Intraoperative Stimulation Mapping in Neurosurgery for Anesthesiologists—Part 1: The Technical Nuances

Abstract Brain mapping has evolved tremendously in the past decade, fueled by advances in functional neuroimaging technology in neuro-oncology and epilepsy surgery. Despite this, wide anatomic-functional interindividual variability and intraoperative brain shift continue to challenge neurosurgeons performing surgery within or near eloquent brain regions. As such, intraoperative direct cortical and subcortical stimulation mapping remains the gold standard for localizing eloquent brain regions with precision for a safe and tailored resection. Intraoperative stimulation mapping (ISM) allows for maximizing the extent of resection while minimizing postoperative neurological deficits, resulting in better patient outcomes. Understanding the technical nuances of ISM is imperative for the anesthesiologist to provide better anesthetic management tailored to the surgery and stimulation mapping planned. A comprehensive search was performed on electronic databases to identify articles describing intraoperative cortical and subcortical mapping, language, and motor mapping. In the first part of this narrative review, we summarize the salient technical aspects of ISM and the common neurophysiological tasks assessed intraoperatively relevant to the anesthesiologist.


Introduction
Advances in neurosurgical techniques have significantly improved overall survival and quality of life in patients with low-grade glioma 1 and medically refractory epilepsy. 2 lesion within or adjacent to an eloquent brain region poses a unique challenge for neurosurgeons, as maximal resection conflicts with the preservation of neurological functions.4][5] As such, despite almost a century of clinical application, direct electrical cortical stimulation (DES) in awake patients remains the gold standard for intraoperative brain mapping of the eloquent cortex due to its high precision and reliability in identifying functional cortical and subcortical structures during resection.In the first part of this narrative review, we summarize the principles, techniques, and applications of intraoperative

Intraoperative Stimulation Mapping Brief History of Direct Electrical Stimulation of the Brain
Direct Electrical Stimulation (DES) of the human cortex was pioneered by Robert Bartholow in 1874 in a patient with an exposed cortex secondary to basal cell carcinoma that demonstrated contralateral motor responses. 6Several clinicians then used it to delineate eloquent parts of the brain, most notably by Penfield in 1937 with his famous description of motor and sensory homunculi. 7In the 1970s, George Ojemann further revolutionized cortical mapping in the modern era by improving the understanding of cortical stimulation responses and recording single neurons' activity in awake patients. 8His innovation in ISM enabled accurate language mapping, resulting in a marked reduction in aphasia after epilepsy surgery.Before the 1990s, DES was performed primarily in awake patients due to the inconsistent cortical response elicited in patients under general anesthesia (GA).In 1993, Taniguchi et al proposed a high-frequency stimulation paradigm in humans for cortical mapping which they found to be effective in triggering distal muscle contraction in patients under GA. 9 This became the scientific basis for current motor mapping under GA.The mapping of the subcortical tract was first described by Skirboll et al in 1996 in a case series of glioma resections. 10[13][14][15][16][17][18] The Physical Basis of Direct Electrical Stimulation of the Brain Electrical stimulation induces a passive increase in the membrane potential of stimulated neurons at the cathodal level, which leads to antegrade or retrograde propagation of an action potential.Once the threshold potential is reached, it is followed by synaptic conduction within the physiological subcircuit of interest. 19Neurons are preferentially activated at the level of the initial segment of axons and nodes of Ranvier, which have the highest density of sodium channels in the neuron. 20,213][24] Preclinical studies have shown that single cortical DES evokes an action potential followed by long-lasting inhibition suggesting that stimulation of cortical afferents disrupts the propagation of cortico-cortical signals beyond the first synapse. 25A comprehensive discussion of the biophysical and mathematical principles underlying DES is beyond the scope of this article and can be found elsewhere. 26

Stimulation Paradigms
Two primary stimulation paradigms form the basis of functional mapping protocols used in contemporary neurosurgery. 27he traditional DES technique, also known as the Penfield technique, uses low-frequency (LF) stimulation (50-60 Hz) via a bipolar stimulator probe (►Fig. 1)with two electrodes 5 mm apart, delivering biphasic square waveform pulses of alternating anodal and cathodal polarity.][30] The second technique, or the Taniguchi technique, employs high-frequency (HF) stimulation (250-500 Hz), monophasic square waveform pulses, delivered as a train of five pulses (range between 4 and 9 pulses) via a monopolar (most commonly) or bipolar probe (►Fig.1). 28,319][30] The electrical field distribution differs by the stimulation probe used.The monopolar probe emits a radial homogenous electrical field, while the bipolar probe delivers a more focused inter-tip electrical field. 32A bipolar probe with LF stimulation increases the focality, but requires an increase in current intensity. 33A specialized monopolar suction stimulator has recently allowed dynamic mapping via concurrent subcortical stimulation and tumor resection (►Fig. 2). 34,35The salient differences between both stimulation paradigms are summarized in ►Table 1.

Physiological Responses to Direct Electrical Stimulation of the Brain
DES can generate either a positive or negative physiological response depending on the brain region being stimulated, the characteristics of the stimulating current, the local organization of the neuronal circuit, and the use of anesthetics and antiepileptic medications. 6,25,36Positive physiological responses to stimulation include involuntary movement, vocalization, paresthesia, and phosphenes.On the contrary, negative responses cause interruption of tasks such as speech arrest, anomia, alexia, memory deficit, and disturbances of other higher cognitive processes. 19,37,38hese responses are used to establish a map of functionally essential areas of the cortex and subcortical tracts to guide resection.This terminology should not be confused with the terms "positive mapping" and "negative mapping," where positive mapping refers to the situation in which functionally important sites are identified after a positive or negative physiological response to stimulation.[40]    A false negative is the nonidentification of a critical eloquent brain region, potentially leading to resection and permanent postoperative neurological deficits.This may be secondary to inadequate stimulation settings, inappropriate neurophysiological tests (for the area being resected), or stimulation during a postepileptic refractory phase. 19The possibility of false negatives should be considered after negative mapping before initiating resection.][40] False negatives can also be minimized by optimizing the intraoperative tasks selected based on preoperative functional assessment combined with functional imaging. 19n the other hand, false positive is the mischaracterization of a noneloquent region as eloquent, potentially leading to premature cessation of resection.Several factors may cause this, including patient fatigue due to the long duration of functional evaluation (typically 2 hours or more), stimulation-induced partial seizures, axonal propagation of stimulation to remote structures, or identification of eloquent structures that could be functionally compensated following resection owing to brain plasticity mechanisms.False positives may be inherent in DES, primarily through the activation of remote structures, and should be considered a possibility during intraoperative decision-making following positive stimulation. 19If false positives are caused by patient fatigue, repeat tests may be performed after a period of rest, and by limiting the duration of assessment.The use of intraoperative electrocorticography recording to detect after discharges (ADs) may reduce false positives from a stimulation-induced partial seizure.ADs are rhythmic transient epileptiform activity induced by DES that persists after the termination of the stimulus.AD results from stimulation of hyperexcitable tissue, which may overlap with an epileptogenic focus. 41AD is also used to select the lowest appropriate stimulus intensity to reduce the incidence of intraoperative seizure. 38,41The mapping threshold and AD thresholds may vary between individuals and between different brain regions in one individual. 36

Neurophysiological Tests during Intraoperative Stimulation Mapping
Language and motor mapping are the two main neurophysiological modalities tested during ISM-guided resection of the eloquent brain regions.Tasks chosen depend on the location of the lesion and the surgical resection planned. 29,30Language mapping is commonly employed during epilepsy surgery as most epileptogenic lesions are near language areas, and this requires an awake patient for speech assessment intraoperatively.In the case of a brain tumor within or near eloquent regions, a combination of motor and speech mapping may be used depending on the tumor site, thus requiring an awake patient during ISM-guided resection.However, if only motor mapping is planned for a perirolandic tumor, this may be done under GA.Recently, two small studies looked at the feasibility of mapping language areas under GA.A case series examined the feasibility of mapping the motor speech area using electromyography (EMG) recordings of the laryngeal muscles. 42ile another study found that the preservation of language was possible via cortico-cortical evoked potential mapping of the arcuate fasciculus under GA. 43

Language Mapping
Most patients planned for intraoperative speech mapping would have a preoperative language assessment performed by a neuropsychologist or speech therapist to assess their baseline language production, comprehension, and language deficits.5][46] Intraoperative tasks include picture naming, counting, text reading, sentence completion, word repetition, spelling, text writing, and language syntax. 4,39Tasks chosen depend on the location of the lesion or tumor, the patient's baseline performance, and local institutional protocol. 30The most common language task is picture naming, where the patient is asked to begin each answer with the phrase "This is a …" before naming the object in the picture shown to them to separate pure aphasia from anomia.Preoperative evaluation also serves the purpose of training patients with the stimulus material.For example, in the picture naming task, pictures that patients do not recognize are removed from intraoperative testing. 47here is limited literature regarding assessment of bilingual and multilingual patients intraoperatively.A recent systematic review reported seven studies of which cortical mapping was performed in multilingual patients with brain tumor.Heterogeneity was noted in the location and number of language areas identified intraoperatively. 48A multilingual picture naming test (MULTIMAP) was recently developed for mapping of eloquent brain regions intraoperatively to address the previous shortcomings of lack of standard tests for different languages. 49uring cortical mapping, the stimulation intensity is started at 2 mA and progressively increased by 0.5 mA to a maximum of 6 mA or 1 mA below which evokes an AD potential.Each site is stimulated at least three times and is considered a positive site when speech arrest, anomia, or alexia occur during at least 2 out of 3 stimulation trials. 38,39Subcortical language tracts are also mapped during surgical resection in awake patients with similar stimulation paradigms. 12Other cognitive functions that may be tested in awake patients during surgery include visuospatial functions, sensory modalities, memory, calculation, and other higher cognitive tasks.][52] Traditionally, the LF stimulation paradigm was used for language mapping using a bipolar probe.More recently, HF stimulation through a monopolar probe has been shown to be a safe and effective technique for language mapping in awake patients. 53,54The distance between the resection margin and the closest positive language site strongly predicts the evolution of postoperative language deficits, making language mapping an essential tool to help preserve language functions. 55

Motor Mapping
7][58][59][60][61][62][63] Several other brain regions also play a crucial role in modulating motor responses; these are the premotor region and the supplementary motor area. 64,65Cortical or subcortical DES of the motor area would produce involuntary overt movement or muscle activity detected by EMG.The use of EMG in asleep conditions also allows the detection of impending seizures. 31,66oth stimulation paradigms can be used for cortical and subcortical motor mapping; LF stimulation with a bipolar probe, or HF stimulation with a monopolar probe. 67,68owever, both paradigms have distinct differences under awake and asleep conditions (refer ►Table 1). 28,29The HF stimulation technique triggers a time-locked compound motor action potential response with measurable amplitudes and latencies, in contrast to the sustained muscle contraction caused by classical LF stimulation. 33HF stimulation induces motor evoked potentials (MEP) when applied over the primary motor cortex or subcortically, and the use of continuous EMG recording (►Fig. 3)allows the use of lower stimulation intensities with increased sensitivity to identify motor pathways compared with visual inspection of overt movement, and thus favorable for use under GA. 31,66,69,70F stimulation paradigm is ineffective during cortical and subcortical mapping under asleep conditions in patients with infiltrative tumors, long history of seizures, and is prone to cause seizures.Thus, LF is not the preferred paradigm for this subset of patients for motor mapping under GA. 31 Monopolar HF stimulation has been associated with a lower incidence of intraoperative seizures. 33,53,71Additionally, patients with epilepsy mapped with HF stimulation under GA do not suffer from more stimulation-induced seizures than nonepileptic patients. 72With monopolar HF stimulation, anodal stimulation is best used on the cortical surface, while cathodal stimulation is optimal in subcortical tissue. 59,70urthermore, monopolar HF subcortical MEP stimulation allows determination of the distance to the CST with a simple rule that 1 mA of stimulation intensity to elicit an MEP response resembles a 1-mm distance to the CST. 56,59Different motor thresholds (MTs) have been suggested to define the limits of resection, with subcortical MT of 3 mA generally considered safe, with a chance of inducing a permanent deficit of less than 2%. 58,61,73In addition, continuous dynamic mapping of the motor tracts can be performed during tumor resection by integrating the monopolar stimulator into the suction tip (►Fig. 2)and gradually reducing the current intensity as resection becomes closer to the CST. 58ortical and subcortical DES motor mapping may also be combined with direct cortical MEP monitoring generated using a subdural electrode strip over the motor cortex, and transcranial MEP, recently termed "triple motor mapping."4][75][76] Somatosensory evoked potential phase reversal is another technique where the central sulcus is identified for localization of the primary motor cortex during surgery to guide mapping. 77,78ince the introduction of the HF paradigm for direct cortical motor mapping by Taniguchi et al in 1993, 9 more resections involving perirolandic tumors have been performed under GA with comparable outcomes to AC. 79,80 However, Rossi et al reported that a significant portion of patients undergoing glioma resection under GA developed hand apraxia after surgery. 81This led to the development of more advanced motor tasks that can be evaluated during AC.Tasks to assess the nonprimary motor areas and sensorymotor integration are the repetitive arm flexion-extension movement 82,83 and the hand-manipulation task. 52,81,83,84

Importance of Intraoperative Mapping in Neurosurgery Variability of Eloquent Area Localization
3][94][95] For example, language sites identified with ISM are often smaller in area than the classically defined Broca and Wernicke areas but are very variable in localization. 3Even without an underlying identifiable anatomic lesion, patients with epilepsy show a wider distribution of language areas on language mapping, extending well beyond the classic Broca and Wernicke areas. 96This variability poses a challenge for neurosurgeons planning resection of tumors adjacent to presumed eloquent brain, since anatomical landmarks alone may not be sufficient to determine the eloquence of a specific brain region.
Furthermore, brain shift during surgery either from physical factors (related to navigation hardware), surgical factors (use of retractors, cerebrospinal fluid, or tissue loss during surgery), or biological factors (tumor type or location, and use of mannitol to reduce intracranial pressure) may render imaging-guided mapping less effective for intraoperative surgical resection. 97[105][106][107]

Outcome Evidence for Intraoperative Stimulation Mapping
Previous retrospective studies have shown that ISM-guided resection has been associated with a greater extent of resection (EOR), less delayed neurological deficits, 40,60,108 and extended survival 109 compared with resection under GA without ISM.1][112][113][114][115][116][117][118] Gross total resection (GTR) of gliomas compared with subtotal resection is associated with improved overall survival, progression-free survival, and seizure control. 119,120he GLIOMAP study, the first international multicenter propensity-matched cohort study, reported similar results that AC with ISM resulted in fewer late neurological deficits (26% vs. 41%), longer overall survival (17 vs. 14 months), and longer median progression-free survival (9 vs. 7.3 months). 121Two recent meta-analyses concluded that ISM use during glioma surgery was associated with a higher rate of GTR, longer median overall survival, lower postoperative complications, 122 and shorter hospital stay. 123

Conclusion
ISM is the standard of care to guide the resection of lesions within or adjacent to eloquent brain tissue.Despite technological advancements in functional neuroimaging, the wide anatomo-functional variability and intraoperative brain shifts confound the precision of real-time resection of the eloquent regions.ISM-guided resection has been proven to result in better seizure control, reduced postoperative deficits, and improved survival.LF and HF are the two stimulation paradigms utilized for DES, with distinct differences in their physical properties and outcomes during awake and asleep conditions.Language and motor are the two primary neurophysiological modalities assessed intraoperatively in neuro-oncological and epilepsy surgery.Understanding these technical aspects of ISM and the neurophysiological tests employed enables the anesthesiologist to provide an anesthetic that may complement the procedure planned.

Fig. 2 (
Fig. 2 (A) Monopolar stimulator (red cable) attached to metal suction tip via a metal clip (red); (B) used by surgeon intraoperatively for continuous dynamic mapping during resection.