This document summarizes Transcranial Direct Current Stimulation (tDCS). It discusses the history of tDCS, how it works, applications in therapeutic and enhancement contexts, physiological effects and basis, safety considerations, and the future of research. tDCS involves applying a weak electrical current to the brain via electrodes to modulate cortical excitability. It has therapeutic potential for conditions like depression, motor rehabilitation, and is being studied for cognitive enhancement. Research suggests its effects are mediated by changes in neuronal membrane potentials and synaptic plasticity.

1. Transcranial Direct Current
Stimulation (tDCS)
Daniel C. Stevenson
daniel.cortez.stevenson@gmail.com
https://www.linkedin.com/in/daniel-c-stevenson/
Presented in Fall, 2015
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2. Agenda
1. History, tDCS vs. TMS, applications, & efficacy
2. Physiological effects of tDCS
3. Physiological basis of tDCS
4. Safety, DIY, and the FDA
5. Future Directions
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3. History
Aldini, 1804
3

4. The Device
4

5. Laboratory-grade tDCS
Neurconn.de
5

6. Commercial tDCS
6

7. DIY-tDCS
• www.reddit.com/r/tDCS
• www.diytdcs.com
• Brain-kit 1.0
– Open-source program for regulating electrode
output and recording EEG signal
• http://brmlab.cz/project/brain_hacking/tdcs
– (not WRAIR-friendly)
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8. tDCS vs. TMS
tDCS
• Electrical stimulation via
positive/negative electrodes
• Modifies ‘cortical
excitability’
• Cheap
• Portable
TMS
• Magnetic stimulation via
figure-8 coil
• Elicits action
potentials
• Expensive
• Large equipment
8

9. Applications
Two broad categories:
1) Therapeutic
– patient populations
2) Enhancement
– healthy populations
9

10. Therapeutic Application
• Pain
• Migraine
• Tinnitus
• Depression
• Addiction
• Schizophrenia
10
• Anxiety
• Dementia
• Stroke
• Alzheimers
• Parkinson’s
• Post-polio syndrome

11. Parkinson’s: Dose-dependent effects
11
Boggio et al. (2006). Journal of Neurological Sciences,
249(1): 31-38.
N=18
Duration=20min
3-Back Working Memory Test during last
5min of stimulation

12. Depression: Combination
Therapy
12Brunoni et al. (2013). JAMA Psychiatry 70(4): 383-91
Dorsolateral Prefrontal Cortex (DLPFC)
Located at F3,F4
N=120
Strength=2mA
Duration=30min
Frequency=1/day for 10 days; 4wks; 6wks

13. Enhancement Application
• Motor learning
• Language learning
• Visual perception
• Working memory
• Attention
• Problem-solving
• Moral judgment
13

14. Target Detection: Task x tDCS effects
14
Clark et al. (2010). NeuroImage, 59(1): 117-128.
RIF=right inferior frontal
Anodal Stimulation
Duration=30min

15. 15
Target Detection: Task x tDCS effects
Clark et al. (2010). NeuroImage, 59(1): 117-128.
N2.0mA=26
N0.1mA=36

16. Lying
16
N=22
Strength=1mA
Duration=13min (Intra-tDCS test)
Electrode size=24cm^2
Karim, A. et al. (2010). Cerebral
Cortex, 20: 205-213.
PO3
Fp2

17. Is there really an effect?
• Horvath, J. C., Forte, J. D., & Carter, O. (2015). Quantitative
review finds no evidence of cognitive effects in healthy
populations from single-session transcranial direct current
stimulation (tDCS). Brain Stimulation, 8(3): 535-550.
• Price, A. R., & Hamilton, R. H. (2015). A re-evaluation of the
cognitive effects from single-session transcranial direct
current stimulation. Brain Stimulation 8(3): 663-665.
• Horvath, J. C. (2015). New quantitative analysis following
Price & Hamilton’s critique do not change original findings
of Horvath et al. Brain Stimulation 8(3): 665-666.
• Nitsche, M. A., Bikson, M., & Bestmann, S. (2015). On the
use of meta-analysis in neuromodulatory non-invasive brain
stimulation. Brain Stimulation 8(3): 666-667.
17

18. The Physiological Effects of tDCS
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19. Methodology
Abductor digiti minimi muscle
of the hand (ADM)
Tendon
Belly
Surface EMG Recordings of TMS
induced Motor Evoked Potentials
(MEPs)
Ag-AgCl
electrodes are
placed in a
“belly-tendon
montage”
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20. Primary Motor Cortex
20

21. Pyrimidal Tract Neurons:
Corticospinal-Upper motor neurons originating
in layer 5 of the cortex terminate in spinal cord and
innervate lower motor neuron
Corticobulbular-terminate in brainstem
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22. tDCS modifies ‘cortical excitability’
Nitsche & Paulus. (2000) J Physiology 527.3: 633-639
N=10; 1mA
4sec stimulation ending with
50ms recording
Anode (+ terminal)
Cathode (- terminal)
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23. Effects Last After Stimulation
Nitsche & Paulus. (2000) J Physiology 527.3: 633-639
Duration=5 min
Strength=1 mA
N=19
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24. Effects are
Dependent on
Duration &
Strength
Nitsche & Paulus. (2000) J Physiology 527.3: 633-639
Duration=5min
Strength=1mA
Filled shapes are
significant!
N=12
N=12
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25. Prolonged Effects of Anodal tDCS
Nitsche & Paulus. (2001) Neurology 57: 1899-1901
7 min 9 min
11 min
5 min
13 min
Strength=1mA
N=12
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26. Prolonged Effects of Cathodal tDCS
Nitsche et al. (2003) Clinical Neurophysiology 114(4): 600-604
5 min
7 min
9 min
Strength=1mA
N=12
26

27. Non-linear effect of cathodal tDCS
27Batsikadze, et al. (2013). J Physiol 591(7): 1987-2000
N2mA=14
N1mA=9
Duration=20min

28. The Physiological Basis for tDCS
28

29. 29

30. Action Potential
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31. The hypothesis
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32. Current modifies elicited neuron firing
(in rats)
32
Anodal Stimulation Cathodal Stimulation
Bindman et al. (1964) J Physiol 172: 369-382
*b,d are control traces

33. Current modifies tonic neuron firing
(in rats)
33
Control
Cathodal
Anodal
Bindman et al. (1964) J Physiol 172: 369-382

34. Na+ Voltage Gated
Channels
Nitsche et al. (2003). J Physiology 533.1: 293-301
CBZ = carbamazepine (600mg);
Na+ channel blocker
* Indicates significant difference
from the respective PLC/Drug
condition
NI=12
N0=12
NI=10
N0=10
No ∆
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During tDCS

35. Conclusions: During tDCS Effects
• Resting membrane potential is modulated by
the electrical current
• Anodal effects are abolished by blocking Na+
channels
• These effects are necessary for longer-term
effects to occur
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36. Long-term potentiation/depression
(LTP/LTD)
• Modulation of synaptic strength
• Occurs within the horizontal connections of
the primary motor cortex (during motor
learning and rehabilitation)
– Glutamatergic interneurons
• NMDA receptors
• AMPA receptors
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37. Early LTP is Ca2+ dependent
37
Lynch, M. A. (2004). Long-term potentiation and memory.
Physiological Reviews 84(1): 87-136.

38. Ca2+ Ligand/Voltage Gated
Channels
Nitsche et al. (2003). J Physiology 533.1: 293-301
FLU = flunarizine;
Ca2+ channel blocker
NI=11
N0=11
NI=14
N0=14
No ∆
38

39. NMDAR antagonism abolishes effects
Nitsche et al. (2003). J Physiology 533.1: 293-301
DMO = dextromethorphane;
NMDA receptor antagonist
NI=12
N0=12
NI=10
N0=10
No ∆
No ∆
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Intra-tDCS

40. NMDAR agonism prolongs effects
Duration=13min anodal;
9min cathodal
Strength=1mA
CYC = D-Cycloserine (100mg);
NMDA receptor agonist
40
Nitsche et al. (2004). Neuropsychopharmacology,
29:1573-1578

41. Conclusions: NMDAR/Ca2+
• NMDAR-mediated LTP is integral to long-term
tDCS effect
– NMDA antagonism eliminates both cathodal and
anodal long-term effects
– NMDA agonism enhances anodal tDCS
• Ca2+ channels mediate short-term tDCS effect
• Ca2+ channels necessary for longer-term
effects
– NMDAR interaction
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42. Conclusions: Physiological Basis
1. Short-term effects are mediated by sub-
threshold alterations in neuron resting
membrane potential
2. Long-term effects are mediated by LTP
involving NMDA receptors
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43. Safety: Adverse Effects
• 63% of studies report 1 mild ‘adverse effect’
– Itching, tingling, headache, burning sensation,
discomfort
• However:
– Active tDCS Rate = Sham Rate
– Except:
• Skin reddening (Tx w/ Ketoprofen)
43
Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early
Online]: 1-14.

44. Safety: Serious Adverse Effects
• Review: No “serious adverse events” since
1998 in >10,000 subjects
• 1964 study: “respiratory and motor paralysis”
– Bifrontal anodal electrodes with leg cathode
– 10x intended current strength (likely ~3mA)
– DIY-tDCS concerns
44
Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early
Online]: 1-14.
Lippold O. C. J., & Redfearn, J. W. T. (1964). Mental changes resulting
from the passage of small direct currents through the human brain.
110(469): 768-772

45. Safety: Physiological Evidence
• No pathological changes in:
– Serum enolase (marker of neuronal damage)
– HRV
– EEG
• 100x the charge density used in humans is
required to cause brain damage in rats
– Discomfort in humans starts at 2-3x
45
Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early
Online]: 1-14.

46. Safety: Maladaptive Plasticity
• “Non-invasive”
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47. Safety: Standard Parameters
• Current strength <2.5mA
• Duration <60min
• ≤2 sessions per day
• This does not imply going beyond these
parameters is not safe!
47
Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early
Online]: 1-14.

48. Safety: Unknowns
• Long-term usage
• Need for more studies on safety
48
Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early
Online]: 1-14.

49. FDA Regulations
• “Medical device”
– Most stimulators are Class II
• “Investigational Device Exception” approval
– “non-significant risk” exception  “expedited IDE”
– NSR overwhelmingly applied
• “Minimal Risk”
• Not cleared for any medical indication
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50. tDCS Research is Accelerating
• 2008: Review of 122 tDCS studies since 1998a
– physiological effects of tDCS
– pharmacological modulation of tDCS
– establishing application protocols
• 2008-2010: ~100 new tDCS studiesb
– enhancing the efficacy of protocols
– defining safety parameters
– broadening the range of application
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a Nitsche et al. (2008). Brain Stimulation, 1: 206-233.
b Nitsche, M. A., & Paulus, W. (2011). Restorative Neurology and Neuroscience, 29:463-492.

51. tDCS Research is Accelerating
51
0
100
200
300
400
500
#ofPublications
Year
PubMed publications on the subject
"transcranial direct current stimulation" since 1998
http://dan.corlan.net/medline-trend.html

52. Future Research Should Explore…
• effects of tDCS on cortical areas outside of M1
– neurotransmitters, receptors, neurons, and
networks are heterogeneous
• interaction of of [Stimulation x Task]
• timing and duration of stimulation (before,
during or after a task)
• multi-electrode stimulation of functional
networks
52
Shin, Y.-I., Foerster, A., & Nitsche, M. A. (2015).
Neuropsychologia, 69: 154-175

53. Overview: tDCS…
• is an exciting and novel electrical stimulation
device with a long history
• has a wide variety of applications
• modifies the resting membrane potential of
cells, and can induce lasting changes in
neuronal plasticity
• is of minimal risk, yet still awaits FDA approval
• tDCS research is booming, but has a long way
to go
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54. That’s it! (Or is it?)
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