Neurobiology of Schizophrenia, Mood Disorders, Anxiety Disorders, PTSD, and OCD | Chapter 19

0:00 Welcome to last minute lecture. This free chapter overview is designed to help students review and understand key concepts. These summaries supplement not replace the original textbook and may not be redistributed or resold. For complete coverage, always consult the official text. You know, usually when we talk about a medical diagnosis, there's this um this expectation of clinical precision, >> right? Yeah. Like it's a math problem or something. >> Exactly. It's almost like engineering. You break your arm, the X-ray shows that, you know, that jagged white line and the doctor just points at the screen and says, "There it is. That is the problem, >> right? It's wonderfully binary." >> Yeah. Broken or not broken. The pathophysiology is just clean. You put a cast on it, the bone knits back together, and you just move on.

0:45 >> And I mean, as humans, we crave that, right? We want our illnesses to be visible, to be neatly categorized into little distinct boxes. And well, most importantly, we want a straightforward mechanical fix. >> Right. Right. But then you step into the world of uh neuro development or psychiatric illness and severe trauma and suddenly that X-ray machine is just utterly useless. >> Completely useless. Yeah. >> We're looking at a diagnostic landscape that is well honestly it's just murky. We are dealing with symptoms that overlap, medications that work on multiple seemingly unrelated conditions and you know patients whose lived experiences just defy simple categorization. >> It is the absolute definition of diagnostic muddy waters. And frankly for a long time the medical community kind of allowed those waters to remain muddy

1:32 >> by doing what? Treating them differently. >> Yeah. By treating psychiatric conditions as if they existed purely in some uh ethereal realm. You know, we [clears throat] used to think of mental illness as a failure of character. or a purely psychological phenomenon completely divorced from the physical flesh and blood of the actual body. >> Wow. And if you are a nursing or health science student waiting into those muddy waters for the very first time trying to grasp advanced pathophysiology, I mean it can feel incredibly overwhelming. >> Oh, absolutely terrifying. >> Which is exactly why we are dedicating this deep dive to clearing that water. We are going to frame this conversation as a one-on-one tutoring power hour designed specifically for you. We're taking the most dense complex neurobiology from chapter 19. So, we're

2:19 talking schizophrenia, mood disorders, anxiety, PTSD, and OCD, and we are going to extract the absolute core mechanisms. >> To set the stage properly though, we need to establish a foundational concept that well, it completely shifts how you might intuitively think about psychiatric illness. >> Okay, lay it on us. We have to violently rip away the idea that mental illnesses are just in the mind as if the mind is some floating abstract entity separate from the brain. >> Right? They are not. >> They are not. These disorders are rooted in highly interconnected physical three-dimensional brain structures. They're modulated by actual chemical neurotransmitters neuropeptides and hormones floating right there in the synapses. They are governed by microscopic gene expression. >> So, we really have to look at this through a strict unforgiving biological

3:05 and physiological lens. Precisely. In biology, normal physiology supports adaptive function. When you have altered cellular function, it inevitably leads to tissue and organ dysfunction. And that organ dysfunction, the physical breaking down of the brain's hardware, is what produces the clinical signs and symptoms your patients will actually present with. >> So like a hallucination isn't a ghost in the machine. It's a chemical misfire in a specific physical pathway. >> Exactly. It's an organ failure of the brain. That is the perfect grounding. Okay, let's unpack this. Let's dive straight into the deep end with a condition that fundamentally alters a person's reality. Schizophrenia, >> right? >> This is a serious psychiatric illness that strikes about 1% of the world's population. It emerges in young adults,

3:52 usually, you know, late teens and early 20s, slightly earlier in males than females. But before we get into the cellular misfires, the history of how we define this is actually pretty fascinating. >> It really is. So back in 1883, Emil Craraplin originally described this condition as dementia precox, which essentially translates to early dementia. Yeah. He saw young people whose cognitive abilities were rapidly declining, basically mimicking the dementia scene in the elderly. But then in 1911, a Swiss psychiatrist named Ogan Boiler came along and realized dementia wasn't quite accurate. So he coined the term schizophrenia. >> And here is where a massive public misconception begins, right? Because the root of that word implies a splitting which Hollywood and pop culture immediately hijacked to mean a split

4:39 personality or dissociative identity disorder. >> Exactly. Which is entirely incorrect. Bler was not describing a splitting of the person into multiple people. He was describing a splitting of the cognitive from the emotional side of one's personality. >> Wait. Okay. Explain what that actually looks like in a patient. How does cognition split from emotion? Well, imagine recalling a deeply traumatic, terrible event from your past, a a severe car accident, for example. Normally, your cognition, the memory of the crash, is tightly tethered to your emotion. The fear, the sadness, the distress. But in schizophrenia, that tether is literally severed. A patient might exhibit a feeling of bright, bubbly happiness when recounting that horrific car crash. >> Oh, wow. Or conversely, they might show total flat emotional indifference when

5:27 describing the birth of their child. The thought and the emotion are just no longer communicating. >> It's a profound discontinuity, a complete break in reality. So, if we are looking at this purely biologically, where does this break originate? If you look at genetic influences, researchers study monozygotic identical twins. And the concordance rate, meaning if one twin gets it, the likelihood the other twin gets it, is somewhere between 30 to 50%. which is a very telling statistic. >> But this is where I want to push back or at least synthesize this for the listener. If two people share the exact same DNA letter for letter and one develop schizophrenia, why wouldn't the other develop it 100% of the time? I mean, if it's genetic, shouldn't it be a simple onoff switch like Huntington's disease? >> That is a crucial distinction and a brilliant question. If you are studying

6:12 pathophysiology, you absolutely must understand the difference between mandelian genetics and complex polygenetic disorders. Huntington's disease is mandelian. If you carry that specific mutated gene, it is fully penetrant. The switch is flipped. You will get the disease regardless of what you eat, where you live, or how much stress you have. Schizophrenia is completely different. It exhibits what we call reduced penetrance. >> Meaning the switch isn't fully flipped. >> Meaning there isn't just one switch. There are dozens, maybe hundreds of tiny switches. Genomewide association studies have identified multiple genetic lossi specific locations on our chromosomes that contribute to the disease. We're looking at genes with names like dispendon neurorulin 1 and disc1

6:59 which literally stands for disrupted in schizophrenia 1. >> So these genes don't code for schizophrenia. What do they actually code for? >> They code for the structural integrity of the brain. They are responsible for how neurons migrate during fetal development, how synapses form, and how receptors function. When these genes are mutated, the brain's architecture is basically built with slightly weaker materials. >> Okay. >> But, and this is the key to your question about the atronical twins, you can carry this genetic vulnerability, this architectural weakness, and never actually manifests the illness. >> So, the genes are the vulnerability, but the environment is the hammer that tests the architecture. >> Precisely. Because the twin concordance rate caps out at 50%. We know with absolute empirical certainty that environmental factors must come into

7:44 play. If the architecture is weak, an environmental storm will cause the building to collapse. >> And what do those environmental storms look like? We are talking about prenatal and paranatal vulnerability factors, right? Things that happen incredibly early in life that interfere with that genetically programmed neural development. We're looking at maternal exposure to viral infections during pregnancy, severe nutritional deficiencies, or paranatal complications like neonatal hypoxia, meaning the baby was temporarily deprived of oxygen during birth. >> Yeah, exactly. >> Even an upbringing in a highly stressful urban environment has been shown to increase risk. >> But here is where the pathophysiology gets intensely interesting regarding the timeline. >> Think about when schizophrenia actually emerges, late teens, early 20s,

8:31 >> right? If the original insult of viral infection or a lack of oxygen happened in uterero or at birth, why does the patient seem perfectly fine for the first 18 years of their life? >> Right? If the brain was damaged at birth, shouldn't we see the symptoms in a 5-year-old? >> You would think so. But the brain is incredibly adaptive and different regions come online at different times. An early brain defect might remain completely silent during childhood because the child isn't heavily relying on those complex higher order structures quite yet. The defect is lying in weight. It doesn't dramatically affect the individual until subsequent development during late adolescence and young adulthood. >> Ah because adolescence is when the brain under goes that massive pruning and rewiring. The prefrontal cortex is finally maturing. >> Exactly. The brain is reaching a stage

9:17 of maturation where it suddenly needs to heavily utilize those specific complex structures for abstract thought and independent adult functioning. It reaches for that architectural support and suddenly because of that early viral infection or genetic mutation, the structural foundation just isn't there. >> The building collapses. >> The building collapses and that is when the first psychotic break occurs. >> That perfectly explains the clinical timeline. Okay. So, if the building collapses, we should be able to see the rubble. Let's talk about the actual neuroanatomic alterations. If you look at modern 3D MRI scans comparing a healthy brain to a brain with schizophrenia, the visual differences are just stark. The most prominent feature is the enlargement of the lateral and third ventricles along with widened frontal fissures and sulsi.

10:04 >> To visualize this, remember that ventricles are the normal fluid-filled cavities deep inside the brain. Cerebral spinal fluid circulates right through them. But if they're enlarged, it's not because the ventricles themselves have some sort of tumor or active growth pushing outward. Right. >> Correct. It is actually the opposite. Think of a sinkhole. >> Okay. >> The ventricles look larger because the surrounding brain tissue, the actual gray matter, has shrunk, atrophied, or just failed to develop properly. The tissue recedes and the server spinal fluid simply rushes in to fill the empty void. >> So ventricular enlargement is actually a surrogate marker for brain tissue loss. >> Precisely. And clinically, when individuals exhibit this cerebral ventricular enlargement, they generally experience more severe cognitive

10:50 impairment, prominent negative symptoms like apathy and lack of emotion. And crucially for anyone managing their care, they respond very poorly to medical treatment. The physical hardware is just too far gone. >> Wow. The MRI scans also show drastically reduced volumes in the phalamus and the temporal lobe areas, specifically the amydala and the hippocampus. How do we connect those specific missing anatomical pieces to the actual lived symptoms of patient experiences? >> Well, if we break down the neuroanatomy, every region has a very specific job. Think of the phalamus as the brain's central relay station. Every piece of sensory information, what you see, hear, and feel, comes into the phalamus and thealamus routes it to the correct part of the cerebral cortex for processing. >> So, it's the air traffic controller of the brain.

11:35 >> Yes. So if the volume of the phalamus is physically reduced, its functional capacity drops. You disrupt the neurotransmission between the frontal cortex and the primary sensory and motor areas. The wires are frayed. The air traffic controller is sending signals to the wrong runways. This is why sensory information gets distorted. >> And what about the amygdala? >> The amydala is the emotional core. It plays a central role in the social brain network assessing threats, reading facial expressions, and processing emotional weight. >> Okay. So if the amigdula is physically shrunken, how does that manifest? Like if you give a patient with schizophrenia a test where they have to look at faces and identify the emotion, fear, anger, happiness, they struggle immensely with it, >> right? Abnormal amydala connectivity

12:21 represents the biological basis for why individuals with schizophrenia have such pronounced difficulties making appropriate social judgments. They can't process emotional cues correctly because the hardware, the amydala, is physically reduced in volume and functionally abnormal. It's not that they aren't paying attention. Their brain literally cannot decode the visual data of a smile versus a grimace. >> That makes profound sense. But as we look deeper into the imaging, there is a finding regarding cortical gray matter loss in adolescence that is quite frankly terrifying. >> Yeah. The heat maps, >> right? When you look at heat maps generated by functional imaging over time tracking teenagers as they age, you see normal teenagers lose about 0 to 1% of their cortical gray matter annually.

13:07 And that is normal. The synaptic pruning making the brain more efficient. >> It's the brain clearing out the underbrush. >> But when you look at the heat map of teenagers diagnosed with early onset schizophrenia, the map is glowing red. They aren't losing 1%. They are aggressively losing 2 to 5% of their gray matter annually, specifically in their parietal, frontal, and temporal cortices. >> It is a profound, rapid, and aggressive tissue loss. The brain is effectively eating its own necessary circuitry. >> And this is where I have to stop and ask a tough clinical question. We have antiscychotic medications. We give them to these patients. But the text says that this aggressive tissue loss is evident by the time they seek treatment and it continues throughout the course of the illness despite the use of those antiscychotic medications.

13:53 >> Right? >> So wait, are we essentially just treating the behavioral symptoms, the hallucinations but completely failing to stop the actual physical deterioration of the brain? >> That is the tragic reality. Yes. And it raises an enormous clinical concern. The progressive loss in frontal lobe volume directly correlates with an increased severity of those negative symptoms, the apathy, the withdrawal, and further cognitive decline. Current antiscychotic medications target neurotransmitter receptors. They're very good at managing the positive symptoms like hallucinations and delusions. They quiet the noise, right? >> But they do not fix the structural integrity of the building. They are completely ineffective at attenuating or reversing the structural loss of frontal brain tissue. So, the disease process is

14:40 still burning down the house. We've just soundproofed the walls, so we can't hear the fire. >> Oh, that is a haunting but very accurate analogy. It highlights an urgent, desperately unmet need in pharmarmacology for neuroprotective therapies. Drugs that actually stop the tissue from dying rather than just masking the chemical misfires. >> Wow. Okay. So, we've looked at the gross anatomy, the shrinking tissue. Let's zoom in further down to the microscopic cellular mechanisms. We mentioned earlier that genes lay the architecture and there are two specific proteins heavily implicated here. Real and nurulin 1 or ng1. >> Let's break those down because they perfectly illustrate how a microscopic protein deficit creates a macroscopic behavioral problem. Rein is an extracellular matrix protein. Think of

15:26 it as a chemical breadcrumb trail. >> Okay, a breadcrumb trail, >> right? During fetal development, when the brain is first forming, baby neurons are born deep in the center of the brain and they have to migrate outward to form the complex layers of the cortex. Real acts like a traffic cop or a guide directing that neuronal migration. >> So if you have a deficit in real during pregnancy, those neurons don't end up in the exact right layers. The wiring is slightly crossed from day one. >> Exactly. And in adulthood, reelin takes on a new job. It's involved in maintaining synaptic function and plasticity. Post-mortem studies of patients with schizophrenia consistently show that reelin is severely reduced in the prefrontal cortex and hippocampus. >> And what about the second protein NRG1? >> Nurulan D-R1 is widely distributed in the frontal cortex, midbrain and

16:12 cerebellum. It regulates a critical process myelination, >> right? The insulation. >> Yes, myelin is the fatty insulation wrapped around the axons of neurons exactly like the rubber insulation around a copper wire. It ensures electrical signals travel fast and efficiently without leaking. NRG-1 also regulates neurotransmitter receptor functions. So if you have deficits in both real and NRG1, your neurons migrated to slightly wrong positions and their electrical wires are poorly insulated. >> And the clinical result of poorly insulated misplaced wiring, a profound compromise in executive functions, specifically attention and working memory. >> Yes, working memory is a highly sophisticated brain function. It's essentially the brain's RAM, right? It's the ability to briefly store and use

16:58 information to complete a task, like holding a complex math equation in your head while you solve it or remembering the beginning of a long sentence by the time you reach the end. So, it actually makes sense. >> Exactly. And neuroiming points us directly to the region responsible for this, the dorsal prefrontal cortex or DLPFC. In a healthy individual, if I ask you to solve a complex working memory puzzle, blood flow and metabolism immediately spike in your DLPFC, we can see the brain rerouting energy to that specific area to solve the problem. >> But in a patient with schizophrenia, >> it remains hypoactive. The blood flow doesn't increase. The region basically fails to activate. And this pathophysiologic change, this dead zone in the dorsal prefrontal cortex is believed to be a major biological driver of the negative symptoms in

17:44 schizophrenia. It explains the profound lack of motivation, the inability to engage in goal-directed activities, and the severe poverty of thought. The hardware required to hold a goal in your mind simply isn't powering up. >> Okay, we absolutely need to talk about neurotransmitters specifically dopamine, because this is where the pharmarmacology, the drugs we actually give these patients, comes into play. I want to build a mental map of the dopamine system. Go for it. Dopamine cell bodies originate deep deep in the primitive parts of the brain. Some are in a region called the substantia negra and they project their axons up to the strriatam that is the nigro streratal pathway which is heavily involved in movement. >> Right? And then you have another cluster of dopamine neurons right next door in the vententral tegmental area the VTA.

18:32 These neurons project their axons outward in two different directions. One pathway projects up to the highly evolved cerebral cortex. We called that the messocortical pathway. >> Meso for midbrain, cortical for cortex. >> Exactly. The other pathway projects from the VTA into the ancient emotional centers, the limbic structures like the amydala and hippocampus. We call that the messolyic pathway. >> Keeping those pathways separated in your mind is absolutely essential for understanding what scientists call the dual dopamine hypothesis because historically the explanation for schizophrenia was simple. You have too much dopamine in your brain. Take a drug to block it. But that is wildly inaccurate, isn't it? >> It is much, much more nuanced. And as a student, you might look at this and immediately hit a wall of confusion. How can a single brain have too much and too

19:19 little of the exact same neurotransmitter at the exact same time? >> Right? Sounds like a paradox. How does that happen? >> It comes down to geography and those distinct pathways we just mapped out. The current modern view, the dual dopamine hypothesis, is that in the messortical pathway, the one projecting up to the prefrontal cortex, there is actually reduced dopamineergic transmission. The cortex is starving for dopamine. >> And because dopamine is involved in motivation and reward, a starving cortex leads to what? >> A hypodamineergic state in the cortex drives the negative symptoms and cognitive alterations. The apathy, the flat effect, the inability to plan for the future. The cortex just doesn't have the chemical fuel it needs. >> Hypo in the cortex equals negative symptoms. >> Got it. But simultaneously in the

20:05 mesolyic pathway, the one innervating the temporal lobe structures like the hippocampus and the emotion-driven amydala, there is a hyperdocamineric secretion. It is flooded with too much dopamine. And this excess, this chemical flooding of the emotional centers is what generates the positive symptoms. The positive symptoms being the things added to reality, the auditory hallucinations, the intense paranoia, the bizarre delusions, the emotional center is overheated and generating false signals. >> Precisely. You have a drought in the cortex and a flood in the lyic system simultaneously. And to add one more layer of complexity, researchers now realize dopamine isn't acting alone. The glutamate hypothesis has entered the picture. >> Glutamate is the brain's primary excitatory neurotransmitter. It turns

20:52 things on, >> right? Specifically, it acts on NMDA receptors. The current evidence suggests that underactivation of these NMDA receptors plays a major role in the pathophysiology of schizophrenia. In fact, we think this glutamate dysfunction might actually be situated upstream of the dopamine imbalances, meaning the failure of glutamate to properly activate its receptors might be the very thing causing the dopamine pathways to go haywire in the first place. >> Wow. This is why the pathophysiology is so complex. It's a cascading failure. Okay, let's tie this microscopic biology back to the macroscopic patient sitting in the examination room. We need to define the clinical manifestations clearly. We group them into positive, negative, and cognitive symptoms. >> Let's start with positive symptoms. Again, positive doesn't mean good. It

21:39 means symptoms that are added to normal behavior. A person experiencing a psychotic episode loses touch with reality. This manifests as auditory hallucinations, hearing voices that aren't there, which are far more common than visual hallucinations. It includes paranoid delusions, which are fixed, false beliefs like thinking the government has planted a chip in their brain. >> You also see disorganized speech. The text describes it as jumping erratically from topic to topic, which clinicians sometimes call word salad, and bizarre aimless behavior. >> Then you have the negative dimensions. These reflect a deficit, a subtraction from normal functioning. And these are often the most debilitating for long-term independence. They include effective flattening, a near total absence of emotional expression or facial movement. The patients face looks

22:25 like a mask. Anhidonia, the complete inability to experience pleasure from activities they used to love. Aloia poverty of speech where they might only give one-word answers and never initiate conversation. And avalition, a profound deficit in spontaneous goal-directed behavior. They might sit in a chair for 10 hours doing nothing. Not because they are tired, but because the neural drive to act is gone. >> So how do we intervene? What is the pharmarmacology? First generation antiscychotic medications, the older ones developed decades ago like haloparidol or chloropromisine are essentially pure D2 receptor blockers. They find the D2 dopamine receptors and they jam them shut preventing dopamine from binding. >> And because they aggressively block dopamine, they are very effective at reducing that flood in the messylic pathway. They reduce the hallucinations.

23:11 But remember our dual dopamine hypothesis, the cortex is already starving for dopamine. If you give a drug that blocks dopamine everywhere, you make the negative symptoms worse. Furthermore, dopamine is deeply involved in motor control in the basil ganglia, >> which leads to the horrific neurologic side effects of those older drugs, things like Parkinson-like tremors, rigidity, and the dreaded tardi disynesia. Yes, tardio of diskynesia is characterized by involuntary repetitive enalic-l like body movements especially of the face, lips and tongue. It occurs in about 7% of individuals taking these older drugs and tragically it is often permanent even after you stop the medication. The receptor blockade actually causes the neurons to permanently alter their firing patterns. >> To combat this, science developed second

23:57 generation atypical antiscychotics drugs like clausipene, resperadone and alanzipene. How are they physiologically different from the first generation? >> Atypical antiscychotics have a much broader mechanism of action. While they still block D2 receptors, they have a lower binding affinity for them. They don't lock on quite as aggressively. But more importantly, they simultaneously block a wide array of other receptors, specifically serotonin, the 5HT2 receptors, as well as neuropenaphrine, colonurgic, and histamine receptors. >> Wait, why does blocking serotonin help a dopamine problem? Because serotonin pathways interact with and modulate dopamine pathways. This higher ratio of serotonin to dopamine blockade seems to help normalize those interactions, cooling off the mesolyic flood without completely starving the cortex or the

24:43 motor pathways. This significantly reduces those severe extrapinal neurologic side effects like tardi diskynesia that we saw with the older drugs. >> That sounds like a massive win, but they're not a magic bullet. And as a clinician, you absolutely must be vigilant about their side effects. You might not see the tremors, but the metabolic consequences are severe, >> very severe. Long-term use of atypical antiscychotics like clausipene or lanzipene drastically alters the body's peripheral metabolism. They disrupt the regulation of glucose and lipid levels. Patients experience intense rapid weight gain, insulin resistance, and dysipidemia. This creates a cascading metabolic syndrome that leads to a very high risk for type 2 diabetes and cardiovascular disease. You are essentially trading a neurologic risk

25:29 for an endocrine and cardiovascular risk. >> And there is one highly specific highly lethal risk associated with cloopene that every board exam will test you on a granuloccytosis. >> Yes, cloopene can induce a potentially lethal blood disorder where the bone marrow simply stops producing white blood cells specifically neutrfils. Without white blood cells, the patients immune system is completely compromised, leaving them vulnerable to fatal infections. >> Which means you cannot just write a prescription for Clausipine and say, "See you in six months." These patients require rigorous, mandatory, ongoing blood draws to monitor their absolute neutrfill count. It is a physiological tightroppe walk. >> It perfectly illustrates why we must view these not as mental disorders, but as complex, multi-yic physical illnesses.

26:15 >> Absolutely. So we just saw how structural loss, genetic vulnerability and neurochemical imbalances in the lyic system, the amydala and hippocampus drive schizophrenia. Nope. Now I want to seamlessly transition to how those exact same brain structures react to a different kind of environmental hammer. Let's look at how the lyic system reacts to chronic unrelenting stress which leads us to mood disorders, depression and bipolar disorder. >> That is a seamless biological transition. We are still looking at the exact same real estate in the brain, the emotional processing centers, but we are observing a fundamentally different pathological cascade. >> Let's ground this in reality with some statistics. Unipolar depression, also known as major depressive disorder, is staggeringly common. It affects roughly 16.2% of the US population over their

27:01 lifetime. Interestingly, there is a stark sex difference. Women have a two-fold greater risk of developing major depression than men, particularly after adolescence. Bipolar disorder, which involves swings between depression and mania, affects about 3 to 5% of the population. >> And we need to reiterate the systemic physical impact here. Loved untreated mood disorders are not just periods of prolonged sadness. The constant physiological stress state they induce leads directly to severe medical illnesses, increased rates of cardiovascular disease, obesity, diabetes, and overall increased mortality. >> Because again, the brain and the body are connected. Just like schizophrenia, we see a heavy genetic blueprint. If we look at those monosygotic identical twins, the concordance rate for bipolar disorder is incredibly high, up to 62%.

27:46 And it's also roughly 62% for unipolar depression. The genetic vulnerability is profound. But what is truly fascinating for researchers is how these genetic architectures overlap across different diagnostic labels. >> Oh, this is the part that blew my mind. The research shows that specific genetic lossi on chromosomes 18 and 22 have been linked to both bipolar disorder and schizophrenia. They share the same faulty blueprints. In fact, individuals with bipolar disorder who exhibit psychotic features like delusions during a manic episode show deficits in real expression linked to chromosome 22. >> Realin the exact same extracellular matrix protein we just spent 20 minutes discussing in relation to schizophrenia's neuronal migration. >> Exactly. It completely shatters the idea

28:31 that these are distinct walled off diseases. It's not one gene equals one disease. It is a shared vulnerability in the brain's construction that manifests differently depending on other factors. But still, a 62% concordance rate means 38% of the time the identical twin doesn't get it. The environment is pulling the trigger. >> Right? Which brings us to the neurochemical and neuroendocrine dysregulation that actually causes the brain to spiral into depression. To understand modern pharmarmacology, we have to trace the history. It all started with a monoamine hypothesis. Monoamines being neurotransmitters like serotonin, noropine and dopamine. >> Right? Decades ago, clinicians made a fascinating observation. They noticed that certain drugs designed for other illnesses which happened to increase norepinephrine levels in the brain

29:17 dramatically elevated a patient's mood. Conversely, drugs that depleted monomine stores cause severe depression. >> So, deductive reasoning led to a simple theory. A deficit in norepinephrine, dopamine or serotonin causes depression and an excess of these chemicals causes the hyperaroused state of mania. >> That monoamine hypothesis was the dominant framework for decades. And to be fair, it is the fundamental mechanism behind almost every major class of anti-depressant we use today. MAIs or monoamine oxidase inhibitors work by physically blocking the enzyme that chews up and degrades neurotransmitters in the suns leaving more of them floating around. Tricyclic anti-depressants SSRIs selective serotonin reuptake inhibitors, and SNRIs all target the reuptake transporters. I

30:05 want to make sure you, the listener, visualize this mechanism clearly. Imagine the syninnapse, the gap between two neurons. Neuron A releases serotonin into the gap to send a signal to neuron B. But neuron A also has these little vacuums on its surface re-uptake transporters that suck the serotonin back up to recycle it. And SSRI physically jams that vacuum. It plugs it up. Because the vacuum is broken, the serotonin lingers in the gap much longer, continuously knocking on neuron B's receptors, creating a stronger sustained signal. >> That is an excellent mechanical description. And for a long time, we thought, great, we fix the chemical imbalance. We cured the depression, but there was a massive glaring hole in this theory. >> The timeline, >> yes, >> when a patient takes an SSRI, that vacuum is jammed within hours. The serotonin levels spike almost immediately, but the patients mood

30:51 doesn't improve for three, four, or sometimes 6 weeks. If it was just a simple chemical deficit, they should feel better by Tuesday. But they don't. Why the delay? >> That crucial timeline discrepancy forced researchers to look deeper. The low serotonin isn't the whole story. It is just a symptom of a much larger systemic breakdown. This pushes us beyond simple neurochemistry and into neuroendocrine dysregulation. Specifically looking at the HPA axis, >> the hypothalamic pituitary adrenal system. This is your body's primary stress response mechanism. >> Let's trace the cascade. When you perceive a threat, say a predator, your brain's hypothalamus secretes corticotropen releasing hormone or CR that travels a tiny distance to the pituitary gland, which then secretes adreninocorticotropic hormone act into

31:38 your bloodstream. That travels down to your adrenal glands sitting on your kidneys, which pump out glucocorticoids, primarily cortisol. Cortisol floods the body, mobilizes glucose for energy, increases heart rate, and focuses your attention to survive the threat. That is a brilliant life-saving evolutionary adaptation if you are running from a bear. >> But it is designed to be acute. It is meant to turn on, save your life, and turn off. What happens when the threat isn't a bear, but chronic uncontrollable psychosocial stress, poverty, abuse, intense academic pressure, trauma? The stress system gets stuck in the on position. The HPA axis never downregulates. >> And the data supports this completely. Research shows that 30% to 70% of people with major depression have chronically elevated glucocorticoid and cortisol

32:26 levels. Their brain thinks they have been running from a bear for 5 years. >> And what does running an engine at the absolute red line for years do? It melts the engine. Chronic exposure to high levels of cortisol is explicitly toxic to brain cells, particularly in the hippocampus. But wait, it gets even more complex because stress doesn't just produce cortisol. Psychosocial stress actively triggers the body's immune system. It causes severe inflammation. >> This is a monumental shift in how we understand psychiatric illness. Chronic stress increases the secretion of pro-inflammatory cytoines immune signaling molecules like interlucan 1 alpha, IL1 beta, TNF alpha, and IL6. If you take blood from a severely depressed patient, you will often find elevated C reactive protein or CRP, which is a

33:11 systemic marker of inflammation. The body is literally inflamed by psychological stress. >> And those inflammatory cytoines cross the bloodb brain barrier and wreak havoc. They actively interfere with serotonin metabolism and further damage neural circuitry. But within this dark cloud of inflammation, there's a fascinating, almost miraculous cellular defense mechanism that researchers uncovered involving omega-3 fatty acids. Ah, the lipid mediator study. This is incredible science. >> I love reading this part of the pathophysiology. We know omega-3s are good for brain health, but here is the actual mechanism. Omega-3 polyunsaturated fatty acids, specifically EPA and DHA, are metabolized by the body into these specialized lipid mediators. Researchers took human hippocample stem cells in a petri dish and exposed them to those

33:57 toxic pro-inflammatory cytoines like IL1 and TNF alpha. Normally those cells would undergo apoptosis, they would wither and die, right? >> But when they pre-treated the cells with EPA or DHA before dumping the toxic cytoines on them, the cells lived. The lipid mediators acted like a physical biochemical shield, preventing cell death and allowing neurogenesis to continue despite the inflammatory attack. >> It is a profound demonstration of how nutrition alters cellular resilience. And this translates clinically. Depressed patients who were administered high therapeutic doses of EPA or DHA showed significantly higher levels of these protective plasma lipid metabolites and a corresponding decrease in the severity of their depressive symptoms. Now, a quick caveat for the listener. The data specifies these are high therapeutic doses usually achieved

34:43 via concentrated supplements. Far higher than what you'd typically absorb just by eating a salmon fillet once a week. >> Right? It's a pharmacological intervention using a natural molecule. >> So, let's summarize the damage. We have low monoamines. We have a hyperactive HPA axis pumping out toxic cortisol. And we have a firestorm of inflammatory cytoines. How does this triple threat physically alter the structure of the brain? This leads us to the most current comprehensive model of depression, the neurotrophic hypothesis. >> If we connect all these pieces, think about what this toxic soup does to a neuron. Animal models subjected to chronic stress and human postmortem studies show that this environment leads to the actual physical atrophy of neurons in the hippocampus.

35:28 >> The hippocampus which is critical for learning, memory, and emotional regulation. >> Yes, the dendrites, the branching arms of the neuron that reach out to communicate with neighbors literally retract and wither. Furthermore, there is a severe deficit in a protein called BDNF, brain derived neurotrophic factor. >> I want to use a specific metaphor here. We often call BDNF fertilizer for the brain, but it's more structural than that. Think of BDNF as the architectural scaffolding that allows a neuron to build and maintain those long reaching branches. Without that scaffolding, the branches just collapse. >> That is an excellent visual. BDNF supports the survival of existing neurons and it is absolutely essential for neurogenesis, the birth of brand new neurons from stem cells in the hippocampus. In severe depression,

36:15 hippocample BDNF levels plummet, neurogenesis grinds to a halt, the branching connections disintegrate, and the hippocampus physically shrinks in volume. And here is the grand aha moment that solves the mystery of the SSRI timeline. We asked earlier why it takes weeks for an antepressant to work if the serotonin increases on day one. >> Because treating depression isn't just about floating more serotonin in the gap. When the SSRI jams the re-uptake vacuum and serotonin pools in the syninnapse, that sustained serotonin signal slowly over days and weeks travels down into the nucleus of the receiving cell and alters its gene expression. It tells the DNA to start manufacturing more BDNF. >> The drug turns the scaffolding factory back on. >> Exactly. And it takes weeks for the cell to manufacture the BDNF, for the

37:01 architectural scaffolding to be shipped out, for the dendrites to physically regrow their branches, and for new neurons to be born and integrate into the circuit. The timeline delay is the time it takes for the brain to physically rebuild the bridge that stress burned down. Anti-depressants literally regrow the neural circuitry. >> That is a staggering realization. The neurotrophic hypothesis encompasses the monoamine hypothesis but expands it showing that the chemical deficit is just the precursor to structural collapse. >> Now as a clinician before you diagnose psychiatric depression you must rule out physiological mimics. The text specifically highlights the thyroid gland. >> Right? The endocrine system can masquerade as a psychiatric illness. Severe hypothyroidism meaning your

37:46 thyroid isn't producing enough hormone causes a massive slowing of your basil metabolic rate. Clinically, this perfectly mimics the features of major depression, profound apathy, psychoot slowing, fatigue, and even cognitive dementia. >> Conversely, hyperyroidism, too much thyroid hormone, mimics the hyperarousal of anxiety, mania, and irritability. However, it is important to note that if you run a blood panel on a patient with primary psychiatric major depression, their thyroid function is usually completely normal. But a TSH thyroid stimulating hormone test must always be on your initial differential diagnosis radar to avoid misdiagnosing an endocrine disorder as a psychiatric one. >> Absolutely. Okay. Let's touch briefly on neuro anatomy again before we get to treatments. The rafé nuclei. These are

38:32 tiny clusters of neurons located deep in the brain stem. But they are the master hub for serotonin production. They synthesize it and send long projection wires everywhere in the brain, including the cortex and hippocampus. Post-mortem imaging of patients with severe depression shows a widespread decrease in serotonin. 5 HT1A receptors and serotonin transporters originating from the dorsal and median raf nuclei. The fundamental hardware system that modulates emotional homeostasis is degraded at its root source in the brain stem. >> Which brings us to the clinical manifestations. How does a patient present? Major depression is characterized by a dysphoric mood, an unremitting feeling of sadness and heavy despair. This is accompanied by severe insomnia or hyperomnia, sleeping too much and anidonidonia, significant weight changes due to loss of appetite

39:18 and profound fatigue. >> Bipolar disorder, on the other hand, swings violently into episodes of mania. >> Mania isn't just being happy. It is a dangerous state of hyperarousal. It is defined by highly inflated self-esteem or grandiosity and aggressively decreased need for sleep. A patient might sleep one hour a night for a week and feel fully energized. They exhibit excessive rapidfire talking, racing thoughts they can't control, and a severe increase in highly risky goal-directed activities like spending life savings or engaging in reckless behaviors. >> So, how are we treating these patients today? We already explored the mechanism of the standard anti-depressants, MAIS, TCAs, SSRIs, and SNRIs. All working to ultimately boost BDNF and regrow synapses. >> But as we noted, those take weeks. And what happens when a patient is acutely

40:05 suicidal right now? Or what if they have treatment resistant depression and the SSRIs just don't work? This is where modern pharmarmacology has introduced an absolute gamecher. Ketamine and its derivative eskeetamine. >> This represents a major paradigm shift in psychiatric treatment. Ketamine does not work on serotonin. It is an NMDA receptor antagonist, meaning it directly blocks glutamate receptors. >> The exact same receptors we discussed being dysfunctional in schizophrenia. >> Yes. Esetamine, which was recently approved as a nasal spray, induces incredibly rapid anti-depressant effects. We are talking about significantly reducing depressive and suicidal symptoms within hours, not weeks. >> How does it rebuild the bridge so fast? >> By blocking the NMDA receptor, it triggers a massive rapid surge in

40:50 glutamate signaling in other pathways, which instantly forces the rapid translation of BDNF and immediately increases synaptic density in cortical neurons. It is like bypass surgery for the brain's emotional circuitry. >> And researchers are pushing the envelope of cellular engineering even further. The text mentions a fascinating experimental approach administering a drug called rapamy prior to the ketamine infusion. Now rapamy is traditionally an amunosuppressant used to prevent organ rejection. Why on earth give it for depression? Because rapamy interacts with the cellular machinery that builds proteins while ketamine causes a rapid burst of new synaptic connections, those connections can sometimes fade quickly. Researchers discovered that tree treating with rapamy seems to alter the

41:35 inflammatory and metabolic environment in a way that protects and preserves those newly formed synapses, significantly prolonging the anti-depressant effects of the ketamine. It is a breathtaking manipulation of cellular biology. >> It truly is. Now for bipolar disorder, the treatments shift. You generally cannot give a bipolar patient an SSRI alone because boosting those monomines can accidentally trigger a manic episode. The standard of care relies on mood stabilizers like lithium which alters intracellular signaling to stabilize firing anti-convulsants or the atypical antiscychotics we mentioned earlier. Sometimes complex combinations are required >> and this brings up a critical pediatric coralate that clinicians must be aware of. Diagnosing psychiatric illness in children is fraught with danger. In the

42:22 DSM5, a new diagnostic category was added, disruptive mood dysregulation disorder or DMD. >> This applies to children usually aged 6 to 10 who exhibit severe chronic irritability and frequent extreme temper outbursts. Now, to the untrained eye, a kid who is manic, irritable, and can't sit still looks a lot like a kid with bipolar disorder or a kid with severe ADHD, >> which raises an incredibly important clinical safety point. Why create this entirely new category of DMD to prevent catastrophic misdiagnosis? >> Walk us through the danger there. If you look at an irritable, hyperactive child and mistakenly diagnose them with ADHD when they actually have an underlying bipolarike pathophysiology, what is the standard treatment for ADHD?

43:07 Central nervous system stimulants like rolin or aderall. >> You are throwing gasoline on a fire. >> Exactly. If you give a stimulant to a child with an underlying bipolar spectrum disorder, you will rapidly and violently exacerbate their manic symptoms, potentially triggering a full psychotic break. The DMD diagnosis gives clinicians a specific category that allows them to pause, acknowledge the severe mood dysregulation, and treat the irritability without immediately reaching for strong, potentially harmful medications meant for distinct disorders is a safeguard. >> That is a crucial distinction for the boards and for real life clinical practice. Finally, as we wrap up, mood disorders, the text features a wonderful section on resilience [snorts] because treating depression isn't just about handing out an SSRI or a ketamine spray.

43:52 True resilience involves a comprehensive multi-pronged approach to the risk factors. >> It requires cognitive behavioral therapy to build psychological coping mechanisms and self-efficacy. But it also explicitly includes improving diet like those omega-3s enforcing rigorous exercise and prioritizing sleep hygiene to build physical biological resilience against inflammation. It also necessitates building diverse social support networks. True resilience acknowledges that the biological, the emotional, and the social environments are deeply, inextricably intertwined. >> You cannot heal the hardware if the environment keeps smashing you with a hammer. All right, [snorts] take a breath. We are transitioning into part three, anxiety disorders. And to bridge the biological gap, my question for you is, we just spent all this time talking

44:38 about how the brain breaks down under chronic unavoidable stress, depression pathway. But what happens when that stress response, the acute fightor-flight system that kept our ancestors from being eaten by a lions, simply refuses to shut off? >> That is the core pathophysiology of an anxiety disorder. Fear and physiological arousal are necessary for survival. But when that fear response becomes chronic, exaggerated, and completely uncontrollable in the absence of a true threat, it undermines daily function. And these are not rare. They are the most prevalent psychiatric illnesses affecting 10 to 30% of the general population. >> And as we step into this, we immediately see a massive diagnostic comorbidity with the depression we just discussed. Many patients have both. Why? Because they share overlapping genetic risk

45:24 factors. The text highlights a massive genomewide association study of nearly 200,000 participants that definitively prove this shared genetic architecture. Two specific genes are mentioned that beautifully illustrate the mechanism. The first is SATB1. >> SATB1 is a gene that modulates the expression of the corticopen releasing hormone or CR gene. >> CR, we just talked about that. That is the very first hormone released by the hypothalamus to kick off the HPA axis stress response. >> Exactly. If you have a mutation in SATB1, your brain might produce more CR or produce it more readily. A hyperactive CR system means a hyperactive HPA axis which leads to a constant state of emotional fear and physiological arousal. The hardware is overly sensitive to stress. >> And the second gene is ESR1 which encodes for estrogen receptors. This is

46:10 absolutely vital because it begins to biologically explain the sex differences we see in clinical practice. Stress related anxiety disorders are far more prevalent in females. The modulation of estrogen pathways is directly tied to how the brain processes fear and anxiety. Let's break down the specific disorders because while they share a root of fear, the mechanisms differ. Let's start with panic disorder or PD. This is not just feeling stressed out about an exam. This is a terrifying spontaneous intense autonomic arousal. >> The patient experiences sudden heart racing, shortness of breath, chest pain, dizziness, and a profound, overwhelming feeling of impending doom. It mimics a heart attack so closely that many patients first present to the emergency room terrify they're dying. And behaviorally, it often leads to a severe

46:56 complication called agorophobia. Because the panic attacks are so random and terrifying, the person begins to avoid places where escape might be difficult, like crowded malls or subways, sometimes becoming completely housebound. >> Genetically, there's a strong familial link. First-degree relatives have a 20% increased risk, and researchers have pointed to the CCK colaine receptor gene on chromosome 11P as a heavily linked factor in panic disorder. But the actual physiological trigger of a panic attack is wild. This is where the textbook blew my mind. Talks about panicens. These are actual chemical substances that if administered to a susceptible individual will reliably elicit a full-blown physical panic attack. We are talking about chemicals like carbon dioxide, heavy doses of caffeine, CCK, or sodium lactate. How on earth does a chemical

47:42 infusion trigger a purely psychological feeling of panic? >> Because the feeling isn't purely psychological. It is a downstream effect of an evolutionary survival mechanism. It comes down to acid base balance and pH. Carbon dioxide and sodium lactate both subtly alter the pH balance of the blood and the brain. >> They make it slightly more acidic. >> Right now, humans have evolved highly sensitive pH cheoensors located in the brain stem, the hypothalamus, and particularly the amygdala. Why? Because a drop in pH usually means you are suffocating. CO2 is building up in your blood. It is the body's ultimate alarm system. >> Okay, let's visualize the neural network here. If we look at the lyic system, we have interconnected structures. The factory bulb, the forex, the singular cortex, the phalamus, the mammalary

48:29 body, the hippocampus, and the amydala. They all talk to each other. >> In a panic-p prone individual, those evolutionary pH sensors in the amydala are hyper sensitive. They are like a smoke detector that goes off when you take a hot shower. When they detect even a microscopic normal fluctuation in brain pH, they falsely signal an immediate life-threatening danger. We are suffocating. And because it's the amigula, it immediately recruits the cerebral cortex to generate the psychological terror. And it slams the brain stem into overdrive to generate massive sympathetic physiological arousal, heart rate spikes, hyperventilation. It is a literal chemical false alarm of the highest magnitude. >> Furthermore, panic disorder also involves a failure in the brain's braking system, specifically a reduction in gabenzoipene

49:15 or BZ receptors. GABA. Gamma amidic acid is your brain's primary inhibitory neurotransmitter. It is the chemical brake pedal. If glutamate is the gas, GABA is the brakes. >> If you have fewer receptors for GABA, your braking system is fundamentally failing. Once the panic alarm sounds, the brain cannot biologically calm itself down, which perfectly explains the pharmacological treatments. Cognitive behavioral therapy helps the cortex rationalize the false alarm while SSRIs attempt to rebuild the baseline circuitry. But in an acute attack, we use benzoazipines as an adjunct therapy. Benzoazipines forcefully bind to those GABA receptors and slam on the chemical brakes, halting the autonomic storm. >> That mechanism makes total sense. Now, let's contrast the random explosions of panic with social anxiety disorder or

50:01 SAD. This typically emerges in adolescence and involve an intense paralyzing fear of social evaluation, scrutiny, and rejection. It's not a fear of suffocating. It's a fear of the tribe turning against you. >> And neuroiming shows exactly where this fear lives. Abnormal hyperactive connections between the prefrontal cortex and the amydala during social situations. The amydala perceives the social gaze as a mortal threat and the prefrontal cortex fails to rationalize it. >> But the key molecule the text highlights here is oxytocin or o. In pop science, we always call oxytocin the cuddle hormone because it's released during childirth and bonding, >> which is a bit reductive, but conceptually close. Oxytocin is a neuropeptide that deeply promotes pro-social behavior, empathy, and

50:47 interpersonal trust. It physically dampens the amydala's fear response when we are around other humans. >> But in individuals with social anxiety disorder, oxytocin secretion is significantly reduced. Furthermore, researchers have identified a specific single nucleotide polymorphism, a tiny genetic mutation in an oxytocin receptor gene that is highly altered in SAD. The biological hardware meant to generate trust and bond with a social group is physiologically impaired. The brain literally lacks the chemical signal to feel safe around others. Which is why treatments here lean heavily on SSRIs and SNRIs to modulate the broader emotional tone combined with specific cognitive therapies to practice and rebuild those social neural pathways. >> Okay, let's look at the third variation. Generalized anxiety disorder or GAD.

51:34 While panic is a sudden autonomic explosion and social anxiety is triggered by specific social evaluations, GAD is a relentless excessive persistent worry about everyday mundane life events. It is a constant low-grade hum of terror about marital relationships, money or health. >> Pathophysiologically, GAD shares similarities with the others. We see abnormalities in the norepinephrine and serotonin systems such as a reduction in alpha 2 adrenergic receptor binding. We also see that reduction in benzipene binding specifically localized to the left temporal hemisphere. The breaks are worn thin. But the most striking visual evidence comes from fMRI studies looking at anticipatory anxiety. The text describes an experiment where they hook adults with GAD up to a brain scanner

52:20 and induce anticipatory anxiety. Essentially, they just ask the patient to think about something bad happening in the future. >> And when they do, the functional imaging shows activity in the singulate cortex spiking abnormally high. The singulate cortex is heavily involved in emotional regulation and anticipating consequences. In GED, it is hyperactive, constantly simulating disastrous future scenarios. >> And importantly, treating these patients with an SNRI like them vaccine for 8 weeks doesn't just make them feel better. The brain imaging proves that the medication actually physically reduces that pathophysiologic singulate cortex activity. The drug is calming the specific hyperactive neural circuit. >> We see evidence of this overtuned threat detection system even in children. In pediatric studies, if you briefly show children with JD mask, angry faces,

53:08 faces flash so fast they barely register consciously, their brain imaging shows a massive heightened activation in the right amydala compared to healthy children. Their radar for threat is turned all the way up, scanning for danger constantly, >> which is a perfect logical bridge to our next topic. Because what happens when that radar doesn't just detect a hypothetical threat, but is shattered by a very real horrific event? This leads us into post-traumatic stress disorder or PTSD. >> While generalized anxiety is an ongoing anticipation of hypothetical everyday threats, PTSD is the deep neurological echo of a specific actual life-threatening trauma. >> It affects roughly 7 to 8% of the population. We frequently see it in combat veterans who are statistically mostly men and assault or rape victims

53:53 who are mostly women as well as children who have suffered severe abuse. The text describes the core pathophysiology of PTSD as a profound dysfunction in the emotional fear memory system. The trauma is so severe that it induces permanent structural and functional alterations in the three key areas we've been talking about all hour. The amygdala, the prefrontal cortex, and the hippocampus. >> Walk through how that loop malfunctions. >> Normally, when you experience something scary, the amydala records the emotional weight. The hippocampus records the contextual memory where and when it happened and later the prefrontal cortex uses logic to say that happened in the past you are safe now. This is called extinction learning. The fear extinguishes. >> But in PTSD extinction learning completely fails.

54:39 >> Exactly. The memory is seared into the hyperreactive amydala. The hippocampus constantly retrieves the memory throwing it back into conscious awareness as an intrusive flashback. and the prefrontal cortex which is physically showing reduced volume and function completely fails to inhibit or contextualize the fear. The brain believes the trauma is happening right now over and over again. >> It is a devastating neurological loop. Treatment typically involves specialized trauma psychotherapy like EMDR or exposure therapy to try and force the prefrontal cortex to rebuild those extinction pathways supported pharmacologically by SSRIs to lower the overall baseline of anxiety. However, the text brings up a very recent, highly encouraging development that circles right back to our depression discussion. >> A sketamine, the rapid acting nasal

55:25 spray. A recent randomized controlled trial showed that repeated ketamine or esetamine administration rapidly alleviated chronic severe PTSD symptoms, the intrusive thoughts, the behavioral avoidance, the negative mood, often within 24 hours. >> The mechanism is likely similar. The same acute glutamate receptor blockade that regrows synapses in severe depression seems to aggressively disrupt the entrenched traumatic fear loop in PTSD, allowing the brain a sudden window of neuroplasticity to escape the memory. It is an incredibly promising frontier for treatment resistant trauma. >> All right, we have arrived at our final clinical destination. We are looking at obsessivempulsive disorder or OCD. We end our deep dive with a condition where anxiety doesn't just cause worry, but actually drives the physical mind into

56:11 an endless mechanical loop of irrational obsessions and ritualized physical acts. >> Oshidi has a lifetime prevalence of roughly 2 to 3%. It is intensely timeconuming. The rituals can take hours every single day and it is profoundly debilitating to normal life function and it has a highly unique set of coorbidities. We frequently see OCD co-cur with Tourette's syndrome, oppositional defiant disorder, ADHD, and severe depression. >> The genetic link to Tourette's syndrome is particularly fascinating. The text points out that first-degree relatives of adults with OCD have a 4.6% risk of developing Tourette's compared to only a 1% risk in the general population. Tourette's is characterized by physical motor ticks. The fact that OCD and Tourette's run in the same families suggests they share common polygenetic

56:58 risk factors and a very similar underlying pathophysiology. >> And that pathophysiology is localized to a very specific deeply entrenched brain circuit. For the students listening, you should memorize this loop because it beautifully illustrates how thought becomes action. The circuit involves the anterior phalamus, the orbrontal cortex, the dorsal anterior singulate cortex,

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