Faculty Bibliography

BACKGROUND: Cochlear implants (CIs) successfully restore hearing in postlingually deaf adults, but in doing so impose a frequency-position function in the cochlea that may differ from the physiological one. PURPOSE: The CI-imposed frequency-position function is determined by the frequency allocation table programmed into the listener's speech processor and by the location of the electrode array along the cochlea. To what extent can postlingually deaf CI users successfully adapt to the difference between physiological and CI-imposed frequency-position functions? RESEARCH DESIGN: We attempt to answer the question by combining behavioral measures of electroacoustic pitch matching (PM) and measures of electrode location within the cochlea. STUDY SAMPLE: The participants in this study were 16 adult CI users with residual hearing who could match the pitch of acoustic pure tones presented to their unimplanted ears to the pitch resulting from stimulation of different CI electrodes. DATA COLLECTION AND ANALYSIS: We obtained data for four to eight apical electrodes from 16 participants with CIs (most of whom were long-term users), and estimated electrode insertion angle for 12 of these participants. PM functions in this group were compared with the two frequency-position functions discussed above. RESULTS: Taken together, the findings were consistent with the possibility that adaptation to the frequency-position function imposed by CIs does happen, but it is not always complete. CONCLUSIONS: Some electrodes continue to be perceived as higher pitched than the acoustic frequencies with which they are associated despite years of listening experience after cochlear implantation.

BACKGROUND: Most head and neck (H&N) cancer patients receive high-dose external beam radiation therapy (RT), often in combination with surgery and/or chemotherapy. Unfortunately, high-dose RT has significant adverse effects on the oral and maxillofacial tissues, some of which persist for the life of the patient. However, dental management of these patients is based largely on individual and expert opinion, as few studies have followed patients prospectively to determine factors that predict adverse oral sequelae. In addition, many previous studies were conducted before wide-spread adoption of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. The objective of this multi-center study is to systematically evaluate the oral health of subjects for 2 years after commencement of RT, with the goal of identifying risk factors that predict adverse oral outcomes post-RT. METHODS: This is a prospective multi-center longitudinal cohort study of H&N cancer patients who receive high-dose RT with curative intent. Planned enrollment is 756 subjects at 6 primary clinical sites (and their affiliated sites) in the USA. A baseline visit is conducted prior to the beginning of RT. Follow-up visits are conducted at 6, 12, 18 and 24 months from the start of RT. The primary outcome measure is the 2-year rate of tooth loss in patients who have received at least one session of external beam RT for H&N cancer. Secondary outcome measures include the incidence of exposed intraoral bone; incidence of post-extraction complications; change in Decayed Missing and Filled Surfaces (DMFS); change in periodontal measures; change in stimulated whole salivary flow rates; change in mouth opening; topical fluoride utilization; chronic oral mucositis incidence; changes in RT-specific quality of life measures; and change in oral pain scores. DISCUSSION: This study will contribute to a better understanding of the dental complications experienced by these patients. It will also enable identification of risk factors associated with adverse outcomes such as tooth loss and osteoradionecrosis. These findings will support the development of evidence-based guidelines and inform the planning of future interventional studies, with the goal of advancing improvements in patient care and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02057510 , registered 5 February 2014.

gamma-Aminobutyric acid (GABA)ergic inputs are strategically positioned to gate synaptic integration along the dendritic arbor of pyramidal cells. However, their spatiotemporal dynamics during behavior are poorly understood. Using an optical-tagging electrophysiological approach to record and label somatostatin-expressing (Sst) interneurons (GABAergic neurons specialized for dendritic inhibition), we discovered a layer-specific modulation of their activity in behaving mice. Sst interneuron subtypes, residing in different cortical layers and innervating complementary laminar domains, exhibited opposite activity changes during transitions to active wakefulness. The relative weight of vasoactive intestinal peptide-expressing (Vip) interneuron-mediated inhibition of distinct Sst interneurons and cholinergic modulation determined their in vivo activity. These results reveal a state-dependent laminar influence of Sst interneuron-mediated inhibition, with implications for the compartmentalized regulation of dendritic signaling in the mammalian neocortex.

Cochlear implant (CI) recipients have difficulty understanding speech in noise even at moderate signal-to-noise ratios. Knowing the mechanisms they use to understand speech in noise may facilitate the search for better speech processing algorithms. In the present study, a computational model is used to assess whether CI users' vowel identification in noise can be explained by formant frequency cues (F1 and F2). Vowel identification was tested with 12 unilateral CI users in quiet and in noise. Formant cues were measured from vowels in each condition, specific to each subject's speech processor. Noise distorted the location of vowels in the F2 vs F1 plane in comparison to quiet. The best fit model to subjects' data in quiet produced model predictions in noise that were within 8% of actual scores on average. Predictions in noise were much better when assuming that subjects used a priori knowledge regarding how formant information is degraded in noise (experiment 1). However, the model's best fit to subjects' confusion matrices in noise was worse than in quiet, suggesting that CI users utilize formant cues to identify vowels in noise, but to a different extent than how they identify vowels in quiet (experiment 2).

INTRODUCTION: Quantitative T2 mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T2 changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38). METHODS: The EMC algorithm uses Bloch simulations to model T2 decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T2 values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation. RESULTS: Compared to conventional exponential T2 modeling, EMC fitting provided more accurate estimations of T2 with less variance across scans, MRI systems, and healthy individuals. Thalamic T2 was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T2 associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T2 differences for different white and gray matter structures. CONCLUSIONS: The EMC algorithm precisely characterizes T2 values, and is able to detect subtle T2 changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T2 variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.

Independently adjustable multielectrode arrays are routinely used to interrogate neuronal circuit function, enabling chronic in vivo monitoring of neuronal ensembles in freely behaving animals at a single-cell, single spike resolution. Despite the importance of this approach, its widespread use is limited by highly specialized design and fabrication methods. To address this, we have developed a Scalable, Lightweight, Integrated and Quick-to-assemble multielectrode array platform. This platform additionally integrates optical fibers with independently adjustable electrodes to allow simultaneous single unit recordings and circuit-specific optogenetic targeting and/or manipulation. In current designs, the fully assembled platforms are scalable from 2 to 32 microdrives, and yet range 1-3 g, light enough for small animals. Here, we describe the design process starting from intent in computer-aided design, parameter testing through finite element analysis and experimental means, and implementation of various applications across mice and rats. Combined, our methods may expand the utility of multielectrode recordings and their continued integration with other tools enabling functional dissection of intact neural circuits.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions. Here, we identified candidate biomolecules contributing to the organic basis for psychosis by deriving an in vivo biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel in silico approach identifies the ensemble of potential drug targets based on the drug's chemical structure and the region-specific gene expression profile of each target in the central nervous system. We subtracted the signature of the action of clozapine from that of a typical antipsychotic, chlorpromazine. Our results implicate dopamine D4 receptors in the pineal gland and muscarinic acetylcholine M1 (CHRM1) and M3 (CHRM3) receptors in the prefrontal cortex (PFC) as significant and unique to clozapine, whereas serotonin receptors 5-HT2A in the PFC and 5-HT2C in the caudate nucleus were common significant sites of action for both drugs. Our results suggest that D4 and CHRM1 receptor activity in specific tissues may represent underappreciated drug targets to advance the pharmacologic treatment of schizophrenia. These findings may enhance our understanding of the organic basis of psychiatric disorders and help developing effective therapies.