The Search for a Cure for Coma

We have made almost no progress in finding a cure for coma for three thousand years. 

By the second millennium BCE, healers in Ancient Mesopotamia were already well-versed in the prognosis and symptoms of coma, yet medicine to wake up coma patients eluded them. In trying to understand this phenomenon, they looked not to the brain (believing it to be merely bone marrow), but instead attributed coma to a supernatural entity named alû: “If something like a stupor continually afflicts [the patient] and his limbs are tense,” dictated one Ancient Mesopotamian medical text, “and his mouth is ‘seized’ so that he cannot talk – hand of an evil alû.” The Ancient Mesopotamians discerned that after one to two weeks, patients in a coma typically either opened their eyes or succumbed to the inevitable: “If he has been sick for 6 days and he does not get a respite on the seventh, they throw water on his face and he does not open his eyes – he will die. If he opens and closes his eyes at the water they throw over him and wails – he will recover.”

Yet, tragically, not all who open their eyes after a coma recover awareness.

This painful truth was not lost on the Ancient Mesopotamians: “My body has donned an alû-demon as one would a garment,” laments the narrator of Ludlul bēl nēmeqi, or The Righteous Sufferer, a haunting poem composed around 1300 BCE. “He covered me with sleep as with a net. My eyes stare but do not see; my ears are open but do not hear. Numbness has gripped my whole body, paralysis has fallen upon my flesh…. I cannot answer the one who questions me.” This phenomenon was observed not only by the Mesopotamians, but also by the ancient Indians: the Caraka-Saṃhitā, a medical text written in India by the physician Charaka around the first century CE (and based on a text from the eighth century BCE), recommended specific treatments for patients who open their eyes from a coma but do not fully regain awareness. The minds of such patients, according to the text’s 24th sūtra, “must be protected from the cause of annihilation” through stimulating therapies such as engaging conversation, music, and the recollection of surprising events.

Yet, for thousands of years, we made little further progress in understanding or finding a cure for coma. 

Verses 42-53 of the Caraka-Saṁhitā, composed in India in the 1st century CE, describing coma and its treatment

In fact, it was not until the second half of the nineteenth century that we saw the first glimmers of change. A series of experiments began to connect the dots between physical pressure on the brain on the one hand, and coma and its multitude of symptoms on the other. Yet, as some pioneering neurologists noted, this could not explain why a stroke or a small brain hemorrhage could also lead to coma. What was the elusive common denominator? Building upon emerging evidence that the cortex is the brain’s principal conductor of consciousness, the neurologist William Richard Gowers postulated in 1888 that all these triggers – brain trauma, hemorrhages, and stroke – must cause sudden interruptions in the cortex’s performance. His theory was prescient, but subsequent discoveries would reveal that the cortex was just one piece of a much larger, more complex puzzle.

The late 1940s witnessed a monumental leap in our understanding of consciousness and its disorders. The neuroscientists Horace Winchell Magoun and Giuseppe Moruzzi turned their attention toward the brainstem reticular formation, a region of the brain that had until then been largely overlooked. Their experiments revealed that electrically stimulating the brainstem reticular formation could produce waking-like brainwaves even under the shroud of anesthesia. Essentially, what they had discovered was the key player of the brain’s “wakefulness” system, now known as the reticular activating system. This breakthrough was crucial to our current understanding of consciousness: conscious thoughts and perceptions are one major dimension of consciousness (and are governed mostly by the cortex), while wakefulness and arousal are another major dimension of consciousness (and are governed mostly by the reticular activating system).

This dichotomy between wakefulness and awareness was pivotal in recognizing that coma is but one of several disorders of consciousness.

There were already hints of this recognition thousands of years ago: both ancient Mesopotamian and Indian physicians seemed to have recognized that not all patients who regain wakefulness after a coma also regain awareness. And, in the 1970s, the neurologists Bryan Jennett and Fred Plum argued that patients who wake up from a coma but do not recover awareness should be diagnosed with a distinct disorder of consciousness. They dubbed this condition the “persistent vegetative state,” now also referred to as “unresponsive wakefulness syndrome.” This disorder is what is commonly misunderstood as a prolonged “coma.” Patients in this state are not in a coma; rather, they have transitioned into unresponsive wakefulness, and they can remain in this state indefinitely. Their “eyes stare but do not see,” to quote the ancient Mesopotamian poem The Righteous Sufferer. They sleep and wake, breathe independently, and their hearts beat unaided. They even display basic reflexes, such as blinking or startling. All of these are telltale signs of a partially or fully functioning brainstem. Yet, they remain locked in unawareness – a testimony to an irreversibly damaged cortex (or inputs to the cortex).

Further research revealed the existence of yet other consciousness disorders. Early in the 2000s, neurologists formally recognized the minimally conscious state as a separate disorder of consciousness. Patients in this state, much like those in the vegetative or unresponsive state, awake from a coma, but only partially reclaim awareness and responsiveness. This state may have also been known to some physicians long ago: it is possible that Charaka, the ancient Indian physician who wrote the Caraka-Saṃhitā, recognized the minimally conscious state when he advised that a patient awakened from a coma with only partial awareness should be stimulated so as to protect their mind “from the cause of annihilation” (indeed, such sensory stimulation does in fact hold promise for patients in this state, as demonstrated by my colleagues Dr. Martin Monti and Dr. Caroline Schnakers and their team in a paper on disorders of consciousness rehabilitation). The partial restoration of awareness in the minimally conscious state likely stems from a partial recovery of activity in the cortex (or, again, inputs to the cortex).

Where different brain states lie along the dimensions of wakefulness versus awareness (from here)

Yet, despite these significant strides in understanding disorders of consciousness, most existing treatments for these conditions were discovered entirely by accident. 

Perhaps the most successful treatment for these disorders – which isn’t saying much – was discovered by chance by Japanese physicians in the 1980s. At the start of the decade, a Japanese woman was admitted to Ehime University Hospital due to her worsening Parkinson’s disease. Shortly after, she slipped into a coma, eventually transitioning into a persistent vegetative state – her eyes open but her mind completely absent. She remained in this state, unchanging, for three more years. Then, in 1984, her physicians increased the dosage of one of her Parkinson’s medications, amantadine. After a consistent regimen of this higher dose, “her eyes met with an attending physicians’ eyes” for the first time in years, as her doctors later reported. Her condition steadily improved, until amantadine was withdrawn and she slipped back into unawareness. Although she experienced occasional periods of regained awareness with further rounds of amantadine, she passed away suddenly in 1986 from respiratory failure. But her case, it turned out, was not an aberration: similar results with amantadine were later reported around the world, and in 2012 it became the first drug proven in a full-blown, placebo-controlled clinical trial to hasten recovery from disorders of consciousness, if only moderately.

Since then, other medications have been found to very occasionally aid these patients, almost all discovered by chance. Perhaps the most surprising of these is zolpidem (brand name Ambien), a drug designed to induce sleep! In 1999, doctors in South Africa prescribed zolpidem to a patient who had suffered from unresponsive wakefulness syndrome (or perhaps a minimally conscious state) for three years. The doctors’ only aim was to quell the patient’s severe restlessness. Astoundingly, the man awakened 15 minutes later and “greeted his mother for the first time in 3 years,” according to the doctors’ case report. But, as the drug’s effects faded, the man slid back into unconsciousness. However, the following morning, the doctors administered zolpidem again, and the same astonishing event unfolded: the man regained awareness and was able to answer simple questions, do basic math, and even feed himself. Since this occurrence, doctors globally have reported similar results in a very small number of these patients for whom zolpidem, a sedative, paradoxically reignites the mind.

These sporadic success stories underscore how much we have yet to learn about these conditions and their treatment. Today, many scientists, including myself, are striving to weave these disparate findings into a cohesive understanding of consciousness disorders, in the hopes of developing more effective treatments. There are many promising avenues, most of them speculative. One I am particularly excited about is non-invasive stimulation of key parts of our brain using ultrasound—an approach being spearheaded by my collaborators Dr. Martin Monti and Dr. Caroline Schnakers.

But, as is often the case, the bottleneck to scientific and medical progress is funding. While funding agencies generously support research into traumatic brain injury, we know that physical trauma is just one of many potential causes of consciousness disorders. It is significantly more challenging to secure funding to study coma resulting from oxygen deprivation, for example. If we aspire to advance our understanding and treatment of these disorders, we need more funding agencies to recognize that prolonged loss of consciousness is a medical phenomenon worthy of specialized research in its own right – and not merely an unfortunate side effect of injury, stroke, oxygen deprivation, or low blood sugar. Until we reach such recognition – and the funding opportunities that come with it – progress in restoring fractured consciousness will remain, as it has been for so long, haphazard and halting.

You have a role to play in this too. Consider donating to foundations such as the Brain Injury Association of America, which supports research into disorders of consciousness. But spreading awareness helps too, as wide-scale recognition of a medical condition is the first step toward focusing funding for research into that condition. So, if I may ask, consider sharing this post – doing so might help us, if only indirectly and in the long run, find cures for patients whose minds are trapped in oblivion.

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