I recently watched the movie Limitless, in which a destitute writer named Eddie, played by Bradley Cooper, stumbles across a life-changing pill which shifts his mind from neutral to fifth gear in a matter of minutes. The movie was entertaining and fast-paced, although not particularly memorable — given that halfway through it I realized I had already seen it before, and possibly needed a pill myself.
NOTE: Be wary of the odd spoiler.
For a neuroscientist, the film has its obligatory groaner moments — such as when the pusher who originally offers Eddie the pill explains, "You know how they say we only use 20% of our brain? Well this pill gives us access to the other 80%;" or when, at the disappointing end of the film, Eddie declares himself to have retained his extraordinary powers even after weaning himself off the drug, because his "synapses are altered;" or when, in desperate need of a re-up, he ingests a few milliliters of blood from a person who had recently taken a pill, and the dosage is miraculously sufficient! Putting these criticisms aside, however, the whole premise of the film remains intriguing simply because it poses the question: assuming this were possible, how would it be possible?
An interesting thought experiment. In what follows, I go through some of the apparent effects of the drug, imaginatively christened "NZT". Given these effects, what neurotransmitter receptors might NZT be targeting? Are the effects plausible or not? Are there real-life examples of such functionality?
Memory
Enhanced memory recall is one of the first effects described in the film, in a scene in which the Eddie is confronted with an angry landlady. To weasel out of his rent, he proceeds to impress her by recalling details from an obscure legal biography she is carrying and (amongst other services) aiding her in the completion of a law school assignment through the use of his own remote memories, which he is suddenly able to access with ease. The accompanying narration suggests that these obscure memories had always been encoded, and yet remained irretrievable (the 80% myth revisited) until unlocked by NZT.
So how plausible is this? We have all likely had the experience of recalling obscure events in our past, seemingly triggered at random. What is going on here?
The prevailing theory of episodic memory entails a process of encoding, consolidation, and recollection. Encoding is the process of converting a sequence of sensory information (an episode) into a sequence of neuronal activations, by altering synaptic weights between ensembles of neurons. The synaptic weights become the medium of persistence; when the same initial ensembles are activated by a similar sensory experience, or by some internal process, the same series of ensembles will be activated as a function of the weights connecting their neurons. The stronger the weights, the more accessible the memory. For the most part, encoding initially occurs in the hippocampus and neighbouring entorhinal cortex. These structures are known to be critical for the formation of long-term memories, as is most dramatically evident in patients who have had lesions to them; Henry Molaison (Patient H.M.) was likely the most famous of these patients, and the corresponding body of work by Brenda Milner and others has been instrumental in defining our current models of episodic memory. (While we're in the realm of pop culture, the film Memento remains for me the best Hollywood-style rendition of this phenomenon).
Consolidation refers to the process of transferring long-term episodic memories from a dependence on limbic structures to storage in other (typically cortical) brain areas. Consolidated memories no longer require the hippocampus or entorhinal cortex to be recalled; Molaison, for instance, could recall most of the events of his past (apart from those experienced within a few months of his surgery for epilepsy), and had an intact intelligence and semantic memory (i.e., memory for words, meanings, etc.). Consolidation likely occurs over a period of days to months, and entails a cycle of recall and re-encoding, a process of which we may or may not be conscious. There is much evidence that the consolidation process occurs largely during sleep, for instance. More speculatively, consolidation likely entails the ongoing incorporation of new evidence into our persistent internal predictive models of the world. As an example, suppose a child learns through experience that all soldiers are male. His first encounter with a female soldier must then be surprising and confusing. Consolidation of this episodic memory would also likely require a generalization of his internal concept of "soldier" to include both sexes.
Finally, recall refers to the process of bringing an encoded/consolidated episodic memory back into working memory, such that it can be used in a cognitive operation (such as updating one's internal model some more, setting the context for a previously-experienced encounter, etc.). Recall likely requires some sort of trigger; i.e., an activation pattern sufficiently similar to that initially evoked by the original experience, which can set the sequence of neuronal activations into action. The generator of such a trigger can be external (re-experiencing a situation, person, object, or linguistic representation), or internal (e.g., a thought process invoking a particular concept or experience). In Eddie's case, a partial view of a book cover was sufficient, with the aid of NZT, to trigger a recall of the initial event and its associated content. However, it is unlikely that such an (at the time) irrelevant experience would have ever become consolidated in the first place.
Why not? While it is likely true that events which get processed by our sensory organs will typically have some impact on our higher-level brain areas, the encoding of a memory to the extent that it can later be retrieved depends on its salience or relevance. As memory formation and maintenance requires energy and time, it is important to be able to prioritize what we encode. We (or more accurately our brains) must make judgements about the relevance of particular memories to our objectives. In the human organism, this objective might be roughly characterized as the general evolutionary rule that a function must ultimately convey some adaptive advantage for the organism. One such advantage is efficiency: it is more efficient to assign adaptive relevance to experiences, and prioritize the consolidation of memories based upon the this relevance assignment, than to encode all experiences equally, regardless of their potential utility.
There indeed does exist empirical evidence for such relevance mechanisms in memory formation. The neuromodulator norepinephrine, which gets released along with peripheral epinephrine (adrenaline) in arousing or stressful situations, has also been shown to strongly modulate long-term potentiation in the hippocampus (see my own work in the lab of Carolyn Harley, for example). Norepinephrine is a good candidate for a relevance signal, as it is released most strongly for events that are novel, unexpected, or generally salient (e.g., sexual, social, threatening, advantageous). In extreme cases, such as traumatic experiences, norepinephrine is released at high rates for a sustained period, leading to memories that are very difficult to extinguish, because each replay re-establishes a noradrenergic release, and the consolidation process becomes a sort of positive feedback cycle. Indeed, this is thought to be the basic mechanism of postraumatic stress disorder (PTSD).
So, are noradrenergic receptors a possible target of our hypothesized mystery drug, NZT? It's unlikely, at least with respect to its effect on memory recall. While animal research highlights an important role of norepinephrine in the encoding and consolidation of memory within a four-day period, retrieval of memories after this period appears to be independent of it (Murchison et al., 2004). It seems more important that norepinephrine be released during the actual event being encoded, and in the consolidation period closely following it, than during its retrieval at some distant point in the future. This makes sense in terms of its role in prioritizing the importance of remembering versus forgetting something — it is doubtful Eddie's noradrenergic system would have been terribly excited by flipping through the pages of a very dry biography of a random judge, and thus this experience would not likely be consolidated with sufficient strength to be retrieved years later.
Exceptional minds
The idea that human memory is rather limited is challenged, however, by the existence of individuals with very extraordinary memories, a capability referred to as eidic memory. One of the most famous of these was a Russian journalist named Solomon Shereshevsky, who was extensively studied by the psychologist Alexander Luria. Shereshevsky was capable of recalling long texts or random sequences and matrices of numbers with near perfect fidelity. Incredibly, he could also do this with sequences he had been exposed to years prior.
Luria proposed two mechanisms for this unprecedented ability. Firstly, Shereshevsky had five-fold synaesthesia, a condition where sensations from one modality (such as sight) activate perceptions in a different modality (such as audition). Such a blending of the senses might have afforded him additional dimensions in which to encode, and recall, memorized episodes. Secondly, he utilized a strategy called the method of loci, a well-known memory trick championed centuries earlier by the Roman statesman Cicero. The method of loci basically entails encoding sequential items (words, numbers, etc.) as particular entities organized along a spatial route, like a road or trail. That this method is so effective corresponds nicely to the theory that our episodic memory abilities actually evolved (through exaptation) from a system that was originally adapted for spatial navigation. Indeed, besides being critical for episodic memory, the hippocampus is also important for navigation.
Individuals with savant syndrome, a developmental disorder often accompanied by autism and other intellectual disabilities, have also been known to have prodigious memories. Stephen Wiltshire, pictured above, has an uncanny ability to remember minute details of cityscapes, even after observing them for a limited amount of time. The New York City drawing he is working on above, for instance, was completed after taking a 20-minute helicopter ride over the city. Wiltshire's drawings are not superficial — he captures details and proportions with near photographic accuracy.
Both savant syndrome and synaesthesia typically involve abnormal development of neural structures and their connectivity. This suggests that we are unlikely to be able to reproduce the unique abilities they confer with a pharmaceutical intervention. However, in rare cases savant-like abilities can be acquired through traumatic brain injury or severe fever. Such was the case with Franco Magnini, described by Oliver Sacks in his book An Anthropologist on Mars. Magnini lived in the Italian village of Pontito as a child, but emigrated to the U.S. with his family at a young age. As a boy, he became seriously ill and experienced fever and delirium during this episode. Subsequently, he began to have vivid dreams of his childhood home, and found that he could paint scenes of the village with astounding accuracy, despite never having returned to it. To date, Magnini has produced hundreds of such illustrations, which can be viewed on his website.
Other cases of acquired savant syndrome have given patients phenomenal musical abilities, stimulated writing, poetry, and other forms of artistic expression, and detailed memory for specific dates extending years into the past. All of these abilities, incidentally, are claimed by our protagonist Eddie in Limitless. While the specific mechanisms of their abilities remain an open question, acquired savant syndrome patients all appear to have suffered some form of irreversible brain damage. A working theory is that the loss of one brain structure can remove its inhibitory/noisy influence on another, resulting in a paradoxical increase in the capacity of the latter structure to perform its specific function. It is thus conceivable, given a hitherto-unknown pharmaceutical intervention, to mimic this effect in a transient way, by blocking or modulating the influence of the first structure in an analogous fashion. As incredible as it sounds, the idea of such an intervention is not completely implausible.
Mind-altering drugs
The use of drugs to alter or even enhance one's state of mind is not a new one. Alcohol, caffeine, and nicotine are the most obvious examples, but there exists a plethora of substances, both naturally-occurring and synthetic, that have specific and predictable effects on brain and body physiology. Cannabis, which has been used for centuries, is a common plant containing substances known to act on cannabinoid receptors, which have a number of interesting modulatory effects upon cognition, social interaction, introspection, and creativity. Many musicians have stated they use cannabis to stimulate creativity, for instance. Cocaine acts primarily by stimulating dopaminergic receptors, influencing risk/reward behaviours, motivation, aggression, and impulse control. There are numerous examples of individuals using cocaine to enhance output, however — the most famous being Sigmund Freud. Psilocybin, which is found in magic mushrooms, and mescaline, found in the peyote cactus, are hallucinogens which cause major alterations to sensory and cognitive functioning. The effects of peyote have been extensively described by Aldous Huxley in The Doors of Perception, and Carlos Castaneda in many of his writings, and include (in their descriptions) an enhanced spirituality and an increased awareness of both internal thought processes and external environments. LSD is another well-known synthetic hallucinogen, its effects described by the popular writings of Timothy Leary and Tom Wolfe.
Many other examples exist of substances that alter mental processes and have the potential to augment the functionality of our "sober" brain in ways we do not yet really understand. Most of these, to various degrees, also entail parallel impairments. Some have chronic detrimental effects on health or have been linked to neurodegeneration. These substances have been studied only to a limited extent in the world of science, largely because they are taboo or legally restricted in most countries. Cannabis research in the U.S., for example, requires an extensive approval process, involving three separate federal agencies, and is typically only permitted for studies of drug abuse. It would be exceedingly difficult to be approved for a study investigating its efficicacy for cognitive enhancement — although the legal landscape is shifting in this regard. One glaring exception to this rule was the work of Alexander Shulgin, an Russian/American biochemist who is credited with the initial synthesis of and independent research on dozens of psychoactive substances. In his research, Shulgin made heavy use of self-experimentation, and documented the various psychological and physiological effects of his substances with professional clarity.
Shulgin operated within the regulatory framework of the U.S., having obtained a DEA license for his activities, which was revoked in 1994 after he published a popular book detailing his analytic results. Nowadays, given the shifting landscape of drug regulatory frameworks, it is unlikely we will see another scientist of this nature. What we do have is pharmaceutical companies, for whom the development of cognitive enhancers, or nootropics, is an attractive potential growth market. Chief amongst these substances are the stimulants — drugs which target noradrenergic and/or dopaminergic receptors. Stimulants are designed to push cognitive activity into a more active state, enhancing attentional and motivational processes. As discussed above, these substances also have an enhancing effect on memory encoding and consolidation. Many of these drugs are taken in the absence of any medical indications, and are used frequently in competitive situations such as students competing for places in popular university programs. In this regard, they are hardly different from the performance enhancing drugs used (and stigmatized) in competitive sports. Moreover, none of these substances really comes close to the sort of true cognitive enhancement portrayed in the film, any more than human growth hormone has a role beyond increasing endurance in cycling competitions.
Synopsis
Limitless is obviously a science fiction film, and doesn't pretend to make any claims about the scientific feasibility of the drug NZT which plays the starring role alongside Bradley Cooper. Nonetheless, the evidence we have from existing examples of both exceptional minds and mind-altering substances suggests that such enhancement could be in theory possible, at least in some limited form. This is not to make any judgement as to whether such a drug would be desirable, which is a tricky sociopolitical question. In any case, given the sometimes exhausting pace at which we humans are discovering things, I wouldn't be surprised to see such compounds emerge within my lifetime. Until then, I'll stick with my coffee.
