Transcranial Direct Current Stimulation tDCS: putative mechanisms of action and clinical effects of

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Transcranial Direct Current Stimulation (tDCS)
putative mechanisms of action and clinical
effects of a simple and powerful method of brain
stimulation

• Felipe Fregni, MD, PhD
• Director, Laboratory of Neuromodulation,
  Spaulding Rehabilitation Hospital
• Berenson-Allen Center for Non-invasive Brain
  Stimulation,
• Beth Israel Deaconess Medical School
• Assistant Professor of Neurology, Harvard Medical
  School

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Rational of Electrotherapy
Broad spectrum (neuropsychiatric,
rehabilitation, cognitive performance)
Individualized therapy Targeted brain
modulation (space time) Adverse effects
(minimal complications counter-indications)
Mechanisms of action vs. mechanisms of disease
Cost
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What are the options?

• Different electrode/coils

Invasive Leads (also Vagus, Spinal..)
Transcranial Electrical
Transcranial Magnetic
Figure from Marom Bikson
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Brain Electrotherapy
Figure from Marom Bikson
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What is tDCS?

• Very simple, safe and powerful technique of
  neuromodulation (not neurostimulation)
• Based on a constant electric field
• Used for more than 200 years - Galvanization
  (Based on the experiments of Aldini - beginning
  of XIX century - Italy - nephew of Galvani)

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Why DC stimulation?

• Modulates spontaneous neuronal activity
• Non-expensive
• Reliable sham condition
• Easy to administer (clinical applications)
• Less adverse effects

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Basic principle of DC stimulation
Charged particles/proteins/ions move along the
gradient of voltage
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How does this affect neuronal activity?
Changes in PH Changes in Membrane Protein Changes
in ions Glial changes?
DC Field
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Direct effects of DC stimulation
Goldring, 1950
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How does transcranial DC stimulation work in
humans?
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ButDoes the current reach the cortex?Mechanisms
of Action

• Computer modeling studies
• Neurophysiological data
• Behavioral data

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Computer modeling

• Several studies have been performed (animal and
  human models)
• They showed that a significant amount of current
  reaches cortical surface - enough to induce
  biological effects if the duration of stimulation
  is appropriate

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tDCS model 1
Wagner et al, - Neuroimage, 2007
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tDCS model 2
Miranda et al, Clinical Neurophysiology, 2006
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tDCS model 3
Bikson et al, Brain Stimulation, 2009
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Neurophysiological data

• Animal studies (experiments conducted in the 50s,
  60s and 70s) - direct neuronal recording
• Human studies (cortical excitability studies -
  use of single pulse TMS, EEG and neuroimaging)

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Intracellular activities and evoked potential
changes during polarization of motor cortex
Purpura and McMurtry, 1964
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Cortical Spreading Depression
Liebetanz, Neuroscience Letters, 2006
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Neuroimaging studies PET study
Lang, European Journal of Neuroscience, 2005
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Lang, European Journal of Neuroscience, 2005
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Neuroimaging studies fMRI study
Grasp-release task
Before, during and after active of sham tDCS
Jang, Neuroscience Letters, 2009
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Preliminary Results from EEG Analysis of Effects
of Transcranial Electrical Stimulation on EEG
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Study Design

• Experiment 1 Constant DC stimulation of
  Dorsolateral Prefrontal Cortex
• Intervention A Anodal Stimulation
• Active, N 20 Sham, N 20
• Intervention B Cathodal Stimulation
• Active, N 15 Sham, N 16

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Study Design

• Experiment 2 Intermittent (1Hz) DC stimulation
  of Dorsolateral Prefrontal Cortex
• Active, N 17 Sham, N 18

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Study Design

• Experiment 3 Sinusoidal (50Hz) stimulation of
  Pre-Auricular area
• Active, N 19 Sham, N 18

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Experiment 1aAnodal tDCS stimulation of
Dorsolateral Prefrontal Cortex
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Experiment 1bCathodal tDCS stimulation of
Dorsolateral Prefrontal Cortex
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Experiment 2Intermittent (1Hz) DC stimulation
of Dorsolateral Prefrontal Cortex
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Experiment 3Sinusoidal (50Hz) stimulation of
the Pre-Auricular Area
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Neuromodulatory effectsSynaptic vs. membrane
effects
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Evidence for synaptic effectsPharmacological
studies intra-effects
CBZ - carbamazepine DMO - N-methyl-D-aspartate
(NMDA)-receptor antagonist dextromethorphan FLU
- (calcium channel blocker) - flunarizine
Drug-induced modulation of tDCS-driven cortical
excitability changes during stimulation
Nitsche, J Physiology, 2003
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Pharmacological effects - after-effects
CBZ - carbamazepine DMO - N-methyl-D-aspartate
(NMDA)-receptor antagonist dextromethorphan
TMS-elicited MEP amplitudes before and after 5
min of anodal and cathodal tDCS, under different
pharmacological conditions
Comparison of post-stimulation MEP amplitudes
after intake of CBZ or placebo
Liebetanz, D. et al. Brain 2002 1252238-2247
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Membrane effect?
Effect of cathodal transcranial direct current
stimulation (tDCS) on resting motor threshold (A)
and on motor evoked potentials (MEP amplitude)
(B,C) elicited by transcranial magnetic
stimulation (TMS)
Effect of cathodal transcutaneous direct current
(DC) stimulation and sham stimulation on the
excitability of ulnar motor axons
Ardolino et al., J Physiol, 2005
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But how tDCS can be used clinically?
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Behavioral effects

• Recent clinical studies
• Stroke
• Parkinsons disease (motor and psychiatric
  symptoms)
• Major depression
• Tinnitus
• Working memory
• Motor learning
• Craving (smoking, food and alcohol)
• However, difference from the studies of 60 and
  70s

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Where can tDCS be explored?

• tDCS might be an optimal tool to modulate
  practice-related learning neural activation
• Changes in network associated with practice
• Enhancement might be useful for initial stages of
  learning during skills acquisition and at later
  stages for learning of new skills
• Can tDCS guide and be used to guide these
  effects?

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• anterior cingulate cortex,
• medial parietal cortex,
• bilateral posterior parietal cortex
• bilateral posterior parietal cortex
• bilateral middle frontal gyrus (DLPFC),
• DLPFC
• Left inferior frontal gyrus (VLPFC),
• left anterior insular cortex
• right middle occipital gyrus
• bilateral fusiform gyrus.

Chein, 2005
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Learning-related activity changes might be
beneficial or detrimental (depending on the
time-point)

• Decreases in regional activity with practice may
  reflect local changes in synaptic efficacy 32.
• Tightening connections between neurons that
  contribute effectively toward task processing and
  weakening connections between those that do not
• Changes on one set of cognitive processes (those
  supporting strategies used in unpracticed
  performance) to dependence on a different set of
  cognitive processes (those supporting strategies
  used in practiced performance)

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Practice
TDCS
Increased activity in related neural networks
Reduction in activity
TDCS
Beneficial
Detrimental?
Behavioral Improvement
Acquisition of new skills Other behaviors
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Scenario 1 Increasing activity at initial
stagesMotor learning in healthy subjects

• Anodal tDCS of the dominant vs. non-dominant M1
• Right-handed subjects
• Motor function evaluation - Jebsen-Taylor Hand
  Function Test

Boggio et al., 2006
Boggio, Neuroscience Letters, 2007
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Scenario 2 Increasing activity later
stagesFalse Memories Experiments

• Memories are not literal representations of the
  past
• Facts are unconsciously constructed to fit our
  schemata, which can lead to false memories
• The anterior temporal lobes (ATL), especially the
  left ATL, are vital for semantic processing -
  responsible for conceptual knowledge, labels and
  categories
• Brain stimulation to increase activity in ATL
  throughout the encoding and retrieval task phases.

Example one list contains words related to bread
(e.g. loaf, sandwich, and so forth), but not the
word bread.
Boggio, PLOS One, 2007
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Boggio, PLOS One, 2009
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Another scenari changing processing of
informationCraving Experiment
Stimulus (cue-provoking craving)
Baseline cortical activity
Craving Behavior
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Experimental Design
Boggio, Neuroscience Letters, 2009
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Day 1
Day 2
Day 5
Day 3
Day 4
Cue-provoked craving
Final Assessment
Cue-provoked craving
Baseline and demographic characteristics
Cue-provoked craving
Cue-provoked craving
Cue-provoked craving
Cue-provoked craving
Cue-provoked craving
tDCS
tDCS
tDCS
tDCS
tDCS
Mood and VAS
Smoking Movie
Cigarette manipulation
VAS
Cue-provoked craving
Figure 1
Boggio, Neuroscience Letters, 2009
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Figure 2
Boggio, Neuroscience Letters, 2009
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Rewiring the brain needs guidance
How do we want the changes to take
place? Coupling brain stimulation behavioral
intervention NEUROMODULATION
Neuromodulation primes a network, not a cell
NEURAL NETWORK
MODULATION
TDCS
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Rewiring the brain needs guidance
How do we want the changes to take
place? Coupling brain stimulation behavioral
intervention NEUROMODULATION
Neuromodulation primes a network, not a cell
NEURAL NETWORK
Input
Behavioral change
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tDCS coupled with behavioral interventions
tDCS in gait rehabilitation
tDCS in chronic pain
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• Further animal / human studies to determine
• safety (long-term use, novel parameters)
• efficacy (long-term effects, combination with
  drugs, use during sleep)
• Technical development
• Portable device
• Online methods of monitoring
• Deep stimulation
• Focal stimulation?
• Potential advantage to be explored (compared to
  other therapeutic methods such as drugs) -
  effects on brain activity are almost immediate
  and thus might be useful in epilepsy, craving
  disorders, mood disorders, pain

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Alternatives Ring ElectrodesMarom Bikson
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Alternatives Ring ElectrodesMarom Bikson