Brain, Vol. 122, No. 12, 2259-2277,
December 1999
© 1999 Oxford University Press
Review article |
Air-puff-induced facilitation of motor cortical excitability studied in patients with discrete brain lesions
Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, Japan
Correspondence to:
Yoshikazu Ugawa, Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Abstract |
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Air-puff stimulation applied to a fingertip is known to exert a location-specific facilitatory effect on the size of the motor evoked potentials elicited in hand muscles by transcranial magnetic stimulation. In order to clarify its nature and the pathway responsible for its generation, we studied 27 patients with discrete lesions in the brain (16, 9 and 2 patients with lesions in the cerebral cortex, thalamus and brainstem, respectively). Facilitation was absent in patients with lesions affecting the primary sensorimotor area, whereas it was preserved in patients with cortical lesions that spared this area. Facilitation was abolished with thalamic lesions that totally destroyed the nucleus ventralis posterolateralis (VPL), but was preserved with lesions that at least partly spared it. Lesions of the spinothalamic tract did not impair facilitation. The size of the N20–P25 component of the somatosensory evoked potential showed a mild correlation with the amount of facilitation. The facilitation is mainly mediated by sensory inputs that ascend the dorsal column and reach the cortex through VPL. These are fed into the primary motor area via the primary sensory area, especially its anterior portion, corresponding to Brodmann areas 3 and 1 (possibly also area 2), without involving other cortical regions. The spinothalamic tract and direct thalamic inputs into the motor cortex do not contribute much to this effect. Some patients could generate voluntary movements despite the absence of the facilitatory effect. The present method will enable us to investigate in humans the function of one of the somatotopically organized sensory feedback input pathways into the motor cortex, and will be useful in monitoring ongoing finger movements during object manipulation.
transcranial magnetic stimulation; sensory cortex; motor cortex; thalamus; air-puff stimulation
FPB = flexor pollicis brevis; M1 = primary motor cortex; MEP = motor evoked potential; NV = nucleus ventralis of the thalamus; S1 = primary sensory cortex; SEP = somatosensory evoked potential; TMS = transcranial magnetic stimulation; VPL = nucleus ventralis posterolateralis of the thalamus
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Introduction |
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The importance of sensory feedback information in performing skilled finger movements is obvious when we consider the difficulty one experiences in tying shoelaces while wearing gloves, even if they are thin plastic gloves that do not mechanically obstruct the movements of the fingers. As another example, imagine practising typing in the air, i.e. without touching the keyboard. Finger movements by themselves could provide some proprioceptive information from the joints, but it would be difficult to continue typing without the aid of tactile input from the fingers. This implies that, although proprioceptive inputs from the joint and muscle receptors are undoubtedly essential for voluntary movements, cutaneous inputs are also essential for guiding ongoing skilled finger movements (Edin and Abbs, 1991
; Edin and Johansson, 1995). While these feedback inputs have been studied mainly in association with the production of long-loop transcortical reflexes (Garnett and Stephens, 1980; Jenner and Stephens, 1982; Palmer and Ashby, 1992; Maertens de Noordhout et al., 1992; Ohki et al., 1994), they may also be important for the continuous adjustment of motor output (Asanuma, 1989). In order for such peripheral sensory inputs to be organized for skilled movements, they should somehow be fed into the motor cortex (Fig. 1).
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Sensory input to the primate motor cortex arrives both directly through the thalamus and indirectly via the somatosensory cortex (Asanuma et al., 1980
); the direct inputs ascend the dorsal column whereas the indirect inputs are mediated through both the dorsal column and the spinothalamic tract. It is also known that the collaterals of afferents travel in the dorsal columns, which themselves ascend in the ventral white matter as part of the spinothalamic tract (Revola and Padel, 1989). Many studies suggest a co-operative role played by each of these multiple pathways, either between the dorsal column and the spinothalamic tract at the lower level, or between the direct and indirect pathways at the thalamic level, for conveying sensory information into the motor cortex before and during the execution of a motor performance (Travis and Woolsey, 1956; Asanuma et al., 1974; Tatton et al., 1975; Asanuma and Arissian, 1984).
Using transcranial magnetic stimulation (TMS), we have demonstrated previously that air-puff stimulation applied to a fingertip produces a location-specific facilitatory effect on the amplitudes of motor evoked potentials (MEPs) in the hand muscles attached to that finger (Terao et al., 1995). This study indicated that the effect is produced in the primary motor cortex (M1) and suggested that cortical efferent zones in the human motor cortex, as demonstrated in primates, receive sensory information from the portion of the limb that is close to the muscle to which they project (Asanuma and Rosén, 1972; Rosén and Asanuma, 1972). Favorov and colleagues proposed a theory, called the `preferential bias theory', which asserts that sensory inputs into the motor cortex change the excitability of the neurons in the cortical efferent zones that are specifically involved in a movement to be executed in the near future by circulating impulses between the cortical columns and the periphery, thereby preparing the neurons for the movement well before it begins (Favorov et al., 1988). If the air-puff-induced facilitation of MEP involved a similar aspect of sensory feedback into the motor cortex, we would expect that the pathway responsible for its generation would play an essential role in guiding skilled finger movements.
Therefore, the goal of the present study was to investigate the pathway responsible for this somatotopically organized feedback input and to elucidate the nature of the sensory feedback input reflected in this facilitatory effect. It was expected that this method would provide us with a new and simple physiological technique for investigating the function of one of the sensory feedback input pathways into the motor cortex in humans.
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Subjects and methods |
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Patients
The following experiments were done with the approval of the Ethics Committee of the University of Tokyo. Twenty-seven patients with discrete lesions in the CNS [cerebral cortex, 16 patients (M1, one patient; S1, four patients; parietal cortex sparing most of S1, four patients; cerebral cortical lesion entirely sparing the sensorimotor areas, seven patients); thalamus, nine patients; brainstem, two patients] participated in the study. All the patients gave their written informed consent prior to the experiments. The clinical features and locations of the lesions are listed in Tables 1 and 2
. Of the 16 cortical lesions, eight were in the parietal cortex and involved the primary sensory cortex (S1), almost totally or partially. Of these eight lesions, four affected the anterior part of S1 (cases 1–4 in Table 1 and Fig. 3A), probably involving Brodmann areas 3 and 1, and possibly also area 2. Another four lesions were in the posterior parietal cortex and possibly affected the posterior portion of S1 but spared its anterior portion, mainly corresponding to Brodmann areas 5 and 7 (cases 6–9 in Table 1 and Fig. 3B). One patient had a lesion at the depth of the bank of the precentral gyrus (M1). In the other seven patients, the entire extent of M1 and S1 was spared.
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Sensory and motor functions
The following tests of sensory and motor functions were performed as part of routine neurological examinations: tactile, pain and thermal senses for superficial sensations; the presence or absence of dysaesthesia or paraesthesia, and their extent if present; positional (identification of joint positions and motion senses) and vibratory senses for deep sensations; the presence or absence of pseudoathetosis; two-point discrimination, graphaesthesia and stereognosis as tests of sensory discriminative abilities. Testing of motor functions included weakness of finger muscles, finger flexor reflexes reflecting possible involvement of the corticospinal tract innervating the finger muscles (the Wartenberg and Trömner reflexes), and disturbance of skilled finger movements such as those required for object manipulation. None of the patients included in this study had attentional deficits as revealed by neurological examination.
Transcranial electrical and magnetic stimulation
Before TMS, transcranial electrical stimulation was performed in each subject using an electric stimulator (Digitimer D180; Digitimer Ltd, Welwyn Garden City, UK) with the cathode placed over the vertex and the anode over the hand motor area. The latency of D waves (MEPs that are induced by cortical stimulation with the shortest latency and are presumed to consist of descending volleys produced by direct activation of the corticospinal neurons) was defined as the latency of MEPs induced by transcranial electrical stimulation, and MEPs evoked by TMS with a latency longer than this were considered to be produced by I waves (Day et al., 1989). Originally, 32 patients were studied, but five were excluded from further investigation because D waves were elicited with the lowest threshold both for electrical and magnetic stimulation; air stimuli have no facilitatory effect on D waves, probably because these waves are relatively independent of changes in cortical excitability (Maertens de Noordhout et al., 1992; Ohki et al., 1994; Terao et al., 1995).
The experimental procedures were the same as those described elsewhere (Terao et al., 1995). All subjects lay comfortably on a reclining chair and were asked to keep their hand muscles relaxed. TMS was given through a round coil (external diameter 14 cm) centred over the vertex using a magnetic stimulator (Magstim 200; Magstim Company, Whitland, UK). When obtaining responses from muscles of the right hand, coil current flowed anticlockwise as viewed from above, and the current was reversed for the muscles of the left hand. MEPs were recorded from surface electrodes (Ag–AgCl gel electrodes) placed over the belly and tendon of the flexor pollicis brevis (FPB) muscle. Signals were amplified through filters set at 100 Hz and 3 kHz, and were fed into a signal processor (DP1200; NEC Medical Systems, Tokyo, Japan). Air-puff stimulation (actually a continuous air flow of 0.867 l/min with a maximal pressure of 1.0 kgf/cm2), was applied to the volar aspect of the thumb tip with an air pump (AP-115RN; Rei-sea Company, Tokyo, Japan) through a plastic tube connected to a nozzle of 2 mm diameter without touching any part of the subject's body.
Vigilance monitoring
Monitoring the vigilance of patients was essential for studying the facilitatory effect. Care was taken to ensure that the subjects were fully awake throughout the experiments because this effect is known to disappear once the subject gets drowsy (Terao et al., 1995). Besides repeated inquiry about the subjective feeling of drowsiness between sessions, we monitored the vigilance of patients by recording the EEG with electrodes spaced widely over the scalp, including those used later for recording somatosensory evoked potentials (SEP) [F3, Fz, F4, C3' (2 cm posterior to C3), Cz, C4' (2 cm posterior to C4), O1 and O2]. In addition, we monitored changes in the sizes of MEPs in consecutive trials because they became quite small and variable as soon as the patients were drowsy. We discarded the data of all sessions during which drowsiness was suspected either from the EEG recording or from the changes in MEP sizes.
Partly because it was difficult for some patients to remain alert for a long time, and because the facilitatory effect was most notable on thumb muscles, we decided to study only the FPB muscle and not other finger muscles (the first dorsal interosseous and abductor digiti minimi muscles were also studied in the previous investigation). At least three or four different intensities of cortical stimuli were selected so that, given alone, they evoked control MEPs of around 0.1, 0.2, 0.5 and 1.0 mV in each relaxed muscle. In order to ensure that the muscle under study was relaxed during the experiments, high-gain audiovisual feedback was provided to both the subject and the examiner. For this purpose, an oscilloscope was connected to a loudspeaker with the gain set at 100 µV/division. All trials contaminated by unintentional muscle contraction and trials in which the subject became drowsy were discarded from analysis. In nine of the 16 patients with cortical lesions (cases 1, 2, 4, 6, 10, 12 and 14–16 in Table 1
) and four of the nine subjects with thalamic lesions (cases 19, 22, 23 and 24 in Table 2), we examined the facilitatory effect bilaterally, i.e. we recorded MEPs from the right FPB when air was applied to the right thumb and from the left FPB when air was applied to the left thumb. In the other patients we studied only the FPB on the side contralateral to the lesion because these patients could not keep their muscles relaxed for a long time and we were not able to collect sufficient data for many sessions. In three cases with lesions involving both hemispheres (cases 6 and 14 in Table 1 and case 24 in Table 2), we studied the facilitatory effect bilaterally and obtained significant facilitation of similar magnitude for the two sides, and the data on MEP size ratios (see below) for the two sides were therefore pooled. For the remaining cases we report mainly the results of facilitation of MEPs on the side contralateral to the lesions, since the facilitatory effect of air stimuli on the ipsilesional side was always normal.
Data collection and analysis
We used a paradigm in which conditioning (air-puff stimuli) and testing (cortical stimuli) were randomized. Responses were obtained when TMS was delivered alone (test trials) and when the onset of air-puff stimulation preceded the magnetic pulse by 0.2 s (conditioned trials; since the air stimulus used consisted of continuous air flow, the duration of the air-puff was 0.2 s). In each session, the test and conditioned trials were intermixed in random order until we had collected eight to 15 responses for the conditioned trials and 10–20 responses for the control trials. We measured the peak-to-peak sizes of single responses in each muscle and calculated their mean and standard deviation. The sizes of the control and conditioned responses were then compared using the unpaired Student's t test. For each session of the experiment, the mean amplitude of each condition was expressed as its ratio to the mean amplitude of the control response (MEP size ratio). If the ratio was significantly greater than 1 (P < 0.05), we judged that air stimuli had a facilitatory effect on the MEP. We investigated how the facilitatory effect changed with the location and extent of the lesion in each case.
The MEP size ratio depends on the size of the control MEP as reported in our previous study, the ratio being large for small control MEPs (<0.5 mV) and small for large control MEPs (>0.5 mV) (Terao et al., 1995). Therefore, patients with significant facilitation were defined as those exhibiting significant facilitation in all of the sessions (at least three consecutive sessions) in which the sizes of the control responses were within the range of 0–0.5 mV. In contrast, patients who, despite being fully awake, failed to show any significant facilitatory effect in five consecutive sessions with control response sizes in this range were defined as lacking significant facilitation. The maximum and mean (± standard error) of size ratios across sessions with control MEP sizes <0.5 mV are presented in Table 3. Although the mean value correlated well with the maximal size ratio, it should be noted that the mean size ratio was sometimes much smaller than the maximum size ratio and was quite variable (i.e. its standard error was large), because the mean (± standard error) was calculated across sessions with various control sizes <0.5 mV.
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SEPs
In 14 out of 27 patients we also recorded SEPs after stimulation of the median nerve at the wrist from active electrodes placed over C3' (2 cm posterior to C3) and C4' (2 cm posterior to C4) with Fz reference using Viking IV [Nicolet Biomedical, Inc., Madison, Wis., USA]. The peak-to-peak amplitude of the N20–P25 component, recorded from electrodes contralateral to the applied sensory stimuli, was plotted as a function of the magnitude of the facilitatory effect, i.e. the MEP size ratio, in order to study the possible correlation of the two. Additionally, SEPs of 45 normal volunteers (26 males and 19 females), ranging in age from 27 to 81 years, were recorded to obtain the normal value of the N20–P25 component (4.12 ± 2.59 µV).
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Results |
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Characteristics of facilitated and unfacilitated MEPs
Figure 2
illustrates the results in one patient (case 2 in Table 1 and Fig. 3A, two lower panels) with a lesion affecting the bank to gyral portion of the left primary sensory area. The MEP size of the right FPB, contralateral to the lesion, was not facilitated by air stimulation applied to the tip of the thumb (Fig. 2, top row; control response size ~0.3 mV). This lack of facilitatory effect was also observed for other control response sizes (0.1, 0.5 and 1.0 mV, not shown in this figure). In contrast, for similar control response sizes, air stimulation clearly facilitated the MEP of the left FPB (bottom row). We proceeded to investigate the locations of lesions in patients with and without facilitation in order to study the correlation between the locations of lesions and the presence or absence of significant facilitation.
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Locations of lesions in patients with and without facilitation
We studied 16 patients with discrete cortical lesions (Table 1
). Of these patients, five had lesions confined to the primary sensorimotor area. Significant facilitation was absent in these patients (cases 1–5, four patients with lesions in the postcentral gyrus and one patient with a lesion in M1). On the other hand, 11 patients (cases 6–16) had cortical lesions sparing most or all of the primary sensorimotor area. These included four patients with lesions in the parietal cortex just posterior to S1 with possible encroachment on its caudal portion (cases 6–9), and seven patients in whom the entire extent of S1 and M1 was spared (two with a parietotemporal lesion, one with a left temporal lesion, two with a frontal lesion, one with combined frontal and parietal lesions and one with a left occipital lesion). Air-puff-induced facilitation was invariably preserved in these seven patients, but the MEP size ratio was somewhat small in some of the former four patients. When the locations of lesions are plotted on a schematic diagram (Fig. 3C; left panels for patients with facilitation, right panels for patients without facilitation), we see that the facilitatory effect was absent in patients with lesions in S1, especially its anterior portion, or in M1, whereas it was normal in patients with a cortical lesion sparing the primary sensorimotor areas or affecting only the posterior portion of S1.
In six out of nine patients with thalamic lesions, air-puff-induced facilitation was noted in the FPB muscles contralateral to the lesion (Table 3). Generally, the effect was abolished when the lesion involved all (Table 2, case 18) or almost all (cases 17 and 19) of the nucleus ventralis (NV) posterolateralis (see also Fig. 4A), while it was preserved if part of this nucleus remained intact (cases 20–25) (Table 2 and Fig. 4B). In particular, it should be noted that normal facilitation was obtained in three subjects who had lesions affecting the presumed locations of the motor thalamus but sparing most of the VPL nucleus; case 23 in Table 2 had a lesion that extended to the border zone between NV lateralis and the VPL nucleus, probably corresponding to the NV posterolateralis pars oralis, but the lesion also involved part of the VPL nucleus. Case 22 in Table 2 received thalamotomy in the nucleus ventro-oralis anterior and posterior (both of these are part of the NV lateralis). Case 25 had a lesion that mainly affected the mediodorsal and centromedian nuclei.
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In patients with cortical and thalamic lesions, the extent of lesions affecting the sensorimotor cortex or the VPL nucleus of the thalamus was related to the presence or absence of the facilitatory effect.
The facilitation did not necessarily disappear even when the lesion partly ablated the VPL nucleus (e.g. see cases 21 and 23 in Fig. 4B). We were able to differentiate between two groups of thalamic patients on clinical grounds: (i) patients in whom the thalamic lesion was relatively large and whose sensory symptoms were grave (cases 17–19 in Table 2); and (ii) patients whose lesions were of small to moderate size and who had relatively mild sensory symptoms (cases 20–25). The ratio was significantly smaller for patients with severe damage to the VPL nucleus than for patients in whom the damage to VPL was mild (Fig. 5, right). For the first group of patients, the MEP size ratio ranged from 0.84 to 1.12 and averaged 0.97 ± 0.08 (mean ± standard error); for the second group the ratio ranged from 1.50 to 2.41 and averaged 1.95 ± 0.14; significant differences existed between the two groups (Student's t test, P = 0.00045). In general, the N20–P25 component of the SEP was greatly diminished or absent in the first group of cases, suggesting severe damage to the VPL nucleus, whereas it was spared in the second group.
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A similar effect of lesion extent was noted in patients with cortical lesions. No facilitation was noted in any patients with lesions destroying either the anterior portion of S1 or the M1 (cases 1–5), whereas lesions that at least partly preserved these cortical regions were always associated with significant facilitation (cases 6–16). Figure 5
(left) shows a comparison of the mean size ratios for the three groups of patients; patients with lesions affecting M1 or the anterior portion of S1 (cases 1–5) had the smallest MEP size ratio [the maximal MEP size ratio ranged from 0.97 to 1.18, with an average of 1.08 ± 0.04 (mean ± standard error)]. On the other hand, patients with lesions sparing the entire extent of S1 and M1 had a large MEP size ratio (in cases 10–16 the maximal ratio ranged from 1.47 to 4.55 with an average of 2.81 ± 0.36). In patients with parietal lesions just posterior to S1 with possible encroachment on its caudal portion (cases 6–9), the maximal MEP size ratio displayed intermediate values, ranging from 1.52 to 1.99 with an average of 1.72 ± 0.11. The cases with anterior S1 lesions had maximal MEP size ratios significantly smaller than those of the latter two groups of patients (Cases 6–9 and 10–16) (Student's t test, P = 0.0051 and P = 0.0031). The grand average of the mean size ratio calculated for normal subjects in our previous study (range 1.76–6.67, average 3.21 ± 0.31) did not differ significantly from those calculated across cases with significant facilitation [Student's t test, P > 0.1 for both cortical (cases 6–16) and thalamic lesions (cases 20–25)], but was significantly greater than those calculated across cases lacking significant facilitation [Student's t test, P = 0.016 and P = 0.012, respectively, for cases with cortical (cases 1–5) and thalamic lesions (cases 17–19), in whom significant facilitation was absent].
Sensory symptoms in patients with and without significant facilitation
Patients with cortical lesions
We describe the sensory symptoms of patients with cortical lesions for the three groups as classified above according to the extent of lesions, namely those with lesions affecting the primary sensorimotor area (cases 1–5), those having posterior parietal lesions with possible encroachment on the caudal portion of S1 (cases 6–9) and those with lesions sparing the entire extent of the primary sensorimotor area (cases 10–16).
Patients with primary sensory cortical lesions (cases 2–4 in Table 1 and Fig. 3A; case 1 was not examined in detail) displayed not only mild to moderate disturbance of superficial (touch, pain and thermal senses) and deep sensations (positional and vibration senses), but also mild to severe impairment in sensory discriminative tests such as stereognosis, two-point discrimination and graphaesthesia. They felt the sensation of the air-puff being applied, i.e. they felt that the air-puff was cool, felt the pressure of the air-puff and recognized the part of the finger to which the air-puff was applied, although the magnitude of the sensations perceived was somewhat diminished. Case 5 (M1 lesion) will be described later. As stated above, facilitation was abolished in these patients.
Cases 7–9 (Fig. 3B) had lesions affecting the posterior parietal cortex, which possibly extended into the caudal portion of S1, as suggested by the mild impairment of superficial sensations. In three of these cases, both deep sensations and sensory discriminative abilities were preserved. Case 6 also exhibited mild disturbance of deep sensations, but stereognosis, two-point discrimination and graphaesthesia were almost normal (case 6 will not be considered further in this paper because the parietal lesion in this case could have been due to congenital brain malformation). In the remaining patients with lesions totally sparing S1 (cases 10–16), there was no deficit either in superficial or deep sensations, as expected from the location of the lesions. Significant facilitation was preserved in these two groups of patients.
No overt weakness was noted in any of these 16 cases. Motor symptoms were virtually limited to those of skilled finger movements such as those required for the manipulation of objects, which was noted only in cases 1–4, whose lesions affected the anterior portion of S1. The impairment of finger movements will be described in the following section.
Comparing cases 2–4 without significant facilitation and cases 7–9 with preserved facilitation, the symptoms that correlated best with the presence or absence of the facilitatory effect were the sensory discriminative abilities tested with two-point discrimination, graphaesthesia and stereognosis.
Patients with thalamic lesions
Most patients with thalamic lesions (cases 17–21, 23 and 24 in Table 2) complained of dysaesthesia and mild numbness of the fingers on the side contralateral to the lesion. Disturbances of deep sensations and sensory discriminative abilities were seen only in cases 17–19 (Table 2). These cases lacked significant facilitation, although the patients felt the coolness and pressure of the air-puff stimuli and recognized the part of body to which air was being applied. Disturbance of skilled finger movements was also noted in these cases. However, since the lesions possibly affected part of the posterior limb of the internal capsule, as demonstrated by mild weakness and the presence of finger flexor reflexes, the symptoms were not readily distinguishable from those resulting from partial damage to the corticospinal tract or those due to disturbance of positional senses.
Clinical description of interesting cases
In the following, we describe some of the interesting cases in further detail.
Patients with primary sensory cortical lesions (cases 1–4 in Table 1)
Interestingly, some patients with primary sensory cortical lesions presented with a peculiar type of clumsiness in skilled finger movements that could be ascribed neither to hemiparesis resulting from corticospinal tract involvement nor to severe loss of joint position senses, because the impairment of deep sensations, although present, was rather mild. Case 2 in Table 1 (subcortical haemorrhage in the primary sensory cortical area) did not show any weakness from the onset. He did not have much difficulty in manipulating objects with his fingers, such as when writing with a pen, as long as he looked at them. However, without visual guidance he soon became unsure whether he was holding the object securely and sometimes even dropped it despite being aware that something was touching his finger. Vibration and position senses on routine neurological examinations were relatively preserved in this patient, but two-point discrimination was severely impaired. Barognosis was mildly affected. These symptoms had persisted since the onset and had not shown any sign of improvement after 7 years of follow-up. Case 4 (lesion in the right postcentral gyrus) exhibited a similar symptom, which was characterized by a similar difficulty in handling objects without continuous visual guidance. Although no overt paresis was present, he could not fasten the buttons of his shirt without looking at his hands. It was also difficult for him to differentiate between two kinds of coins, even of different sizes, by touch alone, indicating disturbance of two-point discrimination. Writing with a pen was also difficult for him even under visual guidance; this difficulty was significantly aggravated without visual input. Astereognosis had persisted from the onset but was mild to moderate, and there was no pseudoathetosis. Case 3 in Table 1 presented with mild left hemiparesis, but this subsided almost completely within a few days. However, he frequently dropped things, and he reported that he required continuous visual monitoring throughout object manipulation. He also suffered from mild astereognosis, but his joint position senses were only slightly impaired. Sensory extinction or inattention was absent in all of these patients. Another patient with a primary sensory cortical lesion (case 1 in Table 1) was not examined in detail.
To summarize, the disturbance of light touch perception as well as thermal and pain sensations was mild to moderate, and vibratory sensation was not affected. Impairment of positional sense was present but relatively mild. The most impressive finding in these patients was mild to severe disturbance of discriminative sensory abilities, including stereognosis, two-point discrimination and graphaesthesia, which persisted for a long time without recovery. Weakness was quite mild to almost absent from the onset of disease, and diminished within a few weeks. The patients found relatively little difficulty in the skilled manipulation of objects under visual monitoring, but this was aggravated soon after it was lost. This combination of symptoms was consistent with lesions of the parietal cortex (Corkin et al., 1970; DeJong, 1979). The symptoms were also suggestive of those described by Hikosaka and colleagues in a primate study, in which reversible inactivation of the somatosensory cortex by injections of muscimol selectively disrupted fine manipulative finger movements but did not disturb reaching and hand-shaping, which required visual guidance (Hikosaka et al., 1985). Air-puff-induced facilitation was not induced in any of these patients.
Patient with a lesion at a depth to the bank of the precentral gyrus (case 5 in Table 1)
This 71-year-old male initially presented with dysarthria and mild left hemiparesis. The symptoms diminished within a few days and the only neurological abnormality detected at this time was slight abduction of the left little finger when he was instructed to put all his fingers together, suggesting mild corticospinal tract involvement. He has not complained of any disturbance in fine finger movements since the initial symptoms subsided. MRI of the brain revealed a discrete infarction confined to the depth of the anterior bank of the right precentral gyrus (Fig. 6, left). TMS at various levels of the CNS was also performed according to the methods of Ugawa and colleagues (Ugawa et al., 1996). The latency of MEP recorded in the contralateral FPB was 20.0 ms with TMS at the cortical level, 17.9 ms at the level of the foramen magnum and 14.2 ms at the spinal level. These values were all within normal limits, demonstrating the integrity of corticospinal tract function innervating the FPB muscle. Significant facilitation was absent in this patient, who had normal sensory and motor function.
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Patient in whom seizures were induced by sensory inputs and the interictal spikes were localized to the parietal cortex (case 10 in Table 1
)Another case of note was a 20-year-old male patient with a form of partial seizure that could be induced by sensory inputs. There was no damage around the perinatal period and his development was normal. His clinical history had been uneventful until age 14, when he had his first seizure. This was a general convulsive seizure with loss of consciousness lasting ~1 min. A week later he had a similar attack. He was referred to a doctor, and was given a diagnosis of epilepsy on the basis of EEG findings, which showed interictal spike and wave complexes mainly in the left frontal and central leads. Since then he had been taking a dose (200 mg) of phenobarbital daily. He had experienced ~10 such seizures, especially on cold days when he forgot to take his regular dose. At the beginning of the attacks the fingers of his right hand suddenly became clenched, and sometimes, as he tried in vain to open them, he became unconscious. MRI of the brain revealed no structural abnormalities. What was peculiar was that the patient could induce an attack himself by rubbing objects with a rough and irregular surface strongly against the dorsum of his right hand, whereas simple tactile as well as simple thermal and pain stimuli, whether innocuous or noxious, were never effective in inducing them. Magnetoencephalographic recordings localized most of the interictal spikes to the left supramarginal gyrus and some to the contiguous caudal portion of the postcentral gyrus. No attack was induced by air-puff stimulation during the present experiment, although this stimulation produced a significant facilitation of MEP size.
The facilitatory effect and SEP
Overall, there was a mild correlation between the amplitude of the N20–P25 component and the MEP size ratio (r2 = 0.219, P = 0.043; Fig. 7). Accordingly, we observed a general tendency for the size of the N20–P25 component to be small (mean ± standard error 1.68 ± 0.89 µV) for patients without significant facilitation and for whom the MEP size ratio was also small (Table 3). Conversely, patients with significant facilitation tended to have a larger N20–P25 component (7.71 ± 1.08 µV). A significant difference was noted between the two groups of patients (Student's t test, P < 0.0005).
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Case 2 in Table 1
had a lesion confined to the left postcentral gyrus. The SEP waveform lacked a discernible N20–P25 component, and the only remaining component was the frontal negative wave, which was taken to reflect the direct thalamic inputs into the motor cortex. This case has been reported in detail by Sonoo and colleagues (Sonoo et al., 1991). In this case the facilitatory effect was abolished (MEP size ratio = 1.07 ± 0.12).
The facilitatory effect in patients with Wallenberg's syndrome
We examined two patients with Wallenberg's syndrome due to left medullary infarction (not shown in the tables). Both patients suffered from hemisensory disturbance of pain and thermal sensations on the right side of the body, and one of them also complained of burning pain on that side. MRIs of the brain disclosed an extensive lesion in the left medulla oblongata involving the entire extent of the left spinothalamic tract in each of the cases. In these patients, the facilitatory effect and the SEP were both normal. They reported that they felt the pressure of the air applied to the fingertip but not the coolness induced by the air flow.
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Discussion |
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The facilitatory effect is mediated by the contralateral sensorimotor area
In this study we showed that the facilitatory effect induced by air-puff stimulation was absent in patients with lesions in S1 and M1, whereas it was normal in patients with cortical lesions sparing these two areas. This suggested that the effect was mediated mostly by the sensorimotor cortices contralateral to the recorded hand muscle, i.e. the facilitatory effect was produced by sensory inputs fed into the sensorimotor area without the involvement of other cortical areas, including the supplementary motor area. The latter area is known to receive abundant projection from areas 1 and 2, and in turn projects densely to the primary motor area (Wiesendanger and Wiesendanger, 1984
; Tokuno and Tanji, 1993); the supplementary motor area was extensively destroyed in case 14 in Table 1 (Sakai et al., 1998) but the facilitatory effect was preserved.
Afferent pathways taken by the feedback inputs into the motor cortex
As stated in the Introduction, sensory input relayed through the thalamus can reach the M1 either by way of S1 or directly through the thalamus, both of which routes can lead to enhanced excitability of the motor cortex. Since lesions in either M1 or S1 alone can abolish the facilitatory effect, it is likely that the sensory inputs were transmitted through S1 into M1.
Other evidence also suggests that the sensory feedback pathway responsible for the effect took this indirect route. The facilitatory effect was absent in patients whose lesion destroyed the major part of the VPL nucleus of the thalamus (cases 17–19 in Table 2), whereas it was preserved in patients with thalamic lesions that also extended to the boundary zone between the NV lateralis and the VPL nucleus, where the NV posterolateralis pars oralis is presumed to be situated, but sparing some of the VPL nucleus (case 23 in Table 2). Asanuma and colleagues demonstrated in monkeys that thalamic neurons in this nucleus, located at the border of NV lateralis and VPL, received inputs from the dorsal column and projected directly to the motor cortex (area 4; Asanuma and Arissian, 1984; Asanuma et al., 1979), which constitutes the shortest circuit of proprioceptive feedback during motor performance (Lemon and Van der Berg, 1979). If this anatomy were also true for humans, the direct thalamic input into the motor cortex would not contribute substantially to the generation of the facilitatory effect investigated in the present study.
The facilitation was abolished in case 2 in Table 1, who had an S1 lesion and in whom the N20/P20–P27/N27 component of SEP was eliminated but the frontal negative wave of SEP was preserved (the frontal negative wave is a component considered to correspond to P22 of SEP in normal humans). In humans, the P22 component of SEP has recently been shown to represent the direct thalamic input into the motor cortex (Yumoto et al., 1996). These findings, taken together, also indicate that direct thalamic input to the motor cortex contributes little to the facilitatory effect. Thus, the effect appears to be mediated by the VPL nucleus into the sensory cortex without the involvement of the NV posterolateralis pars oralis, through which the direct thalamic input travels into the motor cortex. In cats, projection fibres from the VPL into the somatosensory area carry specific information, i.e. topographically organized and usually modality-specific inputs (Asanuma and Fernandez, 1974). On the other hand, inputs from the NV lateralis of the thalamus in cats (corresponding to NV posterolateralis pars oralis in primates) project directly and diffusely into the motor cortex, which carries non-specific and non-topographical information arising from the joints and periostea (Strick, 1973; Asanuma et al., 1974). These results are consistent with the idea that the sensory inputs generating the facilitatory effect travel through the thalamus and somatosensory cortex in a topographical manner, because our previous study demonstrated that the air-puff-induced facilitation is somatotopically organized (Terao et al., 1995).
The facilitatory effect was abolished in cases 1–4 in Table 1, in whom the lesion damaged the anterior part of S1 (Fig. 3A). In contrast, cases 7–9 in Table 1 had lesions affecting the posterior portion of S1 but relatively sparing its anterior portion (Fig. 3B), and the facilitatory effect was preserved in these cases. Together, these findings suggest the importance of the anterior portion of S1, probably corresponding to Brodmann areas 3 and 1, and possibly also area 2, in producing the air-puff-induced facilitation. In addition, the facilitatory effect was abolished in a patient with a discrete lesion at the bottom of the central sulcus extending to the bank of the central sulcus (case 5 in Table 1, and Fig. 6, left), which most probably disrupted the corticocortical projection fibres between the adjoining cortical areas, i.e. M1 and S1. Therefore, the sensory inputs producing the air-puff-induced facilitation probably travelled from the anterior portion of S1 into M1 through the corticocortical projection fibres running through this part of the subcortical white matter.
The peculiar clinical features of case 10 in Table 1, whose seizures were induced by sensory inputs applied to the hand, allowed us to speculate on the neural substrate responsible for generating the facilitatory effect. In this subject, interictal spikes were localized to the posterior portion of S1 and the adjoining supramarginal gyrus, which was more posterior, suggesting an interictal abnormality in these cortical regions. Seizure attacks were induced by rubbing objects with an irregular surface against the dorsum of his right hand, but never by elementary sensory stimuli of a noxious or innocuous nature. Iwamura and colleagues found that most of the neurons in the anterior portion of S1 were devoted to the processing of elementary sensations, whereas neurons processing complex sensations, such as those required for active touch, were found more frequently in the posterior (caudal) portion of S1 (Brodmann areas 5 and 7) (Iwamura et al., 1985a, b). Gordon showed that the posterior part of area 5 is involved in relating limb movements to cutaneous and proprioceptive feedback in active touch (Gordon, 1978). Therefore it is possible that the seizures were never induced as long as the given sensory inputs were simple and only involved neuronal activities confined to the anterior portion of S1, but were induced once the sensory inputs were complex enough to spread into the caudal part of the sensory areas and to aggravate the inherent abnormality, leading to abnormal discharges of the neurons in this cortical region. Since the facilitation in the present study could be induced using a simple sensory stimulus such as an air-puff, it is likely that the facilitatory effect is produced mainly in the anterior portion of S1. In view of the known corticocortical connectivities between the sensory and motor cortex that have been established in primates (Jones, 1986), the major route taken by the afferent signals into the M1 is probably via S1 (areas 3a and 3b, and part of areas 1 and 2) with a subsequent relay to the motor cortex through areas 1 and 2.
Since normal facilitation was observed in two patients with extensive lesions involving the spinothalamic tract, the sensory inputs contributing to the facilitatory effect probably ascend the dorsal column, but not the spinothalamic tract. Recently, Danziger and colleagues described a case with an extensive transection of the thoracic spinal cord sparing only part of the left anterolateral quadrant (Danziger et al., 1996). The patient could detect tactile stimuli applied to the lower limbs by von Frey hairs, but was unable to localize the site of stimulation or identify moving stimuli applied to the same region. PET studies in this patient showed that the sensory information applied to the lower limb reached the primary leg sensory area where, correspondingly, an increase in regional cerebral blood flow was noted. Compared with the activation pattern observed in normal subjects, however, the increase was not restricted to this specific region but extended well into the right foot and left hand areas of the sensory cortex. Therefore, although the sensory information did reach the sensory cortex in part by way of the residual spinothalamic pathway, the processing of information was presumably defective, with considerable loss of topographic selectivity. On the other hand, Tommerdahl and colleagues have shown that the selectivity of cortical activation during repetitive skin stimulation is considerably diminished after dorsal column transection (Tommerdahl et al., 1996). Thus, there probably exist multiple sensory input pathways into the motor cortex that are organized either topographically or non-topographically. The present facilitation employed one of the topographically organized pathways, mediated through the dorsal column.
Attention and the air-puff-induced facilitation
During air stimulation, attention is inevitably directed towards the fingertip, and this, rather than the sensory inputs themselves, could have played some role in producing the effect. However, our results showed that the cortical regions implicated in attention, such as the posterior parietal, prefrontal and cingulate cortices (Mesulam, 1981; Posner and Rothbart, 1992), were not involved in the production of the effect. There are reports of corticocortical connections to the motor cortex from Brodmann areas 5a, 5b and 7 in the cat (Babb et al., 1984). These areas did not seem to be involved in the generation of this effect because facilitation was preserved in patients with damage to these cortical regions. The results suggest that attention, in the usual sense, may not be involved in the facilitation of MEP.
In our previous study (Terao et al., 1995), we investigated the same facilitatory effect on three finger muscles (FPB, first dorsal interosseous and abductor digiti minimi muscles). We excluded attention as the major contributor to the facilitatory effect by arguing that an effect exerted through an alteration of the attention level would not be diffuse rather than focal, and would facilitate the MEPs of all these muscles. Indeed, the facilitatory effect was focal in that air stimuli applied to the tip of the thumb facilitated the MEPs of only the FPB and the first dorsal interosseous but failed to do so for the abductor digiti minimi, while air stimuli applied to the little finger facilitated the MEP of the abductor digiti minimi but not those of the FPB and the first dorsal interosseous, and so on. Secondly, we studied relaxed as well as active muscles and obtained the same results with regard to facilitation. In this case, the level of attention paid to the thumb would not have changed drastically whether or not air was applied to the thumb, since the subject would have had to pay attention to this finger anyway in order to maintain the active contraction.
In the present study, the subjects' attention, directed towards the air stimuli or towards the fingers to which air was applied, tended to abate progressively with repeated trials in a single session and also with repeated sessions, but this was not accompanied by a corresponding decline in the MEP size ratio. The facilitation did not diminish, even when the patients were overtly distracted from the air stimuli or from the finger, as long as they remained alert. Conversely, the MEP size ratio did not change significantly when the subjects were instructed to direct their attention actively towards the somatosensory stimuli. Therefore the major part of facilitation cannot be ascribed to the attention paid to the somatosensory stimuli or to that paid to the body part to which the stimulus is applied.
These observations notwithstanding, the role of attention cannot be entirely excluded. Iriki and colleagues demonstrated an attention-induced increase in the firing of primate S1 neurons engaged in a somatosensory detection task (Iriki et al., 1996). Similarly, PET scans taken from subjects directing attention towards somatosensory stimuli applied to their fingers have invariably demonstrated activation of S1 (Roland, 1981; Meyer et al., 1991) but not consistently of other cortical regions, including M1. Therefore, it is probable that the attention-related modulation is likely to arise primarily in S1 and that the excitability of M1 is subsequently enhanced by the afferent inputs arriving from S1 through the corticocortical link (projection fibres). Another possibility is that air stimuli applied, for example, to the tip of thumb changed the attention level of only the thumb-related motor cortex, inducing a location-specific intention to move; this special type of attention should then be generated primarily within M1. Although we consider that these two possibilities cannot explain the major part of the facilitatory effect, modulation of motor cortical excitability by somatosensory attention certainly warrants future investigation.
The nature of the sensory inputs producing the facilitatory effect
While there was a mild correlation between the size of the N20–P25 component of the SEP and the facilitatory effect, the two were dissociated in some cases [case 6 in Table 1 (bilateral parietal lesion), case 23 in Table 2 (thalamic lesion)]; in these cases the facilitatory effect was normal, although the N20–P25 component was diminished. We also observed a case of multiple sclerosis (not included in this study because the boundary of the lesion was not clear) with a lesion in the subcortical white matter of the parietal cortex, in whom the facilitatory effect was preserved despite the absence of the N20–P25 component. Impairment of superficial and deep sensations as well as those of fine finger movements were present but mild in this patient. This should imply that the production of the facilitatory effect does not depend on the nearly simultaneous arrival of afferent volleys into the sensory cortex, as is essential for the generation of the SEP (Chiappa et al., 1991), but it was present as long as the sensory inputs reached the sensory cortex. It may be that the excitability of cortical efferent zones was enhanced by sensory inputs regardless of whether the inputs arrived all at once or in an intermittent way. Since air stimulation of the fingertips consisted of a continuous flow of air and that the facilitation occurred with TMS delivered between 0.2 and 0.5 s after the onset of air stimulation, we may be looking at a steady state of enhanced excitability in the efferent zones, which takes some time to build up and then persists for a certain period.
The characteristic symptom seen in some patients (cases 2–4 in Table 1) with lesions in the primary sensory area suggests that such sensory inputs were necessary in the continuous monitoring of some types of ongoing finger movements. These patients were relatively good at manipulating objects under visual guidance, but, once they lost it, they soon became unsure about how they were holding the objects. Furthermore, the SEP demonstrated persistence of sensory inputs fed from the NV posterolateralis pars oralis into the motor cortex in one of the subjects (case 2 in Table 1), so that these direct inputs were not useful in such monitoring, in which skin contact with the object conceivably plays an important role.
The facilitatory effect and the extent of lesion
It was remarkable that in most patients with thalamic lesions, air-puff-induced facilitation was preserved even when the lesions apparently involved part of the sensory relay nuclei (VPL). For the effect to disappear, therefore, the lesion had to be extensive enough to destroy the major part of the VPL nucleus and to prevent any afferent inputs from arriving at the motor cortex. Accordingly, both deep and superficial sensations were impaired in patients without significant facilitation. A couple of explanations can be put forward for this. Since thalamic cells responsive to cutaneous inputs are situated in the central core of the ventrobasal complex corresponding approximately to the VPL nucleus in primates (Poggio and Mountcastle, 1963), almost total destruction of the VPL nuclei would be required in order to prevent any cutaneous sensation from reaching the sensory cortex. However, if at least part of the VPL nucleus remained intact, some sensory inputs could `crawl' into the sensory cortex. Such sensory inputs may be enough to produce the facilitatory effect. Another possible explanation is that, although there is a general coupling of inputs and outputs in the motor cortex, the coupling may not be restricted to a small, circumscribed cortical region (Murphy et al., 1978). The efferent zones of thumb muscles could also receive sensory inputs from the skin of parts other than the thumb itself, so that, for the facilitation to disappear, the lesion would have to block sensory inputs arriving from a more widespread skin region. This situation is also seen in Fig. 2 of our previous paper (Terao et al., 1995), which showed that the MEP of the FPB muscle was facilitated by air-puff stimulation applied especially to the tip of the thumb, but also to the tips of the index and middle fingers. Finally, reorganization in thalamocortical fibres could follow partial ablation of the thalamus, providing alternative pathways by which the sensory inputs could reach the motor cortex (Bornschlegl and Asanuma, 1987).
The facilitatory effect and voluntary movements
In case 14 in Table 1, as reported by Sakai and colleagues, the air-puff-induced facilitation was normal (Sakai et al., 1998). The integrity of the corticospinal tract was confirmed by TMS. However, the patient could not perform any voluntary movement because the intact right M1 was disconnected from other cortical regions necessary for the initiation of voluntary movements, such as the supplementary motor cortex, the premotor cortex and the motor cortex of the contralateral side. Meanwhile, some patients in whom facilitation was absent could perform voluntary, though clumsy, finger movements (e.g. cases 1–4 in Table 1). The data for these cases suggest that the integrity of this sensory feedback system was not indispensable for the generation of voluntary movements and that other inputs to the motor cortex were necessary. Jones and colleagues demonstrated that the motor cortex is reciprocally connected to the part of the sensory cortex that receives proprioceptive input from the periphery and suggested that proprioceptive inputs are more important in voluntary movement than exteroceptive inputs (Jones et al., 1978). This is consistent with our results, since we used exteroceptive stimuli for eliciting the facilitatory effect.
In conclusion, the sensory inputs responsible for the facilitatory effect ascend the dorsal column into the VPL nucleus and, through the somatosensory cortex, are finally fed into the motor cortex. Other cortical regions did not contribute substantially to this facilitatory effect. This may constitute one of the peripheral input pathways into the motor cortex, providing it with continuous and somatotopically organized sensory feedback information. This pathway is distinct from that which travels through the motor thalamus directly into the motor cortex, which is more related to voluntary movements, but which is not somatotopically organized. The implication of the present study is that, by applying air to the fingertips, we can establish a transient corticocortical link between the primary motor and sensory cortices, which should likely be within mono- or oligosynaptic distance of each other. In our subjects this link was set up without active participation on the part of the subject, requiring only the maintenance of alertness.
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We wish to thank doctors in the departments of neurology at the Tokyo University Hospital, Kanto Teishin Hospital and Yokohama Rosai Hospital for their helpful assistance. Some of this work was supported by fellowships for young scientists from the Japan Society for the Promotion of Science and grants from the Life Science Foundation of Japan and the research project grant-in-aid for Scientific Research No. 9670640 from the Ministry of Education, Sciences, Sports, and Culture of Japan. Part of the work reported here was presented at the 14th International Congress of EEG and Clinical Neurophysiology (Florence, August 24–29, 1997).
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Received February 16, 1999. Revised May 18, 1999. Accepted June 10, 1999.
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