INVITED REVIEW
Intraoperative Functional Cortical Mapping of Language Ronan D. Kilbride
Summary: Intraoperative neurophysiologic monitoring endeavors to preserve the integrity of the nervous system at a time of potential risk. The examination of language function in the operative setting is a unique task that requires a detailed and systematic approach to be carried out efficiently and reliably in this dynamic environment. In this review, we detail the technique used to identify eloquent language cortex during awake craniotomy. This technique requires a coordinated effort to testing, which is reliant on preoperative assessment and structured approach to functional cortical mapping by the surgical, anesthetic, and neurophysiology teams. Despite the intricate nature of this modality of testing, the accurate identification of language areas facilitates neurosurgeries for tumor and focal epilepsy syndromes in the dominant cerebral hemisphere, which depend on maximal margins of resection for best outcomes.
limitations of such testing and a desire to further examine language function to ensure minimized risk of surgical injury. With this stated goal, the neurophysiologist is uniquely qualified to coordinate and interpret the findings of the intraoperative language examination to ensure accurate identification of eloquent language areas while avoiding misinterpretation of testing. The utilization of neurophysiologic techniques for this endeavor is not new and was pioneered over half a century ago (Penfield et al., 1949) in individuals undergoing surgery for focal epilepsy syndromes. These same techniques, which we outline have been applied to cortical tumor surgeries and even in a modern age of smaller craniotomy imaging–guided neurosurgery, remain as vital now to protecting language function and reducing operative risk as they did when first conceived.
Key Words: Functional cortical mapping, Neurosurgery, Epilepsy, Intraoperative neurophysiology.
RELEVANT ANATOMY
(J Clin Neurophysiol 2013;30: 591–596)
I
ntraoperative neurophysiologic monitoring endeavors to document the integrity of the nervous system at a moment of potential risk. Nowhere is this of greater concern for doctor and patient a like than in the preservation of language function during neurosurgery. Since the nineteenth century, selective deficits in neurologic function by stimulation have lead to understanding of the neuroanatomic localization of cortical function (Barthelow, 1874). The causative relationship between lesional injury and clinical deficit has subsequently been used to identify specific areas of cortical control (Penfield, 1959). Within the map of cortical function, we categorize regions of specific eloquence considered worthy of preservation when approaching a surgical endeavor. Improved understanding of functional neuroanatomy brings the realization that there is great interindividual variability (Ojemann, 1979; Ojeman and Mateer, 1979), and despite an improved ability to test and identify language areas through clinical neuropsychology and functional neuroimaging, it remains a critical concern of surgeons who operate in the dominant hemisphere to adhere to a principle of primum non nocere when trying to protect their patient’s ability to communicate with their fellow man postsurgery. This principle is often at odds with the knowledge that a wider field of resection may improve outcomes with regard to the causative pathology but could render an individual with unacceptable subsequent morbidity. In this setting, we review the approach to intraoperative functional cortical mapping of language using Neurophysiologic techniques. Despite an increasingly high-tech approach to presurgical evaluation (Binder, 1997), there remains recognition of the From the Division of Intraoperative Neurophysiology, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Address correspondence and reprint requests to R. D. Kilbride, MD, MRCPI, Department of Clinical Neurophysiology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland; e-mail: [email protected]. Copyright Ó 2013 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/13/3006-0591
Direct electrical stimulation of the cerebral cortex has been shown to evoke impairment of specific elements of language function in multiple anatomic locations (Hamberger et al., 2001; Lesser et al., 1984; Luders et al., 1986; Ojemann, 1979). A wide array of disparate loci involved in language function have lead to extensive understanding of the complexity of this network and highlights its vulnerability to surgical injury. The occurrence of sequelae in the language domain after temporal, parietal, insular, and frontal surgeries is well recognized, but greatest concern exists when there is potential injury of the inferior frontal gyrus (Broca area), posterior superior temporal gyrus (Wernicke area), and their interconnection through the arcuate fasciculus within the superior longitudinal fasciculus. At the time of surgery, it is these areas that pose greatest concern to the surgeon as the fear for permanent deficit pervades. The reliable localization of these areas relative to pathology remains the most frequent task at hand when undertaking language mapping in the operating theatre. Broca area typically can be found in the inferior frontal gyrus of both right-handed and most left-handed individuals. This location is more reliable in those with newly acquired regional pathology, such as tumor, or later onset epilepsy syndromes, than in those with early life onsets (,5 years old) or developmental pathology, when language areas are more likely to be distributed bilaterally or within the right hemisphere (Duchowny et al., 1996). Broca area is best thought of as the primary language output region, and its injury can lead to a permanent difficult in speech production, broadly thought of as expressive difficulty. Wernicke area is more variable in location. Most commonly situated in the posterior superior temporal gyrus, it is often more widely distributed in topographical area than Broca area and indeed its relationship to the lateral fissure may vary, including overlap in the inferior parietal lobule in both supramarginal and angular gyri. Injury here results in difficult with comprehension of auditory stimuli, including language. Speech may retain its normal rhythm and syntax but be meaningless in terms of content, and as a result, Wernicke area is best thought of as a primary localization of receptive language function. The more compact localization
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
591
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
R. D. Kilbride
of Broca area lends its self to stimulation, and often it is identified at a lower intensity of stimulation than Wernicke area. The superior longitudinal fasciculus consists of bundles of bidirectional neuronal connections between the rostral and caudal regions of the cerebrum of both hemispheres (Fig. 1). This network of white matter pathways represents the interconnections between the frontal lobes and the parietal, temporal, and occipital lobes, in addition to the basal ganglia. Within the superior longitudinal fasciculus of the dominant hemisphere, the arcuate fasciculus originates in the caudal superior temporoparietal region, passing caudal to the Sylvian fissure and traveling within the superior longitudinal fasciculus, terminating in the prefrontal cortex of the frontal operculum (Makris et al., 2005). Injury to this fiber bundle may contribute to permanent language deficit, most evident in repetition ability. Repetition difficulties after arcuate fasciculus injury are termed conduction aphasia (Andersen, 1999).
TECHNIQUE Language mapping in the operative setting requires much planning, skilled human resources, and a teamwork approach to best achieve the desired result. To safely and adequately identify language areas, the surgeon should interrogate the operative field in a systematic fashion. Using a handheld stimulator, one explores the cortical surface to identify positive language areas by transient disruption of cortical function using direct electrical stimulation and a clinical examination. The assessment of a positive response is determined when language production or comprehension is hindered by stimulation. Our ideal is to correctly identify positive language areas at the minimal effective threshold, without disruption of the testing by afterdischarges, provoked electrographic seizure, or electroclinical seizures as these may contribute to false-positive results (Fig. 2). After the identification of true-positive language areas, excluding any false positives, we also aim to identify truenegative language areas (i.e., candidate areas for safe resection).
Electrocorticography should accompany all direct electrical cortical stimulation. The occurrence of afterdischarges or seizure not only runs the risk of false positive in the examination but may also jeopardize the procedure and bring an abrupt end to the mapping endeavor. That apart, in a wakeful patient, the occurrence of seizure may contribute greatly to anxiety associated with the procedure further reducing cooperation with clinical assessment. Similarly, protracted periods of testing may be associated with patient fatigue, which may manifest as a deterioration of language function, further complicating the interpretation of study results. With this in mind, a focused systematic approach to the field promptly moving through the relevant anatomic regions, with incremental stimulation intensity, has the greatest chance of consistently identifying language cortex and safely clearing cortex for resection. When the minimal effective threshold is established and positive language areas are identified, the surgeon may restimulate during resection or postresection to confirm their continuing integrity.
Cortical Stimulation A handheld bipolar cranial gold ball electrode is used with continuous (Penfield method) stimulation parameters of a biphasic rectangular pulse at 1 ms duration at 60 Hz (Fig. 3). Starting at 1 mA and increasing intensity in 0.5 to 1.0 mA increments, up to a maximum of 15 mA (Gordon et al., 1990). In the awake patient, language disruption may be achieved before this degree of stimulation; however, in the case of a negative examination, higher threshold stimulation may be required. In general, stimulation of a brief duration is used to interrupt the clinical examination and yields best results if of at least 1- to 2-second duration, but may be continued up to 10 seconds if needed. Prolonged stimulation increases the likelihood of provoked epileptiform activity. Periodically, stimulation should be paused at each stimulation level to review the EEG for such activity. The threshold at which language function is disrupted may vary between specific anatomic regions. When the surgical resection encroaches within 10 mm of the positively identified language areas,
FIG. 1. Diffusion tensor image (A) shows the left superior longitudinal fasciculus (multicolored) in rostral view, lateral to a left frontal mass lesion (blue). Within the superior longitudinal fasciculus, the arcuate fasciculus connects Broca and Wernicke areas (B). Newer imaging modalities of diffusion tensor imaging and functional magnetic resonance imaging may assist in preoperative planning of functional cortical language mapping but have not eliminated the need to identify these structures by neurophysiologic testing at surgery. 592
Copyright Ó 2013 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
Functional Cortical Mapping of Language
FIG. 2. Typical electrocorticography findings during functional cortical mapping. EEG from an 8-contact subdural strip on the cortical surface is reviewed in bipolar and reference montages, regarding contra-ear (A2 in this case). When language areas are stimulated (A), stimulus artifact can be seen, and an absence of afterdischarge or seizure confirms the result as true positive. When the language examination is interrupted after stimulation (B), electrocorticography detects a provoked seizure, confirming the result as false positive. there is an increased likelihood of language deficit. This cortical stimulation may be continued during resection, or after removal of the cortical mantle, to detect the white matter tracts of the arcuate fasciculus. The later, although technically challenging, may help to delineate the depth of resection tolerable.
stimulus artifact but should be used with caution as filtering may delay the identification of afterdischarges or provoked seizure that may arise within the period of stimulation. EEG should be reviewed with and without filtering periodically in both bipolar and referential montages to promptly identify the occurrence of epileptiform abnormalities.
Electrocorticography EEG is best recorded from an 8-contact subdural strip electrode in the operative field adjacent the regions to be stimulated (Fig. 3). An 8-contact strip electrode placed over the frontoparietal convexity provides sufficient coverage of the cortical surface while not obstructing the operative field. Attention to electrode impedance, securing the recording electrode by dural suture when necessary, saline irrigation of the electrode, and use of a 60-Hz notch filter, all may enhance the quality of EEG recording in this dynamic environment. EEG data should be reviewed live in the operating theatre at sufficient time base to accurately assess for afterdischarges and seizures, usually 30 mm/sec. A notch filter is effective in suppressing Copyright Ó 2013 by the American Clinical Neurophysiology Society
Language Examination Language function can be assessed in a multi-modal fashion. Picture naming, repetition, and sentence completion all may be used with good effect. Word reading, color identification, and self-midline command, all may also have a role, particularly if trying to identify posterior language areas. That said, anomia is a feature common to all types of aphasia and picture naming remains the most reliable task for detection of language disruption by stimulation in the operative setting. Picture naming of common polysyllabic proper nouns at a third grade elementary reading level (e.g., violin, elephant, and octopus) is an effective test of both expressive and 593
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Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
FIG. 3. Technique used in stimulation for cortical mapping of language areas. The surgical field is explored for positive language areas using a handheld bipolar stimulator (A). While the surgeon directly stimulates the cortical surface, the patient undergoes a language examination. Disturbance of language function is noted by the operative team. Electrocorticography is performed to ensure aphasia is not the result of provoked epileptiform activity. B, The surgical team have iced saline ready for irrigation should afterdischarges or electrographic seizures are identified by the neurophysiologist.
receptive language areas. Other modalities of language testing prove more practical in the extraoperative environment (i.e., the Epilepsy Monitoring Unit) where a greater period may be dedicated to testing. The language examination must be considered in the context of an individual patient’s baseline function, and the preoperative evaluation remains the single greatest determinant of the degree to which language maybe assessed in the operating theatre. A preoperative language examination is essential for effective identification of language areas intraoperatively. Where fluency is challenged, the ability to maintain focus or concentration through a series of naming exercises may be poor and one may need to incorporate the use of learned sequences (e.g., days of the week, months of the year, counting by 2s . etc) keeping in mind the ability of aphasic individuals to carry out such automatic speech. When used, this should be considered to be a less sensitive an assessment of language. The examiner observes the patient for an arrest in verbal output, loss of fluency, and naming error. Accurate identification of aphasia as distinct to the motor interruption of speech or dysarthria from stimulation of primary motor areas may prove challenging. With the patient under surgical drapes, the face, mouth, and tongue remain out of direct view to the surgeon and the examiner must be able to interpret the clinical examination to make this distinction. If necessary, a pause in the language examination with continued stimulation and observation of the oral cavity may be required to confirm provoked motor activity. The utilization of microphone and amplifier, video recording of the patient’s face during testing, and repeated methodical evaluation, all help to clarify the occurrence of true language error and minimize the risk of false positives associated with provoked dysarthria.
Anesthetics and Intraoperative Seizure Management Consideration given to the anesthetics used at induction is important in establishing an effective strategy for language mapping. 594
Adequate anesthesia is required for induction and craniotomy; however, shorter acting agents remain favorable, in light of the need to awaken the patient and achieve a reproducible and reliable language examination. The effects of persistent sedation in a patient with a symptomatic lesion may contribute to difficulty avoiding false positives during assessment of language. Propofol (at 50 to 100 mg/kg per minute) in combination with short-acting fentanyl derivatives (e.g., remifentanyl 0.05 to 0.1 mg/kg per minute) provide sufficient anesthetic for induction and craniotomy and allow for subsequent waking and effective language evaluation. During the period of stimulation, there may be the occurrence of afterdischarges, electrographic seizures, or electroclinical seizures. Afterdischarges should prompt a halt in stimulation. Their occurrence often determines the upper limited of the degree to which stimulation may be tolerated in a given cortical region by virtue of the intrinsic threshold or indeed proximity to associated epileptiform areas. If afterdischarges persist or proceed to electrographic seizure, topical iced saline or Ringer lactate solution may be administered liberally by the surgical team. This brings about a local vasoconstriction and transient hypothermia that contributes to arrest of the ictus. Seizures themselves may be associated with hyperemia and local edema that is directly visible in the operative field. This edema or the presence of Todd aphasia may contribute to deterioration in language function effecting performance in any subsequent examination. The risk of seizure may be reduced by the use of antiepileptic drug (AED) therapy, which is usually part of the patient’s drug regime, before surgery. Intravenous substitution and intravenous bolus dosing can be considered on an individual basis to minimize the risk of epileptiform activity. Should electrographic seizure activity persist, evolve to electroclinical focal or generalized seizure, an IV bolus dose of propofol (1 mg/kg) may be required to terminate the event. Similarly, midazolam may be incorporated to assist in seizure control. The use of short-acting anesthetics allows for the minimal degree of delay the further assessment of language regions; however, following the use of benzodiazepines, flumazenil (0.2 mg IV bolus and repeated as required) may be required to assist in shortening any prolonged sedative effect hindering further examination. Copyright Ó 2013 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
Troubleshooting As with all forms of intraoperative neurophysiology, functional cortical mapping may be complicated by the occurrence of unexpected eventualities that may effect completion of the test. The operative environment is dynamic and the complexity of language mapping necessitates the presence of the neurophysiologist in the operating theatre in direct communication with the surgical and anesthetic teams. A well-formulated strategic approach to awake craniotomy contributes greatly to the ability to achieve successful results. A well-documented preoperative language examination is essential. Simple practical matters left unaccounted for, such as unavailable eye glasses or magnifying glass, poor vision, and language barrier, may prove insurmountable practical hurdles to effective testing if neglected. Like all procedures, the ability to problem solving in real time to effect adequate resolution is highly dependent on the neurophysiologist maintaining an expertise not only in the technical aspects of the procedure but also a surgical familiarity of the planned resection and understanding of the pharmacodynamics of any medications administered. Technical failure may occur using a bipolar stimulator if the anode and cathode are too closely spaced or touching. The use of a 60-Hz notch filter in recording electrocorticography may mask the identification of such an ineffective stimulation. Similarly, if the clinical examination is not adequately synchronized to be interrupted by the stimulus or the stimulus of insufficient duration to effect a recognizable change, opportunities to identify eloquent language cortex may be lost. Finally, it is essential to keep in mind that operating in the awake state imparts a degree of fatigue that may affect a patient’s ability to participate in and the results of the clinical examination. Drying of the mouth, pain, and anxiety all may serve as hurdles to the effective completion of the task if the duration of testing is protracted. When this occurs, symptomatic treatments, patient reassurance, and encouragement assist greatly in achieving the desired results.
Functional Cortical Mapping of Language
CLINICAL APPLICATION Functional cortical mapping of eloquent cortex for language function is indicated when there is concern for encroachment of the epileptic zone or tumor in the primary language areas or their interconnections. Whether mapping Broca area, Wernicke area, or their subcortical interconnections, when there is sufficient surgical concern for injury to language areas, awake craniotomy and intraoperative examination provide reassurance. Intraoperative testing aids in the preservation of speech and understanding, independent of any assumed localization of language function based on anatomic grounds or functional preoperative imaging. In practice, however, intraoperative mapping is complimentary to other modalities of assessment and offers an additional layer of confidence by confirming investigational findings in vivo. It may be combined with functional mapping of motor and sensory areas. In epilepsy surgeries, it is often considered in the context of electrocorticography recorded from a wider field to ensure a greater likelihood of seizure control (Fig. 4). This combination, with subcortical mapping, is often used in insular resections.
DISCUSSION The complexity of human language function leaves it particularly susceptible to injury when patients undergo surgeries in the dominant hemisphere. Stimulation studies have outlined the widespread topographic distribution of language function in multiple realms. Even as detailed preoperative neuropsychology and ever improving neuroimaging with functional magnetic resonance imaging and diffusion tensor imaging lend understanding to language function, there remains a desire for surgeons to confirm the integrity of this network at the time of surgery. Despite our improved ability to use intraoperative neurophysiology to monitor other modalities of cerebral and spinal function under anesthesia, the examination of language function in the operating theatre remains a unique crossroads between
FIG. 4. A, Preresection anatomy of the left hemisphere in a 19-year-old right-handed man undergoing awake left-sided craniotomy for control of an imaging negative focal epilepsy syndrome. The seizure onset zone was identified in the posterior superior temporal gyrus (purple marker). B, Positive language area as identified by mapping using a handheld bipolar stimulator and clinical examination. Language areas in the inferior frontal gyrus (Broca area) were identified at a threshold of 3 mA and in the posterior superior temporal gyrus (Wernicke area) at a threshold of 5 mA. C, Postresection anatomy with electrocorticography. Pathology confirmed evidence of focal cortical dysplasia, and the patient remains seizure free with intact language function 3 years postresection. Copyright Ó 2013 by the American Clinical Neurophysiology Society
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the utilization of core neurophysiologic techniques and the clinical neurologic examination. Awake craniotomy is a novel surgical setting, which allows for examination of distinct cortical and subcortical areas with effectively a reversible lesion to assess the potential impact of their resection. Preoperative language evaluation, anesthetic considerations, and a systematic approach to testing by the surgeon and neurophysiologist are needed to achieve this in an efficient and reliable manner. Intraoperative language mapping has limitations. Mapping may prove tedious and unlikely to change the preoperative approach to surgery. Should this be the case, language mapping is best avoided as awake craniotomy and direct cortical stimulation are not without risks. When mapping is warranted, the intraoperative environment can prove a limited one in terms of available time to evaluate a patient and restricted in the number of modalities of language function that may be assessed. Patients with epilepsy often undergo implantation of subdural and depth electrode across a broad field of cortical anatomy. When this is the case, cortical stimulation may be used to a greater degree with the time required to address with a detailed multimodal approach. Should provoked epileptiform activity preclude the identification of language areas, there will be greater reliance of the preoperative data. Similarly, a failure to correctly identify positive areas leaves one with concern for the risk sequelae following a negative map. Negative mapping has been used in dominant hemisphere glioma (Sanai et al., 2008); however, as with all surgeries, intraoperative testing is used to reconfirm a previously formed hypothesis, and positive language mapping helps to define the extent to which the planned surgery can be affected. If language mapping fails to identify primary language areas or testing incomplete as a result of the provocation of epileptiform activity, this must be considered in the context of that hypothesis. The neurophysiologist can serve as a conduit between patient and surgeon to ensure effective and reliable identification of
596
language function during awake craniotomy. Despite the complexity of the task and many potential pitfalls, the opportunity to incorporate clinical examination and neurophysiologic techniques in real time to influence patient outcome is unique, and one that should be welcomed. REFERENCES Anderson JM, Gilmore R, Robert S, Crosson B, et al. Conduction aphasia and the arcuate fasciculus: a reexamination of the Wernicke-Geschwind model. Brain Lang 1999;70:1–12. Barthelow R. Experimental investigations into functions of the human brain. Am J Med Sci 1874;67:305–313. Binder JR. Neuroanatomy of language processing studied with functional MRI. Clin Neurosci 1997;4:87–94. Duchowny M, Jayakar P, Harvey AS, et al. Language cortex representation: effects of developmental versus acquired pathology. Ann Neurol 1996;40:31–38. Gordon B, Lesser RP, Rance NE, et al. Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol 1990;75:371–377. Hamberger MJ, Goodman RR, Perrine K, Tammy T. Anatomical dissociation of auditory and visual naming in the lateral temporal cortex. Neurology 2001;56:56–61. Lesser RP, Luders H, Dinner DS, et al. The location of speech and writing functions in the frontal language area. Brain 1984;107:275–291. Luders H, Lesser R, Hahn J, et al. Basal temporal language area demonstrated by electrical stimulation. Neurology 1986;36:505–510. Makris N, et al. Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI study. Cereb Cortex 2005;15:854–869. Ojemann GA. Individual variability in the cortical localization of language. J Neurosurg 1979;50:164–169. Ojemann GA, Mateer C. Human language cortex: localization of memory, syntax and sequential motor-phoneme sequencing. Science 1979;205:1401–1403. Penfield W. Mapping the speech area. In: Penfield LRW, ed. Speech and Brain Mechanisms. 1959:103–118. Penfield W, Rasmussen T. Vocalization and arrest of speech. Arch Neurol Psychiatr 1949;61:21–27. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med 2008;358:18–27.
Copyright Ó 2013 by the American Clinical Neurophysiology Society
Intraoperative Functional Cortical Mapping of Language Ronan D. Kilbride
Summary: Intraoperative neurophysiologic monitoring endeavors to preserve the integrity of the nervous system at a time of potential risk. The examination of language function in the operative setting is a unique task that requires a detailed and systematic approach to be carried out efficiently and reliably in this dynamic environment. In this review, we detail the technique used to identify eloquent language cortex during awake craniotomy. This technique requires a coordinated effort to testing, which is reliant on preoperative assessment and structured approach to functional cortical mapping by the surgical, anesthetic, and neurophysiology teams. Despite the intricate nature of this modality of testing, the accurate identification of language areas facilitates neurosurgeries for tumor and focal epilepsy syndromes in the dominant cerebral hemisphere, which depend on maximal margins of resection for best outcomes.
limitations of such testing and a desire to further examine language function to ensure minimized risk of surgical injury. With this stated goal, the neurophysiologist is uniquely qualified to coordinate and interpret the findings of the intraoperative language examination to ensure accurate identification of eloquent language areas while avoiding misinterpretation of testing. The utilization of neurophysiologic techniques for this endeavor is not new and was pioneered over half a century ago (Penfield et al., 1949) in individuals undergoing surgery for focal epilepsy syndromes. These same techniques, which we outline have been applied to cortical tumor surgeries and even in a modern age of smaller craniotomy imaging–guided neurosurgery, remain as vital now to protecting language function and reducing operative risk as they did when first conceived.
Key Words: Functional cortical mapping, Neurosurgery, Epilepsy, Intraoperative neurophysiology.
RELEVANT ANATOMY
(J Clin Neurophysiol 2013;30: 591–596)
I
ntraoperative neurophysiologic monitoring endeavors to document the integrity of the nervous system at a moment of potential risk. Nowhere is this of greater concern for doctor and patient a like than in the preservation of language function during neurosurgery. Since the nineteenth century, selective deficits in neurologic function by stimulation have lead to understanding of the neuroanatomic localization of cortical function (Barthelow, 1874). The causative relationship between lesional injury and clinical deficit has subsequently been used to identify specific areas of cortical control (Penfield, 1959). Within the map of cortical function, we categorize regions of specific eloquence considered worthy of preservation when approaching a surgical endeavor. Improved understanding of functional neuroanatomy brings the realization that there is great interindividual variability (Ojemann, 1979; Ojeman and Mateer, 1979), and despite an improved ability to test and identify language areas through clinical neuropsychology and functional neuroimaging, it remains a critical concern of surgeons who operate in the dominant hemisphere to adhere to a principle of primum non nocere when trying to protect their patient’s ability to communicate with their fellow man postsurgery. This principle is often at odds with the knowledge that a wider field of resection may improve outcomes with regard to the causative pathology but could render an individual with unacceptable subsequent morbidity. In this setting, we review the approach to intraoperative functional cortical mapping of language using Neurophysiologic techniques. Despite an increasingly high-tech approach to presurgical evaluation (Binder, 1997), there remains recognition of the From the Division of Intraoperative Neurophysiology, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Address correspondence and reprint requests to R. D. Kilbride, MD, MRCPI, Department of Clinical Neurophysiology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland; e-mail: [email protected]. Copyright Ó 2013 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/13/3006-0591
Direct electrical stimulation of the cerebral cortex has been shown to evoke impairment of specific elements of language function in multiple anatomic locations (Hamberger et al., 2001; Lesser et al., 1984; Luders et al., 1986; Ojemann, 1979). A wide array of disparate loci involved in language function have lead to extensive understanding of the complexity of this network and highlights its vulnerability to surgical injury. The occurrence of sequelae in the language domain after temporal, parietal, insular, and frontal surgeries is well recognized, but greatest concern exists when there is potential injury of the inferior frontal gyrus (Broca area), posterior superior temporal gyrus (Wernicke area), and their interconnection through the arcuate fasciculus within the superior longitudinal fasciculus. At the time of surgery, it is these areas that pose greatest concern to the surgeon as the fear for permanent deficit pervades. The reliable localization of these areas relative to pathology remains the most frequent task at hand when undertaking language mapping in the operating theatre. Broca area typically can be found in the inferior frontal gyrus of both right-handed and most left-handed individuals. This location is more reliable in those with newly acquired regional pathology, such as tumor, or later onset epilepsy syndromes, than in those with early life onsets (,5 years old) or developmental pathology, when language areas are more likely to be distributed bilaterally or within the right hemisphere (Duchowny et al., 1996). Broca area is best thought of as the primary language output region, and its injury can lead to a permanent difficult in speech production, broadly thought of as expressive difficulty. Wernicke area is more variable in location. Most commonly situated in the posterior superior temporal gyrus, it is often more widely distributed in topographical area than Broca area and indeed its relationship to the lateral fissure may vary, including overlap in the inferior parietal lobule in both supramarginal and angular gyri. Injury here results in difficult with comprehension of auditory stimuli, including language. Speech may retain its normal rhythm and syntax but be meaningless in terms of content, and as a result, Wernicke area is best thought of as a primary localization of receptive language function. The more compact localization
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
591
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
R. D. Kilbride
of Broca area lends its self to stimulation, and often it is identified at a lower intensity of stimulation than Wernicke area. The superior longitudinal fasciculus consists of bundles of bidirectional neuronal connections between the rostral and caudal regions of the cerebrum of both hemispheres (Fig. 1). This network of white matter pathways represents the interconnections between the frontal lobes and the parietal, temporal, and occipital lobes, in addition to the basal ganglia. Within the superior longitudinal fasciculus of the dominant hemisphere, the arcuate fasciculus originates in the caudal superior temporoparietal region, passing caudal to the Sylvian fissure and traveling within the superior longitudinal fasciculus, terminating in the prefrontal cortex of the frontal operculum (Makris et al., 2005). Injury to this fiber bundle may contribute to permanent language deficit, most evident in repetition ability. Repetition difficulties after arcuate fasciculus injury are termed conduction aphasia (Andersen, 1999).
TECHNIQUE Language mapping in the operative setting requires much planning, skilled human resources, and a teamwork approach to best achieve the desired result. To safely and adequately identify language areas, the surgeon should interrogate the operative field in a systematic fashion. Using a handheld stimulator, one explores the cortical surface to identify positive language areas by transient disruption of cortical function using direct electrical stimulation and a clinical examination. The assessment of a positive response is determined when language production or comprehension is hindered by stimulation. Our ideal is to correctly identify positive language areas at the minimal effective threshold, without disruption of the testing by afterdischarges, provoked electrographic seizure, or electroclinical seizures as these may contribute to false-positive results (Fig. 2). After the identification of true-positive language areas, excluding any false positives, we also aim to identify truenegative language areas (i.e., candidate areas for safe resection).
Electrocorticography should accompany all direct electrical cortical stimulation. The occurrence of afterdischarges or seizure not only runs the risk of false positive in the examination but may also jeopardize the procedure and bring an abrupt end to the mapping endeavor. That apart, in a wakeful patient, the occurrence of seizure may contribute greatly to anxiety associated with the procedure further reducing cooperation with clinical assessment. Similarly, protracted periods of testing may be associated with patient fatigue, which may manifest as a deterioration of language function, further complicating the interpretation of study results. With this in mind, a focused systematic approach to the field promptly moving through the relevant anatomic regions, with incremental stimulation intensity, has the greatest chance of consistently identifying language cortex and safely clearing cortex for resection. When the minimal effective threshold is established and positive language areas are identified, the surgeon may restimulate during resection or postresection to confirm their continuing integrity.
Cortical Stimulation A handheld bipolar cranial gold ball electrode is used with continuous (Penfield method) stimulation parameters of a biphasic rectangular pulse at 1 ms duration at 60 Hz (Fig. 3). Starting at 1 mA and increasing intensity in 0.5 to 1.0 mA increments, up to a maximum of 15 mA (Gordon et al., 1990). In the awake patient, language disruption may be achieved before this degree of stimulation; however, in the case of a negative examination, higher threshold stimulation may be required. In general, stimulation of a brief duration is used to interrupt the clinical examination and yields best results if of at least 1- to 2-second duration, but may be continued up to 10 seconds if needed. Prolonged stimulation increases the likelihood of provoked epileptiform activity. Periodically, stimulation should be paused at each stimulation level to review the EEG for such activity. The threshold at which language function is disrupted may vary between specific anatomic regions. When the surgical resection encroaches within 10 mm of the positively identified language areas,
FIG. 1. Diffusion tensor image (A) shows the left superior longitudinal fasciculus (multicolored) in rostral view, lateral to a left frontal mass lesion (blue). Within the superior longitudinal fasciculus, the arcuate fasciculus connects Broca and Wernicke areas (B). Newer imaging modalities of diffusion tensor imaging and functional magnetic resonance imaging may assist in preoperative planning of functional cortical language mapping but have not eliminated the need to identify these structures by neurophysiologic testing at surgery. 592
Copyright Ó 2013 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 30, Number 6, December 2013
Functional Cortical Mapping of Language
FIG. 2. Typical electrocorticography findings during functional cortical mapping. EEG from an 8-contact subdural strip on the cortical surface is reviewed in bipolar and reference montages, regarding contra-ear (A2 in this case). When language areas are stimulated (A), stimulus artifact can be seen, and an absence of afterdischarge or seizure confirms the result as true positive. When the language examination is interrupted after stimulation (B), electrocorticography detects a provoked seizure, confirming the result as false positive. there is an increased likelihood of language deficit. This cortical stimulation may be continued during resection, or after removal of the cortical mantle, to detect the white matter tracts of the arcuate fasciculus. The later, although technically challenging, may help to delineate the depth of resection tolerable.
stimulus artifact but should be used with caution as filtering may delay the identification of afterdischarges or provoked seizure that may arise within the period of stimulation. EEG should be reviewed with and without filtering periodically in both bipolar and referential montages to promptly identify the occurrence of epileptiform abnormalities.
Electrocorticography EEG is best recorded from an 8-contact subdural strip electrode in the operative field adjacent the regions to be stimulated (Fig. 3). An 8-contact strip electrode placed over the frontoparietal convexity provides sufficient coverage of the cortical surface while not obstructing the operative field. Attention to electrode impedance, securing the recording electrode by dural suture when necessary, saline irrigation of the electrode, and use of a 60-Hz notch filter, all may enhance the quality of EEG recording in this dynamic environment. EEG data should be reviewed live in the operating theatre at sufficient time base to accurately assess for afterdischarges and seizures, usually 30 mm/sec. A notch filter is effective in suppressing Copyright Ó 2013 by the American Clinical Neurophysiology Society
Language Examination Language function can be assessed in a multi-modal fashion. Picture naming, repetition, and sentence completion all may be used with good effect. Word reading, color identification, and self-midline command, all may also have a role, particularly if trying to identify posterior language areas. That said, anomia is a feature common to all types of aphasia and picture naming remains the most reliable task for detection of language disruption by stimulation in the operative setting. Picture naming of common polysyllabic proper nouns at a third grade elementary reading level (e.g., violin, elephant, and octopus) is an effective test of both expressive and 593
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FIG. 3. Technique used in stimulation for cortical mapping of language areas. The surgical field is explored for positive language areas using a handheld bipolar stimulator (A). While the surgeon directly stimulates the cortical surface, the patient undergoes a language examination. Disturbance of language function is noted by the operative team. Electrocorticography is performed to ensure aphasia is not the result of provoked epileptiform activity. B, The surgical team have iced saline ready for irrigation should afterdischarges or electrographic seizures are identified by the neurophysiologist.
receptive language areas. Other modalities of language testing prove more practical in the extraoperative environment (i.e., the Epilepsy Monitoring Unit) where a greater period may be dedicated to testing. The language examination must be considered in the context of an individual patient’s baseline function, and the preoperative evaluation remains the single greatest determinant of the degree to which language maybe assessed in the operating theatre. A preoperative language examination is essential for effective identification of language areas intraoperatively. Where fluency is challenged, the ability to maintain focus or concentration through a series of naming exercises may be poor and one may need to incorporate the use of learned sequences (e.g., days of the week, months of the year, counting by 2s . etc) keeping in mind the ability of aphasic individuals to carry out such automatic speech. When used, this should be considered to be a less sensitive an assessment of language. The examiner observes the patient for an arrest in verbal output, loss of fluency, and naming error. Accurate identification of aphasia as distinct to the motor interruption of speech or dysarthria from stimulation of primary motor areas may prove challenging. With the patient under surgical drapes, the face, mouth, and tongue remain out of direct view to the surgeon and the examiner must be able to interpret the clinical examination to make this distinction. If necessary, a pause in the language examination with continued stimulation and observation of the oral cavity may be required to confirm provoked motor activity. The utilization of microphone and amplifier, video recording of the patient’s face during testing, and repeated methodical evaluation, all help to clarify the occurrence of true language error and minimize the risk of false positives associated with provoked dysarthria.
Anesthetics and Intraoperative Seizure Management Consideration given to the anesthetics used at induction is important in establishing an effective strategy for language mapping. 594
Adequate anesthesia is required for induction and craniotomy; however, shorter acting agents remain favorable, in light of the need to awaken the patient and achieve a reproducible and reliable language examination. The effects of persistent sedation in a patient with a symptomatic lesion may contribute to difficulty avoiding false positives during assessment of language. Propofol (at 50 to 100 mg/kg per minute) in combination with short-acting fentanyl derivatives (e.g., remifentanyl 0.05 to 0.1 mg/kg per minute) provide sufficient anesthetic for induction and craniotomy and allow for subsequent waking and effective language evaluation. During the period of stimulation, there may be the occurrence of afterdischarges, electrographic seizures, or electroclinical seizures. Afterdischarges should prompt a halt in stimulation. Their occurrence often determines the upper limited of the degree to which stimulation may be tolerated in a given cortical region by virtue of the intrinsic threshold or indeed proximity to associated epileptiform areas. If afterdischarges persist or proceed to electrographic seizure, topical iced saline or Ringer lactate solution may be administered liberally by the surgical team. This brings about a local vasoconstriction and transient hypothermia that contributes to arrest of the ictus. Seizures themselves may be associated with hyperemia and local edema that is directly visible in the operative field. This edema or the presence of Todd aphasia may contribute to deterioration in language function effecting performance in any subsequent examination. The risk of seizure may be reduced by the use of antiepileptic drug (AED) therapy, which is usually part of the patient’s drug regime, before surgery. Intravenous substitution and intravenous bolus dosing can be considered on an individual basis to minimize the risk of epileptiform activity. Should electrographic seizure activity persist, evolve to electroclinical focal or generalized seizure, an IV bolus dose of propofol (1 mg/kg) may be required to terminate the event. Similarly, midazolam may be incorporated to assist in seizure control. The use of short-acting anesthetics allows for the minimal degree of delay the further assessment of language regions; however, following the use of benzodiazepines, flumazenil (0.2 mg IV bolus and repeated as required) may be required to assist in shortening any prolonged sedative effect hindering further examination. Copyright Ó 2013 by the American Clinical Neurophysiology Society
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Troubleshooting As with all forms of intraoperative neurophysiology, functional cortical mapping may be complicated by the occurrence of unexpected eventualities that may effect completion of the test. The operative environment is dynamic and the complexity of language mapping necessitates the presence of the neurophysiologist in the operating theatre in direct communication with the surgical and anesthetic teams. A well-formulated strategic approach to awake craniotomy contributes greatly to the ability to achieve successful results. A well-documented preoperative language examination is essential. Simple practical matters left unaccounted for, such as unavailable eye glasses or magnifying glass, poor vision, and language barrier, may prove insurmountable practical hurdles to effective testing if neglected. Like all procedures, the ability to problem solving in real time to effect adequate resolution is highly dependent on the neurophysiologist maintaining an expertise not only in the technical aspects of the procedure but also a surgical familiarity of the planned resection and understanding of the pharmacodynamics of any medications administered. Technical failure may occur using a bipolar stimulator if the anode and cathode are too closely spaced or touching. The use of a 60-Hz notch filter in recording electrocorticography may mask the identification of such an ineffective stimulation. Similarly, if the clinical examination is not adequately synchronized to be interrupted by the stimulus or the stimulus of insufficient duration to effect a recognizable change, opportunities to identify eloquent language cortex may be lost. Finally, it is essential to keep in mind that operating in the awake state imparts a degree of fatigue that may affect a patient’s ability to participate in and the results of the clinical examination. Drying of the mouth, pain, and anxiety all may serve as hurdles to the effective completion of the task if the duration of testing is protracted. When this occurs, symptomatic treatments, patient reassurance, and encouragement assist greatly in achieving the desired results.
Functional Cortical Mapping of Language
CLINICAL APPLICATION Functional cortical mapping of eloquent cortex for language function is indicated when there is concern for encroachment of the epileptic zone or tumor in the primary language areas or their interconnections. Whether mapping Broca area, Wernicke area, or their subcortical interconnections, when there is sufficient surgical concern for injury to language areas, awake craniotomy and intraoperative examination provide reassurance. Intraoperative testing aids in the preservation of speech and understanding, independent of any assumed localization of language function based on anatomic grounds or functional preoperative imaging. In practice, however, intraoperative mapping is complimentary to other modalities of assessment and offers an additional layer of confidence by confirming investigational findings in vivo. It may be combined with functional mapping of motor and sensory areas. In epilepsy surgeries, it is often considered in the context of electrocorticography recorded from a wider field to ensure a greater likelihood of seizure control (Fig. 4). This combination, with subcortical mapping, is often used in insular resections.
DISCUSSION The complexity of human language function leaves it particularly susceptible to injury when patients undergo surgeries in the dominant hemisphere. Stimulation studies have outlined the widespread topographic distribution of language function in multiple realms. Even as detailed preoperative neuropsychology and ever improving neuroimaging with functional magnetic resonance imaging and diffusion tensor imaging lend understanding to language function, there remains a desire for surgeons to confirm the integrity of this network at the time of surgery. Despite our improved ability to use intraoperative neurophysiology to monitor other modalities of cerebral and spinal function under anesthesia, the examination of language function in the operating theatre remains a unique crossroads between
FIG. 4. A, Preresection anatomy of the left hemisphere in a 19-year-old right-handed man undergoing awake left-sided craniotomy for control of an imaging negative focal epilepsy syndrome. The seizure onset zone was identified in the posterior superior temporal gyrus (purple marker). B, Positive language area as identified by mapping using a handheld bipolar stimulator and clinical examination. Language areas in the inferior frontal gyrus (Broca area) were identified at a threshold of 3 mA and in the posterior superior temporal gyrus (Wernicke area) at a threshold of 5 mA. C, Postresection anatomy with electrocorticography. Pathology confirmed evidence of focal cortical dysplasia, and the patient remains seizure free with intact language function 3 years postresection. Copyright Ó 2013 by the American Clinical Neurophysiology Society
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the utilization of core neurophysiologic techniques and the clinical neurologic examination. Awake craniotomy is a novel surgical setting, which allows for examination of distinct cortical and subcortical areas with effectively a reversible lesion to assess the potential impact of their resection. Preoperative language evaluation, anesthetic considerations, and a systematic approach to testing by the surgeon and neurophysiologist are needed to achieve this in an efficient and reliable manner. Intraoperative language mapping has limitations. Mapping may prove tedious and unlikely to change the preoperative approach to surgery. Should this be the case, language mapping is best avoided as awake craniotomy and direct cortical stimulation are not without risks. When mapping is warranted, the intraoperative environment can prove a limited one in terms of available time to evaluate a patient and restricted in the number of modalities of language function that may be assessed. Patients with epilepsy often undergo implantation of subdural and depth electrode across a broad field of cortical anatomy. When this is the case, cortical stimulation may be used to a greater degree with the time required to address with a detailed multimodal approach. Should provoked epileptiform activity preclude the identification of language areas, there will be greater reliance of the preoperative data. Similarly, a failure to correctly identify positive areas leaves one with concern for the risk sequelae following a negative map. Negative mapping has been used in dominant hemisphere glioma (Sanai et al., 2008); however, as with all surgeries, intraoperative testing is used to reconfirm a previously formed hypothesis, and positive language mapping helps to define the extent to which the planned surgery can be affected. If language mapping fails to identify primary language areas or testing incomplete as a result of the provocation of epileptiform activity, this must be considered in the context of that hypothesis. The neurophysiologist can serve as a conduit between patient and surgeon to ensure effective and reliable identification of
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language function during awake craniotomy. Despite the complexity of the task and many potential pitfalls, the opportunity to incorporate clinical examination and neurophysiologic techniques in real time to influence patient outcome is unique, and one that should be welcomed. REFERENCES Anderson JM, Gilmore R, Robert S, Crosson B, et al. Conduction aphasia and the arcuate fasciculus: a reexamination of the Wernicke-Geschwind model. Brain Lang 1999;70:1–12. Barthelow R. Experimental investigations into functions of the human brain. Am J Med Sci 1874;67:305–313. Binder JR. Neuroanatomy of language processing studied with functional MRI. Clin Neurosci 1997;4:87–94. Duchowny M, Jayakar P, Harvey AS, et al. Language cortex representation: effects of developmental versus acquired pathology. Ann Neurol 1996;40:31–38. Gordon B, Lesser RP, Rance NE, et al. Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol 1990;75:371–377. Hamberger MJ, Goodman RR, Perrine K, Tammy T. Anatomical dissociation of auditory and visual naming in the lateral temporal cortex. Neurology 2001;56:56–61. Lesser RP, Luders H, Dinner DS, et al. The location of speech and writing functions in the frontal language area. Brain 1984;107:275–291. Luders H, Lesser R, Hahn J, et al. Basal temporal language area demonstrated by electrical stimulation. Neurology 1986;36:505–510. Makris N, et al. Segmentation of subcomponents within the superior longitudinal fascicle in humans: a quantitative, in vivo, DT-MRI study. Cereb Cortex 2005;15:854–869. Ojemann GA. Individual variability in the cortical localization of language. J Neurosurg 1979;50:164–169. Ojemann GA, Mateer C. Human language cortex: localization of memory, syntax and sequential motor-phoneme sequencing. Science 1979;205:1401–1403. Penfield W. Mapping the speech area. In: Penfield LRW, ed. Speech and Brain Mechanisms. 1959:103–118. Penfield W, Rasmussen T. Vocalization and arrest of speech. Arch Neurol Psychiatr 1949;61:21–27. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med 2008;358:18–27.
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