Psychiatry & Psychotherapy Podcast - Adverse Childhood Experiences - HPA axis & Brain changes: cortisol, amygdala, hippocampus, cytokines, & epigenetics (Part 3 of ACE series)

Episode Date: July 19, 2024

In this week's episode, we continue our series on Adverse Childhood Experiences by delving deeper into the lasting effect of ACEs on the brain and body. We explore the intricate impact of ACEs on the HPA axis, inflammation, and neurobiology, shedding light on their role in various psychiatric disorders. We highlight how these changes may indicate a shared phenotype resulting from early adversity but that they likely do not explain the entire effect ACEs have on an individual. By listening to this episode, you can earn 1.5 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Welcome to the Psychiatry and Psychotherapy Podcast. I'm your host, David Puter. This is your gateway to the intriguing world of mental health. As one listener put it, this is the podcast that your psychiatrist listens to. And we're incredibly proud of that endorsement. Whether you're a loyal, active listener who's been kind enough to reach out, maybe send an email at DM or put in a review, or you're new to this community. We have an exceptional opportunity for you, not only to learn, but to also, earn continued medical education credits with each episode. Our credits are meticulously designed to empower you in your field, demystify complex mental health topics, and transform your learning journey into a truly rewarding experience. To access this and more, just visit Psychiatrypodcast.com. We're grateful to our valued subscribers who are already reaping the benefits of these credits. Your support is instrumental in allowing us to devote time each week to curate. this podcast, sharing cutting-edge insights, featuring top professionals, and exploring the latest

research. Whether you're here to learn, earn credits, or both, we're thrilled to have you with us. Get ready to deepen your understanding of psychiatry and psychotherapy, one enlightening episode at a time. All right, welcome back to the podcast. I am joined today with Liam Browning. He is a graduating medical student who has been diving into adverse childhood experiences with me. In this episode, we are going to be doing a super deep dive on how adverse childhood experiences lead to changes in the hypothalic pituitary adrenal axis long term. We're going to be talking about how it creates a more blunted cortisol response to stress. How? how it leads to epigenetic changes in the glucocorticoid receptor genes,

which means that the genes upregulate and downregulate how much proteins are produced, how much receptors are produced due to the stresses. We're going to talk about how adverse childhood experiences are associated with changes in the brain, decreased hippocampal volume, decreased white matter integrity in the corpus callosum. We're going to be talking about how adverse childhood experiences increase the level of chronic inflammatory cytokines and increase amygdala reactivity to negative emotional stimuli and reduce the activity of the reward system during reward anticipation. So this is deeper than we could find anywhere else. we've looked at tons of primary research articles, both in humans and in animals.

It is complicated science. If you are listening to this as a patient, please get the handout as well and just realize some of these things you might have to look up. It's complicated science. It's hard to understand for myself. The more I dive into it, it's like super intricate and complex, but I think it's It's important to lay out the science in as much detail as possible. So welcome to the podcast.

Yeah. Thanks for me back on. And yeah, to your point, there is so much complexity in the system that I don't even think our current scientists at the cutting edge of the field even have a grasp on how complex the HP axis is. So we try to compile as much as we could and try to detail it. Yeah. Okay. So what are the biological mechanisms through which the adverse childhood experiences exert their effects?

Let's start there. Yeah, so the last two episodes, we kind of talked about how ACEs increased the risk for not only the psychiatric outcomes, but also the physical health outcomes, like increased cardiovascular disease, stroke, diabetes, lung disease, even premature mortality in some cases. So that kind of leads to the idea that there is a biological disruption by ACEs. And most of the studies looking at this topic of how ACEs change biology, they're kind of rooted in the idea that the HP axis is at the core of this dysfunction. And the HP axis, it's thought that it also has a role in neurodevelopment as well. So it modulates what's called the neuroendocrine system, how the endocrine system communicates with neurons. and glial cells. And these processes such as neurogenesis, synaptogenesis, myelination, these are very vital to neurodevelopment. And if there's disruption in those processes caused

by excess glucocorticoids or dysfunction in HP axis, then there's going to be a disruption in normal neurodevelopment and that this could lead to psychiatric outcomes. So let me try to do my attempt at just putting that in layman's terms. You have stresses that occur in childhood. These lead to increase in stress hormones. Cortisol is like a steroid. So this is something that's released and is supposed to help our body mobilize for a stress. Okay.

So if you are bleeding out, you need this to retain salt, to constrict blood vessels, to make sure the blood gets enough sugar, to release sugar from the body so that you can use that sugar to survive. So the body is built to survive stresses. What happens is, however, has tons of stresses occur, long-term changes occur in our body. Meaning, you know, there's epigenetic changes so that we downregulate and upregulate thousands of things to better combat stress in the future. So was that like a very sort of generic, like broad, like a simplification? But if you want to shoot for that, then I think that's good. We're going to go.

Yeah, we'll go into. Okay, let's do it. Let's go into the detail now. Yeah. So I go broad. You go detailed. All right. Sounds good.

So you can kind of conceptualize the HP axis as having the two main components. The first of which is being that acute stress response, like you mentioned. And then the second of which is sort of the rhythmic day-to-day fluctuations in the cortisol levels. And the first component, the acute stress response component, that is directly in response to a perceived stressor. Whether you're bleeding out, you have a job interview, or you get into an argument with someone, you're going to have an increase in cortisol. And this cortisol is meant to get you to move and to react to a stressor and also to remember the stressor that you experienced. So it acts on many different parts of the brain to increase your memory of the stressor and all those different emotions that are, associated with it so that your body can avoid it in the future essentially. And with the acute

stress response, as you experience a stressor where you perceive it, you essentially have increased activation of cortic regions like the prefrontal cortex, the amygdala, and the hippocampus, and these will cause an increase in corticotropin releasing hormone from the hypothalamus. So this is where you can kind of talk about the pathway of cortisol release. So corticotropin releasing hormone or CRH, a CRH will go to the anterior pituitary. The anterior pituitary will secrete ACTH, and then ACTH can then go through the bloodstream to the adrenals,

and the adrenals will then produce cortisol. And then cortisol can act as a negative feedback system on a secretion at three different levels. It can suppress the activity of the cortic limbic regions that activate hypothalamus, it can also suppress the hypothalamus and the anterior pituitary gland. So it acts in a tight feedback loop. Yeah, so essentially you need the cortisol released, and then you need to stop the cortisol from being released.

And so a negative feedback is cortisol going up and stopping more cortisol releasing hormone from being released, stopping more ACT-H from being released. Exactly. Right. Yeah. That feedback is really, really important that we're not always just mobilizing resources. Right. Jolting out sugar when we don't need to. Right.

And this acute stress response is vital for mobilizing sugar. And cortisol is a very powerful hormone in terms of how it regulates metabolism, inflammation, and solid pretension, and even the autonomic nervous system as well. So it is a very powerful hormone. It is a very important hormone, and so much so that it might actually be involved in regulating the body's internal clocks, making sure that all the cells are in synchronicity with each other. And this kind of leads to the diurnal cortisol response or the day-to-day waking rhythms. So when... We want a little bit of a higher cortisol, you know, first thing in the morning, right?

30 to 45 minutes prior to waking is when you usually get... like an increase in cortisol. Usually peaks about 30 minutes after waking. Yeah. So you have an increase in cortisol right before you get up to actually help wake you up. And then after you wake up, you get another boost of cortisol to help you get through your day. And I'm sure many people are familiar with Andrew Huberman.

He's a big proponent of getting light exposure within 30 minutes. And part of that is to increase this second peak of cortisol that you get right after you wake up. Right. I think that there's a lot of dysfunctions that we know of that have, that have a blunted sort of morning cortisol response. They don't have that nice jolt of morning cortisol, which is good for you. So then you can have like, you know, different types of cortisol patterns when you have a disturbed axis. Do you want to mention that at all? Yeah, so what we know so far is that there are certain psychiatric conditions at least that lead to a more blunted cortisol response in the morning. And that can include like PTSD, some subtypes of depression, and also things like shift work, anything that disrupts sleep can sort of dysregulate that morning cortisol peak.

Right. So blunted cortisol response has been associated with PTSD, Borderal. Rinal personality disorder, atypical depression, and is correlated with adipositis of being overweight, inflammation, poor self-rated health. So there's a lot of, it's like, do you want decreased cortisol all the time? No, not necessarily, right? You need that sort of 30 minutes before you start revving up the cortisol,

peaks at about 30 minutes after you wake up. That's actually a good thing. right and then if you have too much cortisol in the morning that can lead you to early morning awakenings which is seen with depression as well that melancholic depression right and so with the melancholic depression you'll get people who have that jolt too early you know oh dr pewter i'm waking up at three in the morning and waking up with a lot of anxiety yeah and so that's like kind of a HPA access thing as well. So what are we seeing in childhood maltreatment?

What is their pattern that we're seeing in the morning? Now, according to three different meta-analyses, there's been a little bit mixed findings, but when you look at confirmed maltreatment histories that are given by like a third party, like child protective services, you'll find that there's actually lower wake-up cortisol levels, although the effect size in this is relatively small at 0.24.

And lower wake up cortisol level, meaning the cortisol that increases before you actually wake up. The other cortisol responses, like after you wake up, does not seem to be affected. And there's also the idea that, and this is kind of based on animal models and some other studies and humans, that there is a more blunted dary-nol-corrhizal slope. So we mentioned that cortisol increases in the morning while it's supposed to level off and decrease gradually throughout the day. And sometimes, in some cases of maltreatment, there is a more flattening of this curve. Either there is a decrease in the morning cortisol levels or the evening cortisol is increased. And one of these meta-analyses did actually find that there is a higher evening

cortisol levels. And some children exposed to like losing a friend or a loved one. Yeah, I think it's significant to think of this. The third. party sort of yes CPS was called on this person was called on this family right there was maltreatment going on bad enough to call to call CPS and these children were waking up with lower cortisol levels okay and the effect size point to four it's not huge but you have to imagine as the amount of traumas go up, so does the impact of this? Exactly. And then there's also some contention in the field about, you know, if you look at a lot of these studies looking at aces and biology, a lot of them will cite that cortisol is increased

in concentration and children who are exposed to abuse. And this idea pretty much stems from a lot of animal models where they see that this wake-up cortisol or the total body amount of cortisol that the body secretes in the day that this level is actually increased in children and that this leads to a down regulation of cortisol throughout the lifespan. Okay, so the way I understand that is if they're being acutely abused, their cortisol is obviously going to be higher if you measured at that moment, but then long term, there's like a blunting. Is that what you're seeing? Yeah, exactly. And one study that I demonstrated this very well,

was a longitudinal study by Tricket at all. They essentially showed that they're following a group of abused girls during childhood, and then they followed them for 15 years after that. So they found that in childhood, their cortisol was actually higher compared to the non-abuse group. And then over time, cortisol is supposed to increase going into adulthood, like your basal amount of cortisol is that during your body. And what they found is that although they had higher levels during childhood, that this actually led to them having less cortisol

compared to the control group as they grew into adulthood. Specifically, like in the morning or lower level all day long? I believe this was a lower level all day long, a basal mom. Okay. So basically, yeah, what I was saying was that when they're being abused, the cortisol is going to be higher,

but then the body responds epigenetically long term is that they have lower amounts of cortisol being released when they need it or just during the day. Okay. Yes, what are the limitations of these studies? Yeah, and humans, like, they like to measure cortisol after a certain period of time that elapsed. So that's where you'll find some differences in some studies will say that there is hyper-cortisolism, there's increased cortisol, some will see hypocortisolism.

And it seems that this is more so related to the amount of time that's elapsed since the exposure. And then also the way that they group maltreatment or the Aces in these different samples, it varies from study to study. Like some will only include third-party reporting as like a CPS recorded maltreatment as their maltreatment group, essentially. And then they compare that to people who haven't had a CPS. report, but sometimes they don't actually control for self-reported aces in the non-maltreated sample or in the group that doesn't have a CPS report. So that means there's some potential confounding there. Okay, the other thing that was interesting about this was there was no

observed difference between the types of maltreatment in the meta-analysis, abuse versus neglect. I found that very interesting. Yeah, I was going to say that. That also might be your limitation, but it also could be a property of aces in general. It's so hard to control for one type of maltreatment when they tend to cluster in individuals. So it's very hard to control and say, this person only experienced abuse, this person only experienced and neglect.

Yeah, and I think people also sometimes don't really fully register the abuse that they had. You know, complex PTSD that can negate the abuse. If you look at the adult attachment interview, one of the big things about the unresolved type is that they negate or downplay or disregard the abuse. And so I think that's probably why in the study where they actually looked at the third party history, you're getting a more accurate history of like, okay, this occurred, right? So it's not just self-report. Okay, so tell me more about how much. maltreatment is associated with blunted cortisol reactivity to future psychosocial stress, right?

That's what we're saying essentially. So we're saying there's some mechanism for which people who go through a maltreatment, a lot of maltreatment, will in the future have a blunted cortisol reactivity to psychosocial stress. Explain that to me. Yeah, and this is probably where I was most confused in reading this literature because you'd assume that someone with BPD who has a little bit more anxiety, they're a little bit more reactive to interpersonal situations. Like, you would assume that that means that they have a more reactive or sensitized cortisol system, right? But in reality, these three meta analyses that I was able to find, they show that there is actually a more blunted cortisol response. at least to the lab-based stressors that they used.

And the stressor that they used is called the trier social stress test or the T-SST. And essentially, this sounds like a nightmare of a scenario where you have a team of researchers give you five minutes to prepare a speech, and then you present the speech, and you're in front of a panel of judges, and they all act disinterested. So this is supposed to get a very high cortisol response. but what they find in patients with maltreatment or individuals with aces, they see a more blunted cortisol response to this stressor. And the effect sizes are relatively small to moderate.

But I think it's important because essentially, you know, from years and years of stressors, higher amounts of cortisol being released, now it doesn't release as much, which, yeah, is a little bit confusing. but this is not a for someone with borderline precisely or this is not like a breakup this is not an attachment rupture as well this is um a stress that is some strangers which you know maybe they react differently to strangers than they would like a loved one breaking up with them right right

um so in this specific study what we can take away is that they actually have a lower release of cortisol. So that didn't make sense to at first. Yeah, it didn't make sense to me at first. But I think this really led me to understand that the HP axis is far more complicated than just the amounts of cortisol that are in the body. But it does speak to the fact that there is a biological disruption from Aces and that this could impair someone's ability to adapt to the stress that they're experiencing.

Okay, so keep going. What else did you find in regards to these tier social stress tests? Yeah, it seems that I was looking at a more recent meta-analysis, and they found that there was a smaller increase in cortisol in response to this TSST, and it's mainly the peak cortisol levels, so the amount of cortisol that is released in the body, essentially. And there's also no differences on the what's called the Dexamethazone suppression test, which is essentially where he give synthetic cortisol, and that's supposed to suppress this cortisol's release,

and they found no differences in that. So that means there's probably not many changes at the level of receptors in the hypothalamus, but the effect might be more mediated by the psychological, increases in cortisol potentially. Okay, so what you're saying is that when they actually give a substance which would cause an increase in the cortisol, there's no difference.

They both increase. The same? Yeah. Okay. But to this stress test where they're going in, they're giving a speech in front of a panel of judges who are instructed to give flat phases, that actually produces less stress.

that's right you know this makes me think about like i know some professionals who have borderline per sali disorder lawyers doctors and under most circumstances they can perform very well most circumstances as in like stressful circumstances going into court it's really the interpersonal like when they have a close attachment that things get really really really distressing and so i almost wonder if like there's a difference in the cortisol's response to those things. I think that'd be interesting to look into. That's my hypothesis. Okay, let's keep going.

So how about this recent systemic review and meta-analysis that looked at CTQ to measure ACEs? You know, what did they find about greater trauma scores and blunted cortisol reactivity? they found that there is a dose response relationship between the magnitude of trauma severity essentially and with the blunted cortisol response okay so about it's kind of saying the same thing but it's it's saying that the more trauma the more blunted the response exactly okay and i think for those of you are confused on how this might happen just think about like how like if you were to like when I first started squatting

I would think about squatting all day sometimes because I was so dreading squatting but now that I've been doing it for five years I don't think about it at all I just go and I squat it doesn't cause a huge stress but sometimes I need to get I need to like hype myself up I need to get a little stressed you know like I need to get that stress to get that glucose

to get that, you know. So, yeah, I think about it like that. So, okay, keep going. Yeah, one point I did want to make is that, you know, there's this concern about, okay, what about trauma in adulthood? Like, does that also lead to a more blunted cortisol response? Or does stress in childhood mean anything different than adulthood trauma? well, you know, we talked about how PTSD causes a more blunted cortisol response.

And so that would suggest that trauma and adulthood could lead to a more plunded cortisol response. But in terms of day-to-day stress and how that changes cortisol, it seems that maltreatment specifically, so trauma and childhood has a greater predictive effect for like your day-to-day functioning of your cortisol response. as there was one study that looked at total life stress and adult stress and childhood stress. And they found that only participants with childhood stress and current life stress had a blunted cortisol response. And the group that had the same amount of stress, but only in adulthood, they actually didn't have any, didn't have any blunting of the cortisol. Yeah. And so I would say we know from you're more likely to develop PTSD if you've had early life trauma. And so when we're studying PTSD, are we really just studying one traumatic event, how that changed your HPA access?

Probably not. I think it's more the childhood. It's the multiplicity of small stresses over time that have upregulated and downregulated epigenetically. People, that's what makes sense to me. It means to sort of a sensitization to experiencing the effects of later stress, essentially. If you're not able to secrete enough cortisol in response to a stressor, then that could lead to the development of PTSD. I had this one patient who got on cortisol

because she thought this was an issue. So she actually started taking cortisol. But then she would go to stressful events, like weekend seminars where she needed to perform, and she couldn't produce the cortisol. And so she would start vomiting. She would develop, like, symptoms. of hypo cortisol and falling over stuff like that and so for a while um this the temporary solution

while she was on cortisol was to triple the dose for a weekend and that's that's what changed everything like eventually though we're able to i sent her to an endocrinologist who was like no she doesn't need to be on cortisol at all actually and so we got her off of it and she's doing fine now off top. But, and I think there's been a phase of people who are thinking, like, oh, I have this blended thing. I have, I need to be on exogenous cortisol. It's like, no, not necessarily, right?

That's not what we're saying. Okay. Yeah, you want to keep going? Yeah, I just wanted to clarify, like, that the psychiatric disorders that are associated with a more blunted cortisol response are PTSD, borderline percentile disorder. and atypical depression. So I want to make sure that was pretty clear. Right.

And atypical depression, I tend to see a lot more trauma in that group, right? So there could be some overlap. And the PTSD, like we said, people who have had childhood, not treatment, have higher rates of PTSD. So I think it's worth repeating that there's different types of depression. There's the atypical depression and the melancholic depression. Okay. atypical depression. In the atypical depression, they have mood, reactivity, weight gain, hypersomnia,

latent paralysis. They feel like just heavy sensitivity to rejection. Okay, that's that interpersonal reactivity that we see. And they have this hypoactive HPA system. And anything else you want to mention on the atypical depression? Yeah, it's also seeing that. some of these individuals have higher amounts of inflammation as well. And I think that kind of mirrors what's seen in ACEs too. Okay. And then in the melancholic depression, we have that severe anhedonia, so a complete loss of pleasure, early morning awakenings,

psychomotor agitation, retardation, significant weight loss, excessive guilt. and they may have a hyperactivity, a more reactive HPA system, higher basal cortisol, heightened cortisol response, and then the dexamethosone test often shows non-suppression. They have higher CRH.

This is almost the opposite of what we're seeing in this trauma population. And, you know, Melancholic depression, I see this, patients who are in their 60s, 70s, you know, and maybe they had no trauma, after enough, like, very little trauma in their life. So it seems to be like a kind of a different issue, melancholic depression, than borderline personality disorder. I had an attending who would kind of say, like, you see them as two different groupings

in the psychiatric unit. Were they borderline personality disorder with depression? melancholic depression you know maybe he would say keep the melancholic depression patients here a little bit longer they need um sometimes they need ecct even or like you know sometimes what we'd find is like a severe melancholic really hard to treat with just just meds so yeah and care guidelines are the same for atypical and melancholic depression treatment, correct? What? What?

The guidelines for treatment are the same for any type of depression pretty much, right? You know, I mean, the way that I see it is kind of like you have that, the atypical depression, which is kind of more of the borderline personality disorder, and then you have the melancholic depression, which, I mean, maybe the groupings are too bifurcated. but sometimes that melancholic depression responds to ECT, I would say borderline per sali disorder does not respond to ECT. So just a lot of partial for the borderline per sali disorder, right? So atypical depression, you get them into partial,

get them into a lot of therapy, and they respond very well. At melancholic depression, I would still do partial as well, but sometimes it doesn't seem to respond quite as well. so yeah okay hpa axis beyond cortisol low lows of cortisol may increase CRH and lead to increased anxiety depression fear and addictive behaviors tell me about this yeah so there is since we're seeing this low cortisol response you might assume that there is still like an increase in hPA access activity at some point and a lot of different rodent studies and monkey studies, they actually show that there's increased CRH in response to

maternal separation. So essentially, where they take the mom away from the pups every day for a couple of hours, and that's very stressful to the baby mice. And what's found is that in a lot of these studies, these animals have increased CRH, and some of them go on to develop a higher amount of cortisol in their body, others develop low. But it seems to be relatively consistent. But it seems to be relatively consistent is that they have elevated CRH and this is also seen in monkeys where they have elevated CRH in the CSF

following maternal separation and abuse. Acutely, is this acutely elevated CRH in the animal model or is like long term increase? I think this is long term increase. Okay. And the thing about CRH is that it's not

only active at the pituitary to increase ACT-TH release but it also might act as sort of like a neurotransmitter or neuropeptide. Because in animal models, it's been shown to increase anxiety-like behaviors, depressive-like behaviors, and addiction-like behaviors as well. CRH binds to CRH-1 or CRF-1 receptors in the middala, the hippocampus, some reward-related areas and the prefrontal cortex.

And it's thought that this is sort of a cause for the... increased anxiety, depressive, and addiction-like behaviors. But in humans, there's been actually a couple phase two clinical trials looking at these antagonists at these receptors for depression, anxiety, and for alcoholism. And five out of the six studies did not show anything interesting. And actually, the one that did show some response to depression was limited by hepatotoxicity. And ever since then, no one's really been looking at these different molecules. Okay, so in summary, you know, you're going to get a blunted cortisol response, okay, from trauma, and you're going to get an increase in CRH.

And this is corticotropin releasing hormone. Right. So you're trying to release, you know, more cortisol, but not as much as released. CRH is independently, right, provoking, worse, potentiating anxiety, addictive behaviors. And so they thought to themselves, wow, let's block this receptor, the CRH receptor, this thing that it binds to. And really disappointing results. That hepatotoxicity was an issue. So, yeah, really interesting.

So, you know, it's infinitely more complex than just one receptor is the way that I see this. It's like, okay, yeah, we're going to find one receptor that. If we just block that, then all of a sudden we've cured the anxiety, the depression. Only if, only if it was that easy. Right. Okay. So let's talk about epigenetics and how maltreatment is associated with hypermethalation of the glucautocorticoid receptor gene and hypomethylation of FKBP5.

Yeah, so that's a lot of different letters. This section is going to be talking about the epigenetic modifications of two different genes. So the first one of the glucocorticoid receptor, which is called NR3C1, and it's been found that this is hypermethalated and usually increased methylation leads to decreased gene expression and subsequently to decreased protein levels in the cell. So it's thought that NR3C1 is hypermethalated

in patients with history of abuse. There's one study that showed in post-mortem samples that there is decreased expression of glucocoroquine receptors in the hippocampus and that there is actually hypermethalation of NR3C1 in these patients. So when you, when you hypermethylate it, you basically are compacting that area of the genome,

so you're not expressing it as much. So you could have therefore decreased expression of this glucocortico-cordyroid receptor gene is the NR3C1. And we can look at people who died by suicide and look at their brains and see that, yes, they are hypermethylated in their... Right. Yeah, exactly. And this is also seen in rodents as well, where rodents who had kind of maternal separation were in some cases abuse. This also led to a increased methylation in NR3C1. And the inverse is actually true. They found that with increased maternal care, when the mom would lick her pups more and they essentially take care of them, This led to a decreased methylation of that gene, Enter3C1, and this led to increased

glucoporticoid receptors in the hippocampus, and this led to greater hippocampal functioning, and greater stress tolerance into adulthood. So it suggests that this is sensitive to the methylation at this gene could be sensitive to early life stress or maternal care. Okay. Yes, we can see, you know, high amounts of trauma will hypermethylate, decreased expression, positive childhood experiences, enriched environment, decreased methylation, increased expression. Hopefully that isn't too confusing.

I imagine we've dropped off some people by this point who are just struggling. If you're struggling with this, our handout is going to be amazing. it is 20 plus pages 20 plus pages citations are there you can jump on and maybe after listening to this go take a look at that and just kind of allow that information to ferment in yourself okay so yeah anything else on this that you feel is helpful yeah i just wanted to mention that you know some of these human studies they when they look at methylation of NR3C1, a lot of them will use peripheral blood samples, so they're going to be looking at blood cells and not cells of the brain.

So there's been mixed results when you look at it through that approach. So if you're reading some of these studies, you've got to pay attention, where are they taking the sample from? Is it from the brain? Is it from a different cell? So just keep that in mind

because epigenetic changes are specific to cells because in the body, the epigenome suppresses neuronal genes. Like the genes for neurons are in all different cells, but the epigenome suppresses the expression of those neuronal genes. So you want to make sure any epigenic study, make sure you look at what sample that they're using. Yeah, and this is where I feel like if you look at the brains of people who committed suicide, you can actually look at the biological changes that have let, you know, maybe predisposed someone to do that.

And this is one of those changes you can find, or in animal studies. So I think you really have to look at animal studies to study epigenetic changes because you can just, you know, kill the animal and look at their brain right away, look at their different areas. And so, yeah, I agree with you. It's like epigenetic changes are supposed to be very location specific. It's not whole body-wide specific. It's location-specific.

Some of these things are going to be specific to areas like the hippocampus. Are it specifically in the neurons of the hippocampus, even to that level of specificity, not the glial cells. Shall I move on to FKBP5? Let's do it. So this is where

the complexity really takes off. And I think part of that complexity comes from just people not, the researcher is not having a clear understanding of what is actually going on with this protein. So FKABP5 is essentially a downregulator of cortisol's activity at the glucocorticoid receptor. So the glucocorticoid receptor is typically inside of the cell, and cortisol diffuses across the cell membrane goes to the glucocoricoid receptor. FKBP5, it decreases the receptor's ability to bind cortisol, and it decreases the receptor's ability with cortisol to go to the nucleus to change gene transcription.

So it's actually it keeps it in the same spot and it keeps it from binding to cortisol. And it's actually FKBB5 is increased, its expression is increased in response to cortisol binding. So that means it acts in like a negative feedback loop with glucocoricoid. At least that's what's thought at this point. Yeah. So people, studies have consistently linked lower FKBP5 expression with PTSD. So that you'd expect with that finding that you'd have more sensitive glucocorticoid receptors then because FKBP5 is supposed to lead to glucocorticoid receptor resistance.

So if FDB5 is low, then the receptor can work properly. But the thing is that they've also found increased FKABP5 in the brains of individuals with BORonim personality disorder, major depressive disorder, and schizophrenia. And then other findings, they look at specific polymorphisms, essentially different variants of the gene. And they find that individuals with certain risky alleles, certain risky variants, that they are more likely to experience PTSD if they experience maltreatment and childhood. But the thing is, some studies will look at these polymorphisms and they'll say it increases

expression of FKBP5, and that others will say it decreases expression of FKBP5. Some will say it increases glucocorticoid receptor sensitivity. Some will say it makes it more resistant. So at this point, I don't think there's any clear understanding of what FKBP5 does. and I think that actually might be a reflection of the limitations of the literature where we're looking at one single gene, a lot of these studies, where the effective maltreatment is probably far more broad than just affecting one gene. So it could be confounded or a false positive result.

Yeah, and I've looked at studies where they change people's diets and exercise. and it's like tens of thousands of genes are upregulated and downregulated epigenetically, right? And one other piece that's really important here is like, is this permanent? Is epigenetic change is permanent? And no, not necessarily. You know, there was one study that showed maltreated preschoolers who had experienced documented maltreatment within six months of the study. showed higher methylation of this thing we're talking about before the NR3C1.

But there are levels of methylation decreased to levels equal or less than control six months later. So we do know for some kids, especially if the kids are put in an enriched environment, things change back to normal over time. So this is the hope of good therapy. you know the six months of good therapy one year of good therapy hopefully you know it causes a different experience and someone's brain you know to have a to have a stable attachment figure to increase their reflective function maybe and how they view stressors right a deeper deepening of their of their knowledge and information on what their previous attachments what

what caused them, you know, can be really helpful too. So, yeah, so I think there is hope, and we're going to get to more hope as we go along. Okay, we created a chart, and we'll put in the handout on what happens to, you know, things like cortisol, CRH, in animal studies, in adults. You can look at that. All right, so let's talk, let's kind of jump to, kind of the integration. So I talked about the HPA axis.

I think one of the things is that the HPA axis potentially changes the brain over time and specifically a part of the brain that we know is linked to adverse childhood experiences is the hippocampus. We have some decreased volume in the hippocampus with increased adverse childhood experiences. Tell me about the

this kind of research and study here. Yeah, the first findings about decrease hippocampal volume in response to early life stress and chronic stress was seen in animal models, specifically with chronic leukocorticoid receptor and C-R-Rage stimulation. So this finding has translated to humans as well where there is a review of meta-analyses. There are seven different meta-analyses, and they're all looking at brain rate or, brain gray matter volumes, and they found that the hippocampus was decreased in all seven of these studies, and the effect size on that was 0.25. And findings for the amygdala and other brain regions like the prefrontal cortex, they were actually pretty inconsistent, but most of these studies tended to report some reductions in these brain regions. And with the hippocampus,

one of these men analyses, they looked at people with aces without a psychiatric disorder, and they found that people with ACEs, they have a small reduction in their hippocampal volume, and this effect might actually be more specific to women where men didn't see this reduction. And it seems that this is a dose response relationship as well, where there's one in an analysis that looked at multiple trauma exposure compared to single trauma exposure. And they found that only the group with the multiple trauma exposure had a reduction in the hippocampal volume. and that those with the single exposure, they did not. So think about the hippocampus as you're taking the short-term memory

and you're putting it into long-term memory. This is a sensitive area of your brain. We have found in the IOP partial program that I've run. Kids who are in a highly stressed out environment do not perform as well on some cognitive tasks. Now, put them through a bunch of therapy, family therapy, and they go home and do great in school. And so you have like a stressed out brain,

it's going to be harder to focus, concentrate. It's going to be harder to take short-term memory and put it in a long-term memory. And I think there is a dose response here. So it's 0.25 effect size means that, you know, as you jump up in traumas, you could be, you know, if it's like you're four times more traumatized, that the effect size means that it's going to be four times more potentially.

But there's also potentially a step, you know, so when we model information, is it a linear line, you know, like as we go from two traumas to three to four, you know, is it a linear line or is there a jump up where it's like, okay, there's got to be enough trauma to actually cause an impact on the brain and like more of a step. Like it steps up. So I think we're seeing a step up as well when you get to the more severe ranges of trauma. So much so that like if you look at some of the Romanian studies, some of those brains are like literally two standard deviations below the mean in size. these kids who are raised in a very poor orphanage

with very little interpersonal contact at all. We'll get to that study in a bit. Yeah, okay, anything else you want to jump in and say about these things? Yeah, I just want to mention that the effect on the hippocampus, the size difference might actually be only observed in adults. And this kind of goes along with the idea that the hippocampus is one of the brain regions where neurogenesis continues into adulthood,

so the effect on the hippocampus may be delayed over time. And it's also seen in several psychiatric disorders that the hippocampus has decreased, specifically depression and PTSD. They show more consistently that there are decreased hippocampal volumes and also in borderline personality disorder. And there's also some debate in the field about whether this decreased hippocampal volume is actually a marker of maltreatment, and it's not common to all forms of depression. So there's some researchers, Martin Tischer, out of Harvard, he's a very big proponent that this is a specific phenotype of depression that maltrepein is only associated with the decreased hippocampovine. Yeah, and to kind of argue that when we look at the depression

studies, the effect size is quite a bit smaller. We're talking about 0.14. Recurrent depression, 0.17. So these are smaller, whereas with PTSD, we're talking about 0.4. So it's quite a bit larger effect size in the person with the trauma. So is that how you would summarize it as well? Yeah, I'd agree. obviously we're not going to be measuring someone's hippocampus to tell you if they've had trauma or not

because there's so much you know there's so much nuance and subtleties and stuff like that but is that what he's recommending this guy that you can tell like he wants to measure everyone's hippocampus I'm not sure if he wants to measure everyone's hippocampus but I know he's a big proponent that the effects of maltreatment and how that causes depression, the etiology of that type of depression is different from other types of depression. Like, kind of like we talked about atypical versus malacolic. He kind of just fused it in that different light. And you could still have malacolic depression with maltreatment history, but it is a different type of malacolic depression or vice versa with atypical depression. Okay. And then to give you hope, like let's say

you're sitting there and you're thinking like, oh, I went through a lot of trauma. I probably have a small hippocampus. There are numerous cross-sectional, observational, randomized controlled trials in animals and humans that have showed that exercise can increase gray matter volume in the hippocampus. For example, one randomized controlled trial, Erickson et al, 2011, of older adults,

showed that brisk walking, just brisk walking, for one year, not only attenuated age-related gray matter decline, as observed in the stretching group, but it led to a 1 to 2% increase in hippocampal volume. And this increase also correlated with greater spatial memory. So this is my, you know, continual sort of challenge to us, like, okay, let's not like be biological determinists here. You can actually choose to change your environment.

You know, like, oh, I don't have the energy to go work out. Okay, do you have energy to hire someone to push you to do it? You know, maybe you don't. Oh, I don't have the money for that. Oh, do you have a friend who already is doing it or that you could ask to help you? You know, my experience is that most people would love to, help someone learn how to exercise and most people you know going for walks is a lot of fun so let's go let's do it okay any other thoughts on that yeah i just want to say like it seems that this effect is specific to

aerobic exercise too so any even just walking by yourself you can do that just go for a walk it's summer right now so if you hear this and they're inspired go for a walk right now just as long as you start and uh keep it up then you should be able to get some benefits from it because this is a consistently observed finding is that aerobic exercise does help the hippocampus and other parts of the brain too is not just hippocampus. And then in terms of other things that help increase the size of the hippocampus,

there are multiple animal models of environmental enrichment, which is essentially where they give mice a bunch of play partners, a bunch of obstacle courses, essentially, and they get social stimulation and this all leads to increase hippocampal volume too. So having a lot of social connections getting into a community theoretically should help increase the size of the hippocampus too. This is a magical thing about partial, right?

You get someone who's severely depressed, who hasn't left their home for months potentially. You put them at a day treatment program, 700 other individuals with a good therapist who's basically helping them, get along and process with each other and experience life together. And it can be very, very helpful. Just that social milieu, you know.

But then also the supportive environment, you know, a very unique environment, having highly empathic, trained therapists get kind of walking with these people through their stories. Yeah. Okay. Interestingly, IQ is not changed by trauma, at least not severe. When we go up, I think, in the severities, I would challenge that. But in the studies, in general, there was not a huge change in IQ with trauma.

Tell me about that. Yeah, this is coming from the results of this prospective cohort study. They looked at two different cohorts of 1,000 and 2,000 people in the UK and New Zealand. and what they essentially found is that IQ at age 18 and then somewhere in the 30s for the other cohort. IQ at age 3 and age 5 was most predictive of IQ later in life. It wasn't actually trauma. Trauma initially did show an effect on IQ, but when they controlled for other factors like the IQ at age 5 or age 3 and family socioeconomic status, there is no longer an effect of maltreatment on IQ.

So it seems that at least for smaller types of traumas or for a lower dose that there's no effect in IQ or other cognitive capabilities. Yeah. And I think that the Romanian adoptee study, which looked at could you developmentally catch up after severe privation? So these are some of the worst neglect situations you can imagine. The conditions, the quote unquote hospital or orphanages were devastatingly horrific. They had no toys, no playthings, minimal interactions or speech from caregivers. Basic needs like feeding were reduced to things like gruel. served in bottles that were kind of left with the kids.

So this is a very harsh environment, right? Inhumane. And upon arrival to the UK, the majority of these children had a horrible physical condition. Often severe malnutrition, skin disorders, respiratory infections, chronic intestinal infections, you know, parasites, they were around two standard evasions lower in terms of weight, height, head circumference

compared to English children their same age. So two standard variations means they're in the bottom 5%. Yeah. In terms of height, weight, head circumference, okay, so their heads are literally smaller from this level of deprivation. The Denver quotin, for those, adopted before H2 was 76.5. Those adopted between 24 and 42 months was 48. So like you could see

that that's a hundred would be normal. So multiple standard deviations lower for IQ. Retesting at four years showed the impact of the enriched environment and the reversal of the early horrific conditions. Truly amazing how much it reversed it. while they had almost normal weight and height, their head circumference remained about one to one to one point five standard deviations below the mean, and it was worse if entry was after six months. So if they had more than six months of severe neglect, it was worse. The IQ increase was profound and breathed hope into the power of the enriched environment. The Denver quotient was 115 for those who came before six months and 96.7 for those who came after six months.

96 is like almost average IQ. 115 is one standard deviation above the mean, or around one standard deviation above the mean. So what this means is that kids could have severe, severe, you know, weight, height issues. And with the correct enriched environment, they were. immensely helped yeah yeah I think it's a really powerful study to to demonstrate that so it's like not being now nourished and completely deprived of connection and affection even in spite of that if you still experience it later

you can recover to an immense degree and I thought it was a really inspiring study yeah so when we talk about like the biological changes that happen, you know, think about with the correct conditions four years later, five years later, how much of a difference that can be. And so, you know, when we talk about severe, someone who's been through severe neglect, we think about a partial program,

like mentalization-based therapy, one of the initial studies was a year and a half of a couple groups, a couple times a week. You know, 700 hours of therapy, I think in one of the longest parts of the study. And that took people out of that severe suicidleness, and they were able to get off meds. 700 hours is not that long if you think about how many hours there are in a year.

And how many hours of neglect someone went through and abuse they went through to get to that point. A year, two years of therapy, effect size of one or two in most studies, that's 100 hours of therapy. That's not that much if you think about it in the large scope of life, right, to get such a big effect size.

Right, these children experienced like four years, four total years of having an enriched environment where their entire environment was directed at promoting their growth. So if you apply that to an adult, I don't see why that can't be any different. Like if you give someone four years of intensive treatment and connection, then that's, of course, going to change the brain for the positive. But I think it's a matter of how do we get people to have that increase in connection with other people and to be able to change their environments like that. That's where the difficulty is, I think.

Yeah, and I think with those of us who treat patients, it's like, okay, knowing that their biology is impacted. and that they may be more irritable or reactive or can that give you some increased tolerance? Increased compassion. If it gives you increased compassion, then this is a win, right? It's like so much of psychotherapy training, I put it through the lens of like,

does this give you increased compassion and ability to tolerate and be present and empathic and caring with a good frame, with good boundaries towards a patient. And if it does, then it's probably good information. It's probably good education to kind of solidify in your mind that, okay, there are these biological impacts that happen. But with the correct environment, exercise, therapy.

And one of the things I talked about with the people who do mentalization-based therapy was they said, you know, the therapy really changed how they interacted, with loved ones, with friends. So now they're going out in friendships. They're having deeper interpersonal relationships. So that's thousands of more hours of closeness, of intimacy with people. And so that's healing, you know?

So it's like sometimes the therapy gets them to a place where then they are able to find close, meaningful connections outside of the therapy. Yeah, and I think the same can be true of medications as well. Like if someone's taking antidepressant, they have severe depression, and that allows them to get out of bed and allows them to interact with their family. And that's going to be hugely impactful for them as opposed to being in their bed without the medications. Absolutely. I think this is true for social anxiety. It's like, okay,

maybe they get on enough medications to decrease their anxiety to actually be social. Now they're not missing out on four or five years of being social with people and connecting with people. And maybe that leads to them not being able to need to be on the medications to the degree that they're on it. We see this with schizophrenia. Being on medication allows them to interact, connect, and then those connections are healing. they'll probably need to be on some meds for the rest of their life in my mind. But they won't be isolated. Isolation is a form of torture.

I would say it's inhumane torture in prisons. To be severely isolated in a cell actually hurts their brain, decreases their hippocampal volume, impacts them in a very negative way, some of which seems to not reverse after they've got it out. So it's like, you know, imagine a lot of our patients in social isolation. It's like a prison of sorts. Yeah.

Okay, there's a couple other areas of the brain that are impacted. Do you briefly want to talk about those areas? Yeah, yeah, we can go through. So one big field of looking at how ACEs impact the brain is looking at the white matter. So white matter is essentially the long-term projections throughout the brain that have, myelina around them. So there are these axons with myelanid sheath. And these allow for different parts of the brain to communicate with each other in a faster way, essentially. And one of these huge white matter tracks, the biggest in the body in the brain, is the corpus callosum. And this allows for inter-hemispheric

communication between the two different sides of the brain. And it's found that the an aces, this part of the the white matter is actually has decreased integrity you know i find this very interesting so it's this um it's this connection between the orbital frontal cortex and the right hemisphere amygdala that has this decreased connectivity right yeah there's also this other study showing that as well yeah and so you have this violence exposure social deprivation it predicted this kind connectivity issue. The beta is 0.317 less connectivity. And social deprivation, if it wasn't there, then you wouldn't get the decreased connectivity. But it was like social deprivation may exacerbate the effect of the childhood violence leading to developments of a

of having this disconnection. Right. So what this showed me was that like, you know, okay, what is this pathway? Why is it important? You have a threatening, angry face. You know, how are you going to respond to that? So if you don't have a strong track there

because of the trauma, right? because of the combination of social deprivation along with violence, then you have an increased amygdala activation to the threatening stimuli. Okay. So sometimes we call this an error in mentalization where you see people angry, or you have more fear where maybe you don't need to be. So in different types of therapy, what we find is people with like borderline precise, sort of, for example, they may perceive threats where there are no threats.

And this is potentially explained through issues with this track between the orbital frontal cortex and the amygdala. Yeah, and what's really interesting is like, like you mentioned, the social deprivation decreases that track. So that can lead you to think like, okay, maybe kids who grew up around a bunch of different family members, they were able to go through these challenging experiences. they're able to explore outside and maybe in a dangerous neighborhood. And they had someone teaching them like, okay, you don't need to be scared here.

Or they had a sort of buffer to that fearful response where if you didn't develop that buffer, if you didn't have that social connection, then you're probably more likely to be more fearful of these threatening faces. Yeah, I think about it as like this could be reflective function could be the mediator here, right? with increased social contacts, you could have a better ability to reflect upon what's gone on. And then that reflection stays with you, your ability to reflect upon what is true,

what are people's intentions in a more accurate way. And I think that's where mentalization-based therapy or any types of therapy that help you sort of think through what is going on in the therapy session between you and the person, what is going on in interpersonal relationships more accurately is going to lead to long-term positive changes. And then, you know, imagine you don't see, because you did a lot of therapy, threatening faces, scary faces, and people that are good people, then you can have relationships

with those people that could be healing over time. The other thing I find is that some people trauma, they may not see threat where there actually is threats. They may, interact with the wrong people. They may date the wrong person over and over again. And I see that also as a factor of not understanding. Not understanding like the nature of psychopathy, the dark triad. And I think that leads to later a fascination with it. But they may idealize that person in a relationship early on and not see some of the red flags as well. So, you know, the errors in mentalizing could be both ways. Yeah, this idea of like increased and they do a reactivity to negative emotions or negative faces. This is seen across multiple different studies about people

with ACEs. So it is true that to some extent people with ACEs, they process negative emotions differently or negative stimuli, a negative emotional stimuli differently. There might be more attention paid to the negative compared to more neutral or more positive sort of social stimuli. At least that's what these meta-analyses are showing that people with ACEs have high reactivity.

Yeah, and I think this could be another good way, good reason to learn micro-expression, you know. Teach micro-expression to people. If you want to reach out to be my ear, email and I'll help you try to figure out how to learn that but you can you can learn how to read emotional expressions short moments flashes of anger sadness fear pain discussed you can learn it accurate you can learn how to read it accurately and then start to think through the multiplicity of reasons why someone might have those different emotions you don't i don't as even as an expert in this

know why someone necessarily flashes an emotion when they do but I know when they do. And that's incredibly helpful information. Like, oh, huh, I said this thing and then I'm watching this patient's face and they express a flash of anger. Like, what did I say that caused that anger? You know, not to be overly hyperviginal about it, but to be curious about it. And maybe I, you know, said something and they misinterpreted it. And so if learning how to read them can help me sort of maintain a therapeutic alliance and increase my internal reflectiveness of what's going on with them and therefore increase their internal reflectiveness. Okay.

Let's talk about chronic inflammatory cytokines. Yeah. I'll leave most of the details for this for the handout, but in general, some of these meta-analyses of people with ACEs and adults and children, They tend to show increased levels of inflammatory cytokines, such as C-reactive protein or C-R-P, interleukin 6, and TNF alpha, tumor necrosis factor alpha. And this is controlling for age, BMI, which is incredibly important for inflammation, and gender.

So this is seen in children and adults with ACEs. Is there any difference in the type of trauma that elicits changes? I was looking at figure two from this one study and neglect. You want to mention that? Yeah, it seems like there are certain types of abuse that may actually increase particular cytokines. So there's one study that looked at as a goal of sexual abuse. They found that that increased TNF Alpha and IL6, but not CRP. But that CRP seemed to be more so elevated in patients who had rental absence during early development.

Yeah, so we'll put all these things in the handout. It's at Psychiatrypodcast.com. You can check it out. You can download it. You can share it with friends and family. And it's a nice dinner table discussion. You can follow the citations and dig into specific studies that you may want to look at more. Shall we talk about how ACEs decrease reward anticipation?

I feel like that might be an important thing to highlight. Yeah, I thought this was incredibly important. Now, in terms of total ring connectivity changes, I just want to briefly mention that it doesn't seem like there are any consistent changes and patients with ACEs, but it seems like there's more specific task-based dysfunction. So we mentioned increased immigital response to negative stimuli, a negative emotional stimuli. And there's also this idea that ACEs are related to decreased, activity in the reward system in response to some of these rewarding lab-based experiences.

So essentially, what a lot of these studies found is that if someone is completing a what's called a monetary incentive task, they are told how much reward they're going to get if they press a button after a flash of light, if they do it fast enough. And the amount of reward that's presented, say, if you're going to get $10 versus $1,000, that's proportional to how much activity you're going to see in the brain in response to waiting for that reward. And once you get that reward, you get another spike in the reward system. And it seems that in people with ACEs, they have a less high spike of the reward system

when they see the amount of money that's going to be presented. So in anticipation of receiving that reward, there's less dopamine spiking. And this is a finding that's been seen in patients, with substance use disorders and an epidonia. And it's also been seen if you give someone like an inflammatory stressor, like they give a piece of a bacteria and the bloodstream. This has also been seen. So it kind of lends idea,

Lens support to the idea that cases they might increase the risk for addictive type behaviors because of this anadonia. And that may lead to increase liability for using substances. Yeah, so basically think about it like normal things that would cause pleasure don't cause as much pleasure. And so like certain drugs like cocaine or methamphetamines that, you know, increase pleasure centers, maybe sought out to sort of overcome the bluntedness of normal day life. they're chasing after something to feel normal, to feel good inside. I think this can increase our compassion.

We know that addictions are higher in people with a lot of adverse childhood experiences. I think having covered the chemical dependency unit, it's very rare for me to find someone who hasn't been through a lot of trauma who's on addictive substances. whether it's neglect or physical sexual abuse. And so it's like such an important part of the recovery to have people who can weather through the ups and the downs. I personally, the way I do my outpatient practice is

I try to stay with someone longitudinally through the addiction, knowing that it's like there's going to be relapses. I know some psychiatrists who stop treating someone or won't treat them unless they're sober. it's like it's like come on like just can you weather the storms maybe they need that one person who's connected with them longitudinally they may say oh it's a risk or oh you know like they're they're more at risk of death and so i'm not going to be a part of that it's like well that's yeah of course it is but that's when they need to help that's when they need the help i had one person who was like

she would drink herself to a place where she would get withdrawal seizures. And that was like the goal for her. And she would be in and out of the psychiatric unit and in and out of the hospitals. And she told me at one point, you know, the reason why I kept going into psychiatric units was because of you, knowing how much you cared, I didn't want to kill myself. Instead, I would just check myself in.

Now, the parents thought that that was a failure on my part. Like, oh, what is this psychiatrist doing? That's, like, she keeps being admitted to psychiatric hospitals. It's like, no, like, this is she's not. Connection. She's not dying. She's not dying. That's the advantage.

you know so yeah the connection longitudinal connection you know this is this and there was you know some studies i read early on that like does shame increase someone's ability to quit alcohol it's like no you know the opposite it's the opposite right motivational interviewing is what helps shaming someone into you know you had this one attending i would go on when i was a medical student we'd go into the room like wow, he would be like, wow, why are you drinking? You need to go to, hey, you need to do this. And I was just like standing there watching this guy cower in his bed, you know, he's like, and then I read this part in the motivational interviewing textbook as a medical student that was like, shame does not help, you know, connection helps. And you can see why that would be the case for these studies,

right? Kind of like, okay, like what we're talking about today is connection is going to help long term. It's going to change the epigenetics back. in the positive direction. It's going to allow people, you know, maybe in like a connected relationship, they can understand how they're mismentalizing outside of the relationship, you know, mismentalizing in a way

that would lead to more volatile interpersonal relationships. If they can do that, then maybe they can have more stable relationships outside of therapy. You know, one of my desires is for every patient to have deeper interpersonal, relationships with people outside of therapy. Like that's, that's like one of the, the huge goals that I have for each person, you know,

finding meaningful friendships, finding meaningful relationships. So, yeah, I think, I think this is hopefully a hopeful message, as long as, like, a sobering message of like, yeah, there are changes. There, there are long-term impacts. This isn't all in your head in a way that's like, you know, there are things that have actually changed from trauma. Is it, is it a death sentence? I don't think so. I remain hopeful. I think that we can, you know, if you look at that orphanage study four years and their growth went back to normal, IQ was normalized, like there, there's hope, you know. Now I would say with that orphanage study,

those kids may need, you know, therapy for a while. They may need good therapists. They may need long treatment. I think that's going to be a part of it. Yeah, definitely. I think that ACEs, like we see in all these studies that ACEs do have a biological impact, but I'd be curious to see how as the literature progresses, as we have better neuroimaging, better studies looking at patients with complex PTSD, more focused on this topic.

seeing how actually the brain is change in response to maltrapin it, looking at how is the cortex change? Like how can we improve someone's ability to mentalize using the cortex and positive ways that allow people to enhance the connections in their life? Because I think that ACEs, they probably impact the brain at a level that we just can't see yet. And the best way to reverse that at this point that we know of is just increasing that social connection.

Enriched environment, good food, good community, good therapy, good exercise, right? It's like that's the way you enrich that, enrich that brain, right? Cause all the good things to fire. I would say, you know, if you're a therapist listening to this, the other thing is like there are times where vicariously we go through trauma with patients, right? So it's going to be important for us to get treatment, for us to get care, for us to get good supervision, for us to reframe difficult interpersonal situations that inevitably arise, ways to process our countertransference. And I hope that you guys are taking that away from listening to this podcast because I've had a number of people reach out to me by email and say, hey, I got a, I started therapy for the first time two years ago from listening to one of your episodes. and it's been immensely helpful, or I've started supervision,

or I've started a supervision group. Someone said, I got six therapists together, and we just meet once a week and help each other. And that's the kind of stuff that I think is really important. Awesome. Hey, Liam, good to be with you today. Thank you so much for digging into this. You are better than chat GPT in your handouts.

I cannot see chat GPT producing such a nice handout. But, and it's been good to work with you on this, reading articles and talking back and forth and commenting on the document and trying to figure out that, I mean, guys, you have to understand. This is multiple iterations. I think this is, we've, you know, this is our probably third time to record this specific episode where we, like, looked at the handout and we were like, I think we need to go deeper on this. I think we need to add animal models. I think we need to add the orphanage study, you know, so I think we're continually. trying to bring you something that's a value, this one and a half hours that you've listened to or whatnot, is hundreds of hours of work. So I hope you're grateful to Liam for that. And we will leave it there for today. Thanks for having me out. It has a lot of fun doing this project. Yeah. I think when you're like in the glory of medical school without kids, you don't have kids, right?

No. Yeah, it's like, it's a good time to study. All right, man. Talk to you soon. See you.