Human amygdala stimulation effects on emotion physiology and emotional experience
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).
Section snippets
Subjects
Nine patients undergoing intracranial EEG monitoring for drug-resistant epilepsy were recruited to participate in the study (4 female; all right-handed; M(SD)age= 36(10); see Table 1 for detailed patient demographics and epilepsy information). All patients gave written informed consent to a study protocol approved by the Emory University Institutional Review Board. In all 6 of 9 subjects in which functional MRI was obtained, left-hemisphere language dominance was confirmed. Standard
Results
Linear mixed models were fit to a data set collected from 7 participants who completed an average of 45 trials each (range 22–98) across a stimulation range of 0–12 V amplitudes. 84% of trials were stimulated below 9 V; there were 6 trials at 11 V and 13 trials at 12 V. Testing also included 72 single-blinded sham trials interleaved with active stimulation conditions. 150 active trials took place in the amygdala, and 91 trials at positive control locations (lateral temporal cortex), for a total
Discussion
The current study's examination of the effects of human amygdala stimulation on physiological and subjective emotional responses yielded three primary findings. First, we found that amygdala stimulation strongly modulated autonomic activity without eliciting concurrent subjective emotional responses in most patients. Second, we found that these effects were specific to the amygdala relative to lateral temporal lobe stimulation, indicating that the effects were not a general effect of brain or
Acknowledgements
We would like to thank the patients, physicians, and staff of the Emory University Hospital Epilepsy Monitoring Unit for their contributions to this project. We also thank Nigel Pedersen for helpful conversation and providing useful historical brain stimulation context. KRB was supported in part by career development awards from the American Foundation for Suicide Prevention and the NIH (KL2TR000455). JTW was supported in part by career development awards from the Sleep Research Society
Author contributions
C.S.I., K.R.B., D.I.B, S.H., and J.T.W. contributed to the study design. C.S.I., K.R.B., D.I.B., R.F., and J.T.W. contributed to the data collection. J.T.W. and R.E.G. conducted the surgeries. C.S.I., K.R.B., and J.T.W. contributed to the electrode localization. C.S.I. and K.R.B. performed the behavioral, psychophysiological, and statistical analyses. K.R.B. designed the mixed linear models. C.S.I, K.R.B., S.H., and J.T.W. contributed to the interpretation. C.S.I., K.R.B., S.H., and J.T.W.
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