Saturday, April 30, 2022

Nostalgia and Its Analgesia

“Nostalgia is a sentiment of loss and displacement, but it is also a romance with one’s own fantasy. Nostalgic love can only survive in a long-distance relationship. A cinematic image of nostalgia is a double exposure, or a superimposition of two images—of home and abroad, of past and present, of dream and everyday life. The moment we try to force it into a single image, it breaks the frame or burns the surface.”

–Svetlana Boym, Nostalgia and Its Discontents

Nostalgia means different things to different groups of scholars. To historians, nostalgia is bad, “...essentially history without guilt ... an abdication of personal responsibility, a guilt-free homecoming, an ethical and aesthetic failure” (Boym, 2007). To social psychologists, nostalgia is good, “a meaning-providing resource [that] may serve an existential function” by helping us avoid thoughts of death (Routledge et al., 2008).

To cognitive neuroscience types, nostalgia is encapsulated in an fMRI experiment that compares brain responses to pictures of “nostalgic” objects (from childhood) vs. contemporary objects (Yang et al., 2021).1

In this post, my authority on cultural nostalgia is Svetlana Boym, who was the Curt Hugo Reisinger Professor of Slavic and Comparative Literatures at Harvard, a Russian émigré, and an extraordinary thinker, writer, cultural theorist, and photographer. Her 2007 essay was adapted from her influential book, The Future of Nostalgia (2001). She viewed nostalgia as a manifestation of collective memory and longing, with two contrasting types. Reflective nostalgia is exemplified by the displacement of immigrants, who may long for a home that no longer exists (or perhaps never existed). Restorative nostalgia, on the other hand, is a dangerous impulse to return to a “pure” (or nationalistic) state of a distant past. Is it fair for psychologists to consider nostalgia as a private reminiscence devoid of a larger context?

A Blast from the Past

The reconciliation between these different views of nostalgia used to be terror management theory (TMT). In this theory, reminders of death (mortality salience) increase in-group favoritism and defense of one's own world view as a way to assuage existential fear. Thus, restorative nostalgia might be seen in the light (or darkness) of TMT. Indeed, instructing participants to write about a nostalgic event lessened mortality salience (Routledge et al., 2008). However, TMT has failed to replicate in several large studies, so there goes that idea (i.e., the link between social psychology experiments and restorative nostalgia, not the concept of restorative nostalgia itself).

Escape from the Pandemic

The COVID memory vortex altered our perception of time and space and warped the horizon of past and future. A restricted sense of the present (and the lack of new cultural output) caused TV nostalgia and musical nostalgia:

Nostalgia became a default listening mode — and for me, the cumulative oldness felt distressingly new. The old problem with nostalgia was that it made it harder to imagine the future. The new problem with nostalgia was that it made it harder to experience the present.

But wasn't this also a way to avoid ubiquitous thoughts of death and constant media coverage (and lived experience) of overwhelmed essential workers, illness, hospitalization, and relatives dying alone? Was there anything special about nostalgia, or would any absorbing distraction suffice? Nostalgia intervention studies during COVID-19 demonstrated improvements in well-being (Wildschut & Sedikides, 2022), but the control conditions didn't include sourdough bread baking, home improvement projects, or Zoom Peloton sessions.

Comfortably Numb

A fleeting feeling of nostalgia can lessen the perception of physical pain, apparently (Zhang et al., 2022) — although the effect looks quite modest to me.


In this study, visual cues were presented for 8 sec (e.g., childhood or contemporary gum), followed by 3 sec of thermal stimulation (low vs. high), a 7 sec wait, and then a rating of perceived pain intensity on that trial. The next picture-pain cycle would occur 10 sec later. Very small downward modulations of cortical activity were observed with nostalgia, but the impressive associations were in the thalamus.


modified from Fig. 4 (Zhang et al., 2022). During pain encoding, the thalamus showed a positive correlation between the BOLD response and the analgesic effect.

While acknowledging that nostalgia is a complicated emotion, the authors stated that...

These findings suggest that the thalamus might play a key role in the nostalgia and pain information encoding process in the possible brain circuit for nostalgia-induced analgesia.

But nostalgia can also induce feelings of emotional pain and sadness. On the very last day I spent at my childhood home, I walked around the backyard and was struck by a staggering sense of loss. My memories of running around and playing wiffle ball - badminton - croquet - nerf football - frisbee — and building a minimalistic tree house and burying dead animals under a cross — were dim and lonely. I just sold the house and my best friend (who used to live next door) was dead and my mother was dead. I mourned in a way that I never did while inside the house, emptying it of all my mother's possessions.

“Nostalgia is a sentiment of loss and displacement...”



1 This study found that presentation of nostalgic pictures was associated with enhanced mortality salience, along with increased activation in the right amygdala (Yang et al., 2021). Which is the opposite of previous studies...



Boym S. (2007). Nostalgia and its discontents. The Hedgehog Review. 9(2):7-19.

Routledge C, Arndt J, Sedikides C, Wildschut T. (2008). A blast from the past: The terror management function of nostalgia. Journal of Experimental Social Psychology 44(1):132-40.

Wildschut T, Sedikides C. (2022). Benefits of nostalgia in vulnerable populations. European Review of Social Psychology 27:1-48.

Yang Z, Sedikides C, Izuma K, Wildschut T, Kashima ES, Luo YL, Chen J, Cai H. (2021). Nostalgia enhances detection of death threat: neural and behavioral evidence. Scientific Reports 11(1):1-8.

Zhang M, Yang Z, Zhong J, Zhang Y, Lin X, Cai H, Kong Y. (2022). Thalamocortical mechanisms for nostalgia-induced analgesia. Journal of Neuroscience 42(14):2963-72.


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Thursday, March 31, 2022

Machine Yearning - Sad Robots and Prolonged Grief


What is 'machine yearning'?

Intense longing exhibited by cartoon robots? 

Or a clever pun that describes a network analysis of prolonged grief symptoms? (Malgaroli et al., 2022).

My late wife was a writer who was very fond of robots and Futurama. This post is an opportunity to incorporate them all into a brief narrative about the computational psychiatry of prolonged grief disorder.

Prolonged Grief Disorder (PGD) is an ICD-11 diagnosis that overlaps with other formulations of “pathological grief” including “persistent complex bereavement disorder” (PCBD) and “complicated grief”. The ICD-11 definition and symptoms can be found here.

Prolonged grief disorder is a disturbance in which, following the death of a partner, parent, child, or other person close to the bereaved, there is persistent and pervasive grief response characterised by longing for the deceased or persistent preoccupation with the deceased accompanied by intense emotional pain (e.g. sadness, guilt, anger, denial, blame, difficulty accepting the death, feeling one has lost a part of one’s self, an inability to experience positive mood, emotional numbness, difficulty in engaging with social or other activities).”


The symptoms must persist for at least six months, with consideration of differing cultural norms for bereavement. The overlap between PGD and PCBD is shown in purple in the figure below.

click on image for a larger view

Infographic. Disturbed grief: prolonged grief disorder and persistent complex bereavement disorder (BMJ).

Painful and prolonged yearning for the lost loved one is an obvious core symptom.

[NOTE: A celebration of life is viewed as a more adaptive response.]


But there's so much more... An aptly titled paper by Lenferink and Eisma (2018) indicated there are 37,650 ways to have “persistent complex bereavement disorder” yet only 48 ways to have “prolonged grief disorder”. 1 For a PCBD diagnosis (a DSM-5 construct), an individual must have at least one of four Cluster I symptoms and at least six of twelve Cluster II symptoms. For a a PGD diagnosis, an individual must have at least one of two Cluster I symptoms and at least three of five Cluster II symptoms. This is a rather stunning degree of symptom heterogeneity, and much more complicated than the Infographic suggests. It might even limit the usefulness of these diagnostic categories, which may be true of psychiatric diagnoses in general (see RDoC).

Here is where computational methods may assist with understanding symptom profiles and trajectories of grief (Malgaroli et al., 2022). Data driven analyses using unsupervised machine learning methods can identify patterns within the heterogeneity. Network analyses have identified the centrality of loneliness (Fried et al., 2015) and a social/identity symptom cluster that includes role confusion and meaninglessness (Malgaroli et al., 2018). In the review article, the authors thought this was novel and stated that, “A more surprising and emergent result showed meaninglessness and role confusion to be strongly central elements.” 

But I am not surprised at all.

My wife (@blueberrio) wrote microfiction — miniature standalone stories as well as longer collections. Her book Reliant was an entire apocalypse in tweets. After the nuclear crisis occurs in Part 2, the main character channels the agony of loss in a heartbreaking (and prophetic) way.

The bright, hollow sky absorbs my grief as I mourn our lost love. I wail and hug my knees, wishing to die. You can't soothe me, gone.

I don't feel that way too often any more. Which is good, because it's unbearable. But I still feel anxious, confused, disoriented, sad, and lonely.



1 This paper is the younger sibling of 636,120 Ways to Have Posttraumatic Stress Disorder.


Fried EI, Bockting C, Arjadi R, Borsboom D, Amshoff M, Cramer AO, Epskamp S, Tuerlinckx F, Carr D, Stroebe M. (2015). From loss to loneliness: The relationship between bereavement and depressive symptoms. Journal of abnormal psychology 124(2):256.

Lenferink LI, Eisma MC. (2018). 37,650 ways to have “persistent complex bereavement disorder” yet only 48 ways to have “prolonged grief disorder”. Psychiatry Research 261:88-9. [PDF]

Malgaroli M, Maccallum F, Bonanno GA. (2018). Symptoms of persistent complex bereavement disorder, depression, and PTSD in a conjugally bereaved sample: a network analysis. Psychological Medicine 48(14):2439-48.

Malgaroli M, Maccallum F, Bonanno GA. (2022). Machine yearning: How advances in computational methods lead to new insights about reactions to loss. Current Opinion in Psychology 43:13-7. [PDF]

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Monday, February 28, 2022

The Ongoing Debate about Hippocampal Neurogenesis in Adult Humans is over.

modified from Franjic et al. (2022). Cross-species comparison shows transcriptomic signatures of neurogenesis in the hippocampus of adult mouse, pig, and monkey but not human.

Does the adult brain generate new neurons throughout the lifespan? The prevailing view in most of the 20th century was that no new neurons are born in the mammalian brain once development ceases. A series of studies in the 1960s showed otherwise, but these were ignored until the 1990s. A now-historical paper from 2000 recounted the death of a dogma: adult neurogenesis is here to stay, even in humans. Thousand of studies in animals (mostly rodents) demonstrated that new neurons are born in the dentate gyrus region of the adult hippocampus, and they can play an important role in learning and memory.

More recently, several papers have questioned whether adult humans really do generate new neurons in the hippocampus (Sorrells et al, 2018, 2021; Franjic et al., 2022). One such paper examined the morphology of dentate gyrus cells taken from post-mortem brains and from tissue surgically removed from epilepsy patients, with ages ranging from prenatal to elderly (Sorrells et al, 2018). The presence of progenitor cells and young neurons was determined using immunohistochemistry (selective staining methods, visible in green and yellow below).

click on images for larger view

modified from Fig 2a (Sorrells et al, 2018). Human dentate gyrus (DG) proliferation declines sharply during infancy.

modified from Fig 3d (Sorrells et al, 2018). The number of young neurons declines in the human DG from infancy into childhood.

The paper's title succinctly summarized the findings: “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.” Immature neurons were rare in the 7 yr old and 13 yr old samples, and absent entirely in adults.

Despite these seemingly convincing results, critiques have identified shortcomings in the way that post-mortem human brain samples are typically processed, as well as other technical issues that affect immunostaining of neurogenic markers (Moreno-Jiménez et al., 2021).

Transcriptomics to the Rescue?

The latest study used different methodology: single-nucleus RNA-sequencing (snRNA-seq) of neurogenic markers in adult hippocampal subregions (Franjic et al., 2022). In a technical tour de force, the authors microdissected samples from five hippocampal subregions from the brains of pigs, macaque monkeys, and humans. Single brain cell nuclei were isolated according to an incredible complex protocol, followed by cellular barcoding, cDNA amplification, sequencing of libraries, single nuclei expression quantification, and hierarchical tree construction. The goal was to create a taxonomy of cell types categorized by gene expression.


  click on image for larger view

Fig 1 (Franjic et al., 2022). Cell type diversity in the human hippocampal-entorhinal system revealed by snRNA-seq. (E) Dendrogram depicting the hierarchical taxonomy across all cell subtypes.

As a cognitive neuroscientist, this level of cellular diversity is astounding and humbling. If you ever feel like you're learning a lot about the how the brain works from fMRI, take a look at the dendrogram above.

Iterative clustering identified 69 transcriptomically distinct cell clusters across all donors that were organized into a dendrogramatic taxonomy reflecting their unique gene expression patterns.

snRNA-seq reveals a neurogenic trajectory in the macaque, pig, and mouse DG that is virtually absent in humans

Using more comprehensive and less disputed methods than previous studies, and incorporating cross-species comparisons, Franjic and colleagues did not observe any signs of neurogenesis in the hippocampus of adult humans. A companion preview article concluded that human adult neurogenesis is unlikely (Nano & Bhaduri, 2022).

These results don't negate or diminish the excellent and informative work on neurogenesis in rodents, but they suggest that the human hippocampus relies on other forms of neuroplasticity to learn and remember.



Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp AT, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z. et al. (2022). Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110: 452-469
Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. (2021). Evidences for adult hippocampal neurogenesis in humans. Journal of Neuroscience 41(12):2541-53.
Nano PR, Bhaduri A. (2022). Mounting evidence suggests human adult neurogenesis is unlikely. Neuron 110(3):353-5.
Snyder JS. (2018). Questioning human neurogenesis. Nature 555: 315-316
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555(7696):377-81.
Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, Page CE, Sandoval K, Knox A, Connolly A, Huang EJ. (2021). Positive controls in adults and children support that very few, if any, new neurons are born in the adult human hippocampus. Journal of Neuroscience 41(12):2554-65.

Must-see experiment from Snyder Lab (2014)!  

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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

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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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