Brain, Vol. 123, No. 9, 1939-1947,
September 2000
© 2000 Oxford University Press
Time-dependent activation of parieto-frontal networks for directing attention to tactile space
A study with paired transcranial magnetic stimulation pulses in right-brain-damaged patients with extinction
1 IRCCS `S. Lucia', 2 AFaR CRCCS Ospedale Fatebenefratelli, Isola Tiberina, 3 Clinica Neurologica, Università di Roma Tor Vergata, Rome and 4 IRCCS `S. Giovanni di Dio', Istituto Sacro Cuore, Brescia, Italy
Correspondence to:
M. Oliveri, `S. Lucia', Via Ardeatina, 306, 00194 Rome, Italy E-mail: maxoliveri{at}tiscalinet.it
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Tactile extinction has been interpreted as an attentional disorder, closely related to hemineglect, due to hyperactivation of the unaffected hemisphere, resulting in an ipsilesional attentional bias. Paired transcranial magnetic stimulation (TMS) techniques, with a subthreshold conditioning stimulus (CS) followed at various interstimulus intervals (ISIs) by a suprathreshold test stimulus (TS), are useful for investigating intracortical inhibition and facilitation in the human motor cortex. In the present work, we investigated the effects of paired TMS over the posterior parietal and frontal cortex of the unaffected hemisphere in a group of eight right-brain-damaged patients with tactile extinction who were carrying out a bimanual tactile discrimination task. The aim of the study was to verify if paired TMS could induce selective inhibition or facilitation of the unaffected hemisphere depending on the ISI, resulting, respectively, in an improvement and a worsening of contralesional extinction. In addition, we wanted to investigate if the effects of parietal and frontal TMS on contralesional extinction appeared at different intervals, suggesting time-dependent activation in the cortical network for the processing of tactile spatial information. Paired TMS stimuli with a CS and a TS, separated by two ISIs of 1 and 10 ms, were applied over the left parietal and frontal cortex after various intervals from the presentation of bimanual cutaneous stimuli. Single-test parietal TMS stimuli improved the patients' performance, whereas paired TMS had distinct effects depending on the ISI: at ISI = 1 ms the improvement in extinction was greater than that induced by single-pulse TMS; at ISI = 10 ms we observed worsening of extinction, with complete reversal of the effects of single-pulse TMS. Compared with TMS delivered over the frontal cortex, parietal TMS improved the extinction rate in a time window that began earlier. These findings shed further light on the mechanism of tactile extinction, suggesting relative hyperexcitability of the parieto-frontal network in the unaffected hemisphere, which is amenable to study and modulation by paired TMS pulses. In addition, the results show time-dependent processing of tactile spatial information in the parietal and frontal cortices, with a bimodal distribution of activity, at least in the attentional network of the unaffected hemisphere.
tactile extinction; neglect; paired TMS; fronto-parietal
CS = conditioning stimulus; ISI = interstimulus interval; TMS = transcranial magnetic stimulation; TS = test stimulus
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Tactile extinction is a disorder of perception after monohemispheric lesions, in which the patient is able to detect a single contralesional cutaneous stimulation normally, but fails to report it in conditions of bilateral simultaneous stimulation of homologous body surfaces (Bisiach, 1991
; Vallar et al., 1994; Vallar, 1998; Remy et al., 1999). The pathophysiology of tactile extinction is poorly understood, but it has been interpreted as an attentional disorder that is closely related to hemineglect, and is more frequently associated with right hemispheric lesions (Kinsbourne, 1977, 1993, 1994; Moscovitch and Behrmann, 1994; Vallar et al., 1994). These lesions usually involve a distributed anatomo-functional neural network subserving directed attention, relaying in the parietal and frontal areas of both hemispheres (Mesulam, 1990; Vallar et al., 1994; Vallar, 1998). The various network components are connected to each other by extensive and reciprocal monosynaptic connections and are likely to have strict callosal projections to homologous contralateral regions, providing a neural and dynamic balance between opposite systems of the two hemispheres.
According to a proposed attentional model, neglect or contralesional extinction after a unilateral hemispheric lesion could be the effect of an imbalance between the bilateral frontoparietal neural processes, resulting in disinhibition of the unaffected hemisphere (with consequent ipsilesional attentional bias), due to the release of the reciprocal modulation by callosal fibres from the affected one (Kinsbourne, 1977, 1993, 1994; Oliveri et al., 1999b).
In a previous study (Oliveri et al., 1999b), we tested this hypothesis by using single-pulse transcranial magnetic stimulation (TMS) to interfere transiently with the function of the unaffected hemisphere in a group of unilaterally brain-damaged patients carrying out a task consisting of the recognition of unimanual and bimanual cutaneous stimuli. The results demonstrated that the transient, functional disruption of frontal regions of the left hemisphere reduced contralesional tactile extinction in right-brain-damaged patients, providing indirect evidence for the `imbalance' hypothesis, which postulates relative (to the damaged hemisphere) hyperattention towards the ipsilesional corporeal space.
These findings left open the question of the presence and role of increased activity of attentional neurones in the unaffected hemisphere of patients suffering from tactile extinction. By using single-pulse TMS with the intention of delaying or worsening performance of the task at hand, we can provide only indirect evidence about the necessity of a brain region for a particular behavioural accomplishment, either by reducing a normal level of performance or, in the case of pathological hyperactivation, by revealing a `paradoxical gain of function' (Seyal et al., 1992, 1995; Ashbridge et al., 1997; Corthout et al., 1999a; Oliveri et al., 1999a; Walsh and Rushworth, 1999). With these paradigms, and in studies using repetitive TMS, the induced current is supposed to act by adding random noise and disrupting activity in the context of the cortical region or of the corticocortical circuitry involved in the cognitive task (Pascual-Leone et al., 1991, 1994, 1999; Walsh and Cowey, 1998; Walsh and Rushworth, 1999). In this way, stimulus-linked cognitive deficits do not always imply cortical inhibition per se (Pascual-Leone et al., 1999). On the other hand, TMS paradigms able to combine these interfering mechanisms with distinct facilitatory or inhibitory effects on the performance of a task could be useful in investigating the role played by interhemispheric imbalance in determining a particular deficit, such as tactile extinction. This goal might be achieved by paired TMS pulses, with a subthreshold conditioning stimulus followed at various intervals by a suprathreshold test stimulus. It has been demonstrated that this method can activate inhibitory or excitatory intracortical circuits of the motor cortex selectively, thus determining intracortical inhibition or facilitation, depending on the interval between the two stimuli [interstimulus interval (ISI)]. In particular, with short ISIs (1–4 ms) the test responses are inhibited, whereas with longer ISIs (8–15 ms) the test responses are facilitated (Kujirai et al., 1993; Ridding et al., 1995, 1999; Ziemann et al., 1996).
Following this theoretical framework, in the present study we tried to test in other, non-motor, areas the effects of paired TMS paradigms; in particular, we aimed to induce selective intracortical excitatory and inhibitory effects in frontal and posterior parietal regions of the unaffected hemisphere in a group of brain-damaged patients with tactile extinction who were carrying out bimanual tactile discrimination tasks. According to our initial hypothesis, if contralesional extinction really reflects relative hyperexcitability of attentional neurones of the unaffected hemisphere, paired TMS of the latter with ISIs that potentiate inhibitory cortical neurones should be associated with transient improvement in tactile extinction; on the other hand, double TMS pulses with ISIs that potentiate (or do not inhibit) cortical excitability should worsen, or at least leave unchanged, the pattern of contralesional extinction.
Another aim of the study was to verify whether the contributions of the frontal and parietal cortices to the processing of tactile spatial information have different time-courses. This question was addressed by tracing the effects of TMS of the parietal and frontal areas at various intervals after cutaneous stimulation.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients
Eight right-brain-damaged patients with radiological (CT or MRI) and clinical evidence of unilateral lesions were examined (Table 1
). All of them had suffered an ischaemic stroke and none had a history or evidence of previous cerebrovascular disease, dementia or psychiatric disorders. All subjects were right-handed, as assessed by the Edinburgh Inventory (Oldfield, 1971). They gave informed consent to participation in the study, which had the approval of the local ethics committee (IRCCS S. Lucia).
|
Patients were selected from a large group of stroke cases for the presence of tactile extinction. For this purpose, a preliminary assessment of somatosensory deficits was made, using a fixed sequence of random finger stimuli (15 unimanual ipsilesional, 15 unimanual contralesional and 15 bimanual simultaneous stimuli). Tactile extinction was considered to be present if, after bimanual cutaneous stimulation, the patient failed to perceive the stimulus from the left hand in >50% of the trials but perceived at least 80% of unimanual left stimuli.
At this preliminary assessment, all patients showed tactile extinction. The presence of extrapersonal visual neglect was assessed using standard tests (Pizzamiglio et al., 1989).
Tactile stimulation
After the preliminary assessment of extinction, experimental protocols were carried out to test the effects of TMS on contralesional extinction in the subjects. The subject sat comfortably in an armchair, with the hands supinated and the eyes/gaze directed straight ahead.
Because in our previous work we had failed to observe any significant effect of TMS on single contralesional stimuli, in the present experiments we used only fixed sequences of bimanual stimuli (the subjects were falsely informed that they could receive either unimanual or bimanual stimuli). Bimanual symmetrical electrical stimuli were delivered with pairs of surface electrodes applied around the first, third and fifth fingers of each hand (cathode on the first phalanx, anode on the second phalanx). Square-wave pulses, 0.3 ms in duration, were delivered by a dedicated electrical stimulator. Stimulus intensity was set at the level of subjective threshold for perception, determined during unimanual right/left stimulation. The sequence of finger stimulations was randomized and separated by a fixed interval.
TMS
Paired TMS was performed with two Novametrix MagStim 200 magnetic stimulators, connected via a BiStim module (Magstim Company, Dyfed, UK), using a figure-of-eight coil 70 mm in diameter. The coil was placed tangentially to the skull with the handle pointing backwards parallel to the midline, so as to induce a current flowing in a posterior–anterior direction in the underlying brain. Paired TMS stimuli were applied over a frontal and a parietal scalp site of the unaffected (left) hemisphere, corresponding to positions F3 and P3 of the 10–20 EEG system. These stimulation sites show some interindividual variability in their correlation with specific brain structures. On the other hand, anatomical localization of these positions on MRI scans and a three-dimensional brain reconstruction performed in previous studies (Oliveri et al., 1999a, b) has shown rough correspondence of the frontal site with the inferior frontal sulcus and of the parietal site with the intraparietal sulcus in the posterior parietal lobe.
The intensity of stimulation was determined in relation to the resting motor excitability threshold (ET), measured by standard methods (Rossini et al., 1994). The method of stimulation was similar to that used by Kujirai and colleagues (Kujirai et al., 1993), with a subthreshold conditioning stimulus (CS) followed by a suprathreshold test stimulus (TS). The CS was set at 70% of the resting ET and the TS intensity was 130% of ET. The ISIs used were 1 and 10 ms. These ISIs were selected, respectively, as the most inhibitory (disrupting) and most excitatory (facilitatory) intervals for the functioning of posterior parietal areas during a tactile discrimination task (recognition of contralateral tactile stimuli after paired-pulse versus single-pulse TMS) in a group of healthy controls. The two ISIs had similar (i.e. facilitatory and inhibitory) effects on the function of the motor cortex of the patient's unaffected hemisphere, as indicated by the amplitudes of the motor evoked potential.
Procedure
The electrical stimulator triggered the Bistim module after delays of 10, 20, 30 and 40 ms, controlled by a timer; delay was defined as the time between the arrival of the electrical stimulus on the fingers and the arrival of the electromagnetic TS on the brain.
Experiment 1: effects of single-pulse versus paired parietal TMS on contralesional extinction
In this experiment, we tested in each patient the difference between single-pulse and paired TMS at the two ISIs in the detection of contralesional stimuli. The experiment was performed in two blocks (one block for ISI = 1 ms and one block for ISI = 10 ms), each with four sequences of nine trials: nine baseline trials (bimanual finger stimuli without TMS interference); nine trials with bimanual stimuli followed by single-test TMS; nine trials with bimanual stimuli followed by single conditioning TMS; and nine trials with bimanual stimuli followed by paired TMS. The order of the trials was randomized within each block. TMS was delivered on the posterior parietal lobe at a fixed delay of 20 ms.
Experiment 2: effects of paired parietal and frontal TMS on extinction rate as a function of delay time
The patients performed a task with only paired TMS, in four blocks of trials (one block for each of four delay times: 10, 20 30, 40 ms). Within each block, four sequences of nine bimanual stimuli were followed by paired TMS pulses applied over the two scalp sites (frontal and parietal) at the two ISIs (1 and 10 ms), giving a total of 36 TMS trials x block. Baseline trials were intermingled at random with test conditions.
The sequence of the different experimental conditions was according to two blocked, computer-based randomization procedures. The first randomization was on the order of the four delay times (10, 20, 30, 40 ms); the second, executed within each delay time block, was run on the four stimulation conditions, namely frontal and parietal cortex at the two ISIs (1, 10 ms).
In both experiments, after the presentation of individual stimulus pairs (tactile + transcranial stimuli) the subject was requested to report verbally whether he or she perceived the tactile stimuli and to localize them.
Analysis
The mean percentage of contralesional extinction, as indicated by omitted responses to stimuli contralateral to the affected hemisphere, was evaluated in the different experimental conditions. In both experiments, the mean baseline performance was subtracted from the performance during the application of TMS pulses, and the resulting values were analysed (a negative value indicated an improvement in the recognition of contralesional stimuli, and vice versa).
In the first experiment, the effects on contralesional extinction of single-pulse versus paired TMS at the two ISIs were tested by repeated measures ANOVA (analysis of variance), with condition (single-pulse versus paired TMS) and ISI (1 versus 10 ms) as within-subjects factors. The mean percentage of contralesional extinction in trials with the conditioning stimulus alone was compared with the corresponding value for baseline trials by means of the paired t-test. Since the subjects' performance during these control trials was similar to that observed in baseline trials, they were not included as a separate variable in ANOVA.
In the second experiment, the effects on contralesional extinction of paired parietal and frontal TMS at the two ISIs and at different delay times were evaluated with repeated measures ANOVA, with condition (two levels: frontal and parietal), ISI (two levels: 1 and 10 ms) and delay time (four levels: 10, 20, 30, 40 ms) as within-subjects factors.
Tukey's post hoc comparisons were made where appropriate. The level of significance was set at 0.05 for all experiments.
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The mean conditioning stimulus intensity was 38.68 ± 3.45% and the mean test stimulus intensity was 73.31 ± 6.48% of the total stimulator output. No motor twitches or sensory perceptions were elicited by the intensities used.
Table 2 shows the mean number of contralesional extinctions, in baseline and test trials, in the various experimental conditions.
|
Effects of single-test versus paired parietal TMS on contralesional extinction
The patient's performance during the application of the conditioning TMS stimulus alone was not significantly different from that in baseline trials (mean percentage of contralesional extinction: 75.23 ± 19.47 versus 76.38 ± 18.33; P > 0.05, paired t-test).
Repeated measures ANOVA showed a significant ISI x condition interaction [F(1,7) = 27.27; P = 0.002) (Fig. 1). In particular, at the ISI of 1 ms, paired TMS over the left parietal cortex reduced the number of contralesional extinctions significantly more than single-pulse TMS stimuli (P = 0.02); at the ISI of 10 ms, paired TMS induced a slight worsening of performance compared with single test stimuli, which still improved the number of contralesional extinctions (P = 0.05). These results suggest that, whereas single-pulse TMS of the unaffected hemisphere improves contralesional extinction, conditioning–test TMS paradigms can show a dissociation between facilitatory and inhibitory effects depending on the ISI.
|
Effects of paired parietal and frontal TMS on extinction rate as a function of delay time
Repeated measures ANOVA showed a significant main effect of ISI [F(1,6) = 28.88; P = 0.001]. This reflected a huge difference in the performance level depending on the ISI between the conditioning and the test magnetic stimulus. In fact, paired TMS with the short ISI (1 ms) induced a sharp decrease in contralesional extinction compared with baseline (from 76.38 ± 18.95 to 62.88 ± 30.75%), regardless of the site of stimulation; on the other hand, when applying paired TMS pulses with 10 ms ISI, the number of extinctions was slightly higher than in baseline trials (78.65 ± 29.75 versus 76.38 ± 18.95%). The pattern of improvement in extinction with the 1 ms ISI was consistent across all the examined subjects; the pattern of worse extinction with the ISI of 10 ms was observed in five of eight subjects.
Figure 2 shows the pattern of contralesional extinction after the application of paired TMS pulses with ISIs of 1 and 10 ms over the frontal and parietal scalp sites as a function of the peripheral delay after the presentation of finger stimuli.
|
Figure 2A
clearly reveals the presence of two distinct periods of improvement in extinction induced by frontal versus parietal paired TMS with an ISI of 1 ms, the best performance being reached with a delay time of 30 ms during parietal TMS and of 40 ms during frontal TMS. The effect of parietal TMS was also evident at the delay time of 20 ms, whereas frontal TMS was almost ineffective at this interval. No significant TMS effects were found at the delay time of 10 ms. Paired TMS pulses with 10 ms ISI did not induce any significant variation in the tactile stimuli detection rate at either peripheral delay (Fig. 2B). The significance of the reported findings was substantiated by ANOVA, which showed a significant main effect of delay time [F(3,18) = 4.17; P = 0.02], a lack of significance of the condition effect [F(1,6) = 3.53; P = 0.10], and a significant condition x ISI x delay time interaction [F(3,18) = 4.43; P = 0.01].
Post hoc comparisons revealed a significant difference between the two ISIs when parietal TMS was applied at delay times of 20 and 30 ms from the presentation of finger stimuli (P = 0.009 and 0.003, respectively), whereas only a trend in the same direction (worsening and improvement of performance, respectively, with ISIs of 10 and 1 ms) was observed for frontal TMS at the delay time of 40 ms (P = 0.08). This mainly reflected the fact that, at the ISI of 1 ms, parietal TMS was more effective than frontal TMS in improving contralesional extinction, so that only in this condition could a striking difference between the two ISIs emerge.
Concerning the peripheral delay, the difference between the TMS inhibitory effects on the frontal versus parietal sites tended to be significant only for the delay time of 30 ms (P = 0.05) and, to a lesser degree, for 20 ms (P = 0.08). The important point here is that the parietal cortex shows control of corporeal spatial information at earlier times in the stimulus processing period compared with the frontal cortex.
There were no significant differences between the results in the different patients depending on the site of brain injury or duration of the deficit. In fact, in patients with longer disease duration (patients 6 and 8) (Table 1) and a different site of the brain lesion (patient 6), the effects on contralesional extinction produced by paired TMS were similar to those produced in the other patients.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The main results of the present study show that, in patients who had suffered a stroke in the right hemisphere and who had contralesional tactile extinction, selective intracortical inhibition of the unaffected hemisphere, via paired TMS pulses, was associated with a decrease in contralesional extinction. On the other hand, when paired TMS pulses were separated by ISIs exceeding the time epoch for inhibitory effects, performance was worsened or unchanged. Parietal inhibition appeared to be more effective than frontal inhibition in reducing contralesional extinction. In addition, there seemed to be two distinct periods during which the left frontal and left parietal cortex were sensitive to the facilitating effects of TMS on the perception of contralesional stimuli, the effect on the parietal cortex appearing significantly earlier than the effect on the frontal cortex.
These results add strong neurophysiological support to the theory of hemispheric imbalance, with relative hyperactivation of the unaffected hemisphere underlying contralesional space perception deficits in unilaterally brain-damaged patients (Kinsbourne, 1977, 1993, 1994; Smania et al., 1998). The resulting ipsilesional attentional bias, not detectable in conditions of unilateral contralesional stimulation, could be unmasked by the simultaneous presentation of an ipsilesional stimulus (as in bimanual discrimination tasks), activating the unaffected attentional neurones, which could therefore further inhibit the affected hemisphere and/or hyperorient attention towards the unaffected side of the body.
The mechanisms of this ipsilesional hyperorientation have not been elucidated in detail, particularly because of the lack of experimental methods that are able to measure excitatory/inhibitory phenomena directly in the cortical areas involved in spatial attentional tasks.
In the present study, we wanted to address this issue by using the technique of paired TMS, in order to distinguish the cortical disruptive action of the traditional single-pulse or repetitive TMS methods from the eventual induction of facilitatory or inhibitory effects on the activity of frontoparietal regions.
This method of stimulation has many potential applications, especially in the evaluation of the function of the motor cortex in several neurological disorders (Ridding et al., 1995; Ziemann et al., 1996). In the present study, we demonstrated for the first time that distinct effects can also be induced by paired TMS pulses in areas outside the motor cortex. Our results showed that a test stimulus that is disruptive per se can either inhibit or facilitate a performance if it is modulated within a particular time window by a preceding conditioning stimulation, which presumably acts on intracortical interneurones. It is worth noting that our conditioning stimulus was subthreshold not only for the motor but even for the sensory cortex, in that it did not alter the perception of contralateral stimuli at all. On the other hand, the test stimulus intensity was well above the threshold both for inducing motor responses and for suppressing tactile perception. In this sense, paired TMS can be viewed not only as a method for transiently mimicking a lesion, but also as a technique that is able to modulate excitability disorders subserving certain cognitive deficits. Obviously, further studies, involving larger and selected groups of patients with and without contralesional space perception deficits, will be needed in order to confirm these findings and to better clarify if the abnormal perception reflects defective inhibition or increased facilitation in specialized cortical networks.
Our findings can be interpreted as showing that paired TMS pulses with a short ISI transiently inhibited the fronto-parietal network subserving the distribution of attention in the left hemisphere, thereby reducing the stroke-dependent interhemispheric imbalance in conscious sensory perception. This mechanism of action, involving cortical functional inactivation, complements in human subjects the experimental work that has been done in cats and other animal models using cooling probes to study interhemispheric interactions in spatial attention. In fact, these studies showed that cooling the unaffected hemisphere largely reversed visual neglect and restored visual orienting in the previously neglected hemifield after unilateral lesions (Lomber and Payne, 1996; Payne and Lomber, 1999).
The absence in all patients of a clear worsening effect of paired TMS with the 10 ms ISI can probably be explained by the poor performance of three of the eight subjects, who detected only a small number of contralesional stimuli during the baseline trials, thereby showing a sort of ceiling effect. In addition, it is evident that, at the ISI of 1 ms, the disruptive effect of the test stimulus and the inhibitory effect induced by the conditioning stimulus acted concurrently in slowing the functioning of the unaffected hemisphere; on the other hand, at the ISI of 10 ms, the facilitatory effect of the conditioning stimulus was partly masked by the still-present disruption induced by the test stimulus alone. Finally, it is worth noting that the two ISIs were selected for their opposite effects on the function of the posterior parietal cortex, the dissociation being less marked during frontal TMS. Further studies investigating larger series of ISIs on various scalp sites during bimanual discrimination tasks could clarify these findings.
The different effects of TMS at different ISIs seem to argue against a contribution of non-specific factors (such as the TMS-associated click, scalp muscle contraction and blinking) to the observed improvement in extinction. On the other hand, our previous study had already addressed this problem by stimulating sham scalp positions (Oliveri et al., 1999b).
Neuroimaging studies suggest that there is normal function, or even a depression in the activity of the unaffected hemisphere, in patients with contralesional neglect or extinction (Perani et al., 1993; Remy et al., 1999). Indeed, behavioural studies in right-brain-damaged patients which show rightward hyperattention also reveal an overall level of performance of the left hemisphere lower than that of normal subjects, suggesting that the underlying hyperactivation of the unaffected hemisphere is relative to the damaged hemisphere rather than absolute (Smania et al., 1998; Bartolomeo and Chokron, 1999). Therefore, one can speculate that the relative hyperactivation of the left hemisphere during the chronic phases of extinction could be transient and limited to the moment of execution of bilateral sensory detection tasks. This period would be too short to be revealed by the poor temporal resolution of neuroimaging studies, while it could be detected easily by single-pulse or paired TMS, with a time of resolution in the order of milliseconds.
The other main finding of our study is the presence of two distinct periods during which the human parietal and frontal cortices in the unaffected hemisphere are vulnerable to TMS effects, parietal TMS ameliorating tactile extinction at earlier times and to a greater extent than frontal TMS. This suggests the presence of two periods of processing in the parietal and frontal cortices during the tactile exploration of space. In this sense, the power of TMS in terms of temporal resolution makes it a technique of choice for tracing its disrupting effects on different brain structures at different times on the subject's performance in a given task (Ashbridge et al., 1997; Ilmoniemi et al., 1997; Corthout et al., 1999a, b).
With regard to spatial attentional tasks, anatomical and neuroimaging studies have demonstrated the presence of a distributed large-scale anatomo-functional neural network relaying in three main cytoarchitectonic regions of both hemispheres: the dorsolateral posterior parietal cortex, the cingulate cortex and the dorsolateral premotor–prefrontal cortex, each providing a slightly different coordinate system for mapping the environment (Mesulam, 1990; Corbetta, 1998). The core cytoarchitectonic entities of these three regions are linked to each other by extensive and reciprocal monosynaptic connections. Neuroimaging studies suggest that all the three core components are probably engaged simultaneously and interactively by attentional tasks (Hillyard et al., 1995; Corbetta, 1998). On the other hand, the distribution of the latencies of the parietal and the frontal TMS effects in the temporal frame we examined points to the existence of a bimodal distribution of activity of attentional neurones in the unaffected hemisphere of unilaterally brain-damaged patients: a first contingent of cells starts to process sensory information in the posterior parietal lobe, and is followed a few milliseconds later by another group starting in the frontal cortex. Obviously, these considerations cannot be transferred automatically to the cortical networks subserving the distribution of attention in normal humans, and further studies are necessary to address this issue. Moreover, the use of TMS does not allow us to investigate the activity of the subcortical components of the network during the examined task.
The timing of the effects of TMS on contralesional extinction was strictly concordant with the presumed time necessary for somatosensory information from the unaffected side to reach the sensory representations in the contralateral hemisphere [~20–25 ms, as is known from the latencies of evoked potentials to finger stimuli (Rossini et al., 1987)]. If the TMS pulses were delivered on the posterior parietal lobe earlier than 20 ms or later than 30 ms, they did not affect contralesional extinction. In the frontal lobe, the same effects were observed with a temporal shift of 10 ms. In both cases, it is reasonable to assume that the effect of TMS had ended before the necessary cortical processing of contralateral tactile stimuli had started, or had started after the cortical processing itself had ended.
These findings do not necessarily implicate serial processing of information along a temporal hierarchy of functionally related areas. More probably, the two periods of processing (partially overlapping), as revealed by the inhibitory action of paired TMS, could reflect the activity of cells with a unimodal distribution of onset latency, but with a double period of activity depending on the phase of the processing itself. This means that, even if many cells in both parietal and frontal cortices are concurrently active during bimanual discrimination tasks, there could be a limited period when just the parietal or frontal cells may be, in turn, encoding a task parameter. According to this interpretation, it may be that a cortical area (parietal or frontal) is only (or preferentially) vulnerable to TMS during the period when the area codes uniquely for a certain aspect of tactile spatial information processing.
Our findings suggest that parietal inhibition is more effective than frontal inhibition in reducing contralesional extinction. This could depend, at least in part, on the use of a fixed intensity of TMS, related to motor threshold, for stimulating two cortical regions that presumably differ in sensitivity to the effects of TMS due to task-independent (or task-dependent) differences in the excitability threshold; indeed, the motor threshold might not be the same as the threshold for a given effect outside the motor cortical areas, and in this case no measure other than the effects on the examined variable (i.e. extinction) is available.
In conclusion, our results show that selective modulation of the excitability of the unaffected hemisphere by paired TMS pulses can influence the recognition of contralesional stimuli in patients with tactile extinction, suggesting the presence of intracortical excitability disorders of the unaffected hemisphere underlying these deficits. If so, it may be possible to use this technique to monitor the activity of the cortical circuits involved in spatial attention in humans, and perhaps even to develop strategies that would facilitate recovery from their deficits. In addition, the results suggest the presence of a functional time-course in the connections between posterior parietal and frontal areas during spatial attentional tasks, and emphasize the utility of TMS for tracing patterns of connectivity between different brain regions.
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Ashbridge E, Walsh V, Cowey A. Temporal aspects of visual search studied by transcranial magnetic stimulation. Neuropsychologia 1997; 35: 1121–31.[Web of Science][Medline]
Bartolomeo P, Chokron S. Left unilateral neglect or right hyperattention? Neurology 1999; 53: 2023–7.
Bisiach E. Extinction and neglect: same or different? In: Paillard J, editor. Brain and space. Oxford: Oxford University Press; 1991. p. 251–7.
Corbetta M. Frontoparietal cortical networks for directing attention and the eye to visual locations: identical, independent, or overlapping neural systems? [Review]. Proc Natl Acad Sci USA 1998; 95: 831–8.
Corthout E, Uttl B, Ziemann U, Cowey A, Hallett M. Two periods of processing in the (circum)striate visual cortex as revealed by transcranial magnetic stimulation. Neuropsychologia 1999a; 37: 137–45.[Web of Science][Medline]
Corthout E, Uttl B, Walsh V, Hallett M, Cowey A. Timing of activity in early visual cortex as revealed by transcranial magnetic stimulation. Neuroreport 1999b; 10: 2631–4.[Web of Science][Medline]
Hillyard SA, Mangun GR, Woldorff MG, Luck SJ. Neural systems mediating selective attention. In: Gazzaniga MS, editor. The cognitive neurosciences. Cambridge (MA): MIT Press; 1995. p. 665–81.
Ilmoniemi RJ, Virtanen J, Ruohonen J, Karhu J, Aronen HJ, Naatanen R, et al. Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity. Neuroreport 1997; 8: 3537–40.[Web of Science][Medline]
Kinsbourne M. Hemi-neglect and hemisphere rivalry. Adv Neurol 1977; 18: 41–9.[Medline]
Kinsbourne M. Orientational bias model of unilateral neglect: evidence from attentional gradients within hemispace. In: Robertson IH, Marshall JC, editors. Unilateral neglect: clinical and experimental studies. Hove (UK): Lawrence Erlbaum; 1993. p. 63–86.
Kinsbourne M. Mechanisms of neglect: implications for rehabilitation. Neuropsychol Rehabil 1994; 4: 151–3.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol (Lond) 1993; 471: 501–19.
Lomber SG, Payne BR. Removal of two halves restores the whole: reversal of visual hemineglect during bilateral cortical or collicular inactivation in the cat. Vis Neurosci 1996; 13: 1143–56.[Web of Science][Medline]
Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language and memory. [Review]. Ann Neurol 1990; 28: 597–613.[Web of Science][Medline]
Moscovitch M, Behrmann M. Coding of spatial information in the somatosensory system: evidence from patients with neglect following parietal lobe damage. J Cogn Neurosci 1994; 6: 151–5.[Web of Science]
Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.[Web of Science][Medline]
Oliveri M, Rossini PM, Pasqualetti P, Traversa R, Cicinelli P, Palmieri MG, et al. Interhemispheric asymmetries in the perception of unimanual and bimanual cutaneous stimuli. A study using transcranial magnetic stimulation. Brain 1999a; 122: 1721–29.
Oliveri M, Rossini PM, Traversa R, Cicinelli P, Filippi MM, Pasqualetti P, et al. Left frontal transcranial magnetic stimulation reduces contralesional extinction in patients with unilateral right brain damage. Brain 1999b; 122: 1731–9.
Pascual-Leone A, Gates JR, Dhuna A. Induction of speech arrest and counting errors with rapid-rate transcranial magnetic stimulation. Neurology 1991; 41: 697–702.
Pascual-Leone A, Gomez-Tortosa E, Grafman J, Alway D, Nichelli P, Hallett M. Induction of visual extinction by rapid-rate transcranial magnetic stimulation of parietal lobe. Neurology 1994; 44: 494–8.
Pascual-Leone A, Tarazona F, Keenan J, Tormos JM, Hamilton R, Catala MD. Transcranial magnetic stimulation and neuroplasticity. Neuropsychologia 1999; 37: 207–17.[Web of Science][Medline]
Payne BR, Lomber SG. A method to assess the functional impact of cerebral connections on target populations of neurons. J Neurosci Methods 1999; 86: 195–208.[Web of Science][Medline]
Perani D, Vallar G, Paulesu E, Alberoni M, Fazio F. Left and right hemisphere contribution to recovery from neglect after right hemisphere damage. An [18F]FDG pet study of two cases. Neuropsychologia 1993; 31: 115–25.[Web of Science][Medline]
Pizzamiglio L, Judica A, Razzano C, Zoccolotti P. Toward a comprehensive diagnosis of visual-spatial disorders in unilateral brain-damaged patients. Psychol Assess 1989; 5: 199–218.
Remy P, Zilbovicius M, Degos JD, Bachoud-Lévi AC, Rancurel G, Cesaro P, et al. Somatosensory cortical activations are suppressed in patients with tactile extinction. A PET study. Neurology 1999; 52: 571–7.
Ridding MC, Rothwell JC. Afferent input and cortical organisation: a study with magnetic stimulation. Exp Brain Res 1999; 126: 536–44.[Web of Science][Medline]
Ridding MC, Inzelberg R, Rothwell JC. Changes in excitability of motor cortical circuitry in patients with Parkinson's disease. Ann Neurol 1995; 37: 181–8.[Web of Science][Medline]
Rossini PM, Gigli GL, Marciani MG, Zarola F, Caramia M. Non-invasive evaluation of input-output characteristics of sensorimotor cerebral areas in healthy humans. Electroencephalogr Clin Neurophysiol 1987; 68: 88–100.[Web of Science][Medline]
Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. [Review]. Electroencephalogr Clin Neurophysiol 1994; 91: 79–92.[Web of Science][Medline]
Seyal M, Masuoka LK, Browne JK. Suppression of cutaneous perception by magnetic pulse stimulation of the human brain. Electroencephalogr Clin Neurophysiol 1992; 85: 397–401.[Web of Science][Medline]
Seyal M, Ro T, Rafal R. Increased sensitivity to ipsilateral cutaneous stimuli following transcranial magnetic stimulation of the parietal lobe. Ann Neurol 1995; 38: 264–7.[Web of Science][Medline]
Smania N, Martini MC, Gambina G, Tomelleri G, Palamara A, Natale E, et al. The spatial distribution of visual attention in hemineglect and extinction patients. Brain 1998; 121: 1759–70.
Vallar G. Spatial hemineglect in humans. Trends Cogn Sci 1998; 2: 87–97.[Web of Science]
Vallar G, Rusconi ML, Bignamini L, Geminiani C, Perani D. Anatomical correlates of visual and tactile extinction in humans: a clinical CT scan study. J Neurol Neurosurg Psychiatry 1994; 57: 464–70.
Walsh V, Cowey A. Magnetic stimulation studies of visual cognition. Trends Cogn Neurosci 1998; 2: 103–10.
Walsh V, Rushworth M. A primer of magnetic stimulation as a tool for neuropsychology. [Review]. Neuropsychologia 1999; 37: 125–35.[Web of Science][Medline]
Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol (Lond) 1996; 496: 873–81.
Received December 17, 1999. Revised March 22, 2000. Accepted May 15, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Koch, M. Oliveri, and C. Caltagirone Neural networks engaged in milliseconds and seconds time processing: evidence from transcranial magnetic stimulation and patients with cortical or subcortical dysfunction Phil Trans R Soc B, July 12, 2009; 364(1525): 1907 - 1918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Koch, M. Fernandez Del Olmo, B. Cheeran, D. Ruge, S. Schippling, C. Caltagirone, and J. C. Rothwell Focal Stimulation of the Posterior Parietal Cortex Increases the Excitability of the Ipsilateral Motor Cortex J. Neurosci., June 20, 2007; 27(25): 6815 - 6822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Babiloni, F. Vecchio, A. Bultrini, G. Luca Romani, and P. M. Rossini Pre- and Poststimulus Alpha Rhythms Are Related to Conscious Visual Perception: A High-Resolution EEG Study Cereb Cortex, December 1, 2006; 16(12): 1690 - 1700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Derakhshan and M. Oliveri Overestimation of numerical distances in the left side of space Neurology, May 24, 2005; 64(10): 1822 - 1823. [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Payne and R. J. Rushmore Animal Models of Cerebral Neglect and Its Cancellation Neuroscientist, December 1, 2003; 9(6): 446 - 454. [Abstract] [PDF]
|
|
|
|
|
|
M. Oliveri, E. Bisiach, F. Brighina, A. Piazza, V. La Bua, D. Buffa, and B. Fierro rTMS of the unaffected hemisphere transiently reduces contralesional visuospatial hemineglect Neurology, October 9, 2001; 57(7): 1338 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Oliveri, P. Turriziani, G.A. Carlesimo, G. Koch, F. Tomaiuolo, M. Panella, and C. Caltagirone Parieto-frontal Interactions in Visual-object and Visual-spatial Working Memory: Evidence from Transcranial Magnetic Stimulation Cereb Cortex, July 1, 2001; 11(7): 606 - 618. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||