Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges.

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

Identifying the neurophysiological effects of memory-enhancing amygdala stimulation using interpretable machine learning.

BACKGROUND: Direct electrical stimulation of the amygdala can enhance declarative memory for specific events. An unanswered question is what underlying neurophysiological changes are induced by amygdala stimulation. OBJECTIVE: To leverage interpretable machine learning to identify the neurophysiological processes underlying amygdala-mediated memory, and to develop more efficient neuromodulation technologies. METHOD: Patients with treatment-resistant epilepsy and depth electrodes placed in the hippocampus and amygdala performed a recognition memory task for neutral images of objects. During the encoding phase, 160 images were shown to patients. Half of the images were followed by brief low-amplitude amygdala stimulation. For local field potentials (LFPs) recorded from key medial temporal lobe structures, feature vectors were calculated by taking the average spectral power in canonical frequency bands, before and after stimulation, to train a logistic regression classification model with elastic net regularization to differentiate brain states. RESULTS: Classifying the neural states at the time of encoding based on images subsequently remembered versus not-remembered showed that theta and slow-gamma power in the hippocampus were the most important features predicting subsequent memory performance. Classifying the post-image neural states at the time of encoding based on stimulated versus unstimulated trials showed that amygdala stimulation led to increased gamma power in the hippocampus. CONCLUSION: Amygdala stimulation induced pro-memory states in the hippocampus to enhance subsequent memory performance. Interpretable machine learning provides an effective tool for investigating the neurophysiological effects of brain stimulation.

A novel technique for removing a fibrin sheath from a mediport catheter in the pediatric population.

Mediport (also known as port, portacath or Infusaport) is a commonly placed central venous access in pediatric patients. Fibrin sheath formation around the central venous catheter is a common biological response leading to port malfunction in the form of inability to aspirate but preserved capacity for infusion of fluids. If fibrinolytic therapy fails, percutaneous fibrin sheath stripping via transfemoral route or replacement with a new mediport are routine/conventional treatments for a fibrin sheath. We describe a novel technique for removing a fibrin sheath by exteriorizing the catheter through the neck entry site, stripping the fibrin sheath from the catheter manually under sterile conditions and replacing the catheter via a peel-away sheath introduced through the same skin incision as an alternative to complete port replacement or attempted catheter stripping.

NRF2 plays a protective role in diabetic retinopathy in mice.

AIMS/HYPOTHESIS: Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR. METHODS: Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints. RESULTS: NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood-retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes. CONCLUSIONS/INTERPRETATION: These results indicate that NRF2 is an important protective factor regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.

Novel targets against retinal angiogenesis in diabetic retinopathy.

Proliferative diabetic retinopathy (PDR), characterized by pathologic retinal angiogenesis, is a major cause of blindness in the USA and globally. Treatments targeting vascular endothelial growth factor (VEGF) have emerged as a beneficial part of the therapeutic armamentarium for this condition, highlighting the utility of identifying and targeting specific pathogenic molecules. There continues to be active research into the molecular players regulating retinal angiogenesis, including pro-angiogenic factors, anti-angiogenic factors, and integrins and matrix proteinases. New insights have been especially prominent regarding molecules which regulate specialized endothelial cells called tip cells, which play a lead role in endothelial sprouting. Together, these research efforts are uncovering new, important molecular regulators of retinal angiogenesis, which provide fertile areas for therapeutic exploration. This review discusses potential molecular targets, with an emphasis towards newer targets.

Afr2 regulation occurs cell-autonomously in vitro but is not conferred on episomal DNA in transient assays.

Oncofetal antigens such as alpha-fetoprotein (AFP) are expressed in regenerating liver. The level of AFP gene expression during liver regeneration is regulated by the unlinked, autosomal gene, Alpha-fetoprotein regulator 2 (Afr2). C3H/HeJ (Afr2A/A) mice express 10-fold higher levels of AFP than C57BL/6J (Afr2B/B) mice. Here we show that primary hepatocytes isolated from C3H/HeJ and C57BL/6J mice exhibit differential expression of the endogenous AFP gene, which was attributed to the Afr2 gene locus and indicative of a cell-autonomous mechanism. We show that the Afr2-Response Element (ARE), between 1010 and 838 base pairs upstream of the AFP transcriptional start site, did not modulate reporter gene expression in transfection assays of Hep G2, Hep 3B, Hepa 1.6, and HeLa cell lines. Reporter gene expression in transiently transfected primary hepatocytes was also ARE-independent. Finally, gene expression from reporter constructs delivered by hydrodynamics-based transfection to the livers of C3H/HeJ and C57BL/6J mice after CCl4-induced liver regeneration was ARE-independent. In conclusion, ARE-dependent transcription was not found in transient assays performed in three different systems, two of which retained regulation of the endogenous AFP gene, suggesting that the ARE may not function as a simple transcription factor recognition site.