Y Transcranial Direct Current Stimulation (tDCS) P O C T O N Felipe Fregni, MD, PhD O Laboratory of Neuromodulation D Department of Physical Medicine & Rehabilitation Spaulding Rehabilitation Hospital Massachusetts General Hospital Harvard Medical School
Rationale of Electrotherapy Y P • Broad spectrum (neuropsychiatric, rehabilitation, O cognitive performance…) C • Individualized therapy T • Targeted brain modulation (space + time) O • Adverse effects (minimal complications + counter - N indications) O • Mechanisms of action vs. mechanisms of disease D • Cost Is DC stimulation an advantageous technique in this scenario?
What are the options? Y Different electrodes/coils P O C B A C T O N O D Invasive Leads Transcranial Electrical Transcranial Magnetic (also Vagus, Spinal..) Figure from Marom Bikson
Brain Electrotherapy Y P O C T O N O D Figure from Marom Bikson
What is tDCS? Y Very simple, safe and powerful technique of P neuromodulation (not neurostimulation) O C Should we call Transcranial neuromodulation with DC? T O Based on a constant electric field N Used for more than 200 years - Galvanization O (Based on the experiments of Aldini - D beginning of XIX century - Italy - nephew of Galvani) 5
Why DC stimulation? Y P O Modulates spontaneous neuronal activity C No disruptive effects (compared to TMS and DBS) T O Non-expensive N Reliable sham condition O D Easy to administer (clinical applications) Less adverse effects
Basic principle of brain polarization Y P O C Charged particles/ proteins/ions T move along the O gradient of voltage N O D
How does this affect neuronal activity? Y P Changes in PH O DC Field Changes in Membrane Protein C Changes in ions Glial changes? T O N O D
Direct effects of DC stimulation Y P O C T O N O D Goldring, 1950
Y P O C How does transcranial DC T stimulation work in humans? O N O D
Y P O C T O N O D
But…Does the current reach the cortex? Y P O C Computer modeling studies T O N Neurophysiological data O Behavioral data D 12
Computer modeling Y P O Several studies have been performed (animal and human C models) T O They showed that a significant amount of current reaches N cortical surface - enough to induce biological effects if the duration of stimulation is appropriate O D 13
tDCS model 1 Y P O C T O N O D Wagner et al, - Neuroimage, 2007
Y P O C T O N O D
tDCS model 2 Y P O C T O N O D Miranda et al, Clinical Neurophysiology, 2006
tDCS model 3 Y P O C T O N O D Bikson et al, Brain Stimulation, 2009
Neurophysiological data Y P O Animal studies (experiments conducted in the 50s, 60s C and 70s) - direct neuronal recording T O Human studies (cortical excitability studies - use of single N pulse TMS, EEG and neuroimaging) O D 18
Y P O C T O N O D Intracellular activities and evoked potential changes during polarization of motor cortex – Purpura and McMurtry, 1964
Y P O C T O N O D
Initial studies with tDCS/TMS-MEP Y P O Study by Priori et al. - C 1998 T -Short conditioning anodal O DC pulses leads to MEP depression – cathodal N induces no effects O -Differences – electrode montage (extracephalic – D chin) - intensity
Y P O C T O N O D
Additional evidence Y P Neuroimaging studies (PET, fMRI, MRS) O C EEG studies T O N Additional animal studies O D Lang, European Journal of Neuroscience, 2005
Y P O C T O N O D Synaptic vs. non-synaptic effect
Y P O C T O N O D Non-synaptic effects
Y P O C T O N O D Intracellular activities and evoked potential changes during polarization of motor cortex – Purpura and McMurtry, 1964
Membrane effect? Y P Effect of cathodal transcranial direct current stimulation O (tDCS) on resting motor threshold ( A ) and on motor evoked potentials (MEP amplitude) ( B , C ) elicited by C transcranial magnetic stimulation (TMS) T O Effect of cathodal transcutaneous direct current (DC) stimulation and sham stimulation on the excitability of ulnar motor axons N O D Ardolino et al., J Physiol, 2005
Cortical Spreading Depression Y Massive changes in ionic concentrations P O Slow nonlinear chemical waves - speeds on the order of C mm/min T O Cortical effect N O Clearly involved with non-synaptic mechanisms D
Cortical Spreading Depression Y P O C T O N O D Liebetanz, Neuroscience Letters, 2006
Y P O C T O N O D Synaptic effects
Evidence for synaptic effects Pharmacological studies – intra-effects Y CBZ - carbamazepine P DMO - N -methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan FLU - (calcium channel blocker) - flunarizine O C T O N O D Drug-induced modulation of tDCS-driven cortical excitability changes during stimulation Nitsche, J Physiology, 2003
Pharmacological effects - after-effects CBZ - carbamazepine DMO - N -methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan Y P O C T O N O D TMS-elicited MEP amplitudes before and after 5 min of Comparison of post-stimulation MEP amplitudes after anodal and cathodal tDCS, under different pharmacological intake of CBZ or placebo conditions Liebetanz, D. et al. Brain 2002 125:2238-2247
Evidence of LTP Y P O Experiment with mice C In vitro direct current stimulation T Demonstrate anodal O stimulation results in long N term synaptic plasticity (DCS- LTP) O polarity specific D NMDA receptor dependent requires coupling of DCS with repetitive low-frequency synaptic activation (LFS) (Fritsch et al., 2010)
Preliminary Study Y P Study led by Alexander Rotenberg (CHB) O C T op panel: enhanced CA1 EPSP following DC stimulation of hippocampal slice. T O Bottom panel: increased CA1 EPSP slope following DCS of hippocampal slice (blue N line indicates stimulation for 30 min – 75uA). O D
Where can tDCS be explored? Y P tDCS might be an optimal tool to modulate practice- O related learning neural activation C T Changes in network associated with practice O N Enhancement might be useful for initial stages of learning during skills acquisition and at later stages for learning of O new skills D Can tDCS guide and be used to guide these effects?
Other Issues Y P O C T O N O D
Safety of extracephalic reference electrodes in humans Y Study by Vandermeen et al., P 2010 O T esting safety of extracephalic electrodes in tDCS on healthy C human volunteers. Seeing effects on autonomic T functions of brain stem (including respiration, heart rate O etc.) N No significant effects between anodal, cathodal or sham stimulation for BP and HR for O subjects D Figure shows: -- Temporal evolution of the sBP and HR for each group (sham, cathodal, anodal) . Mean +/- 1 SD of the RF by bins of 5 minutes over the monitoring period (3 epochs: baseline, tDCS, post-tDCS). Conclusions from study : stimulation did not significantly modulate brain stem activity, and therfeore may be safe to use in healthy volunteers using same parameters, though this study is limited. Vandermeeren et al. BMC Neuroscience 2010 11 :38
Extracephalic electrodes Y P Clinical and modeling study (study O led by Mariana Mendonca) C Effects of unipolar stimulation in T fibromyalgia O Initial studies have shown that M1 stimulation is associated with N significant analgesic effects O tDCS montage – M1-SO D Unexpected behavioral results
Y P O C T O N O D
Optimal stimulation protocols – duration of effects Y P Can tDCS after-effects be prolonged? O C Repetitive stimulation is already performed in clinical T applications. O N Cathodal tDCS-induced cortical excitability alterations O with different protocols (9-min duration; 1 mA) with an D interstimulation interval of 0 (no break), 3, or 20 min or 3 or 24 h were performed.
Y P O C T O N O D
Y P O C T O N O D
Safety Y Animal study – Liebetanz et P al, 2009 O C 58 rats - cathodal stimulations at 1–1000 lA T for up to 270 min through O an epicranial electrode (3.5 N mm2). O D
Safety issues Y P Systematic review of adverse effects O Aiming to assess tDCS safety in different conditions and C study designs T Systematic review and meta-analysis of tDCS clinical O trials. N Articles from 1998 (first trial with contemporary tDCS parameters) to August 2009. O D
KEYWORDS “ Transcranial direct current stimulation ” OR “ tDCS ” or “ brain polarization ” OR “ galvanic stimulation ” FROM 1998 TO AUGUST 2009 Y 132 articles excluded: 263 articles retrieved -Animal studies P - Review articles O - Duplicate data - other stimulation C techniques 131 articles (157 studies) included T O 87 studies assessed Adverse Events N O D 47 studies reported at least one Adverse Event Six studies quantified Adverse Effects
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