Biology subjects

Schiller, D.

Publications and source records attributed to Schiller, D..

3 recordsLinked to original sources

bioRxiv2021

An interpretable connectivity-based decoding model for classification of chronic marijuana use

BackgroundPsychiatric neuroimaging typically proceeds with one of two approaches: encoding models, which aim to model neural mechanisms, or decoding models, which aim to predict behavioral or clinical characteristics from brain imaging data. In this study, we seek to combine these aims by developing interpretable decoding models that offer both accurate prediction and novel neural insights. We demonstrate the effectiveness of this combined approach in a case study of chronic marijuana use. MethodsChronic marijuana (MJ) users (n=195) and non-using healthy controls (n=128) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic MJ users and non-users based on task-evoked, whole-brain functional connectivity. We then used graph theoretic analyses to identify predictive functional connectivities among brain regions that contributed most substantially to the classification of chronic marijuana use. ResultsWe obtained high (~80% out-of-sample) accuracy across four different classification models, demonstrating that task-evoked, whole-brain functional connectivity can successfully differentiate chronic marijuana users from non-users. Subsequent network analyses revealed key predictive regions (e.g., anterior cingulate cortex, dorsolateral prefrontal cortex, and precuneus) that are often implicated in neuroimaging studies of substance use disorders, as well as some key exceptions. We also identified a core set of networks of brain regions that contributed to successful classification, comprised of many of the same predictive regions. ConclusionsOur dual aims of accurate prediction and interpretability were successful, producing a predictive model that also provides interpretability at the neural level. This novel approach may complement other predictive-exploratory approaches for a more complete understanding of neural mechanisms in drug use and other neuropsychiatric disorders.

neuroscience↗

bioRxiv2020

Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) are heavily infiltrated by CD8+ tumor infiltrating lymphocytes (TILs) and are associated with a better prognosis than the majority of CRCs. The immunogenicity of dMMR CRCs is commonly attributed to abundant neoantigen generation due to their extreme genomic instability. However, lack of neoantigenic overlap between these and other CRCs necessitates study of antigen-independent mechanisms of immune activation by dMMR CRCs in order identify therapeutic strategies for treating MMR proficient CRCs. We show here using organoid cocultures and orthotopic models that a critical component of dMMR CRCs immunogenicity is the activation and recruitment of systemic CD8+ T cells into the tumor epithelium by overexpression of the chemokines CCL5 and CXCL10. This is dependent on endogenous activation of the cGAS/STING and IFN signaling pathways by the damaged DNA in dMMR CRCs. These signaling pathways remain sensitive to exogenous stimulation in other CRCs, identifying an attractive therapeutic avenue for increasing TIL infiltration into normally immune resistant CRC subtypes. We have thus identified a key neoantigen-independent mechanism that underlies the ability for dMMR CRCs to recruit TILs into the tumor epithelium. Given that TIL recruitment is a prerequisite for effective tumor killing either by the endogenous immune system or in the context of immunotherapies, treatments that activate IFN-induced chemokine-production by tumor cells promise to improve the prognosis of patients with many different CRC subsets. Statement of SignificanceA critical component of antitumor immunity in dMMR CRCs is their ability to recruit T cells into the tumor epithelium as a prerequisite to tumor cell killing. This occurs because their extensive genomic instability leads to endogenous activation of cGAS/STING and overexpression of CCL5 and CXCL10.

cancer biology↗

bioRxiv2018

Affective flexibility without perceptual awareness

In an ever-changing environment, survival depends on learning which stimuli represent threat, and also on updating such associations when circumstances shift. Humans can acquire physiological responses to threat-associated stimuli even when they are unaware of them, but the role of awareness in updating threat contingencies remains unknown. This complex process - generating novel responses while simultaneously suppressing learned ones - relies on distinct neural mechanisms from initial learning, and has only been shown with awareness. Can it occur unconsciously? Here we show that it can. Participants underwent classical threat conditioning to visual stimuli that were suppressed from their awareness. One of two images was paired with an electric shock; halfway through the experiment, contingencies were reversed and the shock was paired with the other image. We found that physiological responses reflected changes in stimulus-threat pairings independently of stimulus awareness, demonstrating the sophistication of unconscious affective flexibility.

neuroscience↗