Faculty Bibliography

Effective treatments for chronic pain remain limited. Conceptually, a closed-loop neural interface combining sensory signal detection with therapeutic delivery could produce timely and effective pain relief. Such systems are challenging to develop because of difficulties in accurate pain detection and ultrafast analgesic delivery. Pain has sensory and affective components, encoded in large part by neural activities in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), respectively. Meanwhile, studies show that stimulation of the prefrontal cortex (PFC) produces descending pain control. Here, we designed and tested a brain-machine interface (BMI) combining an automated pain detection arm, based on simultaneously recorded local field potential (LFP) signals from the S1 and ACC, with a treatment arm, based on optogenetic activation or electrical deep brain stimulation (DBS) of the PFC in freely behaving rats. Our multiregion neural interface accurately detected and treated acute evoked pain and chronic pain. This neural interface is activated rapidly, and its efficacy remained stable over time. Given the clinical feasibility of LFP recordings and DBS, our findings suggest that BMI is a promising approach for pain treatment.

The current dominant view of the hippocampus is that it is a navigation "device" guided by environmental inputs. Yet, a critical aspect of navigation is a sequence of planned, coordinated actions. We examined the role of action in the neuronal organization of the hippocampus by training rats to jump a gap on a linear track. Recording local field potentials and ensembles of single units in the hippocampus, we found that jumping produced a stereotypic behavior associated with consistent electrophysiological patterns, including phase reset of theta oscillations, predictable global firing-rate changes, and population vector shifts of hippocampal neurons. A subset of neurons ("jump cells") were systematically affected by the gap but only in one direction of travel. Novel place fields emerged and others were either boosted or attenuated by jumping, yet the theta spike phase versus animal position relationship remained unaltered. Thus, jumping involves an action plan for the animal to traverse the same route as without jumping, which is faithfully tracked by hippocampal neuronal activity.

Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition.

Perceptual similarities between a specific stimulus and other stimuli of the same modality provide valuable information about the structure and geometry of sensory spaces. While typically assessed in human behavioral experiments, perceptual similarities-or distances-are rarely measured in other species. However, understanding the neural computations responsible for sensory representations requires the monitoring and often manipulation of neural activity, which is more readily achieved in non-human experimental models. Here, we develop a behavioral paradigm that enables the quantification of perceptual similarity between sensory stimuli using mouse olfaction as a model system.

How do neurons and networks of neurons interact spatially? Here, we overview recent discoveries revealing how spatial dynamics of spiking and postsynaptic activity efficiently expose and explain fundamental brain and brainstem mechanisms behind detection, perception, learning, and behavior.

Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N = 369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.

Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF^+/-). In contrast to WT mice, evoked DA release did not differ between BDNF^+/- runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety.SIGNIFICANCE STATEMENT Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF^+/- mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression.

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.

PURPOSE/OBJECTIVE:To elucidate long-term sequelae of radiation therapy (RT) in head and neck cancer (HNC) patients, a multi-center prospective study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), was established with tooth failure as its primary outcome. We report tooth failure and associated risk factors. METHODS:Demographics, cancer and dental disease characteristics were documented in 572 HNC patients at baseline and 6, 12, 18, and 24 months after RT. Eligible patients were age 18 or older, diagnosed with HNC, and receiving RT to treat HNC. Tooth failure during follow-up was defined as losing a tooth or having a tooth deemed hopeless. Analyses of time to first tooth-failure event and number of teeth that failed used Kaplan-Meier estimators, Cox regression, and generalized linear models. RESULTS:At 2 years, the estimated fraction of tooth failure was 17.8% (95% confidence interval [CI]: 14.3%-21.3%). Number of teeth that failed was higher for those with fewer teeth at baseline (p<0.0001), greater reduction in salivary flow rate (p=0.013), and non-compliance with daily oral hygiene (p=0.03). Patients with dental caries at baseline had higher risk of tooth failure with decreased salivary flow. Patients who were oral hygiene non-compliant at baseline but compliant at all follow-up visits had the fewest teeth that failed; greatest tooth failure occurred in participants who were non-compliant at baseline and follow-up. CONCLUSION/CONCLUSIONS:Despite pre-RT dental management, substantial tooth failure occurs within 2 years after RT for HNC. Identified factors may help to predict or reduce risk of post-RT tooth failure.

OBJECTIVE:To investigate a new surgical and signal processing technique that provides apical stimulation of the cochlea using a cochlear implant without extending the length of the electrode array. PATIENTS/METHODS:Three adult patients who underwent cochlear implantation using this new technique. INTERVENTIONS/METHODS:The patients received a cochlear implant. The surgery differed from the standard approach in that a ground electrode was placed in the cochlear helicotrema via an apical cochleostomy rather than in its typical location underneath the temporalis muscle. Clinical fitting was modified such that low frequencies were represented using the apically placed electrode as a ground. MAIN OUTCOME MEASURES/METHODS:Pitch scaling and speech recognition. RESULTS:All surgeries were successful with no complications. Pitch scaling demonstrated that use of the apically placed electrode as a ground lowered the perceived pitch of electric stimulation relative to monopolar stimulation. Speech understanding was improved compared with preoperative scores. CONCLUSIONS:The new surgical approach and clinical fitting are feasible. A lower pitch is perceived when using the apically placed electrode as a ground relative to stimulation using an extracochlear ground (i.e., monopolar mode), suggesting that stimulation can be provided more apically without the use of a longer electrode array. Further work is required to determine potential improvements in outcomes and optimal signal processing for the new approach.