In this presentation, Shanthi Gowrinathan, MD, discusses the changes in the brain for patients across the spectrum of neurological disease.
Okay, welcome back everyone from that brief break. Hopefully you were out there moving and meditating and keeping those brains healthy. A little housekeeping again here. Great questions have been coming in. You've got a question box off to the right where you can submit questions. You can also ask questions with the little button below your video feed there. You have the whole agenda and everything below that. So please keep engaged. We're loving the engagement here. And one other piece of housekeeping. You we'll have an evaluation you can complete following the conclusion of the course. Please complete those evaluations. That's how you get your CMI credits. So follow the prompts to complete the evaluation and get your CMI credits. So now without further ado it's a real pleasure to uh to uh introduce another incredible colleague uh adding to our robust interdisciplinary holistic approach here. Dr santiago run Ethan who is a psychiatrist specializing in women's psychiatry and psycho oncology. She's the director of psycho oncology for P. And I. And today she will be presenting on anxiety, depression and neurological disease. Take it away shanty. Thank you scott. So I'm Shelby Gary Nathan. It's nice to get to talk to all of you. Um As scott said I'm the director of psycho oncology psycho oncology basically means I'm a psychiatrist who trained um in medical psychiatry and treats mostly cancer patients. Um And today I'm going to be talking to you about anxiety, depression and neurologic disease. So as a psychiatrist who works with cancer patients. Um My patients often present with a sort of mixed bag of psychiatric and neurologic symptoms. Um Having trained in reproductive psychiatry, I've seen the impact that hormones can have on on a patient's brain. Um Working at the V. A. With female bets, I've seen the impact that Tv I and PTSD can have on the brain. And now as a psycho oncologist um I almost daily see the very real changes that happen in both mood and brain function um from cancer itself as well as cancer treatments. Um The fact is that there are many commonalities across the spectrum of neurologic disease. So um I guess first I should do the disclosure. I have no conflicts to declare. Um And these are the off label use medications I will be discussing and um learning objectives as I said, um understanding kind of neuro behavioral sequelae which I conceptualize this sort of um central in the frontal lobe and then sharing some of the neighboring regions um in terms of neuro behavioral and psychiatric dysfunction, recognizing the impact that these brain changes have on patients across the spectrum of neurologic disease and then discussing potential modalities of treatment, a frontal lobe dysfunction and um neuro behavioral sequelae. So for the purposes of this talk, I am I want to think of uh you know, neurologic disease in terms of these four large categories. Now this will exclude things like seizure disorders. But it does hit some of the really big debilitating um illnesses. So we have traumatic brain injury, um cerebral vascular injury, me a plastic lesions and neurodegenerative disease because I work in brain health. These are areas that I'm you know exposed to and these are patient populations that I work with commonly um T. B. I. Is a different color just because it is sort of externally driven. And the rest of these are sort of internal but otherwise they're very similar in terms of which neuro behavioral sequelae um they present with and the level of distress that causes in patients. Yeah. So what are the vulnerable regions of the brain and what are the sexually that can occur? Um. Uh Yeah. First uh in terms of conceptualizing what vulnerable regions there are and and the areas that control some of the symptoms. Um I like to think about it in terms of traumatic brain injury. The reason for that is traumatic brain injury is interesting in that, you know, due to sort of mechanical forces and where the brain hits the skull. Um There are some focal points of injury. But if you if you look at traumatic brain injury symptoms, they tend to be a little more global. So I think that's a good way of conceptualizing in the first place. Um this kind of dysfunction. So this is a picture of the brain and it's kind of fuzzy, I'm sorry, but these are the areas that are most impacted. So we have the dorsal lateral prefrontal cortex this does executive functioning, working memory, sustained and complex attention, memory, retrieval abstraction judgment inside and problem solving. So it's a big guy, it does a lot um orbitofrontal cortex, emotional and social responding and social comportment. This is a fine tuned section. So this is a section that really takes information from other parts of the brain and makes real time assessments about you know, how we interact with other people um and how we perceive those interactions which becomes very important when you talk about things like social anxiety and depression, um temporal poor polar cortex does the memory retrieval sensory olympic integration. Our amygdala hugely important for a psychiatrist. We love working with the amygdala. It's one of the places that holds our emotional learning memory and our fear conditioning which becomes important in um psychiatric illness such as PTSD and anxiety. Um I apologize, there's two on here that you can't see but use micro. So there's a little lavender area um and that is the entire original hippocampal complex and that's going to be involved in declarative memory um sensory gating and attention. Um sensory gating being the sort of threshold at which um sensory stimuli are going to dis regulate that. So this um uh one example of dysfunction is in Children with autism, the auditory sensitivity. Um and this grayish purple stem over here that's the eventual brain stem and that's gonna do arousal and it has the ascending modular terry um neurotransmitter system. So this is our um this is our sort of awake, alert and oriented area of the brain um and in a lot of neurologic disease, you know, on top of regular depression or regular anxiety, we have issues with arousal. So that becomes important. And then the cerebellum and the cerebellum, you know, is usually associated with gait and balance, but it also has an impact on working memory because we have motor memory that informs what we do. Um It has an impact on working memory and it also has an impact on mood regulation. So um it's kind of an unsung hero. We don't think about it in that way, but um these are all areas that when I used to work with the vets became very important to consider because patients would come in and they're describing a sense of debilitation that is leading to depressive symptoms, but you know, these areas are not functioning well and this is where um I started to focus in on um not just treating you know, for the depression and not just treating for the anxiety, but really looking at how we can treat the dysfunctional brain as a whole. Um this slide is very busy and I don't expect anyone to look at all of it. The reason why it's from this really wonderful article by mcallister uh that I used when I used to work with the vets um in residency, um the point of this is not to know all of this, but the point is if you look across the spectrum of, you know, the different domains of things that can go wrong with the brain, psychiatric symptoms included, um you have cognitive deficits such as working memory, short term memory, and attention processing speed, of course. Um and then you have this executive syndromes such as disinhibition and social comportment, cognition, uh cognitive executive, which is sort of a subcategory um disorders of motivated behavior. And then you have the psychiatric disorders, depression, substance abuse and PTSD. The thing that I find striking about this chart that I loved back in residency was the fact that if you really look at the areas of the brain involved, there's a tremendous amount of overlap and there's only one or two where the frontal lobe is not involved at all. In fact, I think there's like 1.5 and everything else. The frontal lobe of the brain is involved and then the other circuitry that's involved in all areas um that overlap with one another, like the amygdala, the hippocampus, the reward centers of the brain and the temple olympic circuit. So the idea being that the same structures that produce a lot of the neurologic symptoms that go along with these diseases are also capable of producing psychiatric symptoms. Um but they don't just produce psychiatric symptoms. They produce dysfunction across multiple domains. And I think this is important when you're looking at a neurologically ill patient and trying to treat their depression or anxiety. Um it helps you to have not only diagnostic finesse but some finesse in terms of choosing what you're going to use to treat because a lot of the medications that we use psychiatrically um in general psychiatry for plain old depression, if you put it in a patient that's also struggling with attention and processing speed will create further dysfunction actually. So it's really nice to sort of conceptualize it this way and think about the fact that when there's a neurologic dysfunctional process going on um you know you have to take that into consideration when treating someone psychiatric symptoms. Yeah, Next one Chemo Brain. So um I work now as I said, go on colleges. So you know I I largely see cancer patients. I do see some of my lovely colleagues um dementia and Parkinson's and M. S. Patients every once in a while. But this is the majority of what I do and chemo brain people think of in terms of memory. So people say oh you know what I I went through chemotherapy and my memory is not as good, but actually when you look at it um there are self reported patients complain of things across these primarily these four areas. Um they just don't name it this, they will complain to you about things that are going wrong in their life and they really fit I'm sorry, there's ambulances. Um they really fit across the spectrum of executive function, processing speed and attention as well as memory. Um So this is obviously not an official term. This is something that is sort of a layperson term. Again in my mind, this is also frontal lobe dysfunction. Um and frontal lobe dysfunction is actually one of the most common things that I put on a patient's uh diagnosis list on, you know, in addition to depression and anxiety, because this is something that people complain about so commonly. Um Just to give you a sense of uh you know, how prevalent it is uh in 2004, when we were sort of checking for it On a broader scale and not very specifically, about 33% of women in breast cancer cohorts exhibited cognitive impairment. Now it should be clear. This is only chemo, not chemo and radiation. Um and and certainly not a patient with brain meds um and not talking about the aroma taste inhibitors, which would change the picture completely because of the changes in estrogen. Um findings have shown that patients present with subtle cognitive deficits. Again, memory, executive function, concentration, attention, and processing speed. Um But here's the really interesting thing if you take these patients and you do, you know, the full battery of neuro psych testing, they actually come out fairly normal in Jurassic testing and they find this incredibly frustrating. My patients are looking for the reason why they can't function in their life anymore. So um for them to go through this painful process of six hours of testing and come out the other side and be told that they're fairly normal is an unbelievably disappointing. So I stopped doing the neuro psych testing because it's not as helpful for chemo brain. Um these deficits I think are a little bit subtle and therefore patients are able to sort of still perform well on neuro psych testing. Um and for a while I wonder so if they're performing well under a site testing, what else is going on? Why are they? You know, when you look at self report and when you look at distress screening, um the level of distress does not match up with someone who is completely normal and neuroscience testing and the level of dysfunction compared to their baseline before also doesn't match up. So there's something going on here that is not being caught. So um we don't have a lot of really good human studies. Um A lot of the studies that you look up there, they're still in mice or rats. So um there is one really good study that I talk about with patients and they find this incredibly comforting. Um There was a twin study that was done, it was done in mono psychotic twins, only one of whom contracted breast cancer and underwent chemo. Um They were both evaluated with self report measures of cognitive function, standard neuro psych testing and structural and functional MRI which I got really excited about this functional MRI it's my favorite um In terms of looking for subtleties of psychiatric illness um results indicated very little difference in Jurassic testing but striking differences in self reported cognitive complaints and M. R. I. Images. So um you know if you think about it, you know Mona's exotic twins, they're identical and one was reporting a tremendous amount of dysfunction in terms of cognition, not only um in relation to her twin but also in relation to her own baseline. Um And then on structural MRI. They did show for the sake of time, I didn't include that particular site but they did show some white matter changes in the white matter changes were both more diffuse in the patient who had gotten chemo and um also you know a little bit more intense. Um So what was really cool though is the FmRI. So if you look at the FmRI. Yeah. Okay. So the top three of the top three pictures that's gonna be the patient who got chemotherapy and this is the twin who did not get chemotherapy. And they were given with tasks of incrementally increasing difficulty um from left to right. So this is the easy task. This is a difficult task. Um And the color regions are increased brain activation during uh working memory. So if you look at um how much on all levels an easy task at a difficult task but you know it's much more striking with the easy task, how much more recruitment of the brain, the person who got chemotherapy had to use in order to complete a simple task because these two over here, this is a simple task. Um and this is exactly what patients say to me, patients come back and they say you know I have patients who are extremely high functioning. Um One of my patients, she was ceo and she started her own company um highly driven, extremely intelligent and got chemotherapy didn't even get like you know sort of the really toxic chemotherapy tolerated chemotherapy great as she put it, she flew through it, okay. Um and um went back to work and called me from the bathroom crying. So what happens is these people who are extremely intelligent um and had the ability to multitask. Um You know, their frontal lobe was amazing, their ability to sort of organize and plan and um you know throw themselves into the future and then plan in the present. All of these were very very finely tuned and now they're having dysfunction with even the easiest tasks. So um they will say things to me like if the phone rings and the dog barks and my husband asked me a question, I lose it. Um And so if you look at this can in some ways this explains some of the symptoms that people talk about, you know, another symptom that they talk about is that their their ability to stay at work, their endurance is less. So um you know if they do two tasks where before they would do six tasks uh in a couple hours if they do two tasks are now exhausted, their brain now feels like it can't do any more. Um And and they complain a physical fatigue as well. So if it takes this much extra recruitment of the brain to focus and do a simple task, you can imagine that on the level that these people were functioning before upon the return to work none of that is going to work very well. Um And I think it's important to recognize this and normalize this for patients because otherwise they honestly feel like either they're losing their mind or they become stupid and neither of those things are true and I know that because with treatment were able to get people functioning again. So I really love this study. Um uh It was done by Ferguson and all at M. S. K. Ran it and I think it really um is sort of a visual reminder that the brain isn't quite the same after chemotherapy and by the way this doesn't just apply to chemotherapy, although they do less studies um to look at it. Radiation patients complain of the same thing. You know I always uh tell radiation patients that you know it takes a couple of months but we can we can end up with some of these deficits with radiation as well. So um and I think recognition and understanding that we haven't done a good job of quantifying this, but it does happen and it does exist is really helpful to patients. Okay, so why might chemo change the brain? And in the word chemo we would say anything that might be neurotoxic including radiation. Um So some of the some of the theories mostly in animals are um inhibition of hippocampal, neurogenesis, oxidative damage, white matter damage, decreased hypothalamic, pituitary, adrenal axis activity and reduced brain vascular ization and blood flow. Um We also have to remember that there is director of toxicity with chemo, particularly things like methotrexate, the clock, you know across the blood brain barrier. Um And there's also induced hormonal changes in a lot of patients, mostly you know mostly prostate and um breast ovarian. But there are there are other uh other patients as well that experience hormonal changes. Um Chemo is also associated with increased levels of inflammatory cytokines. And you know a lot of the research now in depression really looks at depression as an inflammatory mediated illness and there is evidence uh that that is one of the ways that we could treat. Um And we know that many of the audio immune disorders that have inflammatory etiology also present with morbid depression or anxiety. So you know an inflammatory process can't be ruled out as one of the reasons why chemo might change the brain. Um These are some of the cognitive domains that are typically impaired again, um frontal lobe executive function, um impulse control is a big one and set set shifting and problem solving. Um These are things that patients took for granted before and they find they find it incredibly distressing If they're now yelling at their loved one um and they weren't even, you know, they were never yellow, they were calm person and now they're having some impulse control issues, um attention, short term memory learning and speed of information processing as well as speech and language functions. Um commonly reported changes in personality include impulsivity, irritability, affective instability and apathy. So these are also things that patients commonly will come to me and say, you know my mood goes up and down, I don't even know where my move came from. Uh My favorite example is someone yelling because someone crying because the curtains were banana yellow and not lemon yellow. Um but and then feeling completely ridiculous, but these are these are real problems. They you know, they're a little laughable and we do laugh my patients and I laugh about it but um you know these wear away relationships in our everyday life. So it's important to consider these entreat um lack of awareness deficits as one as well. Um and you know just to put it out there, these if you have a neurologic disease, uh the disease itself is causing some of this, the treatment is causing some of this, but also if these diseases are sort of chronic in nature, the stress of debilitating illness also takes a toll. And this is just a model that talks about the different areas. It's the same areas we've been talking about. Bye um normal behavioral homeostasis in acute stress were able to adapt and allow a person uh to sort of have a reaction and then come back to center with chronic or intense prolonged stress. We can have an inverse reaction, maladaptive patrick patterns and curtail of goal directed actions. This can lead to psychiatric disease. Um and treatment often reduces reactivity but doesn't really address the cognitive and other brain symptoms. Those are some of the symptoms. Um and this picture is just to show you these are the normal fear pathways and again, not to be repetitive, but outside of the sensory thalamus, the rest of these. Again, we're talking about the same areas of the brain that we rely on to tell us what to freak out about and what not to freak out about. Um And and so in things like anxiety and pTSD um these go awry. Yeah. Um in case you're not aware of the sort of criteria for depression, these are some of the criteria, I think it's really important to note a lot of these symptoms are more functional than they are mood related fatigue concentration, insomnia, agitation and weight loss or gain anxiety to Now anxiety comes with some edginess and restlessness, but again, a lot of somatic and or cognitive symptoms. So my favorite thing to say to patients is that anxiety and depression affect the mind, but they live in the brain. Um and the reason why I say this to people because people get very distressed having cancer and then having to come to see a psychiatrist and they're like, well, you know what, this is all in my mind or what if it's just in my head, because that's how we talk to ourselves, particularly in this country. And my answer to that is so what it is in your mind, it is in your head, it lives in your brain. This is, you know, organic brain dysfunction um that's presenting um in our mood. So, you know, we have plenty of evidence that depression lives in the brain and prefrontal cortex, amygdala, hippocampus and the thalamus. And then we have plenty of evidence that anxiety lives actually in the cortex because the cortex allows us to do things like imagine and we can project ourselves into scary situations we can ruminate on the past scary situations. So all these, all this dysfunction is living inside the brain. So we really need to look at the brain of the whole when we're treating so in the last minute and a half. Now people don't do a lot of research on, on these off label uses because I don't know, they don't make money. Um But I wanted to say that um there are some off label uses of medication that can be really useful um for the affective instability, gabapentin can be really helpful. Um So can difficult actually. I use extremely low dose of Depakote that sprinkling of difficult. I call it about 100 and 25 mg to help people with frontal lobe dysfunction when it comes to yelling agitation, losing our temper being more irritable and it works great. And it also helps people sleep as long as their liver is okay. It works. Um I use stimulants um low dose long acting stimulants to help with um processing speed. We've actually had patients who have done really well in terms of their speech getting better because what happens is when you have really slow processing speed you kind of withdraw because people are going too fast for you. And as soon as we add a little bit of stimulant and their people are able to cognitively keep up and it makes a tremendous difference in terms of being able to reengage with the world. Um And then of the medications um that are used for depression. My favorites are the S. N. R. S. And the tricyclics because they have a little more balance and they work better in an already injured brain. Um All these things don't work that well. So I am also a part of research into psilocybin and other psychedelics hoping that we can have a more global way of approaching this, but that's a topic I'm going to save for my colleague Dr Hines, you're like, thank you, thank you so much shanti. Excellent. Excellent. Just a few quick questions here. Uh we're talking about depression, anxiety in the context of neurologic disease. How do you know whether somebody is just sort of adjusting to serious illness versus being truly depressed? So, um, one of my favorite things to ask patients is tell me about what you were like before before this diagnosis, and I think that question gives us so much information about what we need to worry about and what we don't need to worry about. Um if patients had a tremendous amount of difficulty coping all their life, If they're like, I was like this all my life, I'm a little bit less concerned that these are sort of new onset symptoms that are being enlisted either by the neurologic disease or treatment. And the patient has gotten used to that. They've lived with this all their life and they, in their own way, have developed coping to their dysfunction. So, I think finding out what's new and what is, and I will also ask what is bothering you the most, if I could take one thing away, what is bothering you the most and that gives you what you need to understand where the dysfunction is that the patient is not used to and does not know how to deal with. And that gives us an understanding of what has come with this disease and what was okay um what existed before and what and was part of the person Quick one. What about radio brain radiation impacts on cognition. Yeah. So the really cool thing because I get to work with all of you guys. I get to see a spectrum of neurologic disease and it doesn't really matter radiation or chemo. Um You know, so I don't think that the crossing the blood brain barrier is the only thing. I think inflammatory mediators are probably more of a culprit because you can irradiate your big toe and patients will come to me with mental fatigue, slower processing um and difficulty with executive function. So I really do think whether it's radiation or chemo, we have to think of it in terms of the body responded to a stress with inflammatory mediators and affected the brain. Excellent. Well thank you so much. We could talk all day. We're going to keep it moving here. Look forward to seeing you again soon
