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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Tuesday, August 5, 2014

Training for Mars – Mind over Matter

In the laundry list of requirements for the colonization of Mars one important issue that is commonly placed on the back burner is the type of training that will be required for the colonists. The success of any Martian colonization mission will depend on how colonists handle new psychological experiences that will affect their behavior as well as their internal biology. Any belief that current NASA training will be sufficient is shortsighted. The most significant difference between performing scientific experiments on the International Space Station (ISS) and building a colony on Mars is the dearth of resources. While resources are limited on the ISS re-supply from Earth is just a few days away whereas any re-supply from Earth for a Martian colony is at least six months away (three to four months if new propulsion technology is developed). Therefore, not only must potential colonists be trained in certain colony critical specializations, but they also must have appropriate physiological and psychological training to ensure a maximized probability of success.

There are typically two types of astronauts: pilots and mission specialists. Due to the requirements of pilots to fly the launch craft and command missions their training focuses on space station and launch craft systems as well as leadership whereas mission specialists are trained in operation of robotics, spacewalks and other modalities for their specific scientific research. Joint training is also conducted in numerous simulators to emulate the vibrations and noise associated with take-off, guidance for payload docking, and buoyancy training in a pool to emulate movement in a weightless environment. Additional water training involves becoming SCUBA certified and endurance training (i.e. 75 consecutive meters of swimming in a flight suit and treading water continuously for 10 minutes in a flight suit).1 To appreciate the importance of current NASA astronaut training, a six-month mission to the ISS typically involves up to five years of training.

Psychological training will be the greatest difference between current astronaut training and future training involving Martian colonists. Currently the psychological makeup of an astronaut can have breaking points because most of the problems on the ISS can be resolved either through a simple EVA or assistance can be quickly dispatched from Earth. Also mission durations are typically only three to six months, thus any negative influences of monotonous actions or interactions with other crewmembers is limited in scope where astronauts depart before reaching their breaking points. However, for colonists there are no escape routes; problems with the equipment, one’s own self and/or other individuals will have to be addressed. While telecommunications will produce some minor outlets to seek professional counseling to manage some problems, other environmental problems cannot be resolved with outside assistance and instead will require adaptation or increased resolve.

Colonists will also be faced with various psychological stressors or “asthenia” [depressive and dissociative symptoms]. In the past these stressors have typically been divided into three stages: 1) an acute phase with a maximum duration of two months brought on by general biological and psychological adaptation to new surroundings; 2) an intermediate phase with more defined and persistent symptomatology including physical and mental fatigue, irritability and motivation loss; 3) a long-duration phase where the intermediate phase symptoms become permanent to the environment and cause significant damage to performance and intra-crew relationships.2-4

One of the most prevalent psychological stressors facing colonists is how to react to new physical limitations. For example colonists will experience a consistent feeling of physical fatigue due to a lack of sleep, lack of calories, limited ability to refresh (meditation, showers, sex, etc.) and a lack of complete nutrition born from balanced vitamins and minerals. Finally there is a large unknown with regards to nutrient absorption for no one really understands how reduced gravity and reduced calories will change a colonist’s microbiota. This change could increase calorie and nutrient absorption limiting reduced energy symptoms or decrease it further reducing energy levels.

It stands to reason that the notorious type A personalities will have difficulties adjusting to this “new normal” because of such a significant reduction in productivity and energy levels. The ability to neutralize frustration will be a key attribute to warding off negative psychological elements associated with this increased physical fatigue. In addition colonists will need to effectively budget their time to compensate for the reduced energy (i.e. work smarter due to it being more difficult to work harder).

Training to handle an increase in physical fatigue is an interesting issue. On its face one would think that the best way to prepare for this environment would be to emulate it. Potential colonists would have a restricted diet (similar to the one on Mars) and reduced sleep (4-5 hours) to psychologically experience the new physical reality on Mars. However, one question arises with this strategy, when should the “simulation” end? If this strategy is to expose and even acclimate colonists to the physical realities on Mars should it even end, i.e. should the Mars colonization mission simply extend the experiment?

Basically the question comes down to what is more important: ensuring the colonists are at peak physical health immediately before starting the mission, yet also have psychological awareness of how they will physically respond on Mars or not allow their bodies to reacclimate to normal conditions avoiding any discomfort associated with going through the physical adjustment again? In essence is the purpose physical adaptation or mental adaptation? If physical then the “simulation” should not end, but instead simply flow into the launch, if mental then the “simulation” should end with sufficient time for physical recovery before the launch.

A good analogy for this question is to think about a person that will need to tread cool water for two straight hours. Does the person enter the water five hours before the test begins to get them mentally and physically familiar with the temperature of the water and how it will affect them, then the individual leaves the water until the time of the test or does the person enter the water a half-hour before the test to allow his body and mind to acclimate to the change in temperature and then remain in the water until the test begins? Barring any strong and consistent negative biological responses among candidates, it seems better to facilitate mental training and preparedness versus physical training (i.e. the first option from above).

The issue of reduced calories creates a type of “double whammy” effect where not only will the reduction in calories reduce available energy creating greater fatigue, but it may also produce physical and psychological pain. Therefore, colonists will need to psychologically train for the reality that they will be hungry a significant portion of the first few years of colonization, especially because boredom/monotony tends to augment hunger due to a lack of attention occupation. The level of hunger will depend on how much money is spent transporting food both in the initial mission and any future supply missions and the level that colonists rest or sleep. If society is willing to spend enough money this potential psychological drawback can be mitigated completely; however, it stands to reason that society will not be willing to make this payment in full, especially with the ecological damage that the Earth could be suffering during the timeframe of the first Mars colonization mission.

Stress management is important both in reducing the probability of occurrence for stressful events and their associated magnitude of influence. Reducing the magnitude of events should be far easier due to much greater levels of certainty and associated preparation mechanisms like biofeedback systems, relaxation techniques, systematic desensitization, meditation and even the consumption of various drugs (if need be). Addressing the probability that stressful and dangerous events actually occur is difficult because one cannot prepare for everything, various things can go wrong during transit to Mars and after landing during the initial colonization period.

Events that unexpectedly occur outside the interaction between two or more colonists are best prepared for through simple decision making training. The most dangerous events are those that have an unpredictable element either in the timing of their occurrence or what is required to solve the problem (i.e. a new problem one did not expect). The reason for such danger is that the probability for poor decisions increases with respect to the lack of relevant knowledge regarding the current situation. Therefore, one important training exercise would be to give prospective colonists numerous tests that involve unexpected events with a lack of certain information.

Individually these scenarios will help develop important types of thought, both lateral and creative thinking as well as enhancing their ability to organize their ideas and thoughts into coherent strategy. These scenarios will also help colonists cope with panic and stress that comes from having incomplete information to solve an important problem. Within a team environment these types of scenarios should help interpersonal interaction through developing a methodology of how the colonists combine their individual efforts and reactions to these unexpected problems to form a cohesive strategy. The purpose of these tests is not to attempt to cover all possible negative scenarios, but instead familiarize colonists to types of thought processes that will increase their probability of successfully solving problem scenarios no matter what type of scenario occurs.

Some of the existing research on military decision making categorized five principal elements to addressing uncertainty (sometimes referred to as RAWFS): 1) Reduce uncertainty by collecting additional information; 2) Make reasonable assumptions to fill in gaps; 3) Weigh evidence and create multiple competing hypotheses (i.e. do not simply create one solution strategy based on existing information, but multiple ones); 4) Forestalling/foresight through development of future solution strategies that may be need to counter problems stemming from the existing solutions; 5) Suppress future uncertainty (i.e. through limiting its relevance or relying on unwarranted rationalization).5,6

Of these five elements the first four are effective and reasonable components to formulating an effective problem solving strategy. However, the inclusion of the fifth element is somewhat controversial. Obviously one could argue that the fifth element is important because it informs individuals not to place unnecessary emphasis on unknown information otherwise that unknown information could create a conflicting response relative to the known information. This reasoning does make sense, but unknown information should not simply be mitigated or ignored because it still plays a relevant role in future events. Simply ignoring something because it is unknown is not the proper strategy to solving a problem. Instead one must anticipate how the unknown information could influence future solutions and plan accordingly based on how the solution will change the scenario both in a positive and negative manner.

Additional psychological training may be necessary to addressing potential interpersonal problems, depending on the construction of the initial colonist crew. A crew comprised of different religions, different cultures, and even different genders will create additional stressors in the colonization process. While from a logical standpoint a homogenous colonist demographic would be ideal from a standpoint of neutralizing these stressors, it may be difficult for the public to accept 4 30 something heterosexual white males being the first colonists on Mars. Therefore, part of the psychological training could involve potential colonists accepting the fact that they would have to give up most of their specific religious and cultural demonstrations due to a lack of resources, space and conflict with those beliefs possessed by other colonists. This adjustment does not mean that these colonists need to give up their beliefs, but they will not be able to exercise these beliefs as publicly as they currently do.

Some may disagree with the idea that individuals would have to restrict their individualistic displays of culture suggesting that the other colonists should simply be tolerant of such actions. This belief is rather irrational considering the scenario involved with Mars colonization. As available resources and space are reduced individual freedom of expression also must be reduced for the sake of harmony. Some would counter this idea with the old Franklin quote, “Those who would give up essential liberty, to purchase a little temporary safety, deserve neither liberty nor safety.” Unfortunately these individuals appear to be arguing for perfect or unrestrictive freedom, which is foolish. Again colonists are not being told that they should give up their cultural/religious beliefs (the essential freedom), but their more demonstrative demonstrations (dispensable freedom). Those who cannot comply with this requirement have a shallow and too rigid belief structure.

Another problem will be a lack of water. Unfortunately some colonization proponents have this “pie-in-the-sky” idea that incorporating a strict water recycling methodology will neutralize the prospect for any water shortages. Clearly while water recycling will be a critical element in ensuring a maximum amount of water availability, a 100% recycling efficiency is impossible. Therefore, there may be times when individuals will have to manage being thirsty. In addition with a reduction in water use individuals will have less ability to wash themselves increasing levels of body odor. Thus, in most situations individuals will have to deal with unpleasant odors from themselves as well as other colonists.

In addition other psychological pressures like the workload and its survival importance (numerous people state that certain things are life or death, but while this is over-the-top hyperbole, on Mars most things will be), lack of privacy, reduced novel sensory stimulation and reduction in familiar social support could all impact mental health. Smart habitat design should create enough personal secluded areas within the habitat to manage any lack of privacy issues. Early in Mars colonization most colonists, especially those who have not previously been astronauts, will have numerous novel experiences; however, these experiences will soon move from novel to monotonous increasing the probability for negative psychological events. The monotonous reality of early Mars colonization can be overcome by simple psychological discipline as well as common enjoyable and personalized actions. Everyone has a favorite song or food or something that no matter how many times they interact with it they never get tired of it, this psychological attribute can assist colonists in neutralizing less enjoyable monotonous events that will be experienced on Mars.

The lack of familiar social support is only illusionary because communication mediums on Earth have created an environment where individuals are able to interact with family and friends in general whenever they want facilitating a form of communication entitlement. When communication ability is restricted this sense of entitlement is broken creating stress; i.e. this stress is not born from a lack of familial support. This rationality is supported by the fact that most individuals do not have meaningful amounts of unique information to share with friends or family when contact is constant. Interaction with family is still possible through restricted telecommunications and email, so overcoming the psychology of not being able to communicate whenever one wants is the real challenge. Pressures associated with the severity of colonization workload and survival can be managed effectively through positive crew interaction and stable meeting periods removing the “individual” mindset and instilling a “team” mindset neutralizing a significant amount of the pressure.

As most individuals recall from their own high school and college experiences the lull of a break from specific study can catalyze the loss of information. Preparation training is important, but over the course of six months of travel to Mars it stands to reason that skills and training will diminish at some unknown variant rate. Therefore, it is important to equip prospective colonists with the ability to review and augment their training in transit. Simulator software packages already exist that emulate in-flight software, but operation of these simulators can become somewhat tedious after a large number of views due to their stiff instructional nature. One idea that could be further explored to break-up this tedious structure is the creation of a competitive instructional platform.

Basically one could focus on creating a game of sorts to augment training; the computer game could resemble a structure like the game “Trivial Pursuit” where players are assigned certain “occupations” that would exist in the process of Mars colonization. Answering questions pertaining to duties and skills associated with these occupations would results in points eventually crowning a winner. Such a system would also benefit other players through creating a form of “osmotic” redundancy where other colonists may not be an expert at occupation x, but would know enough of the necessary skills to take over duties if the expert become incapacitated. The redundancy would eliminate the biggest flaw in a specialized system structure, what to do when a specialist is not long available to perform his/her duties.

Expanding on that idea obviously while specialization is important the subject training cannot be so myopic that only one potential solution is presented for a given problem. Martian colonists need to be trained to think like physicians: make a diagnosis and then determine the best course of action to address the problem. This training must also coordinate between colonists because studies have shown that high performing teams have fewer interaction patterns as well as engage in shorter more concise interactions.5,7,8 Basically for problem A colonists 1 should have a general idea what colonist 2 wants to do. This training strategy should also help the emotional state of colonists for they will not feel intellectually isolated and pressured as the only individuals to have information about subject A.

Some individuals have claimed that it is important to ensure that the medium utilized to augment training is significantly entertaining. While an entertaining medium will make training more enjoyable, it is not an essential element. Remember that the first colonists will be professionals and will have their lives on the line; the expectation that these individuals will not perform necessary training supplementations due to it being “boring” is rather far-fetched. Therefore, it would be beneficial if the entertainment factor for supplementary material could be enhanced, but effort should only be applied in this area after all other important factors have been addressed.

Current medical care in space for severe conditions involves patient stabilization until a launch craft can retrieve the ill astronaut for transport back to Earth. Unfortunately this aspect of training will have to change for a Mars colonization mission because transport back to Earth for medical care will be impossible. Therefore, medical training will have to be expanded to develop the ability to treat a variety of conditions during transit and on the surface with one of the critical medical strategies will be dealing with secondary motion sickness brought on by microgravity negatively influencing the vetibular system in the inner ear due to a reduced responsiveness of the otoliths.9 Other medical emergencies will involve the failure in part or whole of life support, capsule depressurization or fire.

Astronauts typically have one of three types of medical training: basic training for a medical officer, more advanced training for a paramedic and full training for a physician. 75% of astronauts have either experienced a medical event or utilized medication to treat a non-emergent problem.9 Most of these injuries involve, excluding motion sickness, minor trauma to the skin, various muscle ailments due to too much or improper exercise, space motion sickness (which is very common despite preparation training), sleep deprivation, headaches from excessive CO2 exposure and general psychological fatigue.2,10,11

However, there are limitations involved when focusing on the history of medical outcomes in space largely due to small sample size, genetic variation in astronauts, inaccurate historical information due to changes in data storage over decades and inadequate controls to confirm the significance of the data collected.2,12 Despite all of these caveats historical data is still important to consider in gauging what will be expected for colonists during transit and on Mars and should be incorporated into medical training. Unfortunately the biggest variable in expectant negative medical outcomes involves the duration of exposure to a reduced gravity environment. With most astronauts only staying for a maximum of six months on the ISS, it is difficult to gauge what type of medical training colonists need for permanent stay on Mars at 1/3 the gravity of Earth.

Overall with regards to medical care it would be incredibly valuable to have a fully medically trained physician, most likely a general practitioner, among the first set of colonists. One of the principle reasons for the inclusion of a general practitioner is that while training for a Mars mission will be extensive, becoming a physician involves even more training including various real-world experiences acquired as an intern, resident and practicing physician. Therefore, instead of using some percentage of training time creating an individual with skills inferior to a physician on some level, the physician can receive secondary training in another field further enhancing the effectiveness of the crew. Also an effectively trained physician can reduce the amount of required medical equipment, especially with regards to complexity and redundancy, reducing launch costs. Finally trained physicians have unique perspectives and greater understanding of how to deliver treatment over a short, medium and long-term setting.13,14

The progression of how colonists react to changes in their ability to act, in part due to changes in the autonomic nervous system (ANS), is one of the biggest current question marks due to long-term simulation difficulties. The ANS plays a large role in almost all unconscious/subconscious actions and is made up of three different operations: the enteric systems, the sympathetic system and the parasympathetic system. Sympathetic predominance occurs largely when an individual is awake to facilitate engagement with the surrounding environment, especially those that require quick responses and parasympathetic dominates during sleep to facilitate biological recovery.13

The operation of the ANS can change for astronauts. For example some studies of both pre-flight supine position and habitation of the ISS have shown a decrease in mean arterial blood pressure and heart rate15,16 as well as a decrease in parasympathetic activity,17 which could influence sleep quality, alertness and even nutrient processing. However, the pilot portion (105 days) of the Mars 500 isolation study demonstrated an increase in parasympathetic activity with no significant difference in length or phase of sleep-wake periods.18,19 Either parasympathetic activity radically shifts between 105 days in isolation and 180 days in isolation (in space) or this change is cannot be effectively biological modeled naturally in Earth-based simulations. Thus this significant biological change must either be ignored (which is dangerous) or potentially chemical induced during Mars mission simulations. In addition part of the reduction in physical daily activity levels could be attributed to this change in parasympathetic activity, which could also explain the increased amount of rest seen in the Mars 500 study has the experiment went on.19

Another concern may be how sympathetic activity changes with respects to type and duration of light exposure. Typically sympathetic activity increases with color light wavelength20 and light intensity,21 thus prolonged exposure to most artificial lights, which are normally of lower intensity and color wavelength than natural light, could reduce sympathetic pre-dominance. One way to address this problem could be to incorporate different colored LEDs that would make up for changes in wavelength with intensity and visa-versa.

There are two chief subject areas for training: expected events and unexpected events with three sub-subject areas: biological, equipment, and interpersonal. Not surprisingly expected events are the easiest to manage because they are expected, thus only a proper solution methodology is needed to neutralize them when they arise. The problem with the expected events is ensuring that the determined methodologies are recalled and available when needed. To increase the probability of positive outcomes training should involve redundant learning where multiple individuals have knowledge of a given solution. Such an environment can be created where one individual has detailed knowledge of the entire solution strategy and other individuals understand the solution in broad strokes to ensure redundancy.

Unexpected events must be addressed through intensive preparation of generally unexpected events. Due to training and memory time constraints one cannot directly prepare a crew for an event that does not have a reasonable probability of occurrence; however, the crew can be prepared indirectly through engagement with various unexpected events and then observing the solution methodology that the crew utilizes to solve those events. Understanding and editing the methodology that the crew uses to address unexpected problems will maximize their ability to deal with unexpected problems during colonization. Finally interpersonal events differ somewhat from biological or equipment in their unpredictability. Potential negative crew events must first be marginalized through intelligent and practical crew selection, which may need to sacrifice diversity for simplicity. In addition negative crew events can be neutralized through constant team meetings and interactions so no one feels isolated or unimportant. Overall training for a Mars colonization mission should be exhaustive focusing on increasing psychological fortitude, developing team cooperation and producing effective execution methodologies to develop solutions to both expected and unexpected problems.


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