Human amygdala stimulation effects on emotion physiology and emotional experience

Highlights

• Increasing amplitudes of amygdala stimulation elicited dose-dependent increases in EDA and decreases in heart rate.

• In one patient, amygdala stimulation caused subjective experiences of fear and anxiety, accompanied by increased heart rate.

• Amygdala stimulation reliably elicits changes in autonomic activity in a dose-dependent and safe manner.

• At the amplitudes of stimulation delivered, amygdala stimulation elicits subjective emotional experiences only infrequently.

Abstract

The amygdala is a key structure mediating emotional processing. Few studies have used direct electrical stimulation of the amygdala in humans to examine stimulation-elicited physiological and emotional responses, and the nature of such effects remains unclear. Determining the effects of electrical stimulation of the amygdala has important theoretical implications for current discrete and dimensional neurobiological theories of emotion, which differ substantially in their predictions about the emotional effects of such stimulation. To examine the effects of amygdala stimulation on physiological and subjective emotional responses we examined epilepsy patients undergoing intracranial EEG monitoring in which depth electrodes were implanted unilaterally or bilaterally in the amygdala. Nine subjects underwent both sham and acute monopolar electrical stimulation at various parameters in electrode contacts located in amygdala and within lateral temporal cortex control locations. Stimulation was applied at either 50 Hz or 130 Hz, while amplitudes were increased stepwise from 1 to 12 V, with subjects blinded to stimulation condition. Electrodermal activity (EDA), heart rate (HR), and respiratory rate (RR) were simultaneously recorded and subjective emotional response was probed after each stimulation period. Amygdala stimulation (but not lateral control or sham stimulation) elicited immediate and substantial dose-dependent increases in EDA and decelerations of HR, generally without affecting RR. Stimulation elicited subjective emotional responses only rarely, and did not elicit clinical seizures in any subject. These physiological results parallel stimulation findings with animals and are consistent with orienting/defensive responses observed with aversive visual stimuli in humans. In summary, these findings suggest that acute amygdala stimulation in humans can be safe and can reliably elicit changes in emotion physiology without significantly affecting subjective emotional experience, providing a useful approach for investigation of amygdala-mediated modulatory effects on cognition.

Introduction

The amygdala is an almond-shaped brain structure in the medial temporal lobe that is implicated in a wide range of emotional functions. The amygdala is comprised of multiple subnuclei that differ in their function and projections, yielding extensive modulatory connections to widespread brain regions (Adolphs et al., 1995, Pessoa, 2008, Pessoa and Adolphs, 2010, LeDoux, 2000, Burgdorf and Panksepp, 2006). The role of the amygdala in mediating emotional responses has attracted particular attention with respect to subjective responses (e.g., fear) and physiological affective changes in autonomic nervous system (ANS) activity (Mangina and Beuzeron-Mangina, 1996, Asahina et al., 2003, Guillory and Bujarski, 2014). Considerable evidence from nonhuman animal, human neuroimaging, and lesion studies have shown that the amygdala modulates ANS activity in the context of the processing of affectively salient stimuli (Adolphs et al., 1994, LeDoux, 2000, Bradley et al., 2001, Critchley, 2002, Critchley, 2005, Feinstein et al., 2011). Amygdala lesions have been observed to blunt normal physiological and subjective emotional responses to some types of emotionally salient stimuli, particularly fear-related responses to aversive stimuli (Adolphs et al., 1997; LeDoux, 2017; Davis and Whalen, 2001), though the amygdala's role in emotion likely extends beyond aversive stimuli and fear to encompass positive emotion, reward, and aspects of social processing (Adolphs, 2010, Anderson and Adolphs, 2014; Hamann et al., 1999).

An important current debate in the cognitive neuroscience of emotion concerns the neural representation of emotion in the human brain. Key in this debate is whether individual brain regions have specific emotion functions, or alternately, whether emotions are an emergent property of processing that is distributed across multiple brain regions and networks. Reflecting this debate, current neurobiological theories of emotion propose markedly different functions of the amygdala in mediating emotional responses (Anderson and Adolphs, 2014, Vytal and Hamann, 2010, Barrett and Satpute, 2013, Lindquist and Barrett, 2012, Ekman, 1992, Bradley et al., 2001, Barrett et al., 2007). One theoretical issue concerns whether the amygdala specifically mediates the basic emotion of fear, or alternately, whether the amygdala's role is more general and intrinsic to brain networks mediating multiple emotions (Hamann, 2012, Lindquist and Barrett, 2012, Pessoa, 2010). A closely related issue is the extent to which the amygdala may mediate the emotional dimensions of intensity (arousal) or valence (degree of pleasantness or unpleasantness) that have been proposed by influential psychological dimensional theories of emotion (Barrett and Satpute, 2013, Hamann, 2012, Bradley et al., 2001, Pessoa, 2010).

Although human neuroimaging and neuropsychological lesion studies have provided important evidence regarding the neural representation of emotion in the human brain and the role of the amygdala, both approaches have important limitations (Adolphs, 2016, Vytal and Hamann, 2010, Barrett and Satpute, 2013). Neuroimaging can provide correlational evidence suggesting the amygdala's role in emotion, but such evidence cannot be used to infer a causal or necessary role of the amygdala. Neuropsychological studies of patients with brain lesions incorporating the amygdala have reported variable impairments in the subjective experience of fear in some patients with bilateral amygdala lesions (Adolphs et al., 1999, Feinstein et al., 2011). However, although studies of patients with bilateral lesions have contributed greatly to understanding of amygdala function, such patients are rare and thus these studies have limitations related to small sample sizes, individual differences in post-lesion neural reorganization, developmental differences, and other factors. In addition, human lesions caused by degenerative, ischemic, or post-surgical processes are typically not restricted to the amygdala, although a few patients with bilateral lesions restricted to the amygdala have been extensively studied (Adolphs et al., 1999, Adolphs, 2016).

By contrast, acute electrical brain stimulation of the amygdala and other brain regions may provide more direct causal evidence for specific emotional functions (Burgdorf et al., 2000, Panksepp, 1982), complementing the correlational evidence obtained using methods such as functional neuroimaging and electrophysiological recording (Rutishauser et al., 2015). Discrete focal brain stimulation can produce reliable, temporally precise changes in electrophysiological brain states, measures of peripheral physiology, and subjective mental state in awake human subjects, lending causal evidence to evaluate the predictions of current neurobiological theories of emotion (Mayberg et al., 2005, Selimbeyoglu and Parvizi, 2010, Guillory and Bujarski, 2014). In the current study, we examined both subjective and psychophysiological responses to direct electrical stimulation of the amygdala. While direct amygdala stimulation has been reported in a few studies to elicit subjective emotional responses and changes in emotional physiology, the relationships among stimulation dosage and subjective and physiological measures of emotion have not been determined (Lanteaume et al., 2007, Meletti, 2006, Bijanki et al., 2014, Smith et al., 2006).

Several studies have examined the subjective emotional responses associated with stimulation of several different brain regions (Guillory and Bujarski, 2014). In contrast, the current study focused specifically on the amygdala, a region which has been investigated less frequently and systematically (Halgren et al., 1978, Halgren, 1992, Mangina and Beuzeron-Mangina, 1996, Meletti, 2006, Lanteaume et al., 2007). Four studies have used stimulation mapping of the amygdala and other brain structures in epilepsy patients undergoing intracranial electroencephalographic (iEEG) monitoring to examine the effects of electrical stimulation on subjective emotional experience (Lanteaume et al., 2007, Meletti, 2006, Bijanki et al., 2014, Smith et al., 2006). Electrical stimulation of the amygdala typically elicits subjective responses relatively rarely (Meletti et al., 2006). For example, Meletti and colleagues reported evoked subjective emotional responses in only 12% of amygdala stimulation trials. With respect to the nature of elicited subjective responses, stimulation to the amygdala can induce both positive and negative emotional experiences (e.g., elation or fear), although negative emotional responses are more frequently observed (Bijanki et al., 2014, Lanteaume et al., 2007, Meletti, 2006, Smith et al., 2006). Across stimulation of various regions in the left or right hemisphere, Smith et al. (2006) found that right-hemisphere stimulation produced more dysphoric responses than left-hemisphere stimulation. Similarly, Lanteaume et al. reported that right amygdala stimulation elicited only negative responses (e.g., fear and sadness), whereas left amygdala stimulation elicited both negative and positive responses. In addition, Lanteaume et al. found that amygdala stimulation elicited a larger electrodermal response (EDA) when a subjective emotional experience was also elicited, relative to stimulation conditions in which no emotional experience was elicited. In contrast, Bijanki et al. (2014) reported a significant positive response with relatively high-amplitude, intermittent stimulation (15 V, 5 s On, 5 s Off) to the right amygdala in a patient with severe comorbid depression. Taken together, these studies establish that direct amygdala stimulation can elicit changes in emotion physiology (EDA only) and subjective emotional experience. However, the extent to which these autonomic effects (EDA, heart rate, or respiration) are dependent upon the dose of stimulation (i.e., stimulation amplitude) and the presence or absence of a subjective emotional response, has yet to be established.

Importantly, emotional responses involve changes in three primary domains: neural, behavioral/subjective, and physiological (Bradley and Lang, 2000a, Bradley and Lang, 2000b, Lang, 1995, Lang et al., 1997, Hamann, 2001). For example, encountering a poisonous snake elicits brain activation related to processing threat, behavioral responses such as recoiling or freezing, and physiological changes in autonomic nervous system activity, such as changes in heart rate and skin conductance. The extent to which changes in each affective domain are mediated independently by the amygdala remains to be fully characterized. Accordingly, in the current study we examined how direct electrical stimulation of the amygdala influenced concurrent physiological and behavioral/subjective responses, relative to sham stimulation and stimulation to a positive control region (i.e., the lateral temporal cortex). In addition, the present study examined changes in autonomic reactivity to varying parameters of direct electrical stimulation to the human amygdala (stimulation amplitude, hemisphere, and frequency). Specifically, we measured changes in electrodermal activity (EDA), heart rate (HR), and respiration rate (RR) while delivering long (30 s), intermittent electrical stimulation trains to the human amygdala. We also examined whether there was a relationship between these autonomic changes and the subjective experience of emotion. We hypothesized that even below subjective thresholds, stimulation would produce an amplitude- and location-dependent increase in autonomic arousal when stimulating the amygdala, shown by increased SCR, decreased heart rate, and respiration consistent with orienting and defensive responses observed with aversive visual stimuli in humans (Bradley et al., 2001, Lang and Bradley, 2010) and previous studies strongly implicating the amygdala in emotional arousal processes (Adolphs, 2010, Anderson et al., 2003, Lang and Bradley, 2010).