Faculty Bibliography

BACKGROUND:Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. METHODS:We combined finite-element modeling, cadaver measurements (n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long-Evans rats (n = 11 animals, >500 induced seizures analyzed across conditions). RESULTS:Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. CONCLUSIONS:ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.

The relation between the vocal capacities of animals and those of humans is a long-standing topic of interest for scientists, philosophers, and lay people alike. While similar neural and physiological substrates underlie the production of vocal signals in humans and animals, the most celebrated and prototypical aspects of language are cognitive phenomena that go far beyond speech sensorimotor processes. These include a subset of features that have begun to be systematically investigated in nonhuman animals, namely: (i) the presence of statistical laws, (ii) hierarchical syntactic rules, and (iii) the capacity for meaning and reference. Here we review recent progress describing and quantifying language-like structure in animal vocalizations. We highlight agreement and disagreement about the similarities that may exist between human language and animal vocal repertoires, with an eye toward what these phenomena may reveal about the evolution of language and its neural control.

Vocalizations are ancient behaviours that require the complex coordination of breath and display. Understanding how laryngeal anatomy shapes vocalization provides insights into this diversity, its mechanisms and their evolution. Rodents are ideal for exploring this variation because of their diverse mechanisms and vocal structures. Here, we describe the laryngeal morphology and sound production mechanisms underlying the vocalizations of Alston's singing mouse (Scotinomys teguina) and compare these results to those of other vocalizing mammals. We reconstructed the three-dimensional laryngeal morphology with micro-computed tomography, recorded laryngeal sound production using high-speed video and investigated frequency control using surgical ablations. We found that singing mice use a whistle mechanism that uniquely relies on the inflation of an enlarged air sac called the ventral pouch. Song frequency can be controlled by pouch volume, airflow and cricothyroid muscle action. Singing mouse laryngeal morphology and vocal mechanism are distinct from those of other Neotomids; singing mice appear to use inflation-mediated whistles for both distant and close exchanges. Inflatable air sacs have evolved repeatedly for sound modulation and filtering. Our results indicate a novel role for these structures in being required to generate sound. Together, our results expand on an emerging story of how biomechanic and morphological variation contributes to vocal diversity.

INTRODUCTION/BACKGROUND:Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS:Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS:Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION/CONCLUSIONS:Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.

Vector Doppler Imaging (VDI) addresses the limitations of traditional Doppler imaging by measuring blood flow in axial and lateral directions but will produce incorrect results if aliasing is present. Aliasing becomes more likely when using high transmit frequencies such as in small animal cardiac applications. The use of multiple transmit angles decreases the Nyquist limit, which further increases the likelihood of aliasing. A new transmission scheme, termed StaBle, is proposed to increase the Nyquist limit of conventional sequential angle VDI by multiple fold. StaBle combines the velocity limit extension of staggered multiple pulse repetition frequency (PRF) with a double transmission scheme. With three transmit angles and two PRFs, StaBle was able to achieve a 6-12 times higher velocity limit compared to sequential angle VDI. Simulation and phantom spinning disk experiments were conducted to evaluate StaBle's performance. The simulation results showed a normalized root-mean-squared error of less than 5% compared to an ideal vector field in both axial and lateral directions. Phantom results showed a 9-fold improvement in detecting peak axial velocity over sequential three angle VDI. The ability of StaBle to obtain an unaliased vector field in vivo was demonstrated by imaging a mouse left ventricle where the Doppler signal was corrupted by aliasing artifacts using just a double transmit scheme. The resolved estimated vector velocity showed consistent beat-to-beat variation in velocity, confirming StaBle's robustness under realistic conditions and its potential for use in investigative studies.

BACKGROUND/UNASSIGNED:As life expectancy rises, identifying causes and risk factors for incident acute ischemic stroke (AIS) among the oldest-old (≥80 years) is increasingly important. We examined whether the effect of age at stroke on AIS subtype is mediated by embolic risk factors and whether these factors improve AIS prediction. METHODS/UNASSIGNED:-VASc) and compared preinclusion and postinclusion of embolic risk factors. RESULTS/UNASSIGNED:-VASc: C statistics, 0.63 [95% CI, 0.59-0.67]). CONCLUSIONS/UNASSIGNED:These findings suggest that identification and control of embolic risk factors are critical to reduce stroke risk as people age, and better stroke-specific prediction tools are needed.

Bessel beams are commonly used in two-photon microscopy to extend the depth of field and thereby achieve functional volumetric imaging of the living brain. In practice, this approach suffers from background signals and limited lateral resolution due to the Bessel beam's strong side lobes. We introduce and demonstrate a new approach to side lobe suppression based on non-degenerate two-photon excitation, in which dual wavelength illumination produces an imaging point-spread function that is the product of the two coaxial Bessel beams. This technique can reduce the main side lobe intensity of a Bessel beam by 50% or more. We illustrate the approach conceptually with an analytical paraxial model and use detailed physical simulation to show that the approach is effective in the presence of the symmetry-breaking aberrations that amplify side lobes in high NA systems. We experimentally demonstrated the technique using a refractive axicon and the pump and tunable beams of a femtosecond laser. This work establishes non-degenerate two-photon excitation as a practical and broadly applicable strategy for improving point spread-function quality in high-resolution volumetric microscopy.