Intrinsic neurophysiological properties of hilar ectopic and normotopic dentate granule cells in human temporal lobe epilepsy and a rat model.

Hilar ectopic dentate granule cells (DGCs) are a salient feature of aberrant plasticity in human temporal lobe epilepsy (TLE) and most rodent models of the disease. Recent evidence from rodent TLE models suggests that hilar ectopic DGCs contribute to hyperexcitability within the epileptic hippocampal network. Here we investigate the intrinsic excitability of DGCs from humans with TLE and the rat pilocarpine TLE model with the objective of comparing the neurophysiology of hilar ectopic DGCs to their normotopic counterparts in the granule cell layer (GCL). We recorded from 36 GCL and 7 hilar DGCs from human TLE tissue. Compared with GCL DGCs, hilar DGCs in patient tissue exhibited lower action potential (AP) firing rates, more depolarized AP threshold, and differed in single AP waveform, consistent with an overall decrease in excitability. To evaluate the intrinsic neurophysiology of hilar ectopic DGCs, we made recordings from retrovirus-birthdated, adult-born DGCs 2-4 mo after pilocarpine-induced status epilepticus or sham treatment in rats. Hilar DGCs from epileptic rats exhibited higher AP firing rates than normotopic DGCs from epileptic or control animals. They also displayed more depolarized resting membrane potential and wider AP waveforms, indicating an overall increase in excitability. The contrasting findings between disease and disease model may reflect differences between the late-stage disease tissue available from human surgical specimens and the earlier disease stage examined in the rat TLE model. These data represent the first neurophysiological characterization of ectopic DGCs from human hippocampus and prospectively birthdated ectopic DGCs in a rodent TLE model.

Time-frequency characterization of electrocorticographic recordings of epileptic patients using frequency-entropy similarity: a comparison to other bi-variate measures.

Expert evaluation of electrocorticographic (ECoG) recordings forms the linchpin of seizure onset zone localization in the evaluation of epileptic patients for surgical resection. Numerous methods have been developed to analyze these complex recordings, including uni-variate (characterizing single channels), bi-variate (comparing channel pairs) and multivariate measures. Developing reliable algorithms may be helpful in clinical tasks such as localization of epileptogenic zones and seizure anticipation, as well as enabling better understanding of neuronal function and dynamics. Recently we have developed the frequency-entropy (F-E) similarity measure, and have tested its capability in mapping the epileptogenic zones. The F-E similarity measure compares time-frequency characterizations of two recordings. In this study, we examine the method's principles and utility and compare it to previously described bi-variate correspondence measures such as correlation, coherence, mean phase coherence and spectral comparison methods. Specially designed synthetic signals were used for illuminating theoretical differences between the measures. Intracranial recordings of four epileptic patients were then used for the measures' comparative analysis by creating a mean inter-electrode matrix for each of the correspondence measures and comparing the structure of these matrices during the inter-ictal and ictal periods. We found that the F-E similarity measure is able to discover spectral and temporal features in data which are hidden for the other measures and are important for foci localization.

Novel treatments for cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm is a major cause of cerebral ischemia and poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Despite advances in diagnosis and treatment of SAH, the pathophysiology of vasospasm is still poorly understood and outcomes remain disappointing. Recent advances in understanding the role of hemoglobin in initiating an inflammatory cascade in the subarachnoid space open new avenues for therapy. Preliminary experimental and clinical evidence indicate that targets in the inflammatory and oxidative cascades hold promise in reducing the incidence and impact of cerebral vasospasm.

Cervical spinal cord stimulation in cerebral ischemia.

Spinal cord stimulation (SCS) is a well established therapy in the treatment for chronic pain. SCS has also been shown to increase peripheral blood flow and is now an accepted treatment in the management of ischemic limb pain and angina. There is a growing body of evidence that cervical spinal cord stimulation also increases cerebral blood flow (CBF) in both animal and human models. SCS could potentially impact on the treatment of cerebral vasospasm and stroke by an increase in CBEF The utility of SCS is also being explored in novel applications such as adjunctive tumor therapy, where resistance to therapy conferred by tissue hypoxia may be ameliorated by CBF augmentation.

Parameters influencing augmentation of cerebral blood flow by cervical spinal cord stimulation.

BACKGROUND: Cervical spinal cord stimulation (SCS) has been shown to augment cerebral blood flow (CBF) and protect the brain from focal ischemia. However, the application of SCS in the treatment of cerebral ischemia requires a better understanding of the limits of the cerebrovascular effect and the optimal stimulation parameters. In the present study, we investigated the effects of various stimulation parameters on CBF augmentation, as well as the issue of tachyphylaxis of the CBF response. METHODS: SCS was performed in adult Sprague Dawley rats, and CBF was assessed using cortical laser Doppler flowmetry (LDF). In separate experimental series, stimulation amplitude, frequency, and pulse width were varied, and the effect on the LDF response was recorded. Finally, using the stimulation parameters found to elicit the strongest LDF response, we examined the effect of lengthening the period of SCS. FINDINGS: SCS elicited a robust increase in cortical LDF values as previously demonstrated. The magnitude of the response varied in a dose-dependent fashion with the stimulation amplitude. LDF values increased by more than 80% over baseline with an amplitude of 1.5 mA. The optimal pulse width and frequency of the stimulation were 0.25 ms and 50 Hz, respectively. Lengthening the stimulation period up to 20 minutes resulted in a persistent increase in cerebral LDF values during the entire stimulation period, although the magnitude of this effect diminished to approximately 50% over the baseline after 10 minutes. CONCLUSIONS: SCS elicits a robust augmentation in CBF, which lasts the entire stimulation duration. Stimulation parameters required for optimal cerebrovascular response are within normally used therapeutic ranges in the clinical settings. These results provide further evidence that SCS may provide a novel therapeutic strategy for the treatment of cerebral ischemia.

Vagus nerve stimulation reduces daytime sleepiness in epilepsy patients.

BACKGROUND: Given that vagal afferents project to brainstem regions that promote alertness, the authors tested the hypothesis that vagus nerve stimulation (VNS) would improve daytime sleepiness in patients with epilepsy. METHODS: Sixteen subjects with medically refractory seizures underwent polysomnography and multiple sleep latency tests (MSLT) and completed the Epworth Sleepiness Scale (ESS), a measure of subjective daytime sleepiness, before and after 3 months of VNS. Most subjects (>80%) were maintained on constant doses of antiepileptic medications. RESULTS: In the 15 subjects who completed baseline and treatment MSLT, the mean sleep latency (MSL) improved from 6.4 +/- 4.1 minutes to 9.8 +/- 5.8 minutes (+/- SD; p = 0.033), indicating reduced daytime sleepiness. All subjects with stimulus intensities of < or =1.5 mA showed improved MSL. In the 16 subjects who completed baseline and treatment ESS, the mean ESS score decreased from 7.2 +/- 4.4 to 5.6 +/- 4.5 points (p = 0.049). Improvements in MSLT and ESS were not correlated with reduction in seizure frequency. Sleep-onset REM periods occurred more frequently in treatment naps as compared to baseline naps (p < 0.008; Cochran-Mantel-Haenszel test). The amount of REM sleep or other sleep stages recorded on overnight polysomnography did not change with VNS treatment. CONCLUSIONS: Treatment with VNS at low stimulus intensities improves daytime sleepiness, even in subjects without reductions in seizure frequency. Daytime REM sleep is enhanced with VNS. These findings support the role of VNS in activating cholinergic and other brain regions that promote alertness.

Effects of vagus nerve stimulation on respiration during sleep: a pilot study.

BACKGROUND: Vagus nerve stimulation (VNS) is associated with respiratory effects such as hoarseness, dyspnea, and laryngeal irritation. The effects of VNS on sleep-related breathing in humans have not been reported previously. METHODS: Four epilepsy patients underwent polysomnography (PSG) before and after 3 months of treatment with VNS. Two of the four patients also underwent follow-up PSG to assess the effects of changing stimulus parameters on sleep-related breathing. RESULTS: All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas. Apneas and hypopneas were more frequent during VNS activation than during nonactivation. Apnea-hypopnea index (AHI) for three subjects during VNS treatment PSG was <5 apneas and hypopneas/hour. In one patient with obstructive sleep apnea (OSA) before VNS treatment, AHI rose from 4 (pretreatment) to 11.3 (treatment). In this patient and in another patient without clinically significant OSA, lowering stimulus frequency, but not stimulus intensity, pulse width, or on-time, ameliorated VNS-related apneas and hypopneas. CONCLUSIONS: VNS is associated with adverse changes in respiration during sleep. In patients without preexisting OSA, this VNS effect is probably not clinically significant. In patients with preexisting OSA, VNS should be administered with care. Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA.

Effects of cervical spinal cord stimulation on cerebral blood flow in the rat.

OBJECT: Spinal cord stimulation (SCS) is frequently used for the treatment of chronic pain. Although the mechanisms by which SCS alleviates pain are unclear, they are believed to involve changes within the dorsal horn of the spinal cord. Spinal cord stimulation has also been found to cause significant vasodilation in the peripheral vasculature. The mechanisms underlying this effect are thought to involve sympathetic blockade. A rostral vasodilatory effect has also been described, but changes in cerebral blood flow (CBF) have been poorly delineated. Using laser Doppler flowmetry (LDF), the authors examined the effects of cervical SCS on CBF in rats. METHODS: Cervical SCS was found to result in a significant increase in cortical LDF values (83 +/- 11% [mean +/- standard error of the mean]). The increase in cortical LDF values was not accompanied by a significant increase in systemic blood pressure. Stimulation of the upper cervical spinal cord was more effective in inducing LDF changes than was that of the lower cervical cord. Changes in SDS-induced LDF values were significantly attenuated after spinal cord transection at the cervicomedullary junction and by the administration of the sympathetic blocker hexamethonium. CONCLUSIONS: These results indicate that cervical SCS may induce cerebral vasodilation and that this effect may involve indirect effects on vasomotor centers in the brainstem as well as an alteration in sympathetic tone.

Aseptic meningitis caused by Teflon implantation for microvascular decompression. Case report.

The authors present the case of a 47-year-old man who, after undergoing microvascular decompression for trigeminal neuralgia, experienced symptomatic pain relief but developed prolonged aseptic meningitis. This case is unusual in that the patient remained dependent on steroid medications for nearly 5 months following the initial surgery and the aseptic meningitis did not resolve until after surgical removal of the Teflon used to pad the trigeminal nerve. The pathophysiological characteristics of the body's reaction to implanted Teflon are discussed along with the rationale for removing this substance in cases of prolonged intractable aseptic meningitis.

Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: case report.

OBJECTIVE AND IMPORTANCE: The use of chronic intrathecal morphine for the treatment of intractable, nonmalignant pain is becoming more prevalent. A rare but devastating complication of this therapy is the development of spinal cord compression secondary to the formation of intrathecal granulomas. CLINICAL PRESENTATION: We report three cases of intrathecal granuloma formation in the thoracic subarachnoid space, associated with intrathecal morphine pumps. These three patients were receiving high doses of morphine to control their pain (25 mg/d, 28 mg/d, and 45 mg/d, respectively) when they presented with signs and symptoms of thoracic spinal cord compression. Myelography and postmyelographic computed tomography of the spine revealed masses causing spinal cord compression. INTERVENTION: Two patients underwent thoracic laminectomies for resection of these masses, and the other patient had the intrathecal catheter removed. A pathological examination revealed sterile granulomas in the resected masses. CONCLUSION: Intrathecal granulomas are likely to occur with increasing frequency as the use of chronic intrathecal morphine delivery increases in patients with nonmalignant pain. The cause of intrathecal granulomas is unknown, although it is likely that morphine plays a major role in their formation. We think that those patients receiving high doses of morphine are at greater risk for developing this complication.

Induction of hypercontractility in human cerebral arteries by rewarming following hypothermia: a possible role for tyrosine kinase.

Induction of hypothermia is used routinely in neurosurgical and cardiovascular operations to protect the brain from ischemic insult. However, despite a plethora of experimental evidence supporting the use of hypothermia to protect the brain from ischemia, clinical experience using deliberate hypothermia in humans has not shown a convincing benefit. The authors tested the hypothesis that hypothermia and rewarming alter tone in human cerebral vessels and may interfere with cerebral perfusion in the setting of deliberate hypothermia. They examined human cerebral arteries during hypothermia (32 degrees C and 17 degrees C) and during rewarming to delineate the direct effects of cooling and rewarming on cerebrovascular tone. Artery segments obtained from autopsy material and from specimens excised at elective temporal lobectomies were tested in tissue baths using isometric tension measurements. Temperature-induced changes in vascular tone were measured and quantified with respect to contractile responses to serotonin (5-HT; 10(-6) M). Cooling induced mild relaxation in cerebral vessels (-38 +/- 12% 5-HT response in 50 vessels from autopsy specimens, -69 +/- 10% 5-HT response in 51 vessels from lobectomy specimens). On rewarming, vessels contracted significantly beyond their baseline tone (108 +/- 18% 5-HT response in 50 vessels from autopsy specimens, 42 +/- 12% 5-HT response in 51 vessels from lobectomy specimens). Rewarming-induced hypercontractility was inhibited by the tyrosine kinase inhibitor genistein (-5 +/- 7% vs. 70 +/- 23% 5-HT response, genistein vs. control, 14 segments, p < 0.05) and enhanced by the tyrosine phosphatase inhibitor sodium orthovanadate (339 +/- 54% vs. 104 +/- 20% 5-HT response, sodium orthovanadate vs. control, five segments, p < 0.05), indicating a possible role for tyrosine kinase activation in the rewarming-induced contraction.

Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model.

Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin, and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.

Intraoperative chemonucleolysis as an adjunct to lumbar discectomy.

STUDY DESIGN: This is a report of a series of 104 patients who underwent lumbar discectomy and chemonucleolysis at the University of Virginia between 1985 and 1989. OBJECTIVE: The primary objective was to determine the safety of this procedure. A secondary objective was to begin studying its efficacy. SUMMARY OF BACKGROUND DATA: This is the first report on the use of chymopapain during open surgery. METHODS: Patients with low back pain and radicular symptoms not cured with conservative therapy were selected for participation in the study. Intraoperatively, disc spaces were injected with 2 ml of chymopapain. Patients were followed-up for an average of 5 years. Patients were surveyed regarding pain relief, and failures of the procedure were analyzed. RESULTS: Seventy percent of patients reported good or excellent pain relief. Operative failures, characterized by reoperation at the same level, totaled 9.6%. Recurrent disc herniation at the time of reoperation occurred in 4.8%. CONCLUSION: The procedure is safe and the relief of pain was similar to that in other published series. The suggestion is that the rate of recurrent disc herniation is reduced.

The effects of papaverine on phorbol dibutyrate-induced vasoconstriction in brain slice microvessels.

Papaverine (PPV) is a nonspecific vasodilator with widespread clinical uses in the treatment of arterial spasm. It has also been utilized in an attempt to reverse cerebral vasospasm. Recent angiographic results have demonstrated significant reversal of vasospasm in large vessels after selective intra-arterial application of PPV; however, these impressive results lacked good clinical correlation. In this study, phorbol dibutyrate was used to stimulate protein kinase C in an in vitro model of cerebral microvessels. Papaverine was found to elicit a dose-dependent exacerbation of phorbol dibutyrate-induced microvascular constriction in this model system. Because protein kinase C is thought to play a key role in the development of cerebral vasospasm, PPV-induced vasoconstriction represents a potentially important deleterious effect that may not be apparent on angiography. Such a constrictor response may compromise the beneficial vasodilatory effect seen with intra-arterial injection of PPV.

Cerebral microvascular responses to endothelins: the role of ETA receptors.

The regulatory role of endothelins in cerebral microvessels was investigated in a recently developed model system which allows the study of small cerebral vessels in their normal microenvironment. Using brain slices of the rat neocortex, it was shown that the isopeptide endothelin-3 (ET-3) had no effect on cerebral microvessels, while the isopeptide endothelin-1 (ET-1) produced a potent, dose-dependent vasoconstriction. When a recently developed antagonist of ETA receptors (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]; ETant) was administered prior to treatment with ET-1, the vasoconstrictor response to ET-1 was inhibited in a dose-dependent manner. When ETant was administered after the establishment of a constriction by ET-1, the constrictor response to ET-1 was partially reversed, and this effect was weaker than that seen in the pre-treatment paradigm. These findings indicate that constrictor responses to ET-1 in cerebral microvessels are mediated by ETA receptors. Inasmuch as endothelins have been implicated in pathological forms of vasoconstriction in the CNS, the present findings also suggest that endothelin antagonists may be useful in the treatment of cerebral ischemia.

The role of hemolysate in the facilitation of oxyhemoglobin-induced contraction in rabbit basilar arteries.

The importance of factors within hemolysate in modulating oxyhemoglobin (oxyHb)-induced contraction was examined in an in vitro model of rabbit basilar arteries. When the basilar arteries were exposed to purified oxyHb alone, the contractile response observed was significantly weaker than that seen in arteries exposed to hemolysate containing an equal concentration of oxyHb. In order to delineate the nature of the factors within hemolysate that facilitate contraction, hemolysate was fractionated, and various components were tested individually for their ability to elicit this effect. A low-molecular-weight fraction of hemolysate, ranging from 0.5 to 2.0 kD, elicited only a mild contraction. However, when this fraction was combined with purified oxyHb, the contractile response was comparable in magnitude to that of unfractionated hemolysate. These studies confirm that purified oxyHb is capable of inducing contraction in vitro. The data also demonstrate that oxyHb elicits a significantly weaker contraction than does hemolysate. In addition, the results suggest that low-molecular-weight components in hemolysate (in the 0.5- to 2.0-kD range), while incapable of inducing a potent contraction alone, may act in concert with oxyHb to elicit the vasoconstriction seen following subarachnoid hemorrhage.

Fusion with occipital bone for atlantoaxial instability: technical note.

A technique is described of using autologous occipital bone for posterior atlantoaxial fusions. The advantages include the ease of harvest, the lack of postoperative discomfort, and the suitability of occipital bone for the fusion.

Live computerized videomicroscopy of cerebral microvessels in brain slices.

A model system for studying cerebral microvasculature is presented in which submerged in vitro brain slices are examined by computerized videomicroscopy. Brain slices are superfused continuously with artificial cerebrospinal fluid, while blood vessels are monitored using a transmission light microscope with water immersion objectives. The responses to well-characterized vasoactive compounds indicate that basic physiological characteristics are maintained in this preparation. This model system represents a simple and rapid technique for studying cerebrovascular responses under conditions in which vessels are surrounded by their normal cellular microenvironment. An additional advantage of this technique is the ability to perform simultaneous electrophysiological recordings in identified neurons. This will facilitate the study of interactions between neuronal and vascular elements and may help elucidate mechanisms underlying the local regulation of cerebral microvasculature.