Direct electrical stimulation of cortical structures to investigate anatomical function has been used since the second half of the 19^th century in animals (6). Although the technology at the time was somewhat crude [i.e., the intensity of the stimulation was measured by subjective sensation when applied to the experimenter's tongue (7)], it was not long before translation to the first trial of cortical stimulation of a human by Robert Bartholow in 1874 (8). In this famous case of a patient with basal cell carcinoma and exposed brain, Bartholow inserted electrodes into parenchyma [likely Brodmann area 7 bilaterally (9)] and elicited contralateral muscle contractions reliably from both sides of the brain. Around the turn of the 20th century, this knowledge was put to practical neurosurgical applications by Horsley, Bidwell, Krause, and Cushing (1, 10–12), who continued to use this technique to expand the understanding of brain function over many years.

Initially, there was debate among scholars as to which areas of the cortex contributed to motor and sensory function and which areas did not. Some firmly believed motor and sensory function to be combined as one sensorimotor region, while others believed motor localization to be distinct and belong purely to the region anterior to the central sulcus (13, 14). A significant shift in theory was noted after the work of Grünbaum and Sherrington (13), which led to more a concrete model of an anatomically distinct pre-Rolandic motor cortex and post-Rolandic sensory cortex (15). Their work, along with contributions from Krause, was among the first to illustrate a somatotopic map of the motor cortex (12). Cushing reported using DES in his anesthetized patients (1) as early as 1902 (16), and soon after progressed to using the technique on awake patients, allowing him to interpret sensory information in the post-central gyrus as well (Figure 1).

In the mid-twentieth century, Penfield described the density of cortical organization through the visual representation of the sensorimotor homunculus (13). His work alongside Rasmussen continued to examine localization of cortical functions (17), and his work with Welch expanded knowledge of planning of motor function in the anterior supplementary motor area (SMA), defining a region involved in complex movements and initiation of movements (18).

When Penfield and Rasmussen reported negative effects (e.g., inhibition and muscle relaxation) upon stimulating certain areas of the motor cortex, the nature of Brodmann area 6 began to be questioned once again (17). This finding led some to think motor planning and inhibition may also be involved in this region. Along the way, the model of the motor cortex began to evolve from a simplistic, positive response area whereby “a chain of neurons is activated and an effective impulse passes out to the periphery” (13), to include areas of planning and areas of negative responses resulting in motor inhibition (which will be further described later in this paper).

In sum, DES of the cortex has been the primary tool used to define cerebral anatomical-functional relationships (19) from Penfield's work on sensorimotor systems (20) to Ojemann's studies on language (21). In addition to its use as an investigational tool, it has also been a critical surgical tool used to outline functional-anatomical somatotopy and predict and minimize post-operative deficits. Throughout the 20th century and beyond, DES has become standard of care for patients undergoing resections of brain tumors (22) and epilepsy lesions (23) in eloquent motor and/or language systems (24–38).

Neuronal cell bodies located in layer 5 of the primary motor cortex have axons that project down the corticobulbar and corticospinal tracts to either synapse directly onto motor neurons or interneurons of the brainstem and spinal cord (Figure 2) (39). Layer 5 neurons also have connections with other cortical and subcortical structures, ranging from association fibers to the somatosensory cortex to outputs to the direct and indirect pathways of the basal ganglia (40–42). Because of this complex network of connections, the sum of direct output from the primary motor cortex is not exclusively excitatory. Other nearby anterior motor regions, such as the SMA and premotor areas, as well as some posterior parietal regions, have been shown to be linked to generating intent to perform an action and ordering complex motor movements later effectuated by the motor cortex (18, 43–46). Additionally, there is evidence that the more anterior “planning regions” may have their own direct influence on the spinal cord (47), perhaps in parallel to the corticospinal tract (48). This evidence is consistent with primate experiments supporting a model where primary motor cortex neurons more directly encode muscle activity, or kinetics, to a greater extent than limb position or velocity, or kinematics (49). While the concept of these “anterior planning regions” is generally accepted, this is not a strict, linear hierarchy, as other frontal and parietal areas have been shown to participate in subcortical motor networks (48).

The primary motor cortex has been described as a discrete functional-anatomical interface along a unimodal gradient (50), meaning it is a cortical region with a somatotopic organization where movement intention is translated into action. This unimodal network gradient description may account for the more homogeneous, reproducible results of direct electrical stimulation on the motor system (51) when compared with more transmodal networks like emotion and cognition, for example (50). However, studies of motor connectivity have shown both interindividual variability and plasticity in recovery from deficits (52), suggesting a neural network model that can modulate function in a dynamic fashion (19). This has been demonstrated specifically in the primary motor cortex in patients with infiltrating tumors (53, 54). In other words, in a static model, input A may always lead to output B; however, in a dynamic model, input A may lead to output B, or may lead to output C, depending on inputs from other systems. Stimulation of the motor cortex to induce plasticity has also begun to be explored, showing that durable plastic changes in the motor cortex may also be artificially constructed for therapeutic applications (55).

DES predominantly affects axons (56) by inducing a modulation in membrane potential through a directly applied electric current (57) that triggers a response. The downstream result of this stimulation can vary significantly and depends on a number of factors. Modifiable factors include the stimulating parameters (i.e., pulse type, width, frequency, and intensity) (58), probe configuration (i.e., monopolar or bipolar) (4), and anatomical location. Alterations in these variables can affect which cells are stimulated, to what extent they are stimulated, and what their response to that stimulation might be.

Motor effects can be monitored by visual observation of motor end phenomenon or continuous electromyography (EMG) monitoring (73). Patients must not be chemically paralyzed to observe end motor phenomenon, and anesthetic agents and doses can play a role in the sensitivity and success of motor mapping (74–77).

Historically, responses to direct stimulation of the cortex have been divided into two broad categories, as described by Duffau (19):

When DES results in an NMR, or inhibition of movement without loss of consciousness, this stimulated cortical region is referred to as a negative motor area (NMA) (78). This phenomenon is distinct from activation and contraction of an opposing muscle group, which would still be considered a PMR. While NMAs were previously thought to be either distributed widely along the lateral aspect of a given cortical hemisphere (79–81) or somatotopically located in the inferior frontal gyrus (82), more recent work shows NMAs to be more reliably located in several areas within the precentral gyrus (83), although not exclusively (84). In general, NMAs appear to localize in two main regions, a more medial region which includes the SMA and pre-SMA regions, and a more lateral region which includes the inferior frontal gyrus and the premotor cortex (80). Additional NMAs with clinical relevance include those in the parietal lobe, stimulation of which can lead to hand apraxia (85), for which specific hand-motor tasks can be monitored during DES to avoid post-operative deficits (86).

The mechanism by which NMRs are generated is not yet understood, and there are different viewpoints represented in the literature. Mikuni et al. (79) suggests these NMRs represent external disruption of physiologically excitatory pathways. A similar mechanism has been proposed by Duffau et al., who categorized these NMRs as a “second intermediate level” of functional disturbance due to DES, namely that the task inhibition is due to disruption of a subcircuit network (19). Others have postulated the NMRs represent activation of naturally encoded inhibitory pathways within, or relating to, the motor cortex (87). This has been supported by fMRI studies which have shown motor region activation patterns for muscle relaxation to be similar to activation patterns for muscle contraction (88), with accompanying evidence that these processes are driven by an excitatory, active process as opposed to neuronal suppression (89, 90).

In addition to underlying anatomical physiology, widespread heterogeneity in how DES has been applied may account for some differences in results. In Mikuni et al.'s study, for example, stimulation was performed at 50 Hz in square waves of alternating polarity with 0.3 ms duration for 1 to 5 s between subdural electrodes with intensity ranging between 2 and 15 mA. They found regions where a low stimulation intensity would trigger a NMRs, while higher intensity stimulation in the same region could then induce a PMR (79). More recent studies by Rech et al., however, only stimulated at lower intensities (on the range of 2 mA) due to time constraints at 60 Hz with biphasic current and 1 ms pulse width for 4 s via a bipolar electrode with tip width set at 5 mm, finding no NMAs that eventually produced a PMR (83). This may be due to modulation of the neuronal population recruited in the NMA based on electrophysiological response or could alternatively be explained by a wider recruitment field including PMR-controlling neurons with higher intensity, as increased current travels over larger distances. Ultimately, the gap in understanding the effects of varying stimulation parameters in certain anatomical locations on downstream motor systems outlines the need for future studies in this area.

While DES is undeniably the goal standard to intraoperatively map functional-anatomical somatotopy of the motor system, current DES techniques vary widely. Controversies include awake vs. asleep mapping, complex tasks (i.e., apraxia) vs. simple motor response mapping, bipolar vs. monopolar stimulation, high vs. low frequency stimulation, continuous motor evoked potentials vs. repeated intraoperative stimulation, length and type of stimulus pattern, and gray vs. subcortical mapping. As discussed above, there is a general movement to combine these modalities into more nuanced mapping/resection strategies, as opposed to using one vs. the other. While bipolar stimulation at 50–60Hz has been the most widely employed method for mapping the motor cortex, advantages to high frequency monopolar stimulation may include fewer intraoperative seizures and increased sensitivity (64, 66–68). While there is evidence to support this claim, it has not yet been widely adopted as a cortical stimulation technique. When performing subcortical stimulation in descending motor pathways, the use of a train of multiple high-frequency monopolar stimulation pulses at 250–500 Hz may afford the surgeon similar advantages. In one series, the addition of monopolar stimulation to standard bipolar stimulation for the subcortical regions increased identification of descending motor pathways from 30 to 86.4% (66), similar to Szelényi et al.'s work which improved sensitivity from 54% using bipolar to 92% using monopolar stimulation (65). As mentioned prior, some have chosen to combine bipolar and monopolar stimulation with concurrent motor evoked potential monitoring, termed “triple motor mapping” (66).

Advantages to awake intraoperative mapping include surgeon confidence in the patient's neurological status, fewer intraoperative technical nuances obscuring the meaning of signal loss, and the ability to map more complex motor, cognitive, sensory, and speech-language systems. Disadvantages include patient discomfort and false negative exam responses due to, for example, development of an intraoperative SMA syndrome leading to a smaller extent of resection. Multiple studies have sought to evaluate outcome differences in awake vs. asleep motor mapping; however, the amalgamation of the available evidence does not support one technique over the other. Ultimately, decisions on how to intraoperatively map the motor system across neurosurgical operating rooms will depend on the specifics of case, including surgeon experience, patient goals and abilities, and other necessary functional assessments (i.e., language). The authors do generally advocate a trend toward using bipolar stimulation on the cortex, high frequency monopolar stimulation on the subcortical white matter, and continuous motor evoked potentials during resection wherever possible. Also, for pure motor cases, the authors generally prefer asleep mapping to prevent false positive exam changes from phenomenae such as SMA syndrome that might prematurely conclude the surgery, with the caveat of trending toward awake mapping when more complex task monitoring is needed (i.e., apraxia and/or speech-language).