1. COGNITIVE TRAINING AND ADHD: Can training each day keep impairments at bay? Rosemary Tannock, PhD Erskine Visiting Fellow, University of Canterbury(Feb-April, 2015) Senior Scientist, Neurosciences & Mental Health Research Program The Hospital for Sick Children; & Professor Emerita (Special Education, Psychiatry), University of Toronto rosemary.tannock@utoronto.ca

2. Disclosure: potential conflicts of interest Faculty: Rosemary Tannock, PhD Relationships with commercial interests: Research Grants: Federal grants (IES-USA; CIHR) Research Support: Cogmed; Purdue Pharma Honoraria: Shire; Janssen-Ortho Consulting Fees: Biomed Central (publisher) Editors Advisory Group Other: Royalties: Springer, as Co-Editor of book (Behavioral Neuroscience of ADHD and its Treatment, 2011) Member DSM-5 Workgroup on ADHD, & liaison member to Neurodevelopmental Disorders workgroup (for Learning Disorders) Member International Steering Committee for WHO International Classification of Functioning (ICF)-Core Set for ADHD Affiliate member WHO ICD-11 Specific Learning Disorders subcommittee CFPC CoI Templates: Slide 1

3. Scope of this talk Cognitive training has wide range of meaning Application of self-monitoring & self-reinforcement techniques to enhance functioning (e.g., Abikoff et al., 1988, J Abnorm Child Psychol, 16:411-432) Application of EEG feedback for self-monitoring & sustaining attention – Neurofeedback (e.g., Hurt et al., 2014, Child Adolesc Psychiatric Clin N Am, 23:465- 486) Intensive, adaptive practice of specific cognitive process (e.g., Klingberg, 2010, Trends Cog Sci 14: 317-324) This talk focuses on computerized cognitive training designed to target WM: specifically on a software program called “COGMED”

4. Neuroplasticity Scientific dogma until 1970’s… “In the adult [brain] centres, the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated.” Santiago Ramon v Cajal (1913). Spanish physician, neuroanatomist & Nobel Laureate By contrast, scientists now recognize that the human brain (even in adulthood) shows remarkable neuroplasticity

5. IS WORKING MEMORY CAPACITY A MALLEABLE FACTOR? CAN IT BE IMPROVED BY COMPUTERIZED TRAINING? By improving a person’s WM, beneficial effects should also be expected in various related abilities utilizing WM, including real- world behavior (beyond the Laboratory)

6. COMPUTERIZED COGNITIVE TRAINING Cogmed™ [abbrev. CWMT] Jungle Memory™ Cognifit™ BrainTrain: Captain’s Log™ Lumosity™ Nintendo: Brain Age 6

7. Features of Cogmed WM Training Intensive & adaptive training Adaptive: automatically, continuously adjusted in difficulty relative to individual’s WM capacity Extensive repetition, practice, feedback – designed to enhance the development & efficiency of underlying neural substrates (for WM) Underlying assumption: improvements in WM will generalize or transfer to other tasks or activities that rely on the same neural networks or require WM (Klingberg, 2010) 7

8. Computerized Working Memory Training Computerized Working Memory Training (Cogmed JM/RM/QM)  45 min training/day  5 days/week,5 weeks  Adaptive algorithm ◦ individually-based  Reinforcement ◦ Immediate performance-based feedback; ◦ internal reinforcement activities ◦ external reinforcement for completing pre-specified # sessions  Weekly monitoring calls from licensed provider, using uploaded tracking data Cogmed/Pearson http://www.cogmed.com/rm

9. What does the training entail? EQUIPMENT Software (license per person) $ Computer (per person) linked to internet $ [Headphones for group administration] $ COACHING/Supervision $ Weekly telephone call from a trained & licensed ‘coach’ to give feedback on performance, give advice about training activities, answer questions For youth - Daily supervision of training – parent, school-aide, volunteer, (often by members of research study) 9

10. The beginning…a startling finding suggesting that WM might be mutable – like a muscle! In 2002, Torkel Klingberg, a Swedish researcher challenged the prevailing notion that WM capacity is fixed - he reported that 5 weeks of playing specific memory-based computer games (every day for about 30-45 mins), not only boosted WM, of children with ADHD but also intellectual ability ! But a very small sample ( n ~ 7 per group) Double-blind but not randomized

11. Klingberg et al. (2005) JAACAP Repeat this letters in the same order they are given.... ”2 8 4 7 2 9” Promising findings from first randomized controlled trial! (Klingberg et al, 2005) Adaptive training: n=20 ‘ADHD’ Non-adaptive training: n=24’ ADHD’ ES:.93/.92 ES:.73/?

12. Moreover, training effects appeared to transfer to other cognitive functions!

13. Parent rating of ADHD symptoms (Conners) no evidence of change in teacher ratings Controlled for whether training done at home or school

14. Strong claims for WM training

15. Including those by Cogmed

16. The spread of Cogmed ~58 published studies; 90+ ongoing studies Healthy young adults Older/elderly adults Adults who have had a stroke Individuals with brain injury Children with : WM deficits; ADHD ; cochlear implants; cancer treated with radiation; Down syndrome, low IQ, born prematurely… Cogmed is now operating in > 1000 schools world-wide (& is available in NZ)

17. So, does WM training (cogmed) enhance WM capacity?

18. Cogmed WM Training: Reviewing the Reviews Shinaver*, Entwistle*, Söderqvist*. APPLIED NEUROPSYCHOLOGY: CHILD, 3: 163–172, 2014 (*Pearson Assessment) “Cogmed has indeed demonstrated reliable immediate improvements in WM capacity in samples of typically developing children…& adults….children with ADHD…with poor WM…cochlear implants…very low birth weight…adolescents at extremely low birth weight….pediatric cancer survivors…& brain injured adults” “In a little more than a decade, there is evidence that suggests that Cogmed has a significant impact upon visual-spatial and verbal WM, and these effects generalize to improved sustained attention up to 6 months” “In conclusion, we find that there is a consensus in showing that WM capacity and attention is improved following CWMT.”

21. Cogmed working memory training is sold as a tool for improving cognitive abilities, such as attention and reasoning. At present, this program is marketed to schools as a means of improving underperforming students’ scholastic performance, and is also available at clinical practices as a treatment for ADHD. We review research conducted with Cogmed software and highlight several concerns regarding methodology and replicability of findings. We conclude that the claims made by Cogmed are largely unsubstantiated, and recommend that future research place greater emphasis on developing theoretically motivated accounts of working memory training.

22. Conclusions from recent Meta-Analysis “Collectively, meta-analytic results indicate that claims regarding the academic, behavioral, and cognitive benefits associated with extant cognitive training programs are unsupported in ADHD.” “The methodological limitations of the current evidence base, however, leave open the possibility that cognitive training techniques designed to improve empirically documented executive function deficits may benefit children with ADHD”.

23. Optimal research designs for studies of WM training Randomized control design Active control group – to control for Test-retest effects & Placebo effects; Expectations of trainers/testers/participants Motivation effects; engagement in training Measurement Objective measures (if subjective - blinded informants) Latent changes (more than one measure/construct) Transfer of training effects (far transfer) Duration of changes (sustained effects) Mechanisms of change From: Shipstead, Redick, Engle (2012) Psychol Bull [advance online publication]

24. Published RCTs of WM training in ADHD StudyCogmed N Contro l N Design/lo cation ControlTotal training (min/weeks) Beck 20102724RCT/HWaitlist750/6 weeks Green et al 20121214RCT/HNon- Adaptive 615-1000/5 weeks Klingberg et al 2005 2024RCT/ H -SNon- Adaptive 1000/5 weeks Van Dongan- Boomsma 2014 2724RCT/HNon- Adaptive 375/5 weeks Chacko et al 20144441RCT/HNon- Adaptive 750-1125/5 wk Egeland et al., 2014 3837RCT/SWaitlist750-1125/5-7 w Gropper et al 20143923RCT/HWaitlist750/5 weeks Gray et al., 20123624RCT/SAdaptive750/5 weeks TOTAL243211 24 VERBAL WM: SMD = 0.57 [99%CI.29 -.82] VISUAL WM: SMD = 0.47 [95%CI.23 -.70] CORTESE ET AL.,920150 META ANALYSIS VERBAL WM: SMD = 0.57 [99%CI.29 -.82] VISUAL WM: SMD = 0.47 [95%CI.23 -.70] CORTESE ET AL.,920150 META ANALYSIS

25. 4 RCTs from Tannock Lab Study 1: Does WM training enhance WM & other aspects of cognitive, academic, behavioral functioning in adolescents with severe Learning Disabilities & comorbid ADHD? (Gray et al., 2012, JCPP) Study 2. Does WM training enhance WM & other aspects of cognitive, academic, behavioral functioning in college students with ADHD and/or Learning Disabilities? (Gropper et al., 2014., JAD) Study 3. Working Memory Training in Post-Secondary Students with Attention-Deficit/Hyperactivity Disorder: Pilot Study of the Effects of Training Session Length (Mawjee et al., in press., JAD) Study 4. Does WM training have specific or non-specific effects on WM in college students with ADHD? (Mawjee et al, under review)

26. Two randomized controlled trials Gray et al 2012; Gropper et al, 2014 Study 1: High-school LD/ADHD  Treatment-resistant sample of secondary-school students with severe LD with comorbid ADHD,  Attend semi-residential school funded by Ministry of Education (Ontario)  Sample size = 60  Mean age:14.3 yrs (1.2yr)  All medicated & receiving intense academic remediation Study 2: University ADHD/LD ‣ University students with ADHD and/or LD ‣ Registered with student disability services ( Most taking reduced course load, poor time management, lower academic grades) ‣ Sample size = 62 ‣ Mean age = 27.9 yrs (7.1yr) ‣ None medicated

27. Intervention: treatment arms Study 1: High-school LD/ADHD Comparison of two active, computerized intervention arms Working Memory Training (Cogmed RM) 20 x 45-min sessions Academic Training (Academy of Math) 20 x 45-min sessions During school day Study 2: University ADHD/LD Comparison of active vs inactive intervention arm Working Memory Training (Cogmed QM) 25 x 45-min sessions Wait-List Control with some phone-calls Own schedule (at home/residence)

28. Measures Study 1: High-school ADHD/LD Criterion WISC-IV Digit SPAN F/B CANTAB Spatial Span F Near Transfer CANTAB Spatial WM D2 Test of Attention Far Transfer Academics WRAT-4 Progress Monitoring Behavior (Parent/teacher) SWAN, IOWA Working Memory Rating Scale Study 2: University ADHD/LD Criterion WAIS –IV Digit Span F/B/S CANTAB Spatial Span F Near Transfer CANTAB Spatial WM Paced Auditory Serial Addition Ruff 2& 7 Selective Attention Far Transfer Academics Nelson Denny Reading Test WJ-III Achievement Behavior (self-rating) ASRS, Cognitive Failures

29. Training Compliance Study 1: High-school LD/ADHD  Good overall  Attrition at post-test:16% (n=8) of 60 participants, equally distributed across treatment arms  4 unable to cope with academic load & this study  3 moved & left school mid- program  1 due to computer problems ◦ No difference between completers & non-completers  ANALYSIS: Intent-to-Treat  No Follow-up Study 2: University ADHD/LD Generally good overall Attrition by post-test: 10% (n=6) of 62 participants, equally distributed across treatment arms ANALYSIS: Intent-to-Treat But, attrition by follow-up: 30% from WM group; 30% from wait- list group primarily conflict with exam schedules Thus follow-up analysis based on As-Treated

30. Compliance outcomes WM training group: 70% obtained WM Improvement Index > 17 (Mean Improvement score = 18.85, SD = 6.3) AOM group: 57% mastered >10 skills Mean # skills mastered = 19.81, SD=14.14. WM training Group 97% obtained WM Improvement Index >17 (M=25.72, SD=6.54) 92% completed the required 25 sessions Study 1: High-school LD/ADHD High-school LD/ADHD Study 2: University ADHD/LD

31. Overview of Results Study 1: High-school LD/ADHD Criterion WISC-IV Digit SPAN F/B CANTAB Spatial Span F Near Transfer CANTAB Spatial WM Working Memory Rating Scale D2 Test of Attention Far Transfer Academics WRAT-4 Progress Monitoring Math – trend for Math Training Behavior (Parent/teacher) SWAN, IOWA Study 2: University ADHD/LD Criterion WAIS –IV Digit Span F/B/S CANTAB Spatial Span F Near Transfer CANTAB Spatial WM Paced Auditory Serial Addition Ruff 2& 7 Selective Attention Far Transfer Academics Nelson Denny Reading Test WJ-III Achievement Behavior (self-rating) ASRS, Cognitive Failures

32. Training effects on Criterion Measure DS-Backwards Intent-to-Treat Analysis: Ancova post-test, covarying pretest score ES: Cohen’s d =.55

33. Training effects on WRAT-PM Math 33 p =.08 Standardized Level Equivalent scores (LE)

34. Study 2: Maintenance of gains in criterion measures at 2-month follow-up Analysis: As Treated Repeated measures: Exp(WM): n=23 Wait-List : n=16 Effect size ŋ 2 =.08 Exp Group 28% greater improvement than controls Effect size ŋ 2 =.22 Exp Group 47% greater improvement than controls

35. So our next question was… Does WM training improve WM when controlling for participant’s motivation, engagement & expectancy? (using independent intervention & research teams) Revised manuscript resubmitted to PlosOne Jan 2015

36. Methods: an RCT Participants: 97 post-secondary students with ADHD Treatment arms: standard-length adaptive Cogmed WM training: 45- min/session 5 days /week, 5 weeks, shortened-length adaptive version: 15 min/session, 5 days/week, 5 weeks waitlist control group provided with weekly telephone advice about ADHD, WM, Disability Services etc All three groups received weekly telephone calls from trained, CMWT coaches independent from research team Procedures. Measures taken before, 3 weeks after training period; those in the two CWMT groups were also assessed 3 months post-training.

37. Hypothetical patterns of findings

38. Outcome measures Criterion WAIS–IV Digit Span F/B/S CANTAB Spatial Span F/B WRAML FW F/B Near Transfer CANTAB Spatial WM Kahneman’s Addition Task Far Transfer Symptoms: ASRS Function: BDEFS, CFQ Current symptom validation  ASRS: self- interview, Q other-Q Compliance  # sessions completed & # weeks to complete  # coach calls completed  Cogmed Training Index  Attrition

39. Results: examples

40. An unexpected pattern of findings (ceiling effects? Non- specific training effects?…) These findings are based on analysis at the group level..what about at the individual level?

41. Brinley Plots: A visual approach to displaying data at both group & individual leve calculation of RCI is in progress..

42. But perhaps our neural measures will provide further insight into effects of CWMT on WM

43. Neural measure of training effects on WM

44. ADHD impaired in encoding stage of WM Kim et al., (2014) Clin Neurophysiol ADHD (n=30) lower scores on behavioural working memory tasks compared to CTL (n-25), suggesting impaired behavioural WM performance Smaller P3 amplitude in ADHD group compared to CTL group: both load conditions, at parietal–occipital sites..

45. Group differences in maintenance stage (preliminary findings) ADHD (n= 136, ~50% F); CTL (n=41, ~50% F) ADHD poorer WM on standardized tests of WM ADHD vs CTL Behavioral results: delayed match-to-sample task ADHD tended to perform more poorly (more errors) than CTL Neural results: ADHD lower alpha power, particularly for high load, compared to CTL

46. Preliminary data: training effects on WM during maintenance phase Neural pathways associated with working memory do seem to show treatment changes for the high intensity standard- length training. These effects were only present during the high load condition at parietal sites. No evidence for behavioral task differences were found. Pre Post Waitlist Shortened-lengthStandard-length Alpha power

47. Interpretation & Discussion of results “Half-empty” No robust evidence of transfer of treatment gains to untrained WM activities or daily functioning “Half-full” Robust evidence that computerized cognitive training enhances WM – as measured on standardized neuropsychological tests-& perhaps neurally Or does the program simply result in learning how to do the tests better!

48. Caveat Not yet an evidence-based intervention for ADHD - But premature to discard cognitive training Most of the published research studies have methodological weaknesses (including ours) Need for better studies & more sensitive measures (e.g., measure concurrent behavior & WM) Advances in the training paradigm may yield better outcomes

49. Spencer-Smith M, Klingberg T (2015) Benefits of a Working Memory Training Program for Inattention in Daily Life: A Systematic Review and Meta-Analysis. PLoS ONE 10(3): e0119522.

50. Acknowledgements Collaborating Organizations  Cogmed America Inc ◦ provision of research licenses  JVS-Toronto ◦ licensed Cogmed providers  Ontario Provincial Demonstration Schools  University Disability Services ◦ York University, University of Toronto  The Hospital for Sick Children  Ontario Institute for Studies in Education/University of Toronto Research Team  Drs. H Gottlieb & R Kronitz (JVS)  Desiree Smith, Denise Murnaghan (OPDS)  Peter Chaban, Min-Na Hockenberry, Marisa Catapang (HSC)  Dr Marc Lewis (OISE)  Graduate Students (OISE)  Rachel Gropper, Steven Woltering, Zhongxu Liu, Sarah Gray, Christine Popovich  Dr Torkel Klingberg (consultant) Canada Research Chairs Program (RT) Provincial Centre of Excellence for Child & Youth Mental Health at CHEO (RT) Canadian Institutes of Health Research Banting & Best Award (RG) Funding

51. TIME FOR ME TO STOP! ANY QUESTIONS?