ADHD and insomnia

What even is ADHD?

ADHD is one of the most common neurodevelopmental disorders. A neurodevelopmental disorder is a disorder of how your brain functions. It occurs when your brain and nervous system are still developing. The development of your brain is a tightly regulated process, and so can be easily disturbed by nutrition, physical trauma, metabolic disorders in the mother (such as diabetes) and more! Symptoms of ADHD are varied, including problems with attention, hyperactivity, and impulse control (if you trust the opinion of any of my friends with ADHD, the primary symptoms include a great sense of humor and unparalleledattractiveness. As of yet, the scientific evidence behind this is sparse).

There are three categorized subtypes of ADHD: predominantly inattentive, predominantly hyperactive and impulsive, and combined (Wilens, 2013). Primarily hyperactive might be characterized by excess movement, a lot of fidgeting, a lot of talking. Inattentive types might be easily distracted, have issues with working memory, or they might lose things. This isn't to put anyone into a narrow box - people with ADHD are all different and likely have different symptoms. The categorized subtypes can just be useful in research or in clinical practice. Most people with ADHD are predominantly inattentive, and ADHD-hyperactive-impulsive is the least common subtype (Ayano, 2020)

The cause behind ADHD is relatively poorly understood, but it is thought to be a variety of genetic and environmental factors (Núñez-Jaramillo et. al, 2021). There are a lot (a lot) of possible risk factors for an embryo developing ADHD:

Fetal hypoxia (not enough oxygen) can affect the dopaminergic pathways (pathways in the brain involving the neurotransmitter dopamine). This is because sme enzymes (e.g. tyrosine hydroxylase) required for the synthesis of dopamine need oxygen to function. Therefore, a lack of oxygen will prevent the enzymes from synthesising dopamine, resulting in neural issues. Additionally, some areas of the brain are affected. This includes the substantia nigra, a structure involved in functions such as fine-tuning motor movement and reward pathways, and has been found to be altered in patients with ADHD (Giannopoulou et. al, 2018). If you’re pregnant and really set on ensuring your baby has a normal dopaminergic pathway, I’d advise rescheduling your trip to outer space or the Death Zone of Mount Everest. At least for a few months. Once the baby is born, I’m sure it’s fine.

Pesticide exposure has been shown in rats to induce ADHD symptoms (Richardson et. al, 2015), which I find fascinating. Not the part about ingesting pesticides being bad for you (which I hope we can all agree is relatively common knowledge), but more about rats displaying ADHD symptoms. Do they struggle with executive dysfunction and then feel terrible because they haven't finished their homework? Do they talk over their rat friends? Are they fidgety? Aren't rats always fidgety?

Rat studies aside - please don’t huff pesticides if you’re pregnant. As a matter of fact, try to avoid it even if you’re not pregnant.

Genetic factors: The gene BDNF encodes a protein called BDNF (scientists are inventive with their naming like that). The protein, which is short for Brain Derived Neurotrophic Factor, is important for many things within the Central Nervous System. It promotes the survival, maturation and differentiation of neurons, and enhances synaptic plasticity (Bathina and Das, 2015), which refers to the fact that neurons can weaken or strengthen their connections at synapses, an important feature for memory formation. Some studies have found a correlation between lower levels of BDNF and ADHD - which means issues with making new neurons and maintaining old connections, including in the (you guessed it) dopaminergic pathway (Núñez-Jaramillo et. al, 2021). There’s a lot of other genetic and other factors at play that I haven’t even touched upon, and even the ones we currently suspect we don’t fully understand yet. Considering the scope of the issue and the variety of ADHD presentations, that’s not entirely surprising. Nevertheless, if you happen to come upon some revelation that explains everything, please email me. Or maybe somebody more qualified.

The neurobiology of ADHD

We’ve gone over some ideas of how ADHD can come about, but we haven’t really discussed what’s different about someone with ADHD. You likely already have a relatively good idea of what ADHD is on the psychology side of things - impulsiveness, trouble focusing, issues with time management, problems completing tasks, all that fun stuff (Mayoclinic, 2023). But what about the actual neurobiology? As in, what is the brain of someone with ADHD actually like? We’ll look at two major things: the dysfunction in the reward cascade and the gross brain structure (gross as in, like, big or total, not gross as in disgusting. We’ll look at why the brain is gross later. Don’t skip ahead though, you’ll spoil the ending for yourselves. ²

² Okay fine, I'll spoil it for you already. The brain is gross because it's folds of wet fat sitting inside a bone-cave.

The Reward Cascade

Reward deficiency syndrome (RDS) involves a group of disorders where there is an issue in the brain's reward mechanisms due to dopamine resistance. Dopamine is a neurotransmitter, a chemical messenger that carries signals from one neuron to another, which is heavily involved in the brain's reward and pleasure pathways. Issues with the metabolism of dopamine have been implicated in the etiology of ADHD for a long time. In experiments on mice missing dopamine transporter genes (genes for proteins called transporters that make sure dopamine is recycled and taken back up into the first, or presynaptic, neuron, thus ensuring that we still have dopamine present to carry messages), studies have found signs of hyperactivity (Blum et al., 2008). Guess who else is hyperactive?

That's right. ADHD folks.

Coincidence? I don't think so!

(Don't accuse me of bad science. I know correlation doesn't equal causation. Let me have this one.)

Lesions on dopaminergic neurons in certain parts of the brain have resulted in symptoms of ADHD in studies, showing the link between dopamine deficiency and ADHD. Brain-imaging studies have also helped prove that defects in dopamine explain many of the symptoms behind ADHD (Blum et al., 2008).

Early studies found genes coding for the dopamine receptors to be important in impulsive and addictive behaviors; defects in the dopamine receptor could mean that even if dopamine is present in the brain, its binding to the receptor is somehow defective and so signal transduction is altered. Additionally, genes that code for dopamine transporters are also implicated in ADHD. Dopamine is involved in the reward cascade. It's one of the final steps in a cascade of different neurotransmitters released after a pleasurable stimulus, which also means it's involved in many diverse drug addictions that all result in stimulation of the dopamine pathway. It's produced in the ventral tegmental area or VTA, a structure in the midbrain, which then projects to limbic and cortical areas. The mesolimbic pathway is the major reward-related center in the brain, projecting from the VTA through to the nucleus accumbens, amygdala and hippocampus.

The nucleus accumbens processes the rewarding stimuli that come in and helps reinforce it. We get food, it tastes good, the nucleus accumbens says “Hey, let's do that again!”. It deals with pleasure and generally liking things.

The amygdala processes a lot of emotional learning and behavior. It's also well-known as a ‘fear center' of the brain - whenever you read about scientists traumatizing rodents, it's likely the amygdala is implicated in there somehow (Salzman, 2016). Unless it's just a passion project, in which case my amygdala is lighting up right now.

The hippocampus is also a part of the limbic system and plays a crucial role in learning and memory (Dhikav & Anand, 2012).

Let's say we feed a baby their first donut. They're probably used to weird mashed baby food and parents trying to force-feed them broccoli or something, so the donut will probably release a whole lot of dopamine to the nucleus accumbens . Foods high in sugar have especially been found to stimulate the release of dopamine to the nucleus accumbens, so good for the baby! (Rada et al, 2005).

Maybe not good for the baby. I don't know, I don't think you're supposed to feed them donuts.

In our simplified model of the mesolimbic pathway, this would lead to ‘good' feelings when the amygdala is stimulated, and the hippocampus would go on to store this way in memory. The baby would now associate donuts with happiness.

Maybe not. Babies hippocampuses are probably pretty underdeveloped.

ADHD can result in lack of dopaminergic activity in the brain's pleasure center due to a variety of reasons. This can manifest itself outwardly in a variety of dopamine-seeking behaviors. Any readers with ADHD probably know the feeling of intense, soul-crushing boredom that comes from being under-stimulated. I've gone on 3am runs (and immediately regretted it), doodled all over my school notebooks, bought and lost fidget toys, decided I was going to become a muay thai fighter and told myself I'll teach myself to code and make a website just to ward off the boredom, because oh my God does it suck.

It's nice to know it's not just in your head, right?

I suppose it is in your head, but you get what I mean.

Some studies have actually questioned how crucial the role of dopamine dysfunction in ADHD is. A brain imaging study conducted in Cambridge found that while people with ADHD did worse on tests of attentional performance, they had similar levels of dopamine receptors in their striatum as healthy individuals, and their levels of dopamine increased by similar levels when methylphenidate, commonly known as Ritalin, was administered (del Campo et al., 2013). Therefore, although Ritalin led to improvements in the performance in memory tests of people with ADHD, since it led to similar improvements in non-ADHD people, it likely doesn't treat something intrinsic to ADHD itself.

This led to the researchers questioning the validity of the common claim that ADHD is primarily caused by a dysfunction in the dopamine pathway, and probably some test subjects going home and cleaning the hell out of their houses. For now, let's operate on the assumption that there probably is something off in the dopamine pathway in ADHD brains. Future research might entirely refute this, but current studies lean heavily towards this interpretation.

Brain structure

Aside from chemical differences, the ADHD brain is also physically different. The frontal circuitry, which deals with cognitive processes, is typically implicated in ADHD. Studies of brain volume differences in people with ADHD using MRI smaller cerebrum and cerebellum in ADHD individuals compared to controls. The cerebrum and cerebellum are two different things, but you can't tell me that whoever named those wasn't having a laugh. These differences in brain volume persisted past childhood and into adolescence and adulthood. They were also found in both unmedicated and medicated patients with no significant differences between the two groups, indicating the effect was because of ADHD and not the drugs used to treat it (Castellanos et al. 2002). What are the cerebrum and cerebellum? How might having a smaller volume of both of these impact someone?

The cerebrum is the biggest part of the brain. It's what we usually think of when we think of the brain, the weird folded part at the top (more on that later, though!). The cerebrum deals with 'higher functions; it evolved later on, so rather than being involved in the basics things we need for our survival such as breathing or regulating internal homeostasis, it deals with conscious actions, such as learning, language or memory (Cleveland Clinic, n.d.). It's the brainy, pretentious one, the nerd that might forget to eat and drink water because they're doing maths. In a 90s movie, the cerebrum would be a scrawny kid with glasses who frequently gets pushed into lockers.

While “cerebrum” is Latin for brain, “cerebellum” means little brain. I's like a cute little sibling who's a bit clingy and always attached to the older sibling. Except that the little sibling actually has most of the neurons in the brain - over 50%, despite only accounting for 10% of total brain volume! So maybe that's a poor metaphor. It's like a little sibling who grew to be 6 feet tall when you got back from college and now is the star football player at your old high school while you're looking at them and going “wait, weren't you learning to walk like a week ago?”. Its main function is to do with motor control, although it likely also controls other functions to do with 'higher' brain processes (Knierim, 2020).

Some studies report that differences in volume between ADHD and typical brains is normalized by adulthood (Gehricke et al., 2017). Others have found differences in children and adults with ADHD in terms of which brain structure was impacted. Additionally, the severity of ADHD symptoms could be linked to volume of gray matter and the development of certain brain structures, with more severe ADHD displaying lower gray matter volume (Wu et al., 2019). As an aside, gray matter is the cell bodies of the neurons and dendrites, while white matter consists of the axons, the connections between the cell bodies. If your brain were a bunch of devices linked together with wires, the gray matter would be the devices while the white matter would be the wires. Aside from volume, differences in connectivity are an important marker of ADHD. For example, decreased connectivity between the frontal cortex and the visual network has been associated with an increase in hyperactivity in ADHD patients (Wang et al., 2020). The ADHD brain might just be worse at coordinating itself to do things. Communication in it is a little jangled, so when it wants to do a task, it’s a bit of an effort to get the message “let’s do this task!” to the brain region that could actually execute it.

Why is the brain so gross and how does this relate to ADHD?

Everyone has a unique brain (unless they’ve changed this feature recently and I haven’t been told). The folds (called gyri and sulci for the ridges and grooves respectively) that form during neural development form differently for everyone, but they might be especially pronounced with disorders such as bipolar disorder, autism or (you might have guessed this one) ADHD (Garcia et. al, 2021). It’s not just the chemicals that are acting up - the literal structure of the brain of someone with a neurodevelopmental disorder is different to someone who is neurodivergent. Kinda funky if you think about it!

The research into the effects and reasons behind folding is actually really fascinating, with a lot of intersections between biology, psychology, physics, the whole shebang.

The folds of our brains are pretty darn important. Mice seem to survive okay with smooth brains, but personally, I’ve only ever seen the descriptor “smooth-brained” used in a negative context. Folding gives us a whole lot of surface area and complexity - you might not believe it when meeting some people, but this is why we’re typically smarter than mice. We want that surface area! We want to have the space to make a lot of complex connections, learn, make memories, whatever your non-smooth brain desires.

Alongside the usual factors biologists like to blame (looking at you, genetics) there seems to be a big role for mechanics in the development of the brain. Kara E. Garcia conducted studies where she used mathematical models to stimulate the brain folding and knock-on effects (more specifically, her group modeled folding in the cortex the outer layer of the brain. If you ever think of what the brain looks like, you’re probably thinking about the cortex. It’s the gross part ³. When the brain is growing, before it’s even been folded and it still looks more like a gross, but at least smooth, hunk of fat, we can think of it as made up of two zones (Richman et. al, 1975). The outer zone will become the cortex with all the weird folds, and the inner zone (truly nominative determinism) is under it, hidden inside. Now the question is - does the cortex fold because of forces exerted by the outer layer or the inner layer? A theory proposed by Richman et. al in 1975 describes it as “buckling due to differential expansion”.

Right. That clears things up.

To break that down: the inner layer and the outer layer grow at different rates. The outer layer, which will become the cortex, grows faster than the inner layer. Both layers are mechanically coupled to each other, so the differential expansion (aka the different rates of growth or expansion) exert tension, which leads to the cortex folding (Kroenke & Bayly, 2018). The cortex is big> in comparison to the rest of the brain - it’s the seat of your conscious processes. You'd hope it'd be big. It has to grow a lot more and a lot faster than the layers under it, and this causes it to fold - which is quite beneficial to us, because the increased folding leads to a lot more surface area and connections between different parts of the brain.

Another theory was proposed by Van Essen in 1997 that posited that it was the tension which axons exert in the inner zone that causes folding, as explained in the digrambelow (Xu et al., 2010).

Obviously, cortical folding occurs because tiny little strings attach and move to pull gray areas of the brain towards each other (but also up and down and together and down again and then they relax maybe?). My personal hypothesis is that little gnomes live in our heads and push the folds of our brain together just out of boredom.

The paper is still in the works.

The left side of the digram shows the hypothesis that I explained first, the idea that the different growth rates of the‘layers’ of the brain result in tension which causes folding. The right and wayyy more complicated looking side shows the axon hypothesis, about tension caused by axons causing folding.

Personally, I would have stuck with the left one. Just for appearance’s sake.

Neurons in culture and in-vivo are under tension when they’re stretched, and behave in an elastic manner (Essen, 1997).The theory was thus that this tension creates folding by pulling closely connected areas together, which would also help explain the very individual wirings of different brain. However, more recent studies seem to be showing that axon tension does not likely play a significant role in cortical folding (Xu et al., 2010b). The tension that they exert might still alter brain morphology (the structure of the brain) somewhat, but is likely not enough in itself to actually create the kind of folding that we find in human brains.

That was a bit of a tangent - but a cool tangent at that! So why does any of this matter?

as I mentioned before, differences in cortical folding seem to be a really important property of ADHD, and a lot of other disorders involving the brain (Wolosin et al., 2009). Studying how the brain folds can help us understand how it goes wrong. A lot of factors seem to go into it - environmental factors such as prenatal alcohol exposure or nutrition status might impact the gyrification (a word for the folding of the brain - and isn’t it a great word? Gyrification. Sounds like something a sci-fi author would come up with to describe what happens to people in the dystopian world when they disobey the government and are put into the Meat People Grinder Xtreme) (Gharehgazlou et al., 2020).

It’s really fascinating to think about these differences people with ADHD have, because it’s easy to slip into thinking that mental disorders are just some ephemeral thing which have no physical bases - but our thoughts, our very view of the world, are all based off of the physical structure that is our brain, and our brains can be very, very different!

It might be easy to assume that someone with ADHD is lazy (and maybe they are - we can all be lazy sometimes), but maybe their brain is also just built completely differently. A little geneticist God took the Lego blocks making up our brains, shook them up, and threw them all together haphazardly. Also, the Lego blocks are made mostly of fat. Gross, moist Lego blocks. No wonder it’s hard to put them together in a way that doesn’t make me forget my wallet every week or so on the bus.

If you take away anything from this, it’s that the world is a strange place - and whether you have ADHD or not, your brain it a strange topographical feature with mountains and valleys of wet, pink fat. And it’s all sitting in your skull with its overwhelming weirdness ⁴.

³ All of the brain is actually the gross part. We’re just wet slabs of mostly fat sitting in a bone-cage. That’s inherently gross.

⁴ Well, hopefully it’s sitting in your skull. If not, I’d probably go see a doctor. Or maybe a mortician

The link between iron and anemia

Something which I’ve learned recently and found absolutely fascinating is that anemia (a lack of iron) and ADHD are linked. In fact, lack of iron can be linked to a lot of cognitive deficiences. I know it seems like a relatively strange connection, but buckle up, because it’s pretty cool! Or skip ahead to the end of this section, where I give you a quick tl;dr. Either way.

The first way is cooler, though.

Iron levels are measured using a serum ferritin test. This doesn’t measure iron directly; rather, it measures the levels of ferritin, a protein in the body used to store iron. Several studies have noted the correlation between iron deficiency and exacerbation of ADHD symptoms. One study by Sever et al. tested the effect of supplementing the diet of children with ADHD with iron supplements, and found that not only did the serum ferritin levels increase (from 25.9 ± 9.2 to 44.6 ±18 ng/ml), but their ADHD symptoms seemed to decrease in severity. This was measured by their parents filling out something called a questionnaire called a Connors rating scale, which is supposed to give an indication about ADHD severity. The downside of this study was the smaller sample size and, as always with ADHD studies, it’s very difficult to empirically measure ADHD severity. Nonetheless, this seems promising!

Another study also found links between low serum ferritin, indicative of anemia, and ADHD. This clinical study found that serum ferritin levels were “extremely low” in a third of the children in the study with ADHD, compared to normal levels in control children (Bener, 2015). A link between cognitive issues and iron deficiency has actually long been established. This isn’t to say lack of iron is the big cause behind all ADHD cases, but it may be one of the precipitating factors. It’s likely that ADHD requires a combination of genetics, environmental factors and more to actually become ADHD as we know it but this is still a useful piece of information. The paper also highlighted links between vitamin D levels and ADHD, concluding that supplementing both iron and vitamin D to infants might be a useful way of reducing ADHD risk. Additionally, it might be useful to consider the risk of anemia in patients with ADHD and subsequently supplement their diet with iron to help manage both anemic and ADHD symptoms.

So why does this link between ADHD and iron exist? This is the fun part! Iron is actually involved in the synthesis of dopamine. It acts as a cofactor to an enzyme called tyrosine hydroxylase. A cofactor means it has a job as a ‘helper molecule’ in the enzyme’s work of catalyzing a reaction. Tyrosine hydroxylase converts the dopamine precursor, tyrosine, to dopamine (the name tyrosine hydroxylase is actually an example of the very rare occasion where scientists aren’t obtuse with their naming - it literally hydroxylates tyrosine by adding an oxygen onto it). If we don’t have enough iron, this reaction can’t proceed, and that means we subsequently don’t have enough dopamine. Hey! Hey, wait a second. The whole thing about ADHD is not having enough dopamine! Yup, you're onto something. Here’s your tl;dr if you skipped ahead (and made me sad): Iron is needed to convert the dopamine precursor into dopamine. If we don’t have enough iron, we can’t make enough dopamine. As ADHD is a dysfunction of the dopaminergic pathway, this additional lack of dopamine can easily exacerbate symptoms or possible even help cause ADHD in the first place. Weird, huh?

Don’t go licking nails now though, please. You can get iron supplements at Lidl I’m pretty sure. Less gross and with lower risk of tetanus.

How is ADHD treated?

I just want to throw a little aside into this section before we get started. I am not a doctor. I don’t want you going and telling your parents that you took a random pill your weird neighbor sold you in her garage because an internet writer told you it would help with your ADHD. This section isn’t telling you to do anything at all - it’s purely an overview of how ADHD is being treated and how it might be treated in the future. If there's an angry parent reading this, please don’t sue me. I just wanted to make little comics and read about weird brain stuff. And frankly, if your kids are doing weird shit because a random internet person told them to, you might have to up the parenting. Ever heard of internet safety? Give the kids a talk, sheesh.

Available treatments for ADHD can be split into two categories: pharmacological and non-pharmacological. I’m going to focus primarily on the pharmacological treatment - not because I think it’s more important, but purely because I’m interested in the chemistry of it. Additionally, some medications have the possibility of a relevant side effect - insomnia (Wilens & Spencer, 2010). (And sometimes, that same medication has been found to help insomnia. So maybe we just don’t know anything at all.) The first class of medications available to treat ADHD are stimulants, such as Ritalin or Adderall. These are “sympathomimetic drugs which increase intrasynaptic catecholamines (mainly dopamine and norepinephrine) by inhibiting the presynaptic reuptake mechanism and releasing presynaptic catecholamines” (Wilens & Spencer, 2010). Obviously that should have explained everything. Easy peasy, feel like you can’t focus? Simply increase your intrasynaptic catecholamines (mainly dopamine and norepinephrine) by inhibiting the presynaptic reuptake mechanism and… Christ, that’s a mouthful. And I’m not even speaking, I’m just writing it. Let’s break that down.

Sympathomimetics mimicthe activation of the sympatheticnervous system. The sympathetic nervous system is also called the ‘fight or flight’ system, for pretty obvious reasons. So does that mean sympathomimetic drugs cause people with ADHD to constantly be in fight or flight mode? Wouldn’t that make them super anxious and jumpy? Well, yes and no. Sympathomimetics can have a lot of side-effects that mirror this fight-or-flight response, such as increased heart rate and blood pressure. When you’re running away from something, you want to be pumping a lot of blood to your muscles to oxygenate them. You might also have gastrointestinal issues since your brain has decided it doesn’t need to focus on digestion right now because hey, maybe there’s a bear chasing you (Vitiello, 2008). Or maybe you’re just stressed about a big job interview. The brain still isn’t very good at distinguishing between the two and recognizing that maybe you’d like to be digesting things while discussing your weaknesses and why you’d love to work at this firm or that firm, instead of feeling like you need to go sprint up a hill to get rid of all your nervous energy. So is that it, then? The drugs will just make you super jumpy? Doesn’t seem like it’d help with ADHD much.

We also have to consider the fact that people with ADHD already have less dopamine and norepinephrine or faulty wiring in their brains! With correct dosage,they shouldn’t be jittery, but paradoxically calmer and more focused. For example, a study by Claire Advokat and Mindy Scheithauer found that college students performed better on memory recall tests when medicated compared to their non-medicated counterparts. There was also a reliable improvement in the performance of medicated ADHD students on tasks that required inhibition (e.g. they have to wait before making a choice). In general, stimulants seem to improve concentration, focus, working memory, and some studies have even found increased gray matter volume, or at least a trend towards normalizing gray matter volume (Nakao et al., 2011). Despite this, stimulants can have negative side effects - and, interestingly, might not improve academic performance in people with ADHD. Despite improving working memory and concentration, compared to taking placebo, people with ADHD taking stimulants didn’t perform better in the study by Advokat and Scheithauer. Huh.

This seems a bit weird. If the drugs make someone calmer, more focused and more likely to realize mistakes, shouldn’t that help their academic performance? The researchers tested out a bunch of theories behind why this might be. Say stimulants don’t negatively alter the person's cognitive performance - maybe the issue is with the other effects of the drugs? Amphetamines are used recreationally for lots of reasons, not just making you more focused. Some people abuse them for perceived euphoric effects. If they cause euphoria, that might well explain the lack of improvement in academic performance. After all, euphoric people don’t tend to make the most well thought-out decisions (citation: I don’t know, the whole of Euphoria. I mean, I never actually finished that show, so I don’t know how euphoric anyone was. But I sure know they were abusing the hell out of some stimulants, and I somehow get the feeling they weren’t using them to treat their ADHD). So is it the euphoria? Probably not. McCloskey et al. found that people with ADHD traits seem to enjoy stimulants and experience its euphoric properties less than non-ADHD people. Sorry, ADHD people.

One alternative theory has been that stimulants decrease “cognitive flexibility” (Advokat & Scheithauer, 2013). The idea of cognitive flexibility is the ability to respond differently when the environment changes and the ability to switch ways of thinking. If you’re a weird corporate person, you can interpret this as “thinking outside the box” and throw it onto a poster with clipart of a dancing brain or something. Additionally, stimulants might increase the effects of environmental distractions (if we again consider the fact that they are sympathomimetics and supposed to put you on ‘climb up a tree or go fight a bear with your bare hands’ mode, it makes sense why you might be more primed to pay attention to your environment). And a person paying a lot of attention to their environment rather than the test in front of them is likely to not do super well.

Enough psychology (I mean, it’s been one whole paragraph. I’m a biologist, not a psychologist). How do psychostimulants help people with ADHD manage their symptoms? What do they actually do? Let’s look at Ritalin and Adderall and their methods of action in a bit more detail: Ritalin is an example of a methylphenidate, Adderall is an amphetamine (just like speed! Fun fact of the day. Please don’t take speed to treat your ADHD though, I haven’t done my research on this but my gut says it’s not a good plan). Both methylphenidate and amphetamines increase levels of dopamine and norepinephrine, just in slightly different ways. The first method of action is that both of them inhibit dopamine and norepinephrine transporters (Faraone, 2018). Wait - if we can’t transport dopamine and norepinephrine, wouldn’t that be worse? Don’t you want to be able to transport neurotransmitters around the brain or something? We need a bit of a basic understanding of how signals are sent along the brain to understand this. A signal is sent from one axon to another through a junction, called a synapse. It binds to receptors on the second cell. Transporters ofneurotransmitters then shuttle the neurotransmitter from where it’s acting in the synapse back into the presynaptic cell. In the presynaptic cell, the neurotransmitter is recycled so it can be used again - in the case of dopamine and other monoamines, it’s broken down by an enzyme called MAO (no relation to the former chairman of the Chinese Communist Party. At least, no relation that I know of). The transporters thus act to stop the neurotransmitter from acting on the postsynaptic cell and exciting it. Inhibiting this transporter therefore means the neurotransmitter, in this case dopamine and norepinephrine, stays in the synapse for longer and continues exciting the second neuron. This essentially results in something akin to there being more dopamine and norepinephrine, without actually increasing their levels.

Amphetamine also inhibits the actions of MAO, the enzyme breaking down dopamine in the presynaptic cell, and methylphenidate acts as an agonist to serotonin receptors (i.e. it causes the same reaction as serotonin would by binding to serotonin receptors and mimicking serotonin’s effects) (Faraone, 2018). The primary sites of actions are the cortex and striatum. Remember: the cortex is the wrinkly outer part of the brain. It’s the newest part in terms of our evolutionary history and so it’s also associated with the ‘highest’ level functions, such as thinking, learning, and generally being aware you’re a human and you have a consciousness. Being ‘higher-level’ functions doesn’t make them more important, though - I’ve survived 20 years with barely any reasoning skills, but I’d rather not lose my ability to breathe. The striatum is part of the basal ganglia and controls some movement functions and is involved in the reward cascade.

There’s further cellular and whole-brain effects that I haven’t even touched - it’s a complicated system! It’s important for physicians to consider everything for people with ADHD if they have comorbid issues, because many are due to issues in the same neurobiological pathways. Additionally, we haven’t really talked about the side effects. We can’t really (yet) engineer a drug to act just in the places we want it to. Dopamine and norepinephrine have actions all over the brain, so if we start fiddling around with their levels, it’ll change lots of parts in the brain, too. This can include mood changes and irritability or insomnia (hey, look at me linking the parts of the website together) (Advokat & Scheithauer, 2013). Interestingly, a lot of the side-effects aren’t related to these higher-brain functions, but might include dry mouth, decreased appetite, and other unfortunate symptoms (Psychopharmacology Institute, n.d.) Why is this?

The brain uses the same neurotransmitters for a lot of functions. We can’t really make the dopamine act in just one partof the brain (not yet). Dopamine is involved in the reward and feeding cascade, so increasing dopamine levels will likely make us less hungry. Also, remember that the drugs are sympathomimetics - they activate the sympathetic nervous system. When we activate the sympathetic nervous system and get the fight or flight nervous response, we divert focus away from making saliva or from feeling hunger because again, why would we focus on the fact that we could really go for a burger right now when you’re accidentally steering your car off a cliff. So it makes sense you’d feel less hungry taking some of the drugs for ADHD!

References

N/A, Psychopharmacology Institute. (n.d.). Retrieved August 2, 2023, from https://psychopharmacologyinstitute.com/section/psychostimulants-for-adult-adhd-formulations-prescribing-tips-adverse-effects-and-monitoring-2510-4923
Faraone, S. V. (2018). The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neuroscience & Biobehavioral Reviews, 87, 255–270. https://doi.org/10.1016/j.neubiorev.2018.02.001
Advokat, C., & Scheithauer, M. (2013). Attention-deficit hyperactivity disorder (ADHD) stimulant medications as cognitive enhancers. Frontiers in Neuroscience, 7. https://doi.org/10.3389/fnins.2013.00082
Vitiello, B. (2008). Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function. Child and Adolescent Psychiatric Clinics of North America, 17(2), 459–474. https://doi.org/10.1016/j.chc.2007.11.010
Wilens, T. E., & Spencer, T. J. (2010). Understanding attention-deficit/hyperactivity disorder from childhood to adulthood. Postgraduate Medicine, 122(5), 97–109. https://doi.org/10.3810/pgm.2010.09.2206
Wang, M., Hu, Z., Liu, L., Li, H., Qian, Q., & Niu, H. (2020). Disrupted functional brain connectivity networks in children with attention-deficit/hyperactivity disorder: Evidence from resting-state functional near-infrared spectroscopy. Neurophotonics, 7(01), 1. https://doi.org/10.1117/1.nph.7.1.015012
Gehricke, J.-G., Kruggel, F., Thampipop, T., Alejo, S. D., Tatos, E., Fallon, J., & Muftuler, L. T. (2017). The brain anatomy of attention-deficit/hyperactivity disorder in young adults – a magnetic resonance imaging study. PLOS ONE, 12(4), e0175433. https://doi.org/10.1371/journal.pone.0175433
Wu, Z.-M., Llera, A., Hoogman, M., Cao, Q.-J., Zwiers, M. P., Bralten, J., An, L., Sun, L., Yang, L., Yang, B.-R., Zang, Y.-F., Franke, B., Beckmann, C. F., Mennes, M., & Wang, Y.-F. (2019). Linked anatomical and functional brain alterations in children with attention-deficit/hyperactivity disorder. NeuroImage: Clinical, 23, 101851. https://doi.org/10.1016/j.nicl.2019.101851
Knierim, J. (2020, October 20). Cerebellum (section 3, chapter 5) Neuroscience Online: An Electronic Textbook for the Neurosciences. Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston. https://nba.uth.tmc.edu/neuroscience/m/s3/chapter05.html
Salzman, C. D. (2016, January 14). Amygdala. Encyclopedia Britannica. https://www.britannica.com/science/amygdala
N/A, professional, C. C. medical. (n.d.). Cerebrum. Cleveland Clinic. Retrieved August 2, 2023, from https://my.clevelandclinic.org/health/body/23083-cerebrum
Dhikav, V., & Anand, K. (2012). Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology, 15(4), 239. https://doi.org/10.4103/0972-2327.104323
Rada P, Avena NM, Hoebel BG (2005) Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134:737–744. 10.1016/j.neuroscience.2005.04.043
del Campo, N., Fryer, T. D., Hong, Y. T., Smith, R., Brichard, L., Acosta-Cabronero, J., Chamberlain, S. R., Tait, R., Izquierdo, D., Regenthal, R., Dowson, J., Suckling, J., Baron, J.-C., Aigbirhio, F. I., Robbins, T. W., Sahakian, B. J., & Müller, U. (2013). A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: Implications for ADHD and its treatment. Brain, 136(11), 3252–3270. https://doi.org/10.1093/brain/awt263
Van Essen DC (1997) A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature 385:313–318. doi:10.1038/385313a0 pmid:9002514
Richman DP, Stewart RM, Hutchinson JW, Caviness VS Jr., (1975) Mechanical model of brain convolutional development. Science 189:18–21. doi:10.1126/science.1135626 pmid:1135626) Núñez-Jaramillo L, Herrera-Solís A, Herrera-Morales WV. ADHD: Reviewing the Causes and Evaluating Solutions. Journal of Personalized Medicine. 2021; 11(3):166. https://doi.org/10.3390/jpm11030166
Blum K, Chen AL, Braverman ER, Comings DE, Chen TJ, Arcuri V, Blum SH, Downs BW, Waite RL, Notaro A, Lubar J, Williams L, Prihoda TJ, Palomo T, Oscar-Berman M. Attention-deficit-hyperactivity disorder and reward deficiency syndrome. Neuropsychiatr Dis Treat. 2008 Oct;4(5):893-918. doi: 10.2147/ndt.s2627. PMID: 19183781; PMCID: PMC2626918.
Giannopoulou, I., Pagida, M.A., Briana, D.D. et al. Perinatal hypoxia as a risk factor for psychopathology later in life: the role of dopamine and neurotrophins. Hormones 17, 25–32 (2018). https://doi.org/10.1007/s42000-018-0007-7
Bathina, S., & Das, U. N. (2015). Brain-derived neurotrophic factor and its clinical implications. Archives of medical science : AMS, 11(6), 1164–1178. https://doi.org/10.5114/aoms.2015.56342
Richardson, J. R., Taylor, M. M., Shalat, S. L., Guillot, T. S., 3rd, Caudle, W. M., Hossain, M. M., Mathews, T. A., Jones, S. R., Cory-Slechta, D. A., & Miller, G. W. (2015). Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 29(5), 1960–1972. https://doi.org/10.1096/fj.14-260901
Garcia, K.E., Wang, X. & Kroenke, C.D. A model of tension-induced fiber growth predicts white matter organization during brain folding. Nat Commun 12, 6681 (2021). https://doi.org/10.1038/s41467-021-26971-9
Kroenke, C. D., & Bayly, P. V. (2018). How forces fold the cerebral cortex. The Journal of Neuroscience, 38(4), 767–775. https://doi.org/10.1523/jneurosci.1105-17.2017
Xu, G., Knutsen, A. K., Dikranian, K., Kroenke, C. D., Bayly, P. V., & Taber, L. A. (2010). Axons pull on the brain, but tension does not drive cortical folding. Journal of Biomechanical Engineering, 132(7). https://doi.org/10.1115/1.4001683
Essen, D. C. V. (1997). A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature, 385(6614), 313–318. https://doi.org/10.1038/385313a0 Wolosin, S. M., Richardson, M. E., Hennessey, J. G., Denckla, M. B., & Mostofsky, S. H. (2009). Abnormal cerebral cortex structure in children with ADHD. Human Brain Mapping, 30(1), 175–184. https://doi.org/10.1002/hbm.20496
Gharehgazlou, A., Freitas, C., Ameis, S. H., Taylor, M. J., Lerch, J. P., Radua, J., & Anagnostou, E. (2020). Cortical gyrification morphology in individuals with ASD and ADHD across the lifespan: A systematic review and meta-analysis. Cerebral Cortex, 31(5), 2653–2669. https://doi.org/10.1093/cercor/bhaa381
Castellano sFX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Medical Association. 2002;288(14):1740–1748.)
N/A, Adult attention-deficit/hyperactivity disorder (ADHD) - Symptoms and causes. (2023, January 25). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/adult-adhd/symptoms-causes/syc-20350878
Sever, Y., Ashkenazi, A., Tyano, S., & Weizman, A. (1997). Iron treatment in children with attention deficit hyperactivity disorder. Neuropsychobiology, 35(4), 178–180. https://doi.org/10.1159/000119341
Bener, A. (2015). Higher prevalence of iron deficiency as strong predictor of attention deficit hyperactivity disorder in children. European Psychiatry, 30, 691. https://doi.org/10.1016/s0924-9338(15)30547-2

This section focuses on the neurodevelopmental disorder ADHD. I try to cover some of the theories behind why it comes about, what it entails and possible treatment options.