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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,
Recognize new modalities and research in
expanding the field of neuromodulation and
 Faculty appointment
 The Ohio State University
 Grant support-unrelated topics
 Industry
 Grant support- none
 Consulting- none
 Ownership-none
NeuroRehabilitation in Transition
 Health care reform
 Post acute care strategies
 Decrease cost
 Decrease readmission
 Post acute activity based
therapy discontinued
before plasticity reaches
 Emerging Solutions
 Extend the continuum of post
acute rehabilitation into the
 Gaming strategies to
provide activity based
therapy in the home
 Neuroimaging assessment of
 Activity based therapy
dose response studies
 Interval assessment of a
therapy’s impact on
 Neuromodulation drives
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
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
Post Stroke Impairments:
Predictors of Disability
 Hemiplegia (75-88%)
 Emotional lability (mood swings, depression)
 Cognitive impairments
 Loss of awareness (neglect syndromes)
 Dysphagia
 Aphasia
 Apraxia
 Plasticity (adaptive) is experience dependent.
 maximum impact when coupled with optimal experience
 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
Brain 2011: 134; 1591–1609
Brain 2011: 134; 1591–1609
Harnessing Neuroplasticity for Clinical Applications
Brain 2011: 134; 1591–1609
CNS perturbation
 Stroke
 Aging
 Activity based therapy
 Pharmacology
 Neuromodulation
 Life years
 Positive/negative
 Impairment resolution
 Neurogenesis…
 Functional gain
 Alternate pathway
 Quality of life
 Imaging
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
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
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
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.
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,
Migraine headaches,
 III. NeuroRehabilitation
 Stroke – Hemiplegia, aphasia, neglect
 Brain Injury- mood
TMS Stimulation
On-line stimulation occurs during task performance
Virtual lesions
Functional connectivity
Off-line stimulation occurs without a task
• Depression
• Pain
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 20min 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
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 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
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
TMS in Chronic Aphasia
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
 Neuronal excitability of the targeted brain area can
be modified in a polarity-specific manner
 anodal stimulation increases the excitability
 cathodal stimulation decreases excitability
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,
Basal ganglia
Modulation of motor performance and learning by
transcranial direct current stimulation in healthy
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
Effects of timing of anodal transcranial direct
current stimulation in relation to motor training
Current Opinion in Neurology 2011, 24:590–596
 A tDCS
 A tDCS
Early/late +/?
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
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
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
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.
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.
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.
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
 One option is large, diffuse electrode
over mastoid (Elmer, 2009).
Designing TMS/tDCS Studies
1. Type of stimulation
• Repetitive vs single or paired
2. Choosing control conditions
3. Targeting stimulation
4. Choosing parameters
 Stimulation intensity / duration / rate
 Inter-stimulation interval
 Type of coil
 Type of stimulation / stimulator
 Accessibility
 Number of trials per condition?
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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