1. 1 Transcranial Direct Current Stimulation (tDCS): a new old tool in neurotherapy Kropotov Juri D. Institute of the Human Brain of Russian Academy of Sciences, St.-Petersburg, Russia Norwegian University for Science and Technology (NTNU), Trondheim, Norway Conjunct COST B27 and SAN Scientific Meeting, Swansea, UK, 16-18 September 2006

2. 2 Our Staff Chutko Leonid, MD, PhD, St. Petersburg, Russia – neurological assessment and making tDCS Jan Brunner, Trondheim, Norway – neuropsychological assessment and making tDCS Saraev Sergei, MD, St. Petersburg, Russia – making tDCS Kropotov Juri, Dr., professor, – developing behavioral tasks and methods of analysis

3. 3 Institute of the Human Brain of Russian Academy of Sciences Located 200 meters from the laboratory where Ivan Pavlov carried out his famous research on conditioned reflexes at the beginning of 20th century.

4. 4 Pavlov was the first who suggested an objective method to study the physiological basis of psychological processes. ‘I am very glad that together with Ivan Mikchailovich Sechenov and a regiment of my dearest co-workers we acquired the whole animal organism but not a part of it for the mighty power of the physiological researches. And this is entirely our, Russia merit which cannot be challenged by the world science and human thought’ I.P.Pavlov, 1934

5. 5 Part 1. Method

6. 6 Transcranial Direct Current Stimulation (tDCS) Galvani’s nephew Giovanni Aldini in 1804, reported the successful treatment of patients suffering from melancholia by applying galvanic currents over the head. Many other researchers over the past two centuries made extensive use of galvanic current for the treatment of mental disorders, with variable results. During the last 5 years the interest to Direct Current Stimulation returned. This renaissance is partly associated with a search for alternative (non- pharmacological) methods of brain stimulation.

7. 7 Method of tDCS A constant direct current (DC) (i.e. a flow of electric charge that does not change direction) polarizes (changes membrane potentials of cells) tissues and, sometimes, called polarization technique. DC is applied to the brain by means of two electrodes: the one is an active electrode, localized on the effective site, and the other is a reference electrode, localized on some “silent” part of the body. The electric current is provided by a battery driven device.

8. 8 History (events in Russia) 1960-70 th – polarization technique in patients with implanted electrodes for transient “switching off” target structures in stereotactic neurosurgery (Institute of experimental medicine, Leningrad, USSR, Bechtereva et al.). 1970-80 th – experiments with polarizing brain tissues of animals (cats, dogs). It was found that anodal current activates neurons, while cathodal current inhibits them (IEM, Leningrad, Galdinov et al.). 1980 th - polarization methods are used in clinics for treatment neurological and psychiatric patients (IEM, Leningrad, Vartanian et al.). >2000 – polarization methods are widely used with good success in correcting behavior of ADHD children and for treatment of mentally retarded children (Institute of the human brain, St. Petersburg, Chutko, Kropotov et al.,)

9. 9 Electrophysiology of polarization induced by direct current Two electrodes (positive and negative) on the scalp produce an electric current. A part of the electric current passes through the cortex. The current under the anode electrode induces a lack of positive ions at the basal part of neuronal membrane. This induces depolarization of this part of the membrane. The excitability of the neuron increases and the frequency of the background activity increases. The net effect is anodal activation of neurons. Vice versa, the current under the cathode electrode induces an excess of positive ions near the external part of the basal membrane. This induces hyperpolarization of this part of the membrane. The excitability of the neuron decreases and the frequency of the background activity decreases. The net effect is cathodal suppression of neurons. Hyperpolarization inactivates Ca and Na channels. Depolarization activates these channels.

10. 10 Three states of voltage-gated cation channel The resting closed channel state (upper left panel) is activated by membrane depolarization that causes a fast transition to the open state (upper right). Due to an intrinsic inactivation as present in Na+ and Ca2+ channels and also in some K+ channels, the channel closes (lower panel) from which it reopens very rarely. Repolarization of the membrane leads to recovery from the inactivated (refractory) state back to the resting state (upper left) from which activation is again possible. Note that transition from the resting to the inactivated state is also possible without channel opening, particularly during slow depolarization (socalled accommodation).

11. 11 Part 2. Behavioral patterns

12. 12 Indirect support of the theory: subjective responses of normal subjects DC passed through two frontal electrodes and one electrode over the right knee. DC = up to 0.5 mA. Subjects - 32 normal subjects. Scalp anodal currents induced an increase in alertness, mood and motor activity, whereas cathodal polarization produced quietness and apathy. Lippold OC, Redfearn JW. Mental changes resulting from the passage of small direct currents through the human brain. Br J Psychiatry 1964; 110:768–72. DC stimulation over the occipital cortex. DC= 7 min, 1 mA, electrode area 35 cm 2. 15 normal subjects. Although anodal DC failed to induce changes in contrast sensitivities, they were significantly decreased during and immediately after cathodal DC. Antal A, Nitsche MA, Paulus W. External modulation of visual perception in humans. Neuroreport 2001;12:3553–5.

13. 13 Anodal tDCS of prefrontal cortex enhances working memory The experimental protocol design. Each subject was tested during sham and active stimulation. The two tests runs were randomized within subject and the order active versus sham stimulation) was counterbalanced across subjects. Anode was placed over F3. Cathode – over the contralateral supraorbital area. 1 mA during 10 minutes. Fregni et al., 2005 The sequence of the 3-back letter working memory paradigm. Note that subjects were required to respond (key press) if the presented letter was the same as the letter presented three stimuli previously.

14. 14 Anodal tDCSof prefrontal cortex enhances working memory Number of correct responses during each stimulation condition (active and sham). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. Fregni et al., 2005

15. 15 Indirect support of the theory: subjective responses of patients Anodal scalp DC improved the mood in depressed patients. Costain R, Redfearn JW, Lippold OC. A controlled trial of the therapeutic effects of polarization of the brain in depressive illness. Br J Psychiatry 1964;110:786–99. Ramsay JC, Schlagenhauf G. Treatment of depression with low voltage direct currents. South Med J 1966;59:932–6.

16. 16 Effect of tDCS on behavioral scores of ADHD Anode was placed over F8. Cathode – over Fp2. Current=0.7-1.0 mA. Duration 20 minutes. Electrode area around 4 cm 2. 2-3 days between sessions. 7 sessions. 12 right handed ADHD children. Saraev, Kropotov, Ponomarev, 2002

17. 17 tDCS during Sleep Procedure of the Sleep experiment. Time points of learning and recall of the memory tasks (PAL, MT), psychometric tests (d2, EWL, PANAS), tDCS, blood sampling (arrows), period of lights off (horizontal black bar), and sleep, represented by the schematized hypnogram, are indicated. W, Wake; 1– 4, sleep stages 1– 4; vertical black bar, REM sleep. Marshal et al., 2005

18. 18 tDCS during Sleep improves Declarative Memory Memory performance on the PAL and MT tasks across retention periods of sleep during which either tDCS (hatched bar) or placebo stimulation (white bar) was applied. Marshal et al., 2005

19. 19 Part 3. Changes of excitability measured by TMS

20. 20 Excitability of the motor cortex measured by TMS Surface electromyography was used to record MEPs in the relaxed FDI muscle. Changes in motor cortical excitability were probed using single-pulse TMS. Monophasic pulses were given to the left M1- HAND using a high-power Magstim 200 stimulator (Magstim Company) and a standard figure-of-eight coil, with external loop diameters of 9 cm.

21. 21 Direct evidence: using transcranial magnetic stimulation (TMS) to measure cortical excitability Scalp DC stimulation (for 5 min at 1 mA) in 19 subjects. The after-effects of scalp DC on motor potentials evoked by TMS. The Y-axis is the size of the conditioned motor potential expressed as a ratio with the control unconditioned response, error bars are standard errors. *P, 0:05, paired t-test. Note that after cathodal scalp DC excitability decreased whereas after anodal scalp DC the size of the test evoked response increased in size. Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000;527.3:633–9.

22. 22 Specificity of the tDCS Rapidly induced effects of weak DC stimulation on the size of the motorevoked potential (MEP) in the right abductor digiti minimi (ADM) muscle, revealed by transcranial magnetic stimulation (TMS), using the motor cortex—contralateral forehead arrangement (A). The lack of effect using other diverse electrode positions (B). Normalised MEP amplitudes during stimulation are divided by normalised MEP amplitudes without stimulation. Nitsche, Paulus, 2000

23. 23 Longer anodal DC prolongs aftereffects up to 90 minutes To produce longer effects 1mA currents must be applied for longer durations: anodal current during 13 minutes and cathodal current during 9 minutes. In our studies we used 20 min of 0.6-1.0 mA currents for therapeutical effects.

24. 24 Part 4. Role of ion channels

25. 25 Sodium and calcium channels blockers decrease anodal intra- tDCS effects Anodal intra-tDCS effects are abolished by sodium channel blockers and are significantly suppressed by calcium channel blockers. Cathodal effects remain the same. Nitsche et al., 2003

26. 26 Sodium channel blocker abolishes post-effects of anodal tDCS Blocking sodium channels with the aid of the voltage- dependently acting CBZ resulted in complete abolition of the prolonged excitability enhancement caused by anodal tDCS in the PLC condition. Asterisks indicate significant differences between the drug conditions regarding identical current conditions and time points. Nitsche et al., 2003

27. 27 Calcium channel blocker abolishes post-effects of anodal tDCS Blocking calcium channels with the aid of FLU resulted in complete abolition of the prolonged excitability enhancement caused by anodal tDCS in the PLC condition. Nitsche et al., 2003

28. 28 NMDA receptor antagonist abolishes post-effects of both anodal and cathodal tDCS Blocking NMDA receptors abolished any after-effect caused by prolonged tDCS, thus favouring a prominent role of this receptor in the evolvement of neuroplastic effects induced by tDCS. Note that NMDA receptors are responsible for long term potentiation and depression – neuroplastic cortical mechanisms. Nitsche et al., 2003

29. 29 Part 5. Effect on EEG/ERPs

30. 30 Effect of tDCS on beta EEG power tDCS = 10 min. Active electrode was place at Cz, “passive” at 6 cm left to Oz. Current 1 mA. Y axis the normalized beta power values measured at Fz. Antal et al., 2004

31. 31 QEEG mapping accurately reflects local brain function Methods: EEG mapping was performed simultaneously with H 2 15 O PET scanning in 6 normal adult subjects, both at rest and during a simple motor task. EEG data were processed using 3 different montages; two EEG power measures (absolute and relative power) were examined. Results: Relative power had much stronger associations with perfusion than did absolute power. In addition, calculating power for bipolar electrode pairs and averaging power over electrode pairs sharing a common electrode yielded stronger associations with perfusion than data from referential or single source montages. I.A. Cook et al. / EEG and clinical Neurophysiology 107 (1998) 408–414 Relationship between local PET perfusion values and EEG for different montages and EEG measures. Statistical significance is indicated by horizontal lines representing the magnitude at which a correlation coefficient attains significance: solid line for P  0.05; large dashed line for P  0.05; fine dashed line for P  0.001.

32. 32 Effect of tDCS of sensorimotor cortex on somatosensory ERPs SEPs were elicited by electrical stimulation of right or left median nerve at the wrist before and after anodal or cathodal tDCS in 8 healthy subjects. tDCS was applied for 10 min to the left motor cortex at a current strength of 1 mA (reference electrode was placed above the contralateral orbit). Amplitudes P22/N30 (frontal component) following right median nerve stimulation were significantly increased for at least 60 min after the end of anodal tDCS, There was no effect on SEPs evoked by left median nerve stimulation. Cathodal tDCS had no effect on SEPs evoked from stimulation of either arm. Matsunaga et al., 2004

33. 33 Decrease of averaged coherence in alpha band in ADHD children Left: averaged coherence in normal population. Note a strong maximum of coherency in frontal areas. Right: averaged coherence in ADHD population. No frontal increase of coherency is found. Bottom: difference ADHD – Norms Kropotov et al., in preparation

34. 34 Effect of tDCS on EEG coherence in ADHD Average coherence was computed for each electrode for 8-12 Hz. EC condition, 2 minutes. Maps of this coherence values are presented for EEG recordings made before and after tDCS. Note the the coherence values became normal. Saraev, Kropotov, Ponomarev, 2002

35. 35 Part 6. PET studies

36. 36 PET studies Panel A illustrates the experimental design. Subjects were divided into two groups of eight and received Real-tDCS (anodal or cathodal) and Sham-tDCS on separate days. Immediately afterwards six sequential H15 2 O-PET scans were acquired at rest (R) or during finger movements (M). The order of intervention (RealtDCS vs. Sham-tDCS) and experimental conditions (R vs. M) were counterbalanced across subjects. Panel B illustrates the technique used for tDCS. Weak direct current (1 mA) was applied between two large (35 cm2), wet sponge-electrodes placed over left M1 (optimal representation of right FDI as assessed with TMS) and right frontopolar cortex (above the eyebrow). Polarity of tDCS refers to the M1 electrode. Panel C illustrates the motor task performed by the subjects during PET scanning. Subjects were required to freely select from a set of four previously practised movements and execute brisk flexion movements with fingers II–V of their right hand. They were asked to make a fresh choice on each trial, regardless of previous moves. Movements were paced every 2 s to ensure a constant movement rate across scans. Lang et al., European Journal of Neuroscience, Vol. 22, pp. 495–504, 2005

37. 37 Changes in movement related activity Surface rendering of those voxels showing enhanced movement related activity in left dorsal premotor cortex (PMd) after cathodal tDCS (red area; P < 0.001; uncorrected). The graph (left panel) plots the relative changes in rCBF among the four experimental conditions regarding after effects of cathodal tDCS. Lang et al., European Journal of Neuroscience, Vol. 22, pp. 495–504, 2005

38. 38 Main effect of anodal and cathodal tDCS compared to sham Surface rendering of brain regions showing a relative increase or decrease rCBF after real-tDCS compared to sham tDCS (P < 0.05, whole-brain corrected). Images show (from the top) right lateral surface, left lateral surface, right medial surface, and left medial surface. Note that anode tDCS produces increase of LBF in the motor area, while cathode tDCS produces decrease of LBF in the corresponding area. Note, that widespread areas are involved in tDCS effects. neuroimaging. tDCS is an effective method of inducing lasting changes in synaptic excitability, but the spatial pattern of induced functional interactions may be more complex than previously thought. The specific patterns of regional effects may depend critically on the placement of electrodes over the scalp and on inhomogeneities of electrical conductivity of the skull, cerebrospinal fluid and brain tissue. Lang et al., European Journal of Neuroscience, Vol. 22, pp. 495–504, 2005

39. 39 Part 7. Application for rehabilitation of stroke patients

40. 40 Experimental design (A) Patients participated in three sessions. In the first session, they familiarized themselves with the JTT (Jebsen–Taylor Hand Function Test)and reached a stable level of performance. The second and third sessions started with questionnaires followed by baseline determinations of JTT (JTT1–3), cortical stimulation (tDCS) or Sham in a counterbalanced double-blind design and later by post-intervention JTT (JTT4–6), with JTT4 determined during stimulation and JTT5–6 after stimulation. Questionnaires (Q) in which patients characterized (self-report on visual analogue scales) level of attention and fatigue during the experiment were given at four different times in each session. A fourth session was included later to test the effects of tDCS on motor cortical function tested with TMS. (B) Subtests of the JTT (Jebsen et al., 1969) included: turning over cards, picking up small objects and placing them in a can, pick up beans with a tea spoon, placing them in a can (mimicking a feeding function), stacking chequers, moving large light cans, and moving heavy cans. Hammel et al., 2005

41. 41 Design of tDCS tDCS was delivered through two gel-sponge electrodes (TransQE; IOMED1, Salt Lake City, UT, USA; surface area 25 cm2) embedded in a saline-soaked solution. The anode was positioned on the projection of the hand knob area (Yousry et al., 1997) of the primary motor cortex of the affected hemisphere on the patient’s scalp, and the cathode on the skin overlying the contralateral supraorbital region. The hand knob area of the motor cortex was first identified on each patient’s MRI and then co- registered to the scalp using a frameless neuronavigation system (Brainsight1; Rogue Research Inc., Montreal, Canada). Stimulating electrodes were centred on the projection of this anatomical site on each patient’s scalp. Anodal tDCS was delivered for 20 min in the tDCS session and for up to 30 s in the Sham session using a Phoresor1 II Auto (Model No. PM850; IOMED1). At the onset of both interventions (tDCS and Sham), current was increased in a ramp-like fashion (Nitsche et al., 2003a) eliciting a transient tingling sensation on the scalp that faded over seconds, consistent with previous reports (Nitsche et al., 2003c). Current (1 mA) remained on for 20 min in the tDCS session and for up to 30 s in the Sham session. In both sessions, currents were turned off slowly over a few seconds, a procedure that does not elicit perceptions (Nitsche et al., 2003c) and that was implemented out of the field of view of the patients. The investigator testing motor function (JTT) and the patients were blind to the intervention (tDCS or Sham), which was administered by a separate investigator who did not participate in motor testing or data analysis. Hammel et al., 2005

42. 42 Effects of tDCS/Sham on motor performance JTT total time in the familiarization session (displayed in both A and B for comparison), at baseline (JTT1–3), during and following (JTT4–6) and >9 days after tDCS (A) and Sham (B). Note that patients reached stable JTT performance during the initial familiarization session that was comparable to JTT1–3 baseline levels in Sessions 2 and 3. Additionally, half of the patients did tDCS first and half did Sham first. tDCS (A, asterisk) but not Sham (B) resulted in shorter total times (JTT4–6) relative to baseline (JTT1–3). Performance improvements that appeared during tDCS, persisted beyond the stimulation period for at least 25 min (A, inset) and returned to baseline levels days later (JTT7). Hammel et al., 2005

43. 43 tDCS and sham in patients with neglect ERPs before after all sessions of tDCS Comparison to the normative data are presented before (top) and after 7 tDCS sessions. Current = 250 mcA, duration = 20-40 minutes, anode – P4, cathode – P3. The deviations from normality reflects a compensatory mechanism of the brain The compensation is getting stronger after tDCS The study was made in the Rehabilitation Center of St. Olav’s Hospital of NTNU in Monkvol, Trondheim, Norway.

44. 44 Amplitude spectra before after all sessions of tDCS Spectra before and after all sessions of tDCS are superimposed on each other. Decrease of amplitude is depicted in blue. Map of the difference (after-before) is presented below. Note a decrease of alpha power at the right side, including the area where anode was located.