By Haoyu Li
In our lives, we always experience things we would urge to forget. Broken love, childhood trauma, devastating disasters, lost beyond redemption, and when we recall these experiences, we undeniably want to erase them from our head. However, no matter how hard we try, some memories just would fade as we wish. In some people, they can become more and more vivid, leading to psychological complications such as anxiety and PTSD.
Be it ‘Men in Black’ or ‘Total Recall’, erasing and overriding memory appears only to be in plots of sci-fi movies. Such memory manipulation technologies depend on one big hypothesis we have on the brain: each memory has recognisable characteristics, allowing them to be identified and then incepted or deleted. This nevertheless remains a fantasy. Although synaptic changes are the foundations of simple associative memory representations in invertebrates and recognition of synapse plasticity demonstrate the possibility of memory-rewriting neural instantiation/behavioral expression (Kandel et al., 2014), applying similar techniques to humans is not probable. Part of the reason being that vertebrates have much more sophisticated neuronal representations, hence procedures used to alter synapse plasticity in animal models are not safe in humans. With that said, under the relentless efforts of neural biologists and psychologists, Methods to overcome the previously mentioned obstacle are being theorized. Such methods have particularly promising prospects in purposive human memory editing. Such purposes can include alleviating post-trauma negative emotions or diminishing addiction for drug abuses.
Undeniably, as research progresses, various methods have been developed for emotional memory editing in animal models. Namely optogenetics, a technique that involves the use of light to control neurons that have been genetically modified to express light-sensitive ion channels. However, conversion of success in animal experiments into clinical applications are in deep waters. To be more specific, seemingly problem-free techniques in animals models showed never before observed dismissive results when used in human trials.
To address this, Phelps and Hofmann (2019) published a review on Nature titled ‘Memory editing from science fiction to clinical practice’, focusing on memories of emotional events with greater clinical significance. The review systematically narrates current methodologies of human memory editing, together points to areas of further research.
According to Phelps and Hofmann (2019), implementation of memory editing under clinical setting faces two main challenges. The first being that memories of a single event to the human brain can be an expression in numerous manners, each with a unique neuronal representation. For instance, when presented with cues depicting an accident scene, victims from car accidents manifests brief physiological discomfort and defense responses, along with consciously recalling the course of the event. Although different memory patterns of the same event can be seen as an integrity, each pattern is, as it happens, stored and expressed by different sections of the nervous system. Consequently, editing towards a single memory representation is ill-suited towards the other representation of the same memory, resulting in editorial failure. The second challenge is that, even the simplest of memories have complicated neuronal communication signaling across the whole brain. Mechanically recognising and locating these signal highways is thereby simply infeasible.
With these challenges in mind, Phelps and Hofmann (2019) propose that any memory editing techniques should be executed when the memory is first encoded or when it is reactivated, as these are times that memory vulnerability is at its highest. Such a window of opportunity is longer when the memory is first encoded compared to when reactivated, as primary consolidation of a memory takes a much longer time compared to any reconsolidations.
In animal models, the most widely used agents to induce forgetting of newly coded memory and inhibit memory primary consolidation are protein synthesis inhibitors, but these agents convey low clinical potential due to their lack of safety in humans. Nonetheless, more and more research reveal that stress hormones induced by emotional events can enhance memory consolidation (Wood et al., 2015). Therefore, stress hormone simulating agents (e.g. adrenaline, glucocorticoids) and stress hormone receptor inhibitors (e.g. propranolol, a beta-adrenergic antagonist) can affect beta-adrenergic receptors in the amygdala, and thus regulate memory consolidation of the hippocampus (Cahill et al., 1994). Unlike protein synthesis inhibitors in animal models, these agents have already been used to treat other conditions in humans, hence prove of their safety. Currently, propranolol had been shown to reduce emotional enhance of episodic memories, while cooperation of glucocorticoids intake in exposure therapy amplifies the effectiveness in PTSD (Phelps and Hofmann, 2019). With this said, stress hormone usage has exigent drawbacks, one of them being that they can instead enhance traumatic memory when the memory is newly encoded. Another method currently used is target memory reactivation (TMR) through external cues. Although normally used to enhance memories, research has show that TMR can be used in sleep together with pitch sounds in method known as memory control to make psychological suggestions to the subject, thus dismantling episodic memories (Phelps & Hofmann, 2019).
Despite recognition and successes gained by the above methods, the clinical application of these technologies still has limitations. One of them is that the time for editing memory consolidation is limited to shortly after initial learning. For example, the time window for TMR and memory control is not more than a few days, while the time for stress hormones is limited to within a few minutes to a few hours after the memory is coded (Phelps and Hofmann, 2019). However, people usually ask for help long after the event have occurred. At this time, the memory is often completely consolidated, and the success rate of editing will be greatly reduced.
Consequently, more and more research are beginning to explore editing techniques for the period of memory reconsolidation. Although the window of memory vulnerability is shorter for memory reconsolidation, it is not restricted by the time frame issue with consolidation as addressed in the previous paragraph. Reconsolidation of a memory has two adaptive functions, strengthening and renewal. Pharmacological and behavioral interventions are normally used to edit the reconsolidation of memory. At the same time, studies have shown that antagonistic agents and renewal of threatening memories and strengthening of addictive memories can reduce defense responses and addictive behaviors respectively; while renewal of episodic memory reconsolidation can modify its content or even completely destroys it (Phelps & Hofmann, 2019). In addition, similar to editing during memory consolidation, targeted reconsolidation using stress hormones can both enhance neuronal memory and damage emotional memory. These studies have shown that even after a long period of time after the initial encoding of the memory, the memory can still be edited. Although not completely erased, it can be modified to a certain extent.
Nevertheless, for targeted reconsolidation editing technology to be successfully applied under clinical settings, many issues still need to be addressed. Such issues include determining when the retrieval of memory is unstable, how the time, intensity and complexity of the memory affect the susceptibility of the memory, and how the interactions between different types of memory expression affect the success of memory editing, etc. Furthermore, because the human body lacks markers of memory instability or synaptic plasticity, whether memory editing is successful or whether memory expression is inhibited can often be difficult to verify (Phelps & Hofmann, 2019).
In summary, the selective editing of human memory is no longer just an action in sci-fi movies. Though unlike in sci-fi movies, the current memory editing technology does not completely erase the memory, but selectively modifies it. The memory editing techniques reviewed in this article have all been proven effective at the laboratory level, and some of them have also been applied to clinical in-depth research. In any case, for science fiction to become a reality, many problems remain to be solved, to enhance the clinical success rate and safety of memory editing technologies.
References
Cahill L. et al (1994). β-adrenergic activation and memory for emotional events. Nature 371, 702–704
Kandel E. et al (2014). The molecular and systems biology of memory. Cell 157, 163–186.
Phelps E. and Hofmann S. (2019). Memory editing from science fiction to clinical practice. Nature 572, 43–50.
Wood N. et al (2015). Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies.
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Imperial Bioscience Review 