Emotional experience elicited by direct electrical stimulation: Case series and literature review

Abstract Objective The cortical representation of emotions is complex, and cortical mapping of emotional experience is incomplete. We aimed to contribute to cortical mapping of emotional experience. Methods Clinical data from 400 patients with medically refractory epilepsy who underwent stereo‐electroencephalography implantation for localization of the epileptogenic zone at the Beijing Institute of Functional Neurosurgery between October 2015 and June 2021 were collected retrospectively. Furthermore, we reviewed studies that described cortical mapping of emotional experience through electrical cortical stimulation (ECS). Affective responses similar to ictal aura and electrode contacts located in the SOZ were excluded to investigate emotional experiences in normal brain regions. Results Emotional experiences were evoked by stimulation at 10 electrode contacts in the seven patients, including five contacts that evoked mirth and excitement, one contact that evoked calmness, three contacts that evoked fear, and one contact that evoked sadness. In addition, 21 studies that evaluated emotional experiences in response to cortical electrical stimulation were reviewed. Emotions were distributed in the amygdala, hippocampus, temporal lobe, frontal lobe, insula, frontal operculum, parietal operculum, and cingulate cortex. Significance We provided additional evidence that brain regions including the amygdala, hippocampus, temporal lobe, frontal lobe, insula, frontal operculum, parietal operculum, and cingulate cortex were associated with emotional experience.


| INTRODUCTION
In humans, emotion is complex and is characterized by subjective experience, specific behaviors, typical facial expressions, and physiological changes. 1 Whether emotion resides in a specific brain region or results from distinct circuits within the brain was debated before. 2,3 Damasio proposed that the feeling of emotion was the subjective feeling associated with an emotional stimulus. 4 The dimensional view proposed that emotions consist of valence (positive and negative) and arousal, but that no single anatomical structure was uniquely specialized for individual emotional categories. 5 In addition, emotion is a subjective experience that could lead or not to specific behavior depending on its valence.
For decades, neuroimaging and neuropsychological lesion studies have mapped the neural representation of emotion. However, neuroimaging can only provide correlational evidence, while neuropsychological lesions are extremely rare. [6][7][8] However, subjective emotional experience can be elicited by discrete focal brain stimulation. Electrical cortical stimulation (ECS), which has been used to localize cortical function and epileptic foci for decades, [9][10][11] might provide causal evidence for current neurobiological theories of emotion. 1,12,13 Electrical cortical stimulation studies of emotional symptoms have largely been case reports and case series focused on one kind of emotion. 14 Moreover, both the case reports and the reported emotional responses were scattered. Furthermore, previous studies did not explicitly state whether the emotional responses to ECS were auras of a seizure or pure emotional experiences. Therefore, we used our clinical data to identify brain regions associated with pure emotional experience elicited by ECS. In this study, the emotional experience was subjective experience felt by patients during ECS, and most of the experiences were not accompanied by behavior. Furthermore, we aimed to supplement the literature with additional cortical mapping of emotional experience using ECS.

| Patients
Clinical data for 400 medically refractory epilepsy cases who underwent stereo-electroencephalography (SEEG) implantation for localization of the epileptogenic zone (EZ) at the Beijing Institute of Functional Neurosurgery (Beijing, China) between October 2015 and June 2021 were collected retrospectively. The aim of this study was to investigate the localization of subjective emotional responses in relatively normal brain regions, while it remains uncertain to what degree seizure-related expressions could reflect mechanisms of physiological emotional expression. 15 And, it remains a question that whether the auras or the symptoms in early seizure propagation can reflect the physiological function of the stimulated focal cortex in the epileptogic network. For this reason, we try to investigate the subjective emotional responses in relative normal cortex in this study. Therefore, we exclude the stimuli that induced other symptoms accompanying emotions or even after-discharges. As we know, the afterdischarge could also propagate to certain regions of the brain. It is difficult to localize the exact cortex which induce the emotional response. For these reasons, the inclusion criteria of this study were as follows: (a) patients reporting subjective emotional experiences with or without specific behavior depending on its valence during ECS and (b) patients with complete clinical data. The exclusion criteria were as follows: (a) contacts located in white matter; (b) contacts on which ECS elicited aura, ictal symptoms, or after-discharge; (c) the result of ECS could not be reproduced; and (d) cases with cognitive and psychiatric comorbidities. All patients provided written informed consent, and legal guardians provided consent for underage subjects.

| Presurgical evaluation
All patients underwent high-resolution MRI in a 3.0 T MR scanner (GE Healthcare, Little Chalfont, UK). Spinecho T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences, and 3-dimensional anatomic T1-weighted axial, sagittal, and coronal sequences covering the whole brain volume with a 0.8 or 1-mm section thickness were collected. In addition, magnetoencephalography (Neuromag) and positron emission tomography-computed tomography (PET-CT) scanning were performed to localize the EZ. Furthermore, interictal/ictal scalp EEG was recorded using a video-EEG monitoring system (Micromed, Treviso, Italy) with electrodes

Key points
• We used our clinical data to identify brain regions associated with emotional experience • Emotional experience excluding ictal aura was evoked by electrical cortical stimulation • Studies that described emotional experience by electrical cortical stimulation. were reviewed placed according to the International 10-20 system. Two EEG experts independently analyzed the clinical and neuroimaging data to identify seizure onset and propagation characteristics.

| SEEG electrode implantation
A Cosman-Roberts-Wells human body stereotaxic frame and a Sinovation robotic arm-assisted system were used to place the intracerebral multiple-contact SEEG electrodes (8-16 contacts, length: 2 mm, diameter: 0.8 mm, interelectrode distance: 1.5 mm). The number of electrodes and their anatomic targeting were determined based on information obtained during noninvasive presurgical evaluation and anatomic hypotheses. Using open-source software and toolboxes SPM12, 16 Freesurfer, 17 and 3D slicer, 18 preoperative high-resolution MRI images were registered with postoperative high-resolution CT images. The electrode contacts were reconstructed using the CT images.

| Intracranial video-EEG monitoring
To further lateralize and localize EZs, Intracranial electroencephalography (iEEG) monitoring was performed. The iEEG sampling rate was set at 1024 Hz to record details of seizure propagation. The duration of video-EEG monitoring ranged from 3 to 14 days, and at least three habitual seizures were recorded for each patient. Most of the EZs were visually identified on iEEG traces during long-term iEEG monitoring.

| Electrical cortical stimulation
Electrical cortical stimulation was performed (SD LTM STIM; Micromed) after long-term video monitoring. Bipolar stimulation with a biphasic wave was applied. The stimulation parameters were as follows: pulse width = 0.2 ms, frequency = 50 Hz, duration = 3 s, and current intensity starting from 0.5 mA and increasing in 0.1 mA or 0.2 mA increments up to 6 mA. When symptoms appeared or the current intensity reached 6 mA, ECS was stopped. Stimulations that elicited responses were repeated one or two times, and sham stimulations were performed to make sure the subjective experience was real and causally to the stimulations. Symptoms including after-discharge or seizures were excluded. In addition, patients were not aware of when ECS was performed or the electrode contact sites of ECS. We selected subjective emotional symptoms induced by ECS and the location of related electrode contacts. The emotional experiences in this study were mirth with or without laughter, excitement, calmness, fear, and sadness.

| Literature review
A literature search was performed in PUBMED using the following search terms: electrical cortical stimulation, seizure, epilepsy, mirth, laugh, excitement, calmness, fear, and sadness. We selected articles focused on emotional experiences resulting from ECS. The references of selected articles were also scanned. Articles describing specific emotional responses (including mirth, excitement, calmness, fear, and sadness) and explicit locations of electrode contacts were selected. Overlapping articles were discarded.

| Patient characteristics and the epileptogenic zones
Among the 400 patients who underwent SEEG implantation, seven patients (1.75%; six males, one female; mean age: 24.29 ± 2.60 years; mean duration: 14.14 ± 6.36 years) reported emotional experience during ECS. The emotional experiences were subjective experience felt by patients during ECS. These emotional experiences in this study were mirth with or without laughter, excitement, calmness, fear, and sadness. All seven patients were righthanded. The demographic and clinical profiles of the study subjects are shown in Table 1.

| Anatomic localization of emotional experience
Emotional experiences were evoked by stimulation at 10 electrode contacts in each of the seven patients, and the emotional experiences were different from seizure auras. Patient 1 reported mirth during stimulation of one contact point in the right frontal operculum at a current intensity of 3 mA and one contact point in the right anterior short gyrus of the insula at a current intensity of 4 mA. Patient 1 also reported excitement during stimulation of one contact point in the right frontal operculum at a current intensity of 2 mA. Patient 1 reported fear during stimulation of one contact point in right MCC. Patient 2 reported mirth and laughter during stimulation of 1 contact point in the left posterior long gyrus of the insula at a current intensity of 1 mA. Patient 3 reported mirth   Table 2). In summary, mirth was induced by stimulation of the superior frontal gyrus, frontal operculum, anterior short gyrus of the insula, and posterior long gyrus of the insula. Excitement was activated by stimulation of the frontal operculum. Fear was elicited by stimulation of the middle cingulate gyrus, amygdala, and parietal operculum. Sadness was activated by stimulation of the hippocampus. Calmness was elicited by stimulation of the posterior long gyrus of the insula. (Figure 1).

| Literature regarding emotional experience
As we only focused on emotional experience associated with direct ECS, only 21 studies were reviewed. Details regarding these studies are shown in Table 3.

| DISCUSSION
Emotional experiences such as mirth, excitement calmness, fear, and sadness were elicited by ECS. In this study, we try to investigate the subjective emotional responses in relative normal cortex, while it remains uncertain to what degree seizure-related expressions could reflect mechanisms of physiological emotional expression15. And, it remains a question that whether the auras or the symptoms in early seizure propagation can reflect the physiological function of the stimulated focal cortex in the epileptogic network. Therefore, we exclude the stimuli that induced other symptoms accompanying emotions or even afterdischarges. As we know, the after-discharge could also propagate to certain regions of the brain. It is difficult to localize the exact cortex which induce the emotional response. As a result, even though the number of patients reviewed in this study was large, the number of patients included in the final study was limited. Indeed, the small number of patients included with the strict inclusion criteria is a major limitation of this study. However, the advantage of this inclusion criteria is that we can draw a definite conclusion that certain cortex is related to the generation of emotions. Valence of emotion is the hedonic tone of emotional experience and ranges from unpleasant to pleasant. 5 These emotions are classified as positive valence (mirth, excitement, and calmness) and negative valence (fear and sadness). As excitement is a feeling similar to mirth, excitement was classified as mirth in this study. The results of ECS and anatomical location are shown in   insula and the right superior frontal gyrus with laughter. Excitement was elicited by stimulation of the right frontal operculum. As excitement is a feeling similar to mirth, excitement was classified as mirth in this study. Previous studies showed that mirth and laughter were elicited by ECS of the basal temporal cortex, 19-21 superior frontal cortex, [22][23][24] inferior frontal cortex, 25 supplementary motor area, 22 anterior cingulate cortex (ACC), 26,27 middle cingulate cortex, 28 frontal operculum, 29 amygdala, 30 hippocampus, 31 and posterior insula. 32 In addition, mirth without laughter was induced in one patient by ECS of the anterior insula. 33 We summarized the results of these studies and found that mirth was usually elicited by ECS in the temporal and frontal cortices of the dominant left hemisphere [22][23][24][25] and occurred with laughter simultaneously in most of studies. 22,24,25 Our study did not find that mirth was induced by ECS of cingulate gyrus, the most likely cause is that this study excluded the results occurred with other symptoms. The emotional network of mirth and laughter integrates social and motivational information to generate congruent emotional expressions, which consist of emotional experience and perception. 34,35 It is extremely rare for an individual to experience isolated mirth without emotional expression. Imaging studies showed that the frontal operculum was activated during voluntary and involuntary laughter. [36][37][38][39] The frontal operculum and the premotor cortex are located near each other. Jabbi et al 40 suggested that the frontal operculum was part of a premotor network and participated in the voluntary control of emotional facial expressions. Furthermore, most studies found that frontal areas associated with ECS-induced laughter were located in the left hemisphere [22][23][24][25] and were adjacent to language-related areas including the left superior frontal gyrus (supplementary motor area, SMA), 24 Broca's area, 25 and the left basal temporal language area (BTLA). 19 These findings indicated that language and laughter were closely related. Our patient with left dominant hemisphere reported mirth without laughter during ECS of the right frontal operculum, which might further indicate that the nondominant frontal operculum is not located near language-related areas. However, another patient experienced mirth and laughter in response to ECS of right superior frontal gyrus, which does not support the hypothesis that the nondominant frontal operculum is not located near language sites. Francesca Sperli et al 27 reported a patient who experienced smile and laughter, but no mirth in response to ECS of the right cingulate gyrus. Therefore, the mechanisms that distinguish between mirth and laughter are complicated and require further study.
In addition, we found that the right anterior short gyrus of the insula was involved in isolated mirth without laughter. Previous studies reported that stimulation of the insula elicited pleasant odors or pleasant smells, but rarely mirthful experience. 32,33 The insula was segregated into different subregions by ECS in our study and mirth was induced by ECS of the insula. Precise positioning in the right anterior short gyrus of the insula induced mirth without laughter and positioning in the left posterior long gyrus of the insula induced mirth with laughter. Our studies found that the anterior short gyrus of the insula was involved in mirthful emotional experience without related emotional expression. Craig proposed a model in which the posterior F I G U R E 1 Locations of electrode contacts that evoked emotional experiences.
insula processed interoceptive information from the body and the anterior insula formed emotional experience via the integration of interoceptive information. 41 Therefore, it is likely that the anterior insula and the posterior insula participate in the emotional experience network.
A recent study about emotional behavior during prefrontal seizures of Singh et al 15 found that positive behavioral during seizures had predominant involvement of the frontopolar and anterior orbitofrontal regions. However, our research mainly focused on subjective emotional experiences in relative normal brain regions, so our conclusions were slightly different from the study of Singh et al. 15

| Calmness
Calmness was elicited in our study by stimulation of the left posterior long gyrus of the insula in patient 7.  No previous studies reported calmness elicited by ECS. However, calmness is similar to the symptomatology associated with ecstatic seizure, which was reported as a feeling of complete serenity, total peace, and no worries. 42 Ecstatic seizures are defined as ictal sensations of intense pleasure, joy, and contentment. 43 Studies have shown that the aura of ecstasy is caused by abnormal discharge in the insula, especially in the anterior insula. 42 Craig proposed that the posterior insula processed interoceptive information from the body and emotional experience was formed in the anterior insula via integration of interoceptive information. 41 Therefore, the sense of calmness elicited in our study by ECS of the posterior long gyrus of the insula supports this model.

| Fear
Fear was elicited in our study by stimulation of the right middle cingulate gyrus, the left amygdala, the left parietal operculum, and the right hippocampus. Self-reported experience of fear has been evoked by ECS of the amygdala, 31 those fear experiences were auras. Our study excluded auras and affective responses similar to auras. Therefore, we reported one contact point in the left amygdala that induced fear. Fear, an evolutionarily conserved survival response, is triggered by threats that evoke rapid defensive responses that manifest as escape, immobility, and attack, accompanied by autonomic and hormonal changes. 54 Recently, the role of the amygdala in the fear network has been explored in imaging studies, animal studies, and fear conditioning behavioral paradigm studies. The neuroanatomy of conditioned fear has been characterized by a number of studies. 55,56 Conditioned fear mediated by conditioned and unconditioned stimuli is transmitted to the amygdala, and outputs project from the amygdala to the behavioral, endocrine, and autonomic response control systems located in the brainstem. However, the feeling of fear has rarely been explored in conditioned fear models. In this study, we determined that the amygdala was associated with awareness of fear.
The hippocampus is essential for episodic memory and the amygdala is specialized for processing emotion. 57 Guzmán-Vélez et al 58 found that patients with AD and amnestic syndrome with bilateral damage to the hippocampus could experience prolonged emotions, even when they forgot the cause of the associated emotion. This finding suggested that the hippocampus and amygdala play distinct roles in the emotional network. However, the amygdala and hippocampus interact. In contextual fear conditioning, the amygdala was inactivated by a GABA A receptor agonist, which resulted in attenuation of consolidation of hippocampus-dependent contextual memory. 59 Electrical stimulation of the hippocampus may induce production of fearful experience from amygdala through the interaction between fear circuits in the hippocampus and the amygdala.
The anterior mid-cingulate cortex (aMCC) has been linked to negative affect. 60,61 A study of patients with bilateral anterior cingulotomy (ACING) found that greater overlap between ACING lesions and the negative affect map resulted in greater impairment of fear recognition, but no impairment of recognition of facial expressions of surprise or happiness. 62 This finding highlighted the important role of MCC in perception of fear. In our study, fearful experience was induced by ECS of the MCC, which indicated that the MCC participated in production of fearful feelings. Consistent with our study, a recent review of human neuroimaging and animal studies concluded that the aMCC is associated with negative affect produced by a punishment or nonreward neural activity associated with subjective unpleasantness. 63 We found that the left parietal operculum, a somatosensory area, was related to fearful feelings. Sophie van Rijn et al 64 found that functional disruption of the right parietal operculum by transcranial magnetic stimulation (TMS) led to delayed recognition of negative prosody (fear and sadness) of language instead of positive prosody (happiness). This study indicated that the right parietal operculum was associated with fear perception. Fear experience was elicited in our study by ECS of the left parietal operculum. Therefore, the parietal operculum is likely associated with fearful feeling through perception of fearful prosody.
Singh et al 15 summarized objective movements or expressions and found that passive fear was correlated with mesial temporal structures (especially amygdala) and posterior orbitofrontal cortex and/or anterior cingulate, reflecting the role of the prefrontal cortex in emotional control. While our research mainly focused on subjective emotional experiences. The difference between Singh et al 15 and our study probably due to subjective experience of fear and the objective behavioral function were controlled by different brain networks.

| Sadness
Sad experience was elicited in our study by stimulation of the right hippocampus in patient 6. Previous studies reported that experience of sadness was evoked by ECS of the amygdala 44 and the temporal lobe. 31 In humans, sadness is characterized by specific behaviors (social withdrawal), typical facial expressions (drooping eyelids and lowered lip corners), physiological changes (heart rate), and subjective feeling. 65 Previous studies reported that the amygdala and hippocampus were associated with sadness. 66,67 However, an fMRI study of Diener et al 66 reported no hyperactivation of the hippocampus or amygdala in patients with major depressed disorders, which are characterized by pathological sadness persistently. This finding may have been due to combining emotional and cognitive stimuli, rather than evaluating production of emotional experience. Feinstein et al 68 found that patients with severe amnesia continued to experience sadness despite loss of factual memories of the negative events, which provided direct evidence that experience of negative emotion can endure independent of conscious recollection of the emotion-inducing events. These findings showed that the hippocampus participated in storing negative emotional memory but not in production of sad feelings. However, ECS of the hippocampus activated the associated neural circuit that produces sad feelings.

| Limitations
The implanted electrodes were designed for localizing the epileptogenic zone in this study. We excluded affective responses similar to the ictal aura and electrode contacts located in the SOZ to investigate emotional experiences in normal brain regions. Therefore, the number of implanted electrodes was limited, and the sample area of the cortex was also limited for each patient.