Faculty Bibliography

A brain-computer-interface (BCI)-based attention training game system has shown promise for treating attention deficit/hyperactivity disorder (ADHD) children with inattentive symptoms. However, little is known about brain network organizational changes underlying behavior improvement following BCI-based training. To cover this gap, we aimed to examine the topological alterations of large-scale brain functional networks induced by the 8-week BCI-based attention intervention in ADHD boys using resting-state functional magnetic resonance imaging method. Compared to the non-intervention (ADHD-NI) group, the intervention group (ADHD-I) showed greater reduction of inattention symptoms accompanied with differential brain network reorganizations after training. Specifically, the ADHD-NI group had increased functional connectivity (FC) within the salience/ventral attention network (SVN) and increased FC between task-positive networks (including the SVN, dorsal attention (DAN), somatomotor, and executive control network) and subcortical regions; in contrast ADHD-I group did not have this pattern. In parallel, ADHD-I group had reduced degree centrality and clustering coefficient as well as increased closeness in task-positive and the default mode networks (prefrontal regions) after the training. More importantly, these reduced local functional processing mainly in the SVN were associated with less inattentive/internalizing problems after 8-week BCI-based intervention across ADHD patients. Our findings suggest that the BCI-based attention training facilitates behavioral improvement in ADHD children by reorganizing brain functional network from more regular to more random configurations, particularly renormalizing salience network processing. Future long-term longitudinal neuroimaging studies are needed to develop the BCI-based intervention approach to promote brain maturation in ADHD.

Adaptation is a fundamental process crucial for the efficient coding of sensory information. Recent evidence suggests that similar coding principles operate in decision-related brain areas, where neural value coding adapts to recent reward history. However, the circuit mechanism for value adaptation is unknown, and the link between changes in adaptive value coding and choice behavior is unclear. Here we show that choice behavior in nonhuman primates varies with the statistics of recent rewards. Consistent with efficient coding theory, decision-making shows increased choice sensitivity in lower variance reward environments. Both the average adaptation effect and across-session variability are explained by a novel multiple timescale dynamical model of value representation implementing divisive normalization. The model predicts empirical variance-driven changes in behavior despite having no explicit knowledge of environmental statistics, suggesting that distributional characteristics can be captured by dynamic model architectures. These findings highlight the importance of treating decision-making as a dynamic process and the role of normalization as a unifying computation for contextual phenomena in choice.

Outside of the neurogenic niches of the brain, postmitotic neurons have not been found to undergo efficient regeneration. We demonstrate that mouse Purkinje cells (PCs), which are born at midgestation and are crucial for development and function of cerebellar circuits, are rapidly and fully regenerated following their ablation at birth. New PCs are produced from immature FOXP2+ neural precursors (iPCs) that are able to enter the cell cycle and support normal cerebellum development. The number of iPCs and their regenerative capacity, however, diminish soon after birth and consequently PCs are poorly replenished when ablated at postnatal day five. Nevertheless, the PC-depleted cerebella reach a normal size by increasing cell size, but scaling of neuron types is disrupted and cerebellar function is impaired. Our findings provide a new paradigm in the field of neuron regeneration by identifying a population of immature neurons that buffers against perinatal brain injury in a stage-dependent process.

Genome-scale forward genetic screens elucidate the genetic basis of therapeutic resistance, tumor evolution, and metastasis in diverse human cancers.

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by mutations in the astrocytic filament gene GFAP. While astrocytes are thought to have important roles in controlling myelination, AxD animal models do not recapitulate critical myelination phenotypes and it is therefore not clear how AxD astrocytes contribute to leukodystrophy. Here, we show that AxD patient iPSC-derived astrocytes recapitulate key features of AxD pathology such as GFAP aggregation. Moreover, AxD astrocytes inhibit proliferation of human iPSC-derived oligodendrocyte progenitor cells (OPCs) in co-culture and reduce their myelination potential. CRISPR/Cas9-based correction of GFAP mutations reversed these phenotypes. Transcriptomic analyses of AxD astrocytes and postmortem brains identified CHI3L1 as a key mediator of AxD astrocyte-induced inhibition of OPC activity. Thus, this iPSC-based model of AxD not only recapitulates patient phenotypes not observed in animal models, but also reveals mechanisms underlying disease pathology and provides a platform for assessing therapeutic interventions.

Fiber ball imaging (FBI) provides a means of calculating the fiber orientation density function (fODF) in white matter from diffusion MRI (dMRI) data obtained over a spherical shell with a b-value of about 4000 s/mm² or higher. By supplementing this FBI-derived fODF with dMRI data acquired for two lower b-value shells, it is shown that several microstructural parameters may be estimated, including the axonal water fraction (AWF) and the intrinsic intra-axonal diffusivity. This fiber ball white matter (FBWM) modeling method is demonstrated for dMRI data acquired from healthy volunteers, and the results are compared with those of the white matter tract integrity (WMTI) method. Both the AWF and the intra-axonal diffusivity obtained with FBWM are found to be significantly larger than for WMTI, with the FBWM values for the intra-axonal diffusivity being more consistent with recent results obtained using isotropic diffusion weighting. An important practical advantage of FBWM is that the only nonlinear fitting required is the minimization of a cost function with just a single free parameter, which facilitates the implementation of efficient and robust numerical routines.

Sensory neurons represent stimulus information with sequences of action potentials that differ across repeated measurements. This variability limits the information that can be extracted from momentary observations of a neuron's response. It is often assumed that integrating responses over time mitigates this limitation. However, temporal response correlations can reduce the benefits of temporal integration. We examined responses of individual orientation-selective neurons in the primary visual cortex of two macaque monkeys performing an orientation-discrimination task. The signal-to-noise ratio of temporally integrated responses increased for durations up to a few hundred milliseconds but saturated for longer durations. This was true even when cells exhibited little or no adaptation in their response levels. These observations are well explained by a statistical response model in which spikes arise from a Poisson process whose stimulus-dependent rate is modulated by slow, stimulus-independent fluctuations in gain. The response variability arising from the Poisson process is reduced by temporal integration, but the slow modulatory nature of variability due to gain fluctuations is not. Slow gain fluctuations therefore impose a fundamental limit on the benefits of temporal integration.

The stimulus selectivity of neurons in V1 is well known, as is the finding that their responses can be affected by visual input to areas outside of the classical receptive field. Less well understood are the ways selectivity is modified as signals propagate to visual areas beyond V1, such as V2. We recently proposed a role for V2 neurons in representing the higher order statistical dependencies found in images of naturally occurring visual texture. V2 neurons, but not V1 neurons, respond more vigorously to "naturalistic" images that contain these dependencies than to "noise" images that lack them. In this work, we examine the dependency of these effects on stimulus size. For most V2 neurons, the preference for naturalistic over noise stimuli was modest when presented in small patches and gradually strengthened with increasing size, suggesting that the mechanisms responsible for this enhanced sensitivity operate over regions of the visual field that are larger than the classical receptive field. Indeed, we found that surround suppression was stronger for noise than for naturalistic stimuli and that the preference for large naturalistic stimuli developed over a delayed time course consistent with lateral or feedback connections. These findings are compatible with a spatially broad facilitatory mechanism that is absent in V1 and suggest that a distinct role for the receptive field surround emerges in V2 along with sensitivity for more complex image structure. NEW & NOTEWORTHY The responses of neurons in visual cortex are often affected by visual input delivered to regions of the visual field outside of the conventionally defined receptive field, but the significance of such contextual modulations are not well understood outside of area V1. We studied the importance of regions beyond the receptive field in establishing a novel form of selectivity for the statistical dependencies contained in natural visual textures that first emerges in area V2.

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

BACKGROUND:Elevated stress is associated with adverse cardiovascular disease outcomes and accounts in part for the poorer recovery experienced by women compared with men after myocardial infarction (MI). Psychosocial interventions improve outcomes overall but are less effective for women than for men with MI, suggesting the need for different approaches. Mindfulness-based cognitive therapy (MBCT) is an evidence-based intervention that targets key psychosocial vulnerabilities in women including rumination (i.e., repetitive negative thinking) and low social support. This article describes the rationale and design of a multicenter randomized controlled trial to test the effects of telephone-delivered MBCT (MBCT-T) in women with MI. METHODS:We plan to randomize 144 women reporting elevated perceived stress at least two months after MI to MBCT-T or enhanced usual care (EUC), which each involve eight weekly telephone sessions. Perceived stress and a set of patient-centered health outcomes and potential mediators will be assessed before and after the 8-week telephone programs and at 6-month follow-up. We will test the hypothesis that MBCT-T will be associated with greater 6-month improvements in perceived stress (primary outcome), disease-specific health status, quality of life, depression and anxiety symptoms, and actigraphy-based sleep quality (secondary outcomes) compared with EUC. Changes in mindfulness, rumination and perceived social support will be evaluated as potential mediators in exploratory analyses. CONCLUSIONS:If found to be effective, this innovative, scalable intervention may be a promising secondary prevention strategy for women with MI experiencing elevated perceived stress.