Long-term motor cortex plasticity induced by an electronic neural implant

Transcription

1 Vol Novemer 26 doi:1.138/nture5226 Long-term motor cortex plsticity induced y n electronic neurl implnt Andrew Jckson 1, Jideep Mvoori 2 & Eerhrd E. Fetz 1 It hs een proposed tht the efficcy of neuronl connections is strengthened when there is persistent cusl reltionship etween presynptic nd postsynptic ctivity. Such ctivity-dependent plsticity my underlie the reorgniztion of corticl representtions during lerning, lthough direct in vivo evidence is lcking. Here we show tht stle reorgniztion of motor output cn e induced y n rtificil connection etween two sites in the motor cortex of freely ehving primtes. An utonomously operting electronic implnt used ction potentils recorded on one electrode to trigger electricl stimuli delivered t nother loction. Over one or more dys of continuous opertion, the output evoked from the recording site shifted to resemle the output from the corresponding stimultion site, in mnner consistent with the potentition of synptic connections etween the rtificilly synchronized popultions of neurons. Chnges persisted in some cses for more thn one week, wheres the output from sites not incorported in the connection ws unffected. This method for inducing functionl reorgniztion in vivo y using physiologiclly derived stimulus trins my hve prcticl ppliction in neurorehilittion fter injury. Lerning is ssocited with long-term reorgniztion of sensory nd motor representtions in the neocortex 1 3. Acquisition of motor skills cn lter the somtotopic mp of lim movements in sensorimotor res 4,5, nd plstic chnges hve een implicted in the recovery from disorders such s stroke 6 nd incomplete spinl cord injury 7. He 8 postulted tht synptic efficcy etween two neurons is strengthened if the first repetedly contriutes to firing the second; since then, long-term potentition of motor corticl synpses 9 11 nd ssocited expnsion of movement representtions 12,13 hve een induced with tetnic stimulus trins delivered to individul sites. Long-term potentition is widely ssumed to reflect lerning mechnism, ut its physiologicl relevnce nd reltionship to hein plsticity re often inferred indirectly 14. More recently, spike timing-dependent plsticity consistent with He s criterion of cusl reltionship etween presynptic nd postsynptic firing hs een descried t the cellulr level 15,16. However, it remins to e shown tht such mechnism cn cuse stle, functionl reorgniztion of corticl mps in vivo under norml ehviourl conditions. We re developing implntle electronic circuits 17 (or Neurochips; Supplementry Fig. 1) for neurl recording nd stimultion in freely ehving nimls tht could provide prosthetic connections to replce or ugment dmged pthwys in the nervous system 18.A Neurochip cretes n rtificil connection etween two sites y using ction potentils recorded on one electrode to trigger electricl stimuli delivered to nother (Fig. 1). Once configured with pproprite recording nd stimultion prmeters, the Neurochip opertes utonomously, llowing connections to function continuously over dys of unrestrined ehviour. Becuse the Neurochip cretes cusl reltionship etween neurl ctivities t connected sites, its long-term opertion could lso induce chnges medited y hein Spike detector Amplifiers + filters Dely ICMS Stimultor Current source c Pre-conditioning ICMS mpping Conditioning Neurochip Figure 1 Conditioning protocol nd experimentl design., Digrm of the rtificil connection. Action potentils detected in the signl recorded from the electrode triggered electricl stimuli delivered to the electrode fter predefined dely., Experimentl setup for testing output effects of ICMS on the right wrist. c, Experimentl sequence of ICMS testing nd conditioning with the Neurochip. Post-conditioning ICMS mpping EMGs Torque 1 Deprtment of Physiology nd Biophysics nd Wshington Ntionl Primte Reserch Center, 2 Deprtment of Electricl Engineering, University of Wshington, Settle, Wshington 98195, USA Nture Pulishing Group

2 NATURE Vol Novemer 26 mechnisms. Here we descrie stle reorgniztion of movement representtions in the wrist re of the primry motor cortex (M1) in monkeys resulting from rtificil connections etween pirs of electrodes in chroniclly implnted rry. We found tht the motor output elicited from recording sites shifted towrds the output evoked from stimultion sites. These chnges occurred only when stimuli were delivered within 5 ms of recorded spikes. The output evoked from neighouring control electrodes ws unchnged. This shows tht nturl ptterns of corticl spiking in vivo during norml ehviour cn led to input-specific hein plsticity when pired with pproprite stimultion. Plstic chnges rising from these rtificil connections could hve clinicl pplictions in rehilittion fter motor injury. Conditioning with n rtificil connection The output effects in the contrlterl wrist evoked from corticl electrodes efore, during nd fter conditioning with the rtificil connection were tested with dily intrcorticl microstimultion (ICMS, Fig. 1, c). Figure 2 shows the pre-conditioning verge trjectories of isometric wrist torque (dshed lines) for 2 ms fter trin of stimuli delivered seprtely to ech of three electrodes, designted Neurochip recording (), Neurochip stimultion () nd control (). The men torque, indicted y solid rrows, ws towrds the flexion direction for nd, nd in the rdil-extension direction for. Figure 2 shows verge rectified electromyogrm (EMG) responses to ICMS in three wrist muscles: extensor crpi rdilis (ECR), flexor crpi rdilis (FCR) nd flexor crpi ulnris (FCU). The Neurochip ws then progrmmed to deliver single stimulus pulse to 5 ms fter every ction potentil detected t (Supplementry Fig. 2). The cell t this site fired preferentilly with flexion during torque-trcking nd its ctivity ws correlted with oth wrist flexor nd extensor muscles during free ehviour (Supplementry Fig. 2f, g). The stimulus intensity (4 ma) ws elow the movement threshold for single pulse ut ws sufficient for occsionl ursts of cell ctivity to elicit smll muscle twitches while the monkey st t rest. This connection produced no noticele disruption of the control of ctive movements, proly ecuse the effect of stimultion ws wek in comprison with neurl ctivity generting volitionl movement. The rtificil connection operted continuously for two dys while the monkey moved unrestrined out the home cge. During this period, the Neurochip lso recorded the stimultion rte over consecutive 1-s ins (Supplementry Fig. 2). The men rte of stimultion ws 19 Hz during dytime ehviour nd 9 Hz during the night. This pttern ws consistent with our oservtions of roust correltions etween the firing rte of M1 neurons nd muscle ctivity during nturl ehviour, nd cycles of ctivity nd quiescence during sleep 19. After two dys of conditioning, the men torque generted y ICMS t hd shifted to the rdil direction, towrds the output effect produced from (Fig. 2c). The torque now followed curved trjectory ligned initilly with the trjectory, efore returning to the flexion direction. This curved pth ws produced y new pttern of muscle responses (Fig. 2d), which included initil ctivtion of the extensor muscle ECR (lck rrows), previously elicited only y ICMS t. The output from the control electrode ws unffected, indicting tht the plstic chnge ws cused y the piring of neurl ctivity t the site with the stimultion of. In this cse, the response from the site hd lso incresed slightly (Supplementry Fig. 3), ut this ws not generlly so (see Supplementry Informtion). Figure 2e plots the ngle of men torque produced y ICMS t ech site for the dys efore, during nd fter conditioning. The chnges t the site developed grdully over the two dys of conditioning nd susequently remined stle for one week. Summry of conditioning sessions We investigted the effect of creting rtificil connections etween 17 different pirs of electrodes over seprte conditioning sessions in two monkeys (Y, eight sessions; K, nine sessions). Conditioning lsted for 1 4 dys (men 1.6 dys) with currents in the rnge 25 8 ma (men 48 ma) nd delys of, 1 nd 5 ms interposed etween spike nd stimulus (Supplementry Tle 1). ICMS effects were quntified y the ngle of men wrist torque reltive to the pre-conditioning direction of effect. Control electrodes were chosen to hve similr ICMS effects to those of the preconditioning. Figure 3 summrizes the direction of men torque produced y ICMS efore nd fter ech session. Points lying on the dshed line of identity represent ICMS effects tht were unffected y conditioning; points lying elow the line represent effects tht moved towrds the output effect of. Conditioning hd no significnt effect on the seprtion of site effects from the direction, which chnged y 2.1u 6 2.3u (men 6 s.e.m., two-tiled ECR FCR FCU Direction of men torque e Ext. Rd. Flex. 26 Nture Pulishing Group Flex. Rd. Uln. Ext. d Uln Time (dys) c Figure 2 Reorgniztion of motor output fter conditioning., Averge wrist torque responses to ICMS efore conditioning. Arrows show the mens of ech 2-ms trjectory (dshed lines). Clirtion rs re 6.2 N m ( nd ) nd 6.8 N m ()., Peristimulus verges of the rectified EMG response. The full xis lengths re 25 ms (x) nd.4 mv (y). The r indictes the ICMS trin. c, d, Dt fter two dys of conditioning with n rtificil connection. Arrows indicte incresed ECR response from fter conditioning. e, Angle of torque response over 18 dys. Shding indictes the conditioning period. Error rs show s.e.m. ICMS, 13 pulses t 3 Hz; current, 3 ma (), 4 ma () nd 5 ma (). The dt re given in session 3 of Supplementry Tle 1 nd re verges of 2 stimulus trins. 57

3 NATURE Vol Novemer 26 pired t-test, P 5.4). In contrst, effects moved towrds the direction y 38u 6 9u (men 6 s.e.m., P 5.5). In 13 of 17 individul sessions, effects rotted y n ngle greter thn the 95th centile of the distriution (15u). The ngulr shift per dy of conditioning ws comprle for oth nimls (Y, 24u 6 8u; K, 25u 6 7u; men 6 s.e.m.). Figure 3 shows verge ngulr seprtions of nd effects from the direction efore, just fter nd one dy fter the end of the conditioning period. Supplementry Fig. 4 shows exmple torque trjectories from these experiments. Supplementry Fig. 5 shows the one session in which the chnge t the site grdully wore off, six to eight dys fter the end of conditioning. Dependence on spike -stimulus dely The sence of conditioning effects t control sites suggests tht the timing of stimultion reltive to cell ctivity hd crucil function in inducing plsticity. Neurons distriuted widely throughout the motor cortex exhiit correlted firing on the timescle of movements (typiclly severl hundred milliseconds 19,2 ; Supplementry Figs 2g nd 6). The site specificity of our results therefore indictes tht more precise coincidence etween spikes nd stimultion ws required to induce plstic chnges. We tested this hypothesis in further series of experiments with monkey K y introducing longer delys of 2 2, ms etween the spike nd stimultion pulse (see Supplementry Informtion). Figure 4 summrizes these dt y Seprtion fter conditioning (º) Seprtion from (º) Seprtion efore conditioning (º) Control ** * Pre-cond. Post-cond. + 1 dy Figure 3 Summry of conditioning results., Angulr seprtion of nd ICMS effects from the pre-conditioning direction efore nd fter conditioning for 17 sessions. Control dt (lue) cluster round the dshed line of identity. dt (red) fll elow the line, indicting tht the men torque shifted towrds the response elicited from. Arrows indicte dt in Fig. 2., Averge ngulr seprtion of (red rs) nd (lue rs) effects from the direction efore conditioning. Error rs show s.e.m. 11 dy descries one dy fter the end of conditioning. Asterisk, P 5.1; two sterisks, P 5.5 (n 5 17, two-tiled pired t-test reltive to pre-conditioning dt). 58 plotting the ngulr shift of the effect towrds the direction per dy of conditioning s function of stimulus dely. Significnt shifts (P,.5, two-tiled t-test) were otined for intervls up to 5 ms, indicting tht coincidence of spike nd stimulus within this window ws required for inducing plsticity. The verge ngulr shift for delys of 2 nd 5 ms (35u 6 5u) ws slightly greter thn hd een otined with the shorter delys (24u 6 5u), ut this difference ws not significnt (P 5.25, two-tiled unpired t-test). Discussion These results my e explined y the potentition of horizontl pthwys within the motor cortex 1 such tht ICMS delivered, fter conditioning, to ctivtes dditionl muscle groups through (Fig. 5). Alterntively, plsticity could occur t other corticl or sucorticl trgets of converging projections from nd sites. Repetitive high-frequency stimultion hs een shown to expnd movement representtions in the motor cortex of rts 12,13, ut generl expnsion of locl effects cnnot ccount for the chnges we sw t sites for severl resons. First nd foremost, outputs from neighouring control electrodes were unffected y conditioning. There ws no significnt difference in either the distnce from the site (, mm;, mm; men 6 s.e.m.; two-tiled unpired t-test, P 5.5) or ICMS currents used (, ma,, ma, P 5.5). Second, the ngulr shift of ICMS effects evoked from ws not correlted with distnce from the site (Person s r 52.7). Lst, no shifts occurred when stimuli were delyed y more thn 5 ms reltive to the spikes, lthough the temporl pttern of stimultion ws equivlent. These oservtions ll indicte tht the reltive timing of spikes nd stimultion ws the criticl fctor for inducing plsticity. Cellulr studies of spike timing-dependent plsticity hve shown tht plsticity t individul synpses is triggered y C 21 influx, requiring oth presynptic glutmte relese nd postsynptic depolriztion to relese the Mg 21 lock of N-methyl-D-sprtte chnnels 16. We propose tht in our experiments the depolriztion of locl or downstrem neurons y stimultion t induced the potentition of synpses concurrently ctivted y spikes rriving from the site. Inputs from other sites (nmely electrodes) were not potentited ecuse the timing of this presynptic ctivity hd no consistent correltion with postsynptic depolriztion. Previous studies hve shown tht synptic inputs ctivted fter postsynptic depolriztion cn e depressed 15,16, so lthough some frction of spikes from control sites would hve rrived during the window for synptic potentition, these could e cncelled y comprle Shift in men torque (º) Nture Pulishing Group , Spike stimulus intervl (ms) Figure 4 Dependence of conditioning effects on dely etween spikes nd stimuli. The grph shows ngulr shift of effects towrds effects per dy of conditioning for different spike stimulus intervls. The solid line connects the group mens for ech intervl. Error rs show s.e.m. The dshed line indictes the 95th centile for control electrodes otined from the previous experiment.

4 NATURE Vol Novemer 26 Pre-conditioning ICMS mpping FCR ECR FCU Conditioning Neurochip Post-conditioning ICMS mpping FCR ECR FCU Figure 5 Suggested mechnism for the conditioning effect documented in Fig. 2. Pre-conditioning ICMS predominntly ctivtes distinct descending projections from to FCR, from to ECR, nd from to FCU. Conditioning during unrestrined ehviour induces strengthening of horizontl connections etween nd. Post-conditioning ICMS now ctivtes ECR y mens of horizontl projections to, s well s ctivting FCR y mens of the direct projection. numer of inputs rriving during the window for synptic depression. This would lso explin why delys of out 2 ms tended to produce the strongest conditioning effects. With shorter delys more spikes would hve rrived fter stimultion, during the window for synptic depression. Associtive plsticity hs een demonstrted previously with the use of pired stimultion of two input pthwys in the cereellum 21, hippocmpus 22 nd motor cortex 23. In contrst with those studies, we induced functionl reorgniztion y using in vivo spike ctivity t one site to trigger the stimultion of second site. This constitutes reltively direct test of He s postulte, showing tht nturl ptterns of neuronl firing cn led to input-specific plsticity when pired with pproprite postsynptic depolriztion during norml ehviour. It seems unlikely tht the mgnitude of this reorgniztion cn e ccounted for y ltered projections only from the recorded neuron, ecuse ICMS delivered to presumly ctivted popultions of cells y mens of locl circuitry nd temporl summtion 24. However, neighouring M1 neurons with similr output projections exhiit the mximl degree of synchronous dischrge (Supplementry Fig. 6), so during conditioning mny spikes from this popultion will e temporlly correlted within the coincidence window for synptic potentition. Our method for inducing plsticity shres similrities with cellulr conditioning protocols in vivo in sensory res tht pir spontneous or evoked neuronl ctivity with pproprite sensory stimultion However, the chnges seen t the cellulr level in those studies typiclly lsted for few hours t most nd were reversed y norml ctivity. The continuous conditioning over long periods of nturl ehviour implemented y our Neurochip system my ccount for the strength nd stility of the effects descried here; they re consistent with the finding tht multiple sessions re 26 Nture Pulishing Group required to induce stle long-term potentition in rts in vivo 11. Furthermore, conditioning ws ssocited with volitionl movements rther thn externlly imposed ctivtion nd ws continued during nturl sleep, including rpid eye movement phses when motor corticl neurons cn e highly ctive 19. Sleep hs een implicted in the consolidtion of motor memory 31, ut the reltive contriutions of wking nd sleeping periods to our results remin to e determined. Artificil connections could provide neurl prosthesis to replce dmged pthwys in the nervous system fter injury 18. Our results suggest tht n dditionl rehilittive consequence in cses of prtil injury my e the strengthening of surviving projections etween sites connected y the prosthesis. Functionl reorgniztion is thought to e importnt in recovery from numerous movement disorders 6,7, nd new stimultion protocols re eing developed to id this process Stimultion in rel time triggered from neurl recordings during volitionl movements could provide n effective method of selectively strengthening specific neurl pthwys during rehilittion. METHODS See Supplementry Informtion for dditionl methods. Sujects. Experiments were performed with two mle Mcc nemestrin monkeys: Y (3 yers old; weight 4.3 kg) nd K (3 yers old; weight 4.6 kg). All procedures were pproved y the University of Wshington Institutionl Animl Cre nd Use Committee. Neurochip implnt. A full description of the Neurochip Brin Computer Interfce hs een pulished previously 17. The ttery-powered circuit llows continuous long-term recording nd stimultion during unrestrined ehviour through n rry of 12 chroniclly implnted movele tungsten microwire electrodes in M1 (dimeter 5 mm; impednce.5 MV; interelectrode spcing 5 mm). A microprocessor identified isolted ction potentils from nd instructed stimultor circuit to deliver iphsic, constnt-current pulses (.2 ms per phse) to fter specified dely. Short sections of rw recording (smpled t 11.7 khz) nd stimultion rte in 1-s ins over the durtion of conditioning were stored to on-ord memory. ICMS protocol. ICMS effects were documented with current tht ws just ove the threshold for eliciting torque response efore conditioning, nd the sme current ws used throughout. The monkey st with elow nd hnd immoilized y pdded restrints. A force trnsducer mesured the two-dimensionl isometric torque produced t the wrist in the flexion extension nd rdil ulnr directions. During some sessions, the EMG ws recorded with pirs of stinless steel wires inserted trnscutneously into the wrist muscles. Torque nd EMG were recorded t 5 khz. Offline the torque trce ws smoothed nd downsmpled to 1 Hz. Trins of 13 iphsic ICMS pulses (.2 ms per phse) t 3 Hz were delivered t 2-s intervls. Peristimulus verges of torque nd rectified EMG profiles were compiled from 1 ms efore ech stimulus to 5 ms fter it. Trces in which the torque level efore the stimulus exceeded.2 N m in ny direction were excluded from the verge. The trjectories in Fig. 2 connect the vector verge of two-dimensionl torque cross stimulus trins for consecutive smple points up to 2 ms fter stimultion. The vector verge of this trjectory ws used to determine the direction nd mgnitude of the men torque response to ICMS t ech site. Received 1 My 26; ccepted 29 August 26. Pulished online 22 Octoer Buonomno, D. V. & Merzenich, M. M. Corticl plsticity: from synpses to mps. Annu. Rev. Neurosci. 21, (1998). 2. Snes, J. N. & Donoghue, J. P. Plsticity nd primry motor cortex. Annu. Rev. Neurosci. 23, (2). 3. Monfils, M. H., Plutz, E. J. & Kleim, J. A. In serch of the motor engrm: motor mp plsticity s mechnism for encoding motor experience. Neuroscientist 11, (25). 4. Nudo, R. J., Milliken, G. W., Jenkins, W. M. & Merzenich, M. M. Use-dependent ltertions of movement representtions in primry motor cortex of dult squirrel monkeys. J. Neurosci. 16, (1996). 5. Kleim, J. A., Bry, S. & Nudo, R. J. Functionl reorgniztion of the rt motor cortex following motor skill lerning. J. Neurophysiol. 8, (1998). 6. Nudo, R. J., Wise, B. M., SiFuentes, F. & Milliken, G. W. 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