How does the brain rid itself of waste products? It surprised me that this question was not empirically answered until 10 years ago, by a Danish neuroscientist named Maiken Nedergaard.

Analogous to the lymphatic system, the glymphatic system (named for its dependence on glia) is a vascular waste clearance mechanism in the brain that facilitates transporting of solutes and waste products from cerebrospinal fluid and the interstitial fluid. CSF from the subarachnoid space enters the brain’s periarterial spaces into the interstitium via protein channels (e.g., aquaporin 4) on so-called astrocytic endfeet and exchanges with brain ISF before perivenous drainage of solutes and waste. (In 2014, scientists from the University of Helsinki and the University of Virginia independently published research demonstrating the existence of a meningeal lymphatic system. It was historically believed that both the brain and meninges were devoid of lymphatic vasculature (although suggestions that they existed can be traced back to the 18th century anatomist, Paolo Mascagni.) In general, the work of the Finnish and American scientists is thought to extend that of Nedergaard in identifying the pathway connecting the glymphatic system to the meningeal compartment.)

Much of the interest in the glymphatic system is due to its association with sleep. Glymphatic activity is dramatically enhanced then while its function is suppressed during wakefulness. The sleep state is particularly conducive to convective fluid fluxes and thereby to clearance of metabolites. Thus, a major function of sleep appears to be that the glymphatic system is turned on and that the brain clears itself of neurotoxic waste products produced during wakefulness.

Another important aspect of the glymphatic system is its relation to aging; the system is more effective in younger mammals. A recent assessment of glymphatic function in old vs. young mice showed a dramatic reduction by 80-90% in aged compared to young mice, the suppression of glymphatic activity including both influx of CSF tracers and clearance of radiolabeled beta-amyloid and inulin. The failure of the GS in aging might contribute to accumulation of misfolded and hyper-phosphorylated proteins and thereby render the brain more vulnerable to developing a neurodegenerative pathology or perhaps escalate the progression of cognitive dysfunction.

Other research has suggested that CSF-mediated removal of the tau protein via glymphatic routes is crucial for limiting secondary neuronal damage following traumatic brain injury. Thus, impairment of glymphatic pathway function can be said to promote tau pathology after such a trauma. The large amplitude of interstitial tau may lead to cellular uptake and initiation of fibrillary aggregates, which attracts additional tau leading to formation of neurofibrillary tangles ultimately resulting in a prion-like spread of the pathology.

The development and/or progression of neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases have been linked to glymphatic system failure via proteinopathic phenomena. Abnormal enlargement of the perivascular space is more frequently observed in Alzheimer’s disease compared to age-matched control subjects, suggesting a spiral of glymphatic routes and further reduction in protein clearance and pathology.

However, abnormalities at the perivascular space are also prominent in non-Alzheimer’s dementia. Only surpassed by AD, vascular dementias are the second most common cause of dementia, and these diseases are also characterized by deformation of the perivascular space. Changes in or surrounding cerebral blood vessels due to hypertension, atherosclerosis or hereditary diseases can cause vascular dementia, which is often the result of pathology in small cerebral blood vessels and capillaries, collectively termed small vessel disease. Enlargement of the perivascular space is frequently observed in small vessel disease.

Tying together sleep, aging and dementia, one could say that the slow and consistent brain activity experienced during deep, non-REM sleep is ideal for the brain’s glymphatic system, which effectively “cleans” the brain of toxic proteins like beta amyloid and tau. The buildup of these proteins, as noted, has been linked to the development of dementia. But because sleep becomes lighter and more disrupted as people age, it’s important for older people especially to take the established guidelines of sleep hygiene seriously.

~ Rylan Dray, Ph.D. – November 2023

Years ago, when I was seeing a psychiatrist for complicated bereavement, she noted that I was “demoralized by physical symptoms,” but did not consider me clinically depressed. That’s because these are two separate syndromes. The DSM-V defines major depression (simplified here) as including depressed mood, most of the day, nearly every day; markedly diminished interests or pleasure; psychomotor agitation and depression; feelings of worthlessness or excessive guilt; diminished ability to think or concentrate; and recurrent thoughts of death. In everyday parlance, demoralization is the process of making someone lose confidence, enthusiasm and hope; to deprive a person of spirit, courage, or discipline; to reduce to a state of weakness or disorder. The demoralization syndrome, not an official diagnosis, is the collection of disturbing existential states associated with a failure to cope. The psychiatrist, Richard Shader, in his 2005 article, “Demoralization Revisited,” refers to it “a state in which one develops a sense of ineffectiveness in the face of repeated defeats” and “a state of despair, hopelessness, helplessness, and loss of meaning and purpose in life, accompanied by a sense of subjective incompetence.” Thus, the distinction between depression and demoralization is that the former is characterized by anhedonia while the latter, by a lost sense of efficacy.

A scale to assess demoralization (the DS-II) has been refined and revalidated. A 16-item self-report instrument, it has a more simplified response format than its 24-item predecessor and has been found to be more user-friendly in the advanced cancer setting. An even briefer scale, the SDS, has been developed with only 5 items, corresponding to the following factors: helplessness, disheartedness, loss of meaning, dysphoria, and sense of failure. Both scales have been shown to have strong psychometric properties.

Naturally, demoralization is observed in various medical conditions, such as cancer, Parkinson’s disease, and heart transplant. The preservation of morale may be a final buffer that protects individuals from the terror of dying and death in the face of progressive disease. In patients with advanced cancer, demoralization has been associated with higher symptom burden, less perceived support, and the emergence of anticipatory fears about pain and suffering, and burdening of loved ones

Demoralization is also common in Parkinson’s disease and is associated with motor dysfunction. In a recent study, demoralization but not depression was associated with motor dysfunction. Discordance in the presence of the two syndromes suggests that demoralization is not a simple marker of depression. Cognitive behavioral therapy rather than antidepressant medication is likely a more appropriate form of treatment for demoralization. In a 2011 study of cardiac transplant recipients, compared to non-demoralized patients, the demoralized patients were found to have more impairments in all the dimensions of quality of life, less psychological well-being, especially the components of environmental mastery and self-acceptance, and more severe anxiety, depressive symptoms, somatization, and hostility.

Demoralization has also been associated with suicidal behavior in various populations and conditions. A recent Italian study assessed the effect of the construct in suicidal patients who attended emergency departments. This was a cross-sectional study which examined the role of demoralization, helplessness, and depression on suicidal ideation and suicidal attempts. Demoralization was related to major depressive episodes, but it was confirmed to be a different and probably more sensitive construct for suicidal behavior, validating its specificity in relation to depression. The authors concluded that demoralization can improve suicidal behavior assessment in EDs, particularly among patients whose suicide risk can be unnoticed. Furthermore, demoralization was seen as representing a clinically useful concept to increase comprehension of the suffering of suicidal patient and a possible target for psychotherapeutic intervention.

In his 2013 article, “Existential Inquiry,” psychiatrist J.L. Griffith provides a detailed psychotherapeutic approach to the problem of demoralization, positing eight “existential postures” of vulnerability and resilience. (Vulnerability: confusion, isolation, despair, helplessness, meaninglessness, indifference, cowardice, resentment; and the corresponding factors for Resilience: coherence, communion, hope, agency, purpose, commitment, courage, gratitude). This could be seen as an application of “positive psychology” since the focus is not on pathologizing questions but rather normalizing ones, in that they ask about “adversities that all people, including the clinician, frequently face” (e.g., “What kept you from giving up?”)

In the Hope vs Despair dimension, for example, there was a case cited of a 64-year-old man who was suicidal because he was facing mandatory retirement and for him his whole life had revolved around his work. He was helped by a three-month brief psychotherapy which included beginning with questions such as, “When did you last feel hopeful? What was that like? Which people in your life must help you to stay hopeful?” In the Agency vs Helplessness dimension, there was a case study of a young woman disturbed by early experiences of a dangerous neighborhood and the absence of reliable parents, who arrived at the initial session feeling helpless and defeated. Questions helpful in this situation include “When was a time when you knew that you were managing your life well, despite problems?; What should I know about you as a person that is not a part of your illness?; and How have you managed to keep these problems from taking total control of your life?”

Timing and careful attention in the observation, validating and normalizing of the patient’s experience are essential, “since resilience-building questions asked prematurely fall flat, regarded as naive efforts to solve tragic problems that are insolvable.” A moment of carelessness in the interviewing can thus undermine the therapeutic relationship and derail the treatment.

~ Rylan Dray, Ph.D. – August 2023

.

.

..

..

..

..

.

.

.

..

..

..

.

.

Recently I had another episode of food allergy with shortness of breath as a symptom. Also some time ago, I experienced dyspnea a couple of times because of obstructive sleep apnea. Needless to say, such disruption of a vital function is a disturbing experience. I was reminded of an old, asthmatic friend who suffered recurrent respiratory emergencies and died of COPD. I ran into him after many years, and, holding up two fingers together, he said, “Me and the Reaper are like that.”

Although “shortness of breath” defines dyspnea, a more comprehensive definition would be “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity, deriving from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses.” (American Thoracic Society)

While the pathogenesis of dyspnea is not completely clear, it is thought to be based on the concept of a regulatory circuit that consists of afferent information relayed centrally (from chemoreceptors for pH, CO2, and O2 as well as from mechanoreceptors in the musculature and the lungs, and a corresponding ventilatory response).

The ventilation/perfusion ratio (V/Q) refers to the relation of oxygen movement to degree of blood saturation in the lung capillaries. Most conditions associated with respiratory discomfort are characterized by increases in ventilation in response to derangements in ventilation-perfusion matching as well as increases in dead space, the presence of metabolic acidosis, or stimulation of pulmonary or chest wall receptors.

The peripheral chemoreceptors, located in the carotid bodies and aortic arch, sense changes in the partial pressure of oxygen in arterial blood and are also stimulated by acidosis and hypercapnia. The central chemoreceptors, located in the medulla, respond to changes in pH and arterial tension of carbon dioxide (PaCO2).

Throughout the airways, lungs, and chest wall are a variety of mechanoreceptors that assist the body in monitoring changes in pressure, flow, and volume in the respiratory system. Stimulation of such receptors in the face and upper airway, which are largely innervated by the trigeminal nerve, can reduce the intensity of dyspnea.

Most of the causes are pulmonary, cardiac, hematological, and psychogenic. (However, Diagnosis Pro, an online expert system, listed 497 distinct causes in October 2010!) I’ll just focus on the first two here; specifically, congestive heart failure and chronic obstructive pulmonary disorder.

Heart failure is a complex clinical syndrome in which the heart cannot pump enough blood to meet the body’s requirements. It results from any disorder that impairs ventricular filling or ejection of blood to the systemic circulation. Patients usually present with fatigue and dyspnea, reduced exercise tolerance, and flued retention (pulmonary and peripheral edema). Heart failure remains a highly prevalent disorder worldwide with a high morbidity and mortality rate. It has an estimated prevalence of 26 million people worldwide and contributes to increased global healthcare costs.

Coronary artery disease and diabetes mellitus have become the predominant predisposing factors for heart failure. Other structural causes include hypertension, valvular heart disease, uncontrolled arrhythmia, myocarditis, and congenital heart disease. The most common causes of decompensated CHF are inappropriate drug treatment, dietary sodium restriction, and decreased physical activity.

The main pulmonary causes of dyspnea, as noted, are COPD and asthma. The former is comprised of emphysema and chronic bronchitis, and is now the third leading cause of death in the U.S. Characterized by inflammation and persistent obstruction to airflow through the lungs, usually caused by harmful inhaled particles (e.g., those of tobacco smoke), the disease manifests itself by dyspnea, a productive cough, frequent chest infections, and persistent wheezing. It can sometimes be asymptomatic. Treatment includes smoking cessation, of course, inhalers, pulmonary rehabilitation, and, in rare cases, surgery. COPD cannot be cured or reversed but for some people, treatment can keep it under control. For others, it may worsen despite treatment.

According to the National Institutes of Health, 1 in 6 people with COPD have never smoked. The common factors that participants who didn’t smoke but had COPD shared were: being 40+, having asthma, and having had a severe respiratory disease as a child. Also, indoor and outdoor pollutants can cause COPD in people who don’t smoke. Symptoms tend to be similar for smokers and non-smokers. Some research has found that the severity of COPD is lower in people who don’t smoke than in those who do.

One more thing about my late friend with the asthma. Before he entered hospice, he suffered his worst crisis, which led to his being put on a ventilator for over a month. He struggled mightily to attain some semblance of recovery. Once he was free, we met at a coffee shop. “I’m not what I was,” he said, “but I’m still here.”

. – Rylan Dray, Ph.D. – March 2023

..

.

.

.

.

.

.

.

By Rylan Dray, Ph.D.

UNLIKE STANDARD Magnetic resonance imaging, which generates images of brain (and other bodily) structure for diagnostic purposes, fMRI (functional…) is employed for clinical purposes *and* research into mental processes using a method called BOLD (blood-oxygen-level-dependent) signaling. Neural activity in the brain is usually linked to increases in local cerebral blood flow, leading to an increases in oxygenation that generate the signal. That is, when an area of the brain is in use, blood flow to that region also increases, a phenomenon known as neurovascular coupling. Thus, by measuring changes in blood flow, brain activity is inferred. Clinical uses include assessment of the effects of stroke, trauma or degenerative disease on brain function, monitoring the growth and function of brain tumors, and guiding the planning of surgery and radiation therapy). In research, subjects generally perform a task in the machine to see which area of the brain lights up. In recent years, fMRI has provided new insights into the investigation of language, pain, learning, emotion, and the formation of memories.

The first evidence supporting a coupling between energy metabolism and blood flow in the brain was provided in the late 19th century by Sherrington & Roy. Although they showed that blood volume does change locally in the brain, it was still unclear whether the brain itself was responsible for mediating these changes. It took till 1948 to confirm that blood flow in the brain is regionally regulated by the brain itself. Kety & Schmidt demonstrated that when neurons use more oxygen, chemical signals cause nearby blood vessels to dilate. In 1990, the fMRI proper was developed when Kwong and Ogawa independently discovered and utilized the BOLD effect.

My favorite fMRI experiment is that of Harvard psychologist Joshua Greene who in 2001 published research showing that moral decision-making relies on emotion rather than on pure reason. His group used fMRI to scan subjects as they read about moral dilemmas, and found that brain areas associated with emotion lit up when the more vexing scenarios were considered. However, the use of neuroimaging in psychology has been criticized as being scientifically unsound (about which, more presently), some like neuroscientists Rodolpho Llinas and W. R. Uttal likening it to phrenology, the 19th century pseudoscience that claimed to divine personality traits from skull bumps corresponding to discrete, specialized areas of the underlying organs.

“We are peering into a black box and attempting to draw conclusions,” a neuropsychologist I worked with during my rehab counseling internship told me. “Tricky business at best.” He conceded, though, that Greene’s moral dilemmas study “has at least face validity.” In a personal communication, Joshua Greene said in response that while there is some merit to such criticism — and he agreed that there has been a fair amount of regrettable hype– this merely reflects the lack of development of the science. He expressed optimism that its present crudity will be overcome. “Part of what we’re doing now is just getting our bearings, developing a more detailed functional map of the brain. You can call all that ‘phrenology’, but if it’s accurate…then it’s valuable.”

A 2020 review study had bad news for scientists keen on using task-oriented fMRI to draw conclusions about any one person’s brain. Ahmed Hariri, a Duke University neuroscientist, had been using the technology for many years to predict a person’s patterns of thoughts and feelings during specific mental tasks but started to see unreliable results across individuals when they were tested more than once. His group then re-examined 56 published papers on fMRI data to gauge their reliability across 90 experiments. The team concluded that for 6 out of 7 measures of brain function, the correlation between tests taken about 4 months apart was poor. In their paper, they presented “convergent evidence demonstrating poor reliability of task-fMRI measures…Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery of for individual-differences research.” They added that the situation could be remedied in part if tasks are developed “from the ground up to optimize reliable and valid measurement.”

Of course, test-retest reliability is hardly the only problem fMRI faces. In fact, one article has listed 26 “controversies and challenges” for the technology: Neurovascular coupling; draining veins; linearity; long duration; mental chronometry; negative signal changes; resting state source; dead fish activation; global signal regression; motion artifacts, and so on. Neurovascular coupling, as noted earlier, is the physiological basis of fMRI but the authors write, “We know that the [cerebral] flow response is robust and consistent. We know that in active areas, oxygenation in healthy brains always increases; however, we just don’t understand why it’s necessary.” Just one more comment about this: re: “dead fish activation” – In 2006, scientist Craig Bennett showed BOLD activation in a dead salmon’s brain. (He discovered this when whimsically calibrating the machine, substituting odd items for the standard balloon.) While it illustrated statistical weakness regarding the multiple comparisons problem, the authors concluded that “no matter what statistical test is used, the reality is that the signal and the noise are not fully understood; therefore, all are actually approximations of truth, subject to errors.”

In a 2014 paper titled, “Brain Images, Babies, and Bathwater,” cognitive neuroscientist Martha J. Farah reviewed some of the criticisms of functional resonance imaging, opining that “The concern that fMRI shows us blood oxygenation rather than neural activity directly should be weighed alongside the fact that little of what we call science involves direct observations of the subject matter of interest.” After illustrating her point with references to cosmologists, chemists, and climate scientists, she concludes, “Complaints that functional neuroimages do not ‘show’ brain activity appear to based on a naive view of science and its methods.”

Needless to say, this brings up several issues in the philosophy of science, but that will have to wait for another post.

~ Rylan Dray, Ph.D. – December 2022

I first encountered the term Clostridium when researching botulism many years ago during a food poisoning concern. That’s when I learned that this is also the bacteria responsible for tetanus. And there are other medically relevant species, whereof, more presently. Clostridium refers to any of a genus of rod-shaped, usually gram-positive bacteria, members of which are found in soil, water, and the intestinal tracts of humans and other animals. Most species grow only in the complete absence of oxygen. (The term is derived from the Greek word for “spindle” (klostir). Unlike other endospores which are usually ovoid shaped, this group resembles a bottle or bowling pin.) In the 1890s, a Belgian biologist named van Ermengem published findings of an endospore-forming organism he isolated from spoiled ham, and about a quarter of a century later, this microbe was assigned to the Clostridium genus, which contains about 100 species of bacteria both free-living and pathogenic. (Higher counts may be stated in the popular literature due to confusion over the “true” nature of the genus.)

Botulinum toxin is said to be the most poisonous substance known. Improper home canning is cited as the primary source but occasionally it occurs commercially. One nanogram per kilogram can kill a human. The type A toxin is the most potent, causing muscle paralysis by preventing the release of the signaling neurotransmitter, acetylcholine. The paralysis produced is the opposite of that of C. tetani. Botulin toxin works on the peripheral nervous system, whereas that of tetanus works on the central. There are 3 types: food, infant (ingestion of spores from e.g., honey), and wound. Main symptoms are double-vision, dysphonia, dysphagia, pupil dilation, and dyspnea, and these may take days to come on. Treatment is antitoxin and supportive care until the toxin is washed out. Interestingly, toxin A (botox) treats some medical conditions: focal dystonia, achalasia, vaginismus, and of course, it is also used to tighten up facial wrinkles. Botulism can be fatal in 5 to 10% of cases.

C. tetani is usually found as spores in soil that enter the body through a penetrating wound (e.g., stepping barefoot on a splinter or rusty nail). The spores become bacteria producing a toxin, tetanospasmin, which travels retrograde to the motor neurons, spastic paralysis being the result. A classic symptom is lockjaw (trismus), an inability to open the jaw. Another classic one is risus sardonicus, a sustained spasm of the facial muscles that produces grinning. Treatment includes dehiscence of wounds, the antibiotic metronidazole, tetanus immunoglobulin, and benzodiazepines. Usually, however, the administration of tetanus toxoid vaccine prevents an outcome necessitating pharmacologic measures.

Clostridium perfringens causes a wide range of symptoms, from food poisoning to cellulitis, fasciitis, necrotic enteritis, and gas gangrene; the gas is identifiable on X-ray or CT scans. Only about 5% of the wounds colonized with clostridial organisms will develop an infection. The etymology, from Latin, means, “bursting through”, referring to gas gangrene’s disruption of tissues C. perf., found widely in soil, is highly associated with military wounds and motorcycle accidents and can infect dirty wounds or cause food poisoning (especially after eating undercooked meat). Alpha toxin destroys muscle tissue, causing gas gangrene in soft tissue, which is characterized by crepitus (rattling/crackling lung sounds) and hemolysis (premature destruction of red blood cells). Antibiotics are employed to treat: penicillin or clindamycin.

C. difficile, probably the most widely researched Clostridium species in recent years, is also found in soil and is generally not harmful if the gut flora is normal because colonic flora prevents overgrowth, but it often causes colitis when a person is taking antibiotics. Its toxin A, enterotoxin, causes inflammation and profuse diarrhea; the toxin B, cytotoxin, much more potent, disrupts the cytoskeleton, which leads to cell necrosis.

An increase in the occurrence of C. diff. infection outside hospital settings has been reported. The accumulation of antimicrobial resistance in C. diff. can increase the risk of infection and/or spread. The limited number of antimicrobials for the treatment of this problem is a matter of some concern. The CDC claimed earlier this year that drug-resistant infections had surged by up to 60% during the pandemic and experts fear that antibiotic resistance infections will cause ~ 50 million deaths between now and 2050. Excessive and unnecessary use of antibiotics are generally thought to be the primary reason for this development, and there has been a sharp overuse of antibiotics since the Covid-19 outbreak.. Cases of Candida Auris increased by 60%, the most of any drug-resistant infection the CDC has data for from 2020. Overall, cases and deaths caused by these types of infections increased 15% from 2019 to the first year of the pandemic. Cases of carbapenem-resistant Acinetobacter jumped by 35% from 2019 to 2020. Acinetobacter frequently contaminates facility surfaces and shared medical equipment.

As the WHO recently notes, “A growing list of infections – such as pneumonia, tuberculosis, blood poisoning, gonorrhea, and foodborne illnesses – are becoming harder, and sometimes impossible, to treat as antibiotics become less effective.”

This longstanding problem must be taken more seriously both by individual members of the public and policy makers alike, especially in our Covid-saturated era when collective immunity, despite vaccine success, has been significantly compromised.

~ Rylan Dray, Ph.D. – September 2022

Several years ago, I wrote a piece on uncertainty/ambiguity intolerance, always a timely topic, given the human condition. Now, with the advent and persistence of the Covid pandemic, it seemed to me worth revisiting. In addition to the threat of viral illness, albeit mitigated by vaccinations, there is the economic uncertainty engendered by inflation and the specter of recession as well as the lack of certainty about the presence of climate change.

Medicine’s essential state is partially defined by uncertainty to begin with, but the pandemic thrust everyone into an intensified form of it. “As policy makers and leaders struggled to determine [the way forward],” wrote two physicians in opinion piece last year, ” medical providers were shrouded in the same uncertainty and anxiety that engulfed the general public. Placed under the same blindfold as our patients, we lacked clarity around transmission, infectivity, or treatment options for this new disease.” They go on to say that they underestimated the importance of the virus until multisystem inflammatory syndrome in children happened. Many clinical decisions had to be made without the usual guidelines. The positive side of this, they say, is an opportunity to express greater understanding and empathy toward patients. More generally, they add, “Medical expertise is rarely unambiguous; medical dogma is often challenged and proven wrong, and patients seek and receive…advice within this context.”

Uncertainty is part of the human condition, but not everyone reacts to this continual ambiguity in the same way. Of course, some uncertain situations are more serious than others, but regardless of the gravity involved, some individuals are just more distressed about it. The propensity to react negatively to everyday uncertainties has been associated with generalized anxiety disorder (GAD), obsessive-compulsive disorder, social anxiety and panic disorders, depression, and anorexia/bulimia. (The most frequent measure is the Intolerance of Uncertainty (IU) scale, a 27-item report which has been made more methodologically sound through its abbreviation into the IUS-12.)

Intolerance of uncertainty has been conceptually distinguished from three other constructs (Rosen et al., 2014): intolerance of ambiguity (IA), uncertainty orientation (UO), and need for cognitive closure (NCC). IA focuses on the “here and now” while IU centers on an apprehension about events occurring in the future. NCC and UO are similar in that they appear to have implications for motivation: approach or avoidance. IU and IA tend to foster indecisiveness, a lack of behavioral reaction to the perception of the situation.

On the psychophysiological level, IU has been shown to be related to reward responding and threat amplification, and may be linked to anterior insula response to uncertainty (Gorka, 2016). More recently, and supporting this, IU has been associated with greater insula and amygdala response to uncertainty, with altered event-related potentials regarding rewards and errors, and with deficiencies in safety learning indexed by skin conductance (Tanovic, 2018).

The related concept of ambiguity intolerance (IA) has its own literature, but whereas IU is linked to anxiety, IA is associated with depression. In a classic 1992 study, Andersen & Schwartz concluded that “ambiguity intolerance appears to serve as a vulnerability factor for the certainty of future suffering and for depression.” Two years ago, research in the journal Medical Education noted an association between IA and psychological well-being which provides a window into understanding how stress, burnout. and mental health disorders can develop in medical students and doctors. The construct has also been used in social psychology where research has been conducted on how ambiguity tolerance/intolerance interacts with racial identity, homophobia, marital satisfaction, and pregnancy adjustment.

When I was in graduate school, I brought up the issue of anxiety-provoking ambiguity to the department chair, and he just shrugged it off with a “That’s life” sort of comment. Clearly, some of us have a harder time with this than others. But although recent developments–medical, economic, political–have made the uncertainty more of a thing to be reckoned with in the mass mind, it is, in the final analysis, but an amplification of what was already there. For the neurologically competent, the psychological, or if you prefer, existential, responsibility for resisting the pull of helplessness, has to be met to prevent a drift into dysfunctionality.

~ Rylan Dray, Ph.D. – June 2022

SELECTED REFERENCES

He, Y. & R. J. Vinci (2021). Uncertainty in the COVID-19 pandemic and the art of medicine. Pediatrics, 147 (5); May.

N. O. Rosen et al (2014). Differentiating intolerance of uncertainty from three related but distinct constructs.  Anxiety, Stress, & Coping, 27, 1.

.M. Gorka et al (2016). Intolerance of uncertainty and insula activation during uncertain reward. Cogn Affect Behav Neurosci, 16: 929-39.

E. Tanovic (2018). Intolerance of uncertainty: Neural and psychophysiological correlates of the perception of uncertainty as threatening. Clin Psychol Rev (e-pub). 1/6/2018.

“About 5 weeks in…I was still desperately short of breath, a little bit better than right at the start, it was still coming back in massive waves….”

Scrolling through Twitter, I’ve seen a lot of posts about long covid, many by physicians. A few of these posts are by doctors (and nurses) with long covid themselves. This syndrome has been in the news for some time, and more seems to be published about it each month.

Post-acute Covid-19 consists of a wide range of symptoms that usually come on four weeks after the initial infection and go on for weeks or months. Such symptoms include tiredness, dyspnea, fatigue, brain fogginess, autonomic dysfunction, headache, persistent loss of smell or taste, cough, depression, low-grade fevers, palpitations, dizziness, muscle pain, and joint pains. Effects of treatment are similar to other severe infections and include post-intensive care syndrome (PICS) resulting in extreme weakness and PTSD. Post Covid-19 care clinics are being opened at multiple medical centers across the USA to address these specific needs.

The precise pathophysiology of the syndrome is likely multifactorial. A delicate balance exists between a systemic inflammatory response to infection or trauma and a compensatory anti-inflammatory response, and this determines the immediate clinical outcome and, eventually, the prognosis associated with the infection. SARS CoV2 infection in patients with underlying comorbidities or immunity compromises may lead to excessive and destructive cytokine release called “cytokine storm”. This refers to a hyperinflammatory reaction which cannot turn itself off, thus wreaking damage throughout the body, A subgroup of patients with severe Covid-19 can experience this syndrome, whichis characterized by a fulminant and fatal hypercytokinemia associated with multi-organ failure. (I covered this topic in detail in my October 2020 blog post.)

Based on limited data from multiple international studies (observation and prospective cohort) that evaluated long-term consequences of acute Covid-19, those who required admission to the ICU and/or ventilator support were shown to be at increased risk of developing the post-acute syndrome as were patients with pre-existing, pulmonary conditions, older age, or obesity.

Long covid may adversely affect the heart and blood vessels. A 2021 study notes that signs of cardiovascular autonomic dysfunction appears to be common in LC and are similar to those observed in postural orthostatic tachycardia syndrome (POTS) and inappropriate sinus tachycardia. Recent reports have shown a high prevalence of symptoms several months after disease onset. (However, the researchers note that POTS is a rare medical conditions, and the onset of tachycardia following Covid-19 or any other viral infection can be more frequently explained as a physiological response of a perfectly intact autonomic nervous system.

Following SARS-CoV-2 infection, and in a similar way to the effects reported from SAR-CoV-1 infection, the formation of intra-alveolar thrombosis and airway inflammatory viral damage further contribute to the development of pulmonary fibrosis. SARS CoV-2 can induce pulmonary fibrosis by promoting the upregulation of pro-fibrotic signaling molecules.

Regarding the neurological aspect, post-mortem studies on the cerebral pathology of Covid-19 patients have shown that the virus can pass through the blood-brain barrier, creating the formation of fatal microthrombi and even the occurrence of encephalitis. In addition, the virus may enter the brain by transynaptic transfer, optic, and olfactory nerve channels, and vascular endothelial cells. Although necrosis and apoptosis of infected host cells may seem to reduce the survival of the virus, these effects result in damage to the CNS. Dementia also figures in. Neuroinflammatory responses, synaptic pruning, and neuronal loss are the structural basis of Alzheimer’s Disease, and SARS-CoV-2 infection most likely accelerates these processes. The excitotoxic reaction caused by the imbalance between glutaminergic and GABAergic response is a potential mechanism that promotes neuronal loss and further cerebral tissue damage.

Extrapulmonary (e.g., gastrointestinal or musculoskeletal) symptoms are also experienced during the acute phase. These symptoms are also present after the acute phase. Some studies have reported a prevalence of gastrointestinal post-Covid symptoms ranging from 10% to 25%.

Last month, the Guardian published an article on long covid by a young man who posed four questions about the issue: (1) Why don’t we have diagnostics for microclots? (However, the emphasis on microclots as evidence has been criticized as exaggerated). (2) Why is there still no public health warning? He writes, “In the US, the most conservative estimates are that 1.6 million are already out of the workforce due to long covid, and in the UK, a quarter of employers cite it as a leading reason for long-term absence.” (3) Why haven’t we started meaningful treatment trials for long covid? And finally, (4) What is the plan to support those who’ve lost their jobs and housing due to long covid?

In June, 2021, the journal Nature also published four questions: (1) How many people get long covid, and who is at most risk? (2) What is the underlying biology of the syndrome? (“Most researchers now suspect several [causative] mechanisms are at work, so one person’s long covid might be profoundly different from another’s.” (3) What is the relationship between long covid and other post-infection syndromes? (Of especial interest here is ME/CFS (myalgic encephalitis/chronic fatigue syndrome). And (4) What can be done to help people with long covid? Medicines are still in the testing stage. (Also, by extension, there is the questions of what part vaccines might play. (“Although may of them prevent death and severe illness, scientists do not yet know whether they prevent long covid. What about the impact of vaccines in people who already have long covid?”

As noted at the beginning, much continues to be published about this phenomenon. Personally, I favor a balance of the objective and the subjective, since patients’ reports can inform further research questions.

“Long covid is like running a marathon,” wrote a cardiologist last month on Twitter who goes by “Dr. Alice” – “yet you don’t know your pace, you don’t know what mile you’re on, and aid stations are scarce. But you are one among millions who’ve started the race.”

~ Rylan Dray, Ph.D. – April 2022

A while back, climate activist Greta Thunberg referred to her Asperger’s Syndrome as her “superpower”, meaning that the monomaniacal fixation many autistic people display enables her to stay laser-focused on the climate crisis. As is well known, Aspergers is a mild form of autism, but why is use of this term now “officially” discouraged? Basically, it’s because the doctors involved in producing the Diagnostic & Statistical Manual of Mental Illness voted to do so. But getting into all that is beyond the scope of this little piece. (For criticism of the DSM-5, see the writings of psychiatrist, Allan Francis).

Asperger’s Syndrome (AS) was first described by Hans Asperger in 1944 as the behavioral characterization of individuals who have difficulties in communication and social interactions. They may have odd speech patterns, limited facial expressions, and other peculiar mannerisms. They might engage in obsessive routines and show unusual sensitivity to sensory stimuli. (On YouTube videos of Greta, you can sometimes see her cringe when the audience responds enthusiastically to some of her comments).

Since its introduction, AS has been a topic of significant interest and debate. The diagnosis was put in the DSM-4 in 1994, but was not included in the DSM-5. Instead, the label was encompassed in a more general category of autistic spectrum disorder (ASD), which usually begins in early childhood and is characterized by problems in social communication and interaction, along with behavioral problems such as restricted interests and repetitive behaviors. Due to AS’s extensive history and relatively characteristic clinical presentations, specialists continue to use this diagnosis as a subtype of ASD with no language delay and a normal or superior IQ.

In recent years, considerable media attention has been paid to autism. According to the CDC, about 1 in 58 children in the US have ASD, and the disorder is increasing due, experts say, more to better monitoring and diagnosis rather than an actual rise in the number of children with it.

The cause of autism is unknown, though research has pointed to a combination of genetic and environmental factors. The clearest evidence involves certain events occurring in utero or during birth. These include: advanced parental age at time of conception, prenatal exposure to air pollution or certain pesticides, and maternal obesity. diabetes, or immune system disorders; among others.

There have been numerous fringe theories about environmental causes of autism, including vaccines, poor nutrition, ‘bad’ parenting, and cell phone use. All of these have been debunked.

“Neurodiversity” is said to be an empowering term describing individuals with autism and other neurological differences. It acknowledges that differences in brain function are normal, and it is thought to remove the stigma that these differences are deficits. At a social and political level, the term embraces neurological differences and is used as a social identifier category with a culturally protective aim.

Many autistic people–especially those who have intact language and no learning difficulties such that they can self-advocate– have adopted the neurodiversity framework, coining the term, “neurotypical” to describe the “majority” brain, seeing autism as an example of diversity in the set of all possible diverse brains.

The concept of neurodiversity emerged in the late 1990s to describe variation in brain wiring, which can include autism, depression, ADHD, intellectual and developmental disabilities, dyslexia, and epilepsy.

Activists argue that rather than trying to ‘cure’ or treat the neuro-divergent, society should learn to accept, appreciate and accommodate their needs. Prevailing disability therapies are criticized as designed to make people appear nondisabled, rather than supporting people’s priorities, and these activists are pushing for greater representation within government bodies that oversee research, funding, and policy.

On the medical side, current research is identifying overlapping neurological pathways that are involved in pathogenesis. Treatment involves intensive behavior therapy and educational programming along with traditional ancillary services such as speech/language, occupation and physical therapies. Drug treatments are also used to target certain symptoms and comorbid conditions.

I don’t know what treatment Greta has received for Aspergers but according to her dad, climate activism cured her comorbid depression.

– .. Rylan Dray, Ph.D. – November 2021

I had been having palpitations, and managed to convince my PCP to order a heart test. She wanted me to get a Holter monitor but I insisted on an echocardiogram which turned out to have technical issues (due no doubt to a training situation: in a teaching hospital, an indigent will often be “teaching material”). This led to the sonographer recommending a cardiac MRI. Unlike a previous (spinal) MRI, the noise was tolerable, and the results were normal. I was glad to have gotten some basic personal health information without further exposure to ionizing radiation.

Nicola Tesla discovered the Rotating Magnetic Field way back in 1882, but the specific phenomenon on which MRI is based (nuclear magnetic resonance (NMR)) was not discovered until 1937, when Isidore I. Rabi, a physicist at the Pupin Physics Laboratory in New York, did experiments demonstrating the resonant interaction of magnetic fields and radio-frequency pulses. (“Resonance” in physics refers to a matching of frequencies; in this case, that of the radio waves and the vibrations of the protons from water molecules.) The idea for NMR actually came from an obscure Dutch physicist named Cornelius Gorter, in the previous year, but he could not demonstrate it experimentally due to a limited setup. Rabi, with his superior technological resources, was able to detect magnetic resonance in a ‘macular beam’ of lithium chloride. In practical terms, this meant that the structure of chemical compounds could now be identified spectroscopically. Several years later, Block and Purcell simultaneously demonstrated NMR in condensed matter (water and paraffin, respectively).

When a patient is placed in a MRI machine, a powerful magnet pulls the positively charged protons of the body’s water molecules into alignment, after which a radio wave pulse of the same frequency as the particles’ oscillation knocks them askew. When the radio frequency pulse is turned off, the protons relax and return to alignment, sending back ‘captured’ information about the structure of which they are a part. This signal appears as a diffuse, amorphous image called k-space. To get a coherent version of this image, redundant information must be subtracted from it via a computer algorithm called the Fast Fourier Transform. The result is the remarkably detailed pictures of the brain and other bodily organs we are used to seeing in reproductions. (The Fourier transformation decomposes time signals into sinusoidal components of varying frequency. Thus, it uses mathematics to simplify physical phenomena for technological applications.) A chemist and a physicist (Paul Lautebur and Peter Mansfield) were given the Nobel Prize for the invention of the MRI, but it was a physician, Raymond Damadian, who actually built the first NMR body scanner, which can be viewed in the Smithsonian.

Structural (diagnostic) MRI is generally considered more reliable than functional MRI. The latter has come under fire in recent years for a number of reasons, most notably the generation of spurious results, including brain activity in a dead fish which was said to be used as a control (a bit of humor, no doubt), since the machine required an object to avoid damaging g itself). Unlike diagnostic MRI, fMRI works on the BOLD principle as an indicator of neural activation. (The magnetic resonance signal is an indirect effect related to changes in blood flow from neuronal activation.) This assumption is controversial.

The obvious advantage of MRI as an imaging choice is the absence of ionizing radiation, with its potential to cause cancer.) There is a general professional consensus that ~ 100 milliSieverts puts one in a higher risk category, but for amounts below that (“low-level” radiation) the picture is unclear. And whether sporadic media reports about this over the past decade have had any effect is a matter of speculation. Some companies have provided dosage reduction software, and there are the Image Gently and Image Wisely campaigns to reduce exposure in children and adults respectively. But there is still too much ignorance about the risk, which is more serious for children (as well as for small, relatively young adults). And there is insufficient attention being given to multi phase exams, many of which are unnecessary. Finally, there is the matter of communicating the risk. In Europe, this is done clearly on complete consent forms. In the US. patients are generally not given any idea of the large amount of radiation they will receive from CT scans or nuclear medicine procedures.

-~ Rylan Dray, Ph.D. – December 2020

The popular media began using the term. “cytokine storm”, first employed in connection with skin graft reactions, in the wake of avian H5N1 influenza virus infection (aka “bird flu”) in 2005. An uncontrolled and generalized hyperinflammatory response, this “storm” has also been observed in sepsis, trauma, and hemorrhagic stroke. Public radio has broadcasted reports of its afflicting younger COVID-19 patients, although the medical literature emphasizes its association with immune senescence.

Cytokines are an important part of the immune system. Specifically, they are a broad category of relatively small proteins (< 40 kDa) which are produced and released with the aim of self-signaling. They are polypeptides secreted by leukocytes and other cells that act principally on hematopoietic cells, the effects of which include modulation of immune and inflammatory responses. Synchronizers of immune system responses, their concentrations vary during the course of a disease. Cytokines can have either pro or anti-inflammatory effects, depending on the context. They are classified according to their cell of origin or their mechanism of action. Some, such as epidermal growth a tor, tumor necrosis factor alpha, and interleukin 1-6, can cross the blood-brain barrier; others, such as transforming growth factor alpha & beta-1, accumulate in the vicinity of the barrier and are degraded in the blood circulation.

As noted, the cytokine storm is a hyperinflammatory reaction which cannot turn itself off, thus wreaking damage throughout the body. A subgroup of patients with severe COVID-19 can experience this syndrome, which is characterized by a “fulminant” and fatal hypercytokinemia associated with multi-organ failure. The idea of this hyperinflammation emerged from the observation that COVID-19 patients requiring ICU admissions displayed higher concentrations of CXCL10, CCL2, and TNF-alpha as compared to those in which the infection was less severe and did not require an ICU admission. Moreover, in patients with SARS-Cov-2 infection as opposed to SARS-Cov infection, there is also an increased secretion of Th2-immune-oriented cytokines such as IL-4 and IL-10, whose main effect is to suppress inflammation. The cytokine storm and the subsequent ARDS result from the effects of a combination of many immune-active molecules. Interferons,interleukin, chemokines, colony-stmulating factors, and TNF-alpha represent the main components in the development of the phenomenon. (Colony-stimulating factors are proteins associated with inflammatory conditions and are components of an amplification cascade which increases cytokine production by macrophages at sites of inflammation.)

Developed by Hoffman-LaRoche, tocilizumab is an immunosuppressant drug proposed as a therapeutic agent against the cytokine storm. This is a “humanized” anti-IL-6 receptor immunoglobulin G1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases. (Humanized antibodies are those from non-human species the protein sequences whereof have been modified to increase their similarity to antibody variants produced naturally in humans. The International Non-proprietary Names of humanized antibodies end in -zumab.)

In a University of Michigan study, critically ill Covid-19 patients who received a single dose of IV tocilizumab were 45% less likely to die overall, and more likely to be out of the hospital or off a ventilator one month after treatment, compared to who didn’t receive the drug. The lower risk of death in these patients happened despite the fact that they also had twice the risk of developing an additional infection on top of the novel coronavirus.

~ Rylan Dray, Ph.D. – November 2020