#anterior cingulate cortex

[raffaellopalandri]

Problem-Solving and Decision-Making: A Process-Driven Approach to Mastery

Since when I was a kid, think 5 years old, I discovered that I excelled in both problem-solving and decision-making. Later in life, I became aware that they also are fundamental to our human experience, shaping our lives, careers, and relationships. Photo by Andrea Piacquadio on Pexels.com They are often seen as skills one either possesses or lacks. However, a process-driven perspective reveals…

[jim-fetter-illustrations]

Human Beings are Hardwired for Consciousness.

Did you know the part of your brain we think Consciousness comes from is called the 'Rostral Anterior Cingulate Cortex' that plays a key role in experiencing of emotions,..... and reward-based decision-making and learning, including motivation, cost-benefit calculation, as well as conflict and error monitoring.

It also determines whether our future will be one of clear-blue skies or dark stormy clouds.

This is because Optimism and Pessimism are not hardwired in our brain, and we as the Gods we are determine if we use cognitive behavioral techniques to overcome our natural tendencies towards doom and gloom.

So what do you think you want to do, dwell on mistakes of the past and continue to pick at the scab, or do you make a fresh start, and leave your mistakes in the past where they really belong?

Because we do know our lives are better when we choose Optimism, and that's where consciousness comes into play, because it is hardwired in our brain, we just have to realize it is we who are the God, and we make all of the decisions in our livelihood, not anything outside of ourselves like the Gods man creates to make us think THEY are in charge, because they aren't, we are.

But as I've said those choices aren't Hardwired in our brains, and we can choose to let religions God make all of our decisions for us.

Or we can choose to follow our heart, through your brains consciousness,.... the choice is entirely up to YOU!

[callistocalavarni]

Shifting and using LOA with OCD

I feel like it's important to talk about how harmful it can be to ignore this subject. So if you have ocd or anxiety and still want to shift or use loa this post is for you. I want to stress that it is ok to worry about intrusive thoughts. Just because you dwell on an obssesion does not mean its going to manifest. However, I still feel the need to share ways you can prevent your intrusive thoughts from making you stress while shifting and using loa. First we need to fully know what we are dealing with and then how to fix the issue.

If you are not aware, OCD has four stages:

Obssesion - Unwanted, intrusive, and distressing thoughts, images or urges. (sometimes these thoughts are not clear and can just feel like impending doom without reason.) These intrusions are unwanted and are sent from your areas of your brain including the prefrontal cortex (orbitofrontal and anterior cingulate cortexes), basal ganglia, and thalamus. !!!

Anxiety - Intense fear and discomfort triggered by the obssesions. Dwelling on the thought, worring that you are a bad person by thinking a certian thing ( you are not ) or stressing that the intrusive thought will happen.

Compulsion - Repetitive behaviors or mental rituals performed to reduce the anxiety caused from these thoughts. ex; counting in your head, doing something untill it feels "even", washing your hands a certian amount of times, or even yelling and shunning the thought out of your head.

Temporary relief - The compulsions provide temporary relief from the anxiety, reinforcing the cycle. Once you do your compulsion it tricks your mind into thinking that these obssesions pose a real danger, and that compulsions are necessary in order to be safe. (these are what we want to stop so we can break the cycle.) And yes, telling the thought to go away and cursing at it is also a compulsion.

I'm going to start this of by saying, compulsions are bad. Please try not to give into them. I know it's hard at first and you will feel scared and uncomfortable but thats the point. You have to undo the cycle to build a new one. Compulsions give the intrusive thoughts meaning. We don't want this. If you give the thought meaning or show feelings to it your brain is going to think its important therefore it will keep sending you the thought. There is two ways to stop this, Ignore the thought, or decunsruct the thought (aka ERP.)

Ignoring the thought can go like this: Label the thought as intrusive but do not add emotion to it. But also don't push it away Ex; "This is an intrustive thought, I am going to think about something else now." If the thought becomes overwhelming and you can't get away from it, start manually breathing. This will distract your brain. We want to act like the thought is like any other thought you would have. The avarge human has about 60,000 thoughts a day. Do we remeber all of these? Of course not. This is because we dont attach any emotion or dwell on them. It's kind of ironic because this method is basically using loa. If we act like the thought is usless and not important it will become just that and our brain will stop sending us the thought.

Decunstructing the thought or exposing and response prevention (erp) can be a little more difficult. The goal here is to overcome the fear and expose our selves to the intrusive thoughts completely. I know it sounds scary but remeber if you have no intention of manifesting said thought then it simply won't manifest. (an intrusive thought saying you have intention does not count don't worry) I also use this to re script traumatic events or nightmares. Imagery rescripting is what I am going to call this method of moving away from your intrusive thoughts. Imagery Rescripting is a technique that is often used in therapy to deal with upsetting or significant images that occupy our mind and play a part in keeping our anxiety going. The problematic images that people often struggle with can be memories of the past, nightmares, or intrusive thoughts. You have probably noticed that with all of your intrusive thoughts or images, the common response is to try to avoid the image, to push it away, to shun it out of our minds. This is a very understandable reaction, unfortunately avoiding these thoughts and using a compulsion usually makes it worse. It makes us very fearful of the thought itself, giving the intrusive thoughts power over you, and therefore the thought becomes something more than a "just a thought." By rescripting you are no longer avoiding them. Instead you are actively approaching them. You run the full image/thought in your head and then re write it. You can do this however you want. Rescripting it can range from complete fantasy or staying in the guidelines of this reality. Ex; Inflating the image and adding different hues to it. Making the scary thing in the image look silly; this takes away power from it. Do you want Hatsune Miku to start e dancing on your fears? She totally can! Adding a comfort character or a s/o to the image and letting them change it for you/comfort you can also work. If it is just a thought I would try and see the full sentence of said thought and then change the letters in your head to make it say something else. Or you can make the letters change into silly little characters..make them dance! Important note - You have to first deal with the intrusive thought/image. You cannot skip over this part or else it will just be a compulsion. If it is to triggring have someone else in the room while you do it so they can wake you up from the visualization and help you ground yourself. I would only do this method if you know for a fact that you are ready to face your intrusive thoughts head on.

Crying or experiencing hard emotions while doing ERP is normal. Though, I did this alone, I would recommend someone you trust is there while you are doing it so if things get too overwhelming they can help you. I as well have ocd so most of this is from my personal experience.

If you have any questions about this my asks are open. :)

<3

[please1mistress]

THIS IS NOT HYPNOTIC or EROTIC

If you are curious about what hypnosis does to the brain, you might be interested in learning about the dorsal anterior cingulate cortex (DACC). This is a part of the brain that helps us stay alert and aware of our surroundings. It also plays a role in self-consciousness and emotional regulation. But what happens to the DACC when we are hypnotized? According to a groundbreaking study by Stanford University, hypnosis reduces the activity of the DACC, making us less vigilant and more relaxed. This also means that we are more open to suggestions and less inhibited by our usual worries or fears. Hypnosis can also change the way different brain regions communicate with each other. For example, hypnosis can increase the connection between the dorsolateral prefrontal cortex (DLPFC) and the insula, which are involved in executive control and interception, respectively. This can help us focus on our inner sensations and feelings, and ignore external distractions. On the other hand, hypnosis can decrease the connection between the DLPFC and the posterior cingulate cortex (PCC), which are part of the default mode network (DMN). The DMN is active when we are not engaged in any specific task, and it is associated with self-referential thinking and mind-wandering. By weakening the link between the DLPFC and the PCC, hypnosis can reduce our tendency to ruminate or daydream, and make us more attentive to the present moment. These changes in brain activity and connectivity can explain why hypnosis can be a powerful tool for pain management, anxiety relief, trauma recovery, and many other applications. Hypnosis can help us access a state of mind that is more receptive, flexible, and creative. Isn't that amazing?

[covid-safer-hotties]

Also preserved in our archive

"Just a cold" that changes the structure and mass of your brain

By Nikhil Prasad

Medical News: A groundbreaking study from researchers at the University of California, Los Angeles (UCLA)-USA has shed light on how Long COVID is linked to structural changes in the brain caused by SARS-CoV-2. By using advanced imaging techniques, the team discovered structural changes in the brains of individuals with Long COVID, including increased cortical thickness and gray matter volume in specific regions. This Medical News report will explore the study's key findings, its implications for understanding Long COVID, and what it means for patients suffering from this persistent condition.

Understanding the Research Approach The study involved participants from the UCLA hospital and broader Los Angeles community, with 36 individuals ranging in age from 20 to 67. Among them, 15 had Long COVID symptoms, while others were used as healthy controls. Researchers utilized structural magnetic resonance imaging (MRI) to compare brain differences between these groups. The study focused on specific brain regions, such as the dorsolateral prefrontal cortex (DLPFC) and the cingulate gyrus, which are known to be involved in cognitive and emotional processes. These areas were chosen because they are susceptible to inflammation and have been linked to neuropsychiatric symptoms.

To assess participants' cognitive and emotional health, tools like the Montreal Cognitive Assessment (MoCA) and the Hamilton Anxiety and Depression scales were used. The imaging data were processed using specialized software to measure cortical thickness and gray matter volume, providing a detailed look at the brain's structural changes.

Key Study Findings The study revealed several critical findings that deepen our understanding of Long COVID's impact on the brain. Participants with Long COVID showed:

-Increased Cortical Thickness: Regions such as the caudal anterior cingulate, posterior cingulate, and rostral middle frontal gyrus exhibited significantly higher cortical thickness compared to controls.

-Higher Gray Matter Volume: In areas like the posterior and isthmus cingulate gyri, Long COVID patients had greater gray matter volume.

Interestingly, these structural changes were associated with the severity of clinical symptoms. For example, higher thickness in the cingulate regions correlated with more severe chronic illness scores, while increased insular thickness was linked to anxiety levels.

Such changes suggest that Long COVID might lead to either swelling due to inflammation or compensatory mechanisms like neurogenesis to counteract damage.

How This Study Compares with Previous Research While most COVID-19-related brain studies have shown reductions in gray matter and cortical thickness, this research indicates an increase in these metrics for Long COVID pa tients. Prior studies focused on acute COVID cases often revealed brain shrinkage and cognitive decline. In contrast, this study highlights that Long COVID might involve unique mechanisms, such as prolonged inflammation or a compensatory response to earlier damage.

Implications for Patients and Healthcare Providers These findings are crucial for both patients and healthcare professionals. They suggest that the persistent symptoms of Long COVID, such as brain fog, fatigue, and anxiety, could have a physical basis in brain structure changes. Recognizing this connection can lead to better-targeted treatments and interventions.

The Future of Long COVID Research While this study offers valuable insights, it also leaves many questions unanswered. For example, are these brain changes reversible? Do they worsen over time? The researchers acknowledge the study's limitations, including its small sample size and lack of longitudinal data. Future studies should aim to include larger, more diverse populations and examine changes over time to build a clearer picture of Long COVID's effects.

Conclusions This research from UCLA represents a significant step forward in understanding the neurological impacts of Long COVID. The observed increases in cortical thickness and gray matter volume in certain brain regions provide strong evidence that Long COVID involves measurable structural brain changes. These findings offer hope that by identifying the physical manifestations of this condition, we can develop more effective treatments to alleviate its symptoms. However, the path forward requires continued research to uncover the full extent of these changes and their implications.

The study emphasizes the importance of addressing neuropsychiatric symptoms in Long COVID patients and highlights the need for comprehensive care that includes both physical and mental health support. As we move forward, it is vital to integrate these insights into public health strategies to help those affected by this debilitating condition.

The study findings were published in the peer-reviewed journal: Frontiers in Psychiatry. www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1412020/full

[compneuropapers]

Interesting Papers for Week 44, 2024

The role of the human hippocampus in decision-making under uncertainty. Attaallah, B., Petitet, P., Zambellas, R., Toniolo, S., Maio, M. R., Ganse-Dumrath, A., … Husain, M. (2024). Nature Human Behaviour, 8(7), 1366–1382.

Modeling hippocampal spatial cells in rodents navigating in 3D environments. Aziz, A., Patil, B. K., Lakshmikanth, K., Sreeharsha, P. S. S., Mukhopadhyay, A., & Chakravarthy, V. S. (2024). Scientific Reports, 14, 16714.

Anterior cingulate cortex provides the neural substrates for feedback-driven iteration of decision and value representation. Chen, W., Liang, J., Wu, Q., & Han, Y. (2024). Nature Communications, 15, 6020.

Firing rate adaptation affords place cell theta sweeps, phase precession, and procession. Chu, T., Ji, Z., Zuo, J., Mi, Y., Zhang, W., Huang, T., … Wu, S. (2024). eLife, 12, e87055.4.

Non-Hebbian plasticity transforms transient experiences into lasting memories. Faress, I., Khalil, V., Hou, W.-H., Moreno, A., Andersen, N., Fonseca, R., … Nabavi, S. (2024). eLife, 12, e91421.3.

Gaze-centered gating, reactivation, and reevaluation of economic value in orbitofrontal cortex. Ferro, D., Cash-Padgett, T., Wang, M. Z., Hayden, B. Y., & Moreno-Bote, R. (2024). Nature Communications, 15, 6163.

Modulation of alpha oscillations by attention is predicted by hemispheric asymmetry of subcortical regions. Ghafari, T., Mazzetti, C., Garner, K., Gutteling, T., & Jensen, O. (2024). eLife, 12, e91650.3.

Contributions of cortical neuron firing patterns, synaptic connectivity, and plasticity to task performance. Insanally, M. N., Albanna, B. F., Toth, J., DePasquale, B., Fadaei, S. S., Gupta, T., … Froemke, R. C. (2024). Nature Communications, 15, 6023.

Consequences of eye movements for spatial selectivity. Intoy, J., Li, Y. H., Bowers, N. R., Victor, J. D., Poletti, M., & Rucci, M. (2024). Current Biology, 34(14), 3265-3272.e4.

Prediction error determines how memories are organized in the brain. Kennedy, N. G., Lee, J. C., Killcross, S., Westbrook, R. F., & Holmes, N. M. (2024). eLife, 13, e95849.3.

Neural Representation of Valenced and Generic Probability and Uncertainty. Kim, J.-C., Hellrung, L., Grueschow, M., Nebe, S., Nagy, Z., & Tobler, P. N. (2024). Journal of Neuroscience, 44(30), e0195242024.

Selective consolidation of learning and memory via recall-gated plasticity. Lindsey, J. W., & Litwin-Kumar, A. (2024). eLife, 12, e90793.3.

A synergistic workspace for human consciousness revealed by Integrated Information Decomposition. Luppi, A. I., Mediano, P. A., Rosas, F. E., Allanson, J., Pickard, J., Carhart-Harris, R. L., … Stamatakis, E. A. (2024). eLife, 12, e88173.4.

Memorability shapes perceived time (and vice versa). Ma, A. C., Cameron, A. D., & Wiener, M. (2024). Nature Human Behaviour, 8(7), 1296–1308.

Mixed Representations of Sound and Action in the Auditory Midbrain. Quass, G. L., Rogalla, M. M., Ford, A. N., & Apostolides, P. F. (2024). Journal of Neuroscience, 44(30), e1831232024.

Neural activity ramps in frontal cortex signal extended motivation during learning. Regalado, J. M., Corredera Asensio, A., Haunold, T., Toader, A. C., Li, Y. R., Neal, L. A., & Rajasethupathy, P. (2024). eLife, 13, e93983.3.

Using synchronized brain rhythms to bias memory-guided decisions. Stout, J. J., George, A. E., Kim, S., Hallock, H. L., & Griffin, A. L. (2024). eLife, 12, e92033.3.

Cortical plasticity is associated with blood–brain barrier modulation. Swissa, E., Monsonego, U., Yang, L. T., Schori, L., Kamintsky, L., Mirloo, S., … Friedman, A. (2024). eLife, 12, e89611.4.

Structural and sequential regularities modulate phrase-rate neural tracking. Zhao, J., Martin, A. E., & Coopmans, C. W. (2024). Scientific Reports, 14, 16603.

An allocentric human odometer for perceiving distances on the ground plane. Zhou, L., Wei, W., Ooi, T. L., & He, Z. J. (2024). eLife, 12, e88095.3.

[maths-screaming]

Doing It for the High

For decades now, I've had a consistent gym routine. And, being middle-aged, I am now surrounded by peers and colleagues who want to know how one maintains a consistent gym routine in middle age.

My answer: I exercise for the high.

Not for better health. Not to look better in my jeans. Not to keep up with my students. Not because my doctor says concerning nickel words like "cholesterol" or "osteoporosis." I exercise for one reason only, and that reason is the dopamine.

I have also started doing math for the high.

Specifically: I ordered a set of unit blocks/rods. The ones that come in ones, tens, hundreds, and thousands.

I ordered them because I suck at decimals, and I figured they'd come in handy when trying to deal with those. I started using them for basic addition and subtraction, however, because the Maths-No Problem series encourages students to use them when reviewing at the top of each new lesson.

These books with their cute cartoon children haven't failed me yet. So okay, cute cartoon kids. I'll try the blocks.

And y'all, these little bricks are intensely satisfying to use.

They feel nice. They make cool clicky noises when they bump each other. They sort into neat little countable piles. The ones, tens, and hundreds are different colors, so my brain always knows which column we're in. I can count up to ten in any one pile and trade it in for the next pile up, which is way more satisfying than "carrying the one."

Every moment with these is a tiny dopamine hit. And that's hugely important.

We've known for years that dopamine production plays a key role in learning, though we haven't always understood why. Does dopamine provide motivation? Does it drive formation of neural pathways? Maybe both? It's also doing something in our working memory (a notorious weakness in dyscalculia and ADHD, among others), but what?

As an ADHDer, I already live with a deficit of dopamine in the anterior cingulate cortex - leading to issues with working memory, attention, focus, reward-based motivation, and a host of other ills. On top of that, I started associating math with drudgery, anxiety, and stress at the age of five.

The brain pathways that tell me "numbers are misery, don't try" are well worn in. But those pathways led me where I am today - barely numerate enough to function as an adult. I need new routes.

Fun plastic clicky unit blocks are building those new routes. So heck yes, I'm playing with them. Every math learner should. Make the brain associate math with happy. Do it for the high.

Further Reading:

Roy A. Wise, "Dopamine, Learning and Motivation," in Nature Reviews Neuroscience

"How Does Dopamine Regulate Both Learning and Motivation?", Science Daily

Namboodiri, Vijay MK, "'But why?' Dopamine and causal learning," Current Opinions in Behavioral Sciences

Base Ten Blocks at Hand2Mind (the set I purchased is substantially similar to this one)

[thenarrativeofjohnsmith]

ELECTROCHEMISTRY (Impossible: Failure) - Drink yourself silly and don’t stop just keep drinking it feels so good you should go do it now don’t you miss it?

HALF LIGHT (Easy: Failure) - Kill your self

ENCYCLOPEDIA (Impossible: Success) - The rate of OCD among first-degree relatives of adults with OCD is approximately two times that among first-degree relatives of those without the disorder; however, among first-degree relatives of individuals with onset of OCD in childhood or adolescence, the rate is increased 10-fold. Familial transmission is due in part to genetic factors (e.g., a concordance rate of 0.57 for monozygotic vs. 0.22 for dizygotic twins). Twin studies suggest that additive genetic effects account for ~40% of the variance in obsessive-compulsive symptoms. Dysfunction in the orbitofrontal cortex, anterior cingulate cortex, and striatum have been most strongly implicated; alterations in frontolimbic, frontoparietal, and cerebellar networks have also been reported.

[starpointedscar]

Something I learned about the brain and willpower:

There is a section of the brain in the prefrontal cortex that is responsible for controlling our willpower called the aMCC (Anterior Mid-Cingulate Cortex).

The more hard/inconvenient things you do, the bigger it grows, meaning that those tasks may become easier over time. This then may help us break through mental blocks that are keeping us from doing things we enjoy because as it grows we end up with more willpower to use (kinda like exercising a muscle, the more you use it the more weight you can lift over time. When it comes to being autistic, I almost think of it as adding more spoons to my day)

The things that grow the aMCC are inconvenient tasks (not tasks that put you in danger), like doing the dishes. I hate doing the dishes, but now that I know that I get to strengthen my brain by being mildly inconvenienced for a few minutes. it makes it a little easier to do them. I also struggle with getting out of bed in the morning.

I also learned that learning new things is almost ALWAYS going to be challenging. When we try to pull our brain to attention to learn something new, we are actively suppressing the "autopilot" part of our brain. When this autopilot is suppressed, this pathway releases chemicals that make us anxious and uneasy. This suppression also helps to strengthen our willpower, which in turn makes whatever task we want to learn a little bit easier.

This also happens when you hold back a comment you know you shouldn't say to someone. You are actively suppressing your automatic response, which is why you may feel uncomfortable while keeping yourself from saying something, even if it's a comment you know you shouldn't say.

As a diagnosed autistic person that probably also has ADHD, this information helps me SO much. I really need to know the in depth reason as to why I act a certain way on almost a cellular level for me to really change how I act. I've been struggling with task initiation paralysis, impulsivity when speaking, and decision making. Knowing that my body is wired to feel uncomfortable when I do something out of routine, and I will always feel some level of resistance when trying to do something I don't want to do, helps so much with how I move about my day.

I got this info from Andrew Huberman, a neuroscientist, from his podcast episode about willpower and tenacity.

[brightlotusmoon]

Marijuana Users Have More Empathy And A Greater Understanding Of Other People's Emotions, Study Finds

Researchers said the results suggest a potential association between cannabis use and empathy, though they caution that further research is needed to fully understand the interactions “since many other factors may be at play.”

In attempting to explain the findings, the team of neuroscientists noted that a part of the brain, the anterior cingulate cortex (ACC), “is a region that is prone to the effects of cannabis consumption and is also greatly involved in empathy, which is a multi-component process that can be influenced in different ways.”

“Given that the ACC is one of the main areas that possess CB1 [cannabinoid] receptors and is heavily involved in the representation of the affective state of others,” the study says, “we believe that the differences shown by regular cannabis users in the emotional comprehension scores and their brain functional connectivity could be related to the use of cannabis.”

Despite the qualifiers, the study concludes, “Given previous studies of the effect of cannabis on mood and emotional detection, we believe that these results contribute to open a pathway to study further the clinical applications of the positive effect that cannabis or cannabis components could have in affect and social interactions.”

In other neuroscience research this year, researchers at the University of West Attica in Greece found that medical marijuana use was associated with improved quality of life — including better job performance, sleep, appetite, and energy — among people with neurological disorders.

Another recent study published by the American Medical Association found that medical marijuana was associated with “significant improvements” in quality of life for people with conditions like chronic pain and insomnia—and those effects were “largely sustained” over time.

Other studies have found cannabis may boost the “runner's high” felt during exercise and enhance the practice of yoga.

[psykopathy]

just read an article explaining an observation in the brain function differences between a study of some conservatives and liberals. it says conservatives desire security, predictability and authority more than liberals do, and liberals are more comfortable with novelty, nuance and complexity.

the volume of gray matter, or neural cell bodies, making up the anterior cingulate cortex, an area that helps detect errors and resolve conflicts, tends to be larger in liberals

and the amygdala, which is important for regulating emotions and evaluating threats, is larger in conservatives. makes so much sense.

[msalzaabi]

Rewiring the Heart: How Love and Heartbreak Reshape the Brain

Love and heartbreak take us on a rollercoaster that’s not just emotional but deeply physical, carving their presence into our brains like a storm sweeping through, leaving undeniable marks. Falling in love feels like a firework show going off in your mind. Dopamine, the brain’s pleasure chemical, floods your system like a tidal wave, making everything seem more vivid, more intense. It's that euphoric, “walking on air” feeling that people often describe as being “high,” and biologically, that's exactly what it is. Oxytocin, the "cuddle hormone," kicks in, binding you to your partner, making you feel like you’re floating through life together, untouchable and invincible.

But heartbreak? That crash hits just as hard as the high. The brain, once flooded with love, responds to loss like it would physical pain. The same area that lights up when you stub your toe or burn your hand—the anterior cingulate cortex—activates during heartbreak. It’s not just an expression when people say “heartache”—it’s a real, visceral pain that grips your chest and twists your gut. Your brain, now deprived of that dopamine rush, reacts like an addict in withdrawal. Cortisol, the stress hormone, takes over, leaving you sleepless, anxious, and with that awful knot of dread in your stomach. It's like your body is constantly on high alert, mourning the loss of what once felt so good.

Mentally, it’s a fog. You lose focus, simple tasks become overwhelming, and you just can’t seem to shake that feeling of being off-balance. The brain is essentially grieving, struggling to process the absence of that connection, just as it would mourn the loss of something physical. You’re left reeling, mourning not only what was but what could have been, and the chemical rush that once made you feel so alive now feels impossibly distant.

Yet, despite how all-consuming it seems, the brain has an amazing ability to heal itself. Enter neuroplasticity—the brain's secret weapon. Just like a broken bone slowly mends, neuroplasticity helps the brain rewire and reorganize itself after emotional trauma. Little by little, your brain forms new circuits and starts rebalancing itself, slowly taming the chemical chaos left behind by heartbreak. It’s this gradual rewiring process that allows you to move forward, even if, at times, it feels like you’re stuck in place. The brain’s ability to adapt, to heal, is extraordinary, though heartbreak makes the process feel painfully slow. But with time, those emotional wounds start to close, and your brain finds new ways to cope, rebuild, and eventually thrive again. That’s the beauty of it—the brain is always working to restore balance, even when it feels like it will never end.

[covid-safer-hotties]

Preserved in our archive

A research letter from 2022 highlighting the effects of even "mild" covid on the brain.

Dear Editor,

A recent study published in Nature by Douaud and colleagues1 shows that SARS-CoV-2 infection is associated with longitudinal effects, particularly on brain structures linked to the olfactory cortex, modestly accelerated reduction in global brain volume, and enhanced cognitive decline. Thus, even mild COVID-19 can be associated with long-lasting deleterious effects on brain structure and function.

Loss of smell and taste are amongst the earliest and most common effects of SARS-CoV-2 infection. In addition, headaches, memory problems, confusion, or loss of speech and motility occur in some individuals.2 While important progress has been made in understanding SARS-CoV-2-associated neurological manifestations, the underlying mechanisms are under debate and most knowledge stems from analyses of hospitalized patients with severe COVID-19.2 Most infected individuals, however, develop mild to moderate disease and recover without hospitalization. Whether or not mild COVID-19 is associated with long-term neurological manifestations and structural changes indicative of brain damage remained largely unknown.

Douaud and co-workers examined 785 participants of the UK Biobank (www.ukbiobank.ac.uk) who underwent magnetic resonance imaging (MRI) twice with an average inter-scan interval of 3.2 years, and 401 individuals testing positive for SARS-CoV-2 infection between MRI acquisitions (Fig. 1a). Strengths of the study are the large number of samples, the availability of scans obtained before and after infection, and the multi-parametric quantitative analyses of serial MRI acquisitions.1 These comprehensive and automated analyses with a non-infected control group allowed the authors to dissect consistent brain changes caused by SARS-CoV-2 infection from pre-existing conditions. Altogether, the MRI scan processing pipeline used extracted more than 2,000 features, named imaging-derived phenotypes (IDPs), from each participant’s imaging data. Initially, the authors focused on IDPs involved in the olfactory system. In agreement with the frequent impairment of smell and taste in COVID-19, they found greater atrophy and indicators of increased tissue damage in the anterior cingulate cortex, orbitofrontal cortex and insula, as well as in the ventral striatum, amygdala, hippocampus and para-hippocampal gyrus, which are connected to the primary olfactory cortex (Fig. 1b). Taking advantage of computational models allowing to differentiate changes related to SARS-CoV-2 infection from physiological age-related brain changes (e.g. decreases of brain volume with aging),3 they also explored IDPs covering the entire brain. Although most individuals experienced only mild symptoms of COVID-19, the authors detected an accelerated reduction in whole-brain volume and more pronounced cognitive declines associated with increased atrophy of a cognitive lobule of the cerebellum (crus II) in individuals with SARS-CoV-2 infection compared to the control group. These differences remained significant when 15 people who required hospitalization were excluded. Most brain changes for IDPs were moderate (average differences between the two groups of 0.2–2.0%, largest for volume of parahippocampal gyrus and entorhinal cortex) and accelerated brain volume loss was “only” observed in 56–62% of infected participants. Nonetheless, these results strongly suggest that even clinically mild COVID-19 might induce long-term structural alterations of the brain and cognitive impairment.

The study provides unique insights into COVID-19-associated changes in brain structure. The authors took great care in appropriately matching the case and control groups, making it unlikely that observed differences are due to confounding factors, although this possibility can never be entirely excluded. The mechanisms underlying these infection-associated changes, however, remain to be clarified. Viral neurotropism and direct infection of cells of the olfactory system, neuroinflammation and lack of sensory input have been suggested as reasons for the degenerative events in olfactory-related brain structures and neurological complications.4 These mechanisms are not mutually exclusive and may synergize in causing neurodegenerative disorders as consequence of COVID-19.

The study participants became infected between March 2020 and April 2021, before the emergence of the Omicron variant of concern (VOC) that currently dominates the COVID-19 pandemic. During that time period, the Alpha and Beta VOCs dominated in the UK and all results were obtained from individuals between 51 and 81 years of age. It will be of great interest to clarify whether Omicron, that seems to be less pathogenic than other SARS-CoV-2 variants, also causes long-term brain damage. The vaccination status of the participants was not available in the study1 and it will be important to clarify whether long-term changes in brain structure also occur in vaccinated and/or younger individuals. Other important questions are whether these structural changes are reversible or permanent and may even enhance the frequency for neurodegenerative diseases that are usually age-related, such as Alzheimer’s, Parkinson’s or Huntington’s disease. Previous findings suggest that cognitive disorders improve over time after severe COVID-19;5 yet it remains to be determined whether the described brain changes will translate into symptoms later in life such as dementia. Douaud and colleagues report that none of top 10 IDPs correlated significantly with the time interval between SARS-CoV-2 infection and the 2nd MRI acquisition, suggesting that the observed abnormalities might be very long-lasting.

Currently, many restrictions and protective measures are relaxed because Omicron is highly transmissible but usually causes mild to moderate acute disease. This raises hope that SARS-CoV-2 may evolve towards reduced pathogenicity and become similar to circulating coronaviruses causing mild respiratory infections. More work needs to be done to clarify whether the current Omicron and future variants of SARS-CoV-2 may also cause lasting brain abnormalities and whether these can be prevented by vaccination or therapy. However, the finding by Douaud and colleagues1 that SARS-CoV-2 causes structural changes in the brain that may be permanent and could relate to neurological decline is of concern and illustrates that the pathogenesis of this virus is markedly different from that of circulating human coronaviruses. Further studies, to elucidate the mechanisms underlying COVID-19-associated neurological abnormalities and how to prevent or reverse them are urgently needed.

REFERENCES (Follow link)

[compneuropapers]

Interesting Papers for Week 11, 2025

Visual Processing by Hierarchical and Dynamic Multiplexing. Bonnefond, M., Jensen, O., & Clausner, T. (2024). ENeuro, 11(11), ENEURO.0282-24.2024.

Bifurcation Enhances Temporal Information Encoding in the Olfactory Periphery. Choi, K., Rosenbluth, W., Graf, I. R., Kadakia, N., & Emonet, T. (2024). PRX Life, 2(4), 043011.

Oculomotor Contributions to Foveal Crowding. Clark, A. M., Huynh, A., & Poletti, M. (2024). Journal of Neuroscience, 44(48), e0594242024.

Causal relational problem solving in toddlers. Goddu, M. K., Yiu, E., & Gopnik, A. (2025). Cognition, 254, 105959.

Bilateral Alignment of Receptive Fields in the Olfactory Cortex. Grimaud, J., Dorrell, W., Jayakumar, S., Pehlevan, C., & Murthy, V. (2024). ENeuro, 11(11), ENEURO.0155-24.2024.

An inductive bias for slowly changing features in human reinforcement learning. Hedrich, N. L., Schulz, E., Hall-McMaster, S., & Schuck, N. W. (2024). PLOS Computational Biology, 20(11), e1012568.

A social information processing perspective on social connectedness. Hein, G., Huestegge, L., Böckler-Raettig, A., Deserno, L., Eder, A. B., Hewig, J., Hotho, A., Kittel-Schneider, S., Leutritz, A. L., Reiter, A. M. F., Rodrigues, J., & Gamer, M. (2024). Neuroscience & Biobehavioral Reviews, 167, 105945.

Distinct Modulation of I h by Synaptic Potentiation in Excitatory and Inhibitory Neurons. Herstel, L. J., & Wierenga, C. J. (2024). ENeuro, 11(11), ENEURO.0185-24.2024.

An algorithmic account for how humans efficiently learn, transfer, and compose hierarchically structured decision policies. Li, J.-J., & Collins, A. G. E. (2025). Cognition, 254, 105967.

Conflict during learning reconfigures the neural representation of positive valence and approach behavior. Molina-García, L., Colinas-Fischer, S., Benavides-Laconcha, S., Lin, L., Clark, E., Treloar, N. J., García-Minaur-Ortíz, B., Butts, M., Barnes, C. P., & Barrios, A. (2024). Current Biology, 34(23), 5470-5483.e7.

Anticipating multisensory environments: Evidence for a supra-modal predictive system. Sabio-Albert, M., Fuentemilla, L., & Pérez-Bellido, A. (2025). Cognition, 254, 105970.

How visual experience shapes body representation. Shahzad, I., Occelli, V., Giraudet, E., Azañón, E., Longo, M. R., Mouraux, A., & Collignon, O. (2025). Cognition, 254, 105980.

Learning from conditional probabilities. Strößner, C., & Hahn, U. (2025). Cognition, 254, 105962.

Impact of conflicts between long- and short-term priors on the weighted prior integration in visual perception. Sun, Q., Gong, X.-M., & Sun, Q. (2025). Cognition, 254, 106006.

Neural Transformation from Retinotopic to Background-Centric Coordinates in the Macaque Precuneus. Uchimura, M., Kumano, H., & Kitazawa, S. (2024). Journal of Neuroscience, 44(48), e0892242024.

One-shot entorhinal maps enable flexible navigation in novel environments. Wen, J. H., Sorscher, B., Aery Jones, E. A., Ganguli, S., & Giocomo, L. M. (2024). Nature, 635(8040), 943–950.

Impulsive Choices Emerge When the Anterior Cingulate Cortex Fails to Encode Deliberative Strategies. White, S. M., Morningstar, M. D., De Falco, E., Linsenbardt, D. N., Ma, B., Parks, M. A., Czachowski, C. L., & Lapish, C. C. (2024). ENeuro, 11(11), ENEURO.0379-24.2024.

Neuronal sequences in population bursts encode information in human cortex. Xie, W., Wittig, J. H., Chapeton, J. I., El-Kalliny, M., Jackson, S. N., Inati, S. K., & Zaghloul, K. A. (2024). Nature, 635(8040), 935–942.

Transcranial Direct Current Stimulation over the Posterior Parietal Cortex Increases Nontarget Retrieval during Visual Working Memory. Ye, S., Wu, M., Yao, C., Xue, G., & Cai, Y. (2024).ENeuro, 11(11), ENEURO.0265-24.2024.

Fault-tolerant neural networks from biological error correction codes. Zlokapa, A., Tan, A. K., Martyn, J. M., Fiete, I. R., Tegmark, M., & Chuang, I. L. (2024). Physical Review E, 110(5), 054303.

[religion-is-a-mental-illness]

Introduction

In the last decade, there has been a rapid increase in the numbers of young people with gender dysphoria (GD youth) presenting to health services (Kaltiala et al., 2020). There has also been a marked change in the treatment approach. The previous “common practice” of providing psychosocial care only to those under 18 or 21 years (Smith et al., 2001) has largely been replaced by the gender affirmative treatment approach (GAT), which for adolescents includes hormonal and surgical interventions (Coleman et al., 2022). However, as a recent review concluded, evidence on the appropriate management of youth with gender incongruence and dysphoria is inconclusive and has major knowledge gaps (Cass, 2022). Previous papers have discussed that the weaknesses of the studies investigating the efficacy of GAT for GD youth mean they are at high risk of bias and confounding and, thus, provide very low certainty evidence (Clayton, 2022a, b; Levine et al., 2022). To date, however, there has been little discussion of the inability of these studies to differentiate specific treatment effects from placebo effects. Of note, the term “placebo effect” is no longer used to just simply refer to the clinical response following inert medication; rather, it describes the beneficial effects attributable to the brain-mind responses evoked by the treatment context rather than the specific intervention (Wager & Atlas, 2015). This Letter argues that the current treatment approach for GD youth presents a perfect storm environment for the placebo effect. This raises complex clinical and research issues that require attention and debate.

A Brief Introduction to the Contemporary Concept of the Placebo Effect

The term “placebo effect” can be used variably by different authors. As recently defined in a consensus statement, placebo (beneficial) and nocebo (deleterious) effects occur in clinical or research contexts and are due to psychobiological mechanisms evoked by the treatment (or research) context rather than any specific effect of the intervention. Importantly, placebo and nocebo effects not only occur during the prescription of placebo (inert) pills, but they can also substantially modulate the efficacy and tolerability of active medical treatments (Evers et al., 2018).

The therapeutic ritual, the encounter between a sick person and a clinician, is a powerful psychosocial event. Clinicians, particularly physicians, are our society’s designated healers and their prestige, status, and authority help engender patients’ trust and expectations of relief from suffering (Benedetti, 2021a). Positive clinician–patient interactions are associated with decreased anxiety and increased hope. Complex neurobiological mechanisms are implicated in the placebo effect, including release of neurotransmitters (e.g., endorphins, cannabinoids, dopamine, and oxytocin) and activation of specific areas of the brain (e.g., the prefrontal cortex, anterior insula, rostral anterior cingulate cortex, and the amygdala) (Colloca & Barsky, 2020; Kaptchuk & Miller, 2015). These changes are associated with an increased sense of well-being. They also impact on cardiovascular, respiratory, immune, and endocrine functioning, all of which may contribute to patients’ clinical improvement (Enck et al., 2013; Wager & Atlas, 2015).

Several unconscious psychological mechanisms, including classical conditioning and social learning, play a role in the placebo effect (Benedetti, 2021a). In clinical trials, where patients communicate with each other, a process of social observational learning may be associated with emotional contagion and, thus, placebo and nocebo effects (Benedetti, 2013). The media and social media may also foster these effects and contribute to the dissemination of symptoms and illness throughout the general population (Colloca & Barsky, 2020).

Expectation of outcome is a principal mechanism of the placebo effect and anything that increases patients’ expectations is potentially capable of boosting placebo effects (Evers et al., 2018). Although research has demonstrated that changes in physiological parameters may occur following placebo administration (Wager & Atlas, 2015), these response expectations have been particularly noted in patient-reported outcomes, such as anxiety, pain, life satisfaction, and mood. Expectations and cognitive readjustment can lead to behavioral changes, such as resuming normal daily activities, which can be observer rated. Physicians’ status, whether through the general position given to them in society or through individual personality factors, may contribute to such expectations of benefit. This type of phenomenon has sometimes been termed prestige suggestion. The “Hawthorne effect” describes the phenomenon where clinical trial patients’ improvements may occur because they are being observed and given special attention. A patient who is part of a study, receiving special attention, and with motivated clinicians, who are invested in the benefits of the treatment under study, is likely to have higher expectations of therapeutic benefits (Benedetti, 2021a).

Placebo-induced improvements are real and can be robust and long lasting (Benedetti, 2021b; Wager & Atlas, 2015). Individual patient factors, such as personality and genetics, may be associated with placebo responsiveness (Benedetti, 2021a). The particular illness is also relevant. For example, although placebo treatment can impact symptoms of cancer, there is no evidence that placebos can shrink tumors (Benedetti, 2021b; Kaptchuk & Miller, 2015). However, there is evidence that placebos can act as long-lasting and effective treatments for depression and various pain conditions, such as migraine and osteoarthritic knee pain (Kam-Hansen et al., 2014; Kirsch, 2019; Previtali et al., 2021). Further, some research suggests adherence to placebo medication, particularly in cardiac disease, may be associated with reduced mortality (Wager & Atlas, 2015).

The Research Setting versus the Clinical Practice Setting

Research into new medical treatments aims to control for placebo effects, and this helps ensure true evaluation of the treatment’s efficacy (Enck et al., 2013). The double-blind randomized controlled trial (DBRCT), although not perfect, is the current gold standard for determining the efficacy and safety of a treatment. The DBRCT study design evolved over several centuries and became widely accepted practice in the mid-twentieth century (Lilienfeld, 1982). Of note, the term “blind” is thought to have originated in eighteenth-century France when blindfolds were used to disprove Anton Mesmer’s “animal magnetism” theory and the mesmerism craze of that era (Kaptchuk, 1998). Well-designed DBRCTs minimize the impact of bias, confounding and placebo effects on findings and are the best type of study for determining whether there is a causal relationship between an intervention and an effect (Enck et al., 2013; Kabisch et al., 2011).

The reader may wonder about this requirement of differentiating placebo effects from the specific effects of an intervention and ask: If the patient improves, does it really matter why? Yes, it does, particularly for treatments that have significant risk of adverse effects. There are also broader problems raised by relying on the placebo effect. Consider prescribing antibiotics for viral infections. The patient may experience clinical benefit through a placebo effect. However, not only may some patients experience serious adverse drug reactions, but the health of the whole population is imperiled by the problem of antibiotic resistance (Llor & Bjerrum, 2014). Furthermore, informed consent is an ethical pillar of modern medicine and requires clinician honesty and transparency. Clinicians deceptively utilizing placebo treatments do not meet this requirement (Barnhill, 2012; Kaldjian & Pilkington, 2021). A medical profession that does little to distinguish placebo effects from specific treatment effects risks becoming little different from pseudoscience and the quackery that dominated medicine of past times, with likely resulting decline in public trust and deterioration in patient outcomes (Benedetti, 2021a).

Ideally, in evidence-based medicine, a new treatment undergoes rigorous research and has reasonable evidence of benefit prior to being introduced as routine treatment (although ongoing further research often continues). Clinicians can then reasonably harness and enhance the placebo effect to improve outcomes (Enck et al., 2013). A placebo effect enhancing clinical setting, in which warm and empathic clinicians provide supportive and attentive health care, creates a “therapeutic bias” in patients, giving them hope and expectation of improvement. This is “legitimate” so long as it is done without deception and in a manner consistent with informed consent, trust, and transparency (Kaptchuk & Miller, 2015).

This ideal of clinical interventions having solid evidence of efficacy before being introduced as routine practice is not always a reality. Sometimes, it is more of a situation where the “cart” of clinical practice precedes the “horse” of rigorous research evidence. Then, this catch-up research may be undertaken in a placebo effect-enhancing clinical environment, rather than a placebo effect-controlled research environment. Such situations, especially when DBRCT are not possible, present the researcher and clinician with complex research and clinical conundrums. Some of these will now be explored using the example of the treatment of youth with gender dysphoria.

A Brief Introduction to the Gender-Affirming Treatment Model for Children and Adolescents with Gender Dysphoria

Gender dysphoria is a term used to describe the distress that is frequently felt by people whose sense of gender is incongruent with their natal sex (these people may also self-identify as transgender) and if the dysphoria is intense and persistent, alongside several other features, a DSM-5 diagnosis of gender dysphoria may be made (American Psychiatric Association, 2013). There has been a sharp rise in the numbers of children and adolescents identifying as transgender and being diagnosed with gender dysphoria (Kaltiala et al., 2020; Tollit et al., 2021; Wood et al., 2013). Many are natal sex females presenting in adolescence, and many have neurodevelopmental and psychiatric disorders (Kaltiala-Heino et al., 2018; Tollit et al., 2021; Zucker, 2019). International guidelines and child and adolescent gender clinics (CAGCs) commonly endorse a gender affirmative treatment approach (GAT) (Coleman et al., 2022; Hembree et al., 2017; Olson-Kennedy et al., 2019; Telfer et al., 2018). Key components of GAT include affirmation of a youth’s stated gender identity, facilitation of early childhood social transition, provision of puberty blockers to prevent the pubertal changes consistent with natal sex, and use of cross-sex hormones (CSH) and surgical interventions to align physical characteristics with gender identity (Ehrensaft, 2017; Rosenthal, 2021). This Letter’s discussion focuses primarily on the medical (puberty blockers and cross-sex hormones) and surgical elements of GAT.

GAT can achieve some of the desired masculine or feminine appearance outcomes, but the main arguments used to support the use of these treatments in GD youth are that they improve short- and long-term mental health and quality-of-life outcomes. However, this claim is only underpinned by low-quality (mostly short-term, uncontrolled, observational) studies, which provide very low certainty evidence, complemented by expert opinion (Clayton, 2022a; Hembree et al., 2017; NICE, 2020a,b; Rosenthal, 2021). No randomized controlled trials (RCTs), including none using the previous treatment approach as a comparative, have been undertaken. This low-quality evidence for the efficacy of GAT is of particular concern given the potential risks associated with GAT.

Risks of Gender-Affirming Medical and Surgical Treatments

Impaired fertility is a risk of cross-sex hormones, and the extent of reversibility of this is unclear (Cheng et al., 2019; Hembree et al., 2017). If puberty blockers are commenced in early puberty and followed by cross-sex hormones, there are no proven methods of fertility preservation (Bangalore Krishna et al., 2019). Surgeries, such as gonadectomies and most genital surgeries, will result in permanent sterility. These impaired fertility and sterility outcomes are important because, firstly, as Cheng et al. (2019) reported, the widespread assumption that many transgender people do not want to have biological children is not supported by several recent studies. Secondly, children as young as ten, who do not have capacity for informed consent, are starting a treatment course that will likely render them infertile or sterile and this raises complex bioethical issues (Baron & Dierckxsens, 2021).

Other adverse effects of GAT are based on a more uncertain evidence base. I provide a brief outline of some of the areas of concern. Cross-sex hormones are associated with cardiovascular health risks, such as thromboembolic, coronary artery, and cerebrovascular diseases (Hembree et al., 2017; Irwig, 2018). Cross-sex hormones may also increase the risk of certain cancers (Hembree et al., 2017; Mueller & Gooren, 2008). Puberty blockers may have negative impact on bone mineral density, which may not be fully reversible, with an associated risk of osteoporosis and fractures (Biggs, 2021; Hembree et al., 2017). Recently, findings from animal studies have increased concerns that puberty blockers may negatively and irreversibly impact brain development due to critical time-windows of brain development. In one study on rams, long-term spatial memory deficits induced by use of puberty blockers in the peripubertal period were found to persist into adulthood (Hough et al., 2017). For those young patients who undertake surgery, there are also the risks of surgical complications (Akhavan et al., 2021). One understudied outcome of mastectomies, for those who later want to and can become pregnant, is the grief about inability to breast feed.

Puberty blockers, cross-sex hormones and genital surgery also pose risks to sexual function, particularly the physiological capacity for arousal and orgasm. It is important to be aware there is a dearth of research studying the impact of GAT on GD youth’s sexual function, but I provide a brief discussion of this important topic. Estrogen use in transwomen is associated with decreased sexual desire and erectile dysfunction and testosterone for transmen may lead to vaginal atrophy and dyspareunia (Hembree et al., 2017). It seems widely assumed that testosterone simply improves transmen’s sexual functioning. However, placebo-controlled studies from the non-transgender population indicate the situation is likely more complex. For example, studies indicate that testosterone may impact female sexual desire in a bell-shape curve manner, and at high levels may have no benefit or even have negative impact on sexual function (Krapf & Simon, 2017; Reed et al., 2016). Also of note, in medical conditions that are associated with high testosterone levels, such as polycystic ovarian syndrome, impaired sexual function (e.g., arousal, lubrication, sexual satisfaction, and orgasm) has been reported (Pastoor et al., 2018).

Recently, surgeon and WPATH president-elect, Marci Bowers, raised concern that puberty blockers given at the earliest stages of puberty to birth sex males, followed by cross-sex hormones and then surgery, might adversely impact orgasm capacity because of the lack of genital tissue development (Ley, 2021). One study has reported that some young adults, who had received puberty blockers, cross-sex hormones and laparoscopic intestinal vaginoplasty, self-reported orgasmic capacity (Bouman et al., 2016). However, this finding does not negate Bower’s concerns, as it did not make any assessment of the correlation between Tanner stage at initiation of puberty blockers with orgasm outcome. Of note, some of the patients in the study were over the age of 18 at start of GAT. Further, its findings do not apply to those undergoing penile skin inversion vaginoplasty. Importantly, Bouman et al. found that 32% of their participants self-reported being sexually inactive and only 52% reported having had neovaginal penetrative sex more than once. A recent literature review on sexual outcomes in adults post-vaginoplasty noted the paucity of high-quality evidence but reported that “up to 29% of patients may be diagnosed with a sexual dysfunction due to associated distress with a sexual function disturbance” (Schardein & Nikolavsky, 2022). Another recent systematic review of vaginoplasty reported an overall 24% post-surgery rate of inability to achieve orgasm (Bustos et al., 2021).

Coleman et al. (2022) claimed that “longitudinal data exists to demonstrate improvement in romantic and sexual satisfaction for adolescents receiving puberty suppression, hormone treatment and surgery.” However, the supporting citation requires scrutiny. Bungener et al. (2020) was a cross-sectional study of 113 young adults, 66% of whom were transmen (most who had undergone mastectomy and gonadectomy, not genital surgery). For its claims of post-surgery increases in sexual experience, it relied on recall of pre-surgical experiences. This means it is at high risk of recall bias, especially given surgery was undertaken up to 5 years (mean 1.5 years) prior to assessment. Further, it focused on sexual experiences, which might naturally be expected to increase as adolescents enter young adulthood, and there was no evaluation of sexual function domains, such as arousal, orgasm, or pain. The study did report current sexual satisfaction but failed to compare this to pre-surgical functioning (or to the Dutch peer comparison group). Thus, it is unable to demonstrate whether sexual satisfaction improved following GAT. On the three questions about sexual satisfaction (frequency, how good sex feels, and sex life in general), 59 to 73% were reportedly moderately to very satisfied. This would appear to mean that 27 to 41% were not satisfied, which is a sizeable minority. Importantly, these sexual satisfaction questions had an approximately 45% missing data rate—an issue not discussed by the authors. This means the authors’ conclusion that the majority was satisfied with their sex life is at high risk of bias. Of additional note, at the post-surgical assessment time these young transgender adults were significantly less sexually experienced than their Dutch peers. Thus, in sum, this study provides little reassurance about the sexual function outcomes of GAT in GD youth.

Lastly, in terms of risks, there are increasing reports of discontinuation of hormone treatments, regret and detransition in young people who have received GAT (Boyd et al., 2022; Hall et al., 2021; Littman, 2021; Vandenbussche, 2022). Two recent studies have relied on pharmaceutical prescription records, both using 2018 as the end date of data collection (Roberts et al., 2022; van der Loos et al., 2022). Their reported rates of discontinuation varied widely. For the US cohort, Roberts et al. (2022) reported, for those who had started CSH treatment before age 18, a 4-year CSH discontinuation rate of 25%. For the Dutch cohort, van der Loos et al. (2022) reported on CSH discontinuation rates in adolescents, evaluated according to the “meticulous” Dutch protocol, who had commenced puberty blockers before age 18. People “assigned female at birth” had a CSH discontinuation rate of 1% at a median of 2.3-years follow-up, and those “assigned male at birth” had a 4% discontinuation rate at median 3.5-years follow-up. Previous research from this Dutch group has indicated that average time to detransition was over 10 years (Wiepjes et al., 2018). Thus, given the van der Loos et al. (2022) study’s short median follow-up time and young follow-up age (median 19.2 for people “assigned female at birth” and 20.2 for “assigned male at birth”), it seems likely that these discontinuation rates will increase over time. It is also concerning to note that 75% of the Dutch youth who discontinued CSH had undergone gonadectomies, but at follow-up they were receiving neither CSH nor sex hormones consistent with their birth sex.

Ongoing Research

Currently, several large long-term observational studies are underway which involve collecting and analyzing data on patients receiving routine GAT at CAGCs (Olson-Kennedy et al., 2019; Tollit et al., 2019). The aims of these studies are to provide the urgently needed rigorous empirical data to bolster the weak evidence base that currently underpins the GAT approach. However, as discussed above, it is critical to note that this type of observational research is prone to bias, confounding, and lacks ability to distinguish treatment effects from placebo effects (Fanaroff et al., 2020; Pocock & Elbourne, 2000). Thus, it is unlikely to provide the rigorous empirical data that can convincingly demonstrate a causal relationship between treatment and outcome.

Further, there seems to be a problematic tension between the research and clinical agendas of CAGCs. GAT is being provided in a clinical environment that maximizes the placebo effect. This is the same environment in which the same clinicians are researching GAT’s efficacy. As previously discussed, while a placebo effect-enhancing environment may be appropriate for a clinical environment, it is far from an ideal treatment efficacy research environment, particularly when DBRCTs are not possible and RCTs are not undertaken. In the next section, I delve more deeply into exploring this issue. First, however, I will take a brief detour with an example that illustrates the risks when expert opinion and low-quality evidence are relied on as a basis for medical interventions.

A Recent Example from Medical History of the Dangers of Medical Advice Based on Weak Evidence: The Iatrogenic Tragedy of Prone Infant Sleep Position and Sudden Infant Death Syndrome

Gender medicine clinicians and researchers have consistently stated that RCTs would be unethical (de Vries et al., 2011; Smith et al., 2001; Tollit et al., 2019). However, as Valenstein (1986) discussed in his study of the history of lobotomy, the ethics of implementing new treatments without a rigorous evidence base also need to be considered. The harm that can be done by well-intentioned, but erroneous medical advice based on prestigious physicians’ clinical judgment without an adequate evidence base can be illustrated by infant sleep position and sudden infant death syndrome (SIDS). Prior to the middle of the twentieth century, it was common practice for mothers to place infants on their backs to sleep (Högberg & Bergström, 2000). The influential pediatrician, Benjamin Spock, was an early advocate of the prone position (front sleeping) for infants. He recommended it in his popular book, Baby and Childcare, from the 1956 edition through until 1985 (Gilbert et al., 2005). This recommendation, that became widespread, was mainly based on clinical wisdom that such a position reduced risk of death from aspiration of vomit and had additional benefits such as decreased crying and reduced head flattening. Early research appeared to support this clinical advice. However, by the 1980s, more rigorous research demonstrated that the prone position increased risk of SIDS. Then medical advice gradually changed to strongly recommending infant supine (back) sleeping. A marked drop in SIDS rates followed. Several biases (e.g., the healthy adopter bias and observer bias) are thought to have contributed to the erroneous clinical belief that prone sleeping position was the safest position. It has been estimated that between the 1950s and the 1990s the infant prone sleeping advice, recommended by well-meaning clinicians and prestigious medical organizations, may have contributed to the deaths of tens of thousands of infants (Gilbert et al., 2005; Sperhake et al., 2018).

Gender-Affirming Treatment for Youth with Gender Dysphoria: A Perfect Storm for Placebo Effect

The reader may ask: Why focus on GAT for GD youth? Is GAT any different from other contemporary medical treatments that also are not underpinned by rigorous evidence? I would reply—indeed, this is an issue in other areas of medicine. For example, the response rate in the placebo groups in antidepressant medication clinical trials is known to be high (Benedetti, 2021a). However, in contrast to GAT, we know this because there have been many RCTs comparing antidepressants to placebos. A recent review, that included placebo in the network meta-analysis, found that all the antidepressants under review were more efficacious than placebo in adults with major depressive disorder (Cipriani et al., 2018). This finding has been challenged by some who argue that the benefits of antidepressants beyond placebo effect seem to be minimal (Jakobsen et al., 2020). However, one of the key points to make is that placebo effect in antidepressant medication response is at least known about and discussed by many researchers, clinicians, and their patients (personal clinical experience), rather than not considered at all, as seems to be the situation to date for GAT for GD youth. Gender medicine clinicians and researchers might take note of a recent meta-analysis of antidepressants in pediatric populations, which recommended that the influence of placebo response needs to be considered in pediatric clinical trial design and implementation (Feeney et al., 2022). Furthermore, it seems particularly vital to consider the potential role of placebo effect in GAT outcomes because the stakes are high. Medical and surgical GAT, being given to vulnerable minors, lead to life-long medicalization and hold the risk of serious irreversible adverse impacts, such as sterility and impaired sexual function. Thus, we need strong evidence that they are as efficacious for critical mental health outcomes as claimed and that there are no less harmful alternatives.

In the field of GD youth medicine, there is a combination of features that seems to create a perfect storm setting for placebo effect. Thus, we have a population of vulnerable youth presenting with a condition, which has no objective diagnostic tests, and that is currently undergoing an unexplained rapid increase in prevalence and marked change in patient demographics. The treatment response is mainly based on patient-reported outcomes (yes, this can be the case for other conditions but remember we are considering the combination of features, not just a feature in isolation). Some clinicians, who may be affiliated with prestigious institutions, enthusiastically promote GAT, including on the media, social media, and alongside celebrity patients. Some make overstated claims about the strength of evidence and the certainty of benefits of GAT, including an emphasis on their “life-saving” qualities, and under-acknowledge the risks. Alternative psychosocial treatment approaches are sometimes denigrated as harmful and unethical conversion practices or as “doing nothing.” This combination of features increases the likelihood that there will be a complex interplay of heightened placebo and nocebo effects in this area of medicine, with significant implications for research and clinical practice. Some examples of these types of issues are now provided.

Overstatement of the Certainty of Benefits and Under-Acknowledgment of Risks

Some professional organizations and leading GAT clinicians, in publicly available communications to GD youth, the public, and policy makers, appear to overstate the certainty of GAT’s benefits and provide inadequate discussions of risks (Clayton, 2022a; Cohen, 2021a, b; Olson-Kennedy, 2015, 2019; Telfer, 2019, 2021). For example, GATs have been described in such communications as “absolutely life-saving” (Olson-Kennedy, 2015) and being underpinned by “robust scientific research” (Telfer, 2019). It is notable that these same clinicians in their peer reviewed publications acknowledge the sparse empirical evidence with critical knowledge gaps (Olson-Kennedy et al., 2019), and the urgent need for more evidence for this relatively new treatment approach (Tollit et al., 2019). Thus, there seems to be a kind of Janus-faced narrative, with a placebo effect-enhancing face of overstated certainty/strong evidence of benefit displayed to GD youth, their families, and policy makers, and the more realistic face of uncertainty/lack of evidence turned toward peer reviewers and the research community. Of note, several publications in the peer review literature that have made overstated claims about GAT have recently required correction (Bränström & Pachankis, 2020; Pang et al., 2021; Zwickl et al., 2021).

The Dangers of an Exaggerated Suicide Narrative

A specific issue that is important to discuss is the repeated claims that GD youth are at high suicide risk and that GAT reduces this risk. Parents report being told by clinicians that their child will suicide if a trans identity is not affirmed (Jude, 2021). Clinicians’ public statements also indicate this message is being given, or at least implied, to parents and young people (Cohen, 2021b; Marchiano, 2017). A recent editorial in The Lancet stated puberty blockers reduce suicidality and to remove access to them was to “deny” life (The Lancet, 2021). However, there is no robust empirical evidence that puberty blockers reduce suicidality or suicide rates (Biggs, 2020; Clayton et al., 2021). The authors of the paper, that was the basis for The Lancet’s claim, subsequently clarified that they were not making any causal claims that puberty blockers decreased suicidality (Rew et al., 2021). Another paper, claiming to have found that barriers to gender-affirming care was associated with suicidality, had to withdraw this claim in a significant correction to their article (Zwickl et al., 2021).

Furthermore, the suicidality of GD youth presenting at CAGCs, while markedly higher than non-referred samples, has been reported to be relatively similar to that of youth referred to generic child and adolescent mental health services (Carmichael, 2017; de Graaf et al., 2022; Levine et al., 2022). A recent study reported that 13.4% of one large gender clinic’s referrals were assessed as high suicide risk (Dahlgren Allen et al., 2021). This is much less than conveyed by the often cited 50% suicide attempt figure for trans youth (Tollit et al., 2019). A recent analysis found that, although higher than population rates, transgender youth suicide (at England’s CAGS) was still rare, at an estimated 0.03% (Biggs, 2022).

Of course, any elevated suicidality and suicide risk is of concern, and any at risk adolescent should be carefully assessed and managed by expert mental health professionals. However, an excessive focus on an exaggerated suicide risk narrative by clinicians and the media may create a damaging nocebo effect (e.g., a “self-fulfilling prophecy” effect) whereby suicidality in these vulnerable youths may be further exacerbated (Biggs, 2022; Carmichael, 2017). This type of risk has been discussed in other similar situations involving youth (Abrutyn et al., 2020; Canetto et al., 2021; Shain & AAP COMMITTEE ON ADOLESCENCE, 2016).

An Excessively Negative Portrayal of the Previous Standard and Current Alternative Treatment Options

Clinicians and groups advocating for GAT tend toward framing any non-affirming treatment approaches as harmful, ineffective, and unethical, and sometimes equate psychotherapeutic approaches with conversion practices (Ashley, 2022). However, others argue that there are a range of contemporary therapeutic approaches which are not “affirmative,” but neither are they conversion practices (D’Angelo et al., 2021). Such approaches can include: Careful assessment and diagnostic formulation, appropriate treatment of co-existing psychological conditions, supportive and educative individual/family psychological care, group therapy, developmentally informed gender exploratory psychotherapy, trauma-informed psychotherapy, and a non-promotion of early childhood social transition (sometimes labeled under the umbrella term of “watchful-waiting,” which should not be interpreted as “doing nothing”) (D’Angelo et al., 2021; de Vries & Cohen-Kettenis, 2012; Hakeem, 2012; Kozlowska et al., 2021; Lemma, 2021).

It is important to note that psychotherapeutic approaches for this group of patients are also based on limited evidence. More research into their efficacy is required. One critical consideration here seems to be that ethical psychological approaches do not hold the same adverse risk profiles as do the hormonal and surgical treatments (Baron & Dierckxsens, 2021).

Recently, two Scandinavian youth gender services have drawn similar conclusions and instigated a more cautious approach to hormonal treatments for GD minors, placing a higher emphasis on psychological care (Kaltiala-Heino, 2022; Socialstyrelsen, 2022). Furthermore, in England, the Cass Review into the country’s youth gender services has released its interim report (Cass, 2022). In response, the National Health Service’s “Interim Service Specification” for GD youth specialist services has specified that the primary intervention for youth will be psychosocial support and psychological interventions. A cautious approach to social transition is recommended and puberty blockers will only be available in the context of a formal research protocol (National Health Service, 2022).

Given all this, it is hard to accept the claims that GAT is prima facie the best treatment model for today’s cohort of GD youth. Furthermore, the unwarranted negative portrayal of contemporary psychotherapeutic approaches likely creates nocebo effects and undermines the possibility of providing such ethical care to GD youth (Kozlowska et al., 2021).

Clinicians’ Media and Social Media Promotion of Gender Affirmative Treatment

There is intense media and social media coverage of “trans youth” issues. Some surgeons are promoting their gender-affirming surgeries on social media platforms that are popular with young adolescents (Ault, 2022). Some clinicians encourage the celebratory media coverage of GAT, stating it may empower young trans people to seek GAT (Pang et al., 2020). They largely dismiss concerns that the identified association between positive media stories and increased referral rates to CAGCs may be indicative of a social contagion phenomenon. This is despite the reports of the sudden emergence of gender dysphoria, especially in adolescence, and its association with social influence (Kaltiala-Heino, 2022; Littman, 2018, 2021; Marchiano, 2017). Gender clinicians also condemn and have attempted to prevent what they consider as excessively negative media coverage of GAT (although others judge it as reasonable and balanced) (Australian Press Council, 2021; Pang et al., 2022). These clinicians are likely correct that critical media coverage of GAT could negatively impact referrals to gender clinics and might upset some patients. However, a deliberate strategy of promoting an unbalanced celebratory GAT narrative through the media and social media could contribute to social contagion and placebo effects.

What is the right balance? The Australian Press Council’s judgment on a clinician’s complaints about what she considered as excessively negative press coverage may, arguably, provide an example of some balance on these matters. Of note, while some of the complaints were upheld, many were not and it was judged that “even medical treatment accepted as appropriate by a specialist part of the medical profession is open to examination and criticism…needs to be debated…and was sufficiently justified in the public interest” (Australian Press Council, 2021).

The Exclusive Promotion of Gender-Affirming Treatments within Child and Adolescent Gender Clinics

There is indication of an unbalanced promotion of a celebratory GAT narrative occurring within CAGCs, where, simultaneously, there is a deep enmeshment of the clinical, advocacy, and research agendas. This has already partly been discussed in the sections above, but one detailed example is provided. The Trans20 study is a prospective cohort study based on children and adolescents seen at Melbourne’s Royal Children’s Hospital Gender Clinic (RCHGC) which provides a GAT model of care (Telfer et al., 2018; Tollit et al., 2019). It is important to highlight that this study’s human research ethics committee (HREC) approval was not for the treatment approach, which was implemented as routine clinical care, rather it was for matters such as collection and storage of data, and longitudinal follow-up of discharged patients.

In 2019, an amended HREC approval was granted, allowing a “newsletter blog” to be sent to patients and families with the aim of improving patient engagement with the study. This change was described as raising no new ethical issues. This “first ever” newsletter asked for help with the Trans20 survey completion (Royal Children’s Hospital, 2019). This research request was placed amid positive accounts of the service and its patients. For example, following attendance at the clinic’s single session assessment triage (SSNac) young people were described as feeling “empowered…and more likely to start living as their preferred gender,” and having improvements in mental health and quality of life. A colorful diagram showed the increased rates of social transition that followed SSNac attendance, and the section concluded “Hopefully the improvements after SSNac are a taste of things to come!” One pro-GAT parent/carer support network, that also fundraises for the RCHGC, was spotlighted. There was a “lived experience” piece in which a well-known transitioned, now young adult, patient was pictured receiving an award. This patient provided a personal testimony of the clinic’s medical director: She “will always be one of my biggest heroes…an incredible person: Intelligent, compassionate and strong.”

This newsletter’s communication raises much to think about. The point I want to make here is that sandwiching the requests for a research survey completion between celebratory accounts of the clinic seems likely to magnify the impact of bias and placebo effect on research outcome findings. For example, consider the likely impact on patient bias (patients wanting to please the clinician by giving positive reports), response bias (patients with positive experiences of the clinic more likely to complete the surveys), social learning/contagion, prestige suggestion, and the Hawthorne phenomenon. Furthermore, consider this newsletter as part of the whole therapeutic ritual, enhancing the psychological and neurobiological placebo mechanisms. Apart from this research impact, we can also wonder whether such a newsletter is ideal clinical practice. In my opinion, there are problems. Think, for example, of the young GD patient who may be hesitant to transition. Where is the celebration of this young person’s choices? Communications from the clinic, such as this newsletter, may contribute to feelings that, unless he/she transitions, he/she lacks courage (having not been “empowered”) and that he/she will never be an award-winning celebrated patient. This may act as a covert form of pressure on patients to transition or, for those who do not, act as a nocebo effect negatively impacting their psychological outcomes.

Where to From Here?

There are no easy solutions to the complex research and clinical issues presented in this Letter. Here, I present a few ideas to stimulate discussion. The first step would seem to be more professional awareness and debate. Independent reviews by expert clinicians and methodologists, not currently involved in clinical practice and research in this area (thus, having some emotional distance and minimizing intellectual conflict risk), could helpfully advise further research and clinical strategies. England’s Cass Review is an example of this type of approach (Cass, 2022).

Clinicians should also make measured and honest statements to patients, families, policy makers, and the public about the evidence for GAT’s benefits. Placebo effects could also be noted in the limitations section of any research papers. In addition, in public discourse, the media and clinicians could present not only celebratory transition stories, but also: Realistic positive stories of those with gender dysphoria who have decided not to transition or have delayed transition until maturity; accounts of patients who have benefitted from ethical psychological approaches; and accounts of those who have had negative transition experiences. Detransition, regret, and harm from transition should be acknowledged and publicized as a significant risk. A recent paper detailing the elements of a comprehensive informed consent process is timely and important (Levine et al., 2022). However, while a comprehensive informed consent process is vital, it does not address the issue of how the whole ethos of a clinic and the media/social media milieu may act to influence young patients and their families and undermine the capacity for true informed consent.

Conclusion

In conclusion, this Letter has noted that although GAT for GD youth lacks a rigorous evidence base, it is undertaken as routine medical treatment in a strongly placebo effect enhancing environment. It is within this environment that research into its effectiveness is being undertaken. One consideration raised by this relates to clinical practice: When does such a strongly placebo effect enhancing environment meet optimal clinical practice standards? When, if at all, does it veer into the territory of unethical practice that involves deception and undue influence? This Letter has also highlighted that such a placebo effect enhancing environment presents grave problems for research (particularly non-DBRCT research). It seems unlikely that the current research being undertaken in this field will be able to untangle benefits that are due to the placebo effect from those due to the interventions’ specific effectiveness. Thus, especially given the adverse risk profile of the hormonal and surgical interventions, it may be that yet again well-intentioned physicians are engaging in medical practices that cause more harm than benefit (Clayton, 2022b). The research and clinical conundrums presented in this Letter have no easy answers. However, as a first step, there is an urgent need for more awareness of the placebo effect and for rigorous and thoughtful debate over how best to proceed in research and clinical practice in this area of medicine.

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Chapter 10 of Psychosis, Trauma and Dissociation: Structural Brain Changes in Psychosis

Recent animal and human studies shows that early life adversity can change the developing brain, in ways similar to psychotic disorders. Early life adversity can alter brain development (it modifies process like methylation and acetylation, changing gene expression and as such the structure and functioning of neurons and neural networks.) Because of this, the brain's systems work differently.

This will outline the way brains of people with psychosis will differ, with a focus on schizophrenia. It will go over the hippocampus, amygdala, prefrontal cortex, and insula - and then the relationships between them. (It's gonna get real sciency - I tried my best to paraphrase to simpler terms, but it's kinda hard to do that when we're talking the structure of the brain.)

Hippocampus: The center of a variety of functions, from memory to spatial nagivation to cognitive maps.

Structural changes to the hippocampus were first identified in schizophrenia more than 35 years ago. Needless to say, it's pretty common. It has, bilaterally, 5-10% smaller volume, with the smallest volumes reported in chronic states and elderly patients. Decreased volume was correlated with childhood adversity. All hippocampal subfields were affected, with some studies finding changes in the anterior parts, CA1 and the subiculum while others found stronger results in the posterior parts, CA2-3 and CA4-dendate gyrus. The reduced volume correlates with both positive and negative psychotic symptoms, and increased sensitivity to stress.

Cellularly, changes in schizophrenia were decreased mRNA expression of GR receptors (in all hippocampal subfields), decreased # of apical dendrite spines and spine density in subicular internal pyramidal neurons, reduced size of pyramidal neuron cell bodies, and reduced interneuron activity containing parvalbumin and interneuron density and number. Overall the cellular changes are highly consistent with those found after early adversity (in animal research.)

Amygdala: Made of many different nuclei, it is also involved in a variety of functions - fear conditioning, memory, perception, attention…

The results of studies looking at first epsiode psychosis and schizophrenia have been relatively consistent with lower amygdala volume. There was some evidence of progressively reduced volume in schizophrenia. Some authors argued the sizes were rather small and that large sample sizes were needed for differences to appear in a significant manner.

Earlier studies suggested that reductions in volume were not there in first episode psychosis, but more recent studies contradict that, also noting that the smaller amygdala volume correlated with childhood trauma. In a contrast, one study reported increased amygdala size in adolescents - the mean age at 14 years - with schizophrenia. In response to the range of findings, the book proposes that one explanation could be that the age of which the adversity was experienced and the age at which brain scans were performed differed.

Frontal Lobes: The ones in control of higher order executive functions, from working memory, goal-directed thinking, problem solving, cognitive flexibility, mental representations, to the control of feelings and behavior.

Psychotic disorders have consistently found abnormal frontal lobe functioning. The frontal and prefrontal regions show widespread reduced volume (middle and inferior frontal regions, anterior cingulate, and orbitofrontal and dorsolateral prefrontal cortices.) The volume loss is particularly prominent in the inferior and medial frontal gyrus, and anterior cingulate. In patients with schizophrenia, there is a significant association between sexual abuse and volume loss of the prefrontal cortical.

The following interneuron changes may be significant to the aberrant cortical gamma oscillations and compromised cognitive functions in psychotic disorders: a decrease in GR mNRA expression, reduced dendritic spine density in deep layer three pyramidal cells, and in the anterior cingulate, altered density, size, and shape of pyramidal cells and interneurons. In individuals with schizophrenia, the subpopulation of GABA interneurons expressing parvalbumin are altered - reduced density in the anterior cingulate and reduced activity in the dorsolateral prefrontal cortex. GAD67 expression is reduced in frontal cortical regions.

Frontal lobe volume loss in psychotic disorders is consistent with the fact that the frontal lobes are sensitive to stress, leading to volume loss and a myriad of changes in pyramidal cells and interneurons. It seems to match that of detailed changes seen after early life stressed.

Insula: This piece is involved with the functions like intereoception - awareness of the body and of feelings, saliency detection, integration of external stimuli, self-consciousness, the experience of identity, and individual personality.

In individuals at a very high risk for psychosis, reduced insula volume has been reported. In patients that developed schizophrenia, there was a highly consistently reported reduction in insular volume - right and left, anterior and posterior parts all included - with the mean reduction being 5.2%. Reduced insular volume has been associated with positive symptoms and negative symptoms in those with schizophrenia. Overall, reduced insula volume is a common finding.

Relationships between the different parts: The parts of the brain don't work independently, so of course, this has to be touched on too.

Altered functional connectivity between the amygdala and prefrontal cortex has been found in psychosis, as well as between several other brain regions like the hippocampus, amygdala, insula, and prefrontal cortex. The several findings in psychotic disorders include an increased baseline level of cortisol, cortisol sensitization to new stressors and cortisol habituation to known stressors, as well as dopamine hyperactivity in the striatum and hypoactivity in the prefrontal cortex.

All of these changes are also seen after early life stress! This can suggest that the mechanisms behind the brain's structural alterations seen in psychosis could be the same as those involved with brain changes after early life stress. This raises the question of whether or not adversity is what causes the neurological anomalies in psychotic disorders.

Overall, the book says it can be argued that the experiences of early adversity could be a cause, even a primary cause, for most brain abnormalities in psychotic disorders.