Sunday, April 16, 2023

The origin of pleasant sensations: insight from direct electrical brain stimulation

The origin of pleasant sensations: insight from direct electrical brain stimulation. Cécile Villard et al. Cortex, April 13 2023. https://doi.org/10.1016/j.cortex.2023.03.007

Abstract: Research into the neuroanatomical basis of emotions has resulted in a plethora of studies over the last twenty years. However, studies about positive emotions and pleasant sensations remain rare and their anatomical-functional bases are less understood than that of negative emotions. Pleasant sensations can be evoked by electrical brain stimulations (EBS) during stereotactic electroencephalography (SEEG) performed for pre-surgical exploration in patients with drug-resistant epilepsy. We conducted a retrospective analysis of 10 106 EBS performed in 329 patients implanted with SEEG in our epileptology department. We found that 13 EBS in 9 different patients evoked pleasant sensations (0.60% of all responses). By contrast we collected 111 emotional responses of negative valence (i.e., 5.13 % of all responses). EBS evoking pleasant sensations were applied at 50 Hz with an average intensity of 1.4 ± 0.55 mA (range 0.5−2 mA). Pleasant sensations were reported by nine patients of which three patients presented responses to several EBS. We found a male predominance among the patients reporting pleasant sensations and a prominent role of the right cerebral hemisphere. Results show the preponderant role of the dorsal anterior insula and amygdala in the occurrence of pleasant sensations.

Keywords:Brain stimulationPositive emotionstereoelectroencephalographyAmygdalaInsula

4. Discussion

To our knowledge, our study is the first to focus specifically on the generation of pleasant sensations, in the broad meaning of the term, from a large collection of EBS obtained during SEEG recordings (10 106 stimulations in 329 patients). We found that pleasant sensations were exceptional events during EBS, much rarer than negative sensations, as we observed only 13 positives sensations (0.55%, versus 5.13 % for negative feelings). This is possibly a particularity of the mammalian brain, which is more likely to generate negative emotions for rapid adaptive reactions favoring survival of species, e.g. when facing a danger(Phan et al., 2002). Another explanation lies in the largely subcortical and brainstem location of reward networks(Liu et al., 2011Wise, 2002) when compared to the focus of EBS on cortical structures during SEEG for presurgical evaluation of epilepsy (see limitations).

4.1. Amygdala and anterior insula: two core regions for pleasant sensations

Our results identified two brain regions more frequently involved in pleasant sensations: the anterior insula (AI) and the amygdala. The AI is the source of heterogeneous clinical manifestations when it is involved in seizure or stimulated electrically as it can evoke gustatory, olfactory, auditory, somatosensitive, vestibular, viscerosensitive, visceromotor, experiential or emotional sensations(Mazzola et al., 2006201420172019). Functional neuroimaging highlighted the role played by the insula in the integration of information from our environment and the genesis of adapted emotions, showing the notable role of the AI(Kurth et al., 2010). Our data are congruent with previous EBS studies showing the involvement of AI in pleasant emotions and particularly ecstatic sensations (Bartolomei et al., 2019Nencha et al., 2022aOstrowsky et al., 2000). Gschwind and Picard (2016), in a meta-analysis of ecstatic aura, defined ecstatic sensations as the association of "intense positive emotion (bliss)", "improved physical well-being", "increased self-awareness or increased perception of the external world (clarity)". According to a recent neurocognitive theory, the brain would operate on a prediction model (Clark, 2013), comparing real internal and external stimuli with reference theoretical patterns. The insula would be the key structure for processing the internal states of the body through interoceptive signals. Disruption of the predictive role of AI has been proposed as an explanation of the ecstatic auras(Picard et al., 2021). Recently a feeling of time dilation with a sense of pleasant eternity has been reported during AI stimulation (Sheikh et al., 2022).

The role of amygdala in generating negative emotions, especially fear, is well known both from animal and human studies(Davis & Whalen, 2001LeDoux, 2003). However, the amygdala has also been involved in brain circuits related to happiness and pleasant sensations(Garavan et al., 2001Hamann & Mao, 2002Lanteaume et al., 2007Sabatinelli et al., 2011). Animal studies showed that amygdala neurons respond to conditioning stimuli that have been associated with either appetitive or aversive outcomes (reviewed in Fernando et al., 2013). The activation of the amygdala in response to pleasant stimuli is suggested by human fMRI studies, notably when observing a pleasant image, face, word or scene(Garavan et al., 2001Hamann & Mao, 2002Sabatinelli et al., 2011), or during mental imagery of pleasant situations(Costa et al., 2010). On the other hand, only few publications reported pleasant sensations during EBS in the amygdala (see (Guillory & Bujarski, 2014) for review). Lanteaume et al. (2007) reported sensations of "joy" or "happiness" during left amygdala stimulation in a minority of patients, as most EBS resulted in negative sensations. This study quantified subjective responses using a basic emotion scale (Izard scale). A more recent study found that only one out of 150 amygdala stimulation resulted in a subjective feeling of joy (Inman et al., 2020).

Our study also shows that the anterior cingulate gyrus and the temporal pole may also contribute to pleasant sensations. These observations are consistent with some data from EBS of the temporal pole. Analyzing the semiological aspects of temporal pole stimulation, Ostrowsky et al. (2000) reported a sensation of happiness in 4 out of 150 temporal pole stimulation. Meletti et al. (2006) also described a pleasant and relaxing sensation during EBS in the temporal pole. Similarly, experiments involving recollection of positive autobiographical memories and positive emotions revealed the activation of hippocampus and temporo-polar regions(Markowitsch et al., 2003Zotev et al., 2011)Concerning the anterior cingulate gyrus, in his work on the lateralization of affect, Smith et al. (2006a) described an euphoric sensation after its stimulation. Some functional imaging studies highlighted also the role of the anterior cingulate gyrus in the emotional mechanisms of happiness. Studies reported that when participants were asked to recall and attempt to re-experience and re-enact intense personal emotional episodes, there was an activation of the right insula, right somatosensory cortex, bilateral anterior cingulate cortex and right posterior cingulate cortex (Damasio et al., 2000; Suardi et al., 2016).

While our study highlights the predominant role in the conscious expression of positive affect of the AI and amygdala, these structures are likely embedded in a network of neural structures and probably do not act in isolation. There is evidence that direct high-frequency EBS activates a network of regions depending on the stimulation site and the effect produced(Bartolomei et al., 2019Perrone-Bertolotti et al., 2020). As such, a recent study on a manic state induced by EBS of the right lateral prefrontal cortex demonstrated significant increase of functional coupling between the right hemispheric limbic nodes, the temporal pole and the claustrum(Scholly et al., 2022). There is evidence that the genesis of emotions requires the interaction between several brain networks, widely distributed, although none of them seems to be specific to the "emotion function” (Morawetz et al., 2020Pessoa, 2018). Among these networks, the "salience network", which has been widely studied, would be involved in a larger scale network leading to the generation of emotions. The salience network involves, among others, connections between the anterior cingulate gyrus, the AI, the amygdala and the hypothalamus (Kober et al., 2008; Lindquist et al., 2016; Pessoa, 2018). The relative contribution of each of these regions in positive emotion networks remains to be determined.

A network of brain areas underpinning the experience of positive emotions and pleasant sensations could explain why, in two patients, stimulating different structures evoked the same sensations, with for patient P4, stimulation of the right amygdala and temporal pole evoking a feeling of well-being and for patient P8, stimulation of the right amygdala and AI evoking a feeling of well-being and positive emotion. The dense bidirectional connections between the anterior ventral part of the insula and the amygdala(Jakab et al., 2012Mesulam & Mufson, 1982) and between the AI and the anterior cingulate gyrus (Ghaziri et al., 2017) can account for similar sensations evoked by EBS in distant areas within the same functional network.

4.2. Effect of hemispheric laterality and sex

Our study revealed a right-sided predominance of pleasant sensations. A right-side predominance of negative emotional valence induction for right side stimulations has been reported in previous EBS studies (review in (Guillory & Bujarski, 2014)). A left lateralization of positive emotion during amygdala stimulation has been previously suggested (Lanteaume et al., 2007). This apparent contradiction could be linked to the underrepresentation in the previous studies of the anterior insula stimulation which is the prominent site in our experience for pleasant evoked sensations. Smith et al. (2006b) also reported dysphoric responses primarily during right stimulation, but no lateralization for pleasant emotional responses. No clear lateralization effect was found as a function of emotional valence in amygdala activation in a large neuroimaging meta-analysis(Baas et al., 2004).

There was a predominance of pleasant sensations in men in our study. No previous study using EBS has reported such a predominance of positive emotions, which could be related to the small number of patients in most EBS studies when compared to the large sample investigated here. However, regarding negative emotions Meletti et al. (2006) reported that the feeling of fear occurred significantly more in women than in men.

Data in the literature on gender differences in emotion are often inconsistent (Brody & Hall, 2000Wester et al., 2002). There is evidence, primarily from self-report data, that women experience emotions with greater intensity than men(Whittle et al., 2011). Women have been found to be more reactive to emotional stimuli, and particularly to unpleasant, threatening, or traumatic stimuli. Research has also suggested that gender differences in self-report are greater for negative emotions such as fear and jealousy, and some neuroimaging studies support greater brain activation in women for negative stimuli (review in (Whittle et al., 2011)). There is also evidence that males may be physiologically more reactive to certain pleasurable stimuli, particularly erotic ones (Allen et al., 2007). A study reported that males exhibited greater activity than females in the frontal lobe and amygdala during exposure to photo stimuli with positive valence (Wrase et al., 2003).

Further studies are needed to better define the effects of these two factors in the genesis of pleasant sensations.

4.3. Limitations of the study

The first limitation of our study is its retrospective nature. Responses were systematically collected, but subjective reports may not have been exhaustive. Patients may have described their symptoms in a simplified way because of difficulties in expressing their feelings (Cirignotta et al., 1980). Moreover, how to perceive and express these sensations may depend on education, culture, information given to the patients, context of occurrence, the patients ability to introspection, their vocabulary and therefore vary between patients but also within the same patient (Williams, 1956). To overcome these difficulties, quantification by self-administered questionnaires (Lanteaume et al., 2007) is interesting but was not carried out in the majority of patients in the study. Prospective studies using standardized questionnaires will be particularly useful, especially if coupled with objective measures of the autonomic response, such as the electrodermal response(Inman et al., 2020Lanteaume et al., 2007).

The second limitation is related to the spatial sampling of SEEG as it has been estimated that about 10,000 electrode contacts would be necessary to explore the brain volume covered by functional MRI(Lachaux et al., 2003). This limitation is partially counterbalanced by the large cohort of patients included and the large number of EBS considered in our analysis (the highest in the literature to date) that allow a large spatial sampling. In addition, the included patients cover a large temporal period with variations in the number of implanted electrodes and implanted sites. Insular implantations with orthogonal and especially oblique electrodes became more common from 2010 in our center. We can also note that, for feasibility and safety reasons, some regions cannot be explored, in particular the brainstem whose role in emotional processing is important (Venkatraman et al., 2017).

Third, SEEG was performed in patients with epilepsy, and seven of them reported positive sensations belonging to the subjective symptoms of their usual seizures. Moreover, the stimulated sites were part of the epileptogenic zone in 8 out of 13 cases. Indeed, the organization of brain networks and the excitability of the brain of patients with epilepsy may be different from a non-epileptic subject. Nevertheless, direct brain stimulation in the history of neuroscience has allowed progress in the knowledge of the role of certain regions in subjective phenomena generated by the human brain, such as psychosensory or emotional phenomena (reviewed (Trébuchon & Chauvel, 2016). Moreover, these phenomena can be obtained outside the usual clinical semiology of the patients (patients P1 and P7 in the present study) (Nencha et al., 2022b).

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