Monday, January 17, 2022

Vortioxetine for Post-COVID Brain Fog

If you're relatively young and healthy, is a mild case of COVID-19 really “mild”, like a cold or the flu? Are you still at risk for long COVID a persistent state of fatigue, anxiety, insomnia, exercise intolerance, and “brain fog” (impairments in memory, attention, and concentration) even if you're fully vaccinated?

If you have post-COVID brain fog and live in Toronto, you might be eligible for a clinical trial run by the Brain and Cognition Discovery Foundation. The study will assess the effects of vortioxetine (brand name Trintellix), an FDA-approved antidepressant that may improve cognitive function in people with depression. It has a complex mechanism of action as a “serotonin reuptake inhibitor, agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors.” The clinical trial is a randomized, double-blind, placebo-controlled study that plans to enroll 200 participants.

Trintellix™ was approved by Health Canada in 2014, meaning it's fully covered by the government if you have major depressive disorder (MDD). It's an expensive drug ($423 a month) with no generic version, so too bad if you live in the US and suffer from MDD-related cognitive dysfunction, since most forms of insurance won't cover it.


Are there any differences in outcome between the delta and omicron variants? What about all the long haulers who weren't able to obtain a definitive COVID-19 test? These are only two of many important questions.

Meanwhile, it's well-documented that unvaccinated individuals are 13 times more likely to be hospitalized and 20 times more likely to die than fully vaccinated individuals. Why is this so hard to understand??

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Friday, December 31, 2021

Your Own Personal DBS

The second calendar year of COVID surges to a close, and hospital personnel continue their frenetic pace of caring for the infected (most of whom are defiantly unvaccinated). For the rest of us, Vaccine Scientists are the 2021 Heroes of the Year... surely they will outsmart the latest variant of the sneaky virus. Their astonishing achievements built on less glamorous (and less recognized) work conducted over the course of 20 years. As told by Time magazine:

In 2005, [Dr. Katalin] Kariko and [Dr. Drew] Weissman reported their findings in what they thought would be a landmark paper in the journal Immunity, then waited for the accolades to flood in. “I told Kati the night before the paper was published, Tomorrow our phones are going to ring off the hook,” says Weissman. No one called.

Clinical Neuroscience Heroes of the Year

Another remarkable achievement in 2021 was the demonstration of a “closed-loop” deep brain stimulation (DBS) protocol in a patient with refractory depression (Scangos et al., 2021a, 2021b). This new personalized treatment modality was based on devices and procedures first used in patients with intractable epilepsy. An implanted responsive neurostimulation (RNS) system detects brain waves that predict the onset of a seizure and then delivers pulses to quell the aberrant electrical activity. The device provides stimulation only when needed, thereby “closing the loop” on a self-contained, personalized neurotherapy.

NeuroPace Next Gen RNS® System


Application of this concept to major depressive disorder (MDD) was based on years of research in basic neurophysiology, neural circuits and biomarkers, electrocorticography (ECoG), cognitive neuroscience, neuroengineering, and machine learning. Some of this work was funded by the 2013 BRAIN Initiative, specifically DARPA's SUBNETS program. The goals of DARPA were rather lofty and unattainable (as they usually are) and outlined in a detailed funding announcement. Or, as I quipped at the time:

To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing.


O ye of little faith!

“Someone to hear your prayers
Someone who cares”

Bypassing the “paradigm shift” of another brand of precision psychiatry, a group of scientists and clinicians at UCSF actually achieved this goal in a proof-of-concept n=1 clinical trial, taking personalized psychiatry to its ultimate (albeit prohibitively expensive) destination (Scangos et al., 2021a, 2021b).


The first step in establishing a personalized deep brain stimulation protocol in a single patient with treatment-resistant depression involved 10 days of “mood mapping” while EEG activity was recorded from 160 contacts in 10 target brain regions (Fig 1a, Scangos et al. 2021a).

Electrodes were implanted bilaterally in orbitofrontal cortex, amygdala, hippocampus, ventral capsule/ventral striatum (VC/VS), and subgenual cingulate for 10 days to map mood and identify a “depressive state” biomarker that correlated with symptom ratings. Cross-validated supervised machine learning models identified gamma power in left and right amygdala as the most reliable indicators. Additional results from the mapping of brain stimulation → emotional response are shown below in a schematic figure (click on image for a larger view).

Fig. 1 (Scangos et al. 2021b). Mapping mood across the corticolimbic circuit. (a) Examples of the clinical responses to ~90 s of stimulation. Electrodes that demonstrated a positive or negative mood response to stimulation are enlarged for emphasis and shaded with color of respective region.

Three positive protocols were identified: ‘tingles of pleasure’ with 100-Hz VC/VS stimulation, ‘neutral alertness … less cobwebs and cotton’ with 100-Hz SGC stimulation, and calm pleasure ‘like … reading a good book’ with 1-Hz OFC stimulation.

The team's earlier work on mood mapping was initiated in patients with epilepsy, who were under neurosurgical observation to localize seizure foci using recordings from intracranial electrodes (Kirby et al., 2018; Rao et al., 2018). This actually follows the path outlined by DARPA in their Systems-Based Neurotechnology for Emerging Therapies (SUBNETS) précis:
Through measuring pathways involved in complex systems-based brain disorders [such as MDD] ... SUBNETS will pursue the capability to record and model how these systems function in both normal and abnormal conditions, among volunteers seeking treatment for unrelated neurologic disorders [such as epilepsy] and impaired clinical research participants. SUBNETS will then use these models to determine safe and effective therapeutic stimulation methodologies. These models will be adapted onto next-generation, closed-loop neural stimulators that exceed currently developed capacities for simultaneous stimulation and recording...

Ultimately, stimulation of the right VC/VS was associated with the most consistent and sustained improvement in symptoms (Scangos et al. 2021a). A combination of techniques (evoked potential mapping, graph theory, and deterministic tractography) identified the connectivity between right VC/VS and the amygdala sites. Further sessions suggested that right VC/VS stimulation may be associated with a reduction in gamma activity on trials that saw an improvement in mood. 

After all these mapping sessions, the DBS sites were selected: the NeuroPace RNS System was placed with stimulating leads in right VC/VS and recording leads in right amygdala. Most impressive of all is that detection of the “depressive” gamma biomarker in the amygdala would trigger six seconds of 1 mA intermittent stimulation in VC/VS.

The authors found that the number of detections, defined as gamma power crossing a threshold of 0.8% of full amplitude scale within 10-min recording periods was 87% predictive of symptom severity state and highly correlated with [the patient's self-report on standardized scales]” (Scangos et al. 2021a). The patient's depression improved dramatically within 12 days, and full remission was reached several months later.

The 2021 papers presented an overview of procedures and the results obtained from one patient (Sarah), who was identified by first name and masked photo in press releases and news articles. The n=1 trial was the culmination of hundreds of millions of dollars of federal research funding, so I was kinda fascinated by why the clinical team chose this particular patient (which is protected health information, of course). In an interview, Sarah said, “I was at the end of the line. I was severely depressed. I could not see myself continuing if this was all I’d be able to do, if I could never move beyond this. It was not a life worth living.”

The inclusion criteria for the trial required that the current depressive episode is two or more years in length and treatment-resistant (failure to respond to four adequate trials (including ECT), three classes of medications, one augmentation strategy, and psychotherapy). In the present case, her most recent 4-year episode did not adequately respond to four antidepressants, augmentation with five other meds, electroconvulsive therapy, transcranial magnetic stimulation, or psychotherapy. In other words, closed-loop DBS is only appropriate for the most severe unrelenting cases of depression.

The Future of Depression Treatment is here, but will it work in other patients? And at what cost?
. . .


DARPA has mandated that all depressed Americans must be implanted with its CyberNeuroTron WritBit device, which cost $100 billion to develop. CNTWB is a closed-loop DBS system that automatically adjusts the stimulation parameters at 12 different customized target locations. It uses state-of-the-art syringe-injectable mesh electronics, incorporating silicon nanowires and microvoltammetry. Electrical and chemical signals are continuously recorded and uploaded to a centralized data center, where machine learning algorithms determine with high accuracy whether a given pattern of activity signals a significant change in mood.

The data are compiled, analyzed, and stored by the global search engine conglomerate BlueBook, which in 2032 swallowed up Google, Facebook, Apple, and every other internet data mining company.

Further Reading


And the DARPA deep brain stimulation awards go to...

New Deep Brain Stimulation System Measures Neurotransmitter Release

Who Will Pay for All the New DBS Implants?

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA

Will machine learning create new diagnostic categories, or just refine the ones we already have?


Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EW. (2021a). Closed-loop neuromodulation in an individual with treatment-resistant depression. Nature Medicine 27(10):1696-700.

Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. (2021b). State-dependent responses to intracranial brain stimulation in a patient with depression. Nature Medicine 27(2):229-31.

"Reach out, touch faith"

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Tuesday, November 30, 2021

Is Precision Psychiatry Realistic?

Fig. 1 (Fernandes et al., 2017). Domains related to ‘precision psychiatry’.

The right drug for the right patient” was a catch phrase in the early years of the personalized medicine movement (2000), represented by the emerging field of pharmacogenomics. No more “one size fits all” prescribing — the Human Genome Project will allow doctors to predict how you will respond to any given medication.

The last time I went to the drug store, I picked up my cheap generic prescription without the benefit of genomic testing.

The term “personalized medicine” was outdated by 2011. The National Research Council (PDF) preferred the new and improved “precision medicine” brand because...

...there was concern that the word "personalized" could be misinterpreted to imply that treatments and preventions are being developed uniquely for each individual; in precision medicine, the focus is on identifying which approaches will be effective for which patients based on genetic, environmental, and lifestyle factors.

What is Precision Psychiatry?

If you believe the hype (circa 2017), it's a paradigm shift! It's perfection! [yes, really]...
...a high level of exactness in measurement will be achieved such that, eventually, it will be personalised. It can be conceptualised as a highly sophisticated and intricate classification system, where infinitesimal categories will, ideally, attain perfection in a detailed multidimensional classification.

...It's quixotic (if taken to those lofty extremes). Precision psychiatry is an incredibly popular topic for review papers, but don't hold your breath awaiting its implementation. Especially if you're a patient. 

What is Stratified Psychiatry?

Fig. 1 (Arns et al., 2021). An infographic summarizing the more ‘diagnostic based one-size-fits-all psychiatry’ that is currently in use (left), to more ‘prognostic’ models such as Stratified Psychiatry (right-top) and Precision Psychiatry (right-bottom).

Perhaps Stratified Psychiatry is more realistic, where subgroups of patients with similar biomarker profiles are assigned to treatments predicted to show a higher probability of clinical response. But the infographic above may be conflating precision psychiatry and personalized psychiatry (it seems that way in the text as well). So is stratified psychiatry a more modest version of precision psychiatry, with only a few biomarkers (vs. 35 or so)? Without the grandiosity of anticipating infinitesimal categories with perfect diagnostic accuracy or the absolute faith in RDoC (NIMH Research Domain Criteria)? 

In the end, making promises you can't keep helps no one (see The Lie of Precision Medicine).


Arns M, van Dijk H, Luykx JJ, van Wingen G, Olbrich S. Stratified psychiatry: Tomorrow's precision psychiatry? European Neuropsychopharmacology. 2022 Feb 1;55:14-9.
Fernandes BS, Williams LM, Steiner J, Leboyer M, Carvalho AF, Berk M. The new field of ‘precision psychiatry’. BMC medicine. 2017 Dec;15(1):1-7.

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Sunday, October 31, 2021

Xylological Delusions of Being a Tree

The mythology surrounding reverse inter-metamorphosis, a delusional syndrome that involves transformation into a beast, has frightened and fascinated for hundreds of years. A special instance of reverse inter-metamorphosis is clinical lycanthropy, the delusion that one has been transformed into a wolf (or another animal). A recent review identified 43 cases in the literature between 1852 and today (Guessoum et al., 2021). Psychotic depression and schizophrenia were the most common co-existing psychiatric diagnoses in these individuals.

The article advocates a cultural and person-centered approach to treatment, as did many of the original authors. The wolf has different characteristics and symbolic meanings across various cultures. As in other realms, popular media and folklore shape the content of the delusion. Occasionally, there may be a literal event that triggers the belief of transmogrification.

Clinical Kynanthropy After a Dog Bite

This case report of kynanthropy delusional transformation into a dog was notable because the COVID-19 lockdown might have exacerbated the condition. The patient was a 28-year-old single male who started grinning, barking, and walking on four legs after being bitten by a dog... but not until two years later (Jain et al., 2021).

He was apparently alright until two months before the presentation, when, due to the COVID-19-related nationwide lockdown, he read excessively on the internet about dog bites. ... he developed a feeling that his tongue is moving like a dog’s and began having repetitive thoughts about converting into a dog. Gradually, his sleep reduced to 1–2 hours/day, and he expressed fear that if he sleeps, he might get up as a dog. He sought repeated reassurance from his family that he hasn’t transformed into a dog, to the extent that they got irritated and asked him to see a doctor. These repetitive thoughts would be present for the whole day, and he would chant God's name to get relief from them.

The man had no history of rabies, mood disorder, or substance use. Upon examination, he was anxious but did not present with depression or psychotic features. Instead, he had repetitive doubts about turning into a dog. The patient was diagnosed with moderate OCD (with poor insight) and given a prescription of 20 mg fluoxetine (Prozac). A month later, he reported improvement in his repetitive thoughts, and at three months showed an improvement in social and occupational function. He realized he had spent way too much time on the internet reading and watching videos about dog bites.


Botanical Inter-metamorphosis

A unique arboreal delusion was briefly described in a recent abstract (Bakhshi & Hirsch, 2021): a depressed young woman believed she had been transformed into a tree. The major manifestations were standing still for long periods of time and repeating, "I am a tree."

A 21-year-old right-handed cisgender female, two months prior to presentation, noted stiffness and difficulty with ambulation. One-month prior to admission, she experienced recurrent depression with myriad vegetative and nonvegetative symptoms of depression. On admission her chief complaint was "I am a tree", standing motionless and minimally responding to query. After treatment with quetiapine, mirtazapine and hydroxyzine for a one-week period, her perception of being a tree fully resolved.


The authors considered a range of delusional diagnoses for her condition:

  • Cotard’s syndrome – NO, she did not think she was dead
  • Ekbom syndrome (delusional parasitosis) – NO, she did not think her body was infested with bugs
  • Reverse Inanimate Capgras Syndrome – MAYBE? (but "instead of an imposter replacing a close friend, who then is inserted into the sufferer; a tree has replaced the sufferer.")
  • Intermetamorphosis – NO, misindentification of another, not self
  • Botanical Intermetamorphosis – NO, another person transformed into a plant, not self
  • Reverse Intermetamorphosis – MAYBE? ("However, in this situation, the objects are all human or animate animals not botanicals.") – but isn't this the point, to report on a botanical?
  • Fregoli syndrome – NO, altered physical identity of another, not self
  • Reverse Fregoli syndrome – NO, patient assumes the physical identity of another person, not a plant
  • Botanical Variant of Interparietal Syndrome – NO, she did not have parietal lobe damage. ("In this condition, parts of the body are perceived to be lifeless, due to lesions of the inferior parietal lobe...")

The groundbreaking conclusion was that doctors should check for delusions involving plant life in all of these syndromes, because botanical variants have not been described before.

Further Reading

Werewolves of London, Ontario

Haunting Delusions of Identity

Ophidianthropy: The Delusion of Being Transformed into a Snake

Psychopharmacology of Lycanthropy

The oldest remaining werewolf movie 

Keanu Reeves as Ortiz the Dog Boy in Freaked


Bakhshi HS, Hirsch AR. (2021). Xylological Variant of Reverse Fregoli Syndrome, Delusions of Being a Tree. CNS Spectrums 26(2):145.

Guessoum SB, Benoit L, Minassian S, Mallet J, Moro MR. (2021). Clinical Lycanthropy, Neurobiology, Culture: A Systematic Review. Frontiers in Psychiatry Oct. 13, 1693.

Jain VP, Gupta N, Kale VP. (2021). Clinical Kynanthropy: A Case Report of Psychological Manifestation of a Dog Bite. Indian Journal of Psychological Medicine. Oct 13:02537176211047132.



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Thursday, September 30, 2021

A Curious Case of Auditory-Gustatory Synesthesia... in someone who can't smell


A fascinating case study from 1907 describes the self-reported sensory “taste” experiences evoked by hearing specific words, names, or sounds (Pierce, 1907). The subject was a young woman about to graduate from college. As far as she could tell, she's always had these experiences, and for most of her life she didn't know they were unusual. This surprise upon discovering the uniqueness of one's one internal experience is similar to what is reported by many contemporary individuals with less typical phenomenology, such as aphantasia (the inability to generate visual images).

Pierce noted that the subject was anosmic (had a loss of smell), although this was not formally tested. Nonetheless, he observed:

Coffee burning upon a stove is not noticed, though she may be close by. Camphor placed in the nostrils gives only a stinging sensation. Ammonia can be sniffed without discomfort. And, as with all anosmics, foods are discriminated on the basis of the pure taste qualities, or by the characters of texture, astringency, and so on, which any food-complex may possess. These sensory defects are worth noting for their possible significance in connection with the theory of this special case of synæsthesia.


Some aspects of the report were rather quaint by modern standards (e.g., the first person narration), but others were quite prescient.

But what evidence have we that an actual case of synæsthesia is here being reported, and not a case of artificial association due to a lively dramatic fancy? This is a point that must be raised, for it is very easy to entertain a suspicion that these phenomena are essentially ungenuine. Now, of course, in matters of this kind general impressions and personal knowledge of the subject count heavily. And on both these grounds I have no hesitation in asserting my conviction that the above-cited equivalents are the expression of a genuine synæsthesia.

One key piece of evidence was the consistency of gustatory experiences associated with the same words at a later date:

...the equivalents possess a constancy which would hardly be possible apart from a true synæsthesia. After an interval of six months a number of words were given at random from the original list, with the result that the identical equivalents were described in almost precisely the same language.


Also, there was a somatotopic-like arrangement for some of the gustatory experiences:

Many of the experiences are given quite definite locations in the mouth. Thus the equivalents of Ethel and Hall (tactual) are felt at the tip of the tongue; of lox (irritation) at the back of the throat; of Judith (salt) at the sides of the tongue; of Sarah (cold) on the lips; of amethyst (bitter) "at the back of the mouth, on the roof, where the root of the tongue seems to hit it" ...


Pierce tried to discern whether similar sounds could be related to similar gustatory experiences, but that wasn't the case. Nor were they related to similarities in articulation. He still preferred a physiological explanation, yet...
In attempting to decide whether the above-cited experiences are to be explained by the physiological or by the psychological theory, we are, apparently, in no better and in no worse case than in respect to all varieties of synæsthesia. No decisive facts are at hand.


An interesting commentary in JAMA predated MRI connectivity studies of synesthesia by nearly a century in its speculation about alternative brain wiring:

There is little evidence one way or the other as to whether or not this phenomenon is to be explained on purely physiologic grounds, depending on a cross circuiting of the association fibers between different brain centers.

Pierce concludes his paper with a pithy aphorism that acknowledges the inconclusiveness of the study:
Still, here no less than in all known cases of synaesthesis, we can only regret that our theory is so lame while our facts are so secure.


Pierce AH. (1907). Gustatory audition; a hitherto undescribed variety of synæsthesia. The American Journal of Psychology. Jul 1:341-52.

Commentary (1907). GUSTATORY AUDITION. JAMA. XLIX(10):857-858.

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Tuesday, August 31, 2021

Reading Aloud without a Mask, Olfactory Bulbs, Omega Variant

Here's the latest alarming COVID news to distract you from fires and hurricanes.
{I'm very sorry if you are experiencing either of these disasters personally. Donations ideas: El Dorado Community Foundation and The Mutual Aid Response Network.}

Caldor Fire: Karl Mondon/Bay Area News Group. Hurricane Ida: Edmund D. Fountain/New York Times.



Outbreak Associated with SARS-CoV-2 B.1.617.2 (Delta) Variant in an Elementary School — Marin County, California, May–June 2021

An unvaccinated elementary school teacher was experiencing nasal congestion and fatigue but continued working. The teacher read aloud to the students while maskless and two days later received a positive test for the Delta variant. Half of the class was infected, with the greatest risk among those sitting in front. Transmission to siblings and parents ensued, for a total of 27 cases.

"Among the five infected adults, one parent and the teacher were unvaccinated; the others were fully vaccinated. The vaccinated adults and one unvaccinated adult were symptomatic with fever, chills, cough, headache, and loss of smell."


The CDC created a figure showing the seating chart, transmission pattern, and whether the individual was symptomatic. The desks were six feet apart, an air filter in front, and the door and windows were open. All five children in the front row were infected.


from the CDC: Classroom layout and seating chart for 24 students in index patient’s class, by SARS-CoV-2 testing date, result or status, and symptoms—Marin County, California, May–June 2021

Conclusion and recommendation:

"Ineligibility because of age and lack of vaccination contribute to persistent elevated risk for outbreaks in schools, especially as new SARS-CoV-2 variants emerge. However, implementation of multiple prevention strategies within schools can mitigate this risk."

Olfactory Bulbs 

Speaking of smell, over 20 papers show MRI signal abnormalities in the olfactory bulbs of COVID-19 patients with anosmia (loss of smell). This isn't new, but anosmia has been reported in breakthrough cases as well. The images below show some resolution in a patient from time 1 to time 2.

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

"...we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway and cause an olfactory dysfunction of sensorineural origin."


modified from Fig 2 (Politi et al., 2020). A coronal 2-dimensional FLAIR image shows a slight reduction of the hyperintensity and the thickness of the olfactory bulbs [right side], suggesting a postinfection olfactory loss.

modified from Fig 2 (Politi et al., 2020). FLAIR image showing complete resolution of the previously seen signal alteration within the cortex of the right gyrus rectus [bottom image].

Omega Variant 

OK, I made that up. However (alpha, beta, delta, epsilon, iota, gamma, OTHER):

Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California (preprint):

"These findings suggest that vaccine breakthrough cases are preferentially caused by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage."


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Saturday, July 31, 2021

Why would nasally-transferred coronavirus only affect the left side of the brain?


Q – “I survived a mild case of COVID. Should I be worried about the volume of gray matter in olfactory-related structures in the left hemisphere of my brain?”

A – Most of what you've read on social media may be overstated.

One of the scariest things about SARS-CoV-2 (other than possible death) is that it affects multiple organs, including the brain. The vast majority of studies have compared measures in COVID survivors to those obtained from participants without COVID. These cross-sectional studies cannot determine whether pre-existing differences can account for disease-related 'changes'.

An important new preprint by Douaud and colleagues reported results from a longitudinal study that obtained MRIs from participants before and during the pandemic. Carefully matched cohorts of COVID+ (n=394) and COVID- (n=388) people were given a second scan 3 years after their initial entry into the study. The majority of patients were not hospitalized. The authors hypothesized that brain areas related to smell and taste, senses which show notable decrements in infected patients, would be altered in the COVID-19 population.


from Vaughan & Jackson (2014). The “piriform axis” is an unusual oblique angle that shows primary olfactory cortex (Pir, piriform cortex) in the orbitofrontal region of the frontal lobe and nearby medial temporal lobe structures related to emotion and memory (Am, amygdala and Hip, hippocampus).

The frightening entrée of the virus into the brain may be through the nose. In mice, the S1 subunit of the coronavirus spike protein crosses the protective blood brain barrier and ends up in the olfactory bulb within 10-30 min (Rhea et al., 2021). After that, we don't really know what happens. So it's a stretch to suggest that neurotropism (viral infection of brain cells) causes alterations at a macro level in humans that can be detected by structural MRI. Anyway, that's the hypothesis.

What was unclear to me, however, was the number of other analyses conducted as part of the study. Other than the smell/taste regions of interest (ROIs), there were 2,360 distinct measures of brain structure or function (including resting-state fMRI and task-related fMRI, which we assume were not significantly different in the patients).

Sticking to the ROIs, the authors ran permutation tests that corrected for multiple comparisons and found that only the left hemisphere was affected. WHY?? Despite the Proustian speculation...

“...where the left hemisphere seem [sic] to be more involved in the emotional aspect of olfactory memory (the famous madeleine de Proust association that seemed particularly targeted in COVID-19).”'s mysterious why the virus would have deleterious effects on the brain by only invading the left nostril.


Fig. 1. (Douaud et al., 2021). The three main regions showing significant loss of grey matter (thickness, volume) between the two time-points specifically for the COVID patients are the parahippocampal gyrus, the lateral orbitofrontal cortex, and the superior insula. All results were localised to the left hemisphere.

The other notable aspect of the results was the massive overlap in distribution between the COVID+ and COVID- participants (see snarky commentary in the first figure). The authors helpfully showed the full spread of values for the time 1 vs. time 2 difference (clustered around zero). But did gray matter volume and thickness actually increase in some people? Although the group differences were statistically significant, were there any functional consequences? Severity of smell/taste loss? Effects on memory or emotion? We don't know.

COVID-19 can have persistent, disabling effects in some people, including young and previously healthy individuals (the “long haulers”, see Davis et al., 2021). There is no doubt about the reality of Long Covid.

On the other hand, alarmist coverage of preliminary neuroimaging findings is not helpful. The differences in Fig. 1 of Douaud et al. do not depict a shrinkage of 4 standard deviations, despite what some widely circulated tweets may claim. As one of the authors explains:


In fact, the exploratory analysis showed the largest loss of brain volume was non-specific (and not discussed). And perhaps not due to neurotropic invasion?


Longitudinal studies are extremely valuable, and the authors are to be commended for this. We'll wait for future papers to verify these findings, but for now I'm not totally convinced.


Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, Redfield S, Austin JP, Akrami A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Jul 15. Epub ahead of print. PMID: 34308300.
Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, Lange F, Andersson JL, Griffanti L, Duff E, Jbabdi S, Taschler B. (preprint). Brain imaging before and after COVID-19 in UK Biobank. medRxiv. June 20, 2021.

Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. (2021). The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nature Neuroscience 24(3):368-78.

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