A year into my doctoral training at UCLA, I escape the noisy hustle and bustle of Ronald Reagan Hospital at midday, into a clean and quiet room in the Intensive Care Unit (ICU). Alone, at last. Or am I? Indeed, tasked with assessing the apparently comatose patient who lies before me, that is exactly what I am there to determine. Behavioral assessment of patients recovering from severe brain injury is a subtle art that may take years to master. The degree of residual consciousness behind a patient’s eyes — sometimes wide open, sometimes permanently closed — may be obscured by impaired movement, blindness, deafness, or any number of specific impairments. A consistent wiggle of a finger, blinking at the right time, or a faint utterance can reveal a very real and potentially rich internal life. Disturbingly, the rate of misdiagnosis due to uncareful behavioral assessment is strikingly common. Moreover, even the most experienced observer might fail to detect consciousness in patients whose injuries sever motor pathways and prevent movement entirely. Recent advances in neuroimaging have revealed that perhaps 10-30% of patients who remain completely unresponsive months after injury are covertly conscious, a nightmarish condition known as locked-in-syndrome.
With the difficulties of behavioral assessment in mind, I methodically begin the ritual with my patient, Christopher (name changed). I clap loudly and abruptly just behind the patient’s head. His eyes lightly flutter, telling me that some auditory processing remains functional. Once I have a feel for the patient, I progress to more complex behaviors. I loudly command: “Christopher, raise your left leg!!”
I wait 10 seconds. Nothing. I smile and wave at a nurse through the ICU window who is curious why I am screaming at her patient. “Chris, raise your left leg!!” Three seconds pass and Christopher’s left leg moves… ever so slightly. “Higher!!” The leg is still. Well, that could have been chance, I think. Patients often reflexively shift and tense up to noise. “Again, Chris, raise your left leg!!” It raises slightly then drops. With laser focus on the leg, I exclaim again: “One more time, Chris, raise your left leg!!” It raises slightly. “Higher!!” The leg raises a full six inches above the hospital bed and then, exhausted, drops. I am no longer alone.
I had assessed Christopher before, but I had never seen him respond to a command like this. This striking change in responsiveness was particularly important as it came a day after Christopher had received an experimental new treatment for the symptoms of disorders of consciousness (DOC). DOC describes a host of conditions including a coma, the vegetative state and the minimally conscious state (a state where patients have consciousness, though it is perhaps altered or reduced). The new treatment is known as Thalamic Low Intensity Focused Ultrasound Pulsation, or Thalamic LIFUP — the brainchild of coma-science duo Martin M. Monti and Caroline Schnakers. Like most who study DOC, our work is a mixture of basic science and the application of that science to new clinical treatments. This is critical because, as it stands, there are no satisfactory treatments to promote recovery in hundred of thousands of these patients (3, 4) who may require intensive life-long care. In recent decades, the science of DOC has exploded with the rest of neuroscience; yet novel treatments for patients have not necessarily followed. LIFUP, with its unique ability to precisely target structures anywhere in the brain without surgery, may help us apply the bettering science to the treatment of these devastating DOC conditions.
“LIFUP may help us apply the bettering science to the treatment of these devastating DOC conditions”
What is LIFUP?
The “U” in “LIFUP” — ultrasound— is the same high frequency sound that has been used since the 1950’s in medical imaging and was probably used to take a first picture in the womb.While ultrasound imaging is a household concept, most aren’t aware that the same ultrasound can be a neuromodulator — in other words, passing ultrasound through neural tissue can increase or decrease the activity of the neurons within it. Exactly how neuromodulation with ultrasound works remains unclear, but it likely results from the physical “shaking” of neurons by ultrasonic sound waves. This shaking may physically pull open ion channels or create small bubbles which can alter the electrical properties of neuronal membranes. While it remains debated exactly how LIFUP works as a neuromodulator, that it can work is no longer debated. LIFUP has been used to, for instance, elicit paw kicks in rats when aimed at the motor cortex, change the cognitive performance of macaques performing cognitive tasks when aimed at the frontal lobe, and hasten recovery from anesthesia in rats when aimed at the thalamus. In the last five years, a resurgence in LIFUP research has seen it used in humans. For instance, Korean groups have used LIFUP to elicit visual and tactile hallucinations (7,8), while researchers at the Medical University of South Carolina have used thalamic LIFUP to reduce pain in healthy humans 9.
“Exactly how neuromodulation with ultrasound works remains unclear, but it likely results from the physical “shaking” of neurons by ultrasonic sound waves”
A principal difference between ultrasound imaging and LIFUP is that the ultrasound in LIFUP is applied to a highly select brain region. Think of how a magnifying glass can focus sunlight in a cone to heat a small area. Similarly, focusing ultrasound can change neural activity in only a small region without significantly affecting adjacent tissue — in some cases, even just millimeters away. This precision is a step above other, more established, neuromodulating technologies, such as transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). These older techniques, at best, have a precision of several centimeters. Importantly, LIFUP can also be focused onto very deep brain structures, far from the effective range of both TMS and TES. These are the reasons why the Monti Lab at UCLA chose to use LIFUP in DOC in its very first clinical use: the precision and deep-targeting ability of this technology are perfect for manipulating the small deep-brain nuclei that are consistently associated with DOC.
Why the Thalamus?
If you place a finger just above your ear, such that it is pointing into the center of your skull, you are aiming at your thalamus. The thalamus is a midline structure about the size and shape of your two thumbs placed next to each other, which itself is comprised of a myriad of smaller nuclei. Though once a somewhat ignored structure, cognitive neuroscience of the last two decades has suggested that the physical centrality of the thalamus in the brain is mirrored by its central role in regulating both arousal and cognition. The thalamus receives massive inputs from the arousal regulating structures of the brainstem, midbrain, as well as basal forebrain, and likely plays a role in distributing their signals throughout the rest of the brain to selectively engage select regions. Moreover, it may organize communication in the cortex, selecting which cortical regions participate in the large-scale networks that form during complex cognitive tasks like mental math.
“The thalamus is a midline structure about the size and shape of your two thumbs placed next to each other, which itself is comprised of a myriad of smaller nuclei”
Given the thalamus’ role in arousal and cognitive functioning, it is unsurprising that damage to this structure is associated with DOC, in which both capacities are often impaired. MRI analysis of DOC patients show that thalamic damage is greater in less-responsive DOC patients as well as those that recover more slowly (or not at all) 11. Findings like this have been used to suggest that damage to the thalamus in DOC could reduce arousal in the cortex and disallow for the formation of large-scale cortical networks — thus preventing consciousness, which seems to require both. It is the hope of our group that LIFUP stimulation of this crucial structure may help restore proper cortical functioning in DOC and promote recovery in some patients. This idea is not new. Direct deep brain stimulation (DBS) of the central thalamus using metal electrodes — a more classic approach — has been shown to wake macaque monkeys from anesthesia and has compellingly induced recovery in one minimally conscious patient (12,13). However, the risks inherent to the surgery used to implant DBS electrodes are too great for many of the DOC patients awaiting new treatment options. It is our hope to use the emerging technology of LIFUP to stimulate the central thalamus without ever having to pick up a scalpel.
Results and Future Directions
So far, the results are provocative. While the practical difficulties of working with DOC patients has made a large, controlled study difficult at this time, many of the patients we have enrolled have recovered at remarkable rates that we wouldn’t expect from chance alone. These findings are perhaps most compelling in our “chronic” DOC patients, who have persisted in a state of DOC for over a year and are thus very unlikely to recover spontaneously in the weeks that we closely observe them. Strikingly, the first of these chronic patients who received thalamic LIFUP demonstrated for the first time, the ability to communicate accurately using a yes/no system. This means, according to clinical guidelines, this means he had emerged from his disorder of consciousness. Unfortunately, this patient eventually did regress back to a DOC. However, even this temporary emergence was precious to those who knew him — the wife of this patient remarking that, “This was the first time in over a year that I was able to talk to my husband.”
Results like these suggest that thalamic LIFUP may eventually be seen as an effective treatment for some DOC patients and one that does not require surgery — a flexible and low-risk new treatment for these patients who desperately need one.
Written by Joshua Cain. Illustrated by Sumana Shreshta.
Edited by Rajamani Selvam, Nerissa Culi and Alexa Erdogan.
Do you know anyone that suffers from DOC? Tell us more in the comments below.
Learn more about the use of brain stimulation in disorders of consciousness in this recent interview to Martin Monti at UCLA .
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- Schnakers, C. et al.Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensus versus standardized neurobehavioral assessment. BMC Neurology9, 35 (2009).
- Monti, M. M. et al.Willful Modulation of Brain Activity in Disorders of Consciousness. New England Journal of Medicine362, 579–589 (2010).
- Schnakers, C. & Monti, M. M. Disorders of consciousness after severe brain injury: therapeutic options. Current Opinion in Neurology30, 573–579 (2017).
- Pisa, F. E., Biasutti, E., Drigo, D. & Barbone, F. The prevalence of vegetative and minimally conscious states: a systematic review and methodological appraisal. J Head Trauma Rehabil29, E23-30 (2014).
- Blackmore, J., Shrivastava, S., Sallet, J., Butler, C. R. & Cleveland, R. O. Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety. Ultrasound in Medicine & Biology45, 1509–1536 (2019).
- Bystritsky, A. & Korb, A. S. A Review of Low-Intensity Transcranial Focused Ultrasound for Clinical Applications. Curr Behav Neurosci Rep2, 60–66 (2015).
- Lee, W. et al.Transcranial focused ultrasound stimulation of human primary visual cortex. Scientific Reports6, 34026 (2016).
- Lee, W. et al.Image-Guided Transcranial Focused Ultrasound Stimulates Human Primary Somatosensory Cortex. Sci Rep5, (2015).
- Badran, B. W. et al.Sonication of the Anterior Thalamus with MRI-Guided Low Intensity Focused Ultrasound Pulsation (LIFUP) Changes Pain Thresholds in Healthy Adults: A Double-Blind, Concurrent LIFUP/MRI Study. http://medrxiv.org/lookup/doi/10.1101/2020.04.08.20042853 (2020) doi:10.1101/2020.04.08.20042853.
- Lutkenhoff, E. S. et al.Thalamic atrophy in antero-medial and dorsal nuclei correlates with six-month outcome after severe brain injury. Neuroimage Clin3, 396–404 (2013).
- Lutkenhoff, E. S. et al.Thalamic and extrathalamic mechanisms of consciousness after severe brain injury. Annals of Neurology78, 68–76 (2015).
- Schiff, N. D. Central thalamic contributions to arousal regulation and neurological disorders of consciousness. Ann. N. Y. Acad. Sci.1129, 105–118 (2008).
- Redinbaugh, M. J. et al.Central thalamus modulates consciousness by controlling layer-specific cortical interactions. bioRxiv776591 (2019) doi:10.1101/776591.
- Monti, M. M., Schnakers, C., Korb, A. S., Bystritsky, A. & Vespa, P. M. Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. Brain Stimulation9, 940–941 (2016).