Patternable nanowire sensors for electrochemical recording of dopamine.

Spatially resolved electrochemical recording of neurochemicals is difficult due to the challenges associated with producing nanometer-scale patternable and integrated sensors. We describe the lithographic fabrication and characterization of patternable gold (Au) nanowire (NW) based sensors for the electrochemical recording of dopamine (DA). We demonstrate a straightforward NW-size-independent approach to align contact pads to NWs. Sensors, with NW widths as small as 30 nm, exhibited considerable insensitivity to scan rates during cyclic voltammetry, a nonlinear increase in oxidation current with increasing NW width, and the selectivity to measure submaximal synaptic concentrations of DA in the presence of interfering ascorbic acid. The electrochemical sensitivity of Au NW electrode sensors was much larger than that of Au thin-film electrodes. In chronoamperometric measurements, the NW sensors were found to be sensitive for submicromolar concentration of DA. Hence, the patternable NW sensors represent an attractive platform for electrochemical sensing and recording.

Reversal of transtentorial herniation with hypertonic saline.

OBJECTIVE: To evaluate the role of 23.4% saline in the management of transtentorial herniation (TTH) in patients with supratentorial lesions. METHODS: Consecutive patients with clinically defined TTH treated with 23.4% saline (30 to 60 mL) were included in a retrospective cohort. Factors associated with successful reversal of TTH were determined. RESULTS: Seventy-six TTH events occurred in 68 patients admitted with intracerebral hemorrhage (n = 29), subarachnoid hemorrhage (n = 16), stroke (n = 8), brain tumor (n = 8), subdural hematoma (n = 5), epidural hematoma (n = 1), and meningitis (n = 1). In addition to 23.4% saline, TTH management included hyperventilation (70% of events), mannitol (57%), propofol (62%), pentobarbital (15%), ventriculostomy drainage (27%), and decompressive hemicraniectomy (18%). Reversal of TTH occurred in 57/76 events (75%). Intracranial pressure decreased from 23 +/- 16 mm Hg at the time of TTH to 14 +/- 10 mm Hg at 1 hour (p = 0.002), and 11 +/- 12 mm Hg at 24 hours (p = 0.001) among 22 patients with intracranial pressure monitors. Reversal of TTH was predicted by a >/=5 mmol/L rise in serum sodium concentration (p = 0.001) or an absolute serum sodium of >/=145 mmol/L (p = 0.007) 1 hour after 23.4% saline. Adverse effects included transient hypotension in 13 events (17%); no evidence of central pontine myelinolysis was detected on post-herniation MRI (n = 18). Twenty-two patients (32%) survived to discharge, with severe disability in 17 and mild to moderate disability in 5. CONCLUSION: Treatment with 23.4% saline was associated with rapid reversal of transtentorial herniation (TTH) and reduced intracranial pressure, and had few adverse effects. Outcomes of TTH were poor, but medical reversal may extend the window for adjunctive treatments.

Effect of age on cerebral blood flow velocity and incidence of vasospasm after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Current transcranial Doppler criteria for vasospasm after aneurysmal subarachnoid hemorrhage are not age specific. We analyzed the effect of age on cerebral blood flow velocity changes after subarachnoid hemorrhage and constructed an age-adjusted predictive model of cerebral blood flow velocity in subarachnoid hemorrhage patients. METHODS: We identified patients with aneurysmal subarachnoid hemorrhage admitted between 1991 and 1999 with a prospective transcranial Doppler database. Eighty-one patients, with complete medical records and transcranial Doppler examinations of the vessels of interest, were included. Patients were subdivided into 2 groups by age: younger, <68 years of age (n=47) and older, >/=68 years of age (n=34). Maximum mean flow velocity and incidence of symptomatic vasospasm were reported. Linear and nonlinear regression analyses were performed. RESULTS: Middle cerebral artery and internal carotid artery mean flow velocity were lower in older patients (median 76 versus 114 cm/s and 76 versus 126 cm/s, respectively; P<0.003). Incidence of symptomatic vasospasm was lower in older patients (44% versus 66%; P=0.05). Older patients developed symptomatic vasospasm at lower middle cerebral artery (median 57 versus 103 cm/s; P=0.04) and internal carotid artery (median 54 versus 81 cm/s, P=0.02) mean flow velocity. Relationship between middle cerebral artery and internal carotid artery mean flow velocity and age was quadratic (ANOVA, P<0.0001). CONCLUSIONS: Older patients have a lower incidence of symptomatic vasospasm, and such vasospasm develops at lower cerebral blood flow velocity than younger patients. A quadratic relationship was found between age and cerebral blood flow velocity. This model could be used to create an age-adjusted nomogram that might improve diagnostic capabilities of transcranial Doppler.

Seizures in the adult intensive care unit.

Seizures are a common occurrence in the intensive care unit (ICU). The presentation of seizures is usually as focal or generalized motor convulsions, but other seizure types may occur. Etiologies of the seizures are typically secondary either to primary neurologic pathology or a consequence of critical illness and clinical management. Particularly important as precipitants of seizures are hypoxia/ischemia, drug toxicity, and metabolic abnormalities. It is important to properly diagnose the seizure type and its cause to ensure appropriate therapy. Most seizures occur singly, and recurrence is usually prevented with initiation of anticonvulsant therapy. However, status epilepticus may develop, which requires emergent treatment before irreversible brain injury occurs. Treatment with anticonvulsants is not without untoward risks, however, and primary toxicities of these agents is reviewed. After traumatic head injury, brain surgery, or cerebrovascular accidents, many patients are at risk for seizures. Current data on the benefits of prophylactic therapy for such patients is also reviewed.

Impact of a neuroscience intensive care unit on neurosurgical patient outcomes and cost of care: evidence-based support for an intensivist-directed specialty ICU model of care.

Analysis of patient data from a new neuroscience intensive care unit (NSICU) permitted evaluation of whether such a specialty ICU favorably altered clinical outcomes in critically ill neuroscience patients, and whether such a care model produced an efficient use of resources. A retrospective review was performed to compare (1) the clinical outcomes, as defined by percent mortality and disposition at discharge, between patients with a primary diagnosis of intracerebral hemorrhage treated in 1995 in medical or surgical ICUs and those treated in the same medical facility in an NSICU in 1997; and (2) the efficiency of care, as defined by length of ICU stay, total cost of care, and specific resource use, between patients treated in the NSICU and national benchmark standards for general ICUs during the 1997 fiscal year (FY). In the latter, extracted patient population data on neurosurgery patients requiring ICU treatment during FY 1997 were used with the following adjacent-disease related group (A-DRG)-coded diseases: craniotomy with and without coma or intracerebral hemorrhage, and skull fracture with and without coma lasting longer than 1 hour. Outcome measures of percent mortality and disposition at discharge in patients with intracerebral hemorrhage were significantly improved (P < .05), compared with those in a similar cohort treated 2 years earlier in a general ICU setting. Also, patients treated in the NSICU had shorter hospital stays (P < .01 ) and lower total costs of care (P < .01) than a national benchmark. The data suggest that a neuroscience specialty ICU arena staffed by specialty-trained intensivists and nurses is beneficial.

Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat.

Evidence suggests that a specific subcortical pathway synaptically linking the anterior thalamic nuclear complex (AN) to the hypothalamus and midbrain is important in the expression of pentylenetetrazol (PTZ) seizures. Perturbation of neuronal activity along this path via focal disruption or chemical inhibition significantly raises seizure threshold. Recent data has demonstrated that focal electrical stimulation within the hypothalamic component of this pathway inhibited seizure expression in a current and frequency dependent fashion. Similar experiments were conducted in the AN to investigate the hypothesis that stimulation of this thalamic nuclear region can prevent the propagation of PTZ seizures between cortical and subcortical regions. Our results indicate that high frequency (100 Hz) stimulation of AN did not alter the expression of low dose PTZ induced cortical bursting but did raise the clonic seizure threshold compared to naive animals or those stimulated at sites near, but not in AN (P < 0.01). Low frequency stimulation (8 Hz) was in contrast, proconvulsant and could induce behavioral arrest responses accompanied by rhythmic high voltage EEG even without PTZ challenge. This data further highlights the role of AN in mediating the expression of seizures and provides experimental support for the concept that this thalamic region may be a promising target for focal stimulation to treat intractable seizures in humans.

Spectral analysis of a thalamus-to-cortex seizure pathway.

Physiological evidence has shown that the anterior thalamus (AN) and its associated efferents/afferents constitute an important propagation pathway for one animal model of generalized tonic-clonic epileptic seizures. In this study we extend and confirm the support for AN's role by examining neuroelectric signal indicators during seizure episodes. We show that the electroencephalogram (EEG) recorded from AN is highly coherent with the EEG derived from the cortex (CTX). By removing the effects of another thalamic nucleus, posterior thalamus (PT)-unaffiliated with the tract linking AN to cortex-partial coherence analysis leaves the CTX/AN coherence undiminished. The most robust band of strong CTX-AN coherence is centered around the spike-wave pacing frequency of 1-3 Hz. Partial-multiple coherence analysis techniques are used to remove the possible signal contribution from hippocampus in addition to PT. The CTX-AN coherence still remains undiminished in the low-frequency bands. Conclusive evidence from coherence studies and other spectral measures reaffirm the special role of the AN in the propagation of seizure activity from subcortex to cortex.

Sedation for the critically ill neurologic patient.

OBJECTIVE: To review the scientific basis for sedation of critically ill neurologic patients by summarizing the distinct neurophysiologic disturbances present in this population and presenting the central nervous system effects of sedative agents to permit optimal drug therapy. DATA SOURCES: Review of the English language clinical and scientific literature using MEDline data search. STUDY SELECTION: Literature references were selected through a key word search of sedative therapy, drugs used for sedation, and specific neurologic disorders and processes to provide an in-depth overview of sedative drug mechanisms of action, effects on neurophysiology and intracranial dynamics, pharmacokinetics, and toxicity profile. Special emphasis was placed on neurologic side effects. DATA EXTRACTION: Clinical and scientific literature was reviewed and data relevant to neurophysiologic effects of sedative drug therapy were summarized. Recommendations for institution of sedative therapy and of particular agents were made as a result of analysis of all pooled data. DATA SYNTHESIS: Critically ill patients with neurologic pathology present as a unique subset of individuals cared for in an acute care setting. Because monitoring of neurologic patients requires frequent assessment of the neurologic examination, the goal of sedative therapy should be to enhance, or to minimally perturb elicitation of the examination. Neurophysiologic disturbances introduce distinct risks for sedation and require their identification and understanding before the initiation of any sedative therapy. Sedative drugs, in particular, act to disturb central nervous system function and their effects may result in diagnostic confusion and further neurologic deterioration. The pharmacokinetic and neurophysiologic actions of the common classes of sedative agents, such as benzodiazepines, opioids, barbiturates, and neuroleptics, as well as ketamine, propofol, and clonidine are discussed. Recommendations are presented based on the specific type of sedation required and the underlying neurologic disturbance. Several specific examples, including head trauma, neuromuscular disease, and alcohol withdrawal, are provided. CONCLUSIONS: Preservation of the neurologic examination is paramount in documenting clinical improvement or deterioration in the critically ill neurologic patient. Pharmacologic sedation in this unique population of acute care patients requires careful consideration of the underlying neurophysiologic disturbances and potential adverse effects introduced by sedative drugs.

Dexmedetomidine decreases seizure threshold in a rat model of experimental generalized epilepsy.

BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha 2 agonist with marked sedative and analgesic properties thought to be mediated via reduction of central noradrenergic transmission. Because an anticonvulsant effect is associated with increased noradrenergic activity, we investigated the possible proconvulsant effects of DEX in an experimental model of generalized seizures. METHODS: Male rats (n = 82) were administered 0.9% saline as placebo (n = 18) or pretreatment drug(s) before initiation of an infusion of pentylenetetrazol (PTZ) at 5.5 mg.kg-1.min-1. The total dose of PTZ required to elicit electroencephalographic (EEG) and behavioral seizure activity was assessed. Blood samples were obtained 15 min after initiation of infusion (82.5 mg/kg) for determination of serum PTZ concentrations by gas chromatography. Pretreatment drug groups included DEX (20 micrograms/kg [n = 11], 100 micrograms/kg [n = 14], and 500 micrograms/kg [n = 10]); L-medetomidine (500 micrograms/kg [n = 7]); the alpha 2 antagonist atipamezole (500 micrograms/kg [n = 9]); and atipamezole (500 micrograms/kg) before DEX (100 micrograms/kg [n = 7] and 500 micrograms/kg [n = 6]). RESULTS: In control animals, PTZ 25-35 mg/kg induced EEG evidence of epileptiform activity. The mean dose to EEG epileptiform activity and clonic convulsions was 30 +/- 5.8 (SE) and 59 +/- 3.2 mg/kg, respectively. Infusion of DEX at 100 and 500 micrograms/kg resulted in a marked sedative response and reduced the EEG seizure threshold of PTZ to 18 +/- 1.5 and 7 +/- 1.8 mg/kg, respectively (P < 0.05 at both doses). The clonic convulsant threshold also was significantly decreased in both groups, to 37 +/- 3.2 and 28 +/- 2.3 mg/kg (P < 0.01 at each dose). Before clonic convulsion, a significantly greater number of motor seizure manifestations were scored in the DEX-treated animals at all three dose levels compared with the number scored in control animals. The proconvulsant action of DEX was not a result of alteration of PTZ kinetics, because serum concentrations did not differ between control and DEX-treated animals. Animals treated with L-medetomidine demonstrated more paroxysmal motor phenomena before clonic seizures than controls (P < 0.01) although the clonic seizure threshold was not altered. Atipamezole alone did not alter background EEG, nor did it affect the clonic convulsant threshold. Atipamezole did, however, block the proconvulsant behavioral action at both doses of DEX, raising clonic seizure threshold from 37 +/- 3.2 to 59 +/- 5.8 mg/kg (100 micrograms/kg DEX, P < 0.05) and from 28 +/- 2.3 to 59 +/- 6.9 mg/kg (500 micrograms/kg DEX, P < 0.01). CONCLUSIONS: DEX exerted a significant proconvulsant action in the PTZ experimental seizure model. The pharmacodynamic effect was dose-dependent and stereospecific and was blocked by the selective alpha 2-receptor antagonist atipamezole. These data are consistent with previous data demonstrating that inhibition of central noradrenergic transmission facilitates seizure expression. Further evaluation of DEX for possible clinical proconvulsant effects may be warranted.

Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats.

High-frequency electrical stimulation of mammillary nuclei (MN) of rat posterior hypothalamus resulted in a significant increase in seizure threshold induced by pentylenetetrazol (PTZ). The anticonvulsant effect was frequency and intensity specific. Stimulation at 100 Hz (1-5 V, 30-200 microA) afforded protection against EEG and behavioral manifestations of PTZ seizures. Stimulation of either low frequency (5 Hz), high intensities (8-20 V, 300-800 microA), or outside the histologically verified MN target region did not increase seizure threshold. In some instances, high-intensity stimulation of MN alone elicited spike-wave epileptiform EEG activity accompanied by either arrest of behavior or myoclonic seizures. In animals with ongoing seizure activity, electrical stimulation of MN disrupted the high-voltage synchronous wave forms on cortical EEG. These data support the concept that electrical perturbation of MN in hypothalamus may functionally inhibit generalization of paroxysmal activity required for expression of the EEG and, in particular, the behavioral component of PTZ seizures. These studies provide additional insight into forebrain-brainstem interactions mediating generalized seizure expression.

Interruption of the connections of the mammillary bodies protects against generalized pentylenetetrazol seizures in guinea pigs.

Electrolytic lesions in the anterior and mid-diencephalon and ventral midbrain in guinea pigs were produced to examine the effects of interruption of the fornix (FX), mammillothalamic tracts (MT), and mammillary peduncles (MP), respectively, on the expression of pentylenetetrazol (PTZ) seizures. As a group, all mid-diencephalic lesioned animals had some degree of protection from the electroencephalographic and behavioral convulsant and lethal effects of the drug. Through a composite volume analysis of protected versus unprotected animals, as well as a retrospective comparison between MT and non-MT lesioned animals, it was demonstrated that small mid-diencephalic lesions incorporating only the MTs and their immediate vicinity were capable of completely preventing the convulsant and lethal effects of PTZ. Lesions of the FX and MP were also protective against PTZ seizures but to a lesser degree than the MT lesions. These results demonstrate that the major afferent and efferent connections of the mammillary bodies are involved in expressing PTZ seizure activity and suggest that the MT may be the major pathway mediating paroxysmal activity from brain stem to the thalamus.

Anterior thalamic mediation of generalized pentylenetetrazol seizures.

The effects of microinjection of various neuroactive compounds into the anterior thalamic nucleus (AN) and other selected subcortical regions of guinea pig brain on the expression of pentylenetetrazol (PTZ)-induced behavioral and electrical seizure activity were examined. Excitatory agents, kainic acid (KA), bicuculline (BIC) or PTZ, injected into the AN or other thalamic nuclei, striatum, but not the mammillary bodies (MB), facilitated the EEG convulsant action of systemically administered PTZ. Injection of muscimol into the AN protected against the expression of PTZ-induced repetitive high-voltage EEG seizure discharges and inhibited the facilitatory effects of subcortically applied KA or BIC. Injection of muscimol into the AN was also able to terminate established ongoing seizure discharges. Unilateral application of muscimol to the AN did not prevent the repetitive hypersynchronous EEG discharges following systemic PTZ but did result in the delay in the onset of cortical hypersynchrony in the ipsilateral hemisphere. Muscimol injections into other thalamic nuclei, MB, cortex, striatum or directly into the CSF space had no anticonvulsant effect, however. Microinjection of gamma-vinyl-gamma-aminobutyric acid, a selective GABA transaminase inhibitor, resulted in protection from the behavioral convulsant action and lethal effects of PTZ when administered into the thalamus, especially the AN, but not when injected into the striatum or CSF. These data demonstrate that the AN is an important subcortical nucleus for the mediation of both cortical EEG synchrony and behavioral seizure expression induced by PTZ. In light of previous results establishing a role for the brainstem and diencephalon in PTZ seizure expression, the AN may serve, in part, as a gating mechanism for the propagation of paroxysmal activity between subcortical areas and the cerebral cortex.

Anterior thalamus and substantia nigra: two distinct structures mediating experimental generalized seizures.

Injection of gamma-vinyl aminobutyric acid (GVG) into the anterior thalamus protected rats against pentylenetetrazol (PTZ) seizures but not against maximal electroshock (MES) seizures. Injection of GVG into the substantia nigra protected against MES seizures but not against PTZ seizures. Both types of seizures were prevented by injections into both of the above brain regions. These data indicate that separate neuronal circuits mediate PTZ and MES seizures.

Selective metabolic activation of the mammillary bodies and their connections during ethosuximide-induced suppression of pentylenetetrazol seizures.

Electroencephalographic (EEG) activity and regional [14C]2-deoxyglucose incorporation in brain were examined in guinea pigs treated with pentylenetetrazol (PTZ), ethosuximide (ESM), phenytoin (PHT), or combinations of these drugs. Convulsant doses of PTZ induced EEG epileptiform discharges in paralyzed and ventilated animals and resulted in a large increase in labeled glucose accumulation in essentially all brain areas. ESM alone depressed EEG activity and accumulation of label, whereas PHT alone had little or no effect. Autoradiographs of PTZ-infused animals pretreated with PHT, which facilitated the onset and increased the severity of the PTZ seizures, were similar to those of animals treated with convulsant alone, with additional label uptake in the globus pallidus and substantia nigra. Pretreatment of PTZ-infused animals with sufficient ESM to prevent most EEG spike activity reduced glucose incorporation in most brain regions, but increased it in some. Selective enhancement of label uptake was observed in the mammillary bodies, mammillothalamic tracts, the anterior nuclei of the thalamus, the mammillary peduncles, and the dorsal and ventral tegmental nuclei of the midbrain. These data suggest that the mammillary nuclei and their projections to the anterior thalamic nucleus and their reciprocal projections to and from the tegmental nuclei may be important in the mediation of seizure activity induced by PTZ and/or the anticonvulsant action of ESM.

Interruption of the mammillothalamic tract prevents seizures in guinea pigs.

Interruption of the connection between the mammillary bodies and the anterior nucleus of the thalamus in guinea pigs, by discrete bilateral electrolytic lesions of the mammillothalamic tract, resulted in essentially complete protection from the behavioral and electroencephalographic convulsant action and lethal effect of pentylenetetrazol. This result demonstrates that the mammillary bodies and their rostral efferent connections are important for the propagation and perhaps initiation of generalized seizures.

Immunoreactive neurotensin levels in pancreas: elevation in diabetic rats and mice.

Neurotensin levels in pancreas, but not other tissues, were increased in diabetic animals. The concentration of pancreatic immunoreactiveneurotensin was 138% higher in streptozotocin-diabetic rats, and 68% higher in genetically diabetic (db/db) mice as compared to their respective control animals. Daily administration of insulin (10-15 IU/kg) to diabetic rats completely reversed this effect, and pancreatic neurotensin levels in these animals returned to control values. These findings suggest that elevated levels of pancreatic neurotensin may contribute to some of the metabolic and hormonal disturbances occurring in diabetes.

DNA binding and unwinding activities associated with intracytoplasmic a particles isolated from mouse mammary tumors.

Intracytoplasmic A particles (CAP), previously identified as probably cytoplasmic nucleocapsid precursor structures to mouse mammary tumour virus (MMTV), possess both DNA binding and DNA unwinding activities, CAP proteins bind to both single-stranded (ss)- and double-stranded (ds)DNA, with the ssDNA slightly preferred. This activity was linear over a 30-fold concentration of A particle protein and was not affected by NaCl concentrations as high as 0.6 M or pH changes over a wide range. DNA binding by CAP proteins was sensitive to heat or addition of sodium dodecyl sulphate (SDS) and was neutralized by pre-incubation of CAP with anti-MMTV p14, but not by anti-MMTV p27, p10 or anti-mouse casein. Incubation of CAP with dsDNA led to unwinding of the double helix as measured by its increased sensitivity to S1 nuclease digestion. This activity was also linear over a several-fold concentration of A particle protein and was heat labile. It was not inhibited by pre-incubation of CAP with either anti-MMTV p14 or with anti-MMTV, anti-MMTV p27 and anti-MMTV p10. DNA unwinding was inhibited by anti-A particle antiserum and to a lesser extent by anti-CAP p20-18.