Brain-damaged man awakes from the unconscious after being given sleeping pill!
At first this may seem like too outlandish a claim or just simply clickbait. But what if I told you there was more truth to this than you may expect? Let’s dive into the world of damaged brains, altered states of consciousness and drugs to find out!
In the 90’s a South African man, Louie, gets into a car accident, suffers major brain damage and is left with what is called ‘unresponsive wakefulness syndrome’ (UWS). This meant that while he was technically awake during the day and had reflexes like someone healthy, he was not actually aware of himself or his surroundings and would be lying in bed all day, basically as if in a coma. So he was technically awake and able to for example breathe, blink and chew (reflexive behaviours), but unable to interact with the people around him in a meaningful way.
UWS was formerly known as ‘vegetative state’ (but I bet you can think of the reason why this was changed). It is qualified as a disorder of consciousness, along with for example coma, and is often the result of a traumatic injury to the brain. Typically, brain stem functions are preserved, luckily making it possible for the patient to for example reflexively keep breathing. More complex functions, such as speaking or understanding speech, however, don’t seem to work reliably anymore, making the patient literally unresponsive.
Consciousness in a scientific way is often defined as being awake, while also being aware of yourself and your surroundings. So for example you being able to read and understand this text right now already is a good indication that you are conscious; you are not sleeping and you are processing the language shown on your screen. So when we apply this to UWS, we could probably qualify them as unconscious, since they can be awake, but not reliably aware of what is happening around them. At least it is fair to say that these patients live in a strongly reduced state of consciousness.
So let’s get back to Louie: One day, about 3 years after his injury, his mother decides to feed him Ambien, a common type of sleeping pill, in order to treat an involuntary spasm in his arm. However, unexpectedly, Louie actually seemed to regain consciousness and spoke to his mother for the first time in years. Pretty crazy, isn’t it? So how can this paradoxical effect be explained then? One potential explanation to this is what is called the ‘mesocircuit hypothesis’. Essentially, in a healthy brain the basal ganglia, the thalamus and the cortex are interconnected with a feedback loop going from the striatum to the pallidum (both are part of the basal ganglia), and from there to the thalamus, which relays signals to the cortex, which in turn activates the striatum again. The major role of the pallidum is to inhibit the thalamus, and the pallidum in turn is inhibited by the striatum (red arrows below).
Now the idea goes that due to brain damage, some connections become cut or otherwise inactive, and the striatum is less activated than before. Think about what this may mean for the feedback loop …
When the striatum gets less activating input, it cannot inhibit the pallidum as much anymore. This in turn increases the inhibition from the pallidum to the thalamus dramatically (thick red arrow), which then hinders the communication between thalamus and cortex. This also seems to stop people in this condition to consciously experience the world around them. So this loop, especially the interaction between thalamus and cortex, seems to be highly important for impressions from our senses reaching our conscious perception.
Ambien works by increasing the availability of GABA, the major inhibitory neurotransmitter, in certain regions of the brain. Typically, this has a sedative, sleep-inducing effect. But according to the mesocircuit hypothesis, when Ambien (also called Zolpidem) is given, this majorly inhibits the pallidum (via GABA like we said), helping the striatum to do the job it can’t do anymore. Like this, the thalamus is again only mildly inhibited and can send signals to the cortex more effectively again, leading to patients ‘waking up’ or rather becoming aware of their surroundings on the drug.
Other studies support this hypothesis; using e.g. positron emission tomography they show that Ambien apparently interacts with the mesocircuit, which is often linked to motivation, to restore movements and cognitive functions. There is one big caveat, however: Ambien only is effective for about 7% of UWS patients, probably due to genetic differences in individual GABA receptor types.
So to summarise, Ambien can be an amazing, counterintuitive way to bridge symptoms of UWS if they happen to work for the patient, plus it grants us more insight into the workings of injured brains.
Author: Melanie Smekal
Image created using DALL-E-2 open AI software