Cognitive Dysfunction in the Addictions (CDiA): Protocol for a Neuron-to-Neighbourhood Collaborative Research Program

Yuliya S Nikolova ^1,2,3 Anthony C. Ruocco ^1,2,3,4 Daniel Felsky ^1,2,5 Shannon Lange ^1,2,6,7 Thomas PREVOT ^1,2,8 Erica Vieira ^1,2 Daphne Voineskos ^1,2 Jeffrey D Wardell ^1,2,9 Daniel M Blumberger ^1,2 Kevan P Clifford ^1,2 Ravinder Naik Dharavath ¹ Philip Gerretsen ^1,2 Ahmed Hassan ^1,2 Sheila K Jennings ^10,11 Bernard Le Foll ^1,2 Osnat C Melamed ^1,12 Joshua Orson ¹¹ Peter Tomov Pangarov ¹ Leanne Quigley ¹³ Cayley Russell ¹⁴ Kevin Shield ^1,15,2 Matthew E Sloan ^1,2,3,7,8 Ashley S Smoke ^11,16 Victor Mark Tang ^1,2,7 Diana Valdés Cabrera ^1,17 Wei Wang ¹ Samantha Wells ^1,18,2 Rajith Wickramatunga ¹ Etienne Sibille ^1,2,8 Lena Catherine Quilty ^1,2*

• ¹ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
• ² Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ³ Department of Psychological Clinical Science, University of Toronto, Toronto, Canada
• ⁴ Department of Psychology, University of Toronto Scarborough, Toronto, Ontario, Canada
• ⁵ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ⁶ Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ⁷ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ⁸ Department of Pharmacology and Toxicology, Faculty of Medicine, The University of Toronto, Toronto, Ontario, Canada
• ⁹ Department of Psychology, York University, Toronto, Ontario, Canada
• ¹⁰ Independent researcher, Victoria, British Columbia, Canada
• ¹¹ The Centre for Addiction and Mental Health, Toronto, Ontario, Canada
• ¹² Department of Family and Community Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ¹³ Ferkauf Graduate School of Psychology, Yeshiva University, New York, United States
• ¹⁴ Canadian Research Initiative in Substance Matters, Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ¹⁵ Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
• ¹⁶ The Ontario Network of People Who Use Drugs, Toronto, Ontario, Canada
• ¹⁷ Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
• ¹⁸ Western University, London, Ontario, Canada

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.