Quick review of neural excitability. Resting Membrane Potential. BRAIN POWER: non-invasive brain stimulation in neurorehabilitation

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1 BRAIN POWER: non-invasive brain stimulation in neurorehabilitation Quick review of neural excitability Edelle [Edee] Field-Fote, PT, PhD, FAPTA Director of Spinal Cord Injury Research Shepherd Center Crawford Research Institute Changes in synaptic efficacy underlie changes in neural excitability and responsiveness Resting Membrane Potential Potential Difference Across Cell Membrane...Due to: 1. Inequality of ion concentrations on different sides of membrane. 2. Selective permeability of membrane to different ions. Generally between -80mV to -60mV Kandel, Schwartz & Jessell, Principles of Neural Science, 2000 Changes in synaptic efficacy underlie retention of practice effects RMP maintained by ion channels. When membrane potential is altered by ion flux, the RMP is restored by ion pumps... Ion Channels: permit passive diffusion of specific ions down their concentration ([ ]) gradient. Ion Pumps: actively moves ions against their [ ] gradient. Kandel, Schwartz & Jessell, Principles of Neural Science,

2 Ion Pump: creates [ ] gradient Cellular Excitation axon dendrite receptor Actively moves ions against their [ ] gradient Derives energy by hydrolyzing ATP to ADP Ion channels are gated by different mechanisms they may respond to voltage, chemical, mechanical, or thermal changes. Ion channels: Mechanisms of selectivity 1. Different pore diameters. 2. Different charge characteristics at pore entrance or within channel. Selectivity is incomplete but relatively specific for ions important in excitation States of the voltage-gated cation channel Membrane depolarization results in a rapid transition to the open state Inactivation of Na+ and Ca++ channels (and also some K+ channels) results the channel closure (refractory period) Membrane repolarization leads to recovery from the inactivated state back to the resting state Note: The change from the resting to inactivated state is also possible without channel opening such as during slow depolarization (ie, accommodation) Ion channels: Mechanisms of activity 3. Channels are molecularly similar but come in many flavors. 4. Channels are modulated by NTs. 5. Nature of the response depends on ion channel (not NT). 6. Reminder: extracellular Ca++ is essential for NT release Cellular Excitation Depolarization: membrane potential becomes less negative (less polarized) Hyperpolarization: membrane potential becomes more negative (more polarized) Information is digitized at the axon hillock. 2

3 Correlation between increases in cortical excitability and motor performance History of Transcranial Direct Current Stimulation (tdcs) Giovani Aldini (nephew of Galvani) in 1804 reported successful treatment of melancholia with DC currents to the head. Kim et al, 2006 Mechanisms underlying priming are timing-dependent Gating: rapid mechanisms via disinhibition of intracortical inhibitory circuits ( presynaptic Ca 2+ ) Approach: apply stimulation concurrently with activity Homeostatic plasticity: postsynaptic NMDA receptor modulation stabilizes excitability Approach: apply stimulation prior to activity tdcs changes membrane potential Direct current (unidirectional) polarizes tissue (change in membrane potential) Two electrodes Active positioned on target site Reference positioned elsewhere Current provided by battery-driven device Current passes through intervening tissue Anodal DC depolarizes tissue Modulating cortical excitability: tdcs Current under the anode induces a lack of positive ions near the basal part of the neural membrane, inducing depolarization of this part of the membrane. The excitability of the neuron is brought closer to threshold (depolarized), increasing background activity (anodal activation) Depolarization activates Ca and Na+ channels 3

4 Cathodal DC depolarizes tissue D Arsonval Cage The current under the cathode induces an excess of positive ions near the basal part of the neural membrane The excitability of the neuron is further from threshold (hyperpolarized), decreasing background activity (cathodal suppression) Hyperpolarization inactivates Ca and Na channels Modulating cortical excitability: TMS Transcranial magnetic stimulation (TMS) causes discharge of action potential(s) Faraday s law A time-varying current (di/dt) in a wire loop will induce a magnetic field (B) The magnetic field will induce an electromotive force ( ) in an adjacent conductor History of TMS 1896 D Arsonval introduced idea that nerve cells could be excited by magnetic fields (dizzyness and phosphenes) First published record of a human muscle response to magnetic brain stimulation 1965 Brickford and Fremming considered that currents of sufficient magnitude could stimulate cortical structures 1980 Merton and Morton demonstrated that muscles can be directly stimulated by magnetic fields 1985 Barker demonstrated that human brain can be stimulated by magnetic pulses (Barker et al. 1985) 4

5 Biophysics of TMS: electromagnetic induction Influence of tissue interactions on neural effects of TMS shorter axons, and areas of bending = lower thresholds Wagner et al. Cortex, 2009 Wagner et al. Cortex, 2009 Biophysics of TMS: coil location & orientation Biophysics of magnetic stimulation Wagner et al. Cortex, 2009 Biophysics of TMS: stimulation depth Direction of current flow follows right-hand rule Wagner et al. Cortex,

6 Corticospinal tract Safety Implanted metal in the head Hxof seizure Hx of head trauma Headache 1+ milion fibers Mostly small fiber diameter Betz cells large diameter fibers 30% originates in motor cortex Central recruitment order The induced electric field A. Shape of the inducting coil The recruitment order of spinal motoneurons under increasing voluntary or reflex drive is related to their physical size (Henneman s size principle). B. Location and orientation of the coil with respect to the tissue C. Electrical conductivity structure of the tissue Neurophysiology of single pulse TMS (corticomotor excitability) single- & paired-pulse TMS Repetitive TMS (rtms) Modulatory ( virtual lesion ) rtms Modulatory rtms (clinical uses) Theta-burst stimulation 6

7 COIL POSITIONING Mental practice improves function and promotes cortical plasticity Pascual-Leone et al J Neurophysiol. 1995; 74: Measures of cortical excitability Motor evoked potential (MEP) Intracortical facilitation Intracortical inhibition Why be Interested in Sensory Cortex? It contributes to corticospinal tract Dum & Strick. Physiol Behav, 2002 Projections from sensory to motor cortex by neurons activated from group I muscle afferents Clinically accessible approaches to increasing cortical activation Zarzecki, Shinoda& Asanuma. Exp Brain Res,

8 Sensory input influences corticomotor excitability e2 TENS: what frequency is best? Both low-rate (4Hz)/ high-width TENS and high-rate (100Hz), lowwidth TENS activated the large sensory fibers Asanuma & Mackel Jpn J Physiol, Radhakrishnan R, Sluka KA. J Pain, 2005 Cortical excitability is increased with sensory stimulation TENS improves hand sensory function in individuals with MS (but not ND individuals) Pre MEP Post MEP Ridding et al, Exp Brain Res, 2000 Cuyers et al. Neurorehabil Neural Repair, 2010 TENS to APB 100 Hz 250 µs pulse width 21 days 1hr/day N = 24, 12/group TENS to hand muscle increases size of cortical hand map in ND subjects Transcranial Magnetic Stimulation (TMS) (Magnetically) Induced electrical stimulation Activation of structures oriented horizontal to coil Pyramidal cells through interneuron activation Motor evoked potential Meesen et al. Human Brain Mapping, 2010 (Merabet, Pascual-Leone, 2009; Davey et al, 1999) 8

9 Slide 46 e2 spell abbreviation out the first time efield, 01/04/2011

10 Cortically Evoked Potentials after SCI MEP at 60%MSO in ND individual MEP at 90% MSO in individual incomplete cervical SCI wit Reorganization of cortical map Hoffman & Field-Fote. Phys Ther, 2007 Change in hand function is associated with change in cortical excitability Somatosensory stimulation as an accessible approach to augmenting hand practice Sample thenar MEPs at 80% MSO (avg of 5 traces) Beekhuizen &Field-Fote. Arch Phys Med Rehabil, 2008 TMS cortical mapping to assess cortical plasticity Approaches for direct cortical stimulation Repetitive transcranial magnetic stimulation Activates neurons Studies in persons with stroke High frequency Transcranial direct current stimulation (tdcs) Modulates neuronal excitability Studies in persons with stroke anodal vscathodal 9

11 tdcs represents a clinically accessible approach to direct cortical stimulation Anodal= EXCITATION Cathodal= INHIBITION ANODE CATHODE Bi-hemispheric (anodal/cathodal) more effective than uni-hemispheric (ND subjects) (Fregni & Pascual-Leone, 2007) Vines et al. BMC Neurosci, 2008 Is direct cortical activation more beneficial than indirect (somatosensory) activation? Transcranial direct current stimulation (tdcs) Electrodes applied to the scalp Simple unidirectional direct current 1 ma current Session time: 20 min Mild adverse effects (itching), non-invasive, painless Bihemispheric anodal tdcs Cervical Spinal Cord Injury - Bilateral upper extremity impairment - What about bilateral excitatory stimulation? Uni-hemispheric tdcs in stroke Safety / preliminary efficacy tested in ND subjects Boggio et al. Rest Neurol Neurosci, 2007 Gomes-Osman & Field-Fote. J Motor Behav,

12 Bihemispheric anodal tdcs Methods/Research Design Bilateral anodal corticomotor tdcs (1 ma, 20 min) or sham Outcome Measures: BT and STM tasks OR T E S T I N G MOTOR TRAINING T E S T I N G OR SESSION 30 MIN BREAK T E S T I N G ONE SESSION PER WEEK 3 SESSIONS TOTAL OUTCOME MEASURES Active MEP Threshold Pinch Grip Strength Visuomotor Tracking Task 9-hole peg test Bimanual finger-sequencing scores Third Study- Rationale * Gomes-Osman & Field-Fote. J Motor Behav, 2013 Specific contribution of M1 to voluntary movement Methods/ Research Design Inclusion criteria individuals with a cervical SCI (at least 1 year post-injury), ability to produce visible twitch of thumb Exclusion criteria neurological, orthopedic or cognitive conditions that would affect performance Cross-over, randomized single blind study with concealed allocation Feasibility study no control/comparison group Is direct cortical activation more effective than indirect (somatosensory) activation? Assessment of clinically available approaches tdcs Vibration TENS 11

13 tdcs is associated with most effect TENS also influenced function Spike timing-dependent plasticity for enhanced corticospinal transmission * * * * Dashed line= moderate effect size Gomes-Osman & Field-Fote. J Neurol Phys Ther, 2015 Bunday & Perez. Current Biology, 2012: 22: EVEREST Study Overview Lab-based approaches to increasing cortical activation Phase III, RCT of patients with chronic hemiparesis Targeted cortical stimulation during intensive rehab Randomize 151 subjects (100 implanted, 51 control) 21 sites Primary OMs: Composite endpoint at 4 weeks post Upper extremity Fugl-Meyer (UEFM) Arm Motor Ability Test (AMAT) Secondary outcome at 24 weeks Targeted primary efficacy endpoint: 20% difference between groups Summing cortical & spinal stimulation Outcomes Safety confirmed no adverse effects At 4 weeks (primary end point) clinically meaningful improvements did not meet criteria of 20% difference: 30.8% of patients receiving stim + MP 29.1% of patients MP only At 25 weeks, significantly greater AMAT improvement in stim + MP group Questions raised about dosing levels (EVEREST investigator, Robert Levy) 12

14 rtms in SCI and ND High frequency rtms 10Hz [excitatory]) 80% biceps RMT EVEREST Trial (Phase III) Northstar Neuroscience Cortical hand site identified via fmri Epidural electrode placed over cortical target site Implantable pulse generator Overnight hospital stay Subthreshold stimulation Stim on only during rehab (Pascual-Leone, 1994; Beradelli et al, 1998; Butefish et al, 2004; Kim et al, 2006; Tallelli & Rothwell, 2006) rtms is associated with improved functional scores in persons with SCI rtms in Stroke Dashed line indicates threshold for moderate effect size Gomes-Osman & Field-Fote. Clin Rehabil, 2014 Implanted cortical stimulation Theta-burst stimulation Phase 1: Adams RCT, non-blinded, multicenter study of safety and secondarily of efficacy of subthreshold cortical stimulation with rehabilitation N = 8 (4 control, 4 investigational) Phase II: Baker RCT, blinded, targeted cortical stimulation during intensive rehabilitation for chronic post-stroke hemiparesis N = 24 (12 control, 12 investigational) Outcomes: combined Adams & Baker results Clinically Meaningful Changes ( 3.5 points) in UEFM 75% of stim + MP group showed improvement Significantly more (p< 0.01) than in MP only group Conclusions: Efficacy evaluation suggests that cortical stim+mp improves hand/arm function over rehabilitation alone at primary (4 week) and secondary (3 and 6month) endpoints. 13

15 Activity-dependent accumulation of AMPARs at a perisynaptic site Training itself is an approach to changing neural excitability Yunlei Yang et al. PNAS 2008;105: Conclusions Even in chronic CNS injury there is potential for improvement of hand function. Should we train the brain to reflexes or to voluntary control? Both stimulation & training affect neural structures that underlie movement effects may be additive. There are changes in cortical neurophysiologic measures associated with functional change. Clinically available devices can be employed 3 baseline sessions 300 repetitions/session 12 training sessions (3/wk x 4 wks) Manella, Roach, Field-Fote. J Neurophys, 2013 Neuroplasticity Alterations in the nervous system in response to experience Repeated experience practice May be adaptive or maladaptive Training to voluntary control vs. to reflexes which is associated with greater benefit? Requirements Sufficient intensity Sufficient time } DOSE Manella, Roach, Field-Fote. J Neurophys,

16 Sample SOL Outcome H-reflex M-wave Manella & Field-Fote. J Neurophys, 2013 Outcomes reflexes, strength, walking, EMG TA SOL TA %MVC amplitude Stretch reflex threshold Active dorsiflexor ROM Dorsiflexor strength Step height in walking ** 2MinWT distance TA/SOL co-activation **significant between-group diff Manella, Roach, Field-Fote. J Neurophys, 2013 Outcomes EMG, clinical, walking, reflexes Manella, Roach, Field-Fote. J Neurophys,