By Peter Newsom, MD

Introduction

The short-term effects of COVID-19 on public health have been well documented.  However, COVID-19 has also become increasingly associated with various long-term cognitive and behavioral difficulties, which are often chronic and may be permanent. Patients experiencing these challenges are referred to colloquially as “long-haulers.”¹

The most common cognitive and behavioral difficulties encountered by long-haulers include “brain fog” (an inability to think clearly or concentrate)² and chronic exhaustion. The latter is similar to chronic fatigue syndrome,³ and is often referred to in the literature as myalgic encephalitis/chronic fatigue syndrome (ME/CFS).^4,5 The foregoing challenges manifest themselves in 10% to 60% of all COVID-19 infections⁶ and may occur even in mild or even completely asymptomatic infections.⁶ Other neurological symptoms encountered with long-haulers include a feeling of disorientation or confusion, an inability to feel fully awake, mood swings, and patterns of irritability or emotional lability.⁷

Patients recovering from a COVID-19 illness may exhibit permanent brain damage in various forms. This damage may manifest itself as large, radiographically visible lesions (such as ischemic infarcts), intracranial hemorrhages, venous thromboembolism, MS plaque aggravation, diffuse leukoencephalopathic changes, supratentorial deep and subcortical white matter changes, and punctate microhemorrhages.^8-10 In many of these cases, the neurologic deficits may be considerable, and may result in significant and permanent neurological and psychiatric morbidities or disabilities.¹¹

In this paper, we identify some of the possible physiological origins of the cognitive and behavioral difficulties encountered by long-haulers and propose a low-risk treatment modality that may help to ameliorate them. This treatment modality, known as photobiomodulation (PBM), is ideally accompanied by synchronized sound and augmented with a technique known as gamma flicker. PBM may provide an effective form of treatment for the long-term symptoms experienced by long-haulers that have proven resistant to other treatment modalities.

Brain Physiology

The potential of PBM in treating the long-term symptoms associated with COVID-19 may be appreciated within the context of brain physiology and a few of the anatomical aspects of virally induced brain trauma.

Many of the routine cognitive functions performed by humans on a daily basis require the simultaneous participation of multiple, widely separated locations of the cerebral cortex known as cortical lobules.  These lobules interact with each other via a series of long tracts of nerve fibers known as white matter.¹² White matter allows the cortical lobules to coordinate their activities in carefully regulated degrees of coherence, at times requiring higher degrees of coherence, and at other times requiring lower degrees of coherence.^13,14 Ultimately, the ability of cortical lobules to work together with the proper degree of coherence allows the human brain to perform many of the higher functioning tasks that are necessary and commonplace in daily life.¹⁵

For example, the act of reading requires the coordinated functioning of multiple lobules located in the visual cortex areas and in both prefrontal cortical areas, and further requires the participation of lobules located in the left temporal areas that are associated with the understanding of human speech.^16,17 These disparate lobules are linked by long tracts of white matter and must interact with each other in the requisite manner, and with the necessary degree of coherence, to make reading possible.^18,19 In this respect, these long tracts of white matter may be thought of conceptually as part of the circuitry of the brain. However, the brain is a biological machine and all of its components are living matter. Hence, unlike the inert circuitry found in common electrical devices, the tracts of white matter within the brain form a circuitry that is pulsing with life and is actively working.

How the “Weak Link in the Chain” Can Have Consequences

In order to perform common cognitive functions such as reading, it is necessary for disparate lobules within the brain to be working properly and at their normal, incredibly high rates of speed.  Since these lobules must operate in concert, all of the long fiber tracts of white matter extending between them must be functioning properly.^20,21 If any link in this fragile chain is compromised, then the associated cognitive functions may become difficult or impossible to perform.²² Hence, the aphorism that “A chain is only as strong as its weakest link” is applicable when considering the consequences of physiological trauma to the brain, such as those accompanying a COVID-19 infection.¹²

It will be appreciated from the foregoing that the loss of any discrete cognitive ability as a sequelae to a COVID-19 infection does not require that the entire brain be affected. Rather, a decrease in function can result from any area of impaired functionality. This impairment may arise from disruptions occurring in cortical lobules necessary to the circuit, or from damage to any part of the white matter linking these lobules. Moreover, any of these injuries may prove to be permanent or temporary.

We now have a simple picture to begin with in assessing the long-term effects of a COVID-19 infection. Namely, after the infection resolves, the brain may have suffered damage that manifests itself as one or more neurological symptoms. This damage may occur broadly across wide swaths of the cortex as well as in the deeper parenchyma.^23-25 It may also present as smaller areas of injury peppered across the brain,^26,27 or as a single small area of injury^27,28 that happens to be present in a critical cortical area²⁹ or a critical long tract connecting cortical areas essential to the function in question.

It was recently noted that the MRI of COVID-19 brains showed white matter “littered with tiny lesions.”²⁷ These lesions were posited as a possible cause of neurological problems encountered in COVID-19 patients, including memory lapses, difficulty in concentrating or finding words, or stuttering. In brief, any injury anywhere in the circuit can cause impaired function. 

Latent Viruses and Their Impact on the Brain

Different temporal patterns of neurologic injury may result from viral infections. In many types of viral infections, delayed “post viral syndromes” occur,³⁰ such as those encountered after infection with influenza, mononucleosis, measles, and hepatitis B. This phenomenon is observed in post-COVID-19 patients as well.⁵ In some viral infections, delayed syndromes only occur long after the acute illness has ended. In the case of chickenpox, for example, the virus remains in the body in an inactive form (possibly for decades) after the initial infection, during which time the body appears completely normal. At some later point in time, the virus reemerges to wreak havoc in the form of shingles.³¹ 

The Impact of COVID-19 on Our Immune System and the Brain

Viral infections affect the brain via different pathophysiological pathways.^32,33  In some cases, the virus itself does not actually reach the brain, but nonetheless induces brain pathology. In fact, until recently, many viruses were not thought capable of penetrating the brain tissue itself. This belief was premised on the supposed existence of the  so-called blood brain barrier (BBB), a special type of vasculature that segregates the brain from the circulatory system.³⁴

The BBB is a unique structural characteristic encountered in the arteries supplying oxygen and nutrients to the brain. Within these arteries, endothelial cells (cells which may be anatomically envisioned as tiny bricks that form the tubular walls of the brain’s arteries) are attached to each other by “tight junctions.” These tight junctions may be visualized as a dense or impenetrable “mortar” between the bricks. Together, the endothelial cells and tight junctions form a wall which is theoretically impenetrable to the virus.^35,36

In some viral infections, the virus is believed to remain entirely blood-born, a condition known as viremia.³⁷ In these infections, the virus appears not to actually enter the brain parenchyma itself but can nevertheless cause defects of a cognitive nature. These defects may arise, for example, from the body’s immune response to the virus or from virulence factors associated with the virus.³⁸

One new piece of this pattern may be found in recent research regarding the immune system, whose immunoglobulins and cytokines are also usually unable to get through the BBB.^39,40 According to this research, these complex molecules are able to attach to endothelial cell wall receptors located on the intravascular side of the endothelial cells.^41,42 This appears to then trigger subsequent immune signaling cascades on the parenchymal side (that is, the outside) of those same endothelial cells, thereby allowing these molecules to direct immune events in the brain tissue outside of the bloodstream.⁴³ These immune events then include the microglia, which are the brain’s own immune cells.⁴⁴ This suggests a possible mechanism by which viruses in the bloodstream may be able to communicate with, and influence, the brain’s immune system.

Virally induced damage to the brain can also vary temporally, resulting in temporary or long-term brain dysfunction. In the case of herpetic viral cerebritis known to occasionally affect pregnancy, diffuse damage may occur to the cortex, resulting in long-term scarring.⁴⁵ One consequence of this could be seizures which may be temporary, long-term, or permanent. The scarring and other damage resulting from these infections can also lead to the acute or delayed onset of a variety of psychiatric or cognitive disorders, which themselves may be long-term or permanent. 

How Is the Brain Affected by a Viral Attack?

The brain is protected by both humoral and cellular immunity.⁴⁶ This is due to the presence in the brain of its own dedicated immune system, as well as the presence of immune cells and cytokines that arrive at the brain via the blood supply from other parts of the body (such as, for example, the spleen and thymus).⁴⁷ However, viruses have developed multiple workarounds to these measures, resulting in various forms of possible injury to the brain. Recent work^27,48 has demonstrated the ability of COVID-19 infections to penetrate into the brain parenchyma, and other work has shown its ability to enter the brain in mice. Others have shown that, in some cases, SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, after which it follows neuro-anatomical structures and penetrates defined neuroanatomical areas, including the primary respiratory and cardiovascular control centers in the medulla oblongata.⁴⁹ However, even if the SARS-COV-2 virus does not enter the human brain, viruses in general are known to cause damage to the brain by virtue of the immune response they unleash.⁵⁰ In some instances, viral infections are known to trigger a massive release of immune molecules (including cytokines and chemokines, as well as other inflammatory markers), thus resulting in a particularly powerful immune reaction within the body and brain known as a cytokine storm.⁵¹ Cytokine storms can result in further impairment of BBB function, ultimately resulting in injury to critical brain cells such as neurons and astrocytes.⁵² Cytokine storms can also result in the activation of microglia (the brain’s immune cells), possibly leading to further neuroinflammation and neuronal death.⁵³

  The effect of the SARS-COV-2 virus on the body may be further understood from the perspective of the body’s immune response, which includes the innate immune system and the adaptive immune system.⁵³ The innate immune system functions as a “ready to fire” system, standing by at all times during healthy homeostasis, and ready to repel infections within minutes of the body sensing the presence of any pathogens. The body, in general, and the brain, in particular, have the ability to recognize a wide variety of pathogens, and are also equipped with a store of premade immune biochemicals and immune cells with which to attack them.

The adaptive immune system works in cooperation with, and closely on the heels of, the innate immune system. The adaptive immune system takes a much longer time to attack, often requiring a week or more of preparation before fully responding. During this preparatory period, the adaptive immune system learns to recognize the invading pathogens, ostensibly by cutting them into molecular pieces and chemically recognizing (and subsequently chemically attacking) these molecular pieces and parts.   

What Is Known About Our Immune System’s Ability to Respond to COVID-19?

As previously noted, viruses have developed multiple workarounds for infecting the body, and these workarounds can result in various forms of injury to the brain parenchyma. First, the COVID-19 infection may be able to penetrate into human brain parenchyma. Second, certain deleterious side effects on the brain resulting from the body’s overall immune response to COVID-19 infections have been noted.⁵⁴ It appears that the SARS-COV-2 virus has developed some very powerful abilities to disable or weaken the initial innate immune response (the first line of the human immune response), thus causing it to work inadequately.⁵⁵ Consequently, the virus is able to replicate within the body in the absence of some of the usual early checks on viral replication. This allows the virus to quickly flood the body with a high viral load.5⁶ As a result, the viral invaders may only come under full attack much later in the immune response when the adaptive immune system finally begins producing specific antibodies.  Given the advanced state of the infection at this point in the process, the resulting immune response may need to be much stronger and more overwhelming to accommodate the greatly increased viral load. This situation may account for the dramatic escalation of the immune response and the resulting cytokine storm often observed in severe COVID-19 infections.⁵⁷

A recent article posits that Covid-induced blood flow changes may contribute to brain fog via damage to capillaries, then resulting in decreased O2 delivery to the parenchyma. Thus, capillary damage and persistent inflammation may contribute to these long-haul syndromes, even long after the acute illness is over, resulting in problems with memory, as well as anxiety and depression. It is also a possibility that the decreased O2 delivery plus increased inflammatory markers could also lead to decreases in serotonin, resulting in mood as well as cognitive changes.⁵⁴

The term “cytokines,” as mentioned above, refers to a group of complex protein molecules that serve as signaling molecules to orchestrate the immune response to an infection. These cytokines are not precise in their ability to target exactly where the immune response will actually occur. Rather, the immune attack assumes more of a shotgun approach, and while many of the invading virus particles are hopefully attacked by the indiscriminate fire, significant damage may also be done to the body’s own tissues present at the scene. This fact would then presumably result in all the more extensive damage to nonviral bystander cells in the event of any overwhelming generalized immune response, such as a cytokine storm.⁵⁸

            The foregoing results in significant injury to healthy body tissues and entails the death of some of the body’s own healthy cells. The resulting battle scene leaves behind a significant amount of debris in the form of destroyed virus particles and human cellular debris. If the COVID-19 infection is sufficiently severe, the immune system’s efforts to repair the areas of damaged tissue may leave long-term or permanent scarring in the form of tissue that is now quite possibly less elastic and less able to function physiologically in all the ways the previously normal brain parenchyma would have functioned.  In addition, any damage to the capillaries supplying the brain could presumably further impair physiological function, whether by causing tissue hypoxia or by decreasing the body’s ability to deliver other essential factors needed for healing.⁵⁹

It will be appreciated from the foregoing that, regardless of whether or not the SARS-COV-2 virus actually enters the brain parenchyma during a COVID-19 infection, damage to the brain can theoretically occur simply due to the immune response unleashed by the body’s immune response to the virus. In instances where viral infection appears to trigger a massive release of immune molecules, the resulting cytokine storm can further compromise the BBB.⁶⁰ The compromised BBB may then result in increased leakage of these same cytokines into the brain.³⁹ This may lead to further injury of critical brain cells such as neurons and astrocytes and microglia, as well as the activation of microglia. The extent to which these events ultimately lead to neuroinflammation and neuronal death will vary from case to case.⁶¹ 

After the acute immune response to the virus has concluded, the body attempts to return to a normal, pre-COVID-19 state, a process referred to in physiology as homeostasis.⁶² However, especially in the case of events activating the body’s immune and inflammatory systems, this resolution is sometimes incomplete.⁶³ This may be due to the fact that cytokine signals that might promote strong immune responses or resolution of those immune processes in other areas of the body may have to go through very different mechanisms when it comes to the brain. Moreover, the brain also has its own set of immune cells specialized for the brain (microglia). These cells live within the brain parenchyma. When they become activated, they take part in the killing of bacterial or viral invaders and in the subsequent cleanup.^64,65 However, many aspects of the immune processes that occur within the brain are still poorly understood.

The brain is also known to be generally less able to clean up certain kinds of debris than is the rest of the body. A good example of this is observed when there is bleeding within the brain. When this happens, the hemoglobin protein molecules that leak into the brain parenchyma can be effectively removed and reabsorbed.⁶⁶ However, the iron content of hemoglobin is not as effectively resorbed, and instead, the iron content of the exsanguinated blood can remain in the form of clumps (called hemosiderin or hemosiderin crystals or particles), which then can remain in the brain far longer than the nonferrous protein portion of the hemoglobin molecule.^67,68 These hemosiderin deposits, which have been associated with the pathogenesis of SARS-CoV-2,⁶⁹ can  be an indicator of diffuse axonal injury.⁵³ The amount and location of hemosiderin can be correlated with such neuropsychological  deficits as difficulty with memory and also speed-of-processing tasks.⁵³ Although small, these particles and the axonal injury that accompanies them can disrupt the function of the (frequently extremely small and very finely tuned) neuronal fibers in long tracks.⁷⁰ Originally, these fibers are precisely grouped together in neuronal tracts and are able to efficiently allow information to move around the brain. However, even minute deposits of hemosiderin crystals or diffuse axonal injury can result in disruption of these fibers and therefore also their respective nerve tracts, resulting in significant impairment of higher cognitive abilities.^70,71 As previously noted, any weakening in any part of the chain of any brain circuit can have very significant consequences in terms of the disabilities a patient may suffer as a result of an injury.

How Can We Imagine or Conceptualize an Attack on the Brain Resulting from COVID-19?

As previously noted, once the SARS-COV-2 virus has been allowed to replicate unimpeded for a longer period of time than usual, the resulting viral load may induce an increased immune response. This response may be overwhelming and may reach the level of a “cytokine storm.” Immune responses of this type may result in extensive diffuse or localized damage across a few or many areas of the brain. The foregoing results in significant amounts of cellular and viral debris, which gives rise to a final resolution that may include various patterns of brain scarring.

As previously noted, the weakening of any small link in the chain of any brain circuit can disrupt the entire function of the circuit, especially in tasks requiring large separate networks of neuronal groups spread across the brain. While neurons existing in a given area of the brain prior to any neuronal depletion or thinning in the neuronal ranks due to the COVID-19 infection were presumably perfectly able to carry out their part in whatever large brain network they may have been part of, it may not take much cell destruction, scarring , or capillary injury, or hemosiderin crystals to disrupt or even completely disable the entire circuit. As an example of how sensitive the brain could be to such injury, any remaining neurons in any injured part of the circuit (if there are any) may now be unable to handle the (now increased) load of information processing required for the function of the circuit.

Significant scarring and neuronal loss are likely results of a severe COVID-19 infection,⁷² leading to areas of brain with depleted energy reserves. Neurons are very high energy consumers. Although the brain only accounts for a few percent of our total weight (from 1% to 3% for most adults), it accounts for 20% to 30% of the body’s total energy consumption.⁷¹ Neurons are incredibly energy-hungry, in part because they contain a large number of mitochondria.⁷³ Mitochondria are the ATP generating organs of all cells. In many parts of the body such as adipose tissue, there are comparatively few mitochondria in a given cell. In the average neuron, by contrast, there may be tens of thousands of mitochondria,⁷⁴ due no doubt to the inherent metabolic needs of the other organelles contained within that neuron, as well as their various functions within that neuron. The presence of such a large number of mitochondria in typical neurons therefore reflects the underlying fact that the neuron is an energy-hungry type of cell and is evidence of that fact.⁷⁵ (This fact also has therapeutic implications, which will be described later in this paper.)

In light of the foregoing, it is conceivable that, when parts of a nerve tract have been partially or completely impaired, the strain on the remaining still functional (or partially functional) neurons may be high enough to quickly deplete them of their ATP stores. This may result in diffuse patterns of neuronal exhaustion, due to the presence of groups of depleted or injured neurons that are thereafter unable to keep up with the processing demands that had previously been spread across a much larger number of healthy cells. These patterns of repetitive neuronal exhaustion could then occur for months, or possibly indefinitely.

Interestingly, this pattern may well account for a symptom pattern that chronic fatigue sufferers often refer to,⁷⁶ in which they describe waking up in the morning with enough energy to concentrate or perform some simple task for, say, an hour, and then suddenly feel so depleted that they are then unable to get out of bed for the rest of the day. Such a temporal pattern of exhaustion could be explained by isolated yet critical areas of brain injury (very possibly in the reticular activating system (RAS), for example, an area responsible for maintaining a normal state of being and feeling awake) developing significant ATP depletion⁷⁷ upon comparatively brief exertion. This depletion can then only be repaired quite slowly (by, for example, sleeping through the night), during which downtime the ATP stores in the affected neurons can slowly be regenerated⁷⁷—resulting in a repeat of this pattern the following morning.

The foregoing underscores the importance of the concept of the weak link in the chain: a small percentage of damaged or destroyed neurons in one localized area may be enough to render that entire circuit incapable of functioning at all or functioning as it used to, even though it may be a circuit essential to a key activity such as feeling fully awake. This may also include a number of particular circuits necessary for tasks demanding lots of concentration, the very sort of task many suffers from COVID-19 brain fog now complain of being no longer able to carry out, or of being able to carry out for only a short period of time before becoming exhausted.⁷⁸

The foregoing presents a very rough picture of brain parenchyma that has been injured, either in small, localized areas or in a more diffuse pattern. The end result includes a significant amount of scar tissue spread or peppered across brain areas wherein a smaller group of neurons are now required to do the work previously shared by a larger number. This situation results in work that was previously accomplished quite well now being performed poorly or possibly intermittently, followed by periods of incomplete or complete dysfunction. Moreover, the smaller number of overworked neurons performing the task repeatedly tire out (partially or completely) until they can recharge their mitochondrial batteries.

As a further complication, the brain’s immune system may also be significantly depleted or exhausted from the heavy task of cleaning up all the cellular and viral debris scattered throughout the injured parts of the brain. This may render the brain more prone to reinfections or to entirely new infections with other pathogens. Furthermore, the microglia, the brain’s own specialized immune cells, may themselves also be exhausted, injured or decreased in number, due to the ability of the Covid infection, or the body’s reaction to the virus, to attack microglia just as it is able to attack neurons.

Possible Therapeutic Ramifications

We believe that photobiomodulation (PBM) is a modality that should be considered for cases of post COVID-19 cognitive impairment for the following reasons:

• PBM with red and near infrared (NIR) light (600 to 700 nm, and 760 to 940 nm respectively) has been shown to have various beneficial effects^79,80:
  • Increase synapse formation,⁸¹
  • Increase BDNF (brain derived neurotrophic factor),⁸²
  • Increase glucose metabolism,⁸³
  • Increase antioxidant levels,⁸⁰
  • Decrease inflammation,⁸⁴
  • Decrease edema.⁸⁵
• PBM has been shown to increase brain circulation through the creation of new arterial blood vessel growth, a known effect of red and near infrared wavelengths.⁸⁶
• PBM has also been shown to interact directly with the mitochondria and to help generate ATP and increase mitochondrial membrane potential, O2 consumption, and ATP production, all of which promotes energy generation and mitochondrial metabolic health for the efficient transport of energy within cells.⁸⁷
• PBM with a 40hz (Gamma) synchronized light and sound has also been shown to possibly increase microglial activity, specifically improving phagocytosis of parenchymal debris.⁸⁸
• PBM with Gamma flicker has also been shown to facilitate the replacement and/or resumption of neuronal functions in 5xFAD mice.⁸⁹

PBM has also been shown to help address chronic fatigue in other non-COVID-19 settings.⁹⁰

It is notable that, whereas severe COVID-19 brain injuries (such as, for example, large CVAs or intracranial bleeds) might be marginally helped by PBM,⁹¹ in our opinion, these may not be the cases that are likely to be helped the most by PBM.  Instead, we believe that the cases more likely to be most dramatically helped by PBM may well be those cases wherein the brain pathology arising from the COVID-19 infection is diffuse and quite possibly radiologically normal and pathologically microscopic in nature, and yet still able to cause significant and long-lasting symptoms. Furthermore, there is currently no treatment available for these syndromes, short of waiting and hoping for the best.  Given the severity of post COVID-19 brain fog or COVID-19 induced chronic fatigue, patients experiencing these conditions risk the development of further issues (such as, for example, the development of clinical depression or substance abuse) in the absence of any ameliorative treatment. We believe that PBM may make a dramatic difference in a considerable number of these long-term cases, both by bringing about at least temporarily improved brain function and its accompanying symptomatic relief, as well as the hope such temporary improvement could well provide.

Possibly one of the most significant capabilities of PBM, with respect to its suitability of treating post COVID-19 brain fog or other sorts of cognitive impairment, is its ability, specifically when using the wavelengths in red and near-infrared range, to penetrate the brain to a depth of up to 50 mm.⁹² This factor allows the light to hit a substantial portion of the cortical lobule neurons, as well as neurons making up long tract fibers of many important brain circuits. Furthermore, PBM not only reaches these tissues but also interacts with them in an amazing way by directly causing physiologic changes within the mitochondria, such as increasing the production of ATP.

Mitochondria contain important intracellular organelles known as cytochromes, which have the ability to absorb visible light energy in the red and near infrared wavelengths, and to use the absorbed energy to help generate ATP.⁹³ Light, especially in the red and near-infrared wavelengths, appears capable of activating cytochrome C oxidase in ways previously well described by others.⁷⁹ This ATP can be thought of as the little packets of electrochemical energy that serve as molecular energy currency in many areas of cellular metabolism. Red and near infrared light are also known to decrease inflammation.⁷⁹

A new component of photobiomodulation is 40 Hz gamma synchronized light and sound. Human brains are known to create a constant stream of endogenous EEG waves over the entire cortex. The frequencies of these waves range from 1 Hz delta waves (during sleep) to well over 40 Hz (so-called ‘gamma’ waves).⁹⁴ However, these higher frequency gamma waves also appear to decrease in extent during aging.⁹⁵ The consequences of this are still being investigated, but they may well contribute to the onset of one or more forms of senile dementia.

Recent research conducted by Singer et al^88,96 explored the ability of the combination of PBM delivered with 40 Hz flicker and synchronized sound to affect the function of microglia cells which, as previously noted, comprise the immune cells of the brain. That research featured genetically altered 5xFAD mice, which are known to develop Aβ plaques and phosphorylated tau tangles at a very accelerated rate similar to that seen in humans with Alzheimer’s disease (AD). For reasons that remain unclear, it appears from this research that the microglia of these 5xFAD mice prematurely cease their regular function of cleaning up the brain parenchyma. It was thus speculated that this might be one reasons that AD brains become increasingly less able to function normally. In these experiments, Singer decided to expose these mice to externally produced light and sound. The light was flickered at a frequency of 40 Hz (in the so-called “gamma” frequency range), and the sound was pulsed at the same frequency in a synchronized fashion. When the mice were exposed to these stimuli, the results were astounding. For reasons that are still to be elucidated, the rodent microglia began functioning again, appearing to resume cleaning up the brain, reduce levels of Aβ plaques, and demonstrating other changes suggestive of improved microglial functioning.

A similar, preliminary study was then conducted on human subjects who had minimal cognitive impairment (MCI). In this study,⁹⁷ the subjects were equipped with special goggles and earphones that exposed them to 40 Hz gamma light and sound for sessions lasting an hour a day. The study appears to show that synchronized light and sound flickering at 40 Hz is capable of changing cytokine levels in the human body. The significance of these changes in cytokine levels has yet to be elucidated in any detail. However, treatment with 40 Hz gamma light and sound also appears possibly to have improved a number of cognitive symptoms in the test subjects, thus underscoring the potential that light and sound therapy may have for improving cognitive function in humans. Of course, these results are preliminary and need to be replicated.

Other light therapy benefits have been clinically proven to help significant brain disorders.     At present, large segments of the human population could well be described as significantly light deprived.  The degree to which this light deprivation can cause real decreases in brain functioning has become increasingly clear in the past two decades. These effects are seen, for one example, in cases of seasonal affective disorder (SAD). In cases of SAD, the body can be described as lacking the blue wavelengths found in outdoor light for the winter months once days become short.¹⁶ This lack of blue light if pronounced enough can result in depression and other brain disorders which may advance to the level of severe depression and psychosis, and which sometimes has even culminated in suicide. This is just one example of how profoundly prolonged inadequate light can affect the brain. Light treatment of the sufferers of SAD with blue wavelengths has been found to be extremely effective in the prevention or amelioration of SAD.⁹⁸ In many cases, exposure to light therapy for 20 minutes every morning is found to be effective in preventing the onset of SAD.⁹⁹

PBM has also been shown to ameliorate various forms of brain injury. This may occur as a result of supplying neurons with an additional source of energy, or by furnishing microglia with some of the energy needed to continue or complete the tasks of cleaning up debris in the brain after significant injuries. Furthermore, PBM is essentially risk-free if applied within the constraints that make its usage safe and predictable. These constraints include staying within the safety limits of any given device with respect to light intensity and treatment duration and avoiding the use of this treatment in certain patient populations (such as patients who are bipolar or subject to epileptic seizures or other patients who have demonstrated other negative reactions to light therapy).

Conclusion

Based on what is already known about the effects of a COVID-19 infection on the brain, it appears more and more likely that once the Covid virus is cleared from the body, there will likely be damage left behind in the brain parenchyma, often in the form of inflammation, but possibly also including areas of regional hypoxia where the brain vasculature has been injured or destroyed. In some cases, the damage will be sufficient to cause the patient to develop cognitive symptoms. Although the damage will likely vary from case to case, the resulting inflammation and any viral and nonviral debris will need to be cleared away and resorbed to whatever extent the microglia can do so.

It appears that resolution of a COVID-19 infection may then result in significant impairment in functioning, which may manifest as brain fog, chronic fatigue, and a large number of other neurocognitive syndromes. These long-term effects have been observed following the full spectrum of COVID-19 patients, from those who are largely asymptomatic during the acute phase, to those with severe acute phase COVID-19 presentations.

It is quite possible that a percentage of these cases mild or asymptomatic cases will prove to be radiologically ‘within normal limits,’ or to have minimal and diffuse findings that may not even be radiologically detectable. It is also quite conceivable that, in those instances where post COVID-19 brain fog and/or chronic fatigue are the principal findings, PBM may well prove to be therapeutic due to a number of reasons as discussed above. 

PBM (and more specifically, PBM with 40 Hz synchronized light and sound) is a very low risk therapeutic modality that shows a great promise at possibly being able to offer help with a significant and growing public health problem. We owe these patients a trial with any therapy that can provide a significant chance of symptom alleviation, which has little if any risk, and which is affordable.

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