Describe relationship between neuromodulation, rehabilitation…

1. Brain NeuroModulation for StrokeW. Jerry Mysiw, MDChair, Department of Physical Medicine and RehabilitationWexner 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 • 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. 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 21-65 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 ApplicationsBrain 2011: 134; 1591–1609 CNS perturbation Stroke TBI Aging Intervention • Activity based therapy • Pharmacology • Neuromodulation Neuroplasticity • Positive/negative • Neurogenesis… • Alternate pathway Outcome • Life years • Impairment resolution • Functional gain • Quality of life • Imaging

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 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: • 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

17. A multi-center study on low-frequency rTMScombined with intensive occupational therapy forupper limb hemiparesis in post-stroke patientsKakuda et al. Journal of NeuroEngineering and Rehabilitation 2012, 9:4Methods: 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 < 0.001. change in WMFT logperformance 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 AphasiaNaeser 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 bytranscranial 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. Effects of timing of anodal transcranial direct current stimulation in relation to motor training sessions Current Opinion in Neurology 2011, 24:590–596 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 Early/late +/? +/+ +/? +/= • A tDCS A tDCS • A tDCS A tDCS Training Training Training

24. Transcranial direct current stimulation and‘motor rehabilitation’ in patients with motordeficits 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) Transcranial direct current stimulation 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

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