A new tool to help fight against mental illness?

The history of addressing mental illness has been a tumultuous one in the United States. In the past behaving against the norm commonly landed an individual in jail or an asylum, both which existed on the periphery of society, a location that potentially reduced the ability to produce effective treatment. The location was typically not the only element that reduced the viability of effective treatment as a number of asylums were poorly funded and staffed by a number of individuals who appeared to quickly tire of continuous interaction with “non-normal” individuals reducing their vigor for proper treatment both physically and mentally.

In more modern times a “so-called” enlightenment regarding mental illness was born from deinstitutionalization. The “noble” or liberalized story of deinstitutionalization involves the belief that the development of both Medicare and Medicaid as well as various psychotropic medications allows mentally ill patients to function “normally” and live among the community reducing the stigma of having a mental illness, thereby increasing their ability to assimilate and manage their condition(s). However, the more dirtied history of deinstitutionalization is that after the Supreme Court ruling in Souder v. Brennan prohibited mental hospitals from exchanging patient labor for room and board, forcing these institutions to pay for patient labor at minimum wage levels, there was little opposition to implementing the principles of the Community Mental Health Act of 1963 regardless of execution viability. Unfortunately despite the public’s apparent “zest” to integrate mental patients into society, the networked infrastructure that was to support these patients never materialized in a vast majority of places.

Sadly this early failure in the 60s and 70s has yet to be significantly rectified for while the proportion of individuals in public mental hospitals has dropped from 0.338% (558,000/165 million) in 1955 to 0.016% (50,000/313 million) in 2010,1 the Department of Justice estimated in 2006 that at least 24% of inmates in state prisons and 14% of inmates in federal prisons have mental illness and an additional 15% of state inmates and 24% of local/city inmates meet criteria for psychotic disorders.2,3 It stands to reason based on how mental illness is currently treated that this number has only increased into 2014. In addition at least 50% of a number of ex-cons with significant mental illness are rearrested typically through violations of their parole (these individuals have come to be known as “frequent fliers”).1 Incarceration has its own societal stigmas, imagine how difficult successful community treatment could be with both a criminal record and a mental illness.

Deinstitutionalization has also failed to live up to the idealistic diverse and “normal” environment pictured by its supporters in the associated residential “communities”. To most these “communities” have become a de facto urban asylum that again cares little for the recovery or treatment of the patients reducing the probability of any return to genuine normalcy. Some hold out hope that the focus of the Affordable Care Act on result-based outcomes will be an effective panacea to the squalor conditions of a number of these mental illness communities, but whether or not that reality will emerge is difficult to predict due to numerous unknowns and at the moment seems more unlikely than likely.

These environmental factors notwithstanding, one aspect of treatment that is not typically discussed is the idea of an individual focal add-on treatment where an individual that suffers from mental illness attempts to “commandeer” their brain in effort to regain control. Basically one wonders if too much emphasis has been placed on pharmaceutical, talk therapy and, now in modern times, assertive community treatment resulting in the omission of more personal options? Such abandonment is perplexing because these potential methods have almost no side effects and very little financial cost. With this intention to add an extra tool to the toolbox it must be mentioned that general result-based analysis of treatments for mental illness is almost non-existent. Despite advancements in the ability to treat mental illness almost no one actually studies which of these treatments work, both on an absolute (does treatment A work) and relative (does treatment A work better than treatment B) level.4,5 Therefore, these methods would have to be studied and compared against and in cooperation with existing methods.

One example of an individually driven treatment would be an attempt to control the multiple network firing of schizophrenia by engaging in a task requiring overpowering focus to reduce the firing of the other more spontaneous neuronal elements. For example when a schizophrenic begins to hear voices he/she would begin to play a game of chess, start a logic puzzle, a sudoku puzzle, i.e. a task that requires significant focus in order to be successful. One of the keys to this strategy is to identify a simple task/game that requires focus, but also makes an individual content (not necessarily happy). The necessity of contentment is to ensure a lack of frustration thus affording the ability to maintain focus.

Contentment is an element that seems to be pushed to the side when discussing mental illness, with focus instead placed on happiness and unhappiness. Contentment is important because it is less vulnerable to the negative impacts of more extreme emotional states, which can rapidly cascade into opposing elements (i.e. happiness can quickly become unhappiness and visa-versa), but is still emotionally positive enough to spark focus and enjoyment.

Another option could be producing an overpowering focus through visualization. By focusing on a single place of reference an individual would create a positive non-violent altered reality that could control spontaneously produced changes in mood or sensory information. The complexity of elements assigned to enriching and maintaining the visualization could mute the action potentials associated with the spontaneous firings that create symptoms of mental illness.

Another technique, one more recognizable by many for its ability to assist in mental control, is meditation. In recent years meditation has become an interesting subject of contemplation regarding its potential to manage the negative symptoms of mental disease. For the purpose of this brief discussion meditation is regarded as a physiological state invoking physical and mental relaxation with a reduced metabolic activity.6

The state of meditation is achieved through the reduction of thought processes to a single focused internal dialogue in the mind eliminating mental clutter and spontaneous thoughts. Unsurprisingly the elimination of this mental clutter enhances pure awareness and clarity on the single internal dialogue, usually calm central breathing tethered by the single focal word. Theoretically a meditative state could block the occurrence of negative symptoms from mental illness. This possibility is supported by the reported long-term effects seen in meditation practitioners such as: enhanced concentration attention skills, improved self-control and self-monitoring, increased ability to inhibit irrelevant external and internal stimuli, increased positive mood, emotional stability and improved resilience of stress.7 One issue with meditation is that most of the research has been conducted in small groups with few meaningful controls; therefore, outside of very long term practitioners it is difficult to determine when the advantages of consistent meditation will take hold.

However, meditation does have its share of more serious potential concerns as there is past evidence that during meditation an individual with a mental illness can have an increased probability of exacerbating short-term (non-permanent) psychosis.8 This increased risk for temporary psychosis could be drawn from the increased anxiousness that is common among individuals with mental illness, which makes meditation in general more difficult, but could also make it more beneficial in the long run. Another concern is that individuals with mental illnesses have motivational issues or even defects, which may make inspiring the discipline for routine focal tasks like meditation more difficult.

Note that these above personal add-on strategies differ from cognitive behavioral therapy because they do not seek to change the long-term thinking paradigms held by a particular individual. Instead these techniques are theoretically thought to act as an acute deterrent to be applied upon the onset of a significant negative aspect of a given mental illness.

On a side note numerous individuals think that education is an important aspect to limiting, or even eliminating, stigmas associated with mental illness, which is a reasonable and accurate assessment. However, no one really seems to suggest a means of applying a mandatory aspect to this education element, which would significantly increase its effectiveness. For example one effective means to addressing public education of mental illness would be for all high school students to take a psychology class that would be required for graduation that covers various mental illnesses in depth. Through this class all high school students would learn rudimentary means to identify symptoms of mental illness, manage it, and how to effectively interact with those who have a mental illness limiting uncomfortable and/or inappropriate moments.

Overall many have professed a concern that mental illness will increase in the future due to increases in population and proportion of occurrence.9 This increase is buffered by the concern that most traditional talk therapy treatment will remain centralized in high population affluent areas of the country. Unfortunately there is no evidence that this unequal distribution of certain psychological services will change, thus placing additional pressure on community environmental therapy and pharmaceuticals. To alleviate this pressure new techniques need to be developed. Understand that these techniques are acute immediate response deterrents and are not meant to replace other therapies; it is to say that one should not say that Johnny no longer needs his anti-psychotics because he plays chess. The above strategies appear to be theoretically viable and worthy of further study to determine whether or not they are empirically viable. If so these individual acute strategies could be important elements in reducing the more severe negative attributes associated with mental illness.


Citations –

1. Edmondson, B. “Crazy enough to care.” The American Scholar. Spring 2012. 46-55.

2. Clayton, A, et Al. “The citizenship project part II: impact of a citizenship intervention on clinical and community outcomes for persons with mental illness and criminal justice involvement.” Am. J. Community Psychol. DOI 10.1007/s10464-012-9549.

3. Department of Justice. Mental health problems of prison and jail inmates. Bureau of Justice Statistics Special Report. (2006). NCJ 213600.

4. Morgan, R, et Al. “Treating offenders with mental illness: a research synthesis.” Law Hum Behav. 2012. 36(1): 37–50.

5. Rice, M, and Harris, G. “The treatment of mentally disordered offenders.” Psychology, Public Policy, and Law. 1997. 3:126–183.

6. Young, J, and Taylor, E. “Meditation as a voluntary hypometabolic state of biological estivation.” News in Physiological Sciences. 2001. 13:149–153.

7. Rubia, K. “The neurobiology of meditation and its clinical effectiveness in psychiatric disorders.” Biological Psychology. 2009. 82:1-11.

8. Walsh, R, and Roche, L. “Precipitation of acute psychotic episodes by intensive meditation in individuals with a history of schizophrenia.” Am J Psychiatry. 1979. 136:1085–6.

9. Mathers, C. and Loncar, D. “Updated projections of global mortality and burden of disease, 2002–2030 data sources, methods and results.” Evidence and Information for Policy. 2005.

Reducing Concussions in Football?

The awareness and medical implications of concussions in professional sports have increased significantly over the last half-decade, especially in National Football League (NFL). The direct responsibilities of both the NFL and players to manage the concussion question have previously been outlined in the blog here. Unfortunately neither party, especially the players, has administered those responsibilities appropriately. While behavior still needs to be adjusted to reduce concussion probability, there may be biological strategies that can help maximize positive health outcomes for athletes with regards to concussions.

Various concussion research has involved evaluating rugby-based headgear as well as other helmet designs, custom-fitted mouth guards and face shields (in ice hockey).1-4 The general conclusions are that no particular type of headgear, including rugby-based, reduces the probability of acquiring a concussion any more effectively over most other types of helmets and there is no strong evidence that mouth guards or face shields reduce concussions.4,5 In addition significant amounts of research has focused on post-concussion symptoms and recovery. However, less research has been conducted on secondary factors to developing concussions. For example football has changed significantly in many ways since the early professional days in the 50’s and 60’s; one way that could be very relevant to concussion development is the means in which the brain processes and consumes oxygen.

There are two chief theories that attempt to explain the biological origins of a concussion. First, some believe that the first step involves a significant level of at least one type of force, linear, rotational or angular, that is directly or indirectly applied to the head leading to the disruption of cell membranes in various neurons throughout the brain. This disruption creates an influx of potassium ions to the cells resulting in depolarization and the release of neurotransmitters, usually glutamate.6 The release of glutamate creates a cascade of depolarization among various neuronal networks. Sodium-potassium pumps operate at greater than normal capacity to correct the unnatural and uncontrolled potassium influx, which leads to an energy shortage (excessive consumption of ATP and glucose) resulting in excess lactate accumulation.7-9 All of these elements work in consort to generate neurological imbalance and damage.

Some also believe there is a loss of glucose metabolizing efficiency due to excessive metabolization during the initial stages of the concussion. This loss of metabolizing efficiency is due in part to inefficient lactic acid removal after the concussion event, at least in rodents, which leads to reduced blood flow for a number of days after a concussion event.7,10 Interestingly enough this lack of blood flow could explain why an individual has a higher concussion probability rate (vs. baseline) for a number of days after the initial concussion event because there is less cerebral blood flow and greater ability to produce slosh and other forces. Whether or not calcium accumulation results in cell death through a secondary pathway is unclear.11

Second, some believe that rapid acceleration/deceleration of the brain due to forces and collisions create “slosh” (movement of liquid inside containers that are undergoing motion). Slosh occurs in tissues and fluids with differing densities (white matter, skull, spinal fluid, blood, gray matter, etc.) because they accelerate/decelerate at different rates leading to shearing forces and even hydrodynamic cavitation.12,13 Cavitation is the formation of vapor cavities in liquid born from a rapid change to a lower pressure (below saturated vapor pressure of the liquid). After these cavities are formed an increase in pressure results in their implosion creating shockwaves. These shockwaves create damage throughout the brain.14

Whether or not concussions are driven by functional or structural changes is still an open question. While structural damage has been demonstrated in some brains of humans, commonly resulting in a state similar to Alzheimer’s disease, these changes appear to require numerous concussions over a relatively short period of time (decade or less). Overall it is highly likely that concussions are driven by temporary functional changes, which is why the symptoms are only temporary.

An interesting element about concussions is that both rams and woodpeckers can tolerate head impacts much larger than those that are thought to induce concussions in humans. For example typical football impacts generate 25 to 50-g of force whereas rams ramming each other during demonstrations of supremacy generate 500-g and woodpeckers generate 1200-g numerous times a day.15 This ability to experience head trauma without detrimental outcome is thought to be managed by manipulating intracranial volume and pressure. Both animals have different methodologies behind this ability; rams utilize a carbon dioxide-mediated response to altitude and woodpeckers utilize altered jugular outflow.12,15 These methods create efficient brain compacting, which reduces motion and shearing forces. Clearly altering jugular outflow is not reasonable for humans, but it may be possible to incorporate information from an altitude response to reduce the probability of concussions.

Some of the central features that drive a concussion occur within the skull, which is why no helmet can ever clinically claim to reduce concussions because they cannot directly influence forces inside the cranium. However, playing at an increased altitude (venues at or exceeding 644 ft.) appears to decrease the probability of developing a concussion. A recent study of concussion occurrence in the NFL calculated a 30% reduction at higher altitudes.15 Recall from above that one of the elements that is thought to causes concussions is the brain “sloshing” around creating various forces and cavitation. Clearly one of the methods to reduce the probability of concussions is to increase intracranial volume that would allow the brain to reduce “slosh”.15,16

Some have argued that inadequate adjustment to altitude reduces the ability of players to exert maximum effort thus reducing the amount of force applied when running, blocking and tackling thereby reducing the probability of concussions. However, studies in the past have demonstrated that there is no significant enhancement of fatigue at the 644 ft. threshold; therefore, this “reduced force” reasoning should not be applicable. If concussion probability reduction occurred only at higher altitudes like 2000 ft. then it would be more plausible, but that is not the case.

The protective effect of higher altitudes may directly involve the rate of oxygen flow to the brain. The chief change relative to oxygen at higher altitudes is a drop in oxygen partial pressure throughout the body, especially the brain. For example alveolar oxygen partial pressure drops from 103 to 98 when moving from 0 to 1000 ft.17,18 This reduced partial pressure lowers the available oxygen in the blood for consumption by various organs including the brain. With a greater demand for oxygen cerebral blood flow increases, which increases intracranical volume and decreases the probability of concussion. This relationship between oxygen and altitude could also explain why there is not an empirical linear relationship in the above study between altitude and oxygen for after a certain point players become fatigued by the lack of ambient oxygen and resort to supplementing oxygen consumption with outside sources. This supplementation could explain why Denver, the highest altitude playing field in the NFL, did not have the lowest rate of concussion.15

The relationship between oxygen-related blood flow and concussions also can influence the rate of inertial cavitation. The skull can be considered a rigid vessel with a reduced compliance (due to increased intracranial volume) the probability of inertial cavitation decreases because there is less sudden directional changes in near-by fluids reducing the formation of vapor cavities.13,14,19,20 Therefore, increased cerebral blood flow reduces both the force and the cavitation elements associated with potential concussion progression.

So how is cerebral blood flow controlled naturally? The brain has a much higher metabolic requirement for oxygen than other organs and uses approximately 20% of existing oxygen to maintain normal function. Under normal biological operation blood flow to the brain is constant due to vascular resistance provided by large arteries and parenchymal arterioles and tight gap junctions.21,22 Flow is increased through the dilation of upstream vessels avoiding downstream microvascular pressure.23 Overall blood flow rates are controlled by vasodilation of distal to proximal arterial and myogenic mechanism24 maintaining a cerebral blood flow at approximately 50 mL per 100 g per minute as long as cerebral perfusion pressure (CPP) is between 50-60 and 160 mmHg.25

If CPP falls below 50-60 mmHg cerebral ischemia occurs and the body attempts to compensate by increasing oxygen extraction from blood and increasing blood flow to the brain.26,27 Part of the reason blood flow needs to increase is because the partial pressure of oxygen drops hemoglobin saturation from 100% to 50%.28 There is a rather linear relationship between blood flow and CPP below 50-60 mmHg, but there is little change in metabolism regardless of oxygen partial pressure.28 Under these hypoxic conditions cerebral arteries and arterioles reduce vascular resistance increasing vasodilation and smooth muscle hyperpolarization.

An increase in CO2 concentration has a similar effect to reducing oxygen concentration because of a decrease in oxygen partial pressure. In response cerebral blood flow is increased through similar methods as above (cerebral arteries and arterioles dilation).29 The biological effect of CO2 inhalation is rather significant where a solution of 5% CO2 increases cerebral blood flow by 50% and a 7% CO2 solution increases blood flow by 100%.30 The chief mechanism behind hypercapnic vasodilation is the direct influence of extracellular hydrogen on vascular smooth muscle as changes in CO2 partial pressure along does not change cerebral artery diameter.31,32

With the above information it appears that increasing the ratio of CO2/oxygen in the blood will increase the rate of blood flow to the brain, which will decrease the probability that an individual suffers from a concussion. Outside of playing at altitude what are the methods to increase cerebral blood flow? One long term solution could be breathing conditioning where continuous periods of holding one’s breath would increase CO2 concentration in the blood stream over a very short period of time which could lead to the expansion of carotid arteries increasing blood flow to the brain.

However, breathing conditioning is a long-term solution that many individuals may not have the time or the inclination to undertake, so is there a short-term solution that can temporarily increases cerebral blood flow? One possibility that springs to mind is the consumption of a specific carbonic acid beverage (basically a stronger version of soda/pop). Whether or not this method would be viable is unclear as there is almost no empirical information regarding how the consumption of such a beverage would influence cerebral blood flow or other systems and organs.

Another question is whether or not the use of mouth-to-mask ventilation increases concussion risk by temporarily reducing cerebral blood flow. While there appears to be no direct evidence regarding this question, anecdotal evidence involving the drop-off of concussion reduction at very high altitudes (Mile High Stadium in Denver for example) appears to support this idea.
Basically the technical aspect of this question is how does the brain respond with respects to blood flow to a brief (15-30 seconds) inhalation of 50-100% oxygen and what is the residence time of this response? The answer to this question could change the use of mouth-to-mask ventilation to only emergency situations rather than an augmented pick-me-up after a 26-yard run in order to avoid increasing the chance of a concussion in the next play.

There are numerous behavioral methods to reduce the probability of concussions in football including ensuring that defensive players tackle properly (no leading with the head) and proper neurological evaluation after significant head contact. However, another avenue of concussion prevention has remained generally unexplored. Based on some preliminary evidence it appears that devising a strategy to increase cerebral blood flow to act as a “biological helmet” could go a long way to decreasing the probability of concussion development. The one significant caveat to the development of such a method would be determining any long-term detrimental effects associated with multiple temporary increases to cerebral blood flow. Overall it is important to investigate biological methods as well as material methods and behavioral solutions to prevent concussions in sports.

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Citations –

1. McIntosh, A, et Al. “Does padded headgear prevent head injury in rugby union football?” Med Sci Sports Exerc. 2009. 41:306–13.

2. Benson, B, et Al. “Head and neck injuries among ice hockey players wearing full face shields vs half face shields.” JAMA. 1999. 282:2328–32.

3. Newsome, P, Tran, D, and Cooke, M. “The role of the mouthguard in the prevention of
sports-related dental injuries: a review.” Int J Paediatr Dent. 2001. 11:396–404.

4. Benson, B, et Al. “What are the most effective risk-reduction strategies in sport concussion?” Br. J. Sports Med. 2013. 47:321-326.

5. Benson, B, et Al. “Is protective equipment useful in preventing concussion? A systematic review of the literature.” BJSM. 2009. 43:i56–67.

6. Katayama, Y, et Al. “Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury.” J Neurosurg. 1990. 73(6):889–900.

7. Giza, C, and Hovda, D. “The neurometabolic cascade of concussion.” J Athl Train. 2001. 36(3):228–235.

8. Yoshino, A, et Al. “Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state.” Brain Res. 1991. 561(1):106–119

9. Andersen, B, and Marmarou, A. “Functional compartmentalization of energy production in neural tissue.” Brain Res. 1992. 585(1–2):190–195.

10. Maugans, T, et Al. “Pediatric Sports-Related Concussion Produces Cerebral Blood Flow Alterations.” Pediatrics. 2012. 129:28-38.

11. Meehan, W, and Bachur, R. “Sport-Related Concussion.” Pediatrics. 2009. 123;114-123.

12. Smith, D, et Al. “Internal jugular vein compres­sion mitigates traumatic axonal injury in a rat model by reducing the intracranial slosh effect.” Neurosurgery. 2012. 70:740-746.

13. Turner, R, et Al. “Effect of slosh mitigation on histo­logic markers of traumatic brain injury: laborato­ry investigation.” J Neurosurg. 2012. 117:1110-1118.

14. Goeller, J, et Al. “Investigation of cavitation as a possible damage mechanism in blast-induced traumatic brain injury.” J Neurotrauma. 2012. 29:1970-1981.

15. Myer, G, et Al. “Rates of concussion are lower in National Football League games played at higher altitudes.” Journal of Orthopaedic & Sports Physical Therapy. 2014. 44(3):164-172.

16. Kurosawa, Y, et al. “Basic study of brain injury mechanism caused by cavitation.” Conf Proc IEEE Eng Med Biol Soc. 2009. 7224-7227.

17. Altitude oxygen calculator. Available at: http://www.altitude.org/oxygen_levels.php.

18. Kraemer, W, et Al. “Resistance training and youth.” Pedi­atr Exerc Sci. 1989. 1:336-350.

19. Church, C. “A theoretical study of cavitation generated by an extracorporeal shock wave lithotripter.” J Acoust Soc Am. 1989. 86:215-227.

20. Zhong, P, et Al. “Effects of tissue constraint on shock wave-induced bubble expansion in vivo.” J Acoust Soc Am. 1998. 104:3126-3129.

21. Faraci, F, and Heistad, D. “Regulation of large cerebral arteries and cerebral microvascular pressure.” Circ Res. 1990. 66:8–17.

22. Cipolla, M, et Al. “SKCa and IKCa Channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: effect of ischemia and reperfusion.” Stroke. 2009. 40:1451–1457.

23.Kulik, T, et Al. “Regulation of cerebral vasculature in normal and ischemic brain.” Neuropharmacology. 2008. 55:281–288.

24. Iadecola, C, et Al. “Local and propagated vascular responses evoked by focal synaptic activity in cerebellar cortex.” J Neurophysiol. 1997. 78:651–659.

25. Phillips, S, and Whisnant, J. “Hypertension and the brain.” Arch Intern Med. 1992. 152:938–945.

26. Hossmann, K-A. “Viability thresholds and the penumbra of focal ischemia.” Ann Neurol. 1994. 36:557–565.

27. Iadecola, C. Cerebral circulatory dysregulation in ischemia. In Cerebrovascular Diseases, Ginsberg MD, Bogousslavsky J. (Eds.). Cambridge, MA: Blackwell Science, 1998. 319–332.

28. Steiner, L et Al. “Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity.” Br J Anaesth. 2003. 90:774–786.

29. Reivich, M. “Arterial PCO2 and cerebral hemodynamics.” Am J Physiol. 1964. 206:25–35.

30. Kety, S, and Schmidt, C. “The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest. 1948; 27:484–492.

31. Kontos, H, Raper, A, and Patterson, J. “Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels.” Stroke. 1977. 8:358–360.

32. Kontos, H, et Al. “Local mechanism of CO2 action of cat pial arterioles.” Stroke. 1977. 8:226–229.

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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A Possible Strategy for Dealing with Stroke Damage

Interestingly despite the hype and fear attributed to cancer, stroke is the second leading cause of death in the developed world behind only heart disease and responsible for approximately 10% of deaths worldwide.1,2 There are two major types of stroke: ischemic and hemorrhagic. An ischemic stroke is due to a lack of blood flow largely born from a blockage (arterial embolism, thrombosis, etc.). A hemorrhagic stroke is due to a hemorrhage in the brain resulting in abnormal blood flow creating significant losses in most areas of the brain and overflows in others. Not surprisingly limiting blood flow to the brain can rapidly facilitate the loss of brain function due to cellular malfunction and death resulting in difficulty moving one or more parts of the body, trouble talking and hearing, visual difficulty, as well as other motor and cognitive breakdowns eventually leading to death.

Ischemic strokes are more common than hemorrhagic (approximately 80% to 20%) and have four major causes: 1) Thrombosis; 2) Venous thrombosis; 3) Embolism; 4) Systemic hypoperfusion.1,3 Thrombosis involves the obstruction of a blood vessel due to clot formation in the local region. Embolisms are obstructions, typically clots, fat globules or gas bubbles, that form elsewhere in the body that result in blocked blood flow in some other region away from the location of the obstruction. Systemic hypoperfusion is a general decrease in blood supply born from a psychological condition like shock. Due to the fatal outcomes associated with a stroke numerous methods have been developed to recognize its onset, occurrence and aftermath. The onset of most strokes involve face weakness, arm drift and abnormal speech as early symptoms.4

These symptoms only describe overt strokes; another type of stroke is covert where symptoms are relatively absent. Fortunately covert strokes typically result in less brain damage than overt strokes. However, despite the reduced permanent damage, covert strokes are much more common (5x more probable) and can result in significant mental problems like dementia and depression.5 Unfortunately the ongoing problem with strokes is that despite continuing advances in treatment and rehabilitation a vast majority of people who suffer from a stroke will have a permanent cognitive and/or motor impairment.

Some prevention methodologies have been proposed to reduce the probability of a stroke or reduce the damage that occurs during a stroke. Not surprisingly there is significant support for routine physical activity as a means to reduce the probability of an ischemic stroke.6-8 In fact meta-analysis suggests that the benefits of exercise are indiscriminate with regards to sex and that the most active individuals have a 25% reduced rate of stroke versus those who are least active.7

One rationality for why consistent exercise is able to achieve this result is the improvement of vascular function, which increases blood flow efficiency, reduces hypertension and limits infarct size.9,10 Another possibility may simply be that those who exercise the most have healthier lifestyles on a whole then those who do not exercise a lot; however, this rationality foregoes the general health benefits exercise brings. Unfortunately due to the nature of a stroke there is little one can do from a preventative standpoint beyond live a reasonably healthy life of no smoking, no to very moderate drinking, exercise and proper diet.

Some could argue that one should take anti-coagulants like warfarin or blood thinners like aspirin, but these pharmaceutical agents are more reactionary treatments intended to prevent repeat strokes or secondary short-term strokes (similar to aftershocks) versus reducing damage derived from principle strokes. Aspirin is especially used by individuals who have previously suffered myocardial infarctions or with high cardiovascular risk factors like atherosclerosis.5 Some also support the use of clopidogrel and dipyridamole to increase the probability of platelet flow to avoid platelet aggregation, which can lead to clot formation.5 However, there are some concerns that improper timing in treatment with anti-coagulation agents could create a net physiological detriment.11 After the event ischemic strokes are commonly treated with thrombolysis (i.e. clot busting drugs) or intra-arterial fibrinolysis (site injection through a catheter) whereas hemorrhagic strokes typically require neurosurgery due to the excessive bleeding.5

However, these reactionary methods are active methods for reducing damage born from a stroke, which are largely dependent on the existence of secondary available parties because the suffering individual is frequently rendered incapable of assisting him/herself. The development of a passive method to reduce damage without the need to take drugs would go a long way to increasing the probability for reducing damage from strokes, reducing long-term healthcare costs and increasing qualify of life. One possibility for a more passive “damage prevention” therapy revolves around neutralization of reactive oxygen species (ROS).

In the 80s it was theorized that oxidative stress induced damage from ROS was prevalent in the reperfusion stage of post-ischemic strokes and accounted for a significant amount of damage, especially because cells have a reduced capacity to neutralize ROS in ischemic stroke conditions.12-16 The origin of ROS in cerebral ischemia is derived from the events that occur during reoxygenation after spontaneous or thrombolytic reperfusion. The abnormally large and rapid influx of oxygen after the depravation of oxygen leads to accelerated enzymatic reactions, especially in the electron transport chain facilitating the creation of larger than normal concentrations of ROS.

In addition there is a slower build-up of natural antioxidants due to transcription and translation delays due to the lack of oxygen and other signaling molecules. Unfortunately there are still questions regarding the exact mechanisms of this injury, i.e. if it differs from oxidative damage born from ROS in other parts of the body, but the presence of peroxynitrite (ONOO-) and hydroxyl radicals (OH-) are considered important for significant ischemic damage due to their aggressive and indiscriminate damage potentials.17,18

If the ROS damage theory is correct then an obvious prevention strategy would be to increase antioxidant concentrations. However, increasing these concentrations on a dietary or pharmaceutical level has an immediate problem in that both types of antioxidants have difficulties passing the blood brain barrier, if they can at all. Another problem is that there are questions to the general effectiveness of significant antioxidant concentrations derived from pharmaceutical origins where consumption may actually endanger health rather than improve it due to restraints on the ability of cells to absorb these antioxidants.

Another concern with an antioxidant strategy is that while ROS are cytotoxic at large concentrations most also have important roles as signaling molecules that regulate various processes like cellular differentiation, proliferation and apoptosis or even protect against bacterial infections.19-21 Thus there is the possibility that increasing antioxidant concentration too much can neutralize these signaling operations and create negative biological outcomes. Therefore, an alternative strategy is required if antioxidants are going to be utilized to reduce ROS damage in strokes.

The best strategy seems to be providing a natural reactant molecule that will allow the body to facilitate increased natural antioxidant protection. One option for achieving this “on-site limited neutralization” strategy may be increasing gaseous biological hydrogen. Previous research has demonstrated that hydrogen can selectively reduce ONOO- and OH- and have a protective effect on cerebral, hepatic, intestinal, lung and myocardium I/R injury along with neonatal hypoxia ischemia and cerebral ischemia.22-27 This protective effect seems to depend on hydrogen concentrations of approximately 25 umol/L.22

The antioxidant effect of hydrogen also has various secondary advantages: 1) its high natural permeability allows it to penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus; 2) it appears to have a specific selectivity which targets highly reactive ROS leaving less active ROS to perform their necessary secondary messenger signaling functions; 3) a toxicity threshold that is so high that hydrogen is basically non-toxic at any realistic concentration.22

There are two major methods for increasing gaseous hydrogen concentration in the body. First, direct consumption typically achieved by consuming hydrogen-doped water or inhaling hydrogen gas. Hydrogen water is commonly created through electrolysis increasing free hydrogen concentration to anywhere from 0.6 mM to 0.8 mM whereas inhalation of hydrogen gas typically occurs in a 2% by volume hydrogen mixture.28 Basically the feed is designed to replace nitrogen with hydrogen maintaining oxygen concentration.

The second method for increasing biological hydrogen concentration utilizes bacteria in the intestinal system. Bacteria are able to produce excess amounts of hydrogen as a byproduct of fermentation. In most situations there is little to no biological influence from this hydrogen production due to the typical level of normal hydrogen concentrations.29 However, if an individual consumes certain foods fermentation levels can be increased dramatically producing a biologically relevant effect.

One of these key “hydrogen producing” foods is lactulose. Lactulose is a synthetic sugar comprised of one fructose and one galactose molecule and is commonly used in the treatment of constipation.30 The principle reasons for the hydrogen capacity of lactulose is its complex nature and it cannot be digested by the human digestive infrastructure. 20 grams of lactulose can increase exhaled hydrogen to a similar level as 300 ml hydrogen saline with a longer resident time in the body.2,30 While lactulose is relatively non-toxic from a direct consumption perspective there are some concerns that excessive and routine consumption can result in an increased probability for small intestinal bacterial overgrowth.

What is the methodology behind how hydrogen is able to neutralize ROS? Past research supports increasing hydrogen concentrations leading to increases in HO-1, CAT and SOD all agents that are able to neutralize various ROS.31,32 However, after more detailed analysis hydrogen also seems to increase the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).16 Nrf2 is viewed as one of the principle pathways that governs the expression of molecules which act to neutralize oxidative stressors. Some believe that this activation is based on a form of hormesis where H2 is able to mitigate the effects of more toxic ROS species allowing overexpression of less toxic ROS, which leads to the activation of Nrf2 eventually neutralizing the lesser ROS species.22 In scenarios that lack sufficient H2 concentrations there is a higher probability of the more toxic ROS trigger cell damage and apoptosis limiting the future activation of the Nrf2 pathway leading to a cascade damage effect.

This hormesis process is thought to occur as followed. Under normal conditions Nrf2 is stored in the cytoplasm by Kelch like-ECH-associated protein (Keap1) and is tagged by Cullin 3 for ubiquitination resulting in a typical half-life of only 20 minutes. Under oxidative stress conditions it is thought that cysteine residues in Keap1 are disrupted dramatically reducing the probability of Cullin 3 tagging both through reducing binding efficiency and increasing Nrf2 mobility as disruption of Keap1 allows Nrf2 to translocate into the nucleus. Presence in the nucleus allows Nrf2 to form a heterodimer with small Maf protein and bind antioxidant response element (ARE) that activates numerous anti-oxidative genes initiating their transcription and translation.

However, hormesis is a somewhat controversial idea biologically. So others believe that hydrogen directly activates Nrf2-dependent genes like HO-1 and it is Nrf2 activation that results in the neutralization of ROS. This belief is supported by research where the protective effects of hydrogen were lost in Nrf2-deficient mice.31 While there exists the possibility that hydrogen can directly scavenge ROS the activation of Nrf2 appears to be the dominant method behind the correlation between increased hydrogen concentration and reduced ROS damage. However, the exact relationship between hydrogen, ROS neutralization and Nrf2 activation remains unclear. Despite the lack of specific details in this relationship, both the consumption of hydrogen doped saline/water and the consumption of lactulose increase hydrogen concentrations in vivo and also has neuroprotective effects with regards to strokes.27

Another possible mechanism for hydrogen-induced protection could involve not hydrogen directly, but the conversion of hydrogen to hydrogen sulfide (H2S). There is some evidence to suggest that H2S is a cytoprotective against oxidative stress in similar context to Nrf2,33-36 especially with regards to peroxynitrite (ONOOH/ONOO-) or hypochlorite (HOCL).37,38 While some believe that this antioxidant ability is derived from direct scavenging of oxidants due to its comparable reactivity to cysteine and glutathione,33,38,39 this belief does not seem accurate because the reaction between H2S and ROS is too slow41 and the H2S concentration is too low in vivo40,42 even despite the possibility of metallic catalyst availability.43 Therefore, H2S may interact with Nrf2 increasing expression rates and thereby increasing its protective effects against ROS. Of course one of the problems with theorizing about the role of H2S as an antioxidant is the lack of reliable methods to specifically measure H2S in vivo to tie H2S concentration increases to Nrf2 concentration increases.44,45

There is remaining uncertainty corresponding to increasing gaseous hydrogen concentration in the blood and its role in managing stroke damage, but studies in mice have demonstrated encouraging results regarding stroke induced damage reduction that should drive further study in humans.2,27 In fact some preliminary studies with lactulose has demonstrated reduced symptoms in Parkinson disease patients.27 With the general cost of lactulose or hydrogen doped water being very cheap if this method is applicable to reducing damage from strokes in a passive manner (just drink x amount of hydrogen doped water a day) millions of dollars can be saved in healthcare expenses as well as increasing the quality of life for numerous people. Overall while this hydrogen preventative theory is in its early stages of development, it would be in the best interest of official organizations like the American Stroke Association to investigate human applications of increasing hydrogen concentrations to reduce stroke damage.


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