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1.
Clin Neurol Neurosurg ; 200: 106371, 2021 01.
Article in English | MEDLINE | ID: mdl-33307326

ABSTRACT

BACKGROUND AND PURPOSE: The Dawn and Extend Intra-Arterial (IA) acute stroke intervention trials have proven the benefit of thrombectomy in a select group of patients up to 24 h since their last known well time (LKWT) or time of symptom onset. Following the issuance of new treatment guidelines for large vessel occlusion strokes, we reviewed the paradigm shift effect on transfers for possible thrombectomy in a rural state. HYPOTHESIS: Extended time window for thrombectomy increases the need for better identification of potential transfers for thrombectomy in rural states with few hospitals capable of 24/7 interventional thrombectomy. METHODS: We analyzed all transfers to a comprehensive stroke center (CSC) from January to December 2018 which were specifically transferred for possible further intervention. This time period was selected in accordance with the change in American Heart Association (AHA) guidelines for extended time windows in mechanical thrombectomy (MT) care. RESULTS: A total of 132 patients were transferred for possible thrombectomy and advanced imaging. Thirty-four % patients underwent diagnostic angiogram with 33% patients having successful MT. Of the excluded patients 19% had large core infarcts by the time they arrived at hub hospital, 1.5% had hemorrhagic conversion, 32% had stroke without treatable occlusion not amenable for thrombectomy or cortical strokes on follow-up imaging, and 13.5% did not have stroke or LVO on follow-up imaging. CONCLUSION: Since the AHA's change in time window guidelines for mechanical thrombectomies, there has been an increased effort in identifying good candidates with computerized tomography angiography (CTA). To avoid undue burden on stroke systems of care, CTA identification of these patients at the spoke hospitals is key along with timely transport to appropriate thrombectomy capable sites. Given the rural nature of this state along with limited resources, selection of patients is a practical issue, especially for avoiding futile transfers, which might be true for large areas of the USA.


Subject(s)
Brain Ischemia/surgery , Computed Tomography Angiography/trends , Patient Transfer/trends , Stroke/surgery , Thrombectomy/trends , Time-to-Treatment/trends , Adult , Aged , Brain Ischemia/diagnostic imaging , Cohort Studies , Computed Tomography Angiography/methods , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Transfer/methods , Prospective Studies , Retrospective Studies , Stroke/diagnostic imaging , Thrombectomy/methods , Triage/methods , Triage/trends
2.
J Vasc Interv Radiol ; 30(8): 1244-1250.e1, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31349978

ABSTRACT

PURPOSE: This randomized, placebo-controlled, double-blind, dose-escalation acute ischemic stroke trial was designed to demonstrate maximum tolerated dose, characterize adverse events (AEs), and explore clinical outcomes when intravenous dodecafluoropentane emulsion (DDFPe) was used as neuroprotection. METHODS: Acute ischemic stroke patients (n = 24) with National Institutes of Health Stroke Scale (NIHSS) score of 2-20 were randomized to either 3 doses of intravenous DDFPe or placebo, 1 every 90 minutes, starting within 12 hours of symptom onset. Doses were given without affecting standard stroke care. Each of the 3 dose cohorts included 8 patients, with 2 receiving placebo and 6 receiving DDFPe. Primary outcomes were serious adverse events (SAEs), AEs, NIHSS score, and modified Rankin Score (mRS). RESULTS: No dose-limiting toxicities were encountered, and no maximum tolerated dose was defined. One unrelated delayed death occurred in a DDFPe patient, and another occurred in the placebo group. Group SAEs and AEs were similar in incidence and severity. Early initiation of DDFPe treatment resulted in better NIHSS score response than late initiation (P = .03). Thirty- and 90-day mRS after high-dose therapy suggested clinical improvement (P = .01 and P = .03, respectively). However, the significance of differences in clinical outcomes was limited by small patient numbers and differences in stroke severity between cohorts. CONCLUSIONS: Intravenous DDFPe appears to be safe at all doses tested. Clinical improvements in NIHSS score and mRS were significant but compromised by small sample size.


Subject(s)
Brain Ischemia/drug therapy , Fluorocarbons/administration & dosage , Neuroprotective Agents/administration & dosage , Stroke/therapy , Administration, Intravenous , Arkansas , Brain Ischemia/diagnosis , Brain Ischemia/physiopathology , Disability Evaluation , Double-Blind Method , Drug Administration Schedule , Female , Fluorocarbons/adverse effects , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neuroprotective Agents/adverse effects , Recovery of Function , Stroke/diagnosis , Stroke/physiopathology , Time Factors , Treatment Outcome
3.
Mol Neurobiol ; 54(6): 4764-4770, 2017 08.
Article in English | MEDLINE | ID: mdl-27501802

ABSTRACT

Dodecafluoropentane emulsion (DDFPe), an advanced oxygen transport drug, given IV at 90-min intervals maintains viability in the penumbra during cerebral ischemia in the standard rabbit anterior stroke model (STND). This study investigated shortened dosage schedules of DDFPe in nonstandard posterior (NSTND) strokes following occlusions of the posterior cerebral arteries. DDFPe given at shortened schedules of 30 or 60-min injection intervals will reduce neurological deficits, percent stroke volume (%SV), and serum glutamate levels in NSTND ischemic strokes. New Zealand White rabbits (N = 26) were randomly placed into three groups: A (n = 9) controls given saline injections every 60 min, B (n = 9) 2 % DDFPe given IV every 30 min, and C (n = 8) DDFPe every 60 min. Injections began 1 h after embolization. Groups were subdivided into STND and NSTND based on angiographically verified embolization of the cerebral arteries. Neurological assessments and blood samples were done at 0.5-1-h intervals. Rabbits were euthanized at 7 h following embolization. Stained brain slices were measured for %SV. The 30 and 60-min subgroups did not differ and were combined as DDFPe-STND or DDFPe-NSTND groups. In the DDFPe-STND stroke group, the %SV, neurological assessment scores (NAS), and serum glutamate were decreased vs. STND controls (p = 0.0016, 0.008, and 0.016, respectively). In the DDFPe-NSTND stroke group, %SV, NAS, and serum glutamate did not differ statistically compared to NSTND controls (p = 0.82, 0.097, and 0.06, respectively). More frequent dosage schedules provided no additional improvement. In anterior strokes, DDFPe improves recovery but not in the more severe NSTND strokes.


Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/physiopathology , Fluorocarbons/therapeutic use , Stroke/drug therapy , Stroke/physiopathology , Angiography , Animals , Brain Ischemia/blood , Brain Ischemia/complications , Female , Glutamates/blood , Male , Rabbits , Recovery of Function/drug effects , Stroke/blood , Stroke/complications
4.
J Neurosci Methods ; 212(2): 322-8, 2013 Jan 30.
Article in English | MEDLINE | ID: mdl-23142182

ABSTRACT

PURPOSE: To develop angiographic models of embolic stroke in the rabbit using pre-formed clot or microspheres to model clinical situations ranging from transient ischemic events to severe ischemic stroke. MATERIALS AND METHODS: New Zealand White rabbits (N=151) received angiographic access to the internal carotid artery (ICA) from a femoral approach. Variations of emboli type and quantity of emboli were tested by injection into the ICA. These included fresh clots (1.0-mm length, 3-6h), larger aged clots (4.0-mm length, 3 days), and 2 or 3 insoluble microspheres (700-900 µm). Neurological assessment scores (NAS) were based on motor, sensory, balance, and reflex measures. Rabbits were euthanized at 4, 7, or 24h after embolization, and infarct volume was measured as a percent of total brain volume using 2,3,5-triphenyltetrazolium chloride (TTC). RESULTS: Infarct volume percent at 24 h after stroke was lower for rabbits embolized with fresh clot (0.45±0.14%), compared with aged clot (3.52±1.31%) and insoluble microspheres (3.39±1.04%). Overall NAS (including posterior vessel occlusions) were positively correlated to infarct volume percent measurements in the fresh clot (r=0.50), aged clot (r=0.65) and microsphere (r=0.62) models (p<0.001). CONCLUSION: The three basic angiographic stroke models may be similar to human transient ischemic attacks (TIA) (fresh clot), major strokes that can be thrombolysed (aged clot), or major strokes with insoluble emboli such as atheromata (microspheres). Model selection can be tailored to specific research needs.


Subject(s)
Cerebral Angiography/methods , Disease Models, Animal , Stroke/diagnostic imaging , Stroke/pathology , Animals , Female , Intracranial Embolism/complications , Intracranial Embolism/diagnostic imaging , Male , Rabbits , Stroke/etiology
5.
J Vasc Interv Radiol ; 23(1): 116-21, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22079515

ABSTRACT

PURPOSE: To assess the efficacy of dodecafluoropentane emulsion (DDFPe), a nanodroplet emulsion with significant oxygen transport potential, in decreasing infarct volume in an insoluble-emboli rabbit stroke model. MATERIALS AND METHODS: New Zealand White rabbits (N = 64; weight, 5.1 ± 0.50 kg) underwent angiography and received embolic spheres in occluded internal carotid artery branches. Rabbits were randomly assigned to groups in 4-hour and 7-hour studies. Four-hour groups included control (n = 7, embolized without treatment) and DDFPe treatment 30 minutes before stroke (n = 7), at stroke onset (n = 8), and 30 minutes (n = 5), 1 hour (n = 7), 2 hours (n = 5), or 3 hours after stroke (n = 6). Seven-hour groups included control (n = 6) and DDFPe at 1 hour (n = 8) and 6 hours after stroke (n = 5). DDFPe dose was a 2% weight/volume intravenous injection (0.6 mL/kg) repeated every 90 minutes as time allowed. After euthanasia, infarct volume was determined by vital stains on brain sections. RESULTS: At 4 hours, median infarct volume decreased for all DDFPe treatment times (pretreatment, 0.30% [P = .004]; onset, 0.20% [P = .004]; 30 min, 0.35% [P = .009]; 1 h, 0.30% [P = .01]; 2 h, 0.40% [P = .009]; and 3 h, 0.25% [P = .003]) compared with controls (3.20%). At 7 hours, median infarct volume decreased with treatment at 1 hour (0.25%; P = .007) but not at 6 hours (1.4%; P = .49) compared with controls (2.2%). CONCLUSIONS: Intravenous DDFPe in an animal model decreases infarct volumes and protects brain tissue from ischemia, justifying further investigation.


Subject(s)
Fluorocarbons/pharmacology , Stroke/prevention & control , Animals , Cerebral Angiography , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/prevention & control , Chi-Square Distribution , Disease Models, Animal , Emulsions , Rabbits , Random Allocation , Statistics, Nonparametric , Stroke/diagnostic imaging , Tissue Plasminogen Activator/pharmacology
6.
Acta Neurobiol Exp (Wars) ; 71(3): 348-58, 2011.
Article in English | MEDLINE | ID: mdl-22068744

ABSTRACT

The present study examined how cold pressor stimulation influences electrophysiological correlates of arousal. We measured the P50 auditory evoked response potential in two groups of subjects who immersed their foot in either cold (0-2°C) or room temperature (22-24°C) water for 50 seconds. The P50, which was recorded before and after stimulation, is sleep-state dependent and sensitive to states of arousal in clinical populations. We found a significant reduction in P50 amplitude after exposure to cold, but not room temperature water. In comparison with other studies, these results indicate that cold pressor stimulation in normal subjects may evoke a regulatory process that modulates the P50 amplitude, perhaps to preserve the integrity of sensory perception, even as autonomic and subjective aspects of arousal increase.


Subject(s)
Cold Temperature , Evoked Potentials, Somatosensory/physiology , Adolescent , Analysis of Variance , Electroencephalography , Female , Foot/innervation , Habituation, Psychophysiologic , Humans , Male , Reaction Time , Young Adult
7.
Open Neurol J ; 5: 55-7, 2011.
Article in English | MEDLINE | ID: mdl-21760859

ABSTRACT

Serum levels of S-100B were investigated as a marker for infarct volume and response to treatment following acute ischemic stroke in rabbits. Following subselective angiography, rabbits (n=31) were embolized by injection of a 3-day-old blood clot (0.6x4.0-mm) into the internal carotid artery. Treatment began 1-hr post-embolization, groups included: Control (n=8, embolization only), tissue plasminogen activator (tPA, n=12, 0.9mg/kg), and perflutren lipid microbubbles with transcranial ultrasound (MB+US, n=11, MB at 0.16mg/kg, US at 1-MHz pulsed-wave, 0.8 W/cm(2) for 1-hr). Serum S-100B levels were significantly increased (P<0.01) 24-hours following embolization in control (3.1-fold over baseline) and tPA (2.9-fold) groups, while treatment with MB+US resulted in an attenuated, non-significant (P=0.221) increase (1.6-fold). Twenty-four hour infarct volumes averaged 4.76%±1.16% for controls, 2.25%±0.95% for rabbits treated with tPA (P=0.32 vs. control), and 0.79%±0.99% for rabbits treated with MB+US (P=0.04 vs. control). Twenty-four hour concentrations of S-100B were positively correlated with infarct volume (r=0.59, P=0.0004).

8.
Stroke ; 42(8): 2280-5, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21700942

ABSTRACT

BACKGROUND AND PURPOSE: Microbubbles (MB) combined with ultrasound (US) have been shown to lyse clots without tissue-type plasminogen activator (tPA) both in vitro and in vivo. We evaluated sonothrombolysis with 3 types of MB using a rabbit embolic stroke model. METHODS: New Zealand White rabbits (n=74) received internal carotid angiographic embolization of single 3-day-old cylindrical clots (0.6 × 4.0 mm). Groups included: (1) control (n=11) embolized without treatment; (2) tPA (n=20); (3) tPA+US (n=10); (4) perflutren lipid MB+US (n=16); (5) albumin 3 µm MB+US (n=8); and (6) tagged albumin 3 µm MB+US (n=9). Treatment began 1 hour postembolization. Ultrasound was pulsed-wave (1 MHz; 0.8 W/cm²) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Lipid MB dose was intravenous (0.16 mg/kg) over 30 minutes. Dosage of 3 µm MB was 5 × 109 MB intravenously alone or tagged with eptifibatide and fibrin antibody over 30 minutes. Rabbits were euthanized at 24 hours. Infarct volume was determined using vital stains on brain sections. Hemorrhage was evaluated on hematoxylin and eosin sections. RESULTS: Infarct volume percent was lower for rabbits treated with lipid MB+US (1.0%± 0.6%; P=0.013), 3 µm MB+US (0.7% ± 0.9%; P=0.018), and tagged 3 µm MB+US (0.8% ± 0.8%; P=0.019) compared with controls (3.5%± 0.8%). The 3 MB types collectively had lower infarct volumes (P=0.0043) than controls. Infarct volume averaged 2.2% ± 0.6% and 1.7%± 0.8% for rabbits treated with tPA alone and tPA+US, respectively (P=nonsignificant). CONCLUSIONS: Sonothrombolysis without tPA using these MB is effective in decreasing infarct volumes. Study of human application and further MB technique development are justified.


Subject(s)
Brain Ischemia/therapy , Microbubbles/therapeutic use , Stroke/therapy , Thrombolytic Therapy/methods , Ultrasonic Therapy/methods , Animals , Brain Ischemia/diagnostic imaging , Brain Ischemia/drug therapy , Cerebral Angiography , Fibrinolytic Agents/therapeutic use , Rabbits , Stroke/diagnostic imaging , Stroke/drug therapy , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome , Ultrasonography
9.
Front Neurol ; 2: 3, 2011.
Article in English | MEDLINE | ID: mdl-21441978

ABSTRACT

The P13 potential is the rodent equivalent of the P50 potential, which is an evoked response recorded at the vertex (Vx) 50 ms following an auditory stimulus in humans. Both the P13 and P50 potentials are only present during waking and rapid eye movement (REM) sleep, and are considered to be measures of level of arousal. The source of the P13 and P50 potentials appears to be the pedunculopontine nucleus (PPN), a brainstem nucleus with indirect ascending projections to the cortex through the intralaminar thalamus, mediating arousal, and descending inhibitory projections to the caudal pontine reticular formation (CPRF), which mediates the auditory startle response (SR). We tested the hypothesis that intracranial microinjection (ICM) of glutamate (GLU) or GLU receptor agonists will increase the activity of PPN neurons, resulting in an increased P13 potential response, and decreased SR due to inhibitory projections from the PPN to the CPRF, in freely moving animals. Cannulae were inserted into the PPN to inject neuroactive agents, screws were inserted into the Vx in order to record the P13 potential, and electrodes inserted into the dorsal nuchal muscle to record electromyograms and SR amplitude. Our results showed that ICM of GLU into the PPN dose-dependently increased the amplitude of the P13 potential and decreased the amplitude of the SR. Similarly, ICM of N-methyl-d-aspartic acid or kainate into the PPN increased the amplitude of the P13 potential. These findings indicate that glutamatergic input to the PPN plays a role in arousal control in vivo, and changes in glutamatergic input, or excitability of PPN neurons, could be implicated in a number of neuropsychiatric disorders with the common symptoms of hyperarousal and REM sleep dysregulation.

10.
Exp Neurol ; 227(1): 104-9, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20932828

ABSTRACT

Spasticity is a common disorder following spinal cord injury that can impair function and quality of life. While a number of mechanisms are thought to play a role in spasticity, the role of motoneuron persistent inward currents (PICs) is emerging as pivotal. The presence of PICs can be evidenced by temporal summation or wind-up of reflex responses to brief afferent inputs. In this study, a combined neurophysiological and novel biomechanical approach was used to assess the effects of passive exercise and modafinil administration on hyper-reflexia and spasticity following complete T-10 transection in the rat. Animals were divided into 3 groups (n=8) and provided daily passive cycling exercise, oral modafinil, or no intervention. After 6weeks, animals were tested for wind-up of the stretch reflex (SR) during repeated dorsiflexion stretches of the ankle. H-reflexes were tested in a subset of animals. Both torque and gastrocnemius electromyography showed evidence of SR wind-up in the transection only group that was significantly different from both treatment groups (p<0.05). H-reflex frequency dependent depression was also restored to normal levels in both treatment groups. The results provide support for the use of passive cycling exercise and modafinil in the treatment of spasticity and provide insight into the possible contribution of PICs.


Subject(s)
Benzhydryl Compounds/therapeutic use , Muscle Spasticity/drug therapy , Muscle Spasticity/rehabilitation , Neuroprotective Agents/therapeutic use , Physical Conditioning, Animal/methods , Reflex, Stretch/physiology , Analysis of Variance , Animals , Chronic Disease , Disease Models, Animal , Electromyography/methods , Female , H-Reflex/drug effects , H-Reflex/physiology , Modafinil , Muscle Spasticity/diagnosis , Muscle Spasticity/etiology , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Random Allocation , Rats , Rats, Sprague-Dawley , Reflex, Stretch/drug effects , Severity of Illness Index , Spinal Cord Injuries/complications , Spinal Cord Injuries/rehabilitation , Time Factors , Torque
11.
J Neurovirol ; 16(4): 318-29, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20632796

ABSTRACT

To address the hypothesis that respiratory distress associated with West Nile virus (WNV) is neurologically caused, electromyographs (EMGs) were measured longitudinally from the diaphragms of alert hamsters infected subcutaneously (s.c.) with WNV. The EMG activity in WNV-infected hamsters was consistently and significantly (P

Subject(s)
Diaphragm/innervation , Diaphragm/physiopathology , West Nile Fever/physiopathology , Afferent Pathways/physiopathology , Afferent Pathways/virology , Animals , Brain Stem/physiopathology , Brain Stem/virology , Cervical Vertebrae , Cricetinae , Electromyography , Evoked Potentials, Auditory , Female , Immunohistochemistry , Mesocricetus , Microscopy, Confocal , Neurons/virology , Spinal Cord/virology , West Nile virus
12.
Brain Res Bull ; 83(5): 262-5, 2010 Oct 30.
Article in English | MEDLINE | ID: mdl-20637842

ABSTRACT

This study investigated whether l-dopa (DOPA), locomotor-like passive exercise (Ex) using a motorized bicycle exercise trainer (MBET), or their combination in adult rats with complete spinal cord transection (Tx) preserves and restores low frequency-dependent depression (FDD) of the H-reflex. Adult Sprague-Dawley rats (n=56) transected at T8-9 had one of five treatments beginning 7 days after transection: Tx (transection only), Tx+Ex, Tx+DOPA, Tx+Ex+DOPA, and control (Ctl, no treatment) groups. After 30 days of treatment, FDD of the H-reflex was tested. Stimulation of the tibial nerve at 0.2, 1, 5, and 10Hz evoked an H-reflex that was recorded from plantar muscles of the hind paw. No significant differences were found at the stimulation rate of 1Hz. However, at 5Hz, FDD of the H-reflex in the Tx+Ex, Tx+DOPA and Ctl groups was significantly different from the Tx group (p<0.01). At 10Hz, all of the treatment groups were significantly different from the Tx group (p<0.01). No significant difference was identified between the Ctl and any of the treatment groups. These results suggest that DOPA significantly preserved and restored FDD after transection as effectively as exercise alone or exercise in combination with DOPA. Thus, there was no additive benefit when DOPA was combined with exercise.


Subject(s)
Dopamine Agents/pharmacology , H-Reflex , Levodopa/pharmacology , Spinal Cord Injuries/physiopathology , Animals , Dopamine/metabolism , Electric Stimulation , Exercise , Female , H-Reflex/drug effects , H-Reflex/physiology , Humans , Physical Therapy Modalities , Random Allocation , Rats , Rats, Sprague-Dawley
13.
J Vasc Interv Radiol ; 21(6): 903-9, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20417119

ABSTRACT

PURPOSE: Current rabbit stroke models often depend on symptoms as endpoints for embolization and produce wide variation in location, size, and severity of strokes. In a further refinement of an angiographic embolic stroke model, localized infarctions were correlated to neurologic deficits with the goal to create a rabbit model for long-term studies of therapies after stroke. MATERIALS AND METHODS: New Zealand White rabbits (4-5 kg; N = 71) had selective internal carotid artery (ICA) angiography and a single clot was injected. At 24 hours, neurologic assessment score (NAS) was measured on an 11-point scale (0, normal; 10, dead). Brains were removed and stained to identify stroke areas. All animals with single strokes (n = 31) were analyzed by specific brain structure involvement, and NAS values were correlated. RESULTS: Stroke incidence differed by location, with cortex, subcortical, and basal ganglia regions highest. The middle cerebral artery (MCA), at 52%, and anterior cerebral artery (ACA), at 29%, were most commonly involved, with the largest stroke volumes in the ACA distribution. Brainstem and cerebellum strokes had disproportionately severe neurologic deficits, scoring 2.25 +/- 1.0 on the NAS, which represented a significant (P < .02) difference versus cortex (0.5 +/- 0.2), subcortical (1.3 +/- 0.4), and basal ganglia (0.5 +/- 0.3), all in the frontal or parietal regions. CONCLUSIONS: MCA and ACA distributions included 81% of strokes. These sites were relatively silent (potentially allowing longer-term survival studies) whereas others in the posterior circulation produced disproportionately severe symptoms. Symptoms were not reliable indicators of stroke occurrence, and other endpoints such as imaging may be required. These are important steps toward refinement of the rabbit stroke model.


Subject(s)
Brain/diagnostic imaging , Brain/physiopathology , Disease Models, Animal , Intracranial Embolism/diagnostic imaging , Intracranial Embolism/physiopathology , Stroke/diagnostic imaging , Stroke/physiopathology , Animals , Humans , Intracranial Embolism/etiology , Rabbits , Radiography , Stroke/etiology
14.
J Virol ; 83(9): 4251-61, 2009 May.
Article in English | MEDLINE | ID: mdl-19224990

ABSTRACT

To investigate the hypothesis that neurological sequelae are associated with persistent West Nile virus (WNV) and neuropathology, we developed an electrophysiological motor unit number estimation (MUNE) assay to measure the health of motor neurons temporally in hamsters. The MUNE assay was successful in identifying chronic neuropathology in the spinal cords of infected hamsters. MUNE was suppressed at days 9 to 92 in hamsters injected subcutaneously with WNV, thereby establishing that a long-term neurological sequela does occur in the hamster model. MUNE suppression at day 10 correlated with the loss of neuronal function as indicated by reduced choline acetyltransferase staining (R(2) = 0.91). Between days 10 and 26, some alpha-motor neurons had died, but further neuronal death was not detected beyond day 26. MUNE correlated with disease phenotype, because the lowest MUNE values were detected in paralyzed limbs. Persistent WNV RNA and foci of WNV envelope-positive cells were identified in the central nervous systems of all hamsters tested from 28 to 86 days. WNV-positive staining colocalized with the neuropathology, which suggested that persistent WNV or its products contributed to neuropathogenesis. These results established that persistent WNV product or its proteins cause dysfunction, that WNV is associated with chronic neuropathological lesions, and that this neurological sequela is effectively detected by MUNE. Inasmuch as WNV-infected humans can also experience a poliomyelitis-like disease where motor neurons are damaged, MUNE may also be a sensitive clinical or therapeutic marker for those patients.


Subject(s)
Motor Neuron Disease/virology , West Nile virus/physiology , Animals , Antigens, Viral/immunology , Cricetinae , Electrophysiological Phenomena , Female , Motor Neuron Disease/immunology , Motor Neuron Disease/metabolism , Motor Neuron Disease/pathology , RNA, Viral/genetics , Viral Envelope Proteins/metabolism
15.
Sleep ; 31(12): 1647-54, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19090320

ABSTRACT

STUDY OBJECTIVES: We recorded the effects of administration of the stimulant modafinil on the amplitude of the sleep state-dependent auditory P13 evoked potential in freely moving rats, a measure of arousal thought to be generated by the cholinergic arm of the reticular activating system, specifically the pedunculopontine nucleus (PPN). DESIGN: Groups of rats were implanted for recording auditory evoked responses and the effects on P13 potential amplitude of intracranial injections into the PPN of neuroactive agents determined. MEASUREMENTS AND RESULTS: The effects of intracranial injections into the PPN of modafinil showed that P13 potential amplitude increased in a dose-dependent manner at doses of 100, 200, and 300 microM. The effect was blocked by pretreatment with either of the gap junction antagonists carbenoxolone (300 microM) or mefloquine (25 microM), which by themselves slightly decreased P13 potential amplitude. CONCLUSIONS: These results suggest that modafinil increases arousal levels as determined by the amplitude of the P13 potential, an effect blocked by gap junction antagonists, suggesting that one mechanism by which modafinil increases arousal may be by increasing electrical coupling.


Subject(s)
Benzhydryl Compounds/pharmacology , Carbenoxolone/pharmacology , Central Nervous System Stimulants/pharmacology , Electroencephalography/drug effects , Evoked Potentials, Auditory/drug effects , Gap Junctions/drug effects , Mefloquine/pharmacology , Animals , Injections , Male , Modafinil , Pedunculopontine Tegmental Nucleus/drug effects , Rats , Rats, Wistar , Synaptic Transmission/drug effects
16.
Exp Neurol ; 213(2): 405-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18671970

ABSTRACT

Hyperreflexia develops after spinal cord injury (SCI) in the human and in the spinal cord transected animal, and can be measured by the loss of low frequency-dependent depression of the H-reflex. Previous studies demonstrated normalization of low frequency-dependent depression of the H-reflex using passive exercise when initiated prior to the development of hyperreflexia. We examined the effects of passive exercise prior to compared to after the development of hyperreflexia in the transected rat. Adult female rats underwent complete transection (Tx) at T10. Frequency-dependence of the H-reflex was tested following passive exercise for 30 days, initiated prior to hyperreflexia in one group compared to initiation after hyperreflexia became established, and compared to intact and untreated Tx groups. An additional Tx group completed 60 days of exercise initiated after hyperreflexia was established. Lumbar enlargement tissue was harvested for western blot to compare Connexin-36 protein levels in control vs Tx animals vs Tx animals that were passively exercised. No differences in whole tissue were evident, although regional differences may still be present in Connexin-36 levels. Statistically significant decreases in low frequency-dependent depression of the H-reflex were observed following 30 days of exercise initiated prior to the onset of hyperreflexia, and also after 60 days of exercise when initiated after hyperreflexia had been established, compared with Tx only animals. We concluded that modulation of spinal circuitry by passive exercise took place when initiated before and after the onset of hyperreflexia, but different durations of exercise were required.


Subject(s)
Exercise Therapy/methods , Physical Conditioning, Animal/methods , Physical Conditioning, Animal/physiology , Reflex, Abnormal/physiology , Spinal Cord Injuries/physiopathology , Animals , Connexins/metabolism , Female , H-Reflex/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/complications , Spinal Cord Injuries/metabolism , Time Factors , Gap Junction delta-2 Protein
17.
Neuroreport ; 18(3): 249-53, 2007 Feb 12.
Article in English | MEDLINE | ID: mdl-17314666

ABSTRACT

Rapid eye movement sleep decreases dramatically during development. We tested the hypothesis that some of this decrease may be due to GABAergic inhibition of reticular activating system neurons. Recordings of pedunculopontine neurons in vitro showed that the gamma-amino-butyric acid, receptor agonist muscimol depolarized noncholinergic cells early in the developmental decrease in rapid eye movement sleep, and hyperpolarized them later. Most cholinergic cells were hyperpolarized throughout the period tested. The gamma-amino-butyric acid b receptor agonist baclofen hyperpolarized both cholinergic and noncholinergic cells, although the degree of polarization decreased with age. Part of the gradual decrement in rapid eye movement sleep during development may be due in part to the increasing inhibition mediated by gamma-amino-butyric acid, a receptor on pedunculopontine neurons. This influence, however, appears to be mainly on noncholinergic cells.


Subject(s)
Neural Inhibition/physiology , Pedunculopontine Tegmental Nucleus/growth & development , Reticular Formation/growth & development , Sleep, REM/physiology , gamma-Aminobutyric Acid/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Aging/physiology , Animals , Baclofen/pharmacology , GABA Agonists/pharmacology , GABA-B Receptor Antagonists , Muscimol/pharmacology , Neural Pathways/growth & development , Neural Pathways/metabolism , Pedunculopontine Tegmental Nucleus/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-B/metabolism , Reticular Formation/metabolism , Sleep, REM/drug effects , Sodium Channel Blockers/pharmacology
18.
Brain Res ; 1129(1): 147-55, 2007 Jan 19.
Article in English | MEDLINE | ID: mdl-17156760

ABSTRACT

The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system (RAS), is known to modulate waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, with the majority occurring between 12 and 21 days. We investigated the possibility that changes in the cholinergic, muscarinic and/or nicotinic, input to PPN neurons could explain at least part of the developmental decrease in REM sleep. We recorded intracellularly from PPN neurons in 12-21 day rat brainstem slices maintained in artificial cerebrospinal fluid (aCSF) and found that application of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) depolarized PPN neurons early in development, then hyperpolarized PPN neurons by day 21. Most of the effects of DMPP persisted following application of the sodium channel blocker tetrodotoxin (TTX), and in the presence of glutamatergic, serotonergic, noradrenergic and GABAergic antagonists, but were blocked by the nicotinic antagonist mecamylamine (MEC). The mixed muscarinic agonist carbachol (CAR) hyperpolarized all type II (A current) PPN cells and depolarized all type I (low threshold spike-LTS current) and type III (A+LTS current) PPN cells, but did not change effects during the period known for the developmental decrease in REM sleep. The effects of CAR persisted in the presence of TTX but were mostly blocked by the muscarinic antagonist atropine (ATR), and the remainder by MEC. We conclude that, while the nicotinic inputs to the PPN may help modulate the developmental decrease in REM sleep, the muscarinic inputs appear to modulate different types of cells differentially.


Subject(s)
Acetylcholine/metabolism , Neurons/metabolism , Pedunculopontine Tegmental Nucleus/growth & development , Pedunculopontine Tegmental Nucleus/metabolism , Receptors, Muscarinic/metabolism , Receptors, Nicotinic/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Aging/physiology , Animals , Animals, Newborn , Cell Differentiation/physiology , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Neurons/drug effects , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Organ Culture Techniques , Pedunculopontine Tegmental Nucleus/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Muscarinic/drug effects , Receptors, Nicotinic/drug effects , Sleep, REM/physiology , Sodium Channel Blockers/pharmacology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology
19.
Arch Phys Med Rehabil ; 86(10): 2018-26, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16213248

ABSTRACT

OBJECTIVE: To determine if the P50 midlatency auditory evoked potential, a sleep state-dependent waveform thought to be generated by the reticular activating system, is modulated after surface stimulation of acupuncture points (ie, electroacupuncture). DESIGN: P50 potential recordings were carried out before, during, and after electroacupuncture. SETTING: A clinical research center. PARTICIPANTS: Eighty healthy subjects ages 25 to 55 were recorded in 7 investigations. INTERVENTIONS: Stimulation of 3 specific acupuncture points (Pericardium 6, Heart 3, Liver 3) was compared with no stimulation or with stimulation of control points (Gall Bladder 34, Large Intestine 11, Small Intestine 3). We compared different frequencies of stimulation (5, 60, 100 Hz), unilateral versus bilateral stimulation, and the effects of repeated episodes of stimulation. MAIN OUTCOME MEASURES: P50 auditory evoked potential latency, amplitude (measure of level of arousal), and habituation (measure of sensory gait) at interstimulus interval of 250 ms. RESULTS: Electroacupuncture at specific points decreased P50 potential amplitude versus electroacupuncture at control points (P=.006) or versus no stimulation (P<.001). The optimal effective frequency was 5 Hz (P<.05 at 5 Hz, P>.05 at 60 and 100 Hz), and unilateral electroacupuncture was not as effective as bilateral electroacupuncture (P=.007). Repeated episodes of bilateral electroacupuncture showed additive effects (P<.05). There were no differences in responsiveness across sexes (P=.79), and electroacupuncture did not affect P50 potential habituation (P>.05). CONCLUSIONS: Electroacupuncture may be effectively used to decrease arousal levels, perhaps as adjunct therapy for disorders of hypervigilance.


Subject(s)
Acupuncture Points , Electric Stimulation/methods , Evoked Potentials, Auditory/physiology , Sleep/physiology , Adult , Female , Habituation, Psychophysiologic , Humans , Male , Middle Aged
20.
J Spinal Cord Med ; 28(3): 241-5, 2005.
Article in English | MEDLINE | ID: mdl-16048142

ABSTRACT

BACKGROUND/OBJECTIVES: Spasticity in patients with spinal cord injury (SCI) is difficult to manage. Exercise and stretching is advocated as a management tool, but these activities are difficult to perform for most patients as a result of multiple barriers. This report shows the effect of passive range-of-motion exercise in a walking-like pattern on frequency-dependent habituation of the H-reflex in the lower extremities of an individual with spastic tetraplegia due to SCI. METHODS: The participant, a man with a chronic ASIA B C7 SCI due to a gunshot wound, used a motorized bicycle exercise trainer (MBET) developed at the Jackson T. Stephens Spine & Neurosciences Institute at the University of Arkansas for Medical Sciences that could be operated from the individual's wheelchair. He used the MBET for 1 hour, 5 days a week, for 13 weeks. H-reflex habituation was tested at the beginning of the study and then periodically over the course of 17 weeks, including 4 weeks after exercise had ceased. RESULTS: Significant habituation of the H-reflex was evident beginning at the 10th week of training. The habituation in the H-reflex reached a normal level at 5- and 10-Hz frequencies at 12 weeks. Subjective assessment of spasticity indicated that it was significantly reduced. The H-reflex amplitude was maintained at normal levels during the remaining week of the course of exercise and for 2 additional weeks after exercise ceased. The H-reflex habituation, however, returned to near baseline when reassessed at week 17, 4 weeks after the exercise program had concluded. Subjective assessment indicated that spasticity also had returned to pretraining levels. CONCLUSIONS: Habituation of the H-reflex, and perhaps spasticity, can be managed by a routine passive range-of-motion exercise program using a MBET, but the exercise program may need to be continuous. The benefit of reduced medication for spasticity and possibly improved quality of life could be a motivating factor for an individual with SCI and spasticity to continue the program. Because of the low complexity of the program, ease of use, and small size, this system could be inexpensive and could be used by an individual in the home. Ongoing studies will determine the minimum amount of MBET training required for maintaining long-term H-reflex habituation.


Subject(s)
Bicycling , Cervical Vertebrae , H-Reflex , Habituation, Psychophysiologic , Motor Vehicles , Physical Education and Training/methods , Spinal Cord Injuries/physiopathology , Adult , Humans , Male , Quadriplegia/etiology , Quadriplegia/physiopathology , Spinal Cord Injuries/complications , Time Factors
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