Tuesday, August 26, 2014

Recovery from Coma?

While the number of individuals suffering from long-term unconscious events (comas and coma similar states) is proportionally small relative to the population, the family members and friends of those in comas frequently suffer from significantly negative financial and psychological effects. One of the more prevalent negative effects is the uncertainty associated with comas. Patients and their loved ones can deal with most diseases and similar conditions because they know the cause, the available treatment options and how long to expect before recovery, if recovery is possible; unfortunately these elements are lacking for those in a coma. In addition most people tend to be optimistic and the idea that a person they care about will never regain consciousness is a significant psychological burden as well as a financial one due to resources required for care. Developing a treatment to increase the probability that one recovers from a coma will not produce the overall medical benefits of a cancer or Alzheimer’s cure, but it will produce a treatment for another serious condition that is sufficiently prevalent.

The classic definition of a coma is an individual who exhibits a complete absence of wakefulness and is unable to consciously feel, speak, hear, or move. Traditionally it is believed that consciousness is maintained through two separate components: the cerebral cortex and the reticular activating system (RAS).1 The cerebral cortex is the outermost layer covering the cerebrum and plays a key role in numerous functions including memory, attention, awareness, language, thought and consciousness. RAS is located within the brainstem in a tight association with the reticular formation (RF) and is composed of two tracts, the ascending and descending tract. The ascending tract is principally comprised of acetylcholine-producing neurons, which focus on arousal sending neuronal signals through the RF, then the thalamus and finally the cerebral cortex. The descending tract feeds into the reticulospinal tract, which acts on motor neurons mainly influencing movement and postural control. Basically RAS coordinates the arousal signal and the cerebral cortex acts upon it.

However, on a biological level simply defining unconsciousness, and indirectly a coma, as “the absence of consciousness” does little to facilitate a treatment. There are different gradients of unconsciousness between blows to the head, focal deficits (blindsight), epilepsy, chloroform and other chemical exposure (like anesthesia) and comas/vegetative states.2 Some believe that comas are an emergency response by the body to brain injury to create a better therapeutic environment for self-recovery. Within the context of this theory any damage that is not permanent should eventually be repaired and increase the probability of a return of consciousness.

The general biological methodology of a coma is that a form of injury damages or kills a certain number of neurons, which reduces their ability to send action potentials to other neurons within the range of their synapse. Without consistent action potential activation the otherwise healthy neurons that previously bound neurotransmitters released from these damaged neurons down-regulate their dendritic and post-synaptic receptors limiting their ability to produce action potentials creating a negative feedback across entire networks of neurons. Natural recovery is thought to occur as the damaged neurons repair themselves and once again start sending action potentials (remember that these neurons are essential for consciousness, so consistent action potential generation is the norm) causing adjacent neurons to up-regulate their receptors “rebooting” the previously lost network. The problem, even if this belief is correct, is that there is no timeline for identifying when that recovery will be completed.

In order to achieve an accurate and consistent assessment of the possibility an individual will regain consciousness from an unconscious state (i.e. maximize treatment expectations) each general stage of unconsciousness must be identified. Consciousness itself is divided into two main features: arousal and awareness with arousal incorporating wakefulness and awareness incorporating acknowledgement of environment and oneself.3,4 Note that arousal is a necessary condition for awareness. For the purpose of this discussion four states will be identified: coma, vegetative state, minimum conscious state (MCS) and locked-in syndrome. Brain death is not considered because there is no reasonable and consistent path to recovery.

A coma is principally defined as the absence of arousal, thus also the lack of awareness and the lack of consciousness. In a coma the patient is unresponsive unable to open his/her eyes. Stimulation does not produce spontaneous periods of arousal.3 A coma requires at least one hour of arousal absence to separate it from concussion or syncope (fainting). Fortunately most individuals tend to move beyond a coma state into either a vegetative state or MCS, but after this progression further advancement is less certain.

A vegetative state is defined as sporadic, yet existing arousal with a complete lack of awareness. The term “vegetative” is typically defined as “living merely a physical life devoid of intellectual activity or social intercourse”.5 This state can be acute, persistent or permanent where a persistent vegetative state is one that is prolonged for at least 1 month after brain damage be it acute traumatic or non-traumatic.6 Not surprisingly permanent vegetative states are believed to be irreversible and require at least 3 months after a non-traumatic brain injury or 12 months after a traumatic one for such classification.

A MCS was created as a form of middle ground between full consciousness and a vegetative state, thus it is defined as an individual who has consistent arousal, but inconsistent awareness. Inconsistent awareness is defined as the temporary ability to follow simple commands, gesture or verbally reply “yes or no”, engage in intelligible speech, or produce purposeful behavior.3 Not surprisingly individuals in a MCS have a much higher probability of returning to full consciousness versus individuals in a vegetative state.

Finally locked-in syndrome is defined through sustained arousal and eye opening with awareness of the environment, but the inability to verbally communicate that awareness due to a form of muscle paralysis. Usually communication with other parties is limited to blinking or rarely appendage movements. Typically locked-in syndrome, unlike vegetative states and MCS, originate from neurological damage to the lower portion of the brain versus upper portions of the brain.3 For example one common method of occurrence is derived from quadriplegia and anarthria due to the disruption of corticospinal and corticobulbar pathways.7 Fortunately locked-in syndrome is easy to diagnose, but there is no real treatment.

Initial assessment of the type of lack of consciousness involves the observation of spontaneous exhibited actions as well as responses to vocal and painful stimuli commonly known as AVPU (alert, vocal stimuli, painful stimuli and unresponsive) scale. However, distinguishing between vegetative and a MCS is the real importance of coma evaluation because it is the difference between these two states that largely determines whether or not one should expect the patient to recover using current treatments. Unfortunately, but not surprisingly, these specific elements of voluntary and reactionary behavior can be easily missed or inappropriately linked or dismissed to consciousness making differentiation between different states tricky. Some previously studies indicate that 37-43% of patients diagnosed with the vegetative state later manifested goal-directed behaviors that could be interpreted as a MCS state.8-10

The Glasgow Coma Scale (GCS) is the most widely used method for diagnosing the type of coma state. The GCS defines severity through visual cues like observing the oculocephalic reflex to test the integrity of the brainstem through witnessing opposing movement between a patient’s eyes and their head.11 If both eyes fail to move in the opposite direction (i.e. head turns left eyes move right) then there is more than likely some damage to the affected side. Caloric reflex tests also produce insight to cortical and brainstem function where eye deviation towards an ear that is injected with cold water is anticipated. If no direct eye movement occurs a high probability exists for brainstem damage and no real probability for recovery.12 For example one study identified 47 of 111 patients with at least 1 absent brainstem reflex (pupillary light responses, corneal reflexes, or oculocephalic reflex) where only 2 eventually had a significant improvement over time.12,13

While GCS is popular some believe that there are better evaluation scales like Full Outline of UnResponsiveness (FOUR), Wessex Head Injury Matrix (WHIM) or Coma Recovery Scale-Revised (CRS-R).14 FOUR focuses on detecting and distinguishing between vegetative state, locked-in syndrome, MCS and brain death through the use of a 17-point scale characterizing motor response, eye response, breathing and brainstem reflexes.15-17 The chief strength of FOUR is that it can be applied to patients with endotracheal tubes where GCS cannot. WHIM focuses on the empirically derived sequence of recovery through a 62-point scale among 6 different categories (communication, attention, social behavior, concentration, visual awareness, and cognition) and can effectively distinguish between different awareness levels from vegetative state, MCS and partial recovery.14,18

CRS-R focuses exclusively on vegetative state and MCS and the prospects of transitioning between those states by evaluating 29 hierarchical items categorized in auditory, visual, oromotor/verbal, communication, motor, and arousal.19,20 Some believe that the statistical nature of CRS-R makes it the superior evaluation scale because score summation among the 29 criteria items can be used to track changes in consciousness over time (i.e. linear estimates of ability over time).

However, like GCS these other evaluation scales have their own drawbacks. One of the biggest drawbacks for CRS-R is its limited diagnostic utility due to its lack of diagnostic criteria.11,21 Basically CRS-R develops a diagnosis directly from the rating system. WHIM seems to have a problem measuring recovery as its progression via WHIM is probabilistic and lacking in precision.14 FOUR and GCS have problems measuring the importance of visual fixation.14 This mischaracterization of visual fixation can lead to a misdiagnosis rate of 24% for FOUR and 38% for GCS respectively, typically defining a patient as having a vegetative state versus MCS.22 Elements surrounding the mischaracterization of visual cues in general seem to be the factor that produces the most misdiagnosis.23

It is also widely regarded that recovery from unconsciousness is extremely unlikely in the absence of pupillary light responses, corneal reflexes or bilaterially absent cortical N20 responses 72 hours after unconsciousness.12 Absence of somatosensory-evoked potentials (SEP) after CPR is also a reliable predictor for negative coma outcomes.24,25 A little more controversial is that some believe that high (> 33 ug/liter) neuron-specific enolase (NSE) serum levels also effectively predict low recovery probabilities, but this correlation is questionable in its significance as recovery has been seen in patients with 90+ ug/liter values.26,27 The debate involving the prediction reliability of NSE serum levels is further clouded by the lack of a standard measurement methodology (different laboratories use different methods to determine NSE levels) and outside factors like hemolysis, which increases NSE levels, but does not affect brain function.28,29

One of the problems with evaluating the reliability of biological tests or even the aforementioned scales is the concept of “self-fulfilling prophecy”. For a number of individuals there is a subconscious intent to restrict treatment for patients with characteristics that indicate a low recovery probability, thereby creating a positive feedback loop that further lowers their ability to recover. This problem is compounded by the double-edged sword of experimental testing between required resources and the significance of the result.

For a study to draw significant conclusions there needs to be a large enough number of patients in order to account for outliers; however, the more patients that are enrolled in the study increases the resources required and the overall costs of the study both in manpower and money. Coma studies also have the problem of a lack of reproducibility due to the unique nature behind the origins of the coma both in the event(s) leading to their loss of consciousness and the biological changes that produced it. Overall the best hope is to simply conduct double blind studies separating those doing the initial and future probability evaluations from those applying the actual treatments.

Not surprisingly the advent of modern technology has lead to the use of imaging modalities to attempt to evaluate unconsciousness on a more tiered level. The two most popular strategies to measure consciousness, both in conscious and unconscious patients, are functional magnetic resonance imaging (fMRI) and electro-encephalography (EEG)/magneto-encephalography (MEG).30 Note that some researchers produce a wSMI, which is an analysis technique to determine the shared information between multiple, usually two, EEG signals.31 Both EEG and fMRI information is typically compiled during visual (usually with a bright light), auditory or pain stimulation as well as command following instructions, all of which are designed to produce strong conscious processing reactions. Event-related potentials (ERPs) can also provide insight into improper brain function as they have short latency periods typically reflect activation in low-level sensory receptive structures of the brain.34

Not surprisingly an increasing wSMI (greater synchrony between EEGs) is directly proportional to an increasing probability for coma recovery.30 Increases across centroposterior areas and across medium and long interchannel distances appear especially predictive.31 Another advantage of wSMI over EEGs alone is the comparison reduces the probability of common source artifacts that could create erroneous conclusions about conscious standing.30 EEGs are typically favored versus fMRI due to cost and required procedure.35,36

The advancement of modern imaging technology has provided improvements in navigating the nuances of characterizing a patient as either in a vegetative state or a MCS in that across various studies anywhere from 24%-33% of patients that were originally classified in a vegetative state were reclassified as being in a MCS after EEG analysis.30,35 However, whether or not this new diagnosis was due to missed behavior signs signifying consciousness or a secondary VS subset where neuronal patterns change before outward behavior changes is unclear. This secondary explanation does make sense because neuronal plasticity leads to brain repair from traumatic damage, which would manifest internally before reestablishing external conscious behaviors.
Overall both the inclusion of behavior measures as well as neuroimaging will increase diagnostic accuracy and increase successful treatment probability.

One of the possibly tricky issues surrounding the evaluation of potential conscious signals is that subconscious/non-conscious processing is more advanced than historically thought. For example the brain can subconsciously recognize certain abstractions in pictures, words and faces,37,38 interpret the relationship between similar words,39,40 and the social context of certain objects like money.41-43 There are even questions regarding whether long-distance synchrony can be produced between prefrontal and occipital cortex through long-term potentiation under unconscious conditions.44,45 Fortunately these subconscious triggers rarely manifest into actionable streams, so while subconscious activity can produce behavior priming and small levels of activity in certain networks the rate of their existence is ephemeral. Therefore, despite these concerns, attributing general consciousness cues to conscious brain activity in a currently unactionable state appears more appropriate than attributing these signals to subconscious brain activity.

Another question when using neuroimaging to diagnosis a state of unconsciousness is when it is ideal to measure the “signal of consciousness”. There is a question to whether or not it is best to focus on early or late neuronal responses to sensory stimulation; i.e. how long does it take before the brain produces a conscious response and is everything else signal chatter?46-50 This question is largely contingent on if conscious action can emerge solely from regional reverberating activity and can skip integration or processing. This concern becomes somewhat academic because neuroimaging a patient in a coma-like state typically collects numerous samples to accurately determine whether or not consciousness was demonstrated; therefore, checking late signals should be preferred due to the belief that a majority of conscious thought does require integration. Also integration is essential for consistency of awareness and significant prospects for recovery.

As previously alluded to when determining an existing conscious state the most important distinction is between a vegetative state and a MCS. Both states demonstrate a similar form of preserved arousal, but MCS patients have an additional layer of intentional behavior associated awareness accompanying this arousal. The problem is whether this intentional behavior is absent or the patient is unable to communicate it to the testers. fMRI data has detected blood flow patterns characteristic of consciousness in some vegetative patients.35,36 Both stand-alone EEG and wSMI have also produced certain patterns characterizing consciousness in vegetative patients.51,52 Taking consideration of the above concern regarding unconscious processing, these results could imply that there needs to be an intermediate stage between vegetative and MCS. However, even if this intermediate stage does exist the question is what does it change regarding treatment and conscious awareness?

Another characteristic feature that is used to distinguish vegetative and MCS patients is an EEG of MCS patients typically have increased alpha (at parietal and occipital sources) and theta wave number and a reduced delta wave frequency.30,53 Alpha waves are neural oscillations at a frequency between 7.5 to 12.5 Hz. They originate from the occipital lobe, or possibly the thalamus, when a subject is awake, but resting with closed eyes. Alpha waves are reduced when the subject has open eyes or is asleep. Biologically during alpha wave activity it appears that areas of the cortex not in use are inhibited and there is a non-visual network coordination and communication.54 A second form of alpha wave occurs during REM sleep originating from the frontal lobe area of the brain and has a generally unknown influence, but is thought to have an inverse relationship to REM sleep pressure.54

Delta waves are neural oscillations typically at a frequency between 0 to 4 Hz although some narrow that range to between 0.5 to 2 Hz. They are the slowest waves, but have the highest amplitude and are a common occurrence during deep stages 3 and 4 of sleep (a.k.a. slow-wave sleep (SWS)). Delta waves also indicate an unconscious state with an enhancement of information iteration, which is why this state is thought to increase the probability that declarative and explicit memories are formed.

Theta waves are neural oscillations at a frequency between 4 to 7 Hz. There are two types of theta waves: hippocampal and cortical. Hippocampal are more common to non-human mammals while cortical are more common to humans. Hippocampal theta waves occur through the medial septal area and flow to both the hippocampus and neocortex.55 These waves are related to learning and memory formation and could be related to arousal, sensorimotor processing or even environmental position.56

Interestingly most theta waves involve GABAergic or glutaminergic signals to drive inhibition and excitation versus cholinergic signals.57 Cortical theta waves are common in young children, but lessen in frequency and potency with age occurring later only during meditative or drowsy states. Theta frequencies are especially important as they are thought to mediate a serial stream of consciousness from the fronto-parietal networks.58-60 For a vegetative state these changes are not surprising as increases in low-frequency oscillations like delta waves are classical elements of deep sleep or coma.

One of the key newer elements in judging coma recovery probability is the influence of the posterior cingulated cortex (PCC). The PCC is the central node in the default mode network (DMN) model and along with the precuneus appears to govern wakefulness and awareness, especially relative to anesthetized and various coma-like states.58 Correlation of mesioparietal activity occurs in the PCC as well as pain and episodic memory retrieval.58,59,61 The DMN is quick to activate and deactivate when thoughts are internally directed

Note that the DMN is the active regions of the brain during periods that lack specific attention or focus (i.e. daydreaming, etc.). Its typical characteristic is coherent neuronal oscillations under 0.1 Hz. DMN may also drive self-referential thought and is at optimal function when an individual’s eyes are closed.63 This self-referential thought can manifest in spontaneous inspiration that embodies creativity. It also could have some connection to tying an emotion to a given memory or event. However, the DMN is criticized for its inability to effectively explain the large amounts of processing that occur in a “resting” brain.62

Not surprisingly as one of the critical elements to wakefulness the PCC is one of the most metabolically active regions in the brain with blood flow and consumption rates significantly higher than other brain regions.63 Aside from driving consciousness the PCC is also important to spatial memory, autobiographical memory, configural learning and maintenance of discriminative avoidance learning.31 There is some debate on the role of PCC in triggering internal and external attention and thereby controlling arousal and focus making the PCC a dynamic network over a static brain element.63

A strong associated activation element with the PCC is the precuneus, which is located near the two cerebral hemispheres between the somatosensory cortex and forward of the cuneus. Historically little information has been collected on the precuneus because of its position in the brain, in part it was previously thought to be a homogeneous structure, but now is known to have three subdivisions.64 The precuneus in posterior areas aids episodic and source memory while a second subdivision aids visuospatial imagery. This aid has sometimes been described as “providing context clues” for the hippocampus in memory retrieval.64

With regards to consciousness, similar to the PCC, the precuneus has much higher average metabolic levels and is “deactivated” or compromised during SWS, loss of conscious events during epilepsy, specific brain lesions and vegetative states.63,64 One means to drive rapid activation of the precuneus is to induced language learning through brief flashes attaining supraliminal instead of subliminal characterization.

The idea that the PCC and precuneus are focal points of importance for consciousness also makes sense within the context of corticocortical and thalamocortical degradation, including among medium spiny neurons,65 for these two areas have been functionally linked to thalamus nuclei.66,67 This influence on the synchronization of these cortical networks also appears to correlate to global workspace theory (GWT).68

GWT is a theory designed to describe how the conscious and unconscious mind interact to produce cognitive thought and was first applied to the concept of working memory. Most analogize GWT with a play at a theater where the active consciousness is the actor currently speaking (i.e. the “spotlight” of attention, which has limited reach/range)while other actors compete for the spotlight.69 The seating in the theater along with the attending audience represents the unconscious mind, aware of what is consciously occurring, but not providing any direct influence to the behavior of the actors and of great capacity. Finally the non-actors like the director, stage hands, etc. act like executive processes in that they influence actor behavior, but are not directly witnessed.69 One of the major boons of GWT is that it successfully models certain characteristics of consciousness like managing novel situations, working with capacity limits, and incorporating unconscious processes to conscious processes, a characteristic seen in brain elements like how the dorsal cortical stream influences the visual system.69

This model also applies a competition-cooperation parameter to form a “stream of consciousness” where if two elements are received within 100 ms of each other they will be sensory cooperative vs. being sensory competitive, i.e. when the video and audio of a movie are in or out of synch. Alpha, theta and gamma brain waves correspond to this 100 ms threshold whereas ERPs are in the 200-300 ms domain.70 Most argue that the “stream of consciousness” is not an actual stream with events falling perfectly in place with one another, but instead are “edited” together by conscious and unconscious processes similar to how a movie is put together after various scenes and takes. Overall the chief problem with the GWT is that it does not actually explain consciousness, but instead places boundary conditions on theories that do attempt to explain consciousness.71

One of the initial strategies to increase the probability of recovering from a coma, regardless of its specific classification, involves application of mild hypothermia after patient stabilization, especially those suffering from loss of consciousness related to cardiac arrest. The patient’s body is cooled intravascularly at 32-34 degrees C for 24 hours, which typically lowers core body temperature by 2-3 degrees C.12 Fortunately this strategy has become commonplace for many patients, thus reducing the worst-case scenarios for most individuals who lose consciousness in the long-term.72,73 While the specifics of why hypothermia is a successful deterrent of increased future neuronal damage is unclear, there are theories, which involve the reduction of both electrophysiologic and homeostatic energy use,74 reduction of extracellular concentration of excitatory neurotransmitters like glutamate,75 or the reduction of the post-traumatic inflammatory response.76,77

It must be noted that even when individuals recover from comas or coma-like conditions there will be a transition period where the individual will have reduced cognitive and physical ability. Most individuals who recover from comas required physical therapy, speech therapy and some psychological counseling before they are able to continue with their normal lives, that is assuming that they are able to recover fully at all.

Regarding the treatment of any neurological condition some will note the potential of Deep Brain Stimulation (DBS). DBS involves attaching electrodes to specific portions of the brain and applying an electric current in an attempt to initiate excitatory action potentials, typically in the forebrain neurons. It has already drawn interest in treating degenerative neurological conditions like Parkinson’s and dystonia along with psychiatric disorders like depression, obsessive compulsive disorder and various additions.78 The one major general drawback to DBS is that it is an invasive procedure that comes with standard surgical risks and potential complications.

With regards to the ability of DBS to treat coma and coma-like patients the results are not overwhelmingly positive. Most DBS successes are single isolated MCS patients with no positive correlative trend for improved recovery time.65 While DBS does produce behavioral arousal including widening of the palpebral fissure, increased heart rate and blood pressure along with scattered fragmentary movements these improvements are not sustained.65,79 In vegetative state patients there is almost no positive benefit as DBS triggers a local and slow response that does not facilitate synchronization.

Some may argue that the Yamamoto 2010 study demonstrated a significant impact of DBS on vegetative state patients. However, this study appeared to have some serious sampling bias, especially in the old control group where none of the untreated patients recovered from their vegetative states, which mitigates its usefulness.65,80 The second major problem for the credibility of this study is that a number of the “biggest gainers” from the DBS actually had MCS at the beginning of the DBS treatment.81

The reason reclassification of vegetative state patients as MCS patients is a big concern is that the probability that an individual spontaneously regains consciousness from a MCS is thought to be much higher than a vegetative state. For example about 80% of patients in a MCS after 6 months recover spontaneously after 10 months.82,83 Therefore, there is confusion regarding whether or not the patients naturally recovered or recovered due to DBS.

To be fair populating and controlling a significant study to determine improvements in recovery times for coma patients is difficult. Currently there has been only one such clinical trial involving 200 patients and 200 controls spread over 11 participating institutions and 7 years of data collection.65,84 However, currently there is no evidence that DBS facilitates a significant increased probability of recovery for coma patients that are not already significantly through the process of recovery.65

In addition to DBS, there has been exploration regarding pharmaceutical agents for increasing the probability of coma recovery that has produced inconsistent results from L-dopa, Amantadine, and Zolpidem (Ambient).65,84,85 Amantadine is a mixture of a dopaminergic agonist and NMDA antagonist, which seems to have a strong influence on medium spiny neurons triggering greater action potential firing, which then leads to greater mesial cortical neuron firing stimulating conscious activation.65,84 L-dopa is the precursor to the neurotransmitter dopamine, which supposedly acts on neurons in the striatum and frontal cortex to stimulate action potentials. Zolpidem is an alpha-subtype selective positive allosteric modulator of GABA-A receptors. This pathway interaction seems perplexing to why it could help coma patients, but there is a thought that increased GABA-A activity can inhibit the inhibition of thalamocortical outflow, which can increase awakefulness.85 However, none of these methods appear to be consistent enough to be an effective treatment for coma.

As noted above with DBS, one of the major treatments for individuals in a coma or coma-like condition is brain stimulation. Interestingly enough there is significant evidence that focus/attention can be produced even in an unconscious individual.86,87 One common experiment demonstrating this point is orthogonally manipulating visibility and attention through the use of masked images at the edge of conscious perception (some conscious other subconsciously presented).88 From these types of experiments it was theorized that attention over visibility modulated early occipital activity where visibility over attention modulated late temporal and parieto-frontal activity.88 However, there is a changing structure to when the brain reacts to the external stimuli and when the individual becomes conscious of it.89,90

In addition it is recognized that conscious realization of a stimulus requires exceeding a threshold that separates subliminal and supraliminal processing. Exceeding this threshold demands the consistent accumulation of sensory evidence. However, the brain does have a limited capacity to process external stimuli, which is one of the reasons why multi-tasking produces a significant reduction in efficiency between the applied events. Conscious processing of one element creates a bottleneck resulting in either significant reduction of secondary element processing (psychological refractory period (PRP)) or inhibition of the origin of the secondary element (attentional blink or inattentive blindness).91 There is also competition between different stimuli during processing which can make it less likely that any conscious realization occurs.

Finally the adult brain has significant plasticity to allow for repair, but must be primed to truly maximize the efficiency of that repair. This priming element should explain why a number of individuals do not recover from coma states. Similar to the common psychological adage of “use it or lose it” coma/coma-like patients need to “use it” to drive repair recovery. At a biological level this concept involves the activation of positive feedback systems for given neurological pathways, which reinforce certain neurological thoughts/actions versus the termination of neurological pathways that are not utilized or oppose these thoughts/actions. Taking all of these elements into account and tying it to what is known about the PCC and precuneus and their roles in consciousness another potential stimulation strategy emerges.

The first step is to initiate a visual signal cascade to trigger arousal and focus in the patient. This initiation could trigger through the use of a stroboscope (preferable) or general strobe light, which uses high frequency light pulses at various phases and speeds to produce excitatory reactions in the visual processing regions of the brain. Whether or not sounds should also be included in the stroboscope application is questionable. On one hand it can be argued that the addition of sounds should increase arousal probability and recognition of changes in the environment. On the other hand the addition of sound may create some connective confusion, as noted above, and limit the overall efficiency of producing arousal synchronization.

The second step is to request the patient visualize a significant emotional moment in the past. One of the key operational characteristics of the PCC is that it acts as a central integration center for episodic memory, especially those with emotional overtones. Asking the patient to recall, through visualization, an emotional memory should facilitate significant activation of the PCC and trigger the initialization of consciousness recollection, which could initiate further downstream elements of consciousness.

A third optional step would be to ask the patient to visualize themselves on a field running to catch a football or baseball. This visualization should trigger visuospatial areas of the brain, which would aid in triggering precuneus activity. After a seven-minute period (starting with step 1: 2 minutes, step 2: 3 minutes, step 3: 2 minutes), the stimulation is ended and repeated again multiple times after a ten-minute break. The exact amount is unknown but for the moment three times in an hour period over a 24-hour period seems intuitively appropriate.

The above treatment is simply thought to be a potential new therapy option based on understanding the general biological elements associated with how the body retains remedial consciousness. Currently there is no empirical evidence to support the capability of the proposed theory to aid coma recovery beyond the visual activation elements associated with a stroboscope. However, it stands to reason that testing this method should be rather simple due to the lack of known negative elements like invasive surgery or pharmaceutical side effects. One possible side effect could be an increased probability to invoke a seizure due to the action of the stroboscope, but this possibility appears incredibly unlikely. Overall there are certainly no guarantees that this new proposed method will develop into an effective treatment for vegetative state and MCS patients, but there appears to be little reason not to attempt to study its effectiveness.

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