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1 tcs and EEG Faranak Farzan, PhD Assistant Professor, Simon Fraser University Chair in Technology Innovations for Youth Addiction Recovery and Mental Health 1

2 Why & How

3 Where Did It All Begin? Torpedo Fish 46 AD Guess Game: Maximum Voltage a Torpedo Fish Can Generate? 8 to 220 volts 3

4 Galvanism 46 AD Late 1700s Galvani Le Roy Luigi Galvani Late 18 th century founder of bioelectromagnetics famous for his animal experiments Charles Le Roy Treating blind with electricity

5 Galvanism 46 AD Late 1700s Galvani Le Roy Giovanni Aldini 1804: First report of electricity for treating psychosis and melancholia Aldini s Showmanship DC current stimulation mostly ignored in scientific community 5

6 Today 46 AD Late 1700s Galvani Le Roy ECT 1934 TES s Faraday D Arsonval TMS s Thompson Kolin tdcs 2000 Nitsche Paulus MST Anthony Barker Reza Jalinous Ian Freeston tacs 2008 Antal 6

7 tcs Application Basic & Cognitive Neuroscience Intervene with a function to examine causality Clinical Application Depression Pain Addiction ADHD

8 Mechanism of Action?

9 tcs Outcome? Nitsche & Paulus, 2000: Changes in cortical excitability in humans demonstrated using TMS Motor-Evoked Potentials (MEP)s as a metric Motor Evoked Potentials Latency Peak-to-Peak Amplitude 1 mv 20 ms

10 tcs Outcome? Nitsche et al, 2003: After 5 or 7 minutes of stimulation MEP amplitudes return to baseline within a few minutes. After 9 minutes, effects last for at least 60 minutes. Motor Evoked Potentials Latency Peak-to-Peak Amplitude 1 mv 20 ms

11 Kuo et al, 2012: 4x1 ring tdcs stimulates a smaller area, but the resulting change in cortical excitability is dramatically different tcs Outcome? Motor Evoked Potentials Latency Peak-to-Peak Amplitude 1 mv 20 ms

12 tcs Outcome Depends on Many Factors Copy Stimulation Parameters Duration of stimulation Not Number of electrodes Electrode size and shape Electrode positions Current intensity Brain StateDo

13 Where, When and How Matters Bergmann et al., 2016

14 tcs-induced Outcomes? We know relatively little about the neurophysiological mechanisms in humans; little we know about local effect, and much less about the network effect; Difficulty tailoring its parameters for desired impact. Brain Recording to Rescue? Motor Evoked Potentials Latency Peak-to-Peak Amplitude 1 mv 20 ms

15 Brain Recording? EEG, fmr, PET, DTI, EPSP + IPSP generated by synchronous activity of neurons. Interplay between excitatory pyramidal neurons and inhibitory interneurons. A change in membrane potential, release of neurotransmitters, change in concentration of ions channels may change the state of membrane channels and give rise to an oscillatory activity.

16 Added Value of tcs+eeg EEG may tell us about: Excitability of cortical tissue; excitation/inhibition balance; brain state; the integrity of local and distributed networks. 1- Detailed understanding of the tcs-induced effect on neural activity o To not fall for the circular experimental results/conclusions o Examine both local and network effects in humans, non-invasively 2- Monitor brain state o Brain state influences the tcs effect o Improve tcs protocols considering brain state dynamics o By monitoring dynamical state, design closed-loop systems 3- Guide the tcs input parameters o An infinite number of stimulation parameters to choose from o Guide the Location, Stimulation Parameters, Time of Delivery More efficacious treatments Better understanding of brain-behavior relationship

17 Retrieved from: sfohrgxobi/rih4ndo37zi/aaaaaaaaag8/zws5cbfb3qi/ s320/married+couple+fighting.jpg TCS + EEG

18 System Diagram for Designing tcs+eeg Studies

19 tcs+eeg Approaches Offline Online Record EEG (Rest/+Event) Record EEG (Rest/+Event) Stop EEG Apply tcs Record EEG & Apply tcs EEG-Guided (Online or Offline) Record EEG (Rest/+Event) Apply tcs guided by EEG Stop tcs Record EEG (Rest/+Event) Stop tcs Record EEG (Rest/+Event) Stop tcs Record EEG (Rest/+Event)

20 EEG Signal Processing

21 EEG: History Berger s Waves EEG in humans introduced by Hans Berger in 1920s

22 EEG: Language Delta (1-3Hz) Theta (4-7Hz) Alpha (8-12Hz) Beta (12-28Hz) Gamma (30Hz+) F

23 EEG language Amplitude (or Power) Strength (µv or µv 2 ) Frequency # of Cycles/Second (Hz) Phase (Radians) 10Hz 20Hz 0 π F

24 Time vs. Frequency Domain Frequency Domain imag Phase real X i (f) F

25 When/How to Record EEG? Continuous Recording (No Event) Anesthesia, Sleep Resting (eyes open/closed) Relative to An Event/Stimulation Sensory, motor, cognitive processing Electrical stimulation Event/Stimulus Trial 1 Trial 2 Trial 100 Time: Event Related Potential or Evoked potentials Frequency: Event Related Spectral Perturbation Phase F

26 EEG Features (1) Local Response (2) Connectivity Θ (3) Global Dynamic Adapted from Khanna A, Pascual- Leone A, Farzan F, Adapted from Shafi et al.,

27 System Diagram for Designing tcs+eeg Studies

28 tcs Outcomes: Local Effects Continuous EEG Recording (No Event) Power Change in Power Frequency (Hz) Jacobson et al., 2012 Montage: Anodal rifg, cathodal lofc tdcs Resting EEG: Selective decrease of theta band Zaehle., 2012 (EEG-guided) Montage: Posterior tacs at individual alpha oscillations Resting EEG: Increase in alpha in parieto-central electrodes

29 tcs Outcomes: Local Effects Change in ERP 20 µv EEG + Event 50 ms Keeser et al., 2011 Montage: Anodal tdcs on LDLPFC, cathode on contralateral supraorbital region EEG Rest: Reduced left frontal delta, source analysis localized this to ACC and orbitofrontal regions EEG+ Working Memory: Increased P2 and P3 ERP amplitudes Performance: Reduced error rates in working memory Change in ERSP or ERD/ERS Matsumoto et al., 2010 Montage: Anodal/cathodal tdcs on MC EEG+ Motor Imagery: Mu rhythms ERD increased after anodal tdcs Zaehle., 2011 Montage: anodal or cathodal left DLPFC tdcs EEG+ Working Memory: Enhanced performance and amplified oscillatory power in the theta and alpha bands after anodal tdcs

30 Polania et al, Human Brain Mapping 2011 M1 anodal + contralateral frontopolar cathodal stimulation shifted brain network connectivity at rest and especially during task performance tcs Outcomes: Network Effects Real (before vs after) Sham vs active Sham (before vs after) Gamma during voluntary hand movement

31 tcs Outcomes: Network Effects Beta Pre Post Polania et al, Human Brain Mapping 2011 M1 anodal + contralateral frontopolar cathodal stimulation shifted brain network connectivity at rest and especially during task performance

32 TMS Pulse TMS-EEG Magnetic Field Cortical Evoked Potentials Descending Volleys Motor Evoked Potentials P30 D I 1 I4 N µv 20 µv Peak-to-Peak Amplitude 50 ms 5 ms Latency 1 mv 20 ms 32

33 Inhibition, Connectivity, Plasticity, M1 Neural inhibition DLPFC Daskalakis, Farzan et al., 2008, Neuropsychopharmacology Interhemispheric connectivity Markers ISP MC Voineskos*, Farzan *et al., Biological Psychiatry ISP DLPFC Markers LICI MC LICI DLPFC Inhibition mediated modulation of oscillations Motor Neural inhibition Farzan et al., 2013, NeuroImage DLPF C Farzan et al., 2009, Neuropsychopharmacology Markers LICI MCδ,LICI DLPFCδ LICI MCΘ,LICI DLPFCΘ LICI MCα,LICI DLPFCα LICI MCβ,LICI DLPFCβ LICI MC,LICI DLPFC Markers TEP Amp TEP Dur TEP Peaks TEP Power GMFA AMP GMFA Dur GMFA Peaks GMFA Power 33

34 TMS-EEG in extracting Markers of Health Farzan F et al., Frontiers in Neural Circuits,

35 tcs Outcomes: TMS-EEG Magnetic Field Cortical Evoked Potentials P30 N µv 50 ms Bai, 2017 Differential changes in tdcs-induced cortical excitability in MCS and VS.

36 tcs Outcomes: TMS-EEG Magnetic Field Cortical Evoked Potentials P60 P30 N µv 50 ms Hill, 2017 HD tdcs induced changes in P60.

37 EEG to Guide Stimulation Parameters When/Where/How Designing tcs+eeg Studies

38 EEG-Guided Input Location Faria 2012 EEG evaluation of a patient with continuous spike-wave discharges during slow-wave sleep allowed identification of a spike focus. Cathodal tdcs over the spike focus resulted in a significant decrease in interictal spikes

39 EEG-Guided Frequency of tacs Power Zaehle., 2012 EEG-Guided Frequency (Hz) Montage: Posterior tacs at individual alpha oscillations Resting EEG: Increase in alpha in parieto-central electrodes

40 F3 EEG-Guided P3 Input Time Fronto-Parietal Theta-Phase coupling during a delayed letter discrimination task Polania et al., 2012 Protocol: 6Hz tacs at 0 or 180 phase difference to frontal and parietal regions during task Result: Exogenously induced fronto-parietal theta synchronization (0 degrees) significantly improved visual memory-matching reaction times. Desyncronization (180 degree) deteriorated performance. Brain-Behavior Relationship: Evidence of causality of theta phase-coupling of distant cortical areas for cognitive performance in healthy humans

41 EEG-Guided tcs Cancelli et al, 2016 Simple ad hoc approaches achieved reasonable targeting for the case of a cortical dipole. Only 2 8 electrodes and no need for a model of the head Verified directly only for a theoretically localized source, but may be potentially applied to an arbitrary EEG topography. Can be applied to static (tdcs), time-variant (e.g., tacs, trns, tpcs), or closed-loop tes

42 EEG-Guided tcs Dmochowski, 2017 Optimal use of EEG for targeting tcs (e.g., determine montage) without making assumptions about the underlying source

43 Designing tcs+eeg Studies

44 Closed-Loop Studies in Animal Berenyi et al, 2012: In a rodent model of generalized epilepsy, detection of interictal spikes triggers TES, and aborts the spike-wave discharge bursts

45 Technical Issues Challenges: Record EEG (Rest/+Event) o Placement of EEG and tcs Electrodes o Current may be shunted through EEG electrodes o Stimulation artifact Stop EEG Apply tes Record EEG & Apply tes Stop tes Record EEG (Rest/+Event) tdcs: A DC drift and maybe rhythmic frequencies tacs: Rhythmic frequencies that coincide with the frequency of cortical oscillations

46 Previous Online Studies Faria et al., 2012 tdcs: Same kind of sintered AgCl electrodes for DC stimulation as for EEG recording Current delivered through Phoresor 850 current source 3 Anodes (Fp1, FpZ, FP1 electrodes shorted) 1 Cathode (CP5 electrodes) EEG: 24 Electrodes Ground and reference electrodes placed contralateral to the stimulation site on the mastoid area F

47 Record EEG Faria et al., 2012 Online Studies Record EEG & Apply tcs Artifact High frequency artifact in the neighborhood of cathode Small AC component with a 12Hz multiple period characteristics of the Phoresor 850 functioning Artifact correction can significantly remove the noise Artifact Correction Software package developed for removing gradient artifacts in the MRI environment Independent component analysis (ICA)

48 Online Studies Sehm et al., 2013 SEPs were recorded in the bore of the tdcs ring electrode. no tdcs-induced artifacts could be observed after the application of a standard EEG filter.

49 Online Studies Sehm et al., 2013 Noisy and Filtered Sensory Evoked Potentials

50 online studies Witkowski, 2016: tacs + MEG - Amplitude-modulated tacs using a carrier frequency well beyond the frequencies of interest (e.g. 220 Hz) and modulates the amplitude of the carrier frequency at the frequency of interest (e.g., 23 Hz). - Amplitude-modulated high-frequency tacs may enable the artefact-free assessment of the lower frequency of interest

51 TMS-EEG Signal Processing 51

52 Problems Amplifier Saturation Electrode Heating Eddy Current Capacitor Recharge Movement Capacitance Built up, Slow Decay Auditory Evoked Potentials Blinks Muscle SEP Somatosensory Solutions Pin-and-Hold High Sensitivity, Operational Range DC-Coupling, High Sampling Rate Small Pellet Electrodes Plastic interface Sensor placement Proper Setting in Biphasic Sensor-wire Arrangement Algorithmically Ear plugs, Play Noise Sham Algorithmically** Algorithmically** Algorithmically Subthreshold Control gry_eye_by_sawsa-d4meu5q.jpg Spatial topographies Homunculus1.jpg 52

53 Matthew Frehlich Masters of Engineering University of Toronto Frank Mei Postdoc Electrical Engineering TMS-EEG Software Development Sravya Atluri PhD Biomedical Engineering University of Toronto Nigel Rogasch, PhD Monash University, Australia Atluri et al., 2016, Frontiers in Neural Luis G. Dominguez Postdoc Physics 53

54 Atluri et al., 2016, Frontiers in Neural Matthew Frehlich Masters of Engineering University of Toronto Frank Mei Postdoc Electrical Engineering Nigel Rogasch, PhD School of Psychological Sciences and Monash Biomedical Imaging Monash University, Australia TMS-EEG Software TMSEEG App Sravya Atluri PhD Biomedical Engineering University of Toronto Luis G. Dominguez Postdoc Physics 54

55 RECAP Retrieved from: sfohrgxobi/rih4ndo37zi/aaaaaaaaag8/zws5cbfb3qi/ s320/married+couple+fighting.jpg TCS + EEG

56 Added Value of tcs+eeg EEG may tell us about: Excitability of cortical tissue; excitation/inhibition balance; brain state; the integrity of local and distributed networks. 1- Detailed understanding of the tcs-induced effect on neural activity o To not fall for the circular experimental results/conclusions o Examine both local and network effects in humans, non-invasively 2- Monitor brain state o Brain state influences the tcs effect o Improve tcs protocols considering brain state dynamics o By monitoring dynamical state, design closed-loop systems 3- Guide the tcs input parameters o An infinite number of stimulation parameters to choose from o Guide the Location, Stimulation Parameters, Time of Delivery More efficacious treatments Better understanding of brain-behavior relationship

57 EEG Added Value Summary Different Approaches (Online, Offline, Guided) Online Approach is Becoming Possible (Easier for tdcs than tacs)