Aging, cognitive-motor function, and tcs. Brad Manor, PhD. October 31, 2017 LEASE DO NOT COPY

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1 Aging, cognitive-motor function, and tcs Brad Manor, PhD October 31, 2017

2 Disclosures - NIH / NIA - Michael J. Fox Foundation - U.S.-Israel Binational Science Foundation - Marcus Applebaum Research Award - Harvard Football Players Health Study - Neuroelectrics, Inc.

3 Aging is associated with progressive decline in mobility and mental function. 1 in 3 older adults dies with Alzheimer s disease or related dementia. 1 in 3 older adults fall each year. Are they separate problems?

4 Mobility and mental function are intertwined. n = 256 Lowest quartile = 3x more likely to suffer a fall Highest quartile = Less likely to fall than all others Herman et al, J Gerontol, 2010

5 Mobility and mental function are intertwined. n = 26,000 After adjusting for age, sex, education and cohort source: Cognitive complaints alone: 9% more likely Slow gait alone: Both: 40% more likely 72% more likely Verghese et al, Neurology, 2014

6 Why does measuring one predict the other? Motor output and coordination Sensation Sensory integration Cognition Mood

7 Do we ever just stand or walk? Cognitive dual tasking is the norm and it disrupts our balance!

8 Dual 500, Task 497, Standing Paradigm 494 Standing + Counting Dual task cost

9 We can also measure the dual task cost to walking. Standing Standing + Counting

10 Dual task cost: A functionally relevant measure of cognitive reserve. Proprioceptio n Balance control system Attention, Decision Making Standing Cognitive Resources Reserve Counting Dual task cost

11 tcs can help understand and enhance mobility and mental function in aging. Question 1: Can tdcs improve dual task standing and walking in older adults?

12 Where should we target? Single task: Auditory Single task: Tactile Dual task Dual tasking depends upon the activation of numerous brain regions, including the left dorsolateral prefrontal cortex (dlpfc). Deprez et al, Neuropsychologia, 2013

13 Single sessions of tdcs targeting the left dlpfc mitigate dual task costs. tdcs characteristics - Two, 5x7cm sponge electrodes - Anode: F3 on EEG system - Cathode: Contralateral orbit - 2 ma - 20 minutes - Participant at rest Dual task Assessment tdcs (Real or Sham) Dual task Assessment Manor, Pascual-Leone et al, European Journal of Neuroscience, 2014

14 79 year-old female with previous falls A: Post Sham tdcs Anterioposterior Displacement (cm) Anterioposterior Displacement (cm) B: Post Real tdcs Single-Task Standing Dual-Task Standing Dual Task Cost Cost (% Change in Area) Mediolateral Mediolateral Mediolateral Displacement (cm) Displacement (cm) Displacement (cm)

15 Single sessions of tdcs targeting the left dlpfc mitigate dual task costs. Manor et al, European Journal of Neuroscience, 2014; Journal of Cognitive Neuroscience, 2016

16 Single sessions of tdcs targeting the left dlpfc mitigate dual task costs. 37 healthy adults aged 65 and older Manor et al, European Journal of Neuroscience, 2014; Journal of Cognitive Neuroscience, 2016

17 The functional implications are potentially significant! How long does the effect of one session last? What about multiple sessions? Functionally-limited adults? Applications to sports, mobility, falls Which population?

18 Slow gait, executive dysfunction, and depression are common in older adults. MOBILIZE Boston Study (Lipsitz): 765 older adults Gait speed: Executive function: 34%: preferred speed < 0.9 m/s Depression: 29%: CES-D > 11 Likelihood of having all 3? If random: 3% In cohort: 17% A common pathway? 31%: TMT-B < 1.5 SD below age/education means Hajjar, Lipsitz et al; JGMS; 2009; 64;

19 All 3 symptoms have been linked to reduced functional activation of the prefrontal cortex. Transcranial Doppler Ultrasound N-back cognitive test Fast walkers Slow walkers Sorond, Lipsitz et al, Ann Neurol 2011;70:213-20

20 Can tdcs improve outcomes in those with slow gait, executive dysfunction and depression? Pilot, randomized, sham-controlled trial in adults aged 65 years and older: n = 20 Inclusion Walking speed 1.0 m/s Mild-to-moderate executive dysfunction Evidence of mildly-depressed affect Exclusion Inability to stand/walk unassisted Severe dementia Severe depression Diabetes History of stroke Parkinson s, other neurological disease Contraindications to MRI or tdcs

21 Study procedures: V1 V2 V3-12 V13 V14 V15 Behavioral assessment (cognition/mood/mobility/dual task) MRI (structural, resting state) tdcs intervention (10 sessions) Behavioral assessment MRI Behavioral assessment (2 week follow-up)

22 Individuals were randomized to tdcs targeting the left dlpfc or inactive sham stimulation. Left dorsolateral prefrontal cortex Image courtesy of Neuroelectrics, Inc

23 We successfully recruited a small cohort with concomitant functional limitations. Table 1: Catalyst sample characteristics (mean±sd) Real tdcs Sham tdcs P value Sample (n) Age (years) 83 ± ± Gender (women; 5; 5 6; 4 men) 4m gait speed (m/s) 0.73 ± ± Trail Making Test B (sec) Geriatric Depression Scale (scale 0-12) Mini Mental State Examination (MMSE) 142 ± ± ± ± ± ± No unexpected adverse events; excellent compliance & blinding

24 Multiple sessions of tdcs induced lasting improvements in dual task performance. 500, 497, 494 Dual task cost to standing postural sway speed (%) (3 days) (2 weeks) Trends (p < 0.1) towards increased performance were also observed in: - Timed Up-and-Go (TUG) test of mobility - Preferred gait speed

25 Multiple sessions of tdcs induced lasting improvements in cognitive function. tdcs-related improvements were limited to the executive function sub-score. To do: Are tdcs-related improvements linked to changes in brain function?

26 Is the left dlpfc really the best target? Image courtesy of Neuroelectrics

27 Is the left dlpfc really the best target? 25 older adults with a recent history of falling Multi-target Single-target Sham Inter-subject variability in effectiveness is still high.

28 What s causing such high inter-subject variability? Electrode size Placement Direction of flow Current intensity Current duration Biological aging especially in the presence of disease alters brain structure and function, and thus, the flow and effects of tdcs. Anatomy: - Skin - Skull - CSF - gray mater - White mater Brain physiology Brain state - Off-line (resting) - On-line

29 Brain anatomy can be very different! 68 year old male: - No diagnosed disease - Fast gait - Normal executive function - Regular exercise 79 year old male: - No diagnosed disease - Slow gait - Poor executive function - Sedentary Images courtesy of Neuroelectrics

30 Brain anatomy can be very different! 68 year old: 79 year old: Images courtesy of Neuroelectrics

31 Brain anatomy can be very different! 68 year old: 79 year old: Images courtesy of Neuroelectrics

32 Brain anatomy can be very different! 68 year old: 79 year old: Images courtesy of Neuroelectrics

33 Vastly different montage and current parameters are required to optimize flow to a given region. 68 year old: 79 year old: 79 year old: Images courtesy of Neuroelectrics

34 5 take-home messages: 1. In older adults, mobility and mental function are intertwined and closely dependent upon one another. 2. Dual task paradigms provide further insight into brain health and clinically-meaningful outcomes. 3. tdcs targeting cognitive-motor brain regions appears to improve dual tasking, mobility and mental function, even in vulnerable older adults. 4. The aging process undoubtedly alters the flow and effects of tdcs on the brain. 5. Individual MRIs and flow modeling may be particularly important in this population.

35 Mentors: - Lewis Lipsitz MD - Alvaro Pascual-Leone MD PhD - Jeff Hausdorff PhD - Talia Herman PhD Mobility and Brain Function Program: - Moria Dagan MS - Junhong Zhou PhD - Giulio Ruffini PhD - Amy Lo PhD - Jue Zhang PhD - Azizah Jor dan PhD - Rachel Harrison BS - Wanting Yu MS - Kaliela Osha BS - Ali Ludington BS Thank you! Collaborators: - Mark Halko PhD