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Potentials & Perspectives of repetitive sensory stimulation in stroke rehabilitation 0 100 80 60 40 20 0 0,5 1 1.5 2 2.5 3 Hubert Dinse Institut für Neuroinformatik - Neural Plasticity Lab - Ruhr-Universität Bochum hubert.dinse@neuroinformatik.rub.de

rationale for using sensory stimulation effects in healthy populations effects in patient populations future work 100 80 60 40 20 0 0 0,5 1 1.5 2 2.5 3

restoration of function through neuroplasticity mechanisms training & massed practice

restoration of function through neuroplasticity mechanisms Alternatives: targeted brain activation

how to induce plasticity and learning? humans training

how to induce plasticity and learning? humans training cells/synapses repetitive stimulation (spatio-temporal constraints)

how to induce plasticity and learning? humans training cells/synapses repetitive stimulation (spatio-temporal constraints) humans repetitive stimulation (spatio-temporal constraints)

Nomenclature co-activation repetitive sensory stimulation passive stimulation exposure-based learning peripheral high-frequency stimulation peripheral nerve stimulation Conforto AB, Kaelin-Lang A, Cohen LG (2002) Ann Neuro 51: 122 Celnik P, Hummel F, Harris-Love M, Wolk R, Cohen LG (2007) Arch Phys Med Rehabil 88: 1369 Dinse HR, Kalisch T, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M (2005) Transaction Appl Perc 2: 71 Gutnisky DA, Hansen BJ, Iliescu BF, Dragoi V (2009) Curr Biol 19: 555 Johansson BB, Haker E, von Arbin M, Britton M, Långström G, Terént A, Ursing D, Asplund K (2001) Stroke 32: 707 Kalisch T, Tegenthoff M, Dinse HR (2009) Front Neurosci 3: 96 Ng SS, Hui-Chan CW (2007) Stroke 38: 2953 Sawaki L, Wu CW, Kaelin-Lang A, Cohen LG (2006) Stroke 37: 246 Wu CW, Seo HJ, Cohen LG (2006) Arch Phys Med Rehabil 87: 351 Yavuzer G, Oken O, Atay MB, Stam HJ (2007) Arch Phys Med Rehabil 88: 710

Relation between reorganization & tactile perception tactile co-activation on right index-finger spatial 2-point discrimination Cortical activation: BOLD signals pre 3 h coactivation discrimination improvement [post - pre] (r=0.724; p=0.018) normalized SI enlargement [post - pre] Pleger, Foerster, Ragert, Dinse, Schwenkreis, Nikolas,Tegenthoff (2003) Neuron

Relation between reorganization & tactile perception tactile co-activation on right index-finger spatial 2-point discrimination Cortical activation: SEP recording and electric source localization placebo memantine amphetamine post pre medio-lateral shift [mm pre-post] 12 8 4 0-4 0 0.1 0.2 0.3 0.4 0.5 discrimination improvement [post - pre] memantine placebo amphetamine Dinse, Ragert, Pleger, Schwenkreis, Tegenthoff (2003) Science

Relation between reorganization & tactile perception tactile co-activation on right index-finger spatial 2-point discrimination Cortical excitability: SEPs after median nerve paired-pulse stimulation pre 3 h coactivation decrease in paired pulse suppression (post-pre) r=0.6; p=0.03 psychophysical improvement threshold post-pre (mm) Höffken, Veit, Knossalla, Lissek, Bliem, Ragert, Dinse, Tegenthoff (2005) J Physiol

Effects of repetitive sensory stimulation improvement of tactile & sensorimotor performance tactile acuity (2-point discrimination) frequency (flutter) discrimination reaction times. Braille sign recognition fine motor movements (finger hand) haptic object recognition every day life performance

Effects of repetitive sensory stimulation Thalamus brain activation & induction of plastic reorganization repetitive sensory stimulation Brain stem Spinal cord

Effects of repetitive sensory stimulation Thalamus brain activation & induction of plastic reorganization LTP-like processes Δ synaptic efficacy repetitive sensory stimulation Brain stem Spinal cord Δ sensorimotor processing Δ sensorimotor behavior

Co-activation in healthy elderly subjects Peg board - pin plugging 65 to 89 yrs right hand co-activated 2 days / week for 4 weeks Time gain relative to pre [%] 30 25 20 15 10 5 0 post post 2 weeks post 3 weeks post 4 weeks rec 1 week rec 2 weeks Kalisch, Tegenthoff, Dinse (under revision)

Application of repetitive sensory stimulation in the treatment of impaired subpopulations improvement of sensorimotor performance in patients suffering from stroke targeting:. - touch - proprioception -haptics - motor performance

Application of repetitive sensory stimulation in the treatment of impaired subpopulations improvement of sensorimotor performance in patients suffering from stroke advantages: - easy to apply - easy to use at homes - high compliance - inexpensive

Application of repetitive sensory stimulation in the treatment of impaired subpopulations

Touch threshold Tactile acuity Haptic object/form recognition Moberg Hand tapping 9-hole pegboard Practical tasks (Wolf-Motor/JTHF)

Stimulation statistics: intermittent high-frequency - electrical stimulation of the fingers - trains of pulses with an inter-train interval of 5 s - train duration 1 sec with 20 single pulses @ 20 Hz - single pulse duration 200 microsec. - pulse trains stored digitally and played back via MP3 player allowing unrestricted mobility of the subjects during stimulation stimulation session of 1 hour 12000 stimuli Ragert, Kalisch, Bliem, Franzkowiak, Dinse (2008) BMC Neuroscience

Subacute patients age 55 to 76 years post-stroke: 4.2 ± 1.3 weeks media infarct, thalamic infarct stimulation: 45 minutes 5 days / week, for 2 weeks total: 7.5 h, ~90.000 stimuli follow-up after 3 months complementary treatment: standard physiotherapy

no discrimination ability discrimination threshold (mm) 8 7 6 5 4 3 2 1 0 Baseline mid treatment Endtreatment Follow-up Tactile acuity Grating orientation task

no discrimination ability mid treatment Endtreatment Follow-up discrimination threshold (mm) 8 7 6 5 4 3 2 1 0 Baseline mid treatment Endtreatment Follow-up 0-10 -20-30 -40 Tactile acuity Grating orientation task

80 Time (sec) 60 40 20 0 Baseline Endtreatment Follow-up Moberg Time to pick up and to correctly identify item

Endtreatment Follow-up Time (sec) 80 60 40 20 0 Baseline Endtreatment Follow-up change in performance (% to baseline) 0-10 -20-30 -40-50 -60 Moberg Time to pick up and to correctly identify item

Comparison of restoration effects - subacute 40 improvement (%) 30 20 10 0 Tactile acuity Form recognition Moberg pick up 9-hole pegboard Endtreatment Followup Dinse, Bohland, Kalisch, Kraemer, Freund, Beeser, Hömberg, Stephan (2008) Europ J Neurol

baseline dependence at end-treatment performance at baseline (sec) 0 10 20 30 40 50 0 0 0 20 40 60 80 percent change (%) -10-20 -30 percent change (%) -20-40 -60-40 R 2 = 0.2938-80 R 2 = 0.4402 9-hole pegboard Moberg

baseline dependence at follow-up performance at baseline (sec) 0 10 20 30 40 50 0 0 0 20 40 60 80 percent change (%) -10-20 -30 percent change (%) -20-40 -60-40 R 2 = 0.7106-80 R 2 = 0,576 9-hole pegboard Moberg

Chronic patients age 57 to 67 years post-stroke: 30 ± 1.3 months media infarct stimulation: 90 minutes 4 days / week, for 6 weeks total: 36 h, ~400.000 stimuli follow-up after 4 weeks complementary treatment: n.a.

Improvement in chronic stroke patients Ratio: affected / healthy side 1.0 0.8 0.6 0.4 0.2 0.0 left hemispheric stroke S 1 6 months S 2 18 months baseline mid end follow-up Ratio: affected / healthy side 1.0 0.8 0.6 0.4 0.2 0.0 right hemispheric stroke S 3 60 months S 4 36 months baseline mid end follow-up Smith, Dinse, Kalisch, Johnson, Walker-Batson (in press) Arch Phys Med Rehabil

Improvement in chronic stroke patients Ratio affected / healthy side Ratio affected / healthy side 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 tapping Haptic object baseline mid end follow-up baseline mid end follow-up Smith, Dinse, Kalisch, Johnson, Walker-Batson (in press) Arch Phys Med Rehabil

Chronic patients age 38 to 61 years post-stroke 4.8 ± 2.5 years media infarct, thalamic infarct stimulation: 45 to 60 minutes 5 days / week, for 6 to14 months total: > 1 million stimuli follow-up every 2 to 4 months complementary treatment: n.a. / general physiotherapy

Effect of repetitive sensory stimulation (chronic patient, right-handed, 48 years, left thalamus infarct 1997) touch threshold (Frey Hairs) tactile acuity (GOT, 2PD) haptic object recognition hand/arm motor performance (MLS) multiple choice reaction times (visuo-tactile task) Actigraphy hand functions in daily activities (Jebsen Taylor, video-based) SEPs (high density EEG)

Effect of repetitive sensory stimulation (chronic patient, right-handed, 48 years, left thalamus infarct 1997) Touch threshold threshold (mn) 350 300 250 200 150 100 50 0 no sensation baseline 7 weeks 22 weeks 36 weeks after 36 weeks: ~2 million stimuli digit 2 right digit 4 right healthy left fingers

Effect of repetitive sensory stimulation (chronic patient, right-handed, 48 years, left thalamus infarct 1997) Multiple choice reaction times 1600 RT (ms) 1200 800 400 0 left right baseline 7 weeks 22 weeks 36 weeks

Effect of repetitive sensory stimulation (chronic patient, right-handed, 48 years, left thalamus infarct 1997) 100 Hand dominance test (HDT) 90 extreme right handedness 80 HDT scores 70 60 50 40 30 right handedness 20 10 0 baseline 7 weeks 36 weeks ambidexterity left handedness extreme left handedness

SEPs (high density EEG) air-puff stimulation, right digit 2 baseline

SEPs (high density EEG) air-puff stimulation, right digit 2 after 36 weeks baseline

Future work Optimization & development of RSS protocols Optimization & development of RSS devices Role of neurotrophic factors in RSS Individual strategies for combining RSS with training

Evolution of stimulation devices

Role of neurotrophines in RSS family of growth factors produced in blood and brain Synaptic plasticity Production & maintenance of connections between nerve cells Neurogenesis NGF nerve growth factor BDNF brain-derived neurotrophic factor

Mild / transient Cellular stress Sensory stimulation Growth factors Stress resistance genes Energy metabolism Antioxidant enzymes Heat shock proteins Mattson (2008) Ageing Res Rev

Future work Optimization & development of RSS protocols Optimization & development of RSS devices Role of neurotrophic factors in RSS Individual strategies for combining RSS with training

Summary & Conclusion Repetitive sensory stimulation (RSS) was used as stand-alone or complementary rehabilitation therapy in subacute and in chronic stroke patients RSS consisted of intermittent high-frequency electrical stimulation of the fingers of the affected hand RSS improved hand-arm functions of the affected side for touch, tactile and haptic performance, proprioception and motor performance Improvement was preserved or further enhanced several weeks follow-up Two advantages: RSS is inexpensive and passive, i.e. it does not require the active cooperation of the patient These properties together with the effectiveness make RSS-based principles prime candidates for therapeutic intervention, particularly for out-patients

Tobias Kalisch, Jan Kattenstroth Martin Tegenthoff, Oliver Höffken Volker Hömberg, Klaus Martin Stephan, Matthias Kraemer Wolfgang Greulich, Petra Gerhardt Delaina Walker Batson, Patricia S. Smith Mark Johnson

Thank you for your attention RuhrUniversityBochum