Colin Kealey

TARP |[gamma]|-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity

Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.

THz Medical Imaging: in vivo Hydration Sensing

The application of THz to medical imaging is experiencing a surge in both interest and federal funding. A brief overview of the field is provided along with promising and emerging applications and ongoing research. THz imaging phenomenology is discussed and tradeoffs are identified. A THz medical imaging system, operating at ~525 GHz center frequency with ~125 GHz of response normalized bandwidth is introduced and details regarding principles of operation are provided. Two promising medical applications of THz imaging are presented: skin burns and cornea. For burns, images of second degree, partial thickness burns were obtained in rat models in vivo over an 8 hour period. These images clearly show the formation and progression of edema in and around the burn wound area. For cornea, experimental data measuring the hydration of ex vivo porcine cornea under drying is presented demonstrating utility in ophthalmologic applications.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Objective: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. Methods: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. Results: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59–0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). Conclusions: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. Classification of evidence: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

In vivo terahertz imaging of rat skin burns

A reflective, pulsed terahertz (THz) imaging system was used to acquire high-resolution (d(10-90)/λ~1.925) images of deep, partial thickness burns in a live rat. The rats abdomen was burned with a brass brand heated to ~220°C and pressed against the skin with contact pressure for ~10 sec. The burn injury was imaged beneath a Mylar window every 15 to 30 min for up to 7 h. Initial images display an increase in local water concentration of the burned skin as evidenced by a marked increase in THz reflectivity, and this likely correlates to the post-injury inflammatory response. After ~1 h the area of increased reflectivity consolidated to the region of skin that had direct contact with the brand. Additionally, a low reflecting ring of tissue could be observed surrounding the highly reflective burned tissue. We hypothesize that these regions of increased and decreased reflectivity correlate to the zones of coagulation and stasis that are the classic foundation of burn wound histopathology. While further investigations are necessary to confirm this hypothesis, if true, it likely represents the first in vivo THz images of these pathologic zones and may represent a significant step forward in clinical application of THz technology.

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy

BACKGROUND External trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy. METHODS This was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate. RESULTS Thirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects. CONCLUSION The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.

In vitro hemocompatibility of thin film nitinol in stenotic flow conditions.

Because of its low profile and biologically inert behavior, thin film nitinol (TFN) is ideally suited for use in construction of endovascular devices. We have developed a surface treatment for TFN designed to minimize platelet adhesion by creating a superhydrophilic surface. The hemocompatibility of expanded polytetrafluorethylene (ePTFE), untreated thin film nitinol (UTFN), and a surface treated superhydrophilic thin film nitinol (STFN) was compared using an in vitro circulation model with whole blood under flow conditions simulating a moderate arterial stenosis. Scanning electron microscopy analysis showed increased thrombus on ePTFE as compared to UTFN or STFN. Total blood product deposition was 6.3 ± 0.8 mg/cm(2) for ePTFE, 4.5 ± 2.3 mg/cm(2) for UTFN, and 2.9 ± 0.4 mg/cm(2) for STFN (n = 12, p < 0.01). ELISA assay for fibrin showed 326 ± 42 μg/cm(2) for ePTFE, 45.6 ± 7.4 μg/cm(2) for UTFN, and 194 ± 25 μg/cm(2) for STFN (n = 12, p < 0.01). Platelet deposition measured by fluorescent intensity was 79,000 20,000 AU/mm(2) for ePTFE, 810 ± 190 AU/mm(2) for UTFN, and 1600 ± 25 AU/mm(2) for STFN (n = 10, p < 0.01). Mass spectrometry demonstrated a larger number of proteins on ePTFE as compared to either thin film. UTFN and STFN appear to attract significantly less thrombus than ePTFE. Given TFNs low profile and our previously demonstrated ability to place TFN covered stents in vivo, it is an excellent candidate for use in next-generation endovascular stents grafts.

In vitro and in vivo testing of a novel, hyperelastic thin film nitinol flow diversion stent.

A flexible, low profile, flow diversion stent could replace endovascular coiling for the treatment of intracranial aneurysms. Micropatterned-thin film nitinol (TFN) is a novel biomaterial with high potential for use in next-generation endovascular devices. Recent advancements in micropatterning have allowed for fabrication of a hyperelastic thin film nitinol (HE-TFN). In this study, the authors describe in vitro and in vivo testing of novel HE-TFN based flow diverting stents. Two types of HE-TFN with expanded pores having long axes of 300 and 500 μm were used to fabricate devices. In vitro examination of the early thrombotic response in whole blood showed a possible mechanism for the devices function, whereby HE-TFN serves as a scaffold for blood product deposition. In vivo testing in swine demonstrated rapid occlusion of model wide-neck aneurysms. Average time to occlusion for the 300-μm device was 10.4 ± 5.5 min. (N = 5) and 68 ± 30 min for the 500-μm device (N = 5). All aneurysms treated with bare metal control stents remained patent after 240 min (N = 3). SEM of acutely harvested devices supported in vitro results, demonstrating that HE-TFN serves as a scaffold for blood product deposition, potentially enhancing its flow-diverting effect. Histopathology of devices after 42 days in vivo demonstrated a healthy neointima and endothelialization of the aneurysm neck region. HE-TFN flow-diverting stents warrant further investigation as a novel treatment for intracranial aneurysms.

Intra-aneurysmal flow reductions in a thin film nitinol flow diverter

A novel hyper-elastic thin film nitinol (HE-TFN) covered stent has been developed to promote aneurysm occlusion by diminishing flow in the aneurysm. Laboratory aneurysm models were used to assess the flow changes produced by stents covered with different patterns of HE-TFN placed across the aneurysm neck in the parent vessel. The flow diverters were constructed by covering Wingspan stents (Boston Scientific) with different HE-TFNs (i.e., of 82% and 77% porosity) and deployed in both in vitro wide-neck and fusiform glass aneurysm models. In wide-neck aneurysms, the 82% porous HE-TFN stent reduced mean flow velocity in the middle of the sac by 86 ± 1%, while the 77% porous stent reduced the velocity by 93 ± 5% (n = 3). Local wall shear rates were also significantly reduced by about 98% in this model after device placement. Tests conducted on the fusiform aneurysm revealed smaller intra-aneurysmal flow velocity reduction by 48 ± 3% for the 82% porous stent and by 59 ± 7% for the 77% porous stent. The wall shear was reduced by approximately 50% by HE-TFN stents in fusiform models. These results suggest that HE-TFN covered stents have the potential to promote thrombosis in both wide-neck and fusiform aneurysm sacs.

The potential use of trigeminal nerve stimulation in the treatment of epilepsy

Editorial For reprint orders, please contact reprints@future-science.com Therapeutic Delivery The potential use of trigeminal nerve stimulation in the treatment of epilepsy “ ...after billions of R&D dollars to develop new drugs, this needle has not budged. A new approach is needed. ” Keywords: adjunctive treatment • anti-convulsant • bilateral stimulation • brain stimulation • cranial nerve stimulation • drug resistance • epilepsy • neuromodulation • non-invasive • trigeminal nerve stimulation Among neurological disorders, epilepsy poses an enormous clinical and societal problem, affecting approximately 50,000,000 people worldwide [1] . For individual patients, the presence of a chronic brain disorder marked by episodic convulsions and loss of control of mental and physical actions can limit occupational and social achievement. From a macro perspective, epilepsy is associated with considerable societal economic burden, accounting for a substantial proportion of the ‘disability adjusted life years’ ascribed to neurological illnesses [2] . Critically, approxi- mately a third of patients with epilepsy have ‘drug resistant epilepsy (DRE),’ character- ized as having persistent seizures despite hav- ing tried at least two different antiepileptic drugs (AEDs) [3] . Of the roughly three dozen AEDs used in the USA, approximately half have been introduced over the past four decades, and while strides have been made in improving efficacy and tolerability, the clinical challenge of DRE persists at roughly a third of all patients with epilepsy: stated differently, after billions of R&D dollars to develop new drugs, this needle has not budged. A new approach is needed. Neuromodulation interventions offer an alternative to the administration of phar- maceutical products. These therapies are intended to alter brain function by applying electric or magnetic fields to the CNS, either directly to the CNS as in deep brain stimula- tion, or via peripheral or cranial nerves, as in vagus nerve stimulation. Some key theoretical advantages of neuromodulation over drug 10.4155/TDE.14.120

Advances in biomedical imaging using THz technology with applications to burn-wound assessment

Terahertz (THz) hydration sensing and image has been a topic of increased interest recently due largely to improvements in source and detector technology and the identification of applications where current hydration sensing techniques are insufficient. THz medical imaging is an expanding field of research and tissue hydration plays a key role in the contrast observed in THz tissue reflectance and absorbance maps. This paper outlines the most recent results in burn and corneal imaging where hydration maps were used to assess tissue status. A 3 day study was carried out in rat models where a THz imaging system was used to assess the severity and extent of burn throughout the first day of injury and at the 24, 48, and 72 hour time points. Marked difference in tissue reflectance were observed between the partial and full thickness burns and image features were identified that may be used as diagnostic markers for burn severity. Companion histological analysis performed on tissue excised on Day 3 confirms hypothesized burn severity. The results of these preliminary animal trials suggest that THz imaging may be useful in burn wound assessment where current clinical modalities have resolution and/or sensitivity insufficient for accurate diagnostics.