Faculty Bibliography

Cortical responses to sensory inputs vary across repeated presentations of identical stimuli, but how this trial-to-trial variability impacts detection of sensory inputs is not fully understood. Using multi-channel local field potential (LFP) recordings in primary somatosensory cortex (S1) of the awake mouse, we optimized a data-driven cortical state classifier to predict single-trial sensory-evoked responses, based on features of the spontaneous, ongoing LFP recorded across cortical layers. Our findings show that, by utilizing an ongoing prediction of the sensory response generated by this state classifier, an ideal observer improves overall detection accuracy and generates robust detection of sensory inputs across various states of ongoing cortical activity in the awake brain, which could have implications for variability in the performance of detection tasks across brain states.

The most important variable leading to uric acid stones is low urine pH. Major causal conditions associated with low urine pH are metabolic syndrome and diabetes. In the study by Maalouf et al., treatment of uric acid stone formers with pioglitazone led to small but significant increases in urine pH. Pioglitazone will not supplant alkali administration to prevent uric acid stones, but the study helps confirm that insulin resistance is an important cause of low urine pH that causes uric acid stones.

Multimodal single-cell assays provide high-resolution snapshots of complex cell populations, but are mostly limited to transcriptome plus an additional modality. Here, we describe expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq) for the high-throughput characterization of at least five modalities of information from each single cell. We demonstrate application of ECCITE-seq to multimodal CRISPR screens with robust direct single-guide RNA capture and to clonotype-aware multimodal phenotyping of cancer samples.

PURPOSE/OBJECTIVE:We present a novel, geometrically adjustable, receive coil array whose diameter can be tailored to the subject in order to maximize sensitivity for a range of body sizes. THEORY AND METHODS/UNASSIGNED:A key mechanical feature of the size-adaptable receive array is its trellis structure that was motivated by similar structures found in gardening and fencing. Our implementation is a cylindrical trellis that features encircling, diagonally interleaved slats, which are linked together at intersecting points. The ensemble allows expansion or contraction to be controlled with the angle between the slats. This mechanical frame provides a base for radiofrequency coils wherein approximately constant overlap, and therefore coupling between adjacent elements, is maintained when the trellis is expanded or contracted. We demonstrate 2 trellis coil concepts for imaging lower extremity at 3T: a single-row 8-channel array built on a trellis support structure and a multirow 24-channel array in which the coil elements themselves form the trellis structure. RESULTS:We show that the adjustable trellis array can accommodate a range of subject sizes with robust signal-to-noise ratio, loading, and coupling. CONCLUSION/CONCLUSIONS:The trellis coil concept enables an array of surface coils to expand and contract with negligible effect on tuning, matching, and decoupling. This allows an encircling array to conform closely to anatomy of various sizes, which provides significant gains in signal-to-noise ratio.

Familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5-1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it.

Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

OBJECTIVE/UNASSIGNED:Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS/UNASSIGNED:Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS/UNASSIGNED:In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS/UNASSIGNED:Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

OBJECTIVE:The habenula is a small region in the epithalamus that contributes to the regulation of midbrain dopaminergic circuits implicated in attention-deficit hyperactivity disorder (ADHD). This investigation aims to evaluate the intrinsic functional connectivity (iFC) of the habenula in children with ADHD. METHOD/METHODS:A total of 112 children (5-9 years; 75 ADHD, 37 healthy comparisons) completed anatomical and resting-state functional magnetic resonance imaging (MRI) scans. Habenula regions of interest (ROIs) were identified individually on normalized T1-weighted anatomical images. Seed-based iFC analyses and group comparisons were conducted for habenula ROIs, as well as thalamic ROIs to test the specificity of habenula findings. RESULTS:Children with ADHD exhibited reduced habenula-putamen iFC compared with healthy comparisons. Group differences in thalamic iFC showed no overlap with habenular findings. CONCLUSION/CONCLUSIONS:These preliminary findings suggest that habenula-putamen iFC may be disrupted in children with ADHD. Further work is needed to confirm and elucidate the role of this circuit in ADHD pathophysiology.

Effective pharmacological treatment options for chronic pain remain very limited, and continued reliance on opioid analgesics has contributed to an epidemic in the U.S. On the other hand, non-pharmacologic neuromodulatory interventions provide a promising avenue for relief of chronic pain without the complications of dependence and addiction. An especially attractive neuromodulation strategy is to optimize endogenous pain regulatory circuits. The prefrontal cortex (PFC) is known to provide top-down control of pain, and hence neuromodulation methods that selectively enhance the activities in this brain region during pain episodes have the potential to provide analgesia. In this study, we designed a low-frequency (2 Hz) electrical stimulation protocol to provide temporally and spatially specific enhancement of the prefrontal control of pain in rats. We showed that low-frequency electrical stimulation of the prelimbic region of the PFC relieved both sensory and affective responses to acute pain in naïve rats. Furthermore, we found that low-frequency electrical stimulation of the PFC also attenuated mechanical allodynia in a rat model of chronic pain. Together, our findings demonstrated that low-frequency electrical stimulation of the PFC represents a promising new method of neuromodulation to inhibit pain.

The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV₁) and FOT (resistance at 5 Hz, R₅; resistance at 5 minus 20 Hz, R_5-20). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R₅ and R_5-20) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.