Linking Patterns of Intraoperative Neuromonitoring (IONM) Alerts to the Odds of a New Postoperative Neurological Deficit: Analysis of 27,808 Cervical Spine Procedures From a National Multi-institutional Database.

STUDY DESIGN/SETTING: Retrospective review of a national multi-institutional database of 27,808 extradural cervical spine procedures performed between January 2017 and May 2021. OBJECTIVE: Characterize intraoperative neuromonitoring alerts by the patterns of modalities and nerves/muscles involved and quantify risk of new-onset neurological deficit for patients with a primary diagnosis of myelopathy, stenosis, or radiculopathy. SUMMARY OF BACKGROUND DATA: Phenotyping alert patterns and linking those patterns with risk is needed to facilitate clinical decision-making. METHODS: Cases with alerts were categorized by patterns of modalities or nerves/muscles involved, and alert status at closure. Unadjusted odds ratios (ORs) for new-onset neurological deficit were calculated. A mixed-effects logistic regression model controlling for demographic and operative factors, with random intercepts to account for clustering in outcomes by surgeon and surgical neurophysiologist was also used to calculate ORs and probabilities of neurological deficit. RESULTS: There was significantly increased risk of a new neurological deficit for procedures involving posterior compared with anterior approaches (OR: 1.82, P=0.001) and procedures involving three levels compared with one (OR: 2.17, P=0.001). Odds of a deficit were lower for patients with radiculopathy compared with myelopathy (OR: 0.69, P=0.058). Compared with cases with no alerts, those with unresolved Spinal Cord alerts were associated with the greatest elevation in risk (OR: 289.05) followed by unresolved C5-6 Nerve Root (OR: 172.7), C5-T1 Nerve Root/Arm (OR: 162.89), C7 Nerve Root (OR:84.2), and C8-T1 Nerve Root alerts (OR:75.49, all P<0.001). Significant reductions in risk were seen for resolved Spinal Cord, C5-6 Nerve Root, and C8-T1 nerve alerts. Overall, unresolved motor evoked potential and somatosensory evoked potential alerts were associated with the greatest elevation in risk (OR:340.92) followed by unresolved motor evoked potential-only (OR:140.6) and unresolved somatosensory evoked potential-Only alerts (OR:78.3, all P<0.001). These relationships were similar across diagnostic cohorts. CONCLUSIONS: Risk elevation and risk mitigation after an intraoperative neuromonitoring alert during surgery is dependent on the type and pattern of alert.

Patient Factors Impacting Baseline Motor Evoked Potentials (MEPs) in Patients Undergoing Cervical Spine Surgery for Myelopathy or Radiculopathy.

STUDY DESIGN: Retrospective review of 2532 adults who underwent elective surgery for cervical radiculopathy or myelopathy with intraoperative neuromonitoring (IONM) with motor evoked potentials (MEPs) between 2017 and 2019. OBJECTIVE: Evaluate attainability of monitorable MEPs across demographic, health history, and patient-reported outcomes measure (PROM) factors. SUMMARY OF BACKGROUND DATA: When baseline IONM responses cannot be obtained, the value of IONM on mitigating the risk of postoperative deficits is marginalized and a clinical decision to proceed must be made based, in part, on the differential diagnosis of the unmonitorable MEPs. Despite known associations with baseline MEPs and anesthetic regimen or preoperative motor strength, little is known regarding associations with other patient factors. METHODS: Demographics, health history, and PROM data were collected preoperatively. MEP baseline responses were reported as monitorable or unmonitorable at incision. Multivariable logistic regression estimated the odds of having at least one unmonitorable MEP from demographic and health history factors. RESULTS: Age [odds ratio (OR)=1.031, P <0.001], sex (male OR=1.572, P =0.007), a primary diagnosis of myelopathy (OR=1.493, P =0.021), peripheral vascular disease (OR=2.830, P =0.009), type II diabetes (OR=1.658, P =0.005), and hypertension (OR=1.406, P =0.040) were each associated with increased odds of unmonitorable MEPs from one or more muscles; a history of thyroid disorder was inversely related (OR=0.583, P =0.027). P atients with unmonitorable MEPs reported less neck-associated disability and pain ( P <0.036), but worse SF-12 physical health and lower extremity (LE) and upper extremity function ( P <0.016). Compared with radiculopathy, unmonitorable MEPs in myelopathy patients more often involved LE muscles. Cord function was monitorable in 99.1% of myelopathic patients with no reported LE dysfunction and no history of hypertension or diabetes. CONCLUSION: Myelopathy, hypertension, peripheral vascular disease, diabetes, and/or symptomatic LE dysfunction increased the odds of having unmonitorable baseline MEPs. Unmonitorable baseline MEPs was uncommon in patients without significant LE weakness, even in the presence of myelopathy.

Impact of inhalational anesthetic agents on the baseline monitorability of motor evoked potentials during spine surgery: a review of 22,755 cervical and lumbar procedures.

BACKGROUND CONTEXT: During spine surgery, motor evoked potentials (MEPs) are often utilized to monitor both spinal cord function and spinal nerve root or plexus function. While there are reports evaluating the impact of anesthesia on the ability of MEPs to monitor spinal cord function, less is known about the impact of anesthesia on the ability of MEPs to monitor spinal nerve root and plexus function. PURPOSE: To compare the baseline monitorability and amplitude of MEPs during cervical and lumbar procedures between two cohorts based on the maintenance anesthetic regimen: a total intravenous anesthesia (TIVA) versus a regimen balanced with volatile inhalational and intravenous agents. STUDY DESIGN: Baseline MEP data from a total of 16,559 cervical and 6,196 lumbar extradural spine procedures utilizing multimodality intraoperative neuromonitoring (IONM) including MEPs between January 2017 and March 2020 were obtained from a multi-institutional database. Two cohorts for each region of spine surgery were delineated based on the anesthetic regimen: a TIVA cohort and a Balanced anesthesia cohort. PATIENT SAMPLE: Age 18 and older. Fellowship support for 65,000 for year 2021. OUTCOME MEASURES: Percent monitorability and amplitudes of baseline MEPs. METHODS: The baseline monitorability of each muscle MEP was evaluated by the IONM team in real-time and recorded in the patient's electronic medical record. The relation between anesthetic regimen and baseline monitorability was estimated using mixed effects logistic regression, with distinct models for cervical and lumbar procedures. Subsets of cervical and lumbar procedures from each anesthesia cohort in which all MEPs were deemed monitorable were randomly selected and the average peak-to-trough amplitude of each muscle MEP was retrospectively measured. Mixed-effects linear regression models were estimated (one each for cervical and lumbar procedures) to assess possible differences in average amplitude associated with anesthesia regimen. RESULTS: At the time of surgery, baseline MEPs were reported monitorable from all targeted muscles in 86.8% and 83.0% of cervical and lumbar procedures, respectively, for the TIVA cohort, but were reported monitorable in just 59.3% and 61.0% of cervical and lumbar procedures, respectively, in the Balanced cohort, yielding disparities of 27.5% and 22.0%, respectively. The model-adjusted monitorability disparity between cohorts for a given muscle MEP ranged from 0.2% to 16.6% but was smallest for distal intrinsic hand and foot muscle MEPs (0.2%-1.1%) and was largest for proximal muscle MEPs (deltoid: 10.8%, biceps brachii: 8.8%, triceps: 13.0%, quadriceps: 16.6%, gastrocnemius: 7.8%, and tibialis anterior: 3.7%) where the monitorability was significantly decreased in the Balanced cohort relative to the TIVA cohort (p<.0001). Relative to the TIVA cohort, the model-adjusted amplitude of an MEP in the Balanced cohort was smaller for all muscles measured, ranging from 27.5% to 78.0% smaller. Relative to the TIVA cohort, the model-adjusted amplitude of an MEP was significantly decreased (p<.01) in the Balanced cohort for the most proximal muscles (Percent smaller: deltoid: 74.3%, biceps: 78.0%, triceps: 54.9%, quadriceps: 54.8%). CONCLUSIONS: TIVA is the preferred anesthetic regimen for optimizing MEP monitoring during spine surgery. Inhalational agents significantly decrease MEP monitorability and amplitudes for most muscles, and this effect is especially pronounced for proximal limb muscles such as the deltoid, biceps, triceps, and quadriceps.

Roadmap for Motor Evoked Potential (MEP) Monitoring for Patients Undergoing Lumbar and Lumbosacral Spinal Fusion Procedures.

MEPs are recommended for patients undergoing lumbar and lumbosacral procedures in which intraoperative neuromonitoring (IONM) is being utilized. While electromyography (EMG) provides critical nerve root proximity information, spontaneous EMG discharges are relatively poor at reliably diagnosing spinal nerve root dysfunction. In contrast, research indicates that MEPs are both sensitive and specific in diagnosing evolving spinal nerve root dysfunction. There is conflicting evidence, however, and it must be emphasized that the value of adding MEPs is only realized when practices and techniques are optimized. The ideal anesthetic plan is an optimized total intravenous anesthetic (TIVA) regimen. Selection of appropriate anesthetics and dosing is important for optimizing baseline response amplitudes and promoting diagnostic confidence in analyzing signal changes. An adaptive set of alert criteria that account for baseline amplitude and morphology fluctuations should guide the determination of significant signal change. The therapeutic impact of accurate diagnostic information depends on the timeliness of diagnosis and intervention. Prior to the start of surgery, a plan to obtain MEPs at least once every 10 minutes during the active part of the procedure and after every significant surgical maneuver should be agreed upon, and the intervention plan should include but not be limited to possible removal of hardware and release of retraction or distractive forces. In summary, MEPs can improve monitoring of at-risk nerve root function, but the accuracy and therapeutic impact of such monitoring depend on perioperative planning and communication that optimize use of this modality.

Intraoperative vascular complications during 2278 cerebral endovascular procedures with multimodality IONM: relationship between signal change, complication, intervention and postoperative outcome.

BACKGROUND: Intraoperative neuromonitoring (IONM) is often used during cerebral endovascular procedures. OBJECTIVE: To investigate the relationship between intraoperative vascular complications and IONM signal changes, and the impact of interventions on signal resolution and postoperative outcomes. METHODS: A series of 2278 cerebral endovascular procedures conducted under general anesthesia and using electroencephalography and somatosensory evoked potential monitoring were retrospectively reviewed. A subset of 763 procedures also included motor evoked potentials (MEPs). IONM alerts were categorized as either a partial attenuation or complete loss of signal. Vascular complications were subcategorized as due to rupture, emboli, instrumentation, or vasospasm. Odds ratios (ORs) for new postoperative motor deficits were calculated and diagnostic accuracy was measured using sensitivity, specificity, and likelihood ratios. RESULTS: The overall incidence of new postoperative motor deficit was 1.2%; 20.4% in cases with an IONM alert and 0.09% in cases without an alert. Relative to procedures with no alerts, odds of a new deficit increased if there was partial signal attenuation (OR=210.9, 95% CI 44.3 to 1003.5, p<0.0001) and increased further with complete loss of signal (OR=1437.3, 95% CI 297.3 to 6948.2, p<0.0001). Relative to procedures with unresolved alerts, odds of a new deficit decreased if the alert was fully resolved (OR=0.039, 95% CI 0.005 to 0.306, p<0.002). Procedures using MEPs had slightly higher sensitivity (92.3% vs 85.7%) but slightly lower specificity (96.7% vs 98.2%). CONCLUSIONS: An IONM alert associated with an arterial complication is associated with a dramatic increase in odds of a new postoperative deficit; however, if there is resolution of the alert prior to closure, odds of a new deficit decrease significantly.

Incidence of peripheral nerve injury in revision total shoulder arthroplasty: an intraoperative nerve monitoring study.

BACKGROUND: The incidence of nerve injuries in revision total shoulder arthroplasty (TSA) is not well defined in the literature and may be higher than that in primary procedures, with 1 study reporting a complication rate of 50% for shoulder revisions. Given that continuous intraoperative nerve monitoring (IONM) can be an effective tool in diagnosing evolving neurologic dysfunction and preventing postoperative injuries, the purpose of this study was to report on IONM data and nerve injury rates in a series of revision TSAs. METHODS: A retrospective cohort review of consecutive patients who underwent revision TSA was performed from January 2016 to March 2020. Indications for revision included infection (n = 7); failed total arthroplasty and hemiarthroplasty secondary to pain, dysfunction, and/or loose components (n = 36); and periprosthetic fracture (n = 1). Of the shoulders, 32 underwent revision to a reverse TSA, 6 underwent revision to an anatomic TSA, and 6 underwent spacer placement. IONM data included transcranial electrical motor evoked potentials (MEPs), somatosensory evoked potentials, and free-run electromyography. The motor alert threshold was set at ≥80% signal attenuation in any peripheral nerve. Patients were screened for neurologic deficits immediately following surgery, prior to administration of an interscalene nerve block, and during the first 2 postoperative visits. Additional data collection included surgical indication, sex, laterality, age at surgery, procedure performed, body mass index, history of tobacco use, Charlson Comorbidity Index, medical history, and preoperative range of motion. RESULTS: A total of 44 shoulders in 38 patients were included, with a mean age of 63.2 years (standard deviation, 13.0 years). Of the procedures, 22.4% (n = 10) had an MEP alert, with 8 isolated to a single nerve (7 axillary and 1 radial) and 1 isolated to the axillary and musculocutaneous nerves. Only 1 patient experienced a major brachial plexus alert involving axillary, musculocutaneous, radial, ulnar, and median nerve MEP alerts, as well as ulnar and median nerve somatosensory evoked potential alerts. Age, sex, body mass index, Charlson Comorbidity Index, and preoperative range of motion were not found to be significantly different between cases in which an MEP alert occurred and cases with no MEP alerts. In the postoperative period, no minor or major nerve injuries were found whereas distal peripheral neuropathy developed in 4 patients (9.1%). CONCLUSION: Among 44 surgical procedures, no patients (0%) had a major or minor nerve injury postoperatively and 4 patients (9.1%) complained of distal peripheral neuropathy postoperatively. In this study, we have shown that through the use of IONM, the rate of minor and major nerve injuries can be minimized in revision shoulder arthroplasty.

Utility of motor evoked potentials to diagnose and reduce lower extremity motor nerve root injuries during 4,386 extradural posterior lumbosacral spine procedures.

BACKGROUND CONTEXT: Motor evoked potentials (MEPs) have excellent sensitivity for monitoring the functional integrity of the lateral corticospinal tract of the spinal cord. The sensitivity for nerve root function, however, is not as well established; consequently, MEPs are often not utilized for posterior extradural spine procedures distal to the conus. Spontaneous electromyography (sEMG) and somatosensory evoked potentials (SSEPs) are often included for these procedures, but their limited sensitivity has been well documented. Given the risk of motor nerve root injuries during spine procedures, and specifically increased vulnerability of the L4 and L5 nerves, the sensitivity of MEPs was evaluated for diagnostic accuracy and therapeutic impact. PURPOSE: To determine the diagnostic sensitivity of MEPs during lumbosacral spine procedures and the potential therapeutic impact of the resolution of MEP alerts. STUDY DESIGN: A total of 4,386 posterior extradural lumbosacral spine procedures utilizing multimodality intraoperative neuromonitoring (IONM) with sEMG, SSEPs, and MEPs were abstracted from a multi-institutional database. All cases took place between October 2015 and October 2017. No external funding was provided. OUTCOME MEASURES: Sensitivity and specificity, as well as positive and negative likelihood ratios for new postoperative neurologic deficits were calculated for each modality individually as well as when combined (multimodality). PATIENT SAMPLE: Age 18 and older METHODS: Data entered in the electronic medical record were analyzed. Alerts to sEMG activity, decreases in SSEP amplitude, or decreases in MEP amplitude were documented as well as the status of the alerts at closure: resolved or unresolved. The presence of an sEMG alert or an unresolved MEP or SSEP alert at closure was considered a positive diagnostic result, and these results were assessed relative to presence of new immediate onset neurologic deficits as documented in the electronic record. RESULTS: The sensitivity and specificity of multimodality IONM for new immediate-onset lower extremity motor deficits were 100.0% (95% confidence interval: [64.6, 100.0]) and 92.2% (91.1, 93.1), respectively. Looking at the modalities in isolation, the sensitivity of MEPs was considerably better than either lower extremity sEMG or posterior tibial nerve SSEPs: 100.0% (78.5, 100.0) versus just 14.3% (4.0, 39.9) and 28.6% (8.2, 64.1), respectively. Surprisingly, the specificity of lower extremity MEPs was better than sEMG, 97.9% (97.5, 98.3) versus 95.4% (94.7, 96.0) (χ2=43.0, p<.001). The specificity of lower extremity SSEPs was 99.0% (98.5, 99.3). Only 4.4% of all procedures had a lower extremity MEP alert. There were 14 significant new nerve root injuries and all 14 had unresolved MEPs at closure. Total 85.7% of those nerve root injuries were dorsiflexion foot drop injuries and all had unresolved tibialis anterior MEP alerts. Although the overall rate of nerve root injuries was 0.32% (14/4,386), the rate for procedures with unresolved isolated tibialis anterior MEP alerts was 44.4% (12/27). The therapeutic impact is evident in the 2.0% of cases (87/4,386) with lower extremity MEP alerts that were able to be fully resolved by closure and for which the rate of injury was zero. CONCLUSIONS: The diagnostic accuracy of MEPs for anterior tibialis-related nerve root dysfunction supports the inclusion of this modality during routine posterior extradural lumbosacral procedures, especially when the L4 or L5 nerve roots are at risk. Moreover, therapeutic interventions that lead to the resolution of MEP alerts avert postoperative neurologic injuries.

Practice guidelines for the supervising professional: intraoperative neurophysiological monitoring.

The American Society of Neurophysiological Monitoring (ASNM) was founded in 1989 as the American Society of Evoked Potential Monitoring. From the beginning, the Society has been made up of physicians, doctoral degree holders, Technologists, and all those interested in furthering the profession. The Society changed its name to the ASNM and held its first Annual Meeting in 1990. It remains the largest worldwide organization dedicated solely to the scientifically-based advancement of intraoperative neurophysiology. The primary goal of the ASNM is to assure the quality of patient care during procedures monitoring the nervous system. This goal is accomplished primarily through programs in education, advocacy of basic and clinical research, and publication of guidelines, among other endeavors. The ASNM is committed to the development of medically sound and clinically relevant guidelines for the performance of intraoperative neurophysiology. Guidelines are formulated based on exhaustive literature review, recruitment of expert opinion, and broad consensus among ASNM membership. Input is likewise sought from sister societies and related constituencies. Adherence to a literature-based, formalized process characterizes the construction of all ASNM guidelines. The guidelines covering the Professional Practice of intraoperative neurophysiological monitoring were initially published January 24th, 2013, and subsequently that document has undergone review and revision to accommodate broad inter- and intra-societal feedback. This current version of the ASNM Professional Practice Guideline was fully approved for publication according to ASNM bylaws on February 22nd, 2018, and thus overwrites and supersedes the initial guideline.

Incidence of peripheral nerve injury during shoulder arthroplasty when motor evoked potentials are monitored.

To report the incidence of clinically detectable nerve injuries when utilizing transcranial electrical motor evoked potentials (MEPs) during shoulder arthroplasty. A retrospective review of patients undergoing shoulder arthroplasty with continuous IONM was performed. The criteria for nerve alerts was an 80% amplitude reduction in MEPs. The primary outcome measure was post-operative clinically detectable nerve deficit. An additional retrospective analysis on a subset of cases using an all-or-none (100% amplitude reduction) criterion applied to the deltoid was performed. Two hundred eighty four arthroplasty cases were included. There were no permanent post-operative nerve injuries and two transient nerve injuries (0.7%). MEP alerts occurred in 102 cases (36.2%). Nineteen (6.7%) cases did not have signals return above alert threshold at closure. These cases were significantly associated with post-operative nerve injury (p = 0.03). There were no false negatives, making sensitivity 100% and specificity was 93.9%. In the subset of cases in which an all-or-none criterion was retrospectively applied to just the deltoid, MEP alerts occurred in just 17.9% of cases; specificity improved to 98.0%. We conclude that utilization of the real-time diagnostic MEP data during shoulder arthroplasty aids surgeons in decision making regarding impending peripheral nerve injuries.

Real-Time Detection and Monitoring of Acute Brain Injury Utilizing Evoked Electroencephalographic Potentials.

Rapid detection and diagnosis of a traumatic brain injury (TBI) can significantly improve the prognosis for recovery. Helmet-mounted sensors that detect impact severity based on measurements of acceleration or pressure show promise for aiding triage and transport decisions in active, field environments such as professional sports or military combat. The detected signals, however, report on the mechanics of an impact rather than directly indicating the presence and severity of an injury. We explored the use of cortical somatosensory evoked electroencephalographic potentials (SSEPs) to detect and track, in real-time, neural electrophysiological abnormalities within the first hour following head injury in an animal model. To study the immediate electrophysiological effects of injury in vivo, we developed an experimental paradigm involving focused ultrasound that permits continuous, real-time measurements and minimizes mechanical artifact. Injury was associated with a dramatic reduction of amplitude over the damaged hemisphere directly after the injury. The amplitude systematically improved over time but remained significantly decreased at one hour, compared with baseline. In contrast, at one hour there was a concomitant enhancement of the cortical SSEP amplitude evoked from the uninjured hemisphere. Analysis of the inter-trial electroencephalogram (EEG) also revealed significant changes in low-frequency components and an increase in EEG entropy up to 30 minutes after injury, likely reflecting altered EEG reactivity to somatosensory stimuli. Injury-induced alterations in SSEPs were also observed using noninvasive epidermal electrodes, demonstrating viability of practical implementation. These results suggest cortical SSEPs recorded at just a few locations by head-mounted sensors and associated multiparametric analyses could potentially be used to rapidly detect and monitor brain injury in settings that normally present significant levels of mechanical and electrical noise.

Somatosensory evoked potential changes in neuroendovascular procedures: incidence and association with clinical outcome in 873 patients.

BACKGROUND: Neurophysiological monitoring is routinely used during neurosurgical procedures. Use of neurophysiological monitoring has extended to neuroendovascular procedures, but evidence of its impact on clinical outcome in this arena is limited. OBJECTIVE: To report the incidence of significant intraoperative somatosensory evoked potential (SSEP) changes during neuroendovascular surgery and to correlate SSEP changes with clinical outcomes. METHODS: Patients who underwent neuroendovascular surgery at our institution between 2011 and 2013 were included in the analysis. Medical charts and imaging studies were reviewed retrospectively for sex, age, lesion type and size, clinical presentation, type of endovascular procedure, duration of SSEP change, reversibility of SSEP change, incidence of intraoperative complications and related mortalities, presence of new infarction within 72 hours of intervention, and discharge outcome. RESULTS: Of 873 consecutive patients, 52 (6%) had clinically significant intraoperative SSEP changes. Twenty-four patients (46%) had SSEP changes that were corrected, and 28 patients (54%) had changes that were not reversed before the end of surgery. Both decreased duration and reversal of SSEP changes were associated with a lower incidence of postoperative infarction and more favorable clinical outcome on discharge. The positive predictive value of an irreversible SSEP change for postoperative infarction in our study was 21%, and the negative predictive value was 83%. CONCLUSION: The approximate incidence of SSEP changes is 6% during neuroendovascular procedures. Rapid reversal of SSEP changes is associated with better outcomes. SSEP monitoring may be a valuable tool for preventing complications after neuroendovascular interventions.

Mapping of microstimulation evoked responses and unit activity patterns in the lateral hypothalamic area recorded in awake humans. Technical note.

Major contributions to the understanding of human brain function have come from detailed clinical reports of responses evoked by electrical stimulation and specific brain regions during neurosurgical procedures in awake humans. In this study, microstimulation evoked responses and extracellular unit recordings were obtained intraoperatively in 3 awake patients undergoing bilateral implantation of deep brain stimulation electrodes in the lateral hypothalamus. The microstimulation evoked responses exhibited a clear anatomical distribution. Anxiety was most reliably evoked by stimulation directed ventromedially within or adjacent to the ventromedial nucleus of the hypothalamus, nausea was most reliably evoked by stimulation directed at the center of the lateral hypothalamus, and paresthesias were most reliably evoked by stimulation at the border of the lateral hypothalamus and basal nuclei. Regarding the unit recordings, the firing rates of individual neurons did not have an anatomical distribution, but a small subpopulation of neurons located at the border of the lateral hypothalamus and basal nuclei exhibited a fast rhythmically bursting behavior with an intraburst frequency of 200-400 Hz and an interburst frequency of 10-20 Hz. Based on animal studies, the lateral hypothalamic area and surrounding hypothalamic nuclei are putatively involved with a variety of physiological, behavioral, and sensory functions. The lateral hypothalamus is situated to play a dynamic and complex role in human behavior and this report further shows that to be true. In addition, this report should serve as a valuable resource for future intracranial work in which accurate targeting within this region is required.

Induction of panic attack by stimulation of the ventromedial hypothalamus.

Panic attacks are sudden debilitating attacks of intense distress often accompanied by physical symptoms such as shortness of breath and heart palpitations. Numerous brain regions, hormones, and neurotransmitter systems are putatively involved, but the etiology and neurocircuitry of panic attacks is far from established. One particular brain region of interest is the ventromedial hypothalamus (VMH). In cats and rats, electrical stimulation delivered to the VMH has been shown to evoke an emotional "panic attack-like" escape behavior, and in humans, stimulation targeting nuclei just posterior or anterior to the VMH has reportedly induced panic attacks. The authors report findings obtained in an awake patient undergoing bilateral implantation of deep brain stimulation electrodes into the hypothalamus that strongly implicates the VMH as being critically involved in the genesis of panic attacks. First, as the stimulating electrode progressed deeper into the VMH, the intensity of stimulation required to evoke an attack systematically decreased; second, while stimulation of the VMH in either hemisphere evoked panic, stimulation that appeared to be in the center of the VMH was more potent. Thus, this evidence supports the role of the VMH in the induction of panic attacks purported by animal studies.

Discrete place fields of hippocampal formation interneurons.

The spike discharge of hippocampal excitatory principal cells, also called "place cells," is highly location specific, but the discharge of local inhibitory interneurons is thought to display relatively low spatial specificity. Whereas in other brain regions, such as sensory neocortex, the activity of interneurons is often exquisitely stimulus selective and directly determines the responses of neighboring excitatory neurons, the activity of hippocampal interneurons typically lacks the requisite specificity needed to shape the defined structure of principal cell fields. Here we show that hippocampal formation interneurons have "on" fields (abrupt increases in activity) and "off" fields (abrupt decreases in activity) that are associated with the same location-specific informational content, spatial resolution, and dependency on context as the "place fields" of CA1 principal cells. This establishes that interneurons have well-defined place fields, thus having important implications for understanding how the hippocampus represents spatial information.

Dynamics of excitation and inhibition underlying stimulus selectivity in rat somatosensory cortex.

Neurons in sensory systems respond to stimuli within their receptive fields, but the magnitude of the response depends on specific stimulus features. In the rodent whisker system, the response magnitude to the deflection of a particular whisker is, in most cells, dependent on the direction of deflection. Here we use in vivo intracellular recordings from thalamorecipient neurons in layers 3 and 4 of the rat barrel cortex to elucidate the dynamics of the synaptic inputs underlying direction selectivity. We show that cells are direction selective despite a broadly tuned excitatory and inhibitory synaptic input. Selectivity emerges from a direction-dependent temporal shift of excitation relative to inhibition. For preferred direction deflections, excitation precedes inhibition, but as the direction diverges from the preferred, this separation decreases. Our results illustrate a mechanism by which the timing of the synaptic inputs, and not their relative peak amplitudes, primarily determine feature selectivity.

Stimulus-dependent changes in spike threshold enhance feature selectivity in rat barrel cortex neurons.

Feature selectivity is a fundamental property of sensory cortex neurons, yet the mechanisms underlying its genesis are not fully understood. Using intracellular recordings in vivo from layers 2-6 of rat barrel cortex, we studied the selectivity of neurons to the angular direction of whisker deflection. The spike output and the underlying synaptic response decreased exponentially in magnitude as the direction of deflection diverged from the preferred. However, the spike output was more sharply tuned for direction than the underlying synaptic response amplitude. This difference in selectivity was attributable to the rectification imposed by the spike threshold on the input-output function of cells. As in the visual system, spike threshold was not constant and showed trial-to-trial variability. However, here we show that the mean spike threshold was direction dependent and increased as the direction diverged from the preferred. Spike threshold was also related to the rate of rise of the synaptic response, which was direction dependent and steepest for the preferred direction. To assess the impact of the direction-dependent changes in spike threshold on direction selectivity, we applied a fixed threshold to the synaptic responses and calculated a predicted spike output. The predicted output was more broadly tuned than the obtained spike response, demonstrating for the first time that the regulation of the spike threshold by the properties of the synaptic response effectively enhances the selectivity of the spike output.

Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts.

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABA(A) receptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and--in various combinations--electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, "VFO"); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABA(A) and GABA(B) receptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.

Synaptic responses to whisker deflections in rat barrel cortex as a function of cortical layer and stimulus intensity.

To study the synaptic and spike responses of barrel cortex neurons as a function of cortical layer and stimulus intensity, we recorded intracellularly in vivo from barbiturate anesthetized rats while increasing the velocity-acceleration of the whisker deflection. Granular (Gr; layer 4) cells had the EPSP with the shortest peak and onset latency, whereas supragranular (SGr; layers 2-3) cells had the EPSP with longest duration and slowest rate of rise. Infragranular (Igr; layers 5-6) cells had intermediate values, and thus each layer was unique. The spike response peak of Gr cells was followed by IGr and then by SGr cells. In all cells, depolarization reduced the duration and amplitude of the response, but only in Gr cells did it reveal an early IPSP that cut short the EPSP. This early IPSP was associated with a large decrease in input resistance and an apparent reversal potential below spike threshold; consequently, synaptic integration in Gr cells was limited to the initial 5-7 msec of the response. In contrast, in SGr and IGr cells, results suggest an overlap in time of the EPSP and IPSP, with a small drop in input resistance and an apparent reversal potential above spike threshold, facilitating input integration for up to 20 msec. Decreasing stimulus intensity (velocity-acceleration) reduced the amplitude and increased the peak latency of the response without altering its synaptic composition. We propose that layer 4 circuits are better suited to perform coincidence detection, whereas supra and infragranular circuits are better designed for input integration.