1. Noninvasive Brain Stimulation in the Investigation and Treatment of Neglect Roy Hamilton, MD, MS Laboratory for Cognition and Neural Stimulation University of Pennsylvania

2. Topics Challenges in investigating and treating neglect Induction of neglect-like effects with brain stimulation Interhemispheric interactions in neglect Therapy with brain stimulation

3. Clinical impact of neglect Failure to report, respond, or orient to meaningful or novel stimuli on the contralesional side of space. Up to 2/3 of right hemisphere stroke patients acutely. Poor prognostic indicator: –More limited mobility –Longer hospitalizations –Increased long-term functional disability –Increased family burden

4. Challenges of treating chronic neglect No established treatment Sensory stimulation techniques (e.g. caloric, vestibular, mechanical, or electrical stimulation, prisms) have drawbacks. –Short duration of benefit –Many techniques are uncomfortable

5. Challenges of treating chronic neglect Some paradigms show specific behavioral improvements, but don’t generalize to everyday settings. Effective approaches grounded in the neural basis of neglect are lacking.

6. Challenges of investigating neglect Practical problems Varied phenomenology –Distribution, means of eliciting, & input/output demands –Symptoms vary over time (Hamilton et al., 2008) Large lesions/imprecise localization Frequently short-lived symptoms

7. Challenges of investigating neglect What would be helpful? Experimental models that accurately replicate symptoms Approaches with anatomic specificity Safe, effective, & noninvasive interventions

8. By inducing lateralized deficits of attention or action in healthy individuals, noninvasive brain stimulation can be used to further elucidate the neural mechanism of neglect. Noninvasive brain stimulation as a model of neglect

9. rTMS induces neglect symptoms in animals Valero-Cabre et al., 2006

10. tDCS induces neglect symptoms in animals Schweid et al., 2008

11. Right parietal TMS disrupts visuospatial perception 9 healthy subjects Forced-choice estimation of bisected line-segments Right parietal (P6) and frontal (F4) single- pulse TMS at 115% MT Rightward bias only with parietal TMS 150 ms after stimulus presentation Fierro et al., 2001

12. TMS studies further implicate the right parietal cortex Inhibition of left target detection –Muggleton et al., 2006 Inhibition of visual exploration –Nyffeler et al., 2008 Right temporoparietal junction TMS induces hemiextinction –Meister et al., 2006 Muggleton et al., 2006

13. TMS studies further implicate the right parietal cortex Inhibition of left target detection –Muggleton et al., 2006 Inhibition of visual exploration –Nyffeler et al., 2008 Right temporoparietal junction TMS induces hemiextinction –Meister et al., 2006 Nyffeler et al., 2008

14. TMS studies further implicate the right parietal cortex Inhibition of left target detection –Muggleton et al., 2006 Inhibition of visual exploration –Nyffeler et al., 2008 Right temporoparietal junction TMS induces hemiextinction –Meister et al., 2006 Meister et al., 2006

15. Subsets of neglect symptoms maybe dissociable using TMS Input vs. Output Demands Cannot Attend Cannot Act AttentionalIntentional

16. Substrates of neglect symptoms can be dissociated using TMS Apparatus F4 (middle frontal gyrus) & P6 (interparietal sulcus) Brief trains (5-sec at 5 Hz); MT + 15% Simultaneous with stimulus presentation Stimuli TMS Ghacibeh et al., 2007 Parietal TMS Attentional: –Screen Normal: Skew right –Screen Reversed: Skew left Frontal TMS Intentional: –Screen Normal: Skew right –Screen Reversed: Skew right Predictions Adapted from Na et al., 2007

17. Substrates of neglect symptoms can be dissociated using TMS Ghacibeh et al., 2007

18. Interhemispheric interactions likely play an important role in the phenomenology and treatment of neglect. Interhemispheric inhibition and neglect

19. Transcallosal inhibitory connections may subserve rival networks between the two hemispheres, the dynamic balance of which permits normal redirection of attention. (Kinsbourne, 1977)

20. Interhemispheric inhibition and neglect Two-lesion case studies Sprague (1966): Neglect from cortical lesion can be reversed by contralateral superior colliculus lesion. Vuilleumier et al. (1996): In humans with one lesion, a contralateral second lesion may attenuate neglect.

21. Manipulation of interhemispheric imbalance affects visuospatial attention Dambeck et al., 2006 Unilateral parietal single-pulse TMS impairs contralateral target detection. Biparietal TMS induced no change. Analogous to two-lesion studies.

22. Therapeutic modulation of interhemispheric connections Fregni & Pascual-Leone (2007)

23. Contralesional TMS attenuates neglect 5 subjects with neglect (3 right brain injury; 2 left brain injury) Stimulation over right and left parietal cortex 10 pulses of TMS at 25 Hz, synchronous with stimuli Oliveri et al., 2001

24. Extended rTMS may lead to sustained improvement 3 patients; right brain injury with neglect rTMS to left parietal cortex –900 Pulses –1 Hz (inhibitory) –Every other day x 2 weeks Improvement persisted 15 days after completing TMS Pre-rTMSPost-rTMS Brighina et al., 2003

25. Extended rTMS may lead to sustained improvement 14 Patients: 7 treatment, 7 control 0.5 Hz, 90% MT, 15 min, twice daily x 2 weeks Left P3 stimulated Testing 2 weeks prior, start of treatment, end of treatment, and two weeks later No control site, task, or sham Line Cancellation Line Bisection Song et al., 2009

26. Two chronic neglect patients Six rTMS sessions over two weeks 900 pulses to P5 per session 0.9 Hz, 95% MT Behavioral Inattention Test (BIT) administered at baseline, 2, 4, and 6 weeks. Extended rTMS may lead to sustained improvement Shindo et al., 2006 Subject 1Subject 2

27. Reduction of parietal hyperexcitability correlates with behavioral benefit Koch et al., 2008 Twin-coil TMS test of PPC-M1 influences. 12 RH patients with neglect, 10 without, 8 healthy controls MEP amplitude after conditioning pulse correlated with neglect severity.

28. Reduction of parietal hyperexcitability correlates with behavioral benefit Koch et al., 2008 MEP amplitude in neglect patients reduced after 600 pulses of 1 Hz TMS (90% MT) Stimulation of right PPC also temporarily improved neglect symptoms of visual chimeric test (Sarri et al., 2006)

29. Improved visual scanning after parietal tDCS Line-Bisection Shape-unstructured cancellation Letter-structured cancellation 15 patients with subacute neglect Anodal stimulation 2.0 mA x 20 minutes; sham controlled Right posterior parietal cortex stimulated Ko et al., 2008

30. Fregni & Pascual-Leone (2007) Improved visual scanning after parietal tDCS

31. Line-Bisection Shape-unstructured cancellation Letter-structured cancellation 15 patients with subacute neglect Anodal stimulation 2.0 mA x 20 minutes; sham controlled Right posterior parietal cortex stimulated Ko et al., 2008

32. Future directions? Focal stimulation to achieve improvement of specific neglect symptoms Combining stimulation with therapy +

33. Summary Neglect, a condition affecting many patients with right hemisphere stroke, is associated with poor outcomes and is frequently resistant to currently- used treatments. Interhemispheric interactions may play a key role in both the emergence of neglect after stroke and the potential to treat it by manipulation of contralesional cortical activity. Administration of low-frequency rTMS to the left parietal cortex and anodal tDCS to the right parietal cortex have been associated with improvement in neglect symptoms.