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.

Neuronal axons have traditionally been considered to be the primary mediators of functional connectivity among brain regions. However, the role of astrocyte-mediated communication has been largely underappreciated. Astrocytes communicate with one another through gap junctions, but the extent and specificity of this communication remain poorly understood. Astrocyte gap junctions are necessary for memory formation^1,2, synaptic plasticity^3-5, coordination of neuronal signalling⁶, and closing the visual and motor critical periods^7,8. These findings indicate that this form of communication is essential for proper central nervous system development and function. Despite the importance of astrocyte gap junctional networks, studying them has been challenging. Current methods such as slice electrophysiology disrupt network connectivity and introduce artefacts due to tissue damage. Here, we developed a vector-based approach that labels molecules as they are fluxed by astrocyte gap junctions in awake, behaving animals to overcome these limitations. We then used whole-brain tissue clearing^9,10 to image these intact, three-dimensional astrocyte networks. We show that multiple astrocyte networks traverse the mouse brain. These networks selectively connect specific regions, rather than diffusing indiscriminately, and vary in size and organization. We observe local networks that are confined to single brain regions and long-range networks that robustly interconnect multiple regions across hemispheres, often exhibiting patterns distinct from known neuronal networks. We also demonstrate that astrocyte networks undergo structural reorganization in the adult brain after sensory deprivation. These findings reveal a mode of communication between distant brain regions that is mediated by plastic networks of gap junction-coupled astrocytes.

BACKGROUND/UNASSIGNED:The aging and caregiving population is becoming increasingly diverse in the United States, leading to a growing need for culturally adapted interventions to address the unique needs of underrepresented groups, such as Asian Americans. However, interventions targeting Asian Americans and exploring cultural adaptation strategies remain limited in dementia caregiving research. OBJECTIVE/UNASSIGNED:This study aimed to describe the cultural adaptation process of an evidence-based intervention for Chinese and Korean American dementia caregivers, called the New York University Caregiver Intervention-Enhanced Support. METHODS/UNASSIGNED:We conducted a deductive content analysis and categorized our adaptation strategies into 5 elements: content, context, relationship fidelity and core elements, engagement, and cultural competence. Timing and types of responses to each adaptation strategy were also observed. Two authors conducted the initial analysis, and additional team members finalized the synthesis through discussion. The Template for Intervention Description and Replication (TIDieR) checklist was used to guide the methodological rigor. RESULTS/UNASSIGNED:Twenty-four major adaptations were identified and categorized. For content, we translated materials, used culturally relevant terms, incorporated ethnic-specific surveys and resources, created social media support groups on platforms widely used by the targeted population, and extended the time allocated to complete the 6 counseling sessions. Context adaptation included expanding the range of individuals eligible for family counseling sessions to include fictive kin, using online and social media apps for communication, cultural matching and training of staff, and partnerships with relevant community organizations. Relationship fidelity and core elements involved consulting with community experts, conducting focus group interviews with caregivers, having regular meetings with the developer of the original intervention and an experienced New York University Caregiver Intervention-Enhanced Support clinician as well as experts in Chinese and Korean culture, and continuing regular counseling supervision. To enhance engagement, we provided clear explanations of the study procedure, which emphasized the benefits in participants' native languages and matched participants with social workers who shared the same cultural backgrounds. We also used a step-by-step contact approach and prolonged communication, explained staff roles to build rapport, and offered participant compensation. Finally, cultural competence was reflected in tailoring counseling techniques with respect for cultural beliefs, the use of euphemistic language for taboo subjects, and culturally appropriate refreshments to show respect and build interpersonal relationships. CONCLUSIONS/UNASSIGNED:We systematically adjusted a counseling-based intervention, an approach less familiar among Asian Americans, to fit the cultural characteristics of the target population. A contribution of this study is using an integrated, theory-driven approach that combines 2 cultural adaptation frameworks while also capturing real-time adaptations informed by external feedback and self-reflection. This work provides a practical model for adapting evidence-based interventions to serve Chinese and Korean American dementia caregivers and may inform future adaptations for other East Asian populations.

BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.

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.

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.

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.

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.