Volume 87, Issue 12, Supplement, Pages 77-83 (December 2006)

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Magnetoencephalographic Studies of Language Reorganization After Cerebral Insult

Abstract

Breier JI, Billingsley-Marshall R, Pataraia E, Castillo EM, Papanicolaou AC. Magnetoencephalographic studies of language reorganization after cerebral insult.

We review our experience with the application of magnetoencephalography (MEG) to the study of reorganization of the mechanisms supporting auditory language comprehension. In 3 studies, patient populations with cerebral insult of differing etiology, including epilepsy, surgical resection, and stroke, performed a running recognition task for spoken words while MEG data were collected using a whole-head magnetometer. Increased activation in the right hemisphere after left temporal lobectomy was associated with greater relative activation in that hemisphere preoperatively. Patients with chronic seizure disorder secondary to mesial temporal sclerosis exhibited a tendency toward an interhemispheric shift of language function, and those with epilepsy secondary to neoplasm showed a tendency toward an intrahemispheric shift. Patients with aphasia secondary to unilateral left-hemisphere stroke exhibited a more bilateral and diffuse overall profile of activation within the left hemisphere than control subjects of similar age. Taken together, results provide evidence that reorganization of cortex subserving auditory comprehension can occur well into the fifth and sixth decades and that the nature of the plastic response is dependent on variables such as premorbid language laterality, etiology, and, in specific groups, age at insult.

Key Words: Brain, Brain injuries, Magnetoencephalography, Neuronal plasticity, Rehabilitation

Article Outline

• Abstract

• Methods

• Study 1

• Study 2

• Study 3

• Conclusions

• References

• Copyright

UNTIL RELATIVELY RECENTLY, the nature of reorganization of language function in response to cerebral insult has been indirectly inferred from such observations as the subsequent recovery after loss of function despite destruction of putative premorbid language areas,1, 2, 3 the occurrence of aphasia after insult to areas (eg, the right hemisphere) unlikely to have supported linguistic function premorbidly,4 and a higher incidence of left ear advantage during dichotic listening after stroke.5, 6 With the relatively recent advent of functional imaging methods that are able to directly characterize the spatial and, in some cases, temporal parameters of brain activation associated with the performance of language tasks in vivo, it has become possible to begin to characterize the changes in the cerebral organization of language after insult and to determine the effects of factors that might influence this process. This area of research has potentially important implications for theories of brain plasticity as well as prognosis and for the design of specific pharmacologic and/or behavioral rehabilitative strategies in the treatment of language dysfunction after brain insult.

Evidence for reorganization of language has been observed in the presence of a variety of etiologies including neoplasm,7 epileptic seizures,8, 9, 10, 11 stroke,12, 13, 14, 15 and surgical resection impinging on eloquent cortex.1, 16, 17 Expansion to perilesional areas within the left hemisphere that may be able to support language as well as reorganization in homotopic areas of the right hemisphere3, 13, 18, 19, 20 has been reported.

A role for expansion of language-specific cortex into areas in the left hemisphere other than premorbid language areas is suggested by the increased variability in language maps noted during electrocortical stimulation studies in the left hemisphere in patients with chronic seizures21 as well as functional imaging studies using functional magnetic resonance imaging (fMRI),12, 22 positron emission tomography (PET),14, 15, 23 and magnetoencephalography (MEG)24, 25, 26 that indicate atypical spatial activation patterns in perilesional areas of the left hemisphere when language cortex is affected by the insult.

The possibility of a role for the right hemisphere in recovery of language function is suggested by functional imaging studies indicating relative increases in neurophysiologic,27 metabolic,28, 29 and hemodynamic12, 18, 30, 31, 32, 33, 34 response in the right hemisphere during the performance of linguistic tasks after stroke. A relative increase in neurophysiologic16, 25 and hemodynamic17, 23, 35, 36 response in the right hemisphere has also been observed in patients with chronic seizures, both before and after surgical resection for seizure remediation. Evidence for induction of right-hemisphere activation after remediation for aphasia in stroke patients has also been observed.37, 38

The mechanism and extent of reorganization is potentially dependent on a number of factors, including age at injury,20, 39, 40 sex,41 and the etiology of the injury.25 Although significant reorganization of language function can occur into childhood, including interhemispheric transfer of function,35 and some degree of reorganization can be observed in adults,16, 24 better language recovery occurs when insult is perinatal, suggesting greater plasticity with earlier age.10, 42, 43 In addition, functional imaging studies comparing the relative activation of each hemisphere during the performance of language tasks indicate a greater rightward shift in activation with earlier age of diagnosis in patients with neoplasm,25 suggesting that plasticity in the right hemisphere decreases with age. There is some evidence that age effects may be different in males than females, with women having a shorter, earlier period of heightened plastic response than men.20 In addition, patients with neoplasms may be more likely to exhibit intrahemispheric reorganization of language, whereas those with chronic seizure disorder secondary to mesial temporal sclerosis may be more likely to show interhemispheric reorganization.25

The 3 studies presented below were performed for the purpose of providing data regarding the influence of factors such as age at injury, sex, and etiology on language reorganization using the identical MEG methodology. MEG is substantially different from the functional brain imaging methods that are based on measures of blood flow, which, for some patient populations, may be inappropriate. With MEG, neurophysiologic activity in the form of magnetic flux, generated by intracellular electric currents in large neuronal aggregates, can be measured in a more direct fashion.44, 45, 46 Thus, in addition to having temporal resolution unavailable with fMRI and PET as well as good spatial resolution, MEG may provide a more direct index of sensory, motor, and cognitive task-specific activation than methods that rely on hemodynamic measures. Imaging of brain activation with MEG involves the following steps. Stimuli, whether somatosensory, visual, auditory, or linguistic, are known to evoke brain activity soon after they impinge on the sensory receptors. One basic aspect of such activity is the intracellular flow of ions, which generates electric currents and magnetic fields. Repetitive application of a given stimulus results in repeated evocation of the same currents and fields that, when recorded on the head surface and averaged, result in the well-known evoked or event-related potentials and their magnetic counterparts, the event-related fields. The distribution of the latter on the head surface lends itself, much more readily than the distribution of the former, to mathematical estimates of the location and extent of activation of the sets of brain cells that produce them.

Event-related fields, much like event-related potentials, are waveforms representing variations of brain activity over time, after the onset of an external stimulus. Early portions of the event-related field waveform (ie, up to 150–200ms after stimulus onset) have been shown to reflect neurophysiologic activity in primary sensory cortices.44, 47, 48, 49 Conversely, neurophysiologic activity represented by later portions of the event-related field waveform occurs primarily in association cortices.50, 51, 52, 53, 54, 55, 56, 57 It is by estimation of the regions that contribute to systematic variations in late portions of the event-related field waveform that delineation of the outline of the brain circuits responsible for cognitive and linguistic functions may be accomplished.

Methods

The methods used are described in detail elsewhere.58 Briefly, in all the experiments described here, participants were presented with a continuous list of spoken words during MEG imaging that consisted of abstract English nouns and were asked to raise either their left or right index finger to indicate that they had detected that a word had been repeated. Each stimulus produces an evoked field that is recorded by the scanner. These evoked fields are averaged together across stimuli at the end of the recording session to remove random fluctuations in brain activity and reveal the underlying stimulus-specific activation. This results in early (before the resolution of the N1m or approximately <200ms poststimulus onset) and late (after the resolution of the N1m, or 200–1000ms poststimulus onset) components, the former associated with activity in primary auditory cortex and the latter with association cortex specialized for language comprehension. To identify the intracranial origin of each component, the magnetic field distribution that is recorded simultaneously over the entire head surface at successive points (4ms apart) is analyzed via the application of a mathematical model that considers the intracranial activity sources as equivalent to physical current dipoles59 and is intended to provide estimates of the location and strength of these sources.

The location estimates of each dipolar source are specified with reference to a Cartesian coordinate system, anchored on 3 fiducial points on the head (the nasion and the external meatus of each ear). The same fiducial points are marked with vitamin pills, thus enabling superimposition of the precise location of each dipolar source on the subject’s (or patient’s) magnetic resonance imaging (MRI). Thus, the dipolar sources that account for a particular evoked field component, projected onto the MRI, indicate the brain areas activated during that time interval in response to the stimulus. The degree of activation of a particular area (or the total duration of its activation) after a stimulus is estimated by the total number of successive activity sources that account for the evoked field components.

The validity of this methodology for mapping cortical areas involved in auditory comprehension was established in a programmatic series of investigations verifying that (1) the early components of the evoked fields to words presented aurally are due to bilaterally equivalent activation of primary auditory cortex, whereas late evoked field components reflect predominantly left hemisphere activation involving the posterior temporal and parietal cortex as indicated by the number of temporally continuous activity sources54; (2) the late activation is language-specific and not a general feature of all auditory stimulation49, 60; (3) the activation is reliable across sessions within and between subjects50; and (4) language lateralization as determined by the interhemispheric asymmetry in the number of late activation sources is consistent with the results of the Wada test55, 58, 61 and the location of the sources within the dominant hemisphere is consistent with the results of the electrocortical stimulation procedure26, 62 carried out in patients for the purpose of tailoring cortical resection.

Study 1

In this study16 we wanted to characterize what change, if any, occurs in the maps of auditory comprehension in patients who undergo left temporal lobectomy for the relief of chronic seizure disorder. We also wanted to determine what factors affected such change and whether any changes were associated with changes in language function. Although there have been a number of preoperative functional imaging studies of language organization in surgery candidates, most studies characterizing the change in organization of language after surgery have been single-case studies in children who have undergone left hemispherectomy.17, 35 Not surprisingly these studies find evidence for right-hemisphere activation during the performance of language tasks, suggesting reorganization of language to the right hemisphere. However, little is known about the factors that affect language reorganization after more limited resections.

Twelve right-handed patients with drug-resistant left temporal lobe epilepsy who had undergone left temporal lobe resection after an extensive presurgical evaluation at the Comprehensive Epilepsy Program at the University of Texas Health Science Center participated in the study. All patients had undergone preoperative Wada testing, pre- and postoperative neuropsychologic testing, and MEG language mapping. The postoperative MEG scan and neuropsychologic evaluations were performed 18 to 60 months after surgical treatment. Lateralization of language function was determined based on a laterality index calculated as (R − L)/(R + L), where R represents the number of acceptable late activity sources in the right hemisphere and L the corresponding number in the left hemisphere. Index values between −0.1 and +0.1 were considered as indicative of bilaterally symmetric activation, whereas values greater than +0.1 or less than −0.1 were considered as indicative of right- or left-hemisphere dominance, respectively.

Postoperatively, 3 patients, all of whom had bilateral language representation preoperatively by Wada testing, showed a shift of language representation predominantly to the right hemisphere. Figure 1A shows the pre- and postoperative language maps for one of these latter patients. The upper row represents the preoperative map of activity in Wernicke’s area, and the lower row represents the postoperative map. A clear shift in the relative degree of interhemispheric asymmetry in activity from bilateral to predominantly right is evident. None of the patients with left-hemispheric representation of language preoperatively showed a shift of receptive language lateralization after resection. However, there was a slight inferior shift in the putative location of Wernicke’s area in 3 out of 7 of these patients. Figure 1B shows the pre- and postoperative language map of a patient who showed this type of inferior shift in localization.

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Fig 1. Co-registered MEG-MRI scans (the left hemisphere is on the left side of the image) for (A) a patient with apparent bilateral language representation preoperatively (upper row) and a shift of lateralization to the right hemisphere after anterior temporal lobectomy (lower row) and (B) a patient with left hemisphere representation preoperatively (upper row) who showed an intrahemispheric shift postoperatively (lower row). Green squares show the activity sources observed during the first session and red squares show activity observed during the second session. The region of spatial overlap between the 2 maps within a given hemisphere is marked by a white circle. From Pataraia et al.16 Reprinted with permission.

There was no relation between the intrahemispheric shift of language and age at seizure onset, handedness, or postoperative complications, nor was there a relation between change in language function after surgery and shift in language location, although patients with atypical language lateralization tended to score lower on language tests than those with a more typical, left hemisphere–favoring asymmetry both pre- and post-operatively, a finding that has been previously reported.63

The results of this study suggest that patients with atypical (bilateral) language lateralization on the Wada test were significantly more likely than patients with left-hemisphere dominance to show a shift in language representation toward greater right-hemispheric activity after left temporal lobectomy. Patients with left-hemispheric dominance preoperatively were more likely to show intrahemispheric changes involving a slight inferior shift of the putative location of Wernicke’s area.

Study 2

In this study25 we examined the activation profiles for auditory comprehension in patients with left-hemisphere space-occupying lesions and patients with left temporal lobe epilepsy due to mesial temporal sclerosis to evaluate whether cross-hemispheric and intrahemispheric plasticity for language varies as a function of pathology as well as age.

Twenty-one patients with medically refractory left temporal lobe epilepsy due to mesial temporal sclerosis and 23 patients with lesions of varying etiology (arteriovenous malformation, cavernous hemangioma, dysembrioplastic neuroepithelial tumor, focal cortical dysplasia) in the left–hemisphere participated. Nine of the lesional patients suffered from drug-resistant epilepsy. The groups were matched demographically. Patients were classified as to whether they exhibited typical or atypical lateralization of auditory comprehension based on the laterality index described above as well as typical or atypical localization based on whether the cluster of activity sources overlapped with the traditional Wernicke’s area.

A higher percentage of mesial temporal sclerosis (9/21 [43%]) than lesional (3/23 [13%]) patients showed atypical profiles of laterality for language-specific activity. Figure 2A shows the MEG profile for a patient with intractable epilepsy secondary to mesial temporal sclerosis and right-hemisphere dominance, and figure 2B shows the profile for a patient with a lesion in the left hemisphere and left-hemisphere dominance and atypical localization. In addition, a higher percentage of patients (7/23 [30%]) from the lesional group showed atypical localization of language-specific cortex, whereas only 3 patients (3/21 [14%]) with mesial temporal sclerosis showed atypical localization within the left hemisphere. The majority (7/9 [78%]) of the mesial temporal sclerosis patients with atypical language had a seizure onset in early childhood greater than 6 years of age.

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Fig 2. Co-registered MEG-MRI scans (the left hemisphere is on the left side of the image) for (A) an epilepsy patients with left mesial temporal sclerosis and apparent bilateral language representation and (B) a patient with a pilocystic astrocytoma in the left supramarginal gyrus showing an atypical localization of receptive language in left hemisphere. Green squares show the activity sources observed during the first session and red squares show activity observed during the second session. The region of spatial overlap between the 2 maps within a given hemisphere is marked by a white circle. From Pataraia et al.25 Reprinted with permission.

These findings are consistent with the results of previous studies using invasive brain mapping techniques and also with the results of smaller-scale functional brain imaging studies in showing an increased incidence of atypical lateralization of language in patients with cortical pathology.20, 64 Results are also consistent with findings in other studies that earlier onset of insult is associated with greater probability of atypical language lateralization.20, 39 Findings also indicate that there is an increased probability of at least a partial shift of the brain mechanism responsible for auditory comprehension to the right hemisphere in patients with epilepsy secondary to mesial temporal sclerosis and preoperative atypical lateralization, whereas structural lesions in the dominant hemisphere (other than mesial temporal sclerosis) tend to result in the intrahemispheric reorganization of linguistic function.

Study 3

In the third study24 we were interested in determining if MEG could provide data relevant to hypotheses regarding the nature of reorganization of language after stroke and its relation to behavioral deficit. Six right-handed people ranging in age from 46 to 69 years with a history of first-ever ischemic stroke in the territory of the left middle cerebral artery participated. In addition, 6 right-handed people with no history of stroke or other neurologic disorder, ranging in age from 40 to 57 years, served as controls. Patients were at least 10 months poststroke before imaging and were administered the Western Aphasia Battery (WAB).65

Representative co-registered MEG-MRI scans for a control and a patient are presented in figures 3A and B, respectively. In the control participant left-hemisphere activation is generally predominantly within superior temporal gyrus (STG) and well-organized while activation within right STG is relatively reduced and more dispersed. In contrast, the patient exhibited decreased activation in left STG, with significant activation in left-hemisphere areas outside STG. Relatively increased activation within the right hemisphere is also evident.

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Fig 3. Co-registered MEG-MRI scans (the left hemisphere is on the left side of the image) for (A) a control subject and (B) a subject with a history of left-hemisphere stroke. From Breier et al.24 Reprinted with permission.

The temporal course of activation in left and right STG is shown for controls and patients in figures 4A and 4B, respectively, as the mean number of MEG activation sources within each successive 50-ms epoch between 50 and 1000ms after stimulus onset. Although there is little interhemispheric asymmetry in activation during the early component in either group, significantly greater activation of left as compared with right STG after the resolution of the N1m is evident in the control group. In contrast, patients do not exhibit a hemispheric asymmetry in the degree of activation of left and right STG during this late window that represents language-specific activity. In addition, a significant delay in the latency of onset of late activation in the patient group is evident in the left hemisphere. Within the patient group performance on the WAB comprehension index correlated highly with the latency of onset of activation within left STG (r=−.95, P<.004), with longer latency of activation associated with reduced performance.

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Fig 4. Mean number of sources in each of the consecutive 50-ms epochs for (A) controls and (B) patients within left (solid lines) and right (dashed lines) STG. The arrow indicates the approximate time of onset of late, language-specific activity. Abbreviations: LH, left hemisphere; RH, right hemisphere. Reprinted with permission.24

Results of this study indicate that MEG can provide data relevant to hypotheses regarding the mechanisms of reorganization of language function after stroke and their relation to behavioral deficit. They also provide initial evidence for a disruption in the spatiotemporal profile of language-specific MEG activation within left STG, as well as for increased activation in areas within the left hemisphere outside of STG, including perilesional and other areas that have been implicated in receptive language function. Relations between spatiotemporal parameters of MEG language maps and behavioral function were also consistent with previous reports, suggesting an association between better recovery from aphasia and a greater degree of activation of left STG.28, 29, 30, 31

Conclusions

The studies described above applied the same MEG methodology for providing spatiotemporal maps of cortical areas involved in auditory comprehension to neurologically intact controls and patient groups of varying ages and etiologies of cerebral insult. Taken together they provide evidence that reorganization of cortex subserving auditory comprehension can occur well into the fifth and sixth decades and that the nature of the plastic response is dependent on variables such as laterality of premorbid language laterality, etiology, and, in specific groups, age at insult. In subjects who underwent temporal lobectomy for intractable seizure disorder, increased activation in the right hemisphere (contralateral to the side of operation) was associated with greater relative activation in that hemisphere preoperatively.16 This effect is, interestingly, not dependent on direct impingement on eloquent cortex, because language areas were identified preoperatively and avoided at surgery. Subjects with chronic seizure disorder secondary to mesial temporal sclerosis in the left hemisphere were more likely to exhibit a more bilateral profile of activation25 than those with left-hemisphere neoplasm, whereas the latter group showed a tendency to exhibit an intrahemispheric shift of language representation. Patients with aphasia secondary to unilateral left-hemisphere stroke exhibited a more bilateral overall profile of activation and a more diffuse pattern within the left hemisphere than control subjects of similar age,24 and increasing temporal abnormality in left temporal language areas was associated with greater linguistic deficit in the aphasic patients. All of these studies were relatively small, and findings require replication in larger, and, wherever possible, more homogeneous groups. However, taken together they provide evidence for the utility of the MEG methodology for studying spatiotemporal parameters of plasticity in areas that support auditory comprehension and the factors that affect them.

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Division of Clinical Neurosciences, Department of Neurosurgery, University of Texas – Houston Health Science Center, Houston, TX

Reprint requests to Joshua I. Breier, PhD, Dept of Neurosurgery, Division of Clinical Neurosciences, University of Texas–Houston Health Science Center, 1333 Moursund St, Ste H114, Houston, TX 77030

Supported by the Vivian L. Smith Center for Neurologic Research and the National Institute for Neurological Disorders and Stroke (grant no. P01NS046588).

No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

PII: S0003-9993(06)01261-5

doi:10.1016/j.apmr.2006.07.271

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