Transabdominal motor evoked potential neuromonitoring of lumbosacral spine surgery.

BACKGROUND CONTEXT: Transcranial Motor Evoked Potentials (TcMEPs) can improve intraoperative detection of femoral plexus and nerve root injury during lumbosacral spine surgery. However, even under ideal conditions, TcMEPs are not completely free of false-positive alerts due to the immobilizing effect of general anesthetics, especially in the proximal musculature. The application of transcutaneous stimulation to activate ventral nerve roots directly at the level of the conus medularis (bypassing the brain and spinal cord) has emerged as a method to potentially monitor the motor component of the femoral plexus and lumbosacral nerves free from the blunting effects of general anesthesia. PURPOSE: To evaluate the reliability and efficacy of transabdominal motor evoked potentials (TaMEPs) compared to TcMEPs during lumbosacral spine procedures. DESIGN: We present the findings of a single-center 12-month retrospective experience of all lumbosacral spine surgeries utilizing multimodality intraoperative neuromonitoring (IONM) consisting of TcMEPs, TaMEPs, somatosensory evoked potentials (SSEPs), electromyography (EMG), and electroencephalography. PATIENT SAMPLE: Two hundred and twenty patients having one, or a combination of lumbosacral spine procedures, including anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), posterior spinal fusion (PSF), and/or transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES: Intraoperative neuromonitoring data was correlated to immediate post-operative neurologic examinations and chart review. METHODS: Baseline reliability, false positive rate, true positive rate, false negative rate, area under the curve at baseline and at alerts, and detection of pre-operative deficits of TcMEPs and TaMEPs were compared and analyzed for statistical significance. The relationship between transcutaneous stimulation voltage level and patient BMI was also examined. RESULTS: TaMEPs were significantly more reliable than TcMEPs in all muscles except abductor hallucis. Of the 27 false positive alerts, 24 were TcMEPs alone, and 3 were TaMEPs alone. Of the 19 true positives, none were detected by TcMEPs alone, 3 were detected by TaMEPs alone (TcMEPs were not present), and the remaining 16 true positives involved TaMEPs and TcMEPs. TaMEPs had a significantly larger area under the curve (AUC) at baseline than TcMEPs in all muscles except abductor hallucis. The percent decrease in TcMEP and TaMEP AUC during LLIF alerts was not significantly different. Both TcMEPs and TaMEPs reflected three pre-existing motor deficits. Patient BMI and TaMEP stimulation intensity were found to be moderately positively correlated. CONCLUSIONS: These findings demonstrate the high reliability and predictability of TaMEPs and the potential added value when TaMEPs are incorporated into multimodality IONM during lumbosacral spine surgery.

Intraoperative transabdominal MEPs: four case reports.

Four recent cases utilizing transabdominal motor-evoked potentials (TaMEPs) are presented as illustrative of the monitoring technique during lumbosacral fusion, sciatic nerve tumor resection, cauda equina tumor resection, and lumbar decompression. Case 1: In a high-grade lumbosacral spondylolisthesis revision fusion, both transcranial motor-evoked potentials (TcMEPs) and TaMEPs detected a transient focal loss of left tibialis anterior response in conjunction with L5 nerve root decompression. Case 2: In a sciatic nerve tumor resection, TcMEPs responses were lost but TaMEPs remained unchanged, the patient was neurologically intact postoperatively. Case 3: TaMEPs were acquired during an L1-L3 intradural extramedullary cauda equina tumor resection utilizing a unique TaMEP stimulation electrode. Case 4: TaMEPs were successfully acquired with little anesthetic fade utilizing an anesthetic regimen of 1.1 MAC Sevoflurane during a lumbar decompression. While the first two cases present TaMEPs and TcMEPs side-by-side, demonstrating TaMEPs correlating to TcMEPs (Case 1) or a more accurate reflection of patient outcome (Case 2), no inference regarding the accuracy of TaMEPs to monitor nerve elements during cauda equina surgery (Cases 3) or the lumbar decompression presented in Case 4 should be made as these are demonstrations of technique, not utility.

Misconceptions in IONM Part III: Stimulation Repetition Rate Effects on Intraoperative Somatosensory Evoked Potential Amplitude and Latency.

The rate at which stimulation is applied to peripheral nerves is critical to generating high-quality intraoperative somatosensory evoked potentials (SSEPs) in a timely manner. Guidelines based on a limited study and anecdotal evidence present differing, incorrect, or incomplete stimulation rate recommendations. We examined the effect stimulating the ulnar and tibial nerves at 1.05, 2.79, 5.69, and 8.44 Hz had on cortical, subcortical, and peripheral response amplitude and latency in 10 subjects with neuromuscular blockade (NMB) and 10 without NMB in the operating room under general anesthesia. As the stimulation repetition rate increased, the amplitude of upper and lower extremity cortical responses decreased equally in both groups. The ulnar nerve N20 cortical response amplitude decreased 27.9% at 2.79 Hz, 48.8% at 5.69 Hz, and 53.8% at 8.44 Hz. The tibial nerve P37 cortical response amplitude decreased 30.3% at 2.79 Hz, 53.8% at 5.69 Hz, and 56.8% at 8.44 Hz. Neither upper or lower extremity peripheral or subcortical amplitudes nor upper and lower extremity subcortical or peripheral latencies were affected by increasing repetition rate in either group. Low SSEP stimulation repetition rates ensure the highest quality cortical responses.

Misconceptions in IONM Part II: Does Anodal Blocking Occur and Is Bipolar Stimulation Necessary with Intraoperative Somatosensory Evoked Potentials?

Current intraoperative somatosensory evoked potential (SSEP) guidelines recommend bipolar stimulation with the anode at or near the crease of the wrist and the cathode 2-4 cm proximal to the anode for median nerve SSEPs. The rationale for this cathode proximal bipolar configuration appears to be the avoidance of anodal blocking; however, there is a paucity of experimental support for the existence of anodal blocking. Evidence that bipolar stimulation preferentially drives stimulation from the cathode better than monopolar cathodal or monopolar anodal in peripheral nerves in human neurophysiology is also lacking. This study compared anode proximal to anode distal bipolar stimulation of median nerve SSEPs and the efficacy of monopolar cathode to monopolar anode stimulation in generating median, ulnar, and tibial nerve SSEPs. No difference in median nerve cortical SSEP amplitude was observed between anode proximal and anode distal bipolar stimulation at supramaximal stimulation suggesting cathode proximal bipolar is equal to anode proximal bipolar stimulation at supramaximal intensity. This data suggests that anodal blocking does not occur in intraoperative SSEPs. Furthermore, no differences were observed in ulnar, median, and tibial nerve SSEP cortical or subcortical amplitudes and latencies between monopolar cathodal or monopolar anodal stimulation suggesting monopolar cathode and anode stimulation are equally effective at evincing intraoperative SSEPs at supramaximal intensity.

Misconceptions in IONM Part I: Interleaved Intraoperative Somatosensory Evoked Potential Stimulation.

A misconception in the field of intraoperative neurophysiological monitoring (IONM) is that continuous, multi-nerve (four-limb), interleaved somatosensory evoked potential (SSEP) stimulation, while advantageous, is not universally utilized due to variety of misunderstandings regarding this approach to SSEP stimulation. This article addresses the rationale for this misconception. We find that continuous, multi-nerve, interleaved SSEP stimulation is superior to all other stimulation paradigms in most operative scenarios, allowing the fastest acquisition of SSEPs at low stimulation repetition rates, which generate the highest amplitude cortical responses.

Lateral mass screw stimulation thresholds in posterior cervical instrumentation surgery: a predictor of medial deviation.

OBJECTIVE Normative data exists for stimulus-evoked pedicle screw electromyography (EMG) current thresholds in the lumbar spine, and is routinely referenced during spine surgeries to detect a screw breach, prevent injury of neural elements, and ensure the most biomechanically sound instrumentation construct. To date, similar normative data for cervical lateral mass screws is limited, thus the utility of lateral mass screw testing remains unclear. To address this disparity, in this study the authors describe cumulative lateral mass screw stimulation threshold data in patients undergoing posterior cervical instrumentation with lateral mass screws. These data are correlated with screw placement on postoperative imaging, and a novel correlation is discovered with direct clinical implications. METHODS Using a ball-tip probe, 154 lateral mass screws in 21 patients were electrically tested intraoperatively. In each case, for each screw, the lowest (or threshold) current at which the first polyphasic stimulus-evoked EMG response was reproducibly observed by a neurophysiologist was recorded. All patients underwent postoperative CT. Screw position within the lateral mass was first measured in the axial and sagittal planes for each lateral mass screw using the CT images. Screw placement was also evaluated by 2 independent physicians, blinded to current threshold data, on a binary scale of acceptability. The predictive capacity of screw EMG threshold data was evaluated via multivariable regression analyses and receiver operating characteristic (ROC) analyses. Predictive capacity was examined with respect to screw position within the lateral mass, as well as screw acceptability. RESULTS Lateral mass screw EMG thresholds did not appear to differ significantly for screws considered "acceptable" versus "unacceptable" according to the radiographic criteria. Accordingly, ROC analysis confirmed that EMG current threshold data were of minimal utility in predicting screw radiographic acceptability. However, EMG threshold was significantly predictive of screw medial distance from the spinal canal. A screw stimulating below 7.5 mA correctly identified a screw as being within 2 mm of the spinal canal with 75% sensitivity and 92% specificity (positive predictive value 20%, negative predictive value 99.3%), independent of its distance relative to other lateral mass landmarks. EMG current threshold was not significantly predictive of screw deviation in the superior or inferior directions, and was inversely predictive of screw deviations in the lateral direction. CONCLUSIONS In the context of uncertainty regarding the utility of cervical lateral mass EMG current threshold data, this study found that EMG current thresholds correspond significantly, and exclusively, with screw distance from the spinal canal. This association appears independent of other criteria for screw misplacement. As such, the authors recommend that EMG current thresholds be referenced in the case of a suspected medial breach as an effective means to rule out screw placement too medial to the spinal canal.

Use of Posterior Root-Muscle Reflexes in Peripheral Nerve Surgery: A Case Report.

It is well established that a mixed-agent general anesthetic regimen of volatile gas and intravenous anesthetic or total intravenous anesthetic (TIVA) is required to obtain adequate transcranial motor-evoked potentials (TcMEPs) to detect and hopefully prevent injury during brain, spinal cord, and peripheral nerve surgery. But even under ideal general anesthetic conditions, TcMEPs are not always detectable in every muscle monitored, and are prone to anesthetic fade, especially when neuropathic or injured tissue is monitored. TcMEP sensitivity to general anesthesia can be especially problematic during peripheral nerve surgery where there is often only one or a few essential muscles required to provide adequate monitoring; thus, maximum fidelity is essential. However, there is an anesthetic-resistant high-fidelity modality available to successfully monitor the motor component of distant peripheral nerves originating from the cauda equina. Percutaneus transabdominal electrical stimulation elicits a relatively anesthetic-resistant, robust motor response in muscles innervated by cauda equina nerve roots. We report the successful use of posterior root-muscle (PRM) reflex to monitor the decompression of the sciatic nerve at its bifurcation in a 22-year-old female with a history of severe sciatic nerve neuropathic pain and muscle weakness following benign thigh tumor resection.

Vasculopathy, Ischemia, and the Lateral Lumbar Interbody Fusion Surgery: Report of Three Cases.

Multi-modal neurophysiologic monitoring consisting of triggered and spontaneous electromyography and transcranial motor-evoked potentials may detect and prevent both acute and slow developing mechanical and vascular nerve injuries in lateral lumbar interbody fusion (LLIF) surgery. In case report 1, a marked reduction in the transcranial motor-evoked potentials on the operative side alerted to a 28% decrease in mean arterial blood pressure in a 54-year-old woman during an L3-4, L4-5 LLIF. After hemodynamic stability was regained, transcranial motor-evoked potentials returned to baseline and the patient suffered no postoperative complications. In case report 2, a peroneal nerve train-of-four stimulation threshold of 95 mA portended the potential for a triggered electromyography false negative in a 70-year-old woman with type 2 diabetes, peripheral neuropathy, and body mass index of 30.7 kg/m undergoing an L3-4, L4-5 LLIF. Higher triggered electromyography threshold values were applied to this patient's relatively quiescent triggered electromyography and the patient suffered no postoperative complications. In case report 3, the loss of right quadriceps motor-evoked potentials detected a retractor related nerve injury in a 59-year-old man undergoing an L4-5 LLIF. The surgery was aborted, but the patient suffered persistent postoperative right leg paresthesia and weakness. These reports highlight the sensitivity of peripheral nerve elements to ischemia (particularly in the presence of vascular risk factors) during the LLIF procedure and the need for dynamic multi-modal intraoperative monitoring.

Anesthesia considerations for monitoring TCMEPs in adults diagnosed with poliomyelitis as children: a case report.

UNLABELLED: The use of transcranial motor evoked potentials (TCMEPs) to detect and hopefully prevent injury to the brain, spinal cord, and peripheral nerves intraoperatively has increased greatly in recent years. It is well established that in addition to certain anesthetic agents, patient factors such as advanced age, obesity, diabetes, hypertension, and a collection of neurological and neuromuscular diseases and disorders can greatly reduce or completely eliminate the ability to monitor TCMEPs effectively. One such disease, poliomyelitis (polio), is a highly contagious viral disease that has been mostly forgotten since its near-eradication through vaccination. Over the past three decades there has been increasing recognition of late onset neurological deterioration in individuals who were afflicted by, and apparently recovered from, paralytic poliomyelitis much earlier in life. This condition is known as post-poliomyelitis syndrome (PPS). Patients that appear to have fully recovered from polio, and those with PPS, may require special anesthetic considerations to facilitate effective TCMEP monitoring. CASE REPORT: We report the rapid loss of only lower extremity TCMEPs bilaterally during a C6-C7, C7-T1 ACDF in a 67-year-old female to treat left-sided C7-C8 radiculopathy and C6-T1 foraminal stenosis. The general anesthetic maintenance regimen of 0.3 MAC sevoflurane and 100 microg/kg/min propofol was paused, and a wake-up test was initiated. Full upper and lower extremity motor function was observed. A thorough review of the patient's medical history revealed the potential risk factor of full recovery from poliomyelitis as a child. The sevoflurane was removed from the anesthetic regimen, and the lower extremity TCMEPs returned and were present for the remainder of the surgery.

The role of connexin-36 gap junctions in alcohol intoxication and consumption.

Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol intoxication and consumption. Using behavioral, molecular, and electrophysiological methods, we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls. Compared to WT mice, Cx36 KO mice exhibited significantly more ethanol-induced motor impairment in the open field test, but less disruption in motor coordination in the rotarod paradigm. Cx36 KO mice, and WT mice treated with the Cx36 antagonist mefloquine (MFQ), consumed significantly less ethanol than their WT controls in the drink-in-the-dark procedure. The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC50 of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol. Dopamine neuron GABA-mediated sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice. Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR. These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption.

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions.

Connexin-36 (Cx36) gap junctions (GJs) appear to be involved in the synchronization of GABA interneurons in many brain areas. We have previously identified a population of Cx36-connected ventral tegmental area (VTA) GABA neurons that may regulate mesolimbic dopamine (DA) neurotransmission, a system implicated in reward from both natural behaviors and drugs of abuse. The aim of this study was to determine the effect mefloquine (MFQ) has on midbrain DA and GABA neuron inhibition, and the role Cx36 GJs play in regulating midbrain VTA DA neuron activity in mice. In brain slices from adolescent wild-type (WT) mice the Cx36-selective GJ blocker mefloquine (MFQ, 25 µM) increased VTA DA neuron sIPSC frequency sixfold, and mIPSC frequency threefold. However, in Cx36 KO mice, MFQ only increased sIPSC and mIPSC frequency threefold. The nonselective GJ blocker carbenoxolone (CBX, 100 µM) increased DA neuron sIPSC frequency twofold in WT mice, did not affect Cx36 KO mouse sIPSCs, and did not affect mIPSCs in WT or Cx36 KO mice. Interestingly, MFQ had no effect on VTA GABA neuron sIPSC frequency. We also examined MFQ effects on VTA DA neuron firing rate and current-evoked spiking in WT and Cx36 KO mice, and found that MFQ decreased WT DA neuron firing rate and current-evoked spiking, but did not alter these measures in Cx36 KO mice. Taken together these findings suggest that blocking Cx36 GJs increases VTA DA neuron inhibition, and that GJs play in key role in regulating inhibition of VTA DA neurons. Synapse, 2011. © 2011 Wiley-Liss, Inc.

Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats.

The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn. This shift involves a switch in the gamma-aminobutyric acid type A (GABAA) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.

Acute and chronic ethanol modulate dopamine D2-subtype receptor responses in ventral tegmental area GABA neurons.

BACKGROUND: Ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in drug reward. VTA GABA neuron firing rate is reduced by acute ethanol and enhanced by DA via D2 receptor activation. The objective of this study was to evaluate the role of D2 receptors in acute ethanol inhibition of VTA GABA neuron activity, as well as the adaptation of D2 receptors by chronic ethanol consumption. METHODS: Using electrophysiological methods, we evaluated the effects of intraperitoneal ethanol on DA activation of VTA GABA neurons, the effects of DA antagonists on ethanol inhibition of their firing rate, as well as adaptations in firing rate following chronic ethanol consumption. Using single cell quantitative RT-polymerase chain reaction (PCR), we evaluated the expression of VTA GABA neuron D2 receptors in rats consuming ethanol versus pair-fed controls. RESULTS: In acute ethanol studies, microelectrophoretic activation of VTA GABA neurons by DA was inhibited by acute intraperitoneal ethanol, and intravenous administration of the D2 antagonist eticlopride blocked ethanol suppression of VTA GABA neuron firing rate. In chronic ethanol studies, while there were no signs of withdrawal at 24 hours, or significant adaptation in firing rate or response to acute ethanol, there was a significant down-regulation in the expression of D2 receptors in ethanol-consuming rats versus pair-fed controls. CONCLUSIONS: Inhibition of DA activation of VTA GABA neuron firing rate by ethanol, as well as eticlopride block of ethanol inhibition of VTA GABA neuron firing rate, suggests an interaction between ethanol and DA neurotransmission via D2 receptors, perhaps via enhanced DA release in the VTA subsequent to ethanol inhibition of GABA neurons. Down-regulation of VTA GABA neuron D2 receptors by chronic ethanol might result from persistent DA release onto GABA neurons.

Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels.

The aim of this study was to evaluate the effects of cocaine on gamma-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25-0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0-2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25-2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25-2 mg/kg (IC(50) 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC(50) 13 microm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC(50) 13 microm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement.

Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors.

Several recent studies have established a role for estrogens in ameliorating specific neurodegenerative disorders, mainly those associated with the cholinergic neurons of the basal forebrain and their targets in the cortex and hippocampus. We have previously demonstrated that endogenous and exogenous application of the neurosteroid dehydroepiandrosterone sulfate (DHEAS) markedly reduces GABA-mediated recurrent inhibition and synchronizes hippocampal unit activity to theta rhythm (Steffensen (1995) Hippocampus 5:320-328). In this study, we evaluated the role of muscarinic receptors in mediating the effects of DHEAS and estrone sulfate (ES), the principal circulating estrogen in humans, on short-latency-evoked potential responses, paired-pulse inhibition (PPI), paired-pulse facilitation, and GABA interneuron activity in the dentate gyrus and CA1 subfields of the rat hippocampus. In situ microelectrophoretic application of the muscarinic M2 subtype cholinergic receptor agonist cis-dioxolane, DHEAS, and ES markedly reduced PPI in the dentate and CA1 that was blocked by the M2 receptor antagonist gallamine. Similar to DHEAS, microelectrophoretic administration of ES increased population spike amplitudes, without increasing excitatory transmission, but this effect was not blocked by gallamine. Microelectrophoretic application of cis-dioxolane and ES markedly increased the firing rate of dentate hilar interneurons and CA1 oriens/alveus interneurons and enhanced their synchrony to hippocampal theta rhythm. These findings suggest that select GABA-modulating neurosteroids and neuroactive estrogen sulfates alter septohippocampal cholinergic modulation of hippocampal GABAergic interneurons mediating recurrent, but not feedforward, inhibition of hippocampal principal cell activity.

Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons.

Communication between neurons in the mammalian brain is primarily through chemical synapses; however, evidence is accumulating in support of electrical synaptic transmission between some neuronal types in the mature nervous system. The authors have recently demonstrated that the gap junction (GJ) blocker quinidine suppresses stimulus-induced and dopamine-evoked coupling of gamma amino butyric acid (GABA) neurons in the ventral tegmental area (VTA) of mature rats (Stobbs et al., 2004). The aim of this study was to evaluate the role of connexin-36 (Cx36) GJs in mediating electrical coupling between VTA GABA neurons in P50-80 rats in vivo and P25-50 rats in vitro. Single stimulation of the internal capsule (IC) evoked VTA GABA neuron spike couplets in mature rats when activated antidromically, and multiple poststimulus spike discharges (PSDs) when activated with brief high-frequency stimulation of the IC (ICPSDs). The Cx36 GJ blocker mefloquine (30 mg/kg) suppressed VTA GABA neuron ICPSDs in mature freely behaving rats. VTA GABA neurons recorded via whole-cell patch clamp in the midbrain slice preparation of P25-50 rats showed robust expression of Cx36 transcripts when tested with single-cell quantitative reverse transcription polymerase chain reaction. In P50-80 rats, Cx36 protein immunoreactivity was evident in the VTA and surrounding structures. Dye-coupling between VTA neurons was observed following Neurobiotin labeling of VTA GABA neurons, as well as with the fluorochrome Alexa Fluor 488 using real-time video fluorescent microscopy. Thus, mature VTA GABA neurons appear to be connected by electrical synapses via Cx36 GJs, whose coupling is enhanced by corticotegmental input and by dopamine.

Frontal sinus fractures in children.

OBJECTIVE: To review the epidemiologic characteristics, clinical course, and management of pediatric patients with frontal sinus fractures. METHODS: Retrospective review of 120 patients with maxillofacial fractures who presented to a tertiary children's hospital from 1998 to 2003 revealed 11 patients with frontal sinus fractures. RESULTS: The study group included 9 males and 2 females with a mean age of 9.7 (range 4-14) years. The most common mechanisms of injury were unrestrained motor vehicle accident and all-terrain vehicle accident. All patients suffered concomitant orbital fractures. Other maxillofacial fractures included sphenoid (4), naso-orbitoethmoid (3), midface (2), and mandible (1). Seven (63.6%) patients sustained significant intracranial injuries including intraparenchymal hemorrhage, expanding pneumocephalus, and subdural hematoma. The average age of patients with intracranial injury was younger than those without intracranial injury (8.1 vs. 12.8 years, P = .025). Four patients had a total of six sites of cerebrospinal fluid (CSF) leak. The most common sites of dural injury were the cribriform area (4) and frontal region (2). All patients with CSF leaks had significant intracranial injuries and required bifrontal craniotomy. CONCLUSIONS: Pediatric frontal sinus fractures are likely to involve other maxillofacial injuries, particularly involving the orbit. Frontal sinus fractures in children are associated with increased risk of serious intracranial injury and CSF leak when compared with adults. The most common site of dural injury was the cribriform area. A multidisciplinary approach is necessary to manage concomitant injuries, obtain separation of the sinonasal tract from intracranial contents, and to restore cosmesis to the brow.

Ethanol suppression of ventral tegmental area GABA neuron electrical transmission involves N-methyl-D-aspartate receptors.

Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg i.p.), the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5-20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABA(A) receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas local NMDA enhanced, and the systemic and local GABA(A) receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%), and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions and that the inhibitory effect of ethanol on electrical transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically coupled networks of midbrain GABA neurons.

Targeted disruption of RC3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus.

We used homologous recombination in the mouse to knock-out RC3, a postsynaptic, calmodulin-binding PKC substrate. Mutant brains exhibited lower immunoreactivity to phospho-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but had the same synaptic density as wild type and did not exhibit a gross neuroanatomical phenotype. Basal excitatory synaptic transmission in CA1 was depressed, long-term potentiation (LTP) was enhanced, and the depressant effects of the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine was occluded compared with littermate controls. The frequency-response curve was displaced to the left, and long-term depression (LTD) could not be induced unless low-frequency stimuli were preceded by high-frequency tetani. Depotentiation was much more robust in the mutant, and only one stimulus was required to saturate LTD in primed mutant hippocampi, whereas multiple low-frequency stimuli were required in wild-type slices. Thus, ablation of RC3 appears to render the postsynaptic neuron hypersensitive to Ca(2+), decreasing its LTD and LTP thresholds and accentuating the effects of priming stimuli. We propose an mGluR-dependent CaM-based sliding threshold mechanism for metaplasticity that is governed by the phosphorylation states of RC3 and CaMKII.