1. Brain NeuroModulation for Stroke W
Brain NeuroModulation for Stroke W. Jerry Mysiw, MD Chair, Department of Physical Medicine and Rehabilitation Wexner Medical Center at The Ohio State University
Describe relationship between neuromodulation, rehabilitation…
Recognize new modalities and research in expanding the field of neuromodulation and neurorehabilitation

2. Disclosures Faculty appointment Grant support-unrelated topics
The Ohio State University
Grant support-unrelated topics
NIH
DOE/NIDRR
Industry
Grant support- none
Consulting- none
Ownership-none

3. NeuroRehabilitation in Transition
Health care reform
Post acute care strategies
Decrease cost
Decrease readmission
Post acute activity based therapy discontinued before plasticity reaches plateau
Emerging Solutions
Extend the continuum of post acute rehabilitation into the home
Gaming strategies to provide activity based therapy in the home
Neuroimaging assessment of neuroplasticity
Activity based therapy dose response studies
Interval assessment of a therapy’s impact on plasticity
Neuromodulation drives plasticity

4. Stroke Related Disability
Stroke is a leading cause of adult disability in the US.
Data from GCNKSS/NINDS studies show that about 795,000 people suffer a new or recurrent stroke each year. About 610,000 of these are first attacks
About 6,400,000 stroke survivors are alive today
In 2010, stroke cost the US $73.7 billion in health care services, medications, and lost productivity.
Death risk and disability can be lowered.
Early complications deprive patients of 2 years of optimum health.
Greater numbers of complications are associated with greater loss of healthy life-years.
Stroke is the leading cause of adult disability in the U.S.
References:
CDC: Centers for Disease Control and Prevention (CDC). Stroke Fact Sheets, 2010
AHA: American Heart Association. Heart Disease and Stroke Statistics 2010 Update. Dallas, TX: Circulation. 2010;121:e1-e170.)
CDC; AHA

5. Stroke is the leading cause of Adult Disability

6. Stroke Rehabilitation Outcomes
80% -Independent Mobility
70% -Independent Personal Care
40% -Independent Outside the Home
30%- Return to Work
30% of strokes occur in people under 65
49% RTW rate for people year old
Overall mortality is declining
Long-term survival post-stroke is improving

7. Post Stroke Impairments: Predictors of Disability
Hemiplegia (75-88%)
Emotional lability (mood swings, depression)
Cognitive impairments
Loss of awareness (neglect syndromes)
Dysphagia
Aphasia
Apraxia

8. Neuroplasticity Plasticity (adaptive) is experience dependent.
maximum impact when coupled with optimal experience (therapy)
Motor recovery after stroke illustrate the principle that many forms of neuroplasticity can be ongoing in parallel.
Spontaneous intra-hemispheric changes in representational maps
Inter-hemispheric balance shift - uninjured hemisphere assumes extranormal activity in relation to movement
Changes in the connections between network nodes
Molecular adaptive changes

9. Brain 2011: 134; 1591–1609
Brain 2011: 134; 1591–1609

10. Harnessing Neuroplasticity for Clinical Applications
Harnessing Neuroplasticity for Clinical Applications Brain 2011: 134; 1591–1609
CNS perturbation
Stroke
TBI
Aging
Intervention
Activity based therapy
Pharmacology
Neuromodulation
Outcome
Life years
Impairment resolution
Functional gain
Quality of life
Imaging
Neuroplasticity
Positive/negative
Neurogenesis…
Alternate pathway ↓↓

11. Non-invasive brain stimulation
Objective:
change brain function
promote neuroplasticity
Interventions
Transcranial Magnetic Stimulation
Transcranial Direct Current Stimulation (tDCS)
General assumption is that the application of noninvasive brain stimulation with parameters that enhance motor cortical excitability could secondarily facilitate motor performance and motor learning

12. Major advantages Major limitations
Reversible lesions without plasticity change
Can establish causal link between brain activation and behaviour
Can measure cortical plasticity
Can modulate cortical plasticity
Therapeutic benefits
Major limitations
Only regions on cortical surface can be stimulated
Localisation uncertainty
Stimulation level uncertainty

13. Transcranial magnetic stimulation (TMS)
Very safe, when following current safety guidelines
(Rossi et al., 2009),
Noninvasive
Normal brain activity is disrupted by this induced current
TMS provides a way to produce a transient and reversible period of brain disruption or “virtual lesion.”
TMS can assess whether a given brain area is necessary for a given function rather than simply correlated with it.
Can probe the functional connectivity of different cortical areas in the human cortex using paired-pulse TMS
Repetitive TMS effects persist past the initial period of stimulation. rTMS can increase or decrease the excitability

14. Low Frequency vs. High Frequency TMS
TMS activates a mixed population of inhibitory and excitatory cortical interneurons
Low Frequency Stimulation--inhibitory, more focal effect
High Frequency Stimulation--facilitating, multiple, spread out, global “dendritic, axonal effect”.
When higher frequency rTMS is applied, a longer lasting effect can be induced which is thought to result from a long term potentiation (LTP), or depression (LTD) at the neuronal level. 14

15. What Could TMS Treat? I. Affect/Self Regulation Behaviors: II. Pain
Depression (FDA approval, Oct 2008)
Anxiety-Panic, OCD, PTSD
Addiction- pathologic gambling, food, substance abuse
Schizoaffective disorder.
II. Pain
Neuropathic pains
Phantom pain,
Fibromyalgia,
Migraine headaches,
Tinnitus
III. NeuroRehabilitation
Stroke – Hemiplegia, aphasia, neglect
Brain Injury- mood

16. TMS Stimulation On-line stimulation occurs during task performance
Virtual lesions
Functional connectivity
Off-line stimulation occurs without a task
Plasticity
Interventional
Depression
Pain
Advantages of each (be sure to put in handout).

17. A multi-center study on low-frequency rTMS combined with intensive occupational therapy for upper limb hemiparesis in post-stroke patients Kakuda et al. Journal of NeuroEngineering and Rehabilitation 2012, 9:4 Methods: The study subjects were 204 post-stroke patients with upper limb hemiparesis (mean age 58.5 ± 13.4 years, mean time after stroke 5.0 ± 4.5 years, ± SD) During 15-day hospitalization, each patient received 22 treatment sessions of 20-min low-frequency rTMS and 120-min intensive OT daily. Low-frequency rTMS of 1 Hz was applied to the contralesional hemisphere over the primary motor area. Results: All patients completed the protocol without any adverse effects. The FMA score increased and WMFT log performance time decreased significantly FMA score: median at admission, 47 points; median at discharge, 51 points; p < change in WMFT log performance time: median at admission, 3.23; median at discharge, 2.51; p < 0.001). These changes were persistently seen up to 4 weeks after discharge in 79 patients.

18. TMS and Chronic Aphasia Naeser et al.
rTMS over RH homologue of Broca’s area
Daily for 10 days, 20 min each time
Tested picture naming speed & accuracy
Immediately after 10th session
All patients reliably faster & more accurate than their pre-treatment baseline measures
2 months later & 8 months later
Effects decreased over time, but continued through 8 mos for 3 of 4 patients

19. TMS in Chronic Aphasia

20. Transcranial Direct Current Stimulation
Noninvasive application of weak direct current through a set of two (or more) electrodes
Applied current enters the brain via the positively charged anode, and flows to the negatively charged cathode.
Neuronal excitability of the targeted brain area can be modified in a polarity-specific manner
anodal stimulation increases the excitability
cathodal stimulation decreases excitability

21. Transcranial direct current stimulation
Motor learning is associated with functional and structural changes in a widely distributed cortical network including the
primary motor,
premotor and supplementary motor cortex,
cerebellum
Basal ganglia

22. Modulation of motor performance and learning by transcranial direct current stimulation in healthy subjects
Anodal tDCS applied to M1 in temporal relation to motor practice transiently improves performance within a single session or when given repeatedly in the absence of practice
Anodal tDCS augments prolonged skill acquisition
skill gains between sessions (consolidation)
anodal tDCS-stimulated subjects skill
remained superior to controls even after 3 months
Current Opinion in Neurology 2011, 24:590–596

23. Early/late +/? +/+ +/? +/=
Effects of timing of anodal transcranial direct current stimulation in relation to motor training sessions Current Opinion in Neurology 2011, 24:590–596
Early/late +/? +/+ +/? +/=
A tDCS
A tDCS
A tDCS
A tDCS
Training
Training
Training
Depicted is the relation of anodal tDCS sessions (blue) to training sessions (green) in the time domain, in healthy volunteers. The effect on early and delayed motor performance of each stim/training configuration is shown (, - decrease; =unchanged; + increase; ?, not investigated). A-tDCS, anodal

24. Transcranial direct current stimulation and ‘motor rehabilitation’ in patients with motor deficits after stroke
Proof of principle studies showed that anodal tDCS can transiently improve cognitive and motor function of the upper and lower extremity post brain injury.
Lindenberg et al. showed that bihemispheric tDCS (anodal stimulation applied to the ipsilesional M1, cathodal stimulation to the contralesional M1) combined with 5 days of occupational therapy/physiotherapy improved motor performance in chronic stroke patients(>5 months after stroke)
performance remained superior for at least 1 week

25. Transcranial Direct Current Stimulation (tDCS) and Chronic Aphasia
(Monti et al., 2008)
One session cathodal tDCS to L Broca’s area
improved naming was observed with an increase of 33.6% (SEM 13.8%) immediately post-tDCS
treatment, in eight chronic nonfluent aphasia patients

26. Transcranial direct current stimulation (tDCS) and modulation of motor performance
Simultaneous anodal transcranial direct current
stimulation (tDCS) and training promotes improvement
in motor performance and motor learning in
healthy individuals and chronic stroke patients.
The time-locked application of tDCS and training
appears to be crucial to induce lasting effects.

27. Theoretical tDCS safety concerns
Potential side effects with tDCS
electrode-tissue interface could lead to skin irritation and damage.
Stimulations could lead to excitotoxic firing rates.
Tissue damage due to heating.
Rat studies suggest injury only when current density is several orders of magnitude beyond those used in humans (Liebetanz et al. 2009).
Datta (2009) heating in humans is negligible.
Nitsche et at. (2003) reports that in more than 500 participants the only side effects are initial scalp tingling or sensation of a light flash.
Some studies suggest that higher current densities can lead to skin irritation.

28. Transcranial Direct Current Stimulation (tDCS)
Very inexpensive (~$250 for iontophoresis unit).
Believed to be safe.
Believed to modulate the firing rate of active neurons.
Depending on polarity, tDCS can induce cortical excitability reduction or enhancement can persists for hours.

29. Where to stimulate Stimulation region not well focused.
Must create electrical circuit: both anode and cathode.
If both on scalp, are effects due to facilitation or inhibition?
If one electrode on shoulder/limbs (Baker, 2010), perhaps spinal influence.
One option is large, diffuse electrode over mastoid (Elmer, 2009). + _ _ +

30. Designing TMS/tDCS Studies
Type of stimulation
Repetitive vs single or paired
Choosing control conditions
Targeting stimulation
Choosing parameters
Stimulation intensity / duration / rate
Inter-stimulation interval
Type of coil
Type of stimulation / stimulator
Accessibility
Number of trials per condition?

31. TMS stimulation Single-pulse TMS Paired-pulse TMS
Repetitive TMS (rTMS)
Low frequency rTMS (1 Hz)
High frequency rTMS (>1 Hz)
Theta-burst, etc

32. Creating the future of medicine to improve people's lives
Creating the future of medicine to improve people's lives
through personalized health care