Running Head: COMPUTER-BASED INTERVENTION STUDY 1 Short-Term Effects of Cognitive Training in Adult Cochlear Implant Users By Amit Bansal Master of Philosophy Student, University of Oslo, The Faculty of Medicine, Institute of Health and Society, Department of Community Medicine, Norway Name of Supervisors: I. Aaron Newman, Host Neuroscientist, NeuroCognitive Imaging Lab Director, Associate Professor - Psychology, Psychiatry, Surgery, & Pediatrics (Div. of Neurology), Dalhousie University, Halifax, Nova Scotia, Canada II. Arild Lian, Local External Supervisor, Professor Emeritus Psychology, University of Oslo, Norway III. Christoph Gradmann, Local Internal Co-supervisor, Professor in History of Medicine, University of Oslo, Norway Thesis submitted as a part of the Master of Philosophy Degree in International Community Health May 2014 COMPUTER-BASED INTERVENTION STUDY 2 Changing the brain: Lab-to-bedside approach COMPUTER-BASED INTERVENTION STUDY 3 Disclosure Statement There are no actual or potential conflicts of interest. Dr Bansal and his colleagues do not work for, consult to, own shares in any company or association that would benefit from this thesis, and have no relevant affiliations. The Ivar Helles Legat was received from the University of Oslo, Norway. The sub-investigator had received scholarship from Natural Sciences and Engineering Research Council of Canada‟s The Rehabilitative and Diagnostic Innovation in Applied NeuroTechnology - The Collaborative Research and Training Experience (NSERC‟s RADIANT-CREATE) program. We have collaborated with an industry partner for technical support; however, they are not providing funding. © Amit Bansal, 2014 COMPUTER-BASED INTERVENTION STUDY 4 Acknowledgements This thesis is based upon a clinical trial that was conducted at Dalhousie University in Canada. First and foremost, I would like to express gratitude to all participants of this trial. This study would not have been possible without their involvement. I am grateful to my main supervisor and host neuroscientist at Dalhousie University, Associate Professor Aaron Newman, PhD, who is one of the outstanding researchers I have known, for sharing his knowledge, methodological and analyzing skills with cheer joy and optimism. Aaron and his team‟s effort have lead to completion of this thesis. I am proud to be his first Indian student for the MPhil in International Community Health and RADIANT Graduate Certificate in Translational NeuroTechnology. I would like to thank my main supervisor and Emeritus Professor from the University of Oslo, Arild Lian, DrPhil, for his invaluable guidance, motivation, steadfast integrity and support throughout the project. I am also pleased to thank: Professor Christoph Gradmann, DrPhil, my local internal co-supervisor at the University of Oslo, for taking care of departmental administrative issues, general supervision and his willingness to supervise me. RADIANT faculty members for accepting my application for Graduate Certificate in Translational NeuroTechnology and Graduate Student Scholarship. Ivar Helles Legat from the University of Oslo for financial support. Without their substantial help, this project would not have been feasible. Antoine Tremblay, Post-doc at the NeuroCognitive Imaging Lab (NCIL), for technical assistant in setting up randomization of two treatment arms, teaching me brain imaging (MEG/MRI) data analyses and judo. Alexandria Muise, MSc student at Dalhousie University, for helping out in participant recruitment and taking over this project after I return to Norway. Jillian Bray, NCIL Manager, for supervising the administrative tasks and funny conversations. Anne Johnson, NCIL Research Assistant, for lending a hand in the Canadian research ethics board application. COMPUTER-BASED INTERVENTION STUDY 5 Graduate and undergraduate Dalhousie University students for being a pilot participant or proof-reading data spreadsheets (Anthony Duchesne, Judy Cerny, Kate Thompson, Max Hauser and Vivian Eng). Ariel Shatil, Evelyn Shatil and the entire CogniFit team, for sharing the description of cognitive training games and technical support to aptly run the CogniFit brain training games. Dr Manohar Bance, Professor and Head, Division of Otolaryngology at Dalhousie University, for mentoring my time there as a clinical observer and his dedication to research on the novel approaches for the otological management, combined with great enthusiasm and encouragement, has been very rousing. Staff of the Department of Psychiatry and Surgery: Drs David P. Morris, David Kirkpatrick, Hosam Amoodi, Maggie Aron, Nick Delva, Mr Mark Gulliver, Ms Belinda Nicoll, Jean Lessel, medical students, nurses and residents for their invaluable help and support throughout my clinical observership period. Dr Maneesha Kamra, Neurology Clinical Observer at the Sunnybrook Hospital in Canada, for monograph‟s grammar checking. Ibrahimu Mdala, PhD Research Fellow and Milada C Småstuen, Researcher from the University of Oslo, for their precious time spent in teaching me regression analyses. Christina Lunn, Owner of Hearing Institute Atlantic, for supporting this project. Audiologists at the Cochlear Implant Centre at VG site in Halifax Society of Deaf and Hard of Hearing Nova Scotians (SDHHNS), Canadian Hard of Hearing Association (CHHA), and Deafness Advocacy Association Nova Scotia (DAANS) for supporting this project. Colleagues and friends at the University of Oslo and Dalhousie University, for creating a happy and productive working environment, and for being excellent and encouraging colleagues. My close friends, Drs Jagkirat Singh, Vaibhav Sood and Ms Chi Mai Trieu for being a great source of inspiration, for hugs, and tender loving care. I cherished the great time we had. Last but not least, my parents, brother and sister, for your blessings and love. COMPUTER-BASED INTERVENTION STUDY 6 Abstract Background: There is growing evidence in support of the cognitive remediation following cochlear implantation in children. To the best of our knowledge, the role of generalized cognitive training (CT) in adult cochlear implant users has not been explored. Objectives: To determine the effects of computerized CT with standard therapy on adult cochlear implant users‟ speech comprehension in noise, cognitive functions and auditory ability. Methods: A prospective, unblinded, single-center, randomized controlled trial with cross-over study design and two treatment arms. Participants (N = 12) from the Maritime Provinces in Canada received CT (via CogniFit) either right after the first assessment or ten weeks later in the immediate (n = 7) and delayed (n = 5) treatment groups respectively. Speech comprehension in noise, assessed by AzBio sentence test, was the primary outcome measure. The secondary outcomes were neuropsychological assessments - CANTABeclipse for Clinical Trials, and self- reported auditory ability - Speech Spatial Qualities questionnaire (SSQ). Data from 2 participants were excluded due to lack of follow-up, data from the remaining participants were analyzed by mixed models in SPSS (version 20) and R (version 3.0.2.). Results: Based upon analyses combined across two groups, CT with standard therapy (n = 10) marginally enhanced sentence comprehension in noise, AzBio score, β = 2.58, 95% CI [-2.84, 8.02], p > .05. Furthermore, CT demonstrated statistically significant, but modest improvement in SSQ total scores, β = 0.60, 95% CI [0.14, 1.05] and certain CANTABeclipse test scores. Namely, (i) SOC number of problems solved in minimum moves, β = 1.12, 95% CI [0.29, 1.94], for Spatial Planning (ii) SWM total errors for problems with 4 to 8 boxes, β = -11.32, 95% CI [- 19.82, -2.81] and strategy, β = -3.08, 95% CI [-4.36, -1.81], for Spatial Working Memory, (iii) RVP A′, β = 0.015, 95% CI [0.005, 0.026], for Sustained Attention and (iv) VRM free recall, β = 1.25, 95% CI [0.25, 2.26] and recognition, β = 0.76, 95% CI [0.32, 1.20], for verbal memory. Conclusion: Ten weeks of cognitive training modestly enhanced executive and working memory skills in adult cochlear implant users. This finding suggests adult cochlear implant users‟ brains are malleable. The treatment effect estimates for speech comprehension in noise did not reach a statistically significant level. A longitudinal multicentered trial with a large sample size is needed to make evidence-based recommendation for the routine clinical care of cochlear implant users. Trial Registration: Clinicaltrial.gov unique identifier NCT01732887 Keywords: Cochlear implant, cognitive fitness, cognitive training, deafness, speech intelligibility COMPUTER-BASED INTERVENTION STUDY 7 List of Abbreviations CANTAB: CAmbridge Neuropsychological Test Automated Battery CBI study: Computer-Based Intervention study CF: CogniFit complementary cognitive training program CI: Cochlear Implant CREATE: The Collaborative Research and Training Experience CT: Generalized Cognitive Training DM: Diabetes Mellitus HPAPQ: Healthy Physical Activity Participation Questionnaire FANTASTIC: Family/Friends, Activity, Nutrition, Tobacco/Toxins, Alcohol, Sleep/Seatbelts/Stress/Safe sex, Type of behavior, Insight, Career MMSE: Mini Mental State Examination M. Phil. ICH: Master of Philosophy Degree in International Community Health MOT: MOtor screening task NCERC: Natural Sciences and Engineering Research Council of Canada NCIL: NeuroCognitive Imaging Lab NS: Nova Scotia OTS: One Touch Stockings of Cambridge p: p - value RADIANT: Rehabilitative and Diagnostic Innovation in Applied NeuroTechnology programme RCT: Randomized Controlled Trial RVP: Rapid Visual Information Processing Std Rx: Standard therapy or standard of care SNHL: Sensorineural Hearing Loss SOC: Stockings Of Cambridge SSQ: Speech, Spatial and Qualities of hearing scale SWM: Spatial Working Memory VRM: Verbal Recognition Memory WM: Working Memory 95 % CI: 95 Percent Confidence Interval β : Vector of regression coefficients COMPUTER-BASED INTERVENTION STUDY 8 Definition of Terms Neuroplasticity Neuroplasticity (or brain plasticity) is defined as the ability of the nervous system to change its structure and functional organization that persists beyond its inciting internal or external stimuli (Chen et al., 2014). Generalized Cognitive Training According to Gates and Valenzuela, the generalized multi-domain cognitive training (CT) consists of training in: (a) applied memory strategies and (b) repetitive cognitive exercises. The former include strategies such as the method of loci, mnemonics and visual imagery, and aim to remediate memory and enhance performance. Repetitive cognitive exercises, however, consist of repeated use of certain cognitive abilities following the „reps-sets‟ pattern of resistance physical training. In each session, a particular cognitive task is practiced repeatedly. New tasks are introduced and practiced in subsequent sessions. Finally, users train on a higher level version of the original task (N. J. Gates, Sachdev, Fiatarone Singh, & Valenzuela, 2011; N. Gates & Valenzuela, 2010). Standard Therapy Herein, standard therapy (or standard of care) includes the advice and care given by patient‟s audiologist, family physician, otolaryngologist, speech-language pathologist and other members of the health-care team. Hearing It is essentially a sensory and passive function that helps to perceive sounds by vibrations and discriminate their location, pitch, loudness and quality (Kiessling et al., 2003). Listening Listening is an activity and cognitive process where people engage in hearing with intention and attention (Kiessling et al., 2003). Comprehending Comprehending is the unidirectional understanding of information, meaning and intent. It is an activity that goes beyond the hearing and listening processes (Kiessling et al., 2003). COMPUTER-BASED INTERVENTION STUDY 9 Table of Contents DISCLOSURE STATEMENT 3 ACKNOWLEDGEMENTS 4 ABSTRACT 6 LIST OF ABBREVIATIONS 7 DEFINITION OF TERMS 8 1. INTRODUCTION 11 1.1. Aims of the Present Work 11 1.2. Aetio-pathology of Hearing Loss and its Relationship to Cognitive Impairments 12 1.3. Management Options for Hearing Loss 15 1.4. Explanation for Individual Differences in Cochlear Implant users’ Language Skills 18 2. THE RATIONALE OF PRESENT WORK 19 2.1. Global Demographics of People with Cochlear Implants 19 2.2. Access to Specialized Medical Services after Cochlear Implantation in Canada 20 2.3. Association between Linguistic Skills and Working Memory 21 2.4. Previous Computerized Post Cochlear Implantation Research 22 2.5. Finding an Innovative Cost-Effective Solution 26 2.6. Designing a Research Study 28 2.7. Designing a Phase II Clinical Trial 30 3. OBJECTIVES AND HYPOTHESES OF THE STUDY 31 3.1. Main Objective 32 3.2. Specific Objectives 32 COMPUTER-BASED INTERVENTION STUDY 10 3.3. Research Question 32 3.4. Hypotheses 32 3.5. Expected Outcomes 33 4. METHODOLOGY 33 4.1. Project Methodology 33 4.2. Intervention 50 4.3. Data Collection and Management 51 4.4. Timeline of the trial 52 4.5. Statistical consideration 52 4.6. Ethical and safety issues 54 5. RESULTS 55 5.1. Group Level Analysis for Hearing and Cognitive Outcome Measures of the Adult Cochlear Implant Users 55 5.2. Individual Level Analysis for Hearing Outcome Measures of the Adult Cochlear Implant Users 61 5.3. Individual Level Analysis for Cognitive Outcome Measures (CANTABeclipse Version 5.0) of the Adult Cochlear Implant Users 62 5.4. Analyses Combined Across All Participants 74 6. DISCUSSION 76 6.1. Discussion of the Study Hypotheses 76 6.2. Strengths and Weaknesses of the Present Work 80 7. CONCLUSION 83 8. SUGGESTIONS 83 9. REFERENCES 84