of the procedure. This procedure has resulted in dramatic and sustained symptom resolution.

The relationship between the duration of acute cauda equina compression and functional outcomes in a rat model.

Study Design. Immunohistochemical and behavioral study using a rat model of acute cauda equina syndrome (CES). Objective. To determine the effect of duration of extradural cauda equina compression (CEC) on bladder, sensory, and motor functions. Summary of Background Data. Cauda equina syndrome is a devastating injury treated with surgical decompression. Controversy exists regarding the optimal timing of surgery. Animal models of CES have focused on motor recovery but have not evaluated pain behavior or bladder function. Methods. A 4-mm balloon-tipped Fogarty catheter was inserted between the fifth and sixth lumbar lamina into the dorsal epidural space and inflated to compress the nerve roots at the L5 level. Maximal inflation was maintained at a constant balloon pressure of 304 Kpa for 1 or 4 hours. The catheter was inserted but not inflated in sham animals. During a 4-week period, pain behavior, bladder function, and locomotor function were assessed. Postmortem bladders and the lesion site were collected for analysis. Results. Mechanical allodynia was 2-fold greater in 1-hour CEC rats than 4-hour CEC (P = 0.002) and sham-operated (P = 0.001) rats at 4 weeks after injury. Hind limb locomotor function was not different between groups at 4 weeks after injury. Both the 1-hour and 4-hour CEC group rats retained greater volumes of urine than the sham-operated rats throughout the 4-week period (P < 0.05). At 4 weeks, bladder weight and volume were 2-fold greater in the 4-hour CEC group than in the 1-hour CEC group (P = 0.006 and P = 0.01, respectively). Histology of the bladder wall revealed an overall thinning after 4-hour CEC. Histology of the lesion site revealed a greater overall severity of injury after 4-hour CEC than after 1-hour CEC (P = 0.04) and sham operation (P = 0.002). Conclusion. Our data suggest that recovery of motor function is less affected by the timing of decompression compared with bladder function and pain behavior. Early decompression preserved bladder function but was associated with allodynia. Level of Evidence: N/A

Spontaneous Regression of an Intraparenchymal Cyst Following Deep Brain Stimulator Electrode Implantation: Case Report and Literature Review

BACKGROUND The development of an intraparenchymal cyst following deep brain stimulation (DBS) surgery is an uncommon complication that lacks a clearly defined management strategy. The pathophysiology is not known and may be related to perielectrode edema or cerebrospinal fluid tracking. Previous case reports have described various therapies for symptomatic cysts, including hardware removal or conservative treatment with steroids. CASE DESCRIPTION We present a male patient with bilateral DBS of the ventral intermediate nucleus of the thalamus for management of essential tremor, who developed a cystic cavitation at the left electrode tip and was followed without treatment. This patient developed dysarthria, gait impairment, and unilateral motor deficits 3 months after surgery. Perielectrode edema was initially identified, eventually coalescing into a cystic cavitation at the electrode tip. Cystic regression and symptomatic improvement were observed without any surgical or medical intervention, with full cyst resolution by 17 months. CONCLUSIONS Only 15 additional cases have been reported in the literature, although the true incidence may be underreported because of varying practices in obtaining postoperative scans. Cysts were identified in symptomatic patients on average 6.2 months after surgery. All symptomatic cysts were treated with hardware removal or steroid therapy. Observation alone may be sufficient when a DBS-associated cyst is identified. More reports are needed to characterize this rare complication.

Biomechanical evaluation of the ProDisc-C stability following graded posterior cervical injury

OBJECTIVEThere are limited data regarding the implications of revision posterior surgery in the setting of previous cervical arthroplasty (CA). The purpose of this study was to analyze segmental biomechanics in human cadaveric specimens with and without CA, in the context of graded posterior resection.METHODSFourteen human cadaveric cervical spines (C3-T1 or C2-7) were divided into arthroplasty (ProDisc-C, n = 7) and control (intact disc, n = 7) groups. Both groups underwent sequential posterior element resections: unilateral foraminotomy, laminoplasty, and finally laminectomy. Specimens were studied sequentially in two different loading apparatuses during the induction of flexion-extension, lateral bending, and axial rotation.RESULTSRange of motion (ROM) after artificial disc insertion was reduced relative to that in the control group during axial rotation and lateral bending (13% and 28%, respectively; p < 0.05) but was similar during flexion and extension. With sequential resections, ROM increased by a similar magnitude following foraminotomy and laminoplasty in both groups. Laminectomy had a much greater effect: mean (aggregate) ROM during flexion-extension, lateral bending, and axial rotation was increased by a magnitude of 52% following laminectomy in the setting of CA, compared to an 8% increase without arthroplasty. In particular, laminectomy in the setting of CA introduced significant instability in flexion-extension, characterized by a 90% increase in ROM from laminoplasty to laminectomy, compared to a 16% increase in ROM from laminoplasty to laminectomy without arthroplasty (p < 0.05).CONCLUSIONSForaminotomy and laminoplasty did not result in significant instability in the setting of CA, compared to controls. Laminectomy alone, however, resulted in a significant change in biomechanics, allowing for significantly increased flexion and extension. Laminectomy alone should be used with caution in the setting of previous CA.