Faculty Bibliography

Oral cancer pain is attributed to the release from cancers of mediators that sensitize and activate sensory neurons. Intraplantar injection of conditioned media (CM) from human tongue cancer cell line HSC-3 or OSC-20 evokes nociceptive behavior. By contrast, CM from noncancer cell lines, DOK, and HaCaT are non-nociceptive. Pain mediators are carried by extracellular vesicles (EVs) released from cancer cells. Depletion of EVs from cancer cell line CM reverses mechanical allodynia and thermal hyperalgesia. CM from non-nociceptive cell lines become nociceptive when reconstituted with HSC-3 EVs. Two miRNAs (hsa-miR-21-5p and hsa-miR-221-3p) are identified that are present in increased abundance in EVs from HSC-3 and OSC-20 CM compared to HaCaT CM. The miRNA target genes suggest potential involvement in oral cancer pain of the toll like receptor 7 (TLR7) and 8 (TLR8) pathways, as well as signaling through interleukin 6 cytokine family signal transducer receptor (gp130, encoded by IL6ST) and colony stimulating factor receptor (G-CSFR, encoded by CSF3R), Janus kinase and signal transducer and activator of transcription 3 (JAK/STAT3). These studies confirm the recent discovery of the role of cancer EVs in pain and add to the repertoire of algesic and analgesic cancer pain mediators and pathways that contribute to oral cancer pain.

Vocal communication is a critical feature of social interaction across species; however, the relation between such behavior in humans and nonhumans remains unclear. To enable comparative investigation of this topic, we review the literature pertinent to interactive language use and identify the superset of cognitive operations involved in generating communicative action. We posit these functions comprise three intersecting multistep pathways: (a) the Content Pathway, which selects the movements constituting a response; (b) the Timing Pathway, which temporally structures responses; and (c) the Affect Pathway, which modulates response parameters according to internal state. These processing streams form the basis of the Convergent Pathways for Interaction framework, which provides a conceptual model for investigating the cognitive and neural computations underlying vocal communication across species. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Immune checkpoint blockade (ICB) has transformed the treatment of metastatic cancer but is hindered by variable response rates. A key unmet need is the identification of biomarkers that predict treatment response. To address this, we analyzed six whole exome sequencing cohorts with matched disease outcomes to identify genes and pathways predictive of ICB response. To increase detection power, we focus on genes and pathways that are significantly mutated following correction for epigenetic, replication timing, and sequence-based covariates. Using this technique, we identify several genes (BCLAF1, KRAS, BRAF, and TP53) and pathways (MAPK signaling, p53 associated, and immunomodulatory) as predictors of ICB response and develop the Cancer Immunotherapy Response CLassifiEr (CIRCLE). Compared to tumor mutational burden alone, CIRCLE led to superior prediction of ICB response with a 10.5% increase in sensitivity and a 11% increase in specificity. We envision that CIRCLE and more broadly the analysis of recurrently mutated cancer genes will pave the way for better prognostic tools for cancer immunotherapy.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

Modern optical neuroimaging approaches are expanding the ability to elucidate complex brain function. Diverse imaging contrasts enable direct observation of neural activity with functional sensors along with the induced hemodynamic responses. To date, decoupling the complex interplay of neurovascular coupling and dynamical physiological states has remained challenging when employing single-modality functional neuroimaging readings. A hybrid fluorescence optoacoustic tomography platform combined with a custom data processing pipeline based on statistical parametric mapping is devised, attaining the first noninvasive observation of simultaneous calcium and hemodynamic activation patterns using optical contrasts. Correlated changes in the oxy- and deoxygenated hemoglobin, total hemoglobin, oxygen saturation, and rapid GCaMP6f fluorescence signals are observed in response to peripheral sensory stimulation. While the concurrent epifluorescence serves to corroborate and complement the functional optoacoustic observations, the latter further aids in decoupling the rapid calcium responses from the slowly varying background in the fluorescence recordings mediated by hemodynamic changes. The hybrid imaging platform expands the capabilities of conventional neuroimaging methods to provide more comprehensive functional readings for studying neurovascular and neurometabolic coupling mechanisms and related diseases.

The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.

Learning is widely modeled in psychology, neuroscience, and computer science by prediction error-guided reinforcement learning (RL) algorithms. While standard RL assumes linear reward functions, reward-related neural activity is a saturating, nonlinear function of reward; however, the computational and behavioral implications of nonlinear RL are unknown. Here, we show that nonlinear RL incorporating the canonical divisive normalization computation introduces an intrinsic and tunable asymmetry in prediction error coding. At the behavioral level, this asymmetry explains empirical variability in risk preferences typically attributed to asymmetric learning rates. At the neural level, diversity in asymmetries provides a computational mechanism for recently proposed theories of distributional RL, allowing the brain to learn the full probability distribution of future rewards. This behavioral and computational flexibility argues for an incorporation of biologically valid value functions in computational models of learning and decision-making.

How does craving bias decisions to pursue drugs over other valuable, and healthier, alternatives in addiction? To address this question, we measured the in-the-moment economic decisions of people with opioid use disorder as they experienced craving, shortly after receiving their scheduled opioid maintenance medication and ~24 h later. We found that higher cravers had higher drug-related valuation, and that moments of higher craving within-person also led to higher drug-related valuation. When experiencing increased opioid craving, participants were willing to pay more for personalized consumer items and foods more closely related to their drug use, but not for alternative "nondrug-related" but equally desirable options. This selective increase in value with craving was greater when the drug-related options were offered in higher quantities and was separable from the effects of other fluctuating psychological states like negative mood. These findings suggest that craving narrows and focuses economic motivation toward the object of craving by selectively and multiplicatively amplifying perceived value along a "drug relatedness" dimension.

Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

RATIONALE/BACKGROUND:The coronavirus disease 2019 (COVID-19) pandemic has led to a dramatic increase in the number of survivors of critical illness. These survivors are at increased risk of physical, psychological, and cognitive impairments known collectively as Post-Intensive Care Syndrome (PICS). Little is known about the prevalence of PICS in COVID-19 survivors. OBJECTIVES/OBJECTIVE:To report the prevalence of physical, psychological, and cognitive impairment among COVID-19 intensive care unit (ICU) survivors receiving follow-up care in an ICU recovery clinic, to assess for associations between PICS and ICU-related factors, and to compare the cohort of ICU survivors who attended post-ICU clinic to a cohort of ICU survivors who did not. METHODS:We performed a retrospective cohort study of COVID-19 ICU survivors admitted from March to May 2020 who were subsequently seen in a post-ICU recovery clinic in New York City. We abstracted medical chart data on available clinical screening instruments for physical, psychological, and cognitive impairment. Associations between these outcomes and care-related variables were tested. Baseline characteristics and in-hospital treatments of the post-ICU clinic cohort were compared to COVID-19 ICU survivors from the same institution who were not seen in post-ICU clinic. RESULTS:87 COVID-19 ICU survivors were seen in our post-ICU recovery clinic. The median age was 62 years and 74% were male. The median length of hospitalization was 51 days and the median length of ICU stay was 22 days. At the post-ICU follow-up visit, 29%, 21%, and 13% of patients reported clinically significant levels of depressive symptoms, anxiety, and post-traumatic stress disorder symptoms, respectively. 25% had cognitive impairment. The overall prevalence of PICS was 90%. There were no associations between length of ICU stay, delirium, exposure to benzodiazepines, steroids, or systemic paralytics with positive screens for physical, psychological, or cognitive impairment. Baseline characteristics and ICU-related factors were similar in the cohort of COVID-19 ICU survivors who attended ICU recovery clinic and those who did not. CONCLUSION/CONCLUSIONS:PICS is common in COVID-19 survivors. We did not find any association with length of ICU stay, the use of benzodiazepines, steroids, or paralytics.