Inactivation Methods

Intracarotid Amytal Testing

The IAT was originally developed to determine language dominance in preoperative epilepsy patients who were candidates for temporal lobectomy (1). The IAT remains the current gold standard technique for presurgical determination of language dominance, especially in patients who are suspected of mixed or unusual language dominance. The IAT involves catheterization of the internal carotid artery and injection of sodium amobarbital, which anesthetizes those regions of the cerebral hemisphere supplied by the carotid artery while the patient undergoes a battery of neuropsychological tests. After the appearance of contralateral hemiparesis indicating hemispheric anesthetization, several tests of language and memory function are rapidly administered. Failure in a cognitive domain indicates that it is supported by the hemisphere that was injected.

Although the IAT was developed as a test of language dominance, its use has been extended to testing for memory competence of the medial temporal structures and in the preoperative determination of language dominance in patients with pathological processes other than epilepsy. Patients who have an anomalous circle of Willis, which may result in contralateral injection and anesthesia of the opposite hemisphere, may have inaccurate results from the test. The IAT is also limited in its ability to make fine distinctions in neurocognitive abilities. Both the time constraints imposed by the temporary nature of the induced cerebral anesthesia and the practical constraints imposed by having to test the patient in an angiography suite limit the scope and sensitivity of neuropsychiatric testing that can reasonably be accomplished. The IAT is able to predict lateralization of memory and language functions but cannot localize these functions within the hemisphere. Its use is restricted to determining language dominance patterns and predicting and avoiding global amnesia in patients who cannot support memory with the contralateral mesial temporal lobe (MTL) (2). However, the validity of the Wada test in predicting postoperative memory deficits has been questioned based both on anatomic grounds (in most people the MTL is perfused by the posterior cerebral artery and not by the internal carotid artery) and on clinical outcomes (3,4). This invasive procedure carries a 0.6-1% risk of stroke related to the catheterization (5) as well as puncture site complications in 0.5-10% (6). In addition, the test is quite stressful to patients owing to the temporary hemiparesis and cognitive testing procedures required during the procedure.

Electrocortical Stimulation

Direct ECS testing remains the gold standard method for mapping brain function in preparation for surgical resection. For simple motor mapping, intraoperative cortical stimulation may be performed with the patient under general anesthesia but without muscular paralysis. In this case, low-frequency stimulation causes muscular contractions when they are delivered to the motor cortex. The motor strip may also be localized using somatosensory evoked potentials (SSEPs) and determining the region of phase reversal, although this method is not suited to detailed evaluation of motor function and somatotopy. To test language functions, however, it is necessary that the patient remain awake and able to perform certain tasks such as counting or naming. Meanwhile the surgeon stimulates the cortical surface, inducing a transient disruption in function that mimics the effects of actual resection. This technique requires a wide cran-iotomy, which exposes the tumor and adjacent eloquent cortical regions suspected of being jeopardized by the resection.

There are special anesthetic, surgical, and neuropsychological considerations when one is performing intraoperative cortical mapping. Awake craniotomy for language mapping is typically performed using a combination of local anesthetic field block and short-acting general agents to induce a rapidly reversible hypnotic state. Once the scalp, skull, and dura are opened and the cortical surface exposed, the surgeon localizes the tumor either grossly or with the aid of neuronavigation or ultrasound and marks the boundaries using sterile surface markers. During the cortical stimulation testing, the patient is awake and asked to perform simple tests such as counting or moving fingers to command while the surgeon stimulates the cortical surface using bipolar stimulating electrodes with a 5-mm tip separation. Stimulation parameters are typically set at 60-Hz biphasic square wave pulses (1 ms/phase) with variable peak-to-peak current amplitudes between 2 and 10 mA. The surgeon first maps the relevant somato-sensory cortical regions by eliciting sensory or motor responses in the face and hand. To map language areas, the surgeon asks the patient to count or name objects and records those areas in which cortical stimulation induces speech arrest or other error. In their study of 40 patients undergoing removal of gliomas in the dominant temporal lobe, Haglund et al. (7) reported that for patients without language deficits preoperatively, 87% had no deficits postop-eratively using the above methods. Most surgeons feel that a reasonably safe limit of resection is to allow a 1-cm margin around cortical areas that appear to be functionally eloquent.

In spite of the excellent spatial and temporal resolution of this technique for cortical mapping, the most obvious drawback is that it requires a craniotomy. This technique, therefore, does not allow for presurgical planning, but is reserved for intraoperative assessment and confirmation of results obtained from preop-erative studies. ECS mapping also requires that the patient be able to cooperate in performing these tasks during an awake craniotomy. Most children and some adults are unable to tolerate being awake for such a procedure. Even cooperative patients may have trouble maintaining task performance over the course of the investigation. Awake craniotomy generally requires dedicated and specially trained neuroanesthesia support and a sufficient caseload to provide training and expertise and hence may not be available in many centers. Cortical stimulation testing is also limited by the difficulty of examining the sulcal depths, which comprise as much as two-thirds of the cortical surface (8), the deep structures of the mesial temporal lobe, or the underlying white matter. For example, it is not uncommon for patients who have undergone cortical mapping and resection respecting the boundaries of the eloquent cortex to be left nevertheless with neurological deficits secondary to damage to associated white matter tracts.

ECS can also be performed extraoperatively. This option is used primarily for epilepsy surgery for the mapping of the seizure focus through the chronic (~1 wk) implantation of intracranial electrodes. During this period, cortical stimulation for the determination of eloquent cortex is usually also performed. In order to pursue intracranial electrode placement, there must be sufficient evidence to limit the possible sites of epileptogenesis. On the basis of the scalp electroencephalogram (EEG) and other data, sites are selected for implantation with either depth or subdural electrodes. Depth electrodes are implanted using stereotactic guidance and are most commonly used to monitor the medial temporal lobe structures. Subdural electrodes, arranged in grids and strips, may be used to record from large areas of cortex including intrahemispheric or subtemporal locations.

Each technique has its strengths and limitations in terms of risk, accessible brain areas, and ease of placement, making individualized determination of the appropriate method important (9). In both cases, the electrodes can be used to stimulate as well as record, thereby allowing extraoperative functional mapping (10). When indicated, this technique has the advantage of allowing significant time and a sufficiently relaxed and cooperative patient to allow detailed cognitive testing. However, this technique, like intraoperative ECS, can only sample from limited regions and is therefore not suitable for certain investigations. Because of the necessity of an additional operative session and risks of hemorrhage, infection, or cerebral edema in 1-2 % of patients, this technique has limited indications. In addition, the need for intracranial recording has declined as other less invasive preoperative studies have been developed and validated that allow patients to proceed directly to resective surgery without this step.

Transcranial Magnetic Stimulation

TMS uses electromagnetic energy to stimulate cortical neurons through the intact skull. Combined with a frameless stereotactic system, it has the potential to map brain function in a manner similar to ECS but without the risk of cran-iotomy. The TMS apparatus consists of a power supply that charges a large bank of capacitors, which are then rapidly discharged through a circular or figure-eight coil; the charged coil produces a powerful and focal magnetic field pulse on the order of 1-2 T. The TMS pulses are typically 200 ^s in duration, and the power is concentrated in a band around 5 kHz, well below the frequencies at which body-related field attenuation occurs (11).Therefore, the electromagnetic energy of the TMS pulse is able to pass unimpeded through the scalp and skull to the cortical surface or to deeper structures. On the cellular level, magnetic stimulation by TMS functions very much like electrical stimulation with ECS. The resting membrane potential of excitable cellular membranes is maintained at about -70 mV by the relative intra- and extracellular concentrations of Na+, K+ and Cl- ions maintained by the Na-K pump and passive diffusion. Moving a charge across this membrane, either directly with electrical stimulation or indirectly by magnetic stimulation, creates a transmembrane potential. If this potential reaches about -40 mV, it triggers an action potential in the tar get neurons and causes motor or sensory responses if the TMS is targeted to sensorimotor regions or speech arrest if the TMS is directed to language regions.

The use of TMS for brain mapping is still in the very early stages of development. In 1998, Krings et al. (12) examined the motor cortical representation of 12 muscles of the trunk and upper and lower extremities of 18 healthy controls using TMS combined with a frameless stereotactic system (FSS), allowing the investigators to orient their stimulation sites to the central sulcus rather than to less precise bony landmarks. They observed distinct but overlapping areas of muscle representation for each of these 12 muscles. The also found that the cortical maps changed with increasing stimulus intensity: more muscles became excitable, motor-evoked potential (MEP) amplitude increased, size of the responsive area increased, and latency of the MEP decreased. In 1999, Boroojerdi et al. (13), again using the combination of TMS with FSS, investigated whether the accepted anatomical landmarks on cross-sectional imaging for the location of the intrinsic hand muscles (hand knob shaped like an omega) correlated with the functional areas for hand as mapped by TMS. In all four healthy controls, they observed that the centers of gravity for each MEP elicited by transcranial electric stimuli fell within the anatomical area predicted by the hand-knob gyral configuration and also fell within the area of fMRI activation produced by voluntary hand clenching.

TMS has also been shown to be useful for mapping in the preoperative setting. Krings et al. (14) observed good correlation between the stereotactic TMS motor maps of two patients with tumors near the central sulcus and the corresponding intraoperative motor maps produced using ECS. More recently, the same group has examined the efficacy of using TMS-FSS to map motor function in patients with mass lesions near the central sulcus as compared with motor maps produced using fMRI (15). In their cohort of 10 patients they observed that the peak parenchymal fMRI activation and the cortical area where TMS elicited the maximum MEPs averaged within 0.6 cm of each other, thus demonstrating that even in cases of diseased brain, TMS and fMRI, despite having entirely different physiologic bases, yield concordant (although not identical) results.

TMS may also become a useful method for the preoperative assessment of cortical language organization, however, significant obstacles and outstanding questions remain. Michelucci et al. (16) performed an early study using TMS to determine language dominance in 14 patients with epilepsy. They obtained results that were concordant with hand preference in only half of the patients, concluding that TMS lacked sensitivity. At that time, it was also not uncommon for TMS to cause significant undesirable side effects such as seizures or transient neurologic deficits. Epstein et al. (17) in a review of TMS studies for language mapping, reported that TMS appeared to lead to speech arrest when performed over the facial motor cortex rather than over Broca's area. This suggests that the mechanism behind TMS-induced speech arrest is not a true aphasia but rather a disruption of motor function. In a later study, they also found that language lateralization by TMS did not replicate Wada test results and that right hemisphere or bilateral lateralization were unexpectedly prevalent in the TMS results (18). In addition, there is currently an incomplete understanding of the effects of TMS on cognitive cortical areas, as some stimulation paradigms cause inhibition of function, whereas others appear to facilitate function (19). Based on these findings, a clinical role for TMS language mapping is not yet fully established. There is, however, ongoing interest in refining this technique. For example, Knecht et al. (20) have demonstrated that language function disruption by unilateral TMS is less severe in individuals with more bilateral language representation by functional imaging. These results suggest that a more distributed cortical language representation may be protective in cases of brain damage.

TMS is a promising modality for surgical planning because, like ECS, it mimics the effect of resection but can be performed noninvasively and repeatedly. The use of TMS as a tool for mapping brain function is still very much in its infancy. Although the electromagnetic pulse generated by TMS is very focal, it is still difficult to determine exactly where on the cortex the pulse is targeted, although the continued development of the combination of TMS with frameless stereotactic neuronavigation devices promises to ameliorate this difficulty somewhat. As with fMRI, it also remains to be seen what effects medications, aging, tumor infiltration, or other patient variables will have on an individual's response to TMS Finally, as is the case with many other brain mapping techniques, TMS requires costly special equipment and dedicated personnel.

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