Ipsilateral motor activation in patients with cerebral gliomas

Recent research has begun to show that the paradigm of crossed association, whereby each cerebral hemisphere relates to the contralateral side of the body (the Valsalva doctrine^1,2), can be altered due to damage or disease, with the manifestation of ipsilateral activity reflecting a functional relationship between one hemisphere and the limbs on the same side. Clinical investigations of stroke patients have already indicated ipsilateral involvement,^3-5 but since 1991, functional exploration using PET, transcranial Doppler, and functional MRI (fMRI) has started to document the phenomenon with growing precision.^6-11 Transcranial magnetic stimulation (TMS) is another analytic technique developed in recent years that has contributed to this picture because it is noninvasive, painless, and permits evaluation of corticospinal tracts with respect to several different parameters such as cortical excitability threshold, central conduction time, and silent period duration.^12-15 It has been used to document ipsilateral motor responses in children suffering from hemiplegic cerebral palsy and other congenital diseases, and it has been used after hemispherectomy.^16,17 So far, reorganization of this kind has been found in the wake of lesions occurring before maturation is complete.^18,19 However, the fact that this phenomenon is not only related to prematurity epochs has been demonstrated in recent studies charting ipsilateral responses induced by TMS on adults who recovered from stroke.^20,21 These kinds of studies have revealed that, after stroke, plastic changes in cortical motor output can be manifest in the form of ipsilateral control of the upper limbs and that it might represent a source of possible compensation in loss of motor function.

The current research extends the investigation of brain plasticity by exploring ipsilateral motor connections using TMS in patients suffering from intracerebral tumors. The evidence suggests that the current understanding of the dynamics of movement control is in need of further reassessment. The appearance of ipsilateral responses in adults with intracerebral gliomas opens up new horizons for research on the phenomena underlying brain plasticity and motor recovery.

Methods. The examination included 15 healthy, right-handed control subjects (age, 24 to 71 years) and seven right-handed patients (age, 23 to 73 years) affected by documented intracerebral gliomas all involving the frontoparietal regions, except one patient in whom the tumor was located in the temporo-occipital area. In six patients the tumor affected the left hemisphere.

In addition to being investigated with TMS, all patients underwent both conventional MRI and clinical examination. Motor deficits and aphasia were scored according to the Canadian Neurological Scale.²² Six of our patients later underwent operation, after which the nature of the tumor was assessed by histologic analysis. In the one patient who was not operated (the patient with vast right-hemisphere infiltration) the diagnosis was established on the basis of a biopsy. Histologic diagnoses were made by a single pathologist, and the neuropathologic grading of tumors was performed following the Kernohan classification.²³

All subjects were fully informed as to the nature of the study, and all gave their consent. The procedures utilized in the study were approved by the local ethics committee.

Stimulation parameters. With the subjects lying comfortably in a quiet room, magnetic stimulation of the motor cortex was performed via both nonfocal and focal stimulation. Nonfocal stimulation was delivered by a Cadwell MES 10 (Cadwell, United States) using a regular round coil (bipolar, 9 cm external diameter) whereas focal stimulation was delivered using a Magstim 200 (Magstim, United Kingdom) connected to a figure-of-eight coil (14 cm transverse diameter, 7 cm each wing).

To render the investigation as unbiased as possible, the person in charge of holding the coil was not told whether the subjects under examination were control subjects or patients.

Nonfocal stimulation. The coil was moved on each hemiscalp overlying the central sulcus until the optimal stimulation site (hot spot) was localized for eliciting threshold motor responses in the contralateral hand target muscles during relaxation. The excitability threshold was assessed following the methodology established in a series of papers addressing this aspect,^13,24,25 and was defined as the intensity of stimulation needed to produce responses of about 100 µV in at least 50% of successive trials.

To obtain ipsilateral motor-evoked potentials (iMEPs), recordings were taken during target muscle contraction, and the threshold was determined in this state by applying increasing intensities until reproducible responses of at least 500 µV could be collected.²¹ Stimuli, in ascending steps of 10% from 40 to 80% of stimulator output, were then administered alternatively on both hemispheres with the coil placed over the hand motor area at the hot spot and tilted in such a way that the superior edge was not touching the convexity of the head and was therefore inclined away from the midline. This was done to prevent the risk that ipsilateral responses could arise because of spreading current into the opposite hemisphere. Because the direction of the induced pulse might be critical with respect to the excitability threshold, the direction was maintained for all subjects under investigation. We fixed the maximal intensity allowed for the exploration of patients at 80% of stimulator output, because normal subjects never displayed ipsilateral activation at intensities lower than this level.

Focal stimulation. When using the figure-of-eight coil, the junction between the windings was positioned on both the right and left hemiscalps at the hot spot for contralateral recordings 6 cm lateral to Cz(of the 10-20 International System) and also at 3 cm lateral and 3 cm anterior to Cz. The handle of the coil was maintained in a lateral orientation, almost parallel to the earlobe line, but rotated 10 degrees backward toward the midline, in this way avoiding the possibility of current spreading into the hemisphere not under exploration. The direction of the induced pulse was lateral to medial. These conditions were maintained for both hemispheres in all subjects.

This part of the study was performed on six healthy control subjects and four patients. The patients subjected to this protocol of stimulation were selected because of the ease by which iMEPs were obtained with the usual procedures using the round coil and because of their willingness to undergo a long laboratory session.

In the case of the patients, it was possible to elicit iMEPs not only during contraction, but also during relaxation, so the measurement of threshold was determined accordingly in this state.

Recording parameters. Motor-evoked potentials were obtained from thenar muscles (opponens pollicis) by using surface electrodes applied with a conventional belly-tendon montage. The voluntary activation of the target muscles consisted of a transient opposition of the thumb, performed at about 35% of maximal force (as measured via a force transducer), and an acoustic feedback was provided from the recording electrodes to monitor the background EMG. Recordings, averaged and replicated at least three times with a suitable amplitude calibration, were acquired with a Multibasis Esaote(Otc-Biomedica, Italy) with a filter bandwidth of 20 to 2,000 Hz and a sampling rate of 10 kHz and stored on floppy disks for off-line analysis.

Data analysis. Both ipsilateral and contralateral recordings were evaluated according to the following parameters:

1. Excitability threshold measured as a percentage of maximal stimulator output

2. MEP latency onset during muscle contraction measured at the beginning of the first reproducible negative deflection

3. MEP amplitude measured during muscle contraction, measured peak to peak (statistical analysis included arithmetical means with SDs and paired comparisons with Student's t-test)

Results. Clinical findings. Six of the seven patients had come under investigation immediately following the first episode of a generalized epileptic seizure. Four of these six patients experienced temporary difficulty with word finding due to the location of the tumor infiltrating the left frontoparietal areas. The patient who did not exhibit generalized seizures presented the sole clinical symptom of recurrent clonic fits predominantly in the upper limb contralateral to the tumor.

Further details on clinical findings as well as the tumor grading, extension, and location are provided in table 1.

Cortical stimulation. In agreement with previous reports,^21,26 ipsilateral TMS could induce in hand muscles either a brief silent period without a preceding MEP or nothing at all. However, in six of 15 control subjects occasional iMEPs could be elicited by stimulating the left hemisphere with the round coil at 80% of stimulator output. Such responses were acquired in the form of isolated, single recordings, showing an amplitude in the range of 200 to 500 µV, and a latency similar to that of contralateral MEPs (cMEPs).

None of the six control subjects who underwent focal stimulation of the hot spot for cMEPs showed iMEPs. As in the case of round-coil stimulation, the sporadic occurrence of iMEPs (two of 10 recording trials) was noted in two control subjects by stimulating the left hemisphere at 3 cm lateral and 3 cm anterior to Cz. In none of the control subjects was it possible to record iMEPs on the right side, whatever the type of coil used.

Tables 2 and 3 present the normative values of MEPs recorded contralaterally to the side of cortical stimulation as well as values of those occasional left iMEPs acquired in the form of single recordings in a few control subjects. In contrast to the control group, it was possible with the patients to record iMEPs of considerable amplitude by stimulating the healthy hemisphere (figures 1 and 2) using both round and figure eight coils. Mean values and SDs relating to the parameters analyzed, including those relating to cMEPs, are listed in tables 2 and 3.

Nonfocal stimulation. With the round coil, iMEPs followed by a brief silent period of about 20 msec were obtained in contracted target muscles during stimulation of the unaffected hemisphere, with thresholds ranging between 60 to 70% of stimulator output in five of seven patients. The latencies of iMEPs were longer than those of the cMEPs (p = 0.05), and amplitudes were lower (p < 0.01; see tables 2 and 3). Of the two patients not showing ipsilateral activation, one was the only patient to have a temporo-occipital tumor localization, which did not directly involve the motor areas (Patient 3). The other patient, with a left frontoparietal glioblastoma invading part of the corpus callosum, did, however, display iMEPs during focal stimulation of the unaffected hemisphere.

Patients' cMEP latencies and amplitudes were well within the normal range for control subjects. The excitability threshold for evoking cMEPs differed with respect to the unaffected and affected hemispheres, with higher values in the latter (48% versus 44%, p < 0.01; see table 2).

Focal stimulation. In four patients iMEPs were sought and obtained using the focal, figure-of-eight coil discharged at 80% of stimulator output. The spot giving rise to iMEPs was located exclusively on the unaffected hemisphere at 3 cm lateral and 3 cm anterior to Cz (of the 10-20 International System). Reproducible responses could even be obtained during muscle relaxation. The ipsilateral responses obtained during contraction with respect to the round coil tended to have significantly larger amplitudes (3.3 mV versus 2.2 mV, p < 0.01), although still less than the contralateral amplitudes (see tables 2 and 3).

No ipsilateral response could be induced by stimulating the site considered to be the hot spot for cMEPs. Furthermore, by moving the coil position toward the midline in a parasagittal position (0.5 cm lateral to Cz), iMEPs could be no longer obtained (figure 3).

Discussion. The current study investigates the phenomenon of ipsilateral activation related to a process of motor reorganization triggered by the tumor-infiltrating invasion of one cerebral hemisphere.

Before attempting to understand the nature of the motor reorganization of which iMEPs are a symptom, it is first necessary to ascertain that they are true ipsilateral responses and not the result of a contralateral involvement due to the effect of interhemispheric spread of current. The principal arguments that show that our results reflect ipsilateral activation are:

1. The general absence of ipsilateral responses, using the same procedures, in the case of control subjects. Indeed, the occasional occurrence of low-amplitude iMEPs on the left side in some control subjects shows that ipsilateral pathways normally play a minor or a supplementary role, one that might be enhanced in pathologic conditions.

2. The possibility of recording reproducible iMEPs using a focal figure-of-eight coil, a technique that surely cannot engage the unstimulated hemisphere.¹⁵

3. The evidence that iMEPs are found only in response to the stimulation of the undamaged hemisphere. This effectively contradicts the possibility of current spreading, because the same phenomenon cannot be obtained by stimulating the damaged hemisphere, even with maximal stimulus intensities(see figure 2).

4. The fact that the motor performance in hands contralateral to the affected hemisphere was far less impaired than the size of the damage would lead one to expect. This finding suggests that a degree of motor function can be sustained by ipsilateral control, unless the same phenomenon might be explained by the presence of viable normal tissue, which can remain admixed in slowly infiltrative tumors such as these.

It may also be noted that an fMRI study performed on patients with intracerebral gliomas has revealed activation in the sensorimotor areas of the undamaged hemisphere ipsilateral to the side of hand task motor performance.¹⁰ In more general terms, the outcome of such research is in tune with the various kinds of evidence in favor of ipsilateral activation cited at the beginning of this paper.

Neuroanatomy. By ipsilateral innervation we mean the variable degree of motor control of the ipsilateral soma by corticospinal paths emanating from the homolateral cerebrum.²⁷ The mechanisms involved in ipsilateral activation have yet to be established, but they may recruit preexisting routes that either lay dormant (silent synapses) or undetected in the normal brain. Suppression of ipsilateral pathways when the contralateral system is intact has been proposed in split-brain patients.²⁸ Neuroanatomic studies have revealed that pyramidal fibers feeding contralateral innervation prevail in humans, however roughly 25% of the corticospinal paths are known to remain uncrossed.²⁹ Furthermore, the amount of fiber crossing varies considerably in different individuals, ranging between total crossing on one extreme and no crossing at all on the other extreme.^27,30,31 Of the part that does not cross, a fraction, which represents about 10% of the total, stays in the lateral corticospinal tract (the anterolateral uncrossed corticospinal tract terminating in the ipsilateral spinal anterior horns^32,33) and might contribute to the ipsilateral input toward the upper limbs.^4,29,34

Physiologic evidence of ipsilateral termination in the cord of pyramidal fibers is plentiful and demonstrate that their origin is not confined to area 4 alone, but encompasses other areas including most notably area 6 (the ipsilateral area of Bucy and Fulton³⁵).

After we realized that focal stimulation of the hot spot for cMEPs failed to produce ipsilateral responses, inspired by Bucy and Fulton's studies of 1933,³⁵ we chose area 6 as the locus of focal stimulation (the optimal site of 3 cm anterior and 3 cm lateral to Cz being established empirically). This choice was also supported by several other more recent studies showing that secondary motor areas partake in ipsilateral control.^5,36-38

The occasional left iMEPs recorded in control subjects might reflect a greater left-hemisphere bilateral control as demonstrated by a variety of motor tests including tapping speed³⁹ and manual sequence,⁴⁰ and recently documented by fMRI.^41,42 In addition, a study using repetitive TMS,⁴³ besides documenting the involvement of the ipsilateral motor cortex in finger movements, shows that the left hemisphere is normally more involved in the processing of complex ipsilateral finger movements than the right hemisphere.

Functional relevance. How much of a role in terms of function these uncrossed, ipsilateral tracts play when contralateral pathways are damaged is unknown. It remains possible that iMEPs may just reflect reorganizational changes without specific functional effects. However, it is interesting to note that the sole patient who did not display iMEPs was affected by a temporo-occipital tumor that did not involve the motor areas, a situation in which the need for motor compensation was presumably not required.

Clinical studies have indicated a significant degree of ipsilateral involvement following unilateral cerebral damage.^3-5,21 A mapping study performed on healthy subjects using cortical stimulation revealed occasional ipsilateral responses from hand muscles.⁴⁴ The authors of this last study⁴⁴ reason that such ipsilateral responses may become more functional and perhaps more accessible in the process of recovery from lesions impairing the normal route to the hand from the contralateral hemisphere. Combined with such findings as well as with the neuroanatomic, electrophysiologic, and functional imaging studies mentioned earlier, our investigation suggests that ipsilateral pathways may act as a reserve to be taken up once contralateral routes are damaged.

This hypothesis is suggested particularly by the fact that the considerable size of the tumors infiltrating the cortex of some of the patients in the current study (see figure 1) is not matched by a proportionate loss of motor performance in the limbs contralateral to the tumor. Presumably the gradual nature of the neoplasm permitted plastic changes to keep pace with the progressive damage, changes that include the establishment of a viable element of ipsilateral motor control.