• BrainSightAI Team

TBI: What does it mean to be conscious?

Authors: Laina Emmanuel, Tanvi Sheth

On a fateful day in 1984, Terry Wallis met with a major automobile accident, which rendered him comatose. Doctors pronounced that the accident would unfortunately leave him a quadriplegic, and they believed that due to his brain injury, he would remain in an unconscious state forever.

However, 19 years later, Terry spoke. First, he said “Mama,” in response to a nurse asking him who the other woman in the room was (it was indeed his mother). His second word was “Pepsi.” The relevance of these two words lies in the neurological significance they hold. The words were evidence supporting the fact that Terry was not in a vegetative state, but in a minimally conscious state for all those years (Fins, 2015; Fins, Schiff & Foley, 2007). In this blog we discuss the findings of Dr. Fins on Terry’s progress from an essay he wrote in 2015 on the journey of the diagnosis of a Minimally Conscious State and the advancements brought about by new brain imaging technology in furthering treatment for the same.

Neurological Significance

A major milestone that was achieved due to the Wallis case was the inclusion of the Minimally Conscious State (MCS) in colloquial medical lexicon. The minimally conscious state is defined as severely altered consciousness in which minimal but definite, sustained and/or reproducible behavioral evidence of alertness (wakefulness) and awareness of self or environment is demonstrated (Giancino et al, 2002). Following the recognition of such a state, efforts by researchers to gain deeper insights about this disorder of consciousness began (Fins, 2011).

In 2006, researchers used Diffusion Tensor Imaging (DTI) to study Terry’s brain and understand how he had regained reliable expressive language. The study demonstrated axonal sproutings, or novel anatomical structures, which had been growing over the years. These pathways re-established functional connections which Dr. Fins posits were possibly the neurobiological basis of Terry’s first words in almost two decades (Voss, Schiff et al, 2006).

Dr. Fins goes on to say that Terry’s is not an isolated case. He cites a study by Schnakers et al (2009) that showed that 41 per cent of ‘vegetative’ patients with traumatic brain injury in nursing homes are in fact minimally conscious – they appear vegetative but retain awareness of their environment and sometimes even respond. They are however unable to demonstrate their awareness.

This potential of re-emergence of complete consciousness and possible neurological aid made us think of the possibilities of using VoxelBox, a multi-modal platform, using DTI and rs-fMRI, to understand minimally conscious state and differentiate it from the vegetative state in patients with traumatic brain injury.

The role of cortical networks in TBI

The problems faced by patients in MCS lie on a spectrum, ranging from consciousness to cognition to communication. However, the common understanding is that MCS patients are aware of themselves, others, and their surroundings. Unlike vegetative state patients, MCS patients are conscious, but do not always show that they are. The rarity of behavioural demonstrations in MCS point to a dramatically different neurobiology in their brains (Fins, 2015).

Edlow (2013) in previous research proposed that traumatic coma may be a subcortical disconnection syndrome as a result of disconnection of certain brainstem arousal nuclei from the thalamus and basal forebrain.

The argument of the connectomic analysis and targeted therapy paper by Edlow et al (2020) (which will be elaborated upon in the next section) is that consciousness is no longer tied down to any single node or connection, but is seen as a function of multiple brain networks requiring dynamic interactions. One such cortical “awareness pathway” is the Ascending Arousal Network (AAN), and subcortical injuries to this pathway have been conceptually and clinically proved to be a source of coma (Snider et al, 2019).

However, Edlow et al (2020) say that in animals and humans, with coma caused by severe TBI, some parts of the AAN may be spared, and not all AAN nuclei are lesioned and axons are disconnected. The paper cites both histopathological and MRI studies which reveal that the ventral midbrain, which is home to the dopaminergic (please refer to this blog to learn more about dopaminergic pathways) ventral tegmental area (VTA), is heterogeneously injured by severe TBI, but remains partially intact in some patients. This phenomenon pertains not only to VTA neuronal cell bodies in the midbrain, but also to VTA axons that connect with the diencephalon, basal forebrain, and cortex. Consistent with these observations, the paper further cites nuclear imaging studies that show that signal transmission in dopaminergic circuits is variably altered by severe TBI. Based on these converging lines of evidence, a hypothesis was generated that preserved VTA connections are a potential target for therapeutic modulation in ICU patients with severe TBI.

Personalized Connectome Mapping in the ICU Reveals Preserved Ventral Tegmental Area (VTA) Connections. (Source: Edlow et al., 2020)

Pharmacodynamic intervention

There are currently no evidence-based therapies that promote early recovery of consciousness in patients with brain injuries who are in a vegetative or minimally conscious state. In Terry Wallis' case, his brain was demonstrating evidence of recovery a few years before he regained wakefulness. It is possible that his recovery might have been hastened with some sort of rehabilitation (Fins, 2015). Traumatic brain injury treatments that aim to promote early recovery of consciousness would benefit patients, their families, and doctors by reducing the likelihood of premature withdrawal of life supporting therapies (Edlow et al, 2020).

While mulling over questions related to such rehabilitation, especially those that can be aided by neuroimaging techniques like fMRI and DTI, we came across a paper on Personalized Connectome Mapping, that talks about and tests a new paradigm to promote recovery of consciousness while in the ICU. It introduces the concept of a Connectome-based Clinical Trial Platform, that is based on two innovative mechanisms - first, predictive biomarkers to enroll patients in clinical trials based on connectomes that can be targeted by new therapies; and second, pharmacodynamic biomarkers to measure how targeted therapies modulate networks, reactivate the cerebral cortex and restore consciousness. The scientific premise of this research is that personalized brain network mapping in the ICU can help identify patients whose connectomes are amenable to neuromodulation (Edlow et al, 2020).

Clinical Design and Testing

The paper is based on the premise that for a patient to recover consciousness, the subcortical AAN which modulates wakefulness, must reconnect with the default mode network (DMN) and other cortical networks that mediate awareness. Functional connectivity studies, again cited in the paper, have shown that the VTA activates the DMN via the AAN. To activate the structurally intact, functionally dormant dopaminergic VTA circuits in ICU patients with severe TBI, intravenous methylphenidate (IV MPH) has been shown to be useful. A CCTP-based trial, STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), is used to demonstrate feasibility and utility.

To identify patients with preserved VTA connections, they map the structural AAN connectome on a clinical MRI scanner. To map specific axonal connectivity, high angular resolution diffusion imaging (HARDI) tractography, an MRI technique that maps axonal connectivity based on directional water diffusion, was used. They then use a graph theoretical measure – VTA Hub Strength – as a predictive biomarker for the trial so as to measure both monosynaptic and polysynaptic VTA connections.

The preservation of VTA connections within the AAN connectome predicts a functional connectivity between the VTA and DMN that acts as a pharmacodynamic biomarker to determine the neurobiological effects of IV MPH in patients with severe TBI who have slipped into a comatose state. The research proposes that for patients with preserved VTA connections, IV MPH will reconnect the cerebral cortex, accelerate reemergence of consciousness, and transform the course of their recovery (Edlow et al, 2020).

Scope for TBI recovery

The goal of the CCTP is to provide clinicians with a toolkit of targeted therapies that promote recovery of consciousness in patients on the spectrum of disorders of consciousness. Based on the study, Edlow et al (2020) put forward the suggestion of having multidisciplinary discussions about optimal treatment selection at a Coma Board, similar to the Tumor Board where therapeutic decisions are made by a multidisciplinary team for patients with cancer.

For families of patients and doctors who are bound by the time-sensitive and possibly fatal nature of TBI, it becomes important to assess methods of rehabilitation that can speed up the process of recovery. Dr. Fins (2015) says that such a process may be similar to what occurs in a maturing brain. The developmental process of forming connections between areas of the brain via axonal sprouting is also seen in the service of brain repair. Therefore, techniques like the CCTP which test targeted pharmacological and electrophysiological therapies that reactivate the injured human connectome can serve to improve outcomes for patients like Terry Wallis much faster and with evidence-based tools.

To make use of such innovations with our product, the multi-modal VoxelBox, seems like an exciting avenue. If you are interested in questions like this and would like to collaborate with us please contact us at collaborations@brainsightai.com.



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