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Transcranial Direct Current Stimulation (tDCS)

Daniel C. Stevensondaniel.cortez.stevenson@gmail.com

https://www.linkedin.com/in/daniel-c-stevenson/Presented in Fall, 2015

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Agenda

1. History, tDCS vs. TMS, applications, & efficacy2. Physiological effects of tDCS3. Physiological basis of tDCS4. Safety, DIY, and the FDA5. Future Directions

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History

43-48 CE: Scribonius

Largus - Headache

relief w/ torpedo fish

11th century: Ibn-

Sidah treats epilepsy

w// electric catfish

1799: Alessandro Volta

invents voltaic pile,

which is able to power

DC circuits

1804: Giovanni Aldini

treats melancholia w/

DC currents

1938: Cerletti treats 1st

patient with ECT 1960s: Investigations

into weak electric field

effects on animal

motor cortex

2000: Modern

investigations of tDCS

begin w/ Nitsche &

Paulus

Aldini, 1804

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The Device

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Laboratory-grade tDCS

Neurconn.de

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Commercial tDCS

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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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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

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Applications

Two broad categories:1) Therapeutic – patient populations

2) Enhancement – healthy populations

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Therapeutic Application

• Pain• Migraine• Tinnitus• Depression• Addiction• Schizophrenia

• Anxiety• Dementia• Stroke• Alzheimers• Parkinson’s• Post-polio syndrome

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Parkinson’s: Dose-dependent effects

Boggio et al. (2006). Journal of Neurological Sciences, 249(1): 31-38.

N=18Duration=20min

3-Back Working Memory Test during last 5min of stimulation

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Depression: CombinationTherapy

Brunoni et al. (2013). JAMA Psychiatry 70(4): 383-91

Dorsolateral Prefrontal Cortex (DLPFC)Located at F3,F4

N=120Strength=2mADuration=30minFrequency=1/day for 10 days; 4wks; 6wks

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Enhancement Application

• Motor learning• Language learning• Visual perception• Working memory• Attention• Problem-solving• Moral judgment

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Target Detection: Task x tDCS effects

Clark et al. (2010). NeuroImage, 59(1): 117-128.

RIF=right inferior frontal

Anodal StimulationDuration=30min

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Target Detection: Task x tDCS effects

Clark et al. (2010). NeuroImage, 59(1): 117-128.

N2.0mA=26N0.1mA=36

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Lying

N=22Strength=1mADuration=13min (Intra-tDCS test)Electrode size=24cm^2

Karim, A. et al. (2010). Cerebral Cortex, 20: 205-213.

PO3 Fp2

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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.

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The Physiological Effects of tDCS

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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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Primary Motor Cortex

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Pyrimidal Tract Neurons:Corticospinal-Upper motor neurons originatingin layer 5 of the cortex terminate in spinal cord and innervate lower motor neuronCorticobulbular-terminate in brainstem

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tDCS modifies ‘cortical excitability’

Nitsche & Paulus. (2000) J Physiology 527.3: 633-639N=10; 1mA

4sec stimulation ending with 50ms recording

Anode (+ terminal)

Cathode (- terminal)

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Effects Last After Stimulation

Nitsche & Paulus. (2000) J Physiology 527.3: 633-639

Duration=5 minStrength=1 mAN=19

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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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Prolonged Effects of Anodal tDCS

Nitsche & Paulus. (2001) Neurology 57: 1899-1901

7 min 9 min11 min

5 min

13 min

Strength=1mAN=12

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Prolonged Effects of Cathodal tDCS

Nitsche et al. (2003) Clinical Neurophysiology 114(4): 600-604

5 min

7 min

9 min

Strength=1mAN=12

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Non-linear effect of cathodal tDCS

Batsikadze, et al. (2013). J Physiol 591(7): 1987-2000

N2mA=14N1mA=9

Duration=20min

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The Physiological Basis for tDCS

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Action Potential

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The hypothesis

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Current modifies elicited neuron firing (in rats)

Anodal Stimulation Cathodal Stimulation

Bindman et al. (1964) J Physiol 172: 369-382

*b,d are control traces

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Current modifies tonic neuron firing(in rats)

Control

Cathodal

Anodal

Bindman et al. (1964) J Physiol 172: 369-382

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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=12N0=12

NI=10N0=10

No ∆

During tDCS

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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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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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Early LTP is Ca2+ dependent

Lynch, M. A. (2004). Long-term potentiation and memory. Physiological Reviews 84(1): 87-136.

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Ca2+ Ligand/Voltage Gated Channels

Nitsche et al. (2003). J Physiology 533.1: 293-301

FLU = flunarizine; Ca2+ channel blocker

NI=11N0=11

NI=14N0=14

No ∆

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NMDAR antagonism abolishes effects

Nitsche et al. (2003). J Physiology 533.1: 293-301

DMO = dextromethorphane; NMDA receptor antagonist

NI=12N0=12

NI=10N0=10

No ∆

No ∆

Intra-tDCS

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NMDAR agonism prolongs effects

Duration=13min anodal; 9min cathodal

Strength=1mA

CYC = D-Cycloserine (100mg); NMDA receptor agonist

Nitsche et al. (2004). Neuropsychopharmacology, 29:1573-1578

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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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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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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)

Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early Online]: 1-14.

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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

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

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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

Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early Online]: 1-14.

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Safety: Maladaptive Plasticity

• “Non-invasive”

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Safety: Standard Parameters

• Current strength <2.5mA • Duration <60min• 2 sessions per day

• This does not imply going beyond these parameters is not safe!

Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early Online]: 1-14.

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Safety: Unknowns

• Long-term usage• Need for more studies on safety

Fregni et al. (2014). Clinical Research and Regulatory Affairs, [Early Online]: 1-14.

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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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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

a Nitsche et al. (2008). Brain Stimulation, 1: 206-233. b Nitsche, M. A., & Paulus, W. (2011). Restorative Neurology and Neuroscience, 29:463-492.

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tDCS Research is Accelerating

20132012

20112010

20092008

20072006

20052004

20032002

20012000

19991998

0

100

200

300

400

500

PubMed publications on the subject "transcranial direct current stimulation" since 1998

Year

# of

Pub

licati

ons

http://dan.corlan.net/medline-trend.html

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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

Shin, Y.-I., Foerster, A., & Nitsche, M. A. (2015). Neuropsychologia, 69: 154-175

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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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That’s it! (Or is it?)