ADHD: Behind the Scenes

Most people hear the word ADHD and picture one thing. A kid who can't sit still. That picture is true, bu it's also about a tenth of what this condition actually is.

This episode goes into the neurobiology, what's actually happening in the brain when someone has ADHD. The chemistry, the structures, the networks, and what the research says we can do about it. We're working from Santos da Silva, Grevet, Fagundes Silva, Neves Ramos, Rovaris, and Bau — An Overview on Neurobiology and Therapeutics of Attention-Deficit/Hyperactivity Disorder — published in Discover Mental Health in 2023. And if you were here for Episode 7, you know the booth. We're going back in.

This episode covers: what ADHD actually is and why heterogeneity matters more than almost anything else, the genetics and why seventy to eighty percent heritability changes how you see this condition, the five neurotransmitter systems involved, the brain structure differences and what the imaging research really says, the Default Mode Network model, the clearest way to understand what attention lapses actually feel like from the inside, and a full breakdown of the treatment evidence, including how stimulants work and what the alternatives are.

For anyone who has spent years being told to just try harder. And for anyone who loves someone who has.

Transcript

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You know that feeling when you sit down to do something, you know you need to do it. You actually want to do it, but your brain just won't stay there. Not because you're tired, not because you don't care. It's something about the way the signals transfer from I should start this to actually starting it just isn't the same as it is for other people. Or the opposite. You find something that genuinely interests you, and suddenly two hours have gone by and you haven't moved. Both of these things are the same condition, the same brain running differently. And today we're going into why. What's actually happening in the brain when someone has ADHD, the systems involved, the structures, the chemistry, and what the research says about it. Published in Discover Mental Health in 2023. So let's start from the beginning because I think a lot of people hear the word ADHD and picture one specific thing. A child who can't sit still. And that picture is true, but it's about a tenth of what the actual condition is. Attention deficit, hyperactivity disorder is defined by symptoms of inattention andor hyperactivity and impulsivity that are developmentally inappropriate, meaning they're more intense and more impairing than what you'd expect from someone's age. And they create real issues in school, at work, in relationships, across different areas of life, not just one. Worldwide, ADHD affects around 5 to 7% of children and adolescents and about 2.5% of adults. One of the highest prevalence rates of any neurodevelopmental disorder. We're not talking about something rare or a small number here. And in order to get a diagnosis under the DSM 5, a person needs at least 6 out of 9 symptoms. Five for adults for a minimum of six months. They have to show up in more than one setting: home and school, work and relationships, not just one. And they have to cause actual impairment, not just a presence. There are three presentations: predominantly inattentive, predominantly hyperactive, and combined, where both are present. But here's the part I really want you to hold on to because this is where most conversations about ADHD go wrong. ADHD is highly heterogeneous, and I've used this word before in episode one on autism. It applies here just as much. Heterogeneous means it doesn't look the same in every person, not even close. There are people with ADHD who can't finish a sentence and people with ADHD who run companies. There are children who cannot sit still for five minutes and adults who spend their entire school career being called lazy because their symptoms were inattentive, quiet, invisible, just drifting internally in a way nobody could see. More than 60% of people with ADHD have at least one other psychiatric condition alongside it. Depression, anxiety, conduct disorder, autism spectrum disorder, and a comorbidity picture shifts with age. In children, you tend to see more externalizing disorders. For example, the ones that look disruptive from the outside. In adults, the picture moves a little towards mood disorders, anxiety, substance use, personality disorders. One more thing worth knowing is at least 20% of adult ADHD cases may be late onset, which means that it appears in adolescence or young adulthood with no childhood diagnosis. Research on ADHD is challenging the idea that ADHD is strictly a childhood condition. And honestly, that matters because it means a lot of adults have spent decades looking for language that explains their experience, but they were never able to find it. Before we get into the neuroscience, I want to talk about where all of this comes from. Because the genetic contribution of ADHD is one of the most important and honestly one of the most misunderstood parts of this whole conversation. ADHD has a heritability of 70 to 80%. That means genetics account for the majority of why ADHD runs in families. For context, the heritability of height is usually cited around 80%. ADHD is in that same range. This is not a small finding. It's one of the most replicated facts in psychiatric genetics. The family data is also interesting. If you have an identical twin with ADHD, your risk is 70 times higher than average. For non-identical twins and full siblings, around 8 times higher. Half siblings, two to three times. That gradient tells you something real about the biology of ADHD. Now, for a long time, researchers expected the big genetic study to confirm dopamine and norepinephrine as main factors in ADHD. But interestingly, that's not what happened. The largest ADHD genetic study to date found 27 loci associated with ADHD. And most of them involve genes related to neurodevelopmental and brain architecture, not specifically dopamine or norepinephrine. What this tells us is that ADHD isn't a one-pathway disorder. The genetic architecture is polygenic, which means it has many variations, each with a small effect. Around 7,000 common variants may explain 90% of the genetic variants. It's not one thing that's different, it's thousands of small adjustments throughout the whole structure and they all add up. And I think that's something that really changes your perspective about how you see this condition, because ADHD also shares a substantial genetic overlap with depression, bipolar disorder, schizophrenia, and even metabolic conditions like obesity and type 2 diabetes. These aren't separate things that happen to show up together by coincidence. In a lot of cases, the same genetic factors are contributing to multiple outcomes at once. Okay, so this is the section I've been building up to. And if you were here for episode seven, when we looked at Wender at all, the paper on adults with ADHD, you already have a framework for this, which was the cash booth. Now imagine you're standing inside a cash booth, the kind from like old game shows. You step in and then there's a wind machine that turns on and the cash starts flying everywhere and bills are swirling around the whole booth. And the goal is essentially to grab as much as you can before the time runs out. Now think of the cash in the cash booth as dopamine and the booth itself as your brain. Dopamine is something that's behind reward, motivation, attention, and the ability to sustain effort towards something. When the cash is moving at a pace that you can work with, you can grab it. You can stay with the task, feel the pull of a goal, the signal that just says this is worth continuing. That's dopamine doing its job. In a neurotypical brain, the booth runs at a workable pace. So the cash moves, you reach for it, you get it. Now, at the bottom of the booth, there's a vacuum. Its job is to clear the cash out after it's been released. To pull dopamine back out of the space between neurons once it's done what it needs to do. This vacuum is called the dopamine transporter or DAT. In people with ADHD, research shows a higher density of DAT, which means more transporters than average. So the vacuum is running harder, the cash gets pulled back down before you can even grab it. So essentially, what this means is the signal arrives, you reach for it, and it's gone before you can even catch it. And from the outside, this looks like someone who isn't motivated. But motivation was there, the vacuum just took it before you could do anything about it. Now that distinction matters because there's a real difference between someone who doesn't want to do something and someone whose brain isn't holding the signal that makes starting feel possible. Right next to the dopamine booth, there's a second one. This one runs norepinephrine, closely also related to dopamine, but its speciality is working memory, the ability to hold information in mind while actively using it. Also, alertness and arousal. So for people with ADHD, the norepinephrine transporter shows decreased availability to the networks most involved in sustained attention and executive function. Same problem. Second booth. Essentially, again, the cache gets cleared too fast, and so the signal doesn't hold. Now, here's something important about both systems. They don't just follow a simple more is better rule. They both follow an inverted U shape. Optimal functioning happens in the middle range. Too little activity and everything slows down. Too much, like during acute stress, and performance drops just as badly. So it's not about flooding the booth with cash. It's about getting to the right level, which is why medical treatment is complicated. And we'll get to that a little bit later in this episode. Dopamine and norepinephrine are two central systems, but they're also not the only ones involved. Think of these three as additional booths in the same building, each running a different chemical. Serotonin. Most people know serotonin from conversations about depression, but its role is much broader. It also affects sleep, appetite, mood, emotional regulation. Low serotonin levels have been associated with ADHD. And hyperactivity symptoms specifically have been correlated with serotonin levels in cerebrospinal fluid. It's not a simple relationship. More nuanced than just more serotonin fixes everything. And then there's glutamate, the brain's main excitatory neurotransmitter, the one that drives neurofiring forward. In people with ADHD, the glutamate booth is running super hot. Increased glutamate has been found in the frontal and striatal regions. In the interior cingulate cortex, which is the region that is involved in monitoring your own attention and catching errors, glutamate levels are elevated, which means there's too much cash flying around in a booth that's supposed to be keeping things organized. Then finally, we have GABA. If glutamate is the accelerator, GABA is the brake, the brain's main inhibitory signal. So GABA levels are reduced in the anterior cingulate, somatosensory, and motor corticals in people with ADHD. The brake booth is running low, which is what impulsivity looks like chemically. The difficulty stopping a response once it's already started. It's not a personality thing. The cash in the brake booth just isn't enough. So the full picture of the booth essentially looks like the dopamine booth clearing too fast, the norepinephrine booth not holding signals where it needs to, and the glutamate booth running too hot, the GABA booth running too low, and the serotonin booth contributing in ways we're still mapping. Five booths all connected, all affecting each other, and all of this is happening inside the same physical brain, which is what we're looking at next. So we've talked about the chemistry, now let's talk about the physical brain, well, essentially the structure. And I want to be clear about what this research is and isn't saying, because I think it gets misrepresented quite a bit. Large meta-analysis from the Enigma Consortium, which basically pools neuroimaging data across research groups globally, found that children with ADHD show smaller volumes in several subcortical brain regions, the nucleus accumbens, the amygdala, the caudate, the hippocampus, and the pudimen. They also show decreased cortical surface area, mainly in frontal, cingulate, and temporal regions. So if you've been here since episode one and two, you've heard these names before. The amygdala, the hippocampus, they came up in the ASD episodes, and they're here again. They're showing structural differences in children with ADHD compared to neurotypical children. Important caveat is that these differences are most clearly observed in children. When the analysis is restricted to adults, they're much less pronounced. That doesn't mean ADHD gets resolved. We already know for most people that it doesn't. It means that the brain keeps developing, it keeps changing, and that that's actually a more hopeful framework than a permanent structure deficit. There's also research on white matter, which is the connectivity infrastructure that links different brain regions to each other. The most consistent finding points to the frontostriadal circuitry, which are basically the connections between the prefrontal cortex and the striatum and the corpus callosum, which connects the two different hemispheres. Now, when these connections are different, the communication between the regions that need to coordinate is also affected. I also want to mention something from the functional MRI research, because I genuinely think it's the clearest way to understand what ADHD feels like from the inside. The brain has two large-scale networks that work in opposition. The first is called the default mode network, the DMN. This is what activates when you're not focused on a task, when you're daydreaming, thinking about yourself, mind wandering. The second is the task positive network, the TPN. This one activates when you're actually engaged with something, when you're focused and you're working. In a neurotypical brain, these two alternate. When the TPN turns on, the DMN stops. You focus, the daydreaming quiets down. In people with ADHD, that coordination is completely disrupted. The DMN doesn't quiet down the way it should when the TPN is supposed to be active. The daydreaming network keeps firing during tasks. So attention gets interrupted, not by something external, not by a distraction in the room, but by your own brain default network. So the mind wanders, not because you're not disciplined, but because the network that's supposed to step aside isn't necessarily stepping aside. And honestly, when I read that, I thought about how many people have spent years blaming themselves for something that has a neurobiological explanation. The brain isn't broken, it's just a room that stays open when it's supposed to be closed. There's also one more area I want to mention before we get into treatment, and I want to be upfront about this because it's more of an emerging part of today's paper. The gut brain axis is the bidirectional communication system about the gut microbiota, the trillions of bacteria in your digestive system and the nervous system. The gut microbiome influences the nervous system through neurotransmitter production, the vagus nerve, and the inflammation pathways. So what's happening in your gut isn't separate from what's happening in your brain. They're in constant conversation. Studies have found differences in microbiotic composition between people with ADHD and controls. Some involved in dopamine and GABA production are present in different abundances in ADHD. There's also an inflammation angle, a genus called, I think this is how you pronounce it, Fecalobacterium, which has anti-inflammatory properties, which is also decreased in people with ADHD and inversely related to ADHD severity. But here's where I want to be honest with you. The meta-analysis in this area are inconclusive, so the findings are inconsistent across studies, sample sizes are small, and the methodology varies quite a bit. The gut brain axis in ADHD is genuinely promising though. Okay, so we have the full picture of what's happening. The boots are miscalibrated, the brain structure shows real differences, and the networks aren't coordinating the way they're supposed to. So what can we do about it? There are two main categories for treatment, medicine or no medicine. And I want to be straightforward about what the research says. Psychosocial, cognitive, and behavioral approaches. Therapy that targets the executive function and the cognitive domains most affected by ADHD do produce some benefit over placebo. They're particularly recommended for young children aged six and under and for less severe presentations. For most cases, especially moderate to severe, guidelines consistently recommend medication at first-line treatment. That's not a controversial finding. It's the current consensus across major international guidelines. And before we get into the medications themselves, ADHD medication don't just reduce the symptoms. The research shows that they reduce the risk of criminality, self-harm, suicidality, and risk-taking behaviors in people with ADHD. However, the downstream is quite significant. This isn't just about paying better attention in class. The first line of medications are stimulants. So methylphenidate, which you know that is Ritalin, and amphetamines. Stimulants consistently show the strongest efficacy compared to other medications across all ranges. So remember the booth, the vacuum at the bottom running too hot, pulling dopamine back before you can even grab it. Methylphenidate works by blocking DAT and NET. So the dopamine and norepinephrine transporters, it slows the vacuum down. The cash stays in the air longer so you can actually reach it. Amphetamines go a step further. They don't just slow the vacuum, they also actively push dopamine out into the booth in the first place. So more cash in the air. And it clears also more slowly. So effect sizes for amphetamines are slightly higher than for methylfinidate overall. Both improve attention, inhibitory control, working memory, and sustained attention across all age groups. Side effects are usually mild, usually decreased appetite, dry mouth, irritability, sleep disturbances, headaches. I also want to say this directly. I know that there is a lot of cultural, I would say, disagreements around stimulant medication and ADHD. Questions about addiction, about overdiagnosis, about um whether any of it is actually real. What the research actually shows is that the large registry study does not support a clear association between these medications and serious cardiovascular events. The evidence for effectiveness is actually among one of the strongest in psychiatry. That doesn't mean the medication is the right choice for everyone. It just means that the decision should be made based on evidence and not stigma. For people who cannot tolerate stimulants or where stimulants aren't necessarily helpful, atomoxidine is most commonly used. It's a selective norepinephrine uptake inhibitor. So it basically slows the second booth's vacuum down without interacting with the reward pathway, which is what the stimulants do. Which is also why it carries minimal risk for dependence. It's particularly useful for people with core morbid anxiety or history of substance use. But the downside of this is that it's less effective than stimulants and takes a considerably longer time to work. Sometimes several weeks before you notice anything. Around 40% of people on it still have impairing symptoms and need additional management. Not a first choice for most people, but for the right person, it's the right tool. Both can be used alone or added to stimulant therapy, where the combined effect can improve symptoms or help manage stimulant side effects. So the medications we have are effective. They do not cure anything. And we also do not have genetic tests that tell us in advance which person will respond to which medication. Treatment is still for a lot of people a process of careful trial and error. Okay, so the boothroom. What do we know? The dopamine booth is clearing too fast, the norepinephrine booth is not holding the signals where it needs to be, the glutamate booth is running too hot, the GABA booth is running too low, a brain that shows real structural differences, especially in children, and networks that don't coordinate in the way that they're supposed to. All of this shaped by a genetic architecture involving thousands of small variations, not one single thing that went wrong. ADHD is one of the most heritable conditions in psychiatry. Highly comorbid, changing across the lifespan, and responsive to treatment. Treatment that works because it directly targets the same systems we just spent the whole episode walking through. And here's what I want to leave you with. When someone tells you their brain doesn't work the way the environment was designed for, when they tell you that starting things is hard or staying there is hard, or that the same brain that can't write an email somehow spent three hours going into something nobody asked them to do, this is the research that backs it up. Every part of that experience has a biological explanation. The vacuum is running too loud, the network that won't go quiet, the break booth that's running too low. You stop asking people to just try harder when you understand what's actually happening in their brain. And remember, things can be redesigned, they just have to be built break by break. If today's episode helped, please share it with someone who needs it. Leave a review if you have a minute. And also please don't forget to follow. Next week, we're talking about anxiety. I'm really excited for this one, and I'll see you in the next one.