Long-term reorganization of human motor cortex driven by short-term sensory stimulation

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1 Long-term reorganization of human motor cortex driven by short-term sensory Shaheen Hamdy 1,2, John C. Rothwell 2, Qasim Aziz 1, Krishna D. Singh 3, and David G. Thompson 1 1 University Department of Gastroenterology, Hope Hospital, Salford M6 8HD, UK 2 The MRC Human Movement and Balance Unit, Institute of Neurology, Queen Square, London, WC1N 3BG, UK 3 Department of Psychology, Royal Holloway College, University of London, Egham, Surrey, TW20 0E, UK Correspondence should be addressed to D.G.T. (dthompso@fs1.ho.man.ac.uk) Removal of sensory input can induce changes in cortical motor representation that reverse when sensation is restored. Here we ask whether manipulation of sensory input can induce long-term reorganization in human motor cortex that outlasts the initial conditioning. We report that for at least 30 minutes after pharyngeal, motor cortex excitability and area of representation for the pharynx increased, while esophagus representation decreased, without parallel changes in the excitability of brainstem-mediated reflexes. Therefore increased sensory input can drive long-term cross-system changes in motor areas of the cerebral cortex, which suggests that sensory might rehabilitate dysphagia, a frequent consequence of cerebral injury. Animal data on cortical plasticity indicate that temporary changes in sensory input or motor output can produce persistent changes in the organization of sensory 1,2 and motor 3 areas of the cerebral cortex. Furthermore, changes in sensory input can alter the excitability of motor cortex (cross-system plasticity). Both animal and human studies demonstrate that a reduction in sensory feedback by denervation 4, prolonged positional stasis 5, or ischemic nerve block 6 9 can induce changes in motor representation. Motor representation (or motor map) refers to the area of motor cortex that elicits an electromyographic (EMG) potential in a target muscle, measured after of multiple cortical sites at constant intensity. Motor excitability, by contrast, refers to the size of the EMG potential itself, measured by of a constant site in the corticofugal projection. An important difference between motor representation and motor excitability is that asymmetric changes in the representation reflect effects mainly occurring at the cortical level, whereas changes in excitability may reflect effects at any level in the pathway. In human studies, reduction in sensory input rarely produces motor changes that outlast the manipulation. Although the motor maps theelves show little long-lasting change, there is a residual increase in their sensitivity to other inputs, which may last for up to one hour 8. Given this observation, we wondered whether modifications of the technique may allow changes in sensory input to drive long-term changes in human motor cortex organization. Such an effect would have relevance for the rehabilitation of motor-disabled patients after central nervous system injury. Swallowing is a complex sensorimotor activity, which depends on highly organized interactions among the cerebral cortex, the brainstem swallowing center and cranial nerves V, I, and II (ref. 10). This process has both voluntary and involuntary (reflexive) components, reflecting central regulatory pathways within swallowing centers in the cortex and brainstem respectively. Sensory feedback also see critical to swallowing. Stimulation of afferent fibers from cranial nerves V, I and can initiate or modulate the reflex swallowing process in animals 10,11, whereas a reduction in oropharyngeal sensation, by local anesthesia or affer- Table 1 Effects of pharyngeal on the EMG responses evoked following TMS, TES, trigeminal (TNS) and vagal (VNS) nerve Pharyngeal Amplitudes (µv) Esophageal Amplitudes (µv) TMS TES TNS VNS TMS TES TNS VNS pre- 25±6 28±10 58±15 72±25 46±4 48±10 35±16 62±21 immediate post 38±78* 32±8 66±19 84±24 23±6** 44±12 46±19 85±28 30 min post 60±10** 30±10 52±11 62±20 36±6* 48±10 39±14 70±31 TMS and TES data are from the same subject, to whom the stimuli were presented in a randomized, intermixed manner. TNS and VNS data (n = 5) refer only to the late brainstem-mediated responses, which are more reliably evoked 14. Data expressed as mean ± SEM. *p<0.05, **p<0.01 vs. pre. 64 nature neuroscience volume 1 no 1 may 1998

2 article a Pharyngeal Esophageal b Pharyngeal Esophageal Pre Immediate Amplitude (µv) 30 minutes 60 minutes Fig. 1 Changes in cortical swallowing motor pathway excitability by pharyngeal. (a) The cortically evoked pharyngeal and esophageal EMG responses in one individual are shown, at threshold intensity, before and after pharyngeal. Ten responses are superimposed. The cortical stimulus was applied at 0 ; the position of each asterisk indicates the onset of the EMG responses. (b) The mean cortically evoked pharyngeal and esophageal amplitudes and latencies, before and after pharyngeal, are shown at increasing cortical intensities. Both (a) and (b) show that pharyngeal, immediately and at 30 min, increases the pharyngeal response amplitudes (p<0.01) but reduces the esophageal amplitudes (p<0.005). By 60 min, the responses have returned to pre- levels. The pharyngeal and esophageal latencies remain unaffected. P pre ; p post immediate; L post 30 minutes; l post 60 minutes. ent nerve damage, can disrupt the normal pattern of volitionally initiated swallowing 11,12. We have shown previously that corticofugal pathways to the swallowing musculature can be activated at short latency by transcranial magnetic (TMS) over frontocentral areas of the scalp. Mapping the scalp sites that give the best responses showed that the brain has a bilateral but asymmetric representation of swallowing muscles 13. Furthermore, when one hemisphere is damaged by stroke, recovery see to be associated with an enlargement of the cortical representation (reorganization) in the undamaged hemisphere 13. The aim of the present experiments was to develop a therapeutic technique that might help speed the process of recovery. We began with the observation that in normal subjects, single electrical stimuli to sensory fibers in cranial nerves V, I and facilitate the responses evoked by TMS in pharynx and esophagus for This probably occurs because the sensory stimuli theelves produce a small response in swallowing muscles via a reflex arc through the brainstem; the response to cortical is facilitated because it summates with this reflex. In the present experiment, we sought to improve on this in two ways: first to produce facilitation that would outlast the period of sensory, and second to change the excitability of cortex rather than, or in addition to, brainstem. Latency (ec) Pre Immediate 30 minutes % Threshold intensity % Threshold intensity Results CORTICAL SWALLOWING PATHWAY ECITABILTY The study was performed in eight healthy subjects, who each received ten minutes of repeated (10 Hz) electrical pharyngeal sensory (mean intensity = 16.6 ± 1.8 ma) via swallowed electrodes housed in an intraluminal catheter. Focal TMS, Pharyngeal Esophageal Fig. 2 The reflex pharyngeal and esophageal EMG responses evoked by trigeminal nerve in one individual, before and after pharyngeal. Ten rectified responses have been superimposed. The cranial nerve stimulus was applied at 0 ; the position of each asterisk indicates the onset of the late EMG responses analyzed. In contrast to the cortically evoked responses, the amplitude of reflex responses appear unaltered following pharyngeal. nature neuroscience volume 1 no 1 may

3 a b c Fig. 3 Changes in swallowing motor representation by pharyngeal. Topographic maps of the pharynx and esophagus, before and after pharyngeal, are shown for three subjects (a-c) in one hemisphere (left in (a), right in (b) and (c)). Each map is viewed from above, with the position of the cranial vertex marked. The scale represents the percentage maximum response amplitude in each subject. In all three subjects shown, the area of pharyngeal representation increases after, but that of the esophagus decreases, each displaying asymmetric changes in the extent of their representations. which generates painless and very short, rapidly changing magnetic fields to induce electric current in underlying brain, was applied to motor cortex (mean threshold intensity = 78 ± 3% stimulator output), the best site for being 3 ± 1 cm anterior and 6 ± 2 cm lateral to the cranial vertex. TMS was performed before and then immediately, 30 minutes, and 1 hour after sensory. At each interval, the EMG responses evoked in the pharynx and upper esophagus were recorded from bipolar ring electrodes housed within the swallowed intraluminal catheter (Fig. 1a). Within this intensity range, movements of the fingers of the contralateral hand were occasionally observed due to stimulus spread. Following of the pharynx, reciprocal and reproducible changes in the amplitudes of the evoked pharyngeal and esophageal responses to motor cortex were observed (Fig. 1b). Across all cortical intensities, the pharyngeal response amplitudes increased, both immediately (p<0.005) and at 30 minutes (p<0.01) after pharyngeal, before returning to pre-pharyngeal- levels by 60 minutes. Pharyngeal response latencies were unaffected by pharyngeal. In contrast to the pharynx, esophageal amplitudes decreased, both immediately (p<0.005) and at 30 minutes (p<0.005) after pharyngeal, before returning to pre-pharyngeal- levels at 60 minutes. Esophageal response latencies were also unaffected by pharyngeal. Pre Pharynx Pre Esophagus BRAINSTEM SWALLOWING REFLE ECITABILITY In contrast to the effect on the size of responses evoked by TMS, prior of the pharynx had no effect on the size of reflex responses elicited by magnetoelectric of sensory nerve fibers in cranial nerves V or (Table 1 and Fig. 2), either immediately or 30 minutes afterwards. Because these reflexes are mediated through brainstem pathways 14, this suggests that the effect on TMS-evoked responses occurred because of a prolonged change in excitability of the cortical swallowing center. This would be compatible with the observation that the pharyngeal responses to TMS increased in amplitude without a concurrent shift in latency. The latency of the response includes time taken for excitatory input to depolarize quiescent motoneurons in the bulbar motor nuclei. Thus, if excitability of these motoneurons were raised, then the time taken to reach firing threshold would be reduced, and the response latency should fall. Because we found no reduction in latency after pharyngeal, it is reasonable to presume that brainstem excitability remained constant and to attribute the larger response to a greater, or longer lasting, input from a more excitable motor cortex. This interpretation was substantiated in another subject by showing that prior pharyngeal had no effect on the size of responses evoked by transcranial electrical (TES) of the motor cortex, despite showing an effect with TMS. The TMS was randomly intermixed with TES, to ensure that the subject was unaware which stimulus was going to be presented (Table 1). TES tends to activate corticospinal axons directly rather than trans-synaptically (in contrast to TMS) 15, so that the size of responses to Table 2 Topographic mapping data for each subject pre- and postpharyngeal Pharynx Esophagus Representation Mean Amplitude Representation Mean Amplitude (number of sites) (µv) (number of sites) (µv) Subject Pre Pre Pre Pre a b c Representation is defined as the number of grid sites on the scalp grid that evoked a response. The mean amplitude is the mean value of the five largest responses. Data are also shown for subject five, in whom three studies (a, b, and c) were performed over a six-week period. 66 nature neuroscience volume 1 no 1 may 1998

4 article Fig. 4 MRI co-registration of scalp maps. A series of left lateral oblique surface brain MRI images from one representative subject are shown, onto which the topographic data (colored areas, increasing from red to yellow) have been coregistered 19. The central sulcus is indicated in blue. After pharyngeal, the representation of the pharynx on the anterior aspect of the precentral gyrus and middle and superior frontal gyri expands anterolaterally, whereas that of the esophagus contracts. TES are less affected by changes in cortical excitability than those evoked by TMS. This differential effect between TES and TMS, together with our reflex pathway findings, lead us to conclude that pharyngeal results in a prolonged change of mainly cortical excitability for the projection to swallowing muscles. CORTICAL SWALLOWING MOTOR MAPS We mapped the scalp area from which pharyngeal and esophageal EMG responses were evoked, before and after pharyngeal in five subjects. The size of the EMG response at each site was expressed as a percentage of the amplitude of the maximum response evoked in either the pre- or post- data (whichever was the greatest). The results were plotted in a color code on a two-dimensional grid as topographic maps (Fig. 3). The individual areas of representation and mean amplitudes are shown in Table 2. In all subjects, pharyngeal increased the area of pharyngeal representation in an asymmetric manner, gaining territory in an anterolateral direction. In contrast, the area of esophageal representation decreased asymmetrically, losing territory in a lateral direction (Fig. 3). Repeat studies in one individual showed that the changes were consistent (Table 2). Finally, we coregistered the scalp maps onto individual surfacerendered magnetic resonance imaging (MRI) brain scans (Fig. 4). This suggested that the increase in pharyngeal representation occurred within the anterior aspects of motor and premotor cortex (precentral gyrus, and middle and superior frontal gyri), whereas the decrease in esophageal representation occurred predominantly in regions within and anterior to premotor cortex (middle and superior frontal gyri). Clearly the enlarged pharyngeal area had expanded into the suppressed esophageal area. Discussion Our data demonstrate for the first time that the excitability and organization of human swallowing motor cortex can be altered in a sustained manner after sensory of the pharynx. Most notably, we observed that the increased pharyngeal excitability and decreased esophageal excitability persisted for at least 30 minutes. This reciprocal relationship between the two muscle groups might be related to the finding that in animals, of swallowing afferents can both excite and inhibit the firing of swallowing neurons in cortex 16. Pharyngeal might therefore enhance excitatory projections to areas of cortex controlling the pharynx, while favoring inhibition of areas controlling the esophagus. This could also explain the apparent expansion of the pharyngeal area into the suppressed esophageal area, resulting in a competitive reorganization of swallowing cortex (between pharynx and esophagus). The coregistered data appeared to show that the changes in the representation of pharynx and esophagus occurred in more rostral motor areas of cortex. This agrees with animal data 16,17 and with recent human functional imaging data (Soc. Neurosci. Abs. 23, 1275, 1997), demonstrating that projections to and from the swallowing tract are represented in these non-primary motor areas. However, the projections of the scalp maps onto the cortical surface are only approximate, so in the absence of direct data from of the brain surface, this conclusion must remain speculative. Our observations raise the possibility that pharyngeal may offer therapeutic possibilities for the rehabilitation of swallowing proble after cerebral injury. Following unilateral hemisphere stroke, one third of patients develop oropharyngeal dysphagia 18, putting them at increased risk of aspiration pneumonia and malnutrition. In most patients, swallowing usually recovers over several weeks, probably due to reorganization of swallowing motor areas in the undamaged hemisphere 13. This may be because swallowing has bilateral cortical representation, so there remains some substrate for swallowing control in the undamaged hemisphere, and these intact areas may be more susceptible to reorganization than injured areas in the damaged hemisphere. Thus, an approach that encourages this process could potentially have therapeutic value in restoring motor function. The effect of a ten-minute period of in our study lasted for 30 minutes. However, it is possible that the effects of more prolonged or repeated pharyngeal might be cumulative and therefore lead to an acceleration of swallowing recovery. Methods ELECTROPHYSIOLOGICAL TECHNIQUES. Subjects (n = 8) were healthy adult male volunteers (age range yrs, mean age 33 yrs). None reported any swallowing proble, and all gave informed written consent before the study, which was approved by the Salford Health Authority Ethics Committee. Transcranial focal of the cerebral cortex used a magnetic stimulator (Magstim 200, MAGSTIM Company Limited, Whitland, Wales) connected to either a 70 mm outer diameter figure-of-eight coil or an electrical stimulator (Model D50, Digitimer, Hertfordshire, England). Trigeminal and vagus nerve used the magnetic stimulator connected to a smaller 50 mm outer diameter figure-of-eight coil, placed over the face or neck respectively, as described 14. The EMG responses were detected from the pharynx and the upper esophagus using two pairs of bipolar platinum ring electrodes, built into a 3 mm diameter, intraluminal catheter (Gaeltec, Dunvegan, Scotland). Each electrode pair was connected to a pre-amplifier (CED 1902, Cambridge Electronic Design, England) with filter settings of 5 Hz-2 khz. Response signals were then collected through a laboratory interface (CED 1401 plus) at a sampling rate of 4-8 khz. Two solid-state strain-gauge transducers were also incorporated into the catheter, one between each electrode pair. This enabled the pharyngeal and esophageal electrodes to be maintained in position. Electrical of the pharynx was performed using the pharyngeal electrodes connected to an electrical stimulator (Model DS7, Digitimer) via a trigger generator (Neurolog System, Digitimer), which delivered stimuli (0.1 pulses, 280 V) at 10 Hz. nature neuroscience volume 1 no 1 may

5 EPERIMENTAL PROTOCOL. For each study, the volunteer sat comfortably in a chair, the cranial vertex was marked on the scalp, and the pharyngo-esophageal catheter was inserted transnasally. The optimal site for cortical magnetic was then determined, with the subject at rest, by discharging the figure-of-eight coil over the right hemisphere, using 100% stimulator output. The site evoking the greatest EMG response was identified and marked on the scalp. Next, a series of cortical s were performed over this position, commencing at a subthreshold intensity and increasing by 5% steps until a threshold intensity was found that evoked EMG responses of greater than 20 µv on at least 5 of 10 consutive trials.this site then was stimulated repeatedly at intensities of 90, 95, 100, 105 and 110 % threshold, in a randomized order. Ten stimuli were delivered at each intensity, with an interval of 5 s between stimuli. Electrical sensory of the pharynx was then performed for 10 min at an intensity (for a single test stimulus) that was just perceived by the subject. Following this, cortical was repeated at the above intensities immediately, at 30 min, and at 60 min after pharyngeal. At each interval, ten stimuli were delivered at each intensity, in random order, with an interval of five seconds between each. The individual mean values of the cortically evoked EMG responses across all intensities for each interval after pharyngeal were then compared with those evoked before pharyngeal, using two-way ANOVA. To further examine the level at which the changes in swallowing motor pathway excitability had occurred, similar studies were performed using transcutaneous magnetic of the trigeminal and vagus nerve in five subjects at rest (during TMS mapping studies, see below). In addition, TES of the cortex (with the anode placed over the site of maximal response following TMS) was performed in one subject at rest. Stimulation of the trigeminal and vagus nerves evokes reliable brainstem-mediated responses in the swallowing pathways, which would be affected if brainstem excitability changed 14, whereas TES predominantly evokes direct corticospinal axonal responses, which are less likely to be affected if excitability is altered within interneurons of cortex 15. In each of these experiments, stimuli were applied at 10% above threshold before, immediately after, and at 30 min after pharyngeal sensory. The EMG responses evoked at each stimulus site (ten stimuli for each site, in random order, five seconds apart) at each interval after sensory input were then compared with those evoked before, using two-way ANOVA. To determine the effects of pharyngeal on the topographic representation of the cortical swallowing pathways, five subjects underwent a further detailed single-hemisphere mapping study, one to four weeks later. In addition, one subject was studied on two further occasions at weekly intervals, one month after the first study, to assess intersession variability. Mapping was performed at 110% threshold intensity, determined independently prior to the mapping, and using a 12 cm by 9 cm scalp grid, comprising 70 points, over one hemisphere, with rows 2 cm apart anteroposteriorly and 1 cm apart mediolaterally, and oriented so that the most posterior and medial point on the grid was 2 cm posterior and 2 cm lateral to the vertex. Three stimuli were delivered to each grid point, in random order, at five-second intervals. Then the pharynx was electrically stimulated, and cortical mapping was repeated. Scalp maps representing the areas of response for pharynx and esophagus were then generated before and after pharyngeal. As an aid to anatomical localization, individual surface-rendered MRI brain images and the scalp maps were coregistered 19. After the TMS mapping, the three-dimensional coordinates of each of the grid points were identified using a digitizing pen system (Polhemus Isotrak system, Kaiser Aerospace Inc. Colchester, Vermont, USA), the subject biting on a custom-made bite-bar that houses six fiducial points. This gives the x, y and z coordinates of each grid point, referenced to a radio-frequency magnetic field transmitter. The MRI data were surface rendered and the mapping surface constructed for coregistration. The coordinates from both the TMS and MRI syste were then interpolated using a modified inversion solution method, and the colored contour map was transferred. Acknowledgements The authors thank Mr A. Hobson and Ms J. 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