1. CORTICAL STIMULATION IN APHASIA Richard L. Harvey, MD Rehabilitation Institute of Chicago, Chicago, USA Northwestern University, Feinberg School of Medicine, Chicago, USA

2. LANGUAGE NETWORK Left Hemisphere Right Hemisphere

3. Hickok & Poeppel 2007

4. STROKE

5. Three phases of language reorganisation Saur D et al. Brain 2006;129:1371-1384

6. 9/2/11 2 A Neural Interface for Artificial Limbs: Targeted Muscle Reinnervation INTERHEMISPHERIC INHIBITION IN LANGUAGE Theory: Rebalancing cortical excitability may improve outcome High freq. rTMS Anodal tDCS Intermittant TBS Low freq. rTMS Cathodal tDCS Continuous TBS

7. Naeser MA, et al. Brain and Language. 2005; 93:95-105 LOW FREQUENCY RTMS TO NON-INJURED HEMISPHERE 4 chronic stroke patients with non-fluent aphasia

8. LOW FREQUENCY RTMS TO NON-INJURED HEMISPHERE  1 Hz rTMS to right pars triangularis  20 minute sessions  5 days a week for 2 weeks (10 sessions)  Outcome Boston Diagnostic Aphasia Examination Boston Naming Test Snodgrass and Vanderwart Picture Naming

9. Naeser MA, et al. Brain and Language. 2005; 93:95-105 LOW FREQUENCY RTMS TO NON-INJURED HEMISPHERE

10. Naeser MA, et al. Brain and Language. 2005; 93:95-105 LOW FREQUENCY RTMS TO NON-INJURED HEMISPHERE

11. Naeser MA, et al. Brain and Language 2011; 119: 206-213 OPTIMAL STIMULATION SITE FOR RTMS RIGHT HEMISPHERE

12. Naeser MA, et al. Brain and Language 2011; 119: 206-213

13. OPTIMAL STIMULATION SITE FOR RTMS RIGHT HEMISPHERE Naeser MA, et al. Brain and Language 2011; 119: 206-213

14. Naeser MA, et al. Arch Phys Med Rehabil.2012; 93:S26-S34 CRITICAL ROLE OF PARS OPERCULARIS IN APHASIA RECOVERY

15. LOW FREQUENCY RTMS TO NON-INJURED HEMISPHERE  Randomized double-blind study  N=12  1 Hz rTMS to right pars triangularis vs sham stimulation  20 minute session  5 days a week for 2 weeks (10 sessions)  Outcome Boston Diagnostic Aphasia Examination Boston Naming Test Snodgrass and Vanderwart Picture Naming  Results showed improved picture naming, spontaneous speech and auditory comprehension in intervention group persisting at 2 months post-treatment Barwood CH, et al. Eur J Neurol. 2011; 18: 935-943.

16. INDIVIDUALIZED RTMS THERAPY – BASED ON LANGUAGE DOMINANCE Kakuda et al. Int J Neurosci. 2010; 120: 60-66

17. INDIVIDUALIZED RTMS THERAPY  10 sessions of 1200 pulses 1 Hz rTMS to homologous region of maximal activation over 2 weeks.  Scores improved in all four patients on the following measures: Western Aphasia Battery (WAB) Standard Language Test of Aphasia (SLTA, SLTA-ST)  Benefits persisted for 4 weeks

18. HIGH FREQUENCY RTMS FOR APHASIA  Chronic stroke patients with moderate to severe aphasia  N=8  10 sessions over 2 weeks  Excitatory theta-burst stimulation (iTBS) to brocas area.  6 of 8 patients showed improved verbal fluency (semantic fluency test; p=0.028)  Subjects showed a shift in signal toward left hemisphere (LI change sig. p=0.018) Szaflarski JP, et al. Med Scit Monitor. 2011; 25: 132-139

19. HIGH FREQUENCY RTMS FOR APHASIA

20. tDCS APPLICATION

21. TRANSCRANIAL DIRECT CURRENT STIMULATION FOR APHASIA  Chronic non-fluent aphasic patients  N=8  4 patients received anodal tDCS and sham tDCS over left fronto-temporal region in random order with one week apart.  4 patients received cathodal tDCS and sham tDCS similarly  Outcome Picture naming Monti A et al. J Neurol Neurosurg Psychiatry 2008;79:451-453

22. TRANSCRANIAL DIRECT CURRENT STIMULATION FOR APHASIA Monti A et al. J Neurol Neurosurg Psychiatry 2008;79:451-453

23. ANODAL TDCS ON OVER INJURED LEFT HEMISPHERE WITH NAMING PRACTICE  Chronic fluent aphasia  N=8  Anodal tDCS targeted to perilesional (left) brain areas showing greatest activation on pre-treatment fMRI during naming task  5 sessions daily over a week with A tDCS and 5 sessions with Sham separated by 3 weeks  Treatment combined with computerized naming practice  Outcome: pre-, post-, and 3 weeks post Trained naming task Untrained naming task Fridriksson J et al. Stroke. 2011;42:819-821

24. Reduction in RT after A-tDCS (light gray) and S-tDCS (dark gray). Fridriksson J et al. Stroke. 2011;42:819-821 ANODAL TDCS ON OVER INJURED LEFT HEMISPHERE WITH NAMING PRACTICE

25. TDCS WITH APHASIA THERAPY  Chronic Non-Fluent Aphasia  N=12  Randomized to anodal, cathodal or sham stimulation  Randomization stratified by severity of aphasia Less severe aphasia (AQ>55)  2 subjects receive anodal stimulation  2 subjects receive cathodal stimulation  2 subjects receive sham stimulation More severe aphasia (AQ<55)  2 subjects receive anodal stimulation  2 subjects receive cathodal stimulation  2 subjects receive sham stimulation

26. TREATMENT PROCEDURES

27. 5-point gain on WAB AQ and LQ and a 12-point gain on CETI are considered to be clinically significant. Note the increase in WAB scores between post-treatment and f/up for anodal and cathodal groups – which contrasts with decline for sham group

28. MEAN PERFORMANCE ON TRAINED PROBES (ORAL READING OF SENTENCES - % ACCURACY)

29. MEAN PERFORMANCE ON TRAINED PROBES (ORAL READING OF SENTENCES – RATE WPM)

30. IMPLANTED HIGH FREQUENCY EPIDURAL STIMULATION COMBINED WITH SPEECH THERPAPY  8 subjects with non-fluent aphasia  Six weeks of intensive daily aphasia therapy for all subjects  Four subjects received implants and epidural cortical stimulation during therapy (50Hz, 6.5mA or 50% of motor threshold, 3s pulse train)  Raters blinded (all subjects had head covers) Randomization Control Arm (4 subjects) Investigational Arm (4 subjects) Device Implant Rehab w/o Stimulation 6 & 12 Wk Follow-Up Post Tx Assmnt Device Removal Post Tx Assmnt Rehab and Stimulation Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

31. IMPLANTED EPIDURAL CORTICAL STIMULATOR fMRI used to identify activation site Epidural electrode (2x3 grid; 2.6 x 2.7 cm) placed over cortical target indicated by fMRI (ventral precentral gyrus) Implantable pulse generator Overnight hospital stay Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

32. ANATOMIC LOCALIZATION OF STIMULATION SITE Activation in ventral portion of precentral gyrus or sulcus Intersection between 1.imitation and observation tasks OR 2. imitation and oral reading tasks Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

33. KEY OUTCOME MEASURES  Safety  Endpoints Primary Endpoint after 6 Weeks of Therapy Secondary Analysis at 6 and 12 Weeks Post Therapy  Primary Outcome Measure Western Aphasia Battery (WAB-AQ)  Secondary Outcome Measures Other measures of Speech-Language Impairment Discourse measures (Language sample analyses) Quality of Life Measures  CETI  ASHA Quality of Communication Life Scale fMRI Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

34. SAFETY OUTCOMES  No occurrences of wound infection  Post-operative pain well tolerated  No seizures occurred  Neurological function remained stable (NIH Stroke scale; Box and Blocks; subtests of the Behavioral Inattention Test) Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

35. RESULTS 35 Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

36. OUTCOMES BY SEVERITY Mild-moderate Moderate Moderate-Severe Severe Cherney LR, et al. J Neurol Neurosurg Psych. 2010; 81:1014-1021

37. CONCLUSIONS  Cortical stimulation (CS) has the potential to improve language function post stroke  Both non-invasive and invasive CS may improve long- term language function when combined with speech therapy training  CS targets include sites in both left and right hemisphere and optimal stimulation site may be patient specific  rTMS, tDCS and Epidural stimulation each have advantages and disadvantages  Large, well designed clinical trials are warreted.