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Our objective is to examine the layer and spectrotemporal architecture and laminar distribution of high-frequency oscillations (HFOs) in a neonatal freeze lesion model of focal cortical dysplasia (FCD) associated with a high prevalence of spontaneous spike-wave discharges (SWDs). Electrophysiological recording of local field potentials (LFPs) in control and freeze lesion animals were obtained with linear micro-electrode arrays to detect presence of HFOs as compared to changes in spectral power, signal coherence, and single-unit distributions during \"hyper-excitable\" epochs of anesthesia-induced burst-suppression (B-S). Result were compared to HFOs observed during spontaneous SWDs in animals during sleep. Micro-electrode array recordings from the malformed cortex indicated significant increases in the presence of HFOs above 100 Hz and associated increases in spectral power and altered LFP coherence of recorded signals across cortical lamina of freeze-lesioned animals with spontaneous bursts of high-frequency activity, confined predominately to granular and supragranular layers. Spike sorting of well-isolated single-units recorded from freeze-lesioned cortex indicated an increase in putative excitatory cell activity in the outer cortical layers that showed only a weak association with HFOs while deeper inhibitory units were strongly phase-locked to high-frequency ripple (HFR) oscillations (300-800 Hz). Both SWDs and B-S show increases in HFR activity that were phase-locked to the high-frequency spike pattern occurring at the trough of low frequency oscillations. The spontaneous cyclic spiking of cortical inhibitory cells appears to be the driving substrate behind the HFO patterns associated with SWDs and a hyperexcitable supragranular layer near the malformed cortex may play a key role in epileptogenesis in our model. These data, derived from a mouse model with a distinct focal cortical malformation, support recent clinical data that HFOs, particularly fast ripples, is a biomarker to help define the cortical seizure zone, and provide limited insights toward understanding cellular level changes underlying the HFOs.

Focal cortical dysplasias (FCDs) are a common cause of brain seizures and are often associated with intractable epilepsy. Here we evaluated aberrant brain neurophysiology in an mouse model of FCD induced by neonatal freeze lesions (FLs) to the right cortical hemisphere (near S1). Linear multi-electrode arrays were used to record extracellular potentials from cortical and subcortical brain regions near the FL in anesthetized mice (5-13 months old) followed by 24 h cortical electroencephalogram (EEG) recordings. Results indicated that FL animals exhibit a high prevalence of spontaneous spike-wave discharges (SWDs), predominately during sleep (EEG), and an increase in the incidence of hyper-excitable burst/suppression activity under general anesthesia (extracellular recordings, 0.5%-3.0% isoflurane). Brief periods of burst activity in the local field potential (LFP) typically presented as an arrhythmic pattern of increased theta-alpha spectral peaks (4-12 Hz) on a background of low-amplitude delta activity (1-4 Hz), were associated with an increase in spontaneous spiking of cortical neurons, and were highly synchronized in control animals across recording sites in both cortical and subcortical layers (average cross-correlation values ranging from +0.73 to +1.0) with minimal phase shift between electrodes. However, in FL animals, cortical vs. subcortical burst activity was strongly out of phase with significantly lower cross-correlation values compared to controls (average values of -0.1 to +0.5, < 0.05 between groups). In particular, a marked reduction in the level of synchronous burst activity was observed, the closer the recording electrodes were to the malformation (Pearson's Correlation = 0.525, < 0.05). In a subset of FL animals (3/9), burst activity also included a spike or spike-wave pattern similar to the SWDs observed in unanesthetized animals. In summary, neonatal FLs increased the hyperexcitable pattern of burst activity induced by anesthesia and disrupted field potential synchrony between cortical and subcortical brain regions near the site of the cortical malformation. Monitoring the altered electrophysiology of burst activity under general anesthesia with multi-dimensional micro-electrode arrays may serve to define distinct neurophysiological biomarkers of epileptogenesis in human brain and improve techniques for surgical resection of epileptogenic malformed brain tissue.

The analysis of circulating tumour cells (CTCs) in cancer patients could provide important information for therapeutic management. Enrichment of viable CTCs could permit performance of functional analyses on CTCs to broaden understanding of metastatic disease. However, this has not been widely accomplished. Addressing this challenge, we present a separable bilayer (SB) microfilter for viable size-based CTC capture. Unlike other single-layer CTC microfilters, the precise gap between the two layers and the architecture of pore alignment result in drastic reduction in mechanical stress on CTCs, capturing them viably. Using multiple cancer cell lines spiked in healthy donor blood, the SB microfilter demonstrated high capture efficiency (78–83%), high retention of cell viability (71–74%), high tumour cell enrichment against leukocytes (1.7–2 × 10 3 ) and widespread ability to establish cultures post-capture (100% of cell lines tested). In a metastatic mouse model, SB microfilters successfully enriched viable mouse CTCs from 0.4–0.6 mL whole mouse blood samples and established in vitro cultures for further genetic and functional analysis. Our preliminary studies reflect the efficacy of the SB microfilter device to efficiently and reliably enrich viable CTCs in animal model studies, constituting an exciting technology for new insights in cancer research.

Auditory neurons in the inferior colliculus (IC) of the pallid bat have highly rate selective responses to downward frequency modulated (FM) sweeps attributable to the spectrotemporal pattern of their echolocation call (a brief FM pulse). Several mechanisms are known to shape FM rate selectivity within the pallid bat IC. Here we explore how two mechanisms, stimulus duration and high-frequency inhibition (HFI), can interact to shape FM rate selectivity within the same neuron. Results from extracellular recordings indicated that a derived duration-rate function (based on tonal response) was highly predictive of the shape of the FM rate response. Longpass duration selectivity for tones was predictive of slowpass rate selectivity for FM sweeps, both of which required long stimulus durations and remained intact following iontophoretic blockade of inhibitory input. Bandpass duration selectivity for tones, sensitive to only a narrow range of tone durations, was predictive of bandpass rate selectivity for FM sweeps. Conversion of the tone duration response from bandpass to longpass after blocking inhibition was coincident with a change in FM rate selectivity from bandpass to slowpass indicating an active inhibitory component to the formation of bandpass selectivity. Independent of the effect of duration tuning on FM rate selectivity, the presence of HFI acted as a fastpass FM rate filter by suppressing slow FM sweep rates. In cases where both mechanisms were present, both had to be eliminated, by removing inhibition, before bandpass FM rate selectivity was affected. It is unknown why the auditory system utilizes multiple mechanisms capable of shaping identical forms of FM rate selectivity though it may represent distinct but convergent modes of neural signaling directed at shaping response selectivity for important biologically relevant sounds.

To gain additional insights into the pathogenic cellular and molecular mechanisms underlying different types of brain injury (e.g., trauma versus ischemia), recently attention has focused on the discovery and study of protein biomarkers. In previous studies, using a high-throughput immunoblotting (HTPI) technique, we reported changes in 29 out of 998 proteins following acute injuries to the rat brain (penetrating traumatic versus focal ischemic). Importantly, we discovered that one protein, endothelial monocyte-activating polypeptide II precursor (p43/pro-EMAPII), was differentially expressed between these two types of brain injury. Among other functions, p43/pro-EMAPII is a known pro-inflammatory cytokine involved in the progression of apoptotic cell death. Our current objective was to verify the changes in p43/pro-EMAPII expression, and to evaluate the potentially important implications that the differential regulation of this protein has on injury development. At multiple time points following either a penetrating ballistic-like brain injury (PBBI), or a transient middle cerebral artery occlusion (MCAo) brain injury, tissue samples (6–72 h), CSF samples (24 h), and blood samples (24 h) were collected from rats for analysis. Changes in protein expression were assessed by Western blot analysis and immunohistochemistry. Our results indicated that p43/pro-EMAPII was significantly increased in brain tissues, CSF, and plasma following PBBI, but decreased after MCAo injury compared to their respective sham control samples. This differential expression of p43/pro-EMAPII may be a useful injury-specific biomarker associated with the underlying pathologies of traumatic versus ischemic brain injury, and provide valuable information for directing injury-specific therapeutics. Expression of Concern: Readers are advised that after receiving an alert regarding a comment on the PubPeer platform,1 the Journal of Neurotrauma attempted to contact the authors of a paper published in 2009 entitled, “P43/pro-EMAPII: A Potential Biomarker for Discriminating Traumatic Versus Ischemic Brain Injury,” by Changping Yao, Anthony J. Williams, Andrew K. Ottens, X.-C. May Lu, Ming Cheng Liu, Ronald L. Hayes, Kevin K. Wang, Frank C. Tortella, and Jitendra R. Dave (J Neurotrauma. 2009:26(8):1295-1305.; doi: 10.1089/neu.2008.0811), requesting information and/or clarification on the post which claimed possible figure duplication. After receiving the alert, independent analyses run by the journal confirmed a duplicated panel in Figure 5: M-C 24 and 72 hours, as well as a potential duplication with panels M-C and M-I. One of the co-authors, Dr. Kevin Wang, replied1 directly on the PubPeer platform, indicating: “I agree with you that the control shown as 72 h and at 24 h are likely the same. The data were generated not by our team by at WRIAR, I know that senior author Dr. Dave also passed away many years ago now. If so, it was likely duplicated during image sorting inadvertently. Hope this is helpful.” Journal of Neurotrauma issues this Expression of Concern for readers to take this into consideration. Reference 1. Actinopolyspora biskrensis. https://pubpeer.com/publications/F055E49F03750B813AE6F1752561F5?utm_source=Firefox_utm_medium=BrowserExtension&utm_campaign=Firefox

Acute and delayed cerebral injury was assessed in a recently developed rat model of a penetrating ballistic-like brain injury (PBBI). A unilateral right frontal PBBI trajectory was used to induce survivable injuries to the frontal cortex and striatum. Three distinct phases of injury progression were observed. Phase I (primary injury, 0–6 h) began with immediate (<5 min) intracerebral hemorrhage(ICH) that reached maximal volumetric size at 6 h (27.0 ± 2.9 mm3). During Phase II (secondary injury, 6–72 h), a core lesion of degenerate neurons surrounding the injury track expanded into peri-lesional areas to reach a maximal volume of 69.9 ± 6.1 mm3 at 24 h. The core lesion consisted of predominately necrotic cell death and included marked infiltration of both neutrophils (24 h) and macrophages (72 h). Phase III (delayed degeneration, 3–7 days) involved the degeneration of neurons and fiber tracts remote from the core lesion including the thalamus, internal capsule, external capsule, and cerebral peduncle. Overall, different time courses of hemorrhage, lesion evolution, and inflammation were consistent with complementary roles in injury development and repair, providing key information about these mediators of primary, secondary, and delayed brain injury development. The similarities/differences of PBBI to other focal brain injury models are discussed.

The inferior colliculus and auditory cortex of the pallid bat contain a large percentage of neurons that are highly selective for the direction and rate of the downward frequency modulated (FM) sweep of the bat's echolocation pulse. Approximately 25% of neurons tuned to the echolocation pulse respond exclusively to downward FM sweeps. This review focuses on the finding that this selectivity is generated by multiple mechanisms that may act alone or in concert. In the inferior colliculus, selectivity for sweep rate is shaped by at least three mechanisms: shortpass or bandpass tuning for signal duration, delayed high-frequency inhibition that prevents responses to slow sweep rates, and asymmetrical facilitation that occurs only when two tones are presented at appropriate delays. When acting alone, the three mechanisms can produce essentially identical rate selectivity. Direction selectivity can be produced by two mechanisms: an early low-frequency inhibition that prevents responses to upward sweeps, and the same asymmetrical two-tone inhibition that shapes rate tuning. All mechanisms except duration tuning are also present in the auditory cortex. Discussion centers on whether these mechanisms are redundant or complementary.

Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines, some of which are regulated by the nuclear transcription factor NF-κB. In this study the authors examined mRNA expression levels for several important genes associated with inflammation at five time points (3, 6, 12, 24, and 72 hours) after transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. A sensitive and quantitative technique (TaqMan real-time QRT-PCR) was used to simultaneously measure mRNA levels for key cell adhesion molecules and inflammatory cytokines. Gene expression increased significantly in the injured hemisphere for interleukin (IL)-1β (12-fold increase at 24 hours), IL-6 (25-fold increase at 6 hours) and ICAM-1 (4-fold increase at 24 hours), and the in-terhemispheric differences for these genes were significant for every time point examined (P < 0.05 for all values). Tumor necrosis factor-α mRNA was upregulated in the injured versus uninjured hemisphere from 3 to 24 hours (5-fold increase at 6 hours), while E-selectin showed a significant increase in mRNA levels from 6 to 24 hours after MCAO (10-fold increase at 6 hours) (P < 0.05 for all values). VCAM-1 mRNA levels did not respond differentially to injury at any time point between the two brain hemispheres. At all time points examined, activated NF-κB immunoreactivity was observed in cells throughout the infarct-damaged tissue. These results are consistent with the proinflammatory properties of the induced molecules, which are involved in the initiation of the inflammatory cascade, and may thus contribute to secondary cellular responses that lead to further brain damage.

Ischemic and traumatic brain injuries often induce non-convulsive seizures (NCSs), which likely contribute to the worsening of neurological outcomes. Here, we evaluated the effect of glycyl-l-methylprolyl-l-glutamic acid (NNZ-2566) to lessen the severity of NCSs caused by permanent middle cerebral artery occlusion (pMCAo). Continuous electroencephalographic recordings were performed in rats during pMCAo. Glycyl-l-methylprolyl-l-glutamic acid (3, 10, or 100 mg/kg bolus followed by an infusion of a fixed dose of 3 mg/kg per hour for 12 h) was delivered at 20 mins after pMCAo (before the first NCS event) or delayed until immediately after the first NCS event occurred. Control rats received pMCAo and saline treatment. The results revealed that 91% of the saline-treated animals had NCSs (23 episodes per rat and 1238 secs per rat) with an onset latency of 35 mins after injury. When NNZ-2566 was administered before the NCS events, it dose-dependently reduced the NCS incidence to 36%–80%, decreased NCS frequency to 5–16 episodes per rat, and shortened the total duration of NCS to 251–706 secs per rat. The two high doses significantly reduced the infarct volume by 28%–30%. Delayed treatment also attenuated NCS duration but had no effect on the infarct volume. Results indicate that NNZ-2566 possesses a unique therapeutic potential as a safe prophylactic agent that synergistically provides neuroprotection and reduces injury-induced seizures.

Penetrating brain injury (PBI) is a leading cause of mortality and morbidity in modern warfare and accounts for a significant number of traumatic brain injuries worldwide. Here we characterize the pathophysiology of a new rat model of PBI that simulates the large temporary cavity caused by energy dissipation from a penetrating bullet round. Male Sprague-Dawley rats (250–300 g) were subjected to a simulated ballistic wound to the right frontal hemisphere implemented by an inflatable penetrating probe. Three levels of injury severity were compared to control animals. Neurological and physiological outcome was assessed over a 3-day recovery period and brain tissue collected at 72 h for histopathological evaluation. Brain-injured regions included the ipsilateral frontal cortex and striatum with volumetric increases in intracranial hemorrhage (5–18 mm3) and lesion size (9–86 mm3) related to severity. Similarly, hemispheric swelling increased (3–14%) following PBI, associated with a significant rise in intracranial pressure. Astrogliosis was present in regions adjacent to the core-injury along with microglial and leukocyte infiltration. Injury remote to the lesion was observed in the cerebral peduncle that may have accounted, in part, for observed neurological deficits. Neurological and balance beam testing revealed sensorimotor deficits that persisted through 72 h. Severe electroencephalographic disturbances included the occurrence of cortical spreading depression, slow-waves, and brain seizure activity. In conclusion, this rat PBI model replicates diverse, salient features of clinical PBI pathology, generates reproducible and quantifiable measures of outcome, and is scalable by injury severity, rendering it an attractive vehicle for experimental brain trauma research.