intro to transcranial direct curent stimulation (tdcs)
TRANSCRIPT
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Transcranial Direct Current Stimulation (tDCS)
Daniel C. [email protected]
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?)