Biophysical foundations of transcranial Direct
Current Stimulation (tDCS) and frontiers of
technology optimization.
Marom Bikson
Lucas Parra, Dennis Truong, Abhishek Datta, Davide Reato, Asif Rahman, Belen
Lafon, Thomas Radman, Jacek Dmochowski, Preet Minhas, Yu Huang, Mahtab
Alam, Alexander David, Peter Toshev, Ole Seibt
Department of Biomedical Engineering, The City College of New, New York, NY
$ NIH, NSF, Epilepsy Foundation, Wallace Coulter Foundation, DoD
Disclosure:
Soterix Medical Inc. produces tDCS and High-Definition tDCS.
Marom Bikson is founder and has shares in Soterix Medical.
Some of the clinical data presented may be supported by Soterix
Medical.
Transcranial Direct Current Stimulation (tDCS)
•  Non-invasive, portable, well-tolerated
neuromodulation.
•  Low-intensity (1-2 mA) current passed
between scalp electrodes (10-20 min).
•  Investigated for cognitive neuroscience
and neuropsychiatric treatment.
Depression, pain, migraine, epilepsy,
PTSD, schizophrenia, tinnitus, neglect,
rehabilitation (motor, aphasia), TBI,
OCD, attention, accelerated learning
(reading, motor skills, math, threat
detection), memory…
Ø  Can a “simple” intervention modulate brain function?
Ø  How is specificity of action achieved?
Anatomical Specificity of tDCS
•  tDCS montage (electrode
position) determines brain
current flow patten.
Truong, Bestmann, Nitche
•  Combined with waveform (duration, intensity)
determines dose.
tDCS current flow : anode and cathode, and uniform fields
•  Two pad electrodes placed on head and connected to DC
current stimulator.
•  Current passed between ANODE(+) and CATHODE(-)
•  DC CURRENT FLOW across cortex.
•  Current is INWARD under ANODE and OUTWARD under
CATHODE
Brain current
intensity
Brain current
direction
MRI derived computational model
tDCS modeling work flow
Full work-flow developed
to preserve accuracy and
resolution
MRI sequences optimized
for tDCS modeling (3T at
1x1x1 mm)
Solution provides detail
insight into brain
modulation
Special segmentation tools
perverse resolution in
generation of tissue masks
Conjugate gradient
solver with <1E-8
tolerance
Mesh includes >50 million
elements
Model physics/domains include explicit
consideration of electrode properties.
Scan resolution persevered throughout:
gyri-level precision, individualized
tDCS current flow
•  Two pad electrodes placed on head and connected to DC
current stimulator.
•  Current passed between ANODE(+) and CATHODE(-)
•  DC CURRENT FLOW across cortex.
•  Current is INWARD under ANODE and OUTWARD under
CATHODE
Brain current
intensity
Brain current
direction
MRI derived computational model
tDCS current flow : uniform fields
Rahman et al.
•  While electric field varies over the head (cortex) is varies little across
any given cortical column.
•  On the scale of a cortical neuron, the membrane polarization is
comparable to that produced by a uniform electric field.
•  “Quasi-uniform” assumption: Neuromodulation is represented by
electric field.
Ø  No explicit consideration of cellular morphology (which would have
been impossible anyways).
Ø  Spaghetti morphology concept (something is oriented optimally)
tDCS current flow : anode and cathode, and uniform fields
•  Two pad electrodes placed on head and connected to DC
current stimulator.
•  Current passed between ANODE(+) and CATHODE(-)
•  DC CURRENT FLOW across cortex.
•  Current is INWARD under ANODE and OUTWARD under
CATHODE
Brain current
intensity
Brain current
direction
MRI derived computational model
tDCS current flow : anode and cathode
Current flow
outward
inward
tDCS current flow : anode and cathode
Electro
de
Head Surface
Current flow
outward
inward
Cortical Neuron
tDCS current flow : anode and cathode
Anode
(+)
Head Surface
Current flow
outward
inward
Hyperpolarized cell
compartments
Current
Flow
Depolarized cell
compartments
? Increased Excitability / Plasticity
tDCS current flow : anode and cathode
Cathod
e (-)
Head Surface
Current flow
outward
inward
Depolarized cell
compartments
Current
Flow
Hyper-polarized cell
compartments
Decreased Excitability / Plasticity
Neuron Polarization under DCS
Multi-compartment neuronal
modelling
DC current flow
Optical Mapping with
voltage sensitive dyes
Jefferys, McIntyre
•  Bi-modal linear polarization profile
Ø  (!) morphology/membrane properties independent (Ve)
•  Exception for (afferent) axons terminals (polarization: Eλ)
Neuron Polarization under DCS
Brain slice: Intracellular recording +
Morphological reconstruction
0 mV polarization per
1 V/m electric field
DC Current Flow
0.1 mV polarization per
1 V/m electric field
0.3 mV polarization per
1 V/m electric field
Radman
tDCS current flow : anode and cathode
Depolarized soma
?
Increased
Excitability /
Plasticity
Current flow
outward
inward
Hyperpolarized soma
Decreased
Excitability /
Plasticity
Electric Field max:
0.4 V/m at 2 mA
0.4 V/m * 0.3 polarizarion per V/m=
Somatic polarization max: 0.12 mV
tDCS mechanisms: Neuromodulation
High-intensity Pulses
Over-driving a
neural network
Low-intensity DC
tDCS mechanisms: Neuromodulation
High-intensity Pulses
Over-driving a
neural network
Low-intensity DC
tDCS mechanisms: Neuromodulation
High-intensity Pulses
Over-driving a
neural network
Low-intensity DC
tDCS mechanisms: Neuromodulation
High-intensity Pulses
Over-driving a
neural network
Low-intensity DC
Interacting with
specific activity
in a neural
network
Direct Current Stimulation of Network Oscillations
Network Gamma Activity
Brain Slice
Network Model
Reato et al J Neurosci 2010
Direct Current Stimulation of Network Oscillations
Network Gamma Activity
Brain Slice
Network Model
Anode DCS (6 V/m)
Excitatory neuron / inhibitory neuron network
adaptation
adaptation
Reato et al J Neurosci 2010
Cathode DCS (-6V/m)
Direct Current Stimulation of Network Oscillations
Network Gamma Activity
Brain Slice
Network Model
Ø  Can a “simple” intervention modulate brain function?
Ø  How is specificity of action achieved?
Reato et al J Neurosci 2010
•  When a system is at threshold (e.g. oscillations) what
does “sub” or “supra” threshold stimulation mean
ü  Amplification of weak current stimulation
•  Reponse of active systems to DC is full dependent on
the state and dynamics of the the system
ü  DC can produce more or less gamma
•  tDCS is almost always applied as an adjunct treatment
(e.g. tDCS plus cognitive training, tDCS plus rehabilitation…)
tDCS current flow : anode and cathode, and uniform fields
Anode
electrode
Inward Current
flow
+
Subject training
(therapy)
Depolarized
soma
Enhance of
ongoing activity
(oscillations)
•  Cellular substrate to enhance learning
•  Task-specific facilitation
•  tDCS as a general tool to promote
neuroplasticity
Ø  Can a “simple” intervention modulate brain function?
Ø  How is specificity of action achieved?
Modulation of sensitivity to synaptic input under DCS
Anodal stimulation + evoked response
fEPSP: metric of cellular synaptic efficay
Cathodal stimulation
(soma Hyperpolarized)
Current flow
+
Hyperpolarized
dendrites
Depolarized
soma
Anodal stimulation
(soma Depolarized)
Control
-
+
Synaptic efficacy
Modulation of sustainable synaptic processing
+
+ +
+
…
Input train
(sustained activity)
Anodal stimulation
•  Higher sustained synaptic inputs under anodal stimulation
•  Substrate for plasticity + Pathways specific
Anatomical Specificity of HD-tDCS
•  High-Definition tDCS (HD-tDCS)
array provides high degree of
current flow control.
•  Current at each electrode
controlled to steer targeting
•  Single non-invasive system with
wide configurations: low-cost
•  HD electrodes rated for 2 mA
DC, 22 min – single use
² Disposable
² Diffusion limited
Datta, Bikson, Alam
HD-tDCS Optimization
•  Given target and head anatomy: single
“optimal” montage is close-form solution
•  Linear (quasi-uniform assumption: electric field)
•  Rapid (seconds on a lap-top): physican GUI
•  Optimal montage fully dependent on
Ø  Desired brain current flow
Dmochowski
Bikson, Parra
e.g. regions of interest, focality vs intensity, E-field direction:
çèéêëì
Ø  Safety/tolerability constraints
e.g. maximum current per electrode,
total current, max current density
4x1 HD-tDCS
•  4x1 High-Definition tDCS (HD-tDCS) optimized for cortical
targeting
•  Center electrode detremines polarity
Ø  Uni-directioal modulation
•  Ring radius detemines cortical focality
Ø  Skull resisitivy is not the problem
Cathode
Center
Datta, Bikson
Anode
Center
Outward
Inward
4x1 HD-tDCS Clinical Trials
•  Phase-1 NIH (Wassermann) – tolerability
•  Phase-2 Germany (Nitsche, Paulus) – dose
•  Phase-2 USC Stoke Rehabilitation (Fridrickson):
Aphasia
•  Phase-2 Columbia (Schambra): dose ongoing
•  Phase-2 Burke/Cornell (Edwards): dose Stroke
Rehabilitation - Motor
•  Phase-2b multi-center Stoke Rehabilitation - Aphasia
ongoing
•  Phase-1 Michigan(DaSilva): Imaging neuropathic pain/
migraine ongoing
•  Phase-2 Harvard/Spaulding (Fregni): Fibromyalgia
ongoing
•  Phase-1 Harvard(Rotenberg)/NYU: Status Epilepsy–
safety/tolerability ongoing
4x1 HD-tDCS Clinical Trials
•  Phase-2 Harvard/Spaulding (Fregni): Fibromyalgia
ongoing
Ø  Can a “simple” intervention modulate brain function?
Ø  How is specificity of action achieved?
Neuromodulation Technologies: Anatomical Targeting
•  Neuromodulaiton (brain stimulaiton) technology based
on anatomical targeting (DBS, TMS…)
•  Trade-off between complexity (invasiness) and focality
•  Focality is “relative” for suprathreshold stimulation
Downstream
Target
•  “Functional” targeting (stim+tasks)
Upstream
tDCS specificity: Functional Targeting
Low-intensity DC + specific network activation
tDCS specificity: Functional Targeting
Low-intensity DC + specific network activation
Current flow across entire
region
tDCS specificity: Functional Targeting
Low-intensity DC + specific network activation
Modulation (plasticity) of
only co-activated neurons
Current flow across entire
region
Biophysical foundations of transcranial Direct
Current Stimulation (tDCS) and frontiers of
technology optimization.
Marom Bikson
Lucas Parra, Dennis Truong, Abhishek Datta, Davide Reato, Asif Rahman, Belen
Lafon, Thomas Radman, Jacek Dmochowski, Preet Minhas, Yu Huang, Mahtab
Alam, Alexander David, Peter Toshev, Ole Seibt
Department of Biomedical Engineering, The City College of New, New York, NY
$ NIH, NSF, Epilepsy Foundation, Wallace Coulter Foundation, DoD