Sunday, June 12, 2022

ABCT Apologizes for Past Support of Gay Conversion Therapy


It's 2022, and the Association for Behavioral and Cognitive Therapies (ABCT) has just issued a belated apology because two of their past Presidents published papers on “aversion therapies” for “converting” gay and transgender individuals to the socially prescribed norms of sexuality and gender identity. 

Well, they didn't actually say this, nor did they name the prominent and distinguished clinical psychologists who authored these papers. Although these luminaries signed on to the mea culpa, there was no direct admission of the harm caused by these ill-advised practices. Instead, the document focused on “the courageous and historic role that some of our members have played in advancing SGM [sexual and gender minority] rights and mental health (e.g., Drs. Charles Silverstein and Gerald Davison).” 

Which is great and all.

But. 

This covert history has been hiding in plain sight for 50 years, and I'm surprised the reckoning hasn't come any earlier. I'm not a clinician, nor am I in the field of cognitive behavior therapy research. But in 2013 I wrote a post on Dr. David H. Barlow and Aversion Therapy for Gays. Dr. Barlow had received a prestigious award for his contributions to clinical psychology, which are indeed extensive. But he was also an author on papers that examined aversion therapy in gay men (Barlow et al., 1969; Barlow, 1973; Barlow et al., 1975; Herman et al., 1974; Barlow et al., 1975; Hayes et al., 1983) and exorcism for transsexualism (Barlow et al., 1977). Dr. Barlow and Dr. Steven C. Hayes were Past Presidents of ABCT in 1978-1979 and 1997-1998, respectively. Hayes subsequently developed Acceptance and Commitment Therapy (ACT) and Barlow is known for his work on the treatment of anxiety disorders.


Sorry Seems to Be the Hardest Word

I first learned about the ABCT apology on Twitter, via Lorenzo Lorenzo-Luaces, PhD (@lluaces) and Aaron Fisher (aaronjfisher).

ABCT Apology for Behavior Therapy’s Contribution to the Development and Practice of Sexual Orientation and Gender Identity and Expression Change Efforts

The ABCT Board of Directors and past leadership have released an apology for behavior therapy’s contributions to the development and practice of sexual orientation and gender identity and expression change efforts [SOGIECEs].


More details are in the Full Apology PDF.

...[ABCT] apologizes for our historic role in the development and use of so-called “conversion therapies,” practices that have caused untold harm to members of the sexual and gender minority (SGM) community for over 50 years. To this day, publications written by ABCT members – including members in prominent leadership roles – are used by anti-SGM activists to justify their ongoing use of these damaging so-called “therapies.” ABCT deeply regrets behavior therapists’ role in the creation, study, and use of these practices, and recognizes and accepts responsibility for the ways in which both our actions and inactions have harmed SGM people. ABCT recognizes it is time for us to document our history and legacy and say that we are truly sorry.1


But documentation of this history and legacy is rather sketchy... Without naming names, the Apology cited the recent review of Capriotti and Donaldson (2022), which in turn asked “Why don’t behavior analysts do something?” about retracting the unethical paper of Rekers and Lovaas (1974). The conversion therapy work of Barlow and Hayes was mentioned here as well. 

 

I wrote to Barlow in 2013 to ask him about this early research on SGM people.2  I didn't really expect an answer, especially since I'm an obscure anonymous blogger. Nonetheless, I wanted to give him the opportunity to respond before I posted about his work.

Dear Dr. Barlow,

Congratulations on your receipt of the 2012 James McKeen Cattell Fellow Award from the APS for your distinguished contributions to the field.

I am a blogger writing a post about past treatments for homosexuality and came across references to your early work on aversion therapy in gay men, which I found unfortunate.

I wondered whether you had a statement about that work in light of contemporary views of homosexuality, or whether you had issued such a statement in the past.

Thank you very much for your time.

Sincerely,
The Neurocritic


Then a reader (Jordon) commented on my post in 2015, saying Barlow wrote back when he was asked about aversion therapy. Barlow sent a forthcoming book chapter from his 2016 retrospective, The Neurotic Paradox, Volume 1: Progress in Understanding and Treating Anxiety and Related Disorders. A sort-of not-really apology appeared on p. 6-7:

But it was also during this time [late 60s-early 70s] that I undertook what has come to be from my own personal point of view the most regrettable initiative in my clinical research career. Specifically ... I began treating and evaluating the effects of [covert sensitization]  treatment in individuals with what came to be called paraphilias but what was then called sexual deviation (Barlow, 1974a). While our focus was mostly on pedophilia (e.g. Barlow, Leitenberg, & Agras, 1969), the aggressive behavior of rapists (e.g. Abel, Barlow, Blanchard, & Guild, 1977), and other paraphilias (e.g. Hayes, Brownell, & Barlow, 1978), included in this series of studies were participants presenting with same-sex arousal patterns with consenting adults. (e.g., Barlow, Leitenberg, & Agras, 1969). At that time homosexuality was considered a disorder in all systems of nosology and, under extreme pressures from society and the associated stigma, these individuals sought out treatment; so very few clinicians even gave it a second thought. But by the mid-1970s several individuals began questioning these treatment goals.

 

These practices were “embedded in the continually shifting landscape of cultural values and mores” and homosexuality wasn't de-pathologized until “later in the decade” of the 1970s [it was actually 1973] and “most of the work was on paraphilias” [but many papers were on attempted conversion of gay men and transgender women (who were called male transsexuals)]. Most importantly, Barlow did not acknowledge the harm inflicted on the recipients of his treatments.

Besides the bizarre exorcism in a transsexual article, three more papers described covert modeling procedures and a “therapeutic package” to change the gender identity of transgender youth and young women (Barlow et al., 1973, 1979; Hay et al., 1981). Given the Increasing Criminalization of Gender-Affirming Care for Transgender Youth in many Southern states, it's critical for all psychological organizations to disown past practices used to justify such discriminatory and inhumane treatment.

 

What else should I be?
All apologies
What else could I say?
Everyone is gay

--Nirvana


Footnotes

1 One of the action items is that disclaimers will be added to SOGIECE papers previously published in ABCT journals. My initial search turned up only one. Barlow DH (1973). Increasing heterosexual responsiveness in the treatment of sexual deviation: A review of the clinical and experimental evidence. Behavior Therapy 4:655-671

2 The SGM terminology was unfamiliar to me before now. I also wondered whether the acronym SOGIECE was real, but apparently it is.

 

ADDENDUM (June 12 2022): Dr. Hayes has issued a personal apology for his role in conversion therapy. Also, he has published on ACT to lessen the impact of internalized homophobia (which is quite common in LGBTQ+ persons, as I know from personal experience).

Yadavaia JE, Hayes SC. (2012). Acceptance and commitment therapy for self-stigma around sexual orientation: A multiple baseline evaluation. Cognitive and behavioral practice 19(4):545-59.
 

Bibliography
(refs discussed in Dr. David H. Barlow and Aversion Therapy for Gays)

Barlow DH (1973). Increasing heterosexual responsiveness in the treatment of sexual deviation: A review of the clinical and experimental evidence. Behavior Therapy 4:655-671.

Barlow DH, Abel GG, & Blanchard EB (1977). Gender identity change in a transsexual: an exorcism. Archives of sexual behavior, 6 (5), 387-95. PMID: 921523

Although the prevention of transsexualism is the ideal, work in this area has been fraught with ethical problems, and data on the possibility of prevention, or even what to prevent, are not available...

Barlow DH, Agras WS, & Leitenberg H (1972). The contribution of therapeutic instruction of covert sensitization. Behaviour research and therapy, 10 (4), 411-5. PMID: 4637499

Barlow DH, Agras WS, Abel GG, Blanchard EB, Young LD. (1975). Biofeedback and reinforcement to increase heterosexual arousal in homosexuals. Behav Res Ther. 13:45-50.

The patient descriptions are distressing, e.g. a boy raped by a male relative: “The first S was a 15-yr-old male who had engaged in homosexual behavior for 4 yr after being seduced [sic] by an uncle.”

Barlow DH, Leitenberg H, & Agras WS (1969). Experimental control of sexual deviation through manipulation of the noxious scene in covert sensitization. Journal of abnormal psychology, 74 (5), 597-601. PMID: 5349402

Hayes SC, Brownell KD, & Barlow DH (1983). Heterosocial-skills training and covert sensitization. Effects on social skills and sexual arousal in sexual deviants. Behaviour research and therapy, 21 (4), 383-92, PMID: 6138027

Herman SH, Barlow DH, Agras WS. (1974). An experimental analysis of exposure to "explicit" heterosexual stimuli as an effective variable in changing arousal patterns of homosexuals. Behav Res Ther. 12:335-45.


Additional References

Barlow DH, Abel GG, Blanchard EB. (1979). Gender identity change in transsexuals: Follow-up and replications. Archives of General Psychiatry 36(9):1001-7.

Barlow DH, Agras WS. (1973). FADING TO INCREASE HETEROSEXUAL RESPONSIVENESS IN HOMOSEXUALS. Journal of Applied Behavior Analysis. 6(3):355-66.

“Heterosexual responsiveness, measured by penile responses and reports of behavior, was strengthened in three homosexuals through a fading procedure [slides of nude females superimposed on slides of nude males.]. ... The results suggest that fading was responsible for altering stimulus control of sexual arousal and that aversive techniques may not be necessary in the treatment of sexual deviation.” [well that's a relief...]

Barlow DH, Hayes SC, Nelson RO, Steele DL, Meeler ME, Mills JR. (1979). Sex role motor behavior: A behavioral checklist. Behavioral Assessment. 1:119-38. [I could not find a copy of this; however, the items appear in Hayes et al. 1984].  Examples:

  • Firm Wrist Action Versus Limp Wrist Action.
  • Hand(s) in Pocket. 
  • Frequent or Exaggerated Hand or Arm Movements.
Barlow DH, Reynolds EJ, Agras WS. (1973). Gender identity change in a transsexual. Archives of General Psychiatry 28(4):569-76.

Brownell KD, Hayes SC, Barlow DH. (1977). Patterns of appropriate and deviant sexual arousal: the behavioral treatment of multiple sexual deviations. Journal of Consulting and Clinical Psychology 45(6):1144.

  • one cis-male cross-dresser into BDSM (among the rapists, pedophiles, and exhibitionists) listened to arousing scenarios followed by humiliating consequences while his penile circumference was measured.
  • no gay or trans subjects here, but other papers have used the D word (“deviant”).
Hay WM, Barlow DH, Hay LR. (1981). Treatment of stereotypic cross-gender motor behavior using covert modeling in a boy with gender identity confusion. Journal of consulting and clinical psychology 49(3):388.

Hayes SC, Nelson RO, Steele DL, Meeler ME, Barlow DH. (1984). Instructional control of sex-related motor behavior in extremely masculine or feminine adults. Sex Roles 11(3):315-31.


Leonard SR, Hayes SC. (1983). Sexual fantasy alternation. Journal of behavior therapy and experimental psychiatry. 14(3):241-9.

  • four bisexual men (three white, one black) who were “confused” about their sexual orientation
  • but only the black man was medicated (with a potent antipsychotic)
“Subject 3 was a 32 yr old, black, married, blue collar worker and father of five. His heterosexual history was extensive. He reported a 3 yr history of homosexual activity ocurring during drinking episodes. At the time of referral and throughout the study, he received medication (Thorazine 25 mg daily) from a physician at the referring agency.”

 


 

 

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Tuesday, May 31, 2022

THIS device may not nudge your brain into deep sleep


The Washington Post used this picture of a saline-filled 280-channel Geodesic Head Web1 to illustrate a new wearable device that aims to enhance slow wave sleep (SWS). The device delivers low-level current (0.5 mA) at 0.5 Hz to mimic the frequency of EEG naturally recorded during SWS (0.5-1 Hz). However, this is impossible with saline sensors, which would also dry out well before the night is over. 


 

The WaPo article accurately showed different stages of applying the net, including measuring the head, checking impedences, and filling sensors with saline (above). A published journal article used similar Geodesic technology but using 256 electrodes filled with conductive gel (Hathaway et al., 2021). This setup was able to deliver transcranial electrical stimulation (TES) at 0.5 Hz.  Time spent in deep sleep was increased by 13% for active vs. sham stimulation. The BEL website shows people snoozing while wearing this headgear.

 

Footnote

1 This net is made by BEL Company and is the latest iteration of the 256-channel Geodesic Sensor Net made by EGI/Philips. Both designs were developed by Dr. Don Tucker at the University of Oregon. In 2017 he sold his company Electrical Geodesics, Inc. to Philips for $37 million. He now runs Brain Electrophysiology Laboratory (BEL) Company.



Reference
 
Hathaway E, Morgan K, Carson M, Shusterman R, Fernandez-Corazza M, Luu P, Tucker DM. (2021). Transcranial Electrical Stimulation targeting limbic cortex increases the duration of human deep sleep. Sleep Medicine 81:350-7.
 

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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...”

 

Footnote

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...

 

References

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.

Bereaved
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.

 

Footnote

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


References

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.

 

References

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?
 
. . .


2035

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

A Tale of Two BRAINS: #BRAINI and DARPA's SUBNETS

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?


References

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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