Faculty Bibliography

Transcutaneous electric stimulation (TES) using weak currents has been used extensively in attempts to influence brain activity. In vitro and in vivo experiments in rodents and computational modeling suggest that the magnitude of voltage gradient of the induced electric field should exceed 1 mV/mm to instantaneously and reproducibly alter neuronal spiking and consequent brain network patterns. Evidence for immediate and unconditional neuronal effects of TES in the human brain is still lacking, mainly due to the saturation of the recording amplifiers by the large induced electromagnetic fields. For many therapeutic applications, it is desirable to affect neurons in a regionally constrained manner to reach maximum on-target effects and reduce side effects on unintended brain networks. Here, we determine the needed TES currents in human cadavers to achieve 1 mV/mm fields. Scalp stimulation greatly reduced the generated intracerebral electric fields (>50% in cadavers) and these measurements predicted that ~5 mA is needed to achieve 1mV/mm electric field gradient via scalp stimulation. To reach the desired intracerebral field strength without the adverse peripheral effects of >5 mA currents, we introduce a spatially focused multiple site, Intersectional Short-Pulse (ISP) stimulation. We demonstrate the instantaneous entraining effect of ISP on alpha waves in human subjects and on neuronal spiking in rats. Immediate effects of TES can be best utilized in disorders with sudden, major electrographic changes such as epileptic seizures. We showed earlier that thalamocortical seizures can be quickly terminated by temporally targeted, diffuse transcranial stimulation, however secondarily generalized temporal lobe seizures are more resistant to these diffuse interference interventions. ISP also has the capacity to spatially focus its effect, thus it is capable to overcome the unwanted mirror effect (anodal vs cathodal) of the traditional TES protocols. We report here a novel stimulation pattern, that can simultaneously entrain both hippocampi. To evaluate its utility, temporal lobe seizures were induced in rats by electrical kindling, and each electrically kindled seizures were automatically detected and silenced by a closed loop ISP stimulation. By comparing to closed-loop diffuse TES, we found that ISP with bilateral foci is more effective in early seizure termination. Lastly, we introduce our prototyping efforts to implement an implantable, minimal-invasive, transcranial closed-loop seizure termination device, aiming for human clinical applications.

Introduction: The mammalian enteric nervous system (ENS) regulates intestinal function in response to luminal changes in nutrients and microbiota. The ENS also modulates immune cells to control microbial homeostasis and fight infections. Enteric neurons signal to the brain via the vagus nerve, providing a mechanism by which microbiota can influence neural activity and behavior at homeostasis or during infections with gut pathogens. However, little is known about the relation between vagus nerve activity and 'sickness behaviors' such as decreased attention, increased irritability and depression, and decreased interest and energy. Here we aimed to record vagus nerve responses in behaving animals towards understanding this gut-brain signaling connection in sickness behavior. Method(s): Custom nerve cuff electrodes were used to monitor vagus nerve activity of wild-type male mice. Cuffs were made with 0.2 mm micro-renathane tubing to surround the upper branch of the sensory vagus nerve and connected to socket gold pins and medwire. Chronic nerve cuffs were implanted in mice aged 6-12 weeks. Surgery consisted of securing gold pins to the cranial vertex and connecting electrodes to the vagus nerve in the neck, around which the cuff was placed. The grounding wire was secured near the cuff. One to two weeks post-surgery, each mouse underwent sickness induction via lipopolysaccharide (LPS) injection. LPS solution was formulated with 9.5/g muL of 0.9% saline solution and 0.5/g muL of pure LPS via intraperitoneal injection. Electrophysiological activity of the vagus nerve was recorded together with video monitoring of behavior, prior to injection to first establish a baseline, and post-injection activity was recorded for up to 24 hours. Sickness behavior was ethogrammed and neural activity analyzed in each animal. Result(s): LPS injection led to reduction of several different behaviors including overall motion in the homecage for hours afterwards. Analysis of simultaneously-recorded vagus activity is ongoing. Conclusion(s): We here describe an integrated system that combines long-term videography and behavioral analysis with recordings of the peripheral nerve activity using a custom chronic nerve cuff for the mouse vagus. Using this system, we have begun to relate neural activity in the sensory vagus to physiological state and behavioral changes in mice for the first time.

Introduction: Vagus nerve stimulation is currently used as a medical treatment for those suffering from severe epilepsy or depression, but the mechanisms underlying vagus nerve stimulation are poorly understood. The vagus nerve helps connect essentially all peripheral organs to the central nervous system, sending afferents to the nucleus tractus solitarius. Recent studies indicate that vagus nerve stimulation can produce long-lasting plasticity in the cerebral cortex, leading to improved sensory processing and recovery of motor behavior after stroke (Boreland et al, Brain Stimul (2016). An understanding of the circuit mechanisms by which vagus nerve stimulation can produce these results would be important for enhancing behavioral outcomes and developing less invasive or non-invasive neuromodulatory therapeutic techniques. Method(s): Studies in mice provide an opportunity for monitoring and manipulating various aspects of neural circuits involved in behavior. One difficulty in the mouse model is the lack of vagus nerve cuff electrodes given the small size of the mouse vagus nerve. We first built a novel vagus nerve cuff electrode for mice and demonstrated reliable low-impedance recordings and stimulation during behavior in mice chronically implanted for months. Two-photon imaging of the auditory cortex was used to track neural responses to tones paired with vagus nerve stimulation. Animals are then trained on either a paired go/no-go or two-alternative forced choice auditory detection and recognition task (Martins and Froemke, Nat Neurosci 2015; Kuchibhotla et al. Nat Neurosci 2017). Result(s): Stimulation of the vagus nerve was calibrated to transiently reduce respiration without affecting other physiological processes (e.g., heart rate). Using two-photon imaging, we found that pairing target tones with vagus nerve stimulation for five minutes led to a short-term enhancement of sensory responses in the mouse auditory cortex. After several days of these brief 5-minute pairing sessions, long-term plasticity was observed with increases in representation of the target tone for at least days thereafter. Conclusion(s): These changes are reminiscent of the effects of basal forebrain stimulation (Froemke et al. Nature 2007) and we are now investigating how vagus nerve stimulation might lead to direct or indirect activation of central modulatory systems to improve plasticity and behavior in mice.

BACKGROUND:Genetic variation in ion channel genes ('channelopathies') are often associated with inherited arrhythmias and sudden death. Genetic testing ('molecular autopsies') of channelopathy genes can be used to assist in determining the likely causes of sudden unexpected death. However, different in silico approaches can yield conflicting pathogenicity predictions and assessing their impact on ion channel function can assist in this regard. METHODS AND RESULTS/RESULTS:channels, as determined with biotinylation assays, suggesting that all of the variants led to an enhanced open state. CONCLUSIONS:channels in the heart and specialized cardiac conduction, vascular smooth muscle and respiratory neurons, it is conceivable that electrical silencing of these cells may contribute to the vulnerability element, which is a component of the triple risk model of sudden explained death in infants. The gain-of-function phenotype of these ABCC9 variants should be considered when assessing their potential pathogenicity.

Targeting tau with immunotherapies is currently the most common approach taken in clinical trials of patients with Alzheimer's disease. The most prominent pathological feature of tau is its hyperphosphorylation, which may cause the protein to aggregate into toxic assemblies that collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser³⁹⁶/Ser⁴⁰⁴ has received particular attention for therapeutic targeting because of its prominence and stability in diseased tissue. Herein, we present the antigen-binding fragment (Fab)/epitope complex structures of three different monoclonal antibodies (mAbs) that target the pSer⁴⁰⁴ tau epitope region. Most notably, these structures reveal an antigen conformation similar to a previously described pathogenic tau epitope, pSer⁴²², which was shown to have a β-strand structure that may be linked to the seeding core in tau oligomers. In addition, we have previously reported on the similarly ordered conformation observed in a pSer³⁹⁶ epitope, which is in tandem with pSer⁴⁰⁴. Our data are the first Fab structures of mAbs bound to this epitope region of the tau protein and support the existence of proteopathic tau conformations stabilized by specific phosphorylation events that are viable targets for immune modulation. The atomic coordinates and structure factors have been deposited in the RCSB Protein Data Bank under accession codes 6DC7 (8B2 apo), 6DC8 (8B2), 6DC9 (h4E6), and 6DCA (6B2).

OBJECTIVE:Sleep spindles have been implicated in memory consolidation and synaptic plasticity during NREM sleep. Detection accuracy and latency in automatic spindle detection are critical for real-time applications. APPROACH/METHODS:Here we propose a novel deep learning strategy (SpindleNet) to detect sleep spindles based on a single EEG channel. While the majority of spindle detection methods are used for off-line applications, our method is well suited for online applications. MAIN RESULTS/RESULTS:Compared with other spindle detection methods, SpindleNet achieves superior detection accuracy and speed, as demonstrated in two publicly available expert-validated EEG sleep spindle datasets. Our real-time detection of spindle onset achieves detection latencies of 150-350 ms (~2-3 spindle cycles) and retains excellent performance under low EEG sampling frequencies and low signal-to-noise ratios. SpindleNet has good generalization across different sleep datasets from various subject groups of different ages and species. SIGNIFICANCE/CONCLUSIONS:SpindleNet is ultra-fast and scalable to multichannel EEG recordings, with an accuracy level comparable to human experts, making it appealing for long-term sleep monitoring and closed-loop neuroscience experiments. &#13.

BACKGROUND:, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. METHODS:, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. RESULTS:, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD. CONCLUSIONS:Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline.

BACKGROUND:Patient-specific 3D models are being used increasingly in medicine for many applications including surgical planning, procedure rehearsal, trainee education, and patient education. To date, experiences on the use of 3D models to facilitate patient understanding of their disease and surgical plan are limited. The purpose of this study was to investigate in the context of renal and prostate cancer the impact of using 3D printed and augmented reality models for patient education. METHODS:Patients with MRI-visible prostate cancer undergoing either robotic assisted radical prostatectomy or focal ablative therapy or patients with renal masses undergoing partial nephrectomy were prospectively enrolled in this IRB approved study (n = 200). Patients underwent routine clinical imaging protocols and were randomized to receive pre-operative planning with imaging alone or imaging plus a patient-specific 3D model which was either 3D printed, visualized in AR, or viewed in 3D on a 2D computer monitor. 3D uro-oncologic models were created from the medical imaging data. A 5-point Likert scale survey was administered to patients prior to the surgical procedure to determine understanding of the cancer and treatment plan. If randomized to receive a pre-operative 3D model, the survey was completed twice, before and after viewing the 3D model. In addition, the cohort that received 3D models completed additional questions to compare usefulness of the different forms of visualization of the 3D models. Survey responses for each of the 3D model groups were compared using the Mann-Whitney and Wilcoxan rank-sum tests. RESULTS:All 200 patients completed the survey after reviewing their cases with their surgeons using imaging only. 127 patients completed the 5-point Likert scale survey regarding understanding of disease and surgical procedure twice, once with imaging and again after reviewing imaging plus a 3D model. Patients had a greater understanding using 3D printed models versus imaging for all measures including comprehension of disease, cancer size, cancer location, treatment plan, and the comfort level regarding the treatment plan (range 4.60-4.78/5 vs. 4.06-4.49/5, p < 0.05). CONCLUSIONS:All types of patient-specific 3D models were reported to be valuable for patient education. Out of the three advanced imaging methods, the 3D printed models helped patients to have the greatest understanding of their anatomy, disease, tumor characteristics, and surgical procedure.

Choice impulsivity is an important subcomponent of the broader construct of impulsivity and is a key feature of many psychiatric disorders. Choice impulsivity is typically quantified as temporal discounting, a well-documented phenomenon in which a reward's subjective value diminishes as the delay to its delivery is increased. However, an individual's proclivity to-or more commonly aversion to- risk can influence nearly all of the standard experimental tools available for measuring temporal discounting. Despite this interaction, risk preference is a behaviourally and neurobiologically distinct construct that relates to the economic notion of utility or subjective value. In this opinion piece, we discuss the mathematical relationship between risk preferences and time preferences, their neural implementation, and propose ways that research in psychiatry could, and perhaps should, aim to account for this relationship experimentally to better understand choice impulsivity and its clinical implications. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.

The effects of childhood exposure to perfluoroalkyl substances (PFASs) on lung function remain mostly unknown. Previous research indicates that children living or going to school near the World Trade Center (WTC) disaster were exposed to high levels of PFASs, among other toxic chemicals. To explore the effects of PFAS exposure on lung function, we measured serum PFASs in a cohort of children from the WTC Health Registry and a matched control group. Perfluorooctanesulfonate had the highest median concentrations in both groups (WTCHR = 3.72 ng/mL, Comparison = 2.75 ng/mL), while the lowest median concentrations were seen for perfluoroundecanoic acid (WTCHR = 0.12 ng/mL, Comparison = 0.01 ng/mL). Lung function outcomes were measured by spirometry, plethysmography, and oscillometry. Asthma diagnosis and serum eosinophil count were also recorded. We examined the relationships of each PFAS with lung function parameters and eosinophil count using linear regressions. Odds ratios for asthma were obtained for each PFAS using logistic regression. The effect of total PFASs on these outcomes was also assessed. All regression models were adjusted for sex, race/ethnicity, age, body mass index (BMI) and tobacco smoke exposure. We found that serum PFASs were not statistically associated with the measured lung function parameters, asthma diagnosis, or eosinophil count in this cohort (p < 0.05). These findings highlight the need for more longitudinal studies to explore the long-term effects of childhood PFAS exposure on lung function past adolescence and early adulthood.