Cognitive Dysfunction in the Addictions (CDiA): protocol for a neuron-to-neighbourhood collaborative research program

Substance use disorders (SUDs), including Alcohol Use Disorder, are pressing global public health problems. Executive functions (EFs) are prominently featured in mechanistic models of addiction. However, significant gaps remain in our understanding of EFs in SUDs, including the dimensional relationships of EFs to underlying neural circuits, molecular biomarkers, disorder heterogeneity, and functional ability. Transforming health outcomes for people with SUDs requires an integration of clinical, biomedical, preclinical, and health services research. Through such interdisciplinary research, we can develop policies and interventions that align with biopsychosocial models of addiction, addressing the complex cognitive concerns of people with SUDs in a more holistic and effective way. Here, we introduce the design and procedures underlying Cognitive Dysfunction in the Addictions (CDiA), an integrative research program, which aims to fill these knowledge gaps and facilitate research discoveries to enhance treatments for people living with SUDs. The CDiA Program comprises seven interdisciplinary projects that aim to evaluate the central thesis that EF has a crucial role in functional outcomes in SUDs. The projects draw on a diverse sample of adults aged 18-60 (target N=400) seeking treatment for SUD, who are followed over one year to identify specific EF domains most associated with improved functioning. Projects 1-3 investigate SUD symptoms, brain circuits, and blood biomarkers and their associations with key EF domains (inhibition, working memory, and set-shifting) and functional outcomes (disability, quality of life). Projects 4 and 5 evaluate interventions for SUDs and their impacts on EF: a clinical trial of repetitive transcranial magnetic stimulation and a preclinical study of potential new pharmacological treatments in rodents. Project 6 links EF to healthcare utilization and is supplemented with a qualitative investigation of EF-related barriers to treatment engagement. Project 7 uses whole-person modeling to integrate the multi-modal data generated across projects, applying clustering and deep learning methods to identify patient subtypes and drive future cross-disciplinary initiatives. The CDiA Program will bring scientific domains together to uncover novel ways in which EFs are linked to SUD severity and functional recovery, and facilitate future discoveries to improve health outcomes in individuals living with SUDs.