Darrin J. Lee

A comparative study of human and rat hippocampal low-frequency oscillations during spatial navigation

Rhythmic oscillations within the 3–12 Hz theta frequency band manifest in the rodent hippocampus during a variety of behaviors and are particularly well characterized during spatial navigation. In contrast, previous studies of rhythmic hippocampal activity in primates under comparable behavioral conditions suggest it may be less apparent and possibly less prevalent, or even absent, compared with the rodent. We compared the relative presence of low‐frequency oscillations in rats and humans during spatial navigation by using an oscillation detection algorithm (“P‐episode” or “BOSC”) to better characterize their presence in microelectrode local field potential (LFP) recordings. This method quantifies the proportion of time the LFP exceeds both a power and cycle duration threshold at each frequency, characterizing the presence of (1) oscillatory activity compared with background noise, (2) the peak frequency of oscillatory activity, and (3) the duration of oscillatory activity. Results demonstrate that both humans and rodents have hippocampal rhythmic fluctuations lasting, on average, 2.75 and 4.3 cycles, respectively. Analyses further suggest that human hippocampal rhythmicity is centered around ∼3 Hz while that of rats is centered around ∼8 Hz. These results establish that low‐frequency rhythms relevant to spatial navigation are present in both the rodent and human hippocampus, albeit with different properties under the behavioral conditions tested.

Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis.

Recent evidence suggests that astrocytes may be a potential new target for the treatment of epilepsy. The glial water channel aquaporin-4 (AQP4) is expressed in astrocytes, and along with the inwardly-rectifying K(+) channel K(ir)4.1 is thought to underlie the reuptake of H(2)O and K(+) into glial cells during neural activity. Previous studies have demonstrated increased seizure duration and slowed potassium kinetics in AQP4(-/-) mice, and redistribution of AQP4 in hippocampal specimens from patients with chronic epilepsy. However, the regulation and role of AQP4 during epileptogenesis remain to be defined. In this study, we examined the expression of AQP4 and other glial molecules (GFAP, K(ir)4.1, glutamine synthetase) in the intrahippocampal kainic acid (KA) model of epilepsy and compared behavioral and histologic outcomes in wild-type mice vs. AQP4(-/-) mice. Marked and prolonged reduction in AQP4 immunoreactivity on both astrocytic fine processes and endfeet was observed following KA status epilepticus in multiple hippocampal layers. In addition, AQP4(-/-) mice had more spontaneous recurrent seizures than wild-type mice during the first week after KA SE as assessed by chronic video-EEG monitoring and blinded EEG analysis. While both genotypes exhibited similar reactive astrocytic changes, granule cell dispersion and CA1 pyramidal neuron loss, there were an increased number of fluorojade-positive cells early after KA SE in AQP4(-/-) mice. These results indicate a marked reduction of AQP4 following KA SE and suggest that dysregulation of water and potassium homeostasis occurs during early epileptogenesis. Restoration of astrocytic water and ion homeostasis may represent a novel therapeutic strategy.

Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus

Mice deficient in the water channel aquaporin-4 (AQP4) demonstrate increased seizure duration in response to hippocampal stimulation as well as impaired extracellular K+ clearance. However, the expression of AQP4 in the hippocampus is not well described. In this study, we investigated (i) the developmental, laminar and cell-type specificity of AQP4 expression in the hippocampus; (ii) the effect of Kir4.1 deletion on AQP4 expression; and (iii) performed Western blot and RT-PCR analyses. AQP4 immunohistochemistry on coronal sections from wild-type (WT) or Kir4.1-/- mice revealed a developmentally-regulated and laminar-specific pattern, with highest expression in the CA1 stratum lacunosum-moleculare (SLM) and the molecular layer (ML) of the dentate gyrus (DG). AQP4 was colocalized with the glial markers glial fibrillary acidic protein (GFAP) and S100β in the hippocampus, and was also ubiquitously expressed on astrocytic endfeet around blood vessels. No difference in AQP4 immunoreactivity was observed in Kir4.1-/- mice. Electrophysiological and postrecording RT-PCR analyses of individual cells revealed that AQP4 and Kir4.1 were co-expressed in nearly all CA1 astrocytes. In NG2 cells, AQP4 was also expressed at the transcript level. This study is the first to examine subregional AQP4 expression during development of the hippocampus. The strikingly high expression of AQP4 in the CA1 SLM and DG ML identifies these regions as potential sites of astrocytic K+ and H2O regulation. These results begin to delineate the functional capabilities of hippocampal subregions and cell types for K+ and H2O homeostasis, which is critical to excitability and serves as a potential target for modulation in diverse diseases.

Medial Septal Nucleus Theta Frequency Deep Brain Stimulation Improves Spatial Working Memory after Traumatic Brain Injury

More than 5,000,000 survivors of traumatic brain injury (TBI) live with persistent cognitive deficits, some of which likely derive from hippocampal dysfunction. Oscillatory activity in the hippocampus is critical for normal learning and memory functions, and can be modulated using deep brain stimulation techniques. In this pre-clinical study, we demonstrate that lateral fluid percussion TBI results in the attenuation of hippocampal theta oscillations in the first 6 days after injury, which correlate with deficits in the Barnes maze spatial working memory task. Theta band stimulation of the medial septal nucleus (MSN) results in a transient increase in hippocampal theta activity, and when delivered 1 min prior to training in the Barnes maze, it significantly improves spatial working memory. These results suggest that MSN theta stimulation may be an effective neuromodulatory technique for treatment of persistent learning and memory deficits after TBI.

An algorithm for extracting intracranial pressure latency relative to electrocardiogram R wave

Intracranial pressure (ICP) latency is defined as the time interval between the peak of the QRS complex of the electrocardiogram (ECG) and the corresponding onset of intracranial pressure (ICP) pulse. Due to its inherent relationship with arterial pulse wave velocity, ICP latency may allow continuous monitoring of pathophysiological changes in the cerebrovasculature. The objective of the present work was to develop and validate a computerized algorithm for extracting ICP latency in a beat-by-beat fashion. The proposed ICP latency extraction algorithm exploits the mature technique of ECG QRS detection and includes a new adaptive peak detection methodology. The results were validated by comparing the performance of two human observers versus the algorithm in terms of locating the onset points of ICP pulses for 59 recordings extracted from 25 adult patients. The average ICP latency was 72.6+/-19.5 ms (range 40.0-159.8). The ICP pulse detection algorithm demonstrated a baseline sensitivity of 0.97 and a positive predictivity of 0.88. No difference was found in the mean location errors from comparing the results obtained by the two observers and those from comparing the results from the algorithm to those from the two observers. Further investigation is needed to demonstrate the role of ICP latency in characterizing dynamic cerebral vascular pathophysiological changes in clinical states such as subarachnoid hemorrhage and traumatic brain injury.

Potential role of the glial water channel aquaporin-4 in epilepsy

Recent studies have implicated glial cells in novel physiological roles in the CNS, such as modulation of synaptic transmission, so it is possible that glial cells might have a functional role in the hyperexcitability that is characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors and transporters have all been associated with the epileptic state. This paper focuses on the potential roles of the glial water channel aquaporin-4 (AQP4) in modulating brain excitability and in epilepsy. We review studies of seizure phenotypes, K(+) homeostasis and extracellular space physiology of mice that lack AQP4 (AQP4(-/-) mice) and discuss the human studies demonstrating alterations of AQP4 in specimens of human epilepsy tissue. We conclude with new studies of AQP4 regulation by seizures and discuss its potential role in the development of epilepsy (epileptogenesis). Although many questions remain unanswered, the available data indicate that AQP4 and its molecular partners might represent important new therapeutic targets.

Frontal bur hole through an eyebrow incision for image-guided endoscopic evacuation of spontaneous intracerebral hemorrhage.

OBJECT Surgical evacuation of spontaneous intracerebral hemorrhage (sICH) remains a subject of controversy. Minimally invasive techniques for hematoma evacuation have shown a trend toward improved outcomes. The aim of the present study is to describe a minimally invasive alternative for the evacuation of sICH and evaluate its feasibility. METHODS The authors reviewed records of all patients who underwent endoscopic evacuation of an sICH at the UCLA Medical Center between March 2002 and March 2011. All patients in whom the described technique was used for evacuation of an sICH were included in this series. In this approach an incision is made at the superior margin of the eyebrow, and a bur hole is made in the supraorbital bone lateral to the frontal sinus. Using stereotactic guidance, the surgeon advanced the endoscopic sheath along the long axis of the hematoma and fixed it in place at two specific depths where suction was then applied until 75%-85% of the preoperatively determined hematoma volume was removed. An endoscopes camera, then introduced through the sheath, was used to assist in hemostasis. Preoperative and postoperative hematoma volumes and reduction in midline shift were calculated and recorded. Admission Glasgow Coma Scale and modified Rankin Scale (mRS) scores were compared with postoperative scores. RESULTS Six patients underwent evacuation of an sICH using the eyebrow/bur hole technique. The mean preoperative hematoma volume was 68.9 ml (range 30.2-153.9 ml), whereas the mean postoperative residual hematoma volume was 11.9 ml (range 5.1-24.1 ml) (p = 0.02). The mean percentage of hematoma evacuated was 79.2% (range 49%-92.7%). The mean reduction in midline shift was 57.8% (p < 0.01). The Glasgow Coma Scale score improved in each patient between admission and discharge examination. In 5 of the 6 patients the mRS score improved from admission exam to last follow-up. None of the patients experienced rebleeding. CONCLUSIONS This minimally invasive technique is a feasible alternative to other means of evacuating sICHs. It is intended for anterior basal ganglia hematomas, which usually have an elongated, ovoid shape. The approach allows for an optimal trajectory to the long axis of the hematoma, making it possible to evacuate the vast majority of the clot with only one pass of the endoscopic sheath, theoretically minimizing the amount of damage to normal brain.

Aquaporin-4-dependent edema clearance following status epilepticus

We investigated the role of aquaporin-4 in the development of cerebral edema following kainic acid-induced status epilepticus (SE) using specific gravimetry and T2 MRI techniques at 6 h, 1 day, 4 days and 7 days after SE. Our results indicate significantly greater tissue edema and T2 MRI changes in AQP4(-/-) compared to AQP4(+/+) mice that peaks at about 1 day after SE (greater in hippocampus relative to cortex). These results have implications for the mechanisms of edema formation and clearance following intense seizure activity.

Intraoperative computed tomography for intracranial electrode implantation surgery in medically refractory epilepsy

OBJECT Accurate placement of intracranial depth and subdural electrodes is important in evaluating patients with medically refractory epilepsy for possible resection. Confirming electrode locations on postoperative CT scans does not allow for immediate replacement of malpositioned electrodes, and thus revision surgery is required in select cases. Intraoperative CT (iCT) using the Medtronic O-arm device has been performed to detect electrode locations in deep brain stimulation surgery, but its application in epilepsy surgery has not been explored. In the present study, the authors describe their institutional experience in using the O-arm to facilitate accurate placement of intracranial electrodes for epilepsy monitoring. METHODS In this retrospective study, the authors evaluated consecutive patients who had undergone subdural and/or depth electrode implantation for epilepsy monitoring between November 2010 and September 2012. The O-arm device is used to obtain iCT images, which are then merged with the preoperative planning MRI studies and reviewed by the surgical team to confirm final positioning. Minor modifications in patient positioning and operative field preparation are necessary to safely incorporate the O-arm device into routine intracranial electrode implantation surgery. The device does not obstruct surgeon access for bur hole or craniotomy surgery. Depth and subdural electrode locations are easily identified on iCT, which merge with MRI studies without difficulty, allowing the epilepsy surgical team to intraoperatively confirm lead locations. RESULTS Depth and subdural electrodes were implanted in 10 consecutive patients by using routine surgical techniques together with preoperative stereotactic planning and intraoperative neuronavigation. No wound infections or other surgical complications occurred. In one patient, the hippocampal depth electrode was believed to be in a suboptimal position and was repositioned before final wound closure. Additionally, 4 strip electrodes were replaced due to suboptimal positioning. Postoperative CT scans did not differ from iCT studies in the first 3 patients in the series and thus were not obtained in the final 7 patients. Overall, operative time was extended by approximately 10-15 minutes for O-arm positioning, less than 1 minute for image acquisition, and approximately 10 minutes for image transfer, fusion, and intraoperative analysis (total time 21-26 minutes). CONCLUSIONS The O-arm device can be easily incorporated into routine intracranial electrode implantation surgery in standard-sized operating rooms. The technique provides accurate 3D visualization of depth and subdural electrode contacts, and the intraoperative images can be easily merged with preoperative MRI studies to confirm lead positions before final wound closure. Intraoperative CT obviates the need for routine postoperative CT and has the potential to improve the accuracy of intracranial electroencephalography recordings and may reduce the necessity for revision surgery.

Morphological changes of intracranial pressure pulses are correlated with acute dilatation of ventricles

BACKGROUND Potentially useful information may exist in the morphological changes in intracranial pressure pulse therefore their extraction by automated methods is highly desirable. METHODS Long-term continuous recordings of intracranial pressure and electrocardiogram (ECG) signals were analyzed for four patients undergoing intracranial pressure (ICP) monitoring with their implanted shunts externalized and clamped. A novel clustering algorithm was invented to process hours of continuous ICP recordings such that a dominant ICP pulse was extracted every 5 min. Morphological characteristics of dominant ICP pulses were then extracted after detecting characteristics points of a dominant ICP pulse that include the locations of ICP pulse onset, the first (P1), the second (P2), and the third peaks (P3) (or inflection points in the absence of peaks). FINDINGS It was found that ratios of P2 amplitude to P1 amplitude and P3 amplitude to P1 amplitude showed a strong increasing trend for a patient whose lateral ventricles were significantly enlarged (bi-frontal distance was 33 cm on day 0 and 37 cm on day 2) while there were no consistent trends in these morphological features of ICP pulse for the three patients whose ventricles size was not altered during the monitoring period. CONCLUSION The present work demonstrates the usefulness of this novel ICP pulse analysis algorithm in terms of its potential capabilities of extracting predictive pulse morphological features from long-term continuous ICP recordings that correlate with the development of ventriculomegaly.