Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation (2024)

Abstract

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (η_p² = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (η_p² = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.

SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

Introduction

Extinction learning is core to most effective therapies for disorders of fear and anxiety (Bisson et al., 2013). Exposure therapy, for instance, results in the formation of an extinction memory that suppresses fear expression. Relapse of pathological fear is nevertheless common (Maren, 2011; Dunsmoor et al., 2015b). Improving extinction learning is therefore an important goal of translational research into fear-related disorders (Dunsmoor et al., 2015b). Pharmacological treatments have proven effective in preventing fear recovery in animal models (Nader et al., 2000), but these methods are often not applicable in humans (Nader et al., 2000) or have yielded inconsistent results in experimental models with humans (Kindt et al., 2009; Bos et al., 2012). New noninvasive techniques have been developed that target reconsolidation of the original memory rather than enhance standard extinction learning (Schiller et al., 2010). Although these results are promising, their clinical utility is so far unclear.

Clinically effective treatments are not always derived from such experimental models. One example is eye movement desensitization and reprocessing (EMDR; Bisson et al., 2013), an evidence-based therapy and part of mental health care guidelines in many countries (Bisson et al., 2013; Lee and Cuijpers, 2013). Despite its wide use, a mechanistic, neurobiological understanding of EMDR is lacking. During treatment, patients divide their attention between recalling traumatic memories and making lateral eye movements directed by the therapist's hand. Eye movements are central to the procedure, but it is unclear whether they play any role in the therapeutic outcome above normal extinction (Lee and Cuijpers, 2013). Insight into the potential role of eye movements and the neurobiological mechanisms underlying this manipulation is not only crucial to further optimize this therapy but would also importantly advance our fundamental understanding of extinction learning.

One lead into a neural mechanistic account is that goal-directed eye movements are associated with activations in the dorsal frontoparietal network, including frontal eye fields (FEFs; Corbetta and Shulman, 2002), similar to working-memory tasks that require goal-directed attention. Critically, working-memory tasks are accompanied by robust deactivations in a posterior-medial network (Qin et al., 2009), including the amygdala. Interestingly, a similar activation of the dorsal frontoparietal network and deactivation of the amygdala has been found during cognitive regulation of emotion as well (Ochsner and Gross, 2005). This is important because targeting the amygdala following memory reactivation, by blocking protein synthesis, prevents fear recovery in rodents (Nader et al., 2000). Similarly, systemic administration of propranolol, a β-adrenoceptor antagonist, presumably exerts its effects on fear recovery via inhibition of protein synthesis in the amygdala (Dębiec and Ledoux, 2004). Amygdala reactivity measured with blood oxygenation level-dependent (BOLD)-fMRI in humans is furthermore decreased after propranolol administration (Hurlemann et al., 2010). Indeed, it has been shown that working memory-like tasks, such as a game of Tetris (Holmes et al., 2009; James et al., 2015) can affect the emotionality of memories. We therefore hypothesized (1) that goal-directed eye movements could be used as a noninvasive tool to transiently suppress amygdala activity, comparable to working-memory tasks, and (2) that a well timed application of this deactivation following memory reactivation could reduce fear recovery.

To test our hypotheses, in experiment 1 (n = 24), participants performed a two-back working-memory task and goal-directed eye movements in a block design while undergoing functional MRI. We tested whether both tasks would suppress amygdala activity as well as alter the coupling between the amygdala and dorsal lateral prefrontal cortex. In the second experiment (n = 24), we integrated eye movements into an established Pavlovian fear conditioning/extinction/recall paradigm and tested whether goal-directed eye movements prevent fear recovery via this amygdala deactivation.

Materials and Methods

Results

Discussion

This study aimed to test the hypotheses that goal-directed eye movements, as used in EMDR therapy, can enhance extinction through amygdala suppression. First, we found that goal-directed eye movements (Experiments 1 and 2) as well as a working-memory task (Experiment 1) deactivated the amygdala. Second, we found that both tasks (Experiment 1) altered connectivity between the amygdala and the dorsal frontoparietal network as well as connectivity between the amygdala and the ventromedial prefrontal cortex. Third, a precisely timed application of the eye movements during extinction learning blocked spontaneous recovery 24 h later (Experiment 2). Fourth, although fear responses on average recovered after reinstatement, recovery was attenuated when participants had stronger amygdala deactivations during eye movements (Experiment 2). Given that we found similar amygdala suppression in another task taxing working memory (Experiment 1), the reported effects on fear recovery are likely not specific to eye movements.

A potential explanation for why amygdala deactivation occurs, is that large-scale brain networks act reciprocally (Fox et al., 2005) and compete for resources (Hermans et al., 2014). Acute stress engages the amygdala but impairs dorsal frontoparietal network functioning (Hermans et al., 2014). Our data confirm that engaging the dorsal frontoparietal network has the opposite effect of deactivating the amygdala. We furthermore found coupling between the amygdala and dorsolateral as well as ventromedial prefrontal pathways. The vmPFC plays a crucial role in extinction learning and is thought to mediate dorsolateral PFC–amygdala interactions (Delgado et al., 2008). Our finding aligns closely with the literature on cognitive regulation of emotion (Ochsner and Gross, 2005), while revealing that mere eye movements are sufficient to engage these pathways.

A consequence of this resource competition might be that fear expression is attenuated. Startle responses, for instance, are reduced when performing a working-memory task (Vytal et al., 2012) and patients with amygdala lesions show enhanced working memory performance (Morgan et al., 2012). If this mechanism underlies the role of eye movements in reducing traumatic symptoms, then any task taxing working memory should have similar effects. Indeed, emotionality and vividness of autobiographical memories as well as intrusive memories are reduced when memory reactivation is paired with working-memory tasks (Holmes et al., 2009; Engelhard et al., 2010; James et al., 2015). Last, other types of cognitive control, such as emotion regulation, suppress amygdala activity and alter emotionality during autobiographical memory recollection (Denkova et al., 2015). Our data therefore provide an explanation for how both eye movements and tasks involving cognitive control could affect the emotionality of memories.

Spontaneous recovery was diminished after extinction with eye movements. The dominant view on post-extinction recovery (Maren, 2011; Dunsmoor et al., 2015b) holds that this can be due to updating the original CS-US association or to the formation of a stronger new extinction memory. In line with the latter account, differential fear responses recovered after reinstatement, indicating the CS–US association was not fully eliminated. A similar reduction in spontaneous recovery was observed in a study in which the US was replaced by a nonaversive tone during extinction (Dunsmoor et al., 2015a). One possibility, therefore, is that eye movements following the CS presentation, similar to a tone, strengthen extinction by reducing the ambiguity of the CS either predicting the US or not predicting anything. Unlike a tone, however, eye movements suppress amygdala activity and possibly attenuate fear responses (Vytal et al., 2012). This may allow for additional learned controllability over conditioned responses via subsequent suppression. This interpretation aligns with findings of reduced spontaneous recovery in rats when trained to actively avoid the US during extinction learning (Moscarello and LeDoux, 2013).

The amygdala is, additionally, crucially involved in encoding the CS-US association (Maren, 2011). Amygdala suppression following reactivation could therefore also have led to updating of the CS–US association (e.g., as less aversive) rather than only facilitating new learning. Although the finding that fear recovered following reinstatement would speak against this explanation, this finding is not conclusive on whether the eye movements in EMDR therapy induce unlearning or new learning. Disentangling unlearning from new learning in a laboratory experiment relying on behavioral observations in humans is problematic, since any behavioral outcome is consistent with multiple explanations. Moreover, recent views on safety learning challenge a strict dichotomy between unlearning and new learning (Clem and Schiller, 2016). Future studies using an animal model of EMDR, in combination with techniques with which a memory trace modification can be measured, could shed more light on this matter. For example, using engram-based tagging techniques, a recent study showed how specific neurons are activated during learning and recall of fear memories, and how these are related to fear attenuation (Khalaf et al., 2018). Together, we propose that eye movements during extinction learning may affect fear recovery by enhancing extinction via newly learned instrumental control over CS-evoked fear responses following memory reactivation (Moscarello and LeDoux, 2013), possibly through pathways engaged during cognitive regulation of emotion (Ochsner and Gross, 2005).

The observed amygdala suppression was located toward the dorsal rather than ventral part. However, we are hesitant in assigning this deactivation to a specific subregion. A comparison between dorsal and ventral is difficult due to inherent problems of gradient EPI sequences, such as signal loss or distortions, which are increased toward the ventral part of the brain (Merboldt et al., 2001; Sladky et al., 2013). These inherent problems (i.e., distance between a brain area and the head coil or cavities) cannot be fully resolved (Merboldt et al., 2001; Sladky et al., 2013). Whether the effect we observed can be attributed to a specific subregion of the amygdala therefore remains an open question.

We found anticipatory FEF activation in response to the CS coupled with eye movements before eye movements took place. This is in line with anticipatory responses observed using electrophysiological recordings in monkeys (Zhou and Thompson, 2009). In our study, the CS+_eye and CS−_eye always predicted an eye-movement block, therefore anticipatory responses could be expected. Only five of 24 participants reported the association between the CS and the eye-movement blocks. Excluding these participants did not affect the results. The FEF activation, moreover, did not predict the reduction in spontaneous recovery, suggesting the anticipatory responses in the FEF did not affect fear recovery.

Despite EMDR being an evidence-based therapy (Bisson et al., 2013; Lee and Cuijpers, 2013), it has received substantial criticism (Devilly, 2002; Rogers and Silver, 2002). Our results shed new light on the working mechanisms of this treatment. One account of EMDR holds that, unlike exposure therapy (Maren, 2011; Bisson et al., 2013), EMDR induces unlearning (Shapiro, 1989; Devilly, 2002; van den Hout and Engelhard, 2012). We found evidence speaking against this claim, since fear recovered following reinstatement. However, as explained above, it is possible that our design did not capture all processes that occur during EMDR treatment, therefore, further research is necessary to investigate whether EMDR may involve unlearning. Future studies could focus on incorporating eye movements in paradigms that more likely capture reconsolidation (Schiller et al., 2013; James et al., 2015).

Another controversy regarding EMDR concerns the role of eye movements, which some regard as crucial (Shapiro, 1989), whereas others argue they have no added value (Rogers and Silver, 2002) or merely serve as a distractor (Devilly, 2002). Our data demonstrate that eye movements have added value above standard extinction learning. However, the data from Experiment 1 suggest that any task taxing working memory would suppress amygdala activity and have similar effects. Indeed, there is a large body of research indicating that working-memory tasks reduce the emotionality of memories (Engelhard et al., 2011) as well as memory intrusions (Holmes et al., 2009; James et al., 2015; Iyadurai et al., 2018). These manipulations have also been shown to be effective in a clinical setting (Iyadurai et al., 2018). Only tasks with a working-memory load appear to have such effects, whereas visual distraction by itself does not (Onderdonk and van den Hout, 2016). Our data are also in line with studies using other types of focused attention, such as emotion regulation strategies (Denkova et al., 2015), which are accompanied by amygdala suppression as well. In sum, although other manipulations may have a similar effect, our data support the view that eye movements have a functional role in EMDR.

Several limitations regarding our study need to be mentioned. First, some of our findings are only just statistically significant, and were obtained in a limited sample (n = 24 in each experiment). Although amygdala suppression due to eye movements was replicated across experiments, the effect on extinction learning was only tested in Experiment 2 and therefore awaits independent replication. Second, the experimental model of EMDR we developed in this study has inherent limitations because it is impossible to capture every aspect of this therapy (e.g., regarding timing of trauma recall and eye movements, or effects of repeated sessions) in a controlled experiment. Future studies should therefore focus on (1) establishing the reproducibility and generalizability of our findings, (2) investigating the specificity of the observed effects on extinction learning to eye movements, and (3) further illuminating the causal chain from taxing working memory to amygdala suppression and enhanced extinction learning.

In conclusion, our findings show eye movements have added value in safety learning above standard extinction alone. This effect, while likely not specific to eye movements, is associated with amygdala deactivation possibly as a consequence of reciprocally coupled activation of the dorsal frontoparietal network, via ventromedial prefrontal pathways similar to those involved in cognitive regulation of emotion. A key advantage of amygdala deactivation through behavioral manipulations, rather than via pharmacological treatments, is that they are noninvasive, precise in time and duration, and shown to be clinically effective (Bisson et al., 2013). Our findings provide a parsimonious account for how a wide range of behavioral manipulations including working-memory tasks, a game of Tetris, and eye movements can alter retention of emotional memories.

Footnotes

• This work was supported by Grants from the EMDR Research Foundation and the European Research Council (ERC-2015-CoG 682591). Funding sources had no role in study design, data analysis, or writing of the paper. We thank Sasha Bouman, Frederiek Wijers, and Juul Willering for expert advice on EMDR, and Laura van Weerdenburg for help with data collection.

• The authors declare no competing financial interests.

• Correspondence should be addressed to Lycia D. de Voogd,Donders Institute for Brain, Cognition and Behavior (Radboudumc), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.devoogd.ld{at}gmail.com

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