Wherever I may roam-Human activity alters movements of red deer (Cervus elaphus) and elk (Cervus canadensis) across two continents.

Human activity and associated landscape modifications alter the movements of animals with consequences for populations and ecosystems worldwide. Species performing long-distance movements are thought to be particularly sensitive to human impact. Despite the increasing anthropogenic pressure, it remains challenging to understand and predict animals' responses to human activity. Here we address this knowledge gap using 1206 Global Positioning System movement trajectories of 815 individuals from 14 red deer (Cervus elaphus) and 14 elk (Cervus canadensis) populations spanning wide environmental gradients, namely the latitudinal range from the Alps to Scandinavia in Europe, and the Greater Yellowstone Ecosystem in North America. We measured individual-level movements relative to the environmental context, or movement expression, using the standardized metric Intensity of Use, reflecting both the directionality and extent of movements. We expected movement expression to be affected by resource (Normalized Difference Vegetation Index, NDVI) predictability and topography, but those factors to be superseded by human impact. Red deer and elk movement expression varied along a continuum, from highly segmented trajectories over relatively small areas (high intensity of use), to directed transitions through restricted corridors (low intensity of use). Human activity (Human Footprint Index, HFI) was the strongest driver of movement expression, with a steep increase in Intensity of Use as HFI increased, but only until a threshold was reached. After exceeding this level of impact, the Intensity of Use remained unchanged. These results indicate the overall sensitivity of Cervus movement expression to human activity and suggest a limitation of plastic responses under high human pressure, despite the species also occurring in human-dominated landscapes. Our work represents the first comparison of metric-based movement expression across widely distributed populations of a deer genus, contributing to the understanding and prediction of animals' responses to human activity.

Large carnivores avoid humans while prioritizing prey acquisition in anthropogenic areas.

Large carnivores are recovering in many landscapes where the human footprint is simultaneously growing. When carnivores encounter humans, the way they behave often changes, which may subsequently influence how they affect their prey. However, little research investigates the behavioural mechanisms underpinning carnivore response to humans. As a result, it is not clear how predator-prey interactions and their associated ecosystem processes will play out in the human-dominated areas into which carnivore populations are increasingly expanding. We hypothesized that humans would reduce predation risk for prey by disturbing carnivores or threatening their survival. Alternatively, or additionally, we hypothesized that humans would increase predation risk by providing forage resources that congregate herbivorous prey in predictable places and times. Using grey wolves Canis lupus in Jackson Hole, Wyoming, USA as a study species, we investigated 170 kill sites across a spectrum of human influences ranging from heavily restricted human activities on protected federal lands to largely unregulated activities on private lands. Then, we used conditional logistic regression to quantify how the probability of predation changed across varied types and amounts of human influences, while controlling for environmental characteristics and prey availability. Wolves primarily made kills in environmental terrain traps and where prey availability was high, but predation risk was significantly better explained with the inclusion of human influences than by environmental characteristics alone. Different human influences had different, and even converse, effects on the risk of wolf predation. For example, where prey were readily available, wolves preferentially killed animals far from motorized roads but close to unpaved trails. However, wolves responded less strongly to humans, if at all, where prey were scarce, suggesting they prioritized acquiring prey over avoiding human interactions. Overall, our work reveals that the effects of large carnivores on prey populations can vary considerably among different types of human influences, yet carnivores may not appreciably alter predatory behaviour in response to humans if prey are difficult to obtain. These results shed new light on the drivers of large carnivore behaviour in anthropogenic areas while improving understanding of predator-prey dynamics in and around the wildland-urban interface.

Evidence supporting deep brain stimulation of the medial septum in the treatment of temporal lobe epilepsy.

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial.

Anterior-posterior pattern formation in ciliates.

As single cells, ciliates build, duplicate, and even regenerate complex cortical patterns by largely unknown mechanisms that precisely position organelles along two cell-wide axes: anterior-posterior and circumferential (left-right). We review our current understanding of intracellular patterning along the anterior-posterior axis in ciliates, with emphasis on how the new pattern emerges during cell division. We focus on the recent progress at the molecular level that has been driven by the discovery of genes whose mutations cause organelle positioning defects in the model ciliate Tetrahymena thermophila. These investigations have revealed a network of highly conserved kinases that are confined to either anterior or posterior domains in the cell cortex. These pattern-regulating kinases create zones of cortical inhibition that by exclusion determine the precise placement of organelles. We discuss observations and models derived from classical microsurgical experiments in large ciliates (including Stentor) and interpret them in light of recent molecular findings in Tetrahymena. In particular, we address the involvement of intracellular gradients as vehicles for positioning organelles along the anterior-posterior axis.

Eyes on the herd: Quantifying ungulate density from satellite, unmanned aerial systems, and GPScollar data.

Novel approaches to quantifying density and distributions could help biologists adaptively manage wildlife populations, particularly if methods are accurate, consistent, cost-effective, rapid, and sensitive to change. Such approaches may also improve research on interactions between density and processes of interest, such as disease transmission across multiple populations. We assess how satellite imagery, unmanned aerial system (UAS) imagery, and Global Positioning System (GPS) collar data vary in characterizing elk density, distribution, and count patterns across times with and without supplemental feeding at the National Elk Refuge (NER) in the US state of Wyoming. We also present the first comparison of satellite imagery data with traditional counts for ungulates in a temperate system. We further evaluate seven different aggregation metrics to identify the most consistent and sensitive metrics for comparing density and distribution across time and populations. All three data sources detected higher densities and aggregation locations of elk during supplemental feeding than non-feeding at the NER. Kernel density estimates (KDEs), KDE polygon areas, and the first quantile of interelk distances detected differences with the highest sensitivity and were most highly correlated across data sources. Both UAS and satellite imagery provide snapshots of density and distribution patterns of most animals in the area at lower cost than GPS collars. While satellite-based counts were lower than traditional counts, aggregation metrics matched those from UAS and GPS data sources when animals appeared in high contrast to the landscape, including brown elk against new snow in open areas. UAS counts of elk were similar to traditional ground-based counts on feed grounds and are the best data source for assessing changes in small spatial extents. Satellite, UAS, or GPS data can provide appropriate data for assessing density and changes in density from adaptive management actions. For the NER, where high elk densities are beneath controlled airspace, GPS collar data will be most useful for evaluating how management actions, including changes in the dates of supplemental feeding, influence elk density and aggregation across large spatial extents. Using consistent and sensitive measures of density may improve research on the drivers and effects of density within and across a wide range of species.

Restoration of cellular integrity following "ballistic" pronuclear exchange during Tetrahymena conjugation.

During sexual reproduction or conjugation, ciliates form a specialized cell adhesion zone for the purpose of exchanging gametic pronuclei. Hundreds of individual membrane fusion events transform the adhesion zone into a perforated membrane curtain, the mating junction. Pronuclei from each mating partner are propelled through this fenestrated membrane junction by a web of short, cris-crossing microtubules. Pronuclear passage results in the formation of two breaches in the membrane junction. Following pronuclear exchange and karyogamy (fertilization), cells seal these twin membrane breaches thereby re-establishing cellular independence. This would seem like a straightforward problem: simply grow membrane in from the edges of each breach in a fashion similar to how animal cells "grow" their cytokinetic furrows or how plant cells construct a cell wall during mitosis. Serial section electron microscopy and 3-D electron tomography reveal that the actual mechanism is less straightforward. Each of the two membrane breaches transforms into a bowed membrane assembly platform. The resulting membrane protrusions continue to grow into the cytoplasm of the mating partner, traverse the cytoplasm in anti-parallel directions and make contact with the plasma membrane that flanks the mating junction. This investigation reveals the details of a novel, developmentally-induced mechanism of membrane disruption and restoration associated with pronuclear exchange and fertilization in the ciliate, Tetrahymena thermophila.

Plasticity in elk migration timing is a response to changing environmental conditions.

Migration is an effective behavioral strategy for prolonging access to seasonal resources and may be a resilient strategy for ungulates experiencing changing climatic conditions. In the Greater Yellowstone Ecosystem (GYE), elk are the primary ungulate, with approximately 20,000 individuals migrating to exploit seasonal gradients in forage while also avoiding energetically costly snow conditions. How climate-induced changes in plant phenology and snow accumulation are influencing elk migration timing is unknown. We present the most complete record of elk migration across the GYE, spanning 9 herds and 414 individuals from 2001 to 2017, to evaluate the drivers of migration timing and test for temporal shifts. The timing of elk departure from winter range involved a trade-off between current and anticipated forage conditions, while snow melt governed summer range arrival date. Timing of elk departure from summer range and arrival on winter range were both influenced by snow accumulation and exposure to hunting. At the GYE scale, spring and fall migration timing changed through time, most notably with winter range arrival dates becoming almost 50 days later since 2001. Predicted herd-level changes in migration timing largely agreed with observed GYE-wide changes-except for predicted winter range arrival dates which did not reflect the magnitude of change detected in the elk telemetry data. Snow melt, snow accumulation, and spring green-up dates all changed through time, with different herds experiencing different rates and directions of change. We conclude that elk migration is plastic, is a direct response to environmental cues, and that these environmental cues are not changing in a consistent manner across the GYE. The impacts of changing elk migration timing on predator-prey dynamics, carnivore-livestock conflict, disease ecology, and harvest management across the GYE are likely to be significant and complex.

A Systematic Review of Lower Lip Anatomy, Mechanics of Local Flaps, and Special Considerations for Lower Lip Reconstruction.

Reconstruction of defects of the lower lip can be very challenging. The aim of this review is to analyze the unique characteristics of lower lip anatomy and provide a systematic approach for lower lip reconstruction. A review of current literature was performed using the PubMed database. Articles analyzing the anatomic and histologic characteristics of the lower lip, mechanics of local faps, and different lower lip reconistruction techniques were included. Articles focused on lower lip reconstruction with free faps were excluded. The orbicularis oris has been described as the main supportive mechanism, however, a number of other structures have been shown to provide mechanical support to the lower lip, including septations of connective tissue extending from the epithelium to the orbicularis oris, a fbroelastic meshwork located in the mentolabial sulcus, and subdermal muscular fibers with dermal terminations in the area of the modiolus. Depending on the location, size, and depth of the wound, a number of reconstruction options are available. Preservation of the competency of orbicularis oris, relation-ship of the modiolus with associated muscles, and sensation, are critical components of functional reconstruction. Primary closure and local faps are assessed for these 3 components and analysis is provided. In conclusion, knowledge of the static and dynamic structural support of the lower lip, as well as the characteristics of different reconstructive options, is imperative for optimal functional and aesthetic outcomes.

Membrane dynamics at the nuclear exchange junction during early mating (one to four hours) in the ciliate Tetrahymena thermophila.

Using serial-section transmission electron microscopy and three-dimensional (3D) electron tomography, we characterized membrane dynamics that accompany the construction of a nuclear exchange junction between mating cells in the ciliate Tetrahymena thermophila. Our methods revealed a number of previously unknown features. (i) Membrane fusion is initiated by the extension of hundreds of 50-nm-diameter protrusions from the plasma membrane. These protrusions extend from both mating cells across the intercellular space to fuse with membrane of the mating partner. (ii) During this process, small membrane-bound vesicles or tubules are shed from the plasma membrane and into the extracellular space within the junction. The resultant vesicle-filled pockets within the extracellular space are referred to as junction lumens. (iii) As junction lumens fill with extracellular microvesicles and swell, the plasma membrane limiting these swellings undergoes another deformation, pinching off vesicle-filled vacuoles into the cytoplasm (reclamation). (iv) These structures (resembling multivesicular bodies) seem to associate with autophagosomes abundant near the exchange junction. We propose a model characterizing the membrane-remodeling events that establish cytoplasmic continuity between mating Tetrahymena cells. We also discuss the possible role of nonvesicular lipid transport in conditioning the exchange junction lipid environment. Finally, we raise the possibility of an intercellular signaling mechanism involving microvesicle shedding and uptake.

Expanded indications for the deep plane cervicofacial flap: aesthetic reconstruction of large combined temporofrontal and brow defects.

The deep plane cervicofacial (DPCF) rotation advancement flap has been well described for coverage of cheek and lower eyelid defects. The extension of this flap for coverage of complex combined temporofrontal and brow defects has not been previously described. The primary investigator (E.L.C.) performed a chart review of all 7 DPCF flaps performed for reconstructive purposes at the University of Texas Medical Branch, Galveston, Tex, from November 2011 through August 2012. Three patients with complex combined temporal and brow defects were identified. Three patients underwent coverage of complex combined temporofrontal and brow defects using the DPCF flap. Adequate coverage was provided with good skin color match. No flap loss or tip necrosis was seen, despite immediate excision of the resulting cheek standing cone deformity in 2 of the 3 patients at the time of reconstruction. All patients had suture fixation of the DPCF flap to cheek periosteum. All had none or mild lateral canthal distortion, with less than 1 mm of asymptomatic ectropion at a minimum follow-up of 4 months. The DPCF flap is a safe, effective, and reliable means to provide coverage for complex combined temporofrontal and brow defects. The deep plane elevation and musculocutaneous blood supply may improve flap mobility, viability, and resistance to tension. The standing cone deformity resulting from flap advancement can be primarily excised without risking flap necrosis. With further study, indications for the DPCF flap may include adjacent areas of the face currently being reconstructed using other means.

Is there a role for anterior zone sampling as part of saturation trans-rectal ultrasound guided prostate biopsy?

BACKGROUND: The prostatic anterior zone (AZ) is not targeted routinely by TRUS guided prostate biopsy (TRUS-Pbx). MRI is an accurate diagnostic tool for AZ tumors, but is often unavailable due to cost or system restrictions. We examined the diagnostic yield of office based AZ TRUS-Pbx. METHODS: 127 men at risk for AZ tumors were studied: Patients with elevated PSA and previous extended negative TRUS-Pbx (group 1, n = 78) and actively surveyed low risk prostate cancer patients (group 2, n = 49). None of the participants had a previous AZ biopsy. Biopsy template included suspicious ultrasonic areas, 16 peripheral zone (PZ), 4 transitional zone (TZ) and 6 AZ cores. All biopsies were performed by a single urologist under local peri-prostatic anaesthetic, using the B-K Medical US System, an end-firing probe 4-12 MHZ and 18 ga/25 cm needle. All samples were reviewed by a single specialized uro-pathologist. Multivariate analysis was used to detect predictors for AZ tumors accounting for age, PSA, PSA density, prostate volume, BMI, and number of previous biopsies. RESULTS: Median PSA was 10.4 (group 1) and 7.3 (group 2). Age (63.9, 64.5), number of previous biopsies (1.5) and cores (17.8, 21.3) and prostate volume (56.4 cc, 51 cc) were similar for both groups. The overall diagnostic yield was 34.6% (group 1) and 85.7% (group 2). AZ cancers were detected in 21.8% (group 1) and 34.7% (group 2) but were rarely the only zone involved (1.3% and 4.1% respectively). Gleason ≥ 7 AZ cancers were often accompanied by equal grade PZ tumors. In multivariate analysis only prostate volume predicted for AZ tumors. Patients detected with AZ tumors had significantly smaller prostates (36.9 cc vs. 61.1 cc p < 0.001). Suspicious AZ ultrasonic findings were uncommon (6.3%). CONCLUSIONS: TRUS-Pbx AZ sampling rarely improves the diagnostic yield of extended PZ sampling in patients with elevated PSA and previous negative biopsies. In low risk prostate cancer patients who are followed by active surveillance, AZ sampling changes risk stratification in 6% but larger studies are needed to define the role of AZ sampling in this population and its correlation with prostatectomy final pathological specimens.

Seizure event detection using intravital two-photon calcium imaging data.

Significance: Intravital cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging. Aim: To demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging-including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population-level activity and that of individual cells. Approach: We developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awake in vivo two-photon calcium imaging during pentylenetetrazol-induced seizures in mice. Results: We demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves. Conclusions: Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.

Organellular imaging in vivo reveals a depletion of endoplasmic reticular calcium during post-ictal cortical spreading depolarization.

During cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.

SAFE-OPT: a Bayesian optimization algorithm for learning optimal deep brain stimulation parameters with safety constraints.

Objective.To treat neurological and psychiatric diseases with deep brain stimulation (DBS), a trained clinician must select parameters for each patient by monitoring their symptoms and side-effects in a months-long trial-and-error process, delaying optimal clinical outcomes. Bayesian optimization has been proposed as an efficient method to quickly and automatically search for optimal parameters. However, conventional Bayesian optimization does not account for patient safety and could trigger unwanted or dangerous side-effects.Approach.In this study we develop SAFE-OPT, a Bayesian optimization algorithm designed to learn subject-specific safety constraints to avoid potentially harmful stimulation settings during optimization. We prototype and validate SAFE-OPT using a rodent multielectrode stimulation paradigm which causes subject-specific performance deficits in a spatial memory task. We first use data from an initial cohort of subjects to build a simulation where we design the best SAFE-OPT configuration for safe and accurate searchingin silico. Main results.We then deploy both SAFE-OPT and conventional Bayesian optimization without safety constraints in new subjectsin vivo, showing that SAFE-OPT can find an optimally high stimulation amplitude that does not harm task performance with comparable sample efficiency to Bayesian optimization and without selecting amplitude values that exceed the subject's safety threshold.Significance.The incorporation of safety constraints will provide a key step for adopting Bayesian optimization in real-world applications of DBS.

Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity.

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space.Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters.Main results.We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly 'artificial' (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity.Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization.

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson's disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico ( p < 0.0056 , N = 1000 ) and in vivo ( p = 0.0036 , N = 20 ) . This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

Refining Brain Stimulation Therapies: An Active Learning Approach to Personalization.

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson's disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico (p<0.0056, N=1,000) and in vivo (p=0.0036, N=20). This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.

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.

Neural pathway activation in the subthalamic region depends on stimulation polarity.

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD); however, there is limited understanding of which subthalamic pathways are recruited in response to stimulation. Here, by focusing on the polarity of the stimulus waveform (cathodic vs. anodic), our goal was to elucidate biophysical mechanisms that underlie electrical stimulation in the human brain. In clinical studies, cathodic stimulation more easily triggers behavioral responses, but anodic DBS broadens the therapeutic window. This suggests that neural pathways involved respond preferentially depending on stimulus polarity. To experimentally compare the activation of therapeutically relevant pathways during cathodic and anodic subthalamic nucleus (STN) DBS, pathway activation was quantified by measuring evoked potentials resulting from antidromic or orthodromic activation in 15 PD patients undergoing DBS implantation. Cortical evoked potentials (cEP) were recorded using subdural electrocorticography, DBS local evoked potentials (DLEP) were recorded from non-stimulating contacts and EMG activity was recorded from arm and face muscles. We measured: 1) the amplitude of short-latency cEP, previously demonstrated to reflect activation of the cortico-STN hyperdirect pathway, 2) DLEP amplitude thought to reflect activation of STN-globus pallidus (GP) pathway, and 3) amplitudes of very short-latency cEP and motor evoked potentials (mEP) for activation of cortico-spinal/bulbar tract (CSBT). We constructed recruitment and strength-duration curves for each EP/pathway to compare the excitability for different stimulation polarities. We compared experimental data with the most advanced DBS computational models. Our results provide experimental evidence that subcortical cathodic and anodic stimulation activate the same pathways in the STN region and that cathodic stimulation is in general more efficient. However, relative efficiency varies for different pathways so that anodic stimulation is the least efficient in activating CSBT, more efficient in activating the HDP and as efficient as cathodic in activating STN-GP pathway. Our experiments confirm biophysical model predictions regarding neural activations in the central nervous system and provide evidence that stimulus polarity has differential effects on passing axons, terminal synapses, and local neurons. Comparison of experimental results with clinical DBS studies provides further evidence that the hyperdirect pathway may be involved in the therapeutic mechanisms of DBS.

Novel requirements for HAP2/GCS1-mediated gamete fusion in Tetrahymena.

The ancestral gamete fusion protein, HAP2/GCS1, plays an essential role in fertilization in a broad range of taxa. To identify factors that may regulate HAP2/GCS1 activity, we screened mutants of the ciliate Tetrahymena thermophila for behaviors that mimic Δhap2/gcs1 knockout phenotypes in this species. Using this approach, we identified two new genes, GFU1 and GFU2, whose products are necessary for membrane pore formation following mating type recognition and adherence. GFU2 is predicted to be a single-pass transmembrane protein, while GFU1, though lacking obvious transmembrane domains, has the potential to interact directly with membrane phospholipids in the cytoplasm. Like Tetrahymena HAP2/GCS1, expression of GFU1 is required in both cells of a mating pair for efficient fusion to occur. To explain these bilateral requirements, we propose a model that invokes cooperativity between the fusion machinery on apposed membranes of mating cells and accounts for successful fertilization in Tetrahymena's multiple mating type system.