 Dr. Fassbender is an assistant professional researcher within the UC Davis Department of Psychiatry and Behavioral Sciences. She is a cognitive neuroscientist whose interests include understanding the neural correlates of cognitive control processes in the typically developing brain, in ADHD and in substance abuse, through the use of behavioral functional neuroimaging and electrophysiological methods. Dr. Fassbender's goal is to better understand the cognitive impairments in ADHD in order to inform targeted treatments and to identify patterns of brain and behavior that will inform the early identification of individuals vulnerable to substance dependence with the goal of prevention. Please join me in welcoming Dr. Fassbender to the stage. Bear with us for a second, there might be a technical issue. I just want to make sure we have the right talk. Once again, thank you so much for inviting all of us. I think I speak on behalf of us all when I say what a pleasure it's been to be able to participate in this wonderful symposium and it's just fantastic to see so much excitement and interest in these topics. I'm a cognitive neuroscientist, so my perspective is a little bit different. I'll be talking today a little bit about the brain. You'll be seeing a lot of slides with brain regions popping up and I'll also talk about some of the tasks that we use to examine impairments in clinical disorders. Thank you. This is the right one. This talk is all about ADHD and substance abuse. I'll talk a little bit about the theories behind why ADHD and substance abuse are often comorbid. I'll mainly focus on the dual process theory, which is one that we look at a lot in our laboratory in the air lab but also in my own substance abuse work. I'll also talk about the interactions between reward and cognition, which is part of the dual process theory. Then I'll talk a little bit about ADHD and risk for substance abuse as it relates to medication treatment for ADHD at the end. As many of you might know, more individuals with ADHD use and abuse alcohol, tobacco and substances compared to people who don't have that diagnosis. In adolescence, which already represents a heightened risk period in development, it turns out that the MTA study, which was a longitudinal study of hundreds of kids with ADHD and without, and follow-ups have found that there's greater substance use in ADHD versus non-ADHD groups throughout adolescence, early to late adolescence. There's also a faster progression from initial use of substances to heavier use of substances. About 27% of adolescents with ADHD are comorbid for substance use issues, and that rises dramatically to over half of people in adulthood who have issues with substances, alcohol, drugs. When it comes to people who are seeking treatment for substance use issues, there's a wide-ranging estimation, but it ranges from about 10% to about 44% of them. They either have diagnosed or undiagnosed ADHD. In my work, I've worked a lot with methamphetamine users, and that was one striking thing I noticed when they came through, was that I would say about 95% of them had high risk for ADHD. They were coming up as having red flags for ADHD all over the place, and they were never diagnosed with ADHD when they were children or even currently. This comorbidity is especially problematic when it comes to treatment. People who have ADHD and substance use issues tend to have problems sticking to treatment in the first place, and then they relapse more when they're actually completed with treatment, so it's a real problem. Again, individuals with this comorbidity, they begin using substances earlier. They use them more often than their peers, and they move between different substances more, and they also transition from abuse to dependence more quickly. They have lower rates of full remission, which is what I just mentioned. They relapse more, not so good sticking with treatment and sobriety. Just briefly, I'll talk a little bit about conduct disorder. Dr. Pacirek mentioned this, that if you have conduct disorder co-occurring with ADHD, it dramatically increases your risk of having problems with substance use and abuse. Originally, people thought that once you had controlled for conduct disorder, that ADHD no longer posed a significant risk for substance abuse. However, more recently, people have pointed out some problems with those, studies some potential problems with how they recruited subjects for their studies, and the more common thought now is that actually they do represent separate disorders that contribute differently to risk for substance abuse, and one recent study actually of nearly a thousand people found that even when you do control for conduct disorder, ADHD still represents a risk for substance abuse. So, there are a number of different theories as to why this might be the case. Why do so many people with ADHD have this heightened risk for substance abuse? Some of them range from the causal pathway hypothesis, which says ADHD symptoms are associated with doing poorly academically, with social problems, these things will lead to dissatisfaction, and eventually you'll go down the route of engaging in behaviors that you shouldn't be engaging in and substance use. There's the common underlying etiology, the externalizing disorder, commonality. The one thing that I will focus on is this dual process theory in addiction because it looks more at the brain and what's happening in the brain in terms of circuitry in the brain, and that's what I like to do, so I'm going to talk about that more. So, the dual process system, you can think of it as a tension between these two systems in the brain. There's the cognitive system, which is at the reasoning system. It's slow, it's effortful, it's deliberative. It's controlled processing, there's regulation involved, it's volitional, it takes effort for you to do it, and it's rule governed. As opposed to reward processing, which tends to be more automatic, visceral, it's emotional, there's an intuitiveness to it. It's fast, effortless, and you could argue impulsive. So, I like to think of this balance between the cognitive system and the reward system that's going on every day in our brains. I'll give you an example of this. So, you might want some chocolate, but then you might think, well, is that the best option for me? Maybe I should go for something that's a little healthier. That's really going to be better for me in the future. The chocolate's going to feel good right now, but I'm not going to feel so good about it tomorrow. Same thing, cupcake or salad. So, there's a reason that we have this reward system in our brain. It's so healthy to have this. It motivates us to approach food and other things that are important for our survival. The problem occurs when you don't have this deliberative system engaged, which weighs up the pros and cons of going for something that might feel good now versus something that's going to benefit you in the future, or even something that if you engage in this behavior now might really have bad consequences for you in the future. Another example of a substance that lights up the reward system is money. So, you know, do I go on a shopping spree now, or should I save money for my future, maybe put it away for college? These are all examples of how this dual system is controlling our lives on a daily basis. So, a task that we commonly use to look at this tension between these two systems is called temporal discounting or delay discounting paradigm, and it's really, really simple. You just offer people a series of choices. We offer them a smaller amount of money more immediately versus a larger amount of money, but that's removed in time at some point in the future. So, for instance, here it would be, would you like $5 today, or would you like $10 in one week? And by introducing a series of questions to people over and over with different monetary amounts and different delays, we can work out this value, which is K, which is this impulsivity factor. So, it's the point at which you will opt for the sooner reward over the delayed reward. And as I said, sometimes it's a really easy decision. Would you like $10 now or $10 one cent in a year? Who's going to wait a year for one cent? Nobody. But the point is that you need to be weighing up this decision. What's good for you in the immediate time versus what's good for you in the future? And the brain regions that are associated with this task are, bear up what we know about this task, that there are two systems involved. There's the reward system, which is going to fire when you are offered this money. Money now especially is going to light up this reward system. And you see these regions in the brain, which are classic reward regions. And then when people are making decisions about whether they should wait or not, you see these, which we call cognitive control regions that are more active, especially when people are choosing the delayed option. So when they want to wait for the money, you see these regions really coming on board. So you've got this nice interplay between these two sets of regions going on in the brain as you actively go through your decisions. Sometimes you'll choose the immediate reward, sometimes you'll choose the delayed reward. So when it comes to development, this is one aspect of reward and cognition that we're really interested in in our lab and the Air Lab. This is a project that's spearheaded by Dr. Schweitzer. And it looks at the development of reward and cognition across adolescence and into early adulthood. And we're looking at typical development, but also at ADHD. And the theory behind this is that in adolescence, there's this peak in risk-taking behavior, as any of you will know who have adolescence in your home. And it turns out that it's possible that these reward regions are really peaking in their development around adolescence and then they sort of calm down again into later development. Whereas when you look at the prefrontal cortex, what's happening is it's slowly developing across time. And it may not finish developing fully until mid-20s. So you've got an overactive reward system and a relatively underactive cognitive control system in adolescence, which may be the reason that we have problems with these types of behaviors. One of the things that we're interested in looking at as well in this study, among other things are substance abuse, but also academic outcomes. So again, you can see your GPA, your attendance, your achievement, all of that is going to depend on how much you value future over present. Am I going to message my friends on my phone, or am I going to sit down and study for this test? It's a constant decision-making process of immediate versus future. And it turns out that people with ADHD are not particularly good at this. Many studies have shown altered functioning in reward and cognitive control-related regions in ADHD. One other way of thinking about this forward thinking behavior is future orientation versus present hedonism. So that just means again, looking towards the future or really being focused on the current situation. And this is another study from one of our colleagues in the Netherlands. And he found in this study, it looked like when he looked at present hedonism, there was no change across age, but when he looked at future orientation, it increased with age. And when you looked at the K-value, which is impulsivity, it was going significantly down with age as well. So as future orientation increases, impulsivity goes down. So they're less likely to go for the immediate reward. And that also tied together nicely with some findings in the prefrontal cortex and development. So the main take-home from this paper was that the cognitive part was the really important part across time. This is some preliminary data from the study that we're engaging in the longitudinal study looking at the development of reward and cognition. And we again used this task money now versus money later, and we found again one of the regions in the cognitive control system, this parietal lobe, was less active in ADHD compared to typically developing controls. But interestingly, again, development seems to be important because in the older kids with ADHD, there was more activity, so it was sort of normalizing across time. So some of these things may be represented by delay in development. This is just a slide from another group showing that it's not only about cognitive control, that reward regions are implicated again as well. So this was again using a delay discounting task, and they found differences in the orbital frontal cortex, which is a region that's involved in reward processing in kids with ADHD. So a practical implication of this problem with impulsivity and this lack of self-control in our study we also saw that the degree of self-control is also the best predictor for math performance. So more self-control, you do better at math. And this can possibly relate to other achievement measures as well. We're continuing with this study at the moment, so we'll know more as time unfolds. So context is also really, really important when it comes to valuing future rewards. So you may have heard the saying, never shop on an empty stomach. That's the context. So you're hungry, you're more likely to go for options that are not very optimal and probably not as good for your health. And if you're hungry, you're more likely to take the chocolate bar rather than the salad. Well, we found that in one of our tasks as well. We looked at ADHD and we looked at typical development and we used this delay discounting paradigm again. This time we put a bit of a twist on it. So in one condition, we had, would you like $5 now or $10 in a week? In our second condition, we used a very simple manipulation. It was, would you like $5.32 now versus $10.75 later? And just by adding in those decimal places, those cents, it made people, we think, slow down and think about it a little bit more. So it was less of an impulsive decision. So you can see, simply by just adding a couple of numbers on, impulsivity went down in both ADHD and healthy controls. So it's interesting. You can manipulate impulsivity with context and that might be a very important message. So just to sum up this part, the dual process theory suggests that there's some sort of imbalance between the cognitive system and the reward processing system in the brain. There are different takes on this. Some people think that the cognitive system is way too weak. Some people think that the reward system is hypersensitive. And other people think that it's a problem with the balance or interaction between the two. It may be all three of those. Because as I mentioned, all three have been implicated in ADHD. So they have altered reward processing. They have differential cognitive control activity. And there's some suggestion that the connectivity might be different too. The common task that we use is the delay discounting paradigm. And both reward and cognitive brain regions have been implicated in ADHD. Context matters. So what is impulsivity if we break it down a little bit more? Well, it's a reflexive action. And it's very often something that's inappropriate. We shouldn't be doing it. It's thought of as an inability to suppress a prepotent response. So you're a really good example of that in one second. Just to help you understand what I mean by that. So you really want to stop, but you can't stop yourself. That's called response inhibition. That process, which is responsible for slamming on the brakes when you really need to stop. And it's thought of as a cognitive control process. Response inhibition involves those classic cognitive control regions, the frontal cortex and the parietal lobe. And interestingly, impulsivity is obviously really a core impairment in ADHD because it's one of the diagnostic criteria. So response inhibition is often looked at in ADHD and it is very often associated with ADHD impairment. They're not so good at response inhibition and they have altered responses in the brain when they're engaging in response inhibition. There's also heightened impulsivity in substance use. So when you think about one of the diagnostic criteria for substance dependence, it's that inability to stop, even though it's destroying your life, it's having completely negative impacts on every single aspect of your life, your family life, your job, your finances, your health. And still in the face of all these negative consequences, you're unable to stop yourself. So you can see already the commonality between ADHD and substance abuse. They both involve these bad decision making processes and this impulsive behavior. So at this point I like to give an example. So I'm going to be using a lot of driving examples, just as in heads up. In Ireland, we take a lot of public transportation but I think a lot of people in America like to drive so most people should relate to these examples. So when you're driving in your car and you're sort of on automatic pilot, you're driving along and your intention is to go to the dry cleaners but you're thinking about your day, what you're about to do, picking the kids up from school. Before you know it, you've gotten off the exit to your house. Has that ever happened to anybody? Yeah. So that's because you're in automatic behavior and that's okay, you know, it frees up the brain to think about other things but often it can lead you down a dangerous path. So that's where cognitive control comes in. You realize you're getting off at the exit. Oh my goodness, I'm going home instead of going to the dry cleaners. So I like to think of it as a little referee stepping in and going, hey, your behavior is not appropriate here. Snap out of automatic mode and get back into focus and you'll turn around and you'll go on with your day. So response inhibition is really, really important for that because you need to stop what you're doing and do something different. So it's like slamming on the brakes at a red light. So these are the regions that have been implicated in response inhibition and as you can see again, it's those same candidates, the prefrontal cortex and the parietal lobe. Now it's after lunch, everybody's a little bit snoozy so I'm going to wake you all up now with some audience participation. I'm going to have you do a response inhibition task with me. So the rules are as follows. I'm going to show you a number of slides. You're going to see X's and Y's presented in succession. It's going to go X, Y, X, Y, X, Y. I want you to clap your hands as quickly as you can. Each time an X or a Y comes up. When the X's and Y's are in alternating sequence, you're going to clap X, Y, X, Y. Your job is to stop yourself from clapping if you see that sequence broken. So if two X's are presented in a row or two Y's are presented in a row, you have to stop yourself from clapping. Okay, so are we ready? Okay, here we go. Oh, sorry. Oh, okay, that didn't work. Sorry. So what happens is it's really, really hard to stop yourself when that happens, especially if you've been clapping along to the X's and Y's a lot. It's really, really hard to stop yourself because this is what a pre-potent response is. You've built up this automatic tendency to respond. And then when you have to stop yourself, you really have to slam on the brakes hard. So that messed up, but you were all supposed to clap when it happened. So that's what's referred to as response inhibition. It's when it's really, really difficult to stop yourself doing something, you really have to slam on the brakes. And that's a really important aspect of cognitive control. When you make that mistake by clapping on the second X, a little signal goes off in your brain. It's called the rabbit effect or the oops effect, as I like to call it. So rabbit noticed that people tend to slow down after they make an error. So your brain sends off a signal, lets you know you've made a mistake, and then it sends in that referee to make a corrective action. So now you're going to say, we need to slow down here, we need to pay attention to what we're doing, get back on track. So the error signal that goes off in your brain is thought to arise from the anterior cingulate, which is right in the middle of your brain in the center. And it's thought to signal the prefrontal cortex, which now is the referee that's jumping in to say, slow down, we've got to take our time here. We don't want to make a mistake again. So it's like that driving example, you realize you've gotten off at the wrong exit, you have to do a U-turn or whatever you need to do to get back to the dry cleaners again. So your brain is sent off an error signal and now you're implementing the corrective action. And this is what we call performance monitoring. Now you don't actually have to make a mistake to change your behavior. And this is where another aspect of performance monitoring comes into play and it's called response conflict. So you might also be familiar with this feeling. So you're in your car, you're in the left turn lane and there's also a lane, a separate lane, which is for straight ahead. And there's two separate lights for that. The green arrow turning left means that you can go left. So a lot of the time when you're sitting there daydreaming, the light will go green for the straight ahead traffic and you'll start to roll forward. And then you'll slam on the brakes because you realize, oh no, it's not the green arrow, it's only for them, it's not for me. So that's an example of response conflict because you have two competing responses activated at the same time. So that need to go and the need to stop. And response inhibition is engaged to stop you in that case. So this is another trigger for us to adjust our behavior. So our brain tells us response conflict is going off in our brain. It's a very similar region of the midline of the brain. It's telling the referee to step in. We don't want to make a mistake here. We don't want a car to crash into us. So we better adjust our behavior appropriately. Another task that we use to measure this is the flanker. And I hope this is going to work this time. So what I need you to do is imagine that these are arrows and they're flying to the left, okay? I want you to focus on the middle arrow. So every time you see the middle arrow flying to the left you're going to raise your left hand. Every time you see the middle arrow flying to the right you're going to raise your right hand, okay? So here we go. Remember you're focusing on the middle and ignoring the flanking or surrounding arrows. So here we go. Okay, great, that worked. So you may have noticed when you throw in some conflicting information in there the flanking arrows are pointing in a different direction to the center arrow, you get confused and you're like right hand, left hand. That's response conflict. But you may have noticed on the second one that was also conflicting you were able to put your hand up faster. Did anybody notice that? That it was the first one that really tripped you up? That's what cognitive control is. So on the first one you're all confused, response conflict kicks in, it tells the brain, okay, we really have to focus on the center one again. We're getting confused by these flankers. And then on the next one you respond more quickly again. So that's response conflict and attention control in action. So the flanker is a really nice task to look at this and also errors. And as I mentioned this all occurs in the center, the midline of the brain. So errors usually activate this more anterior part of the anterior cingulate and conflict activates usually this area that's a little bit further back. So I like to think of it as the two responses kind of duking it out and whichever is the stronger one is ultimately going to be the one that wins. So if you weren't sure right hand, left hand and you just stuck one up that was the dominant one that won the fight. So just to recap, you get these signals in the brain and they trigger attention control. Attention control steps in and you change your behavior based on those signals. And this is something that people with ADHD have consistently been found to have a problem with. Some studies find that they have a problem with the OOP signal that it's just not as strong. Others find that they don't really slow down their behavior after they make a mistake and others have found that they have a problem with response conflict. So this performance monitoring attention control is problematic for ADHD and as it turns out for substance abuse as well. So there's another commonality between the two disorders. These are just some brain regions that we found activated in the flanker in a study that I did quite a while ago. But you can see again these usual regions of the prefront cortex and the parietal lobe. So these cognitive control regions. Again, when we think about the dual process theory, it's suggesting an imbalance between these systems. You can think of the reward system as being the gas of the car and it responds to appetite of stimuli. It tends to be really visceral and automatic. You can think of the cognitive control system as the brakes and it's more deliberative and it helps you to make your optimal decision whether it's the reward now or the reward later. And in a healthy situation they work together really nicely going back and forward, balancing back and forward. But if you've got a problem between this connectivity between them then impulsivity is the result. So I just want to switch gears a little bit and talk about the role of dopamine in reward. So many of you might know that a lot of the stimulant medication in ADHD although other neurotransmitters are obviously involved, dopamine is a very important neurotransmitter when it comes to ADHD medication and stimulant medication. So I'm going to talk a little bit about dopamine reward and learning and then about dopamine and ADHD and dopamine and substance abuse. So this was a seminal paper that came out quite a while ago but it's really a neat study. So this was directly recording from the brain that was in Monkeys and they were looking at how the brain responds to reward. So what they did was they had a cue which was something like a light going off and then they would present the reward and they would do this over and over again. So at the beginning of the experiment you can see when the reward is given you get this little dopamine burst. As time goes on the dopamine burst moves from the reward itself back to the cue. So this is kind of like the Pavlov's dog you know when you ring the bell and you present the food and the dog starts salivating it's a similar idea. So the dog has now associated the bell with the reward and that is a real thing that happens in your brain so the dopamine firing moves to the cue. So this is really important for learning you are learning that there's an association between this cue and the reward and if you really pay attention to the cue then you're going to know when the reward is going to come on. What's also interesting is when you looked at occasions where the cue was presented but no reward was given you see this drop in dopamine. So it's also predicting when there's an error and it's also instigated when there's an error in your prediction model so you predict that there's going to be a reward and there is no reward so your brain is taking a note of that and the dopamine system is taking a note of that so it's really critical for learning and reward-related learning. So interestingly it turns out that in ADHD there's alterations in dopaminergic functioning in the brain. So this was a study by Nora Volkov who's the director of National Institute on Drug Abuse and she looked at dopamine receptor and dopamine transporter levels in the brains of people with ADHD and she found that they were lower so you can see. So this is kind of involved and you don't really need to focus too much on all of this but this is just showing the complicated network of regions that's involved in motivation and learning and reward and cognition. They're all intertwined with each other so the ventral tegmental area and you know there's dopamine feeding up to the prefrontal cortex the nucleus accumbens which is really the reward center and all these regions and they're all affected by the amygdala so when people are under stress or they're anxious this affects your motivation and it affects your decision making process and interestingly this correlates with motivation in people with ADHD so those people who had higher levels of transporters and receptors were having the least problems with motivation so these are just some really nice graphs showing that. So dopamine and the basal ganglia which are these regions the nucleus accumbens and the striatum they are central to reward processing, motivation and learning. There's evidence of altered response to rewards and impairments in these regions in people with ADHD and dopamine and in the regions themselves so the very perceptive people in the audience might have noticed in the title of this slide that it says a neural basis of addiction on this slide so it turns out that this very cognitive motivation learning reward circuitry is critical to addiction as well. So in addiction this normal reward motivation learning system is completely hijacked by the drug so things that would normally be really rewarding to addicts like food and positive social interactions praise all of that goes way down and the only thing that really cuts it anymore is the drug or the high. So this whole system this whole learning system is hijacked and what if you remember this if you remember the slide with the dopamine burst where the dopamine moves to the cue that's really important because drug addicts have lots of cues for drugs in their environments they will take normal everyday people situations, items and they will suddenly become a cue to drug use and it's a really important part of addiction because you start craving the drug and ruminating about it and then all of a sudden you know you're back on the street corner it can be places like the street corner it can be people that you know that are associated with drug use many addicts that I've worked with have said when it's payday and they put their hand in their pocket and they feel those dollar bills in there that's an immediate cue it's like bingo it goes off in their brain I really really want to get high now dopamine is really important in drug abuse as well because one of the critical factors in addiction is that feeling of high so you like the feeling at the beginning and that's the binge intoxication phase so you've got the nucleus accumbens firing there's a lot of dopamine dopamine is released mainly in stimulants but also in opiates and marijuana all sorts of drugs of abuse you get a dopamine burst when you get high this is paired with what happens when you go into withdrawal so when you don't have the drug in your system you start to have a negative affect the amygdala starts to light up and as you saw it's part of that circuitry it's really really important you start to feel stressed out it affects your decision making you're automatically in a more weakened state in terms of decision making and you're going to go for that immediately rewarding drug instead of thinking of the long term then you have this preoccupation and this wanting that's caused by these cues that's where the prefrontal cortex comes in it's ruminating about thoughts of drug use and that's lowering your ability it's taking up your cognitive resources and it's lowering your ability to engage in things like response inhibition and performance monitoring you're just completely preoccupied with the drug getting your hands on it and using it so you can see how all of these parts are really important in the whole addiction cycle and the maintenance of addiction it's shaped by really really powerful reinforcers so the first reinforcer is that positive reinforcement where you take the drug you get the dopamine surge it feels really good then you have that paired with this negative reinforcement which is the removal of the aversive stimulus especially in drugs like opiates where you start to feel sick and ill if you don't have the drug as soon as you get the drug on board now everything's okay I feel normal again so these are two really really really powerful reinforcers that just keep this addiction cycle going so again I'm just reminding you of the Q and how important that was the learning cycle addiction just is hijacked and learning is completely thrown off so the Q becomes a really powerful reinforcer so this projection from the prefrontal cortex to the nucleus accumbens the reward center is sort of thought to be this final common pathway for addiction and it's really really affected by the amygdala and by stress so you get the Q the prefrontal cortex is firing it's triggering your reward system it's anticipating this reward and that's how the drug abuse continues so the nucleus accumbens the basal ganglia the prefrontal cortex they're all involved in this establishing of a habitual drug use pattern there's an increased craving and wanting of the drugs and that increased craving has been shown to predict who relapses so if you put people in an experiment and you show them drug cues like needles if they're users of IV heroin or piles of cocaine or whatever it is you present these stimuli to them and you ask them how much on a scale of 1 to 10 are you craving that drug right now those people that score really highly on that are the ones that are more likely to relapse and again under conditions of stress this decision poor already poor decision making deteriorates even more so this slide is showing a bunch of different drug users so we're looking at cocaine methamphetamine alcohol and heroin these are typical people that don't abuse drugs and these are the drug users this red here is looking at dopamine receptor availability so you can see the nice red dopamine receptor availability in controls but then you can see it's much reduced in all these drugs of abuse so remember the slide I showed you earlier with the people with ADHD similar regions similar story there's an alteration in dopaminergic functioning in both of these disorders so when you give drug users these temporal discounting paradigms it's a very similar story they will also be impulsive in their choices so they will also be much more likely to choose the immediate reward over the delayed reward so obviously the question is well is that because they're really really impulsive from the start or is that because they've been using this really really powerful drug all these years and it's been damaging their brain and damaging these reward centers is that why they're more impulsive well some preliminary data that I have that's unpublished looks at just this so we had we separated the methamphetamine dependent users into those that were less than a year clean versus all the others who had been clean for over a year and what we found was that they are both more impulsive than controls but if you look at the long term absent they are less impulsive than the short term absent and when you break them up into this less than a year more than a year and look at the data points you can see this dramatic decrease in impulsivity in the first year of sobriety and then this sort of you know flat line for the rest of it but that's a very interesting point because when you're in treatment for drug use that's the message you're given get to the year mark after you've been clean for a year things start to improve it lifts a little bit you can see the real benefits of staying clean and it becomes much easier and that's borne out by lots of different research looking at the neurochemicals in the brain but also as you can see in behaviour again across a bunch of different substances it's the same story in alcoholics, tobacco users and drug abusers they tend to value distant rewards less impulsive that K that delay discounting measure it actually predicts treatment outcomes in adolescents and adults with substance abuse so people that are less impulsive tend to do better in treatment there's also a hypoactivity in even cigarette smokers in these reward circuits and all these different predictors of impulsivity they're associated with early substance use and the development of substance use again this is really relevant to ADHD so they're at a much higher risk and the thought is that it's largely due to impulsivity and bad decision making so again is it a cause or effect and this is obviously very difficult to tease out in the research unless you have a cohort of individuals that you follow across the lifespan and you take measures on them and that's very time intensive and costly so most of the research is looking at currently dependent substance abusers and we have to sort of figure it out from there but it's likely again going back to this personalized medicine approach it's going to be different factors for different people so Nora Volkov one of her theories that I saw her present on quite some time ago was that the levels of dopamine in your brain can be really important so some people here might really love coffee and others will hate the way it makes them feel they'll get jittery it's sort of like that if you've got low levels of dopamine in your brain the surge in dopamine is going to feel quite nice whereas if you've already got quite high levels of dopamine in your brain it's going to be an unpleasant feeling and these individual differences are really really important so why do we care about reward processing and cognitive control well it can be really really important in terms of trying to get the best treatments for these people some people if they've got some impairment in their cognitive control system might benefit from cognitive therapies training from cognitive enhancers even others who have a problem with their reward system might work much better with a token system so actually paying them to stay sober and that has been shown to work Warren Bickel also has this method that he has just suggested might be useful where you try to make people think as much as you can into the future and he showed that when you put cigarette smokers in a room with all the cigarettes they can smoke it reduced the amount of smoking in the people that we're trying to think into the distant future so it's very very important to understand what's going on in the brain so that we can create effective treatments for the individual that's affected by the disorder sorry this isn't moving on for some reason oh there we go skipped a couple so dopamine and impulsive behavior and they're all tied up together are heavily implicated in the development of substance dependence so implicated in ADHD addiction alters these cognitive reward and this learning circuitry and it hijacks the system into this compulsive drug seeking behavior it may be pre-existing but high impulsivity may be a risk factor but it's also clearly from the behavioral study I showed it's affected by the use of drugs as well and the brain is amazingly plastic and resilient there is some recovery in the brain with time sober some of the people that I've been working with they've been using methamphetamine on a daily basis for 25 years so they're really heavily addicted to the substances but even they will show some recovery of function it will never recover to the pre-drug levels but I think it's really important message to give people that are struggling with addiction that your brain can recover much easier and you know there's a positive message to keep to stay clean so this brings me to ADHD and stimulant medication so how many of you think that maybe medicating kids with stimulants might actually increase the risk for future drug abuse? Does anybody here think that? Okay that is something that's very commonly thought a very important issue to look at stimulants are very commonly prescribed for ADHD so two of the very common ones are Ritalin and methamphetamine and Adderall which is a form of amphetamine so they're chemically pretty similar to stimulant drugs of abuse however there's a big difference between them and a very important difference so this is showing cocaine entering the system so you can see this big spike here that's cocaine the dopamine surge is very very rapid when you snort or inject cocaine it gets into your system very very fast there's a rapid burst of dopamine and you can see people self reports of feeling high is just practically completely overlapping especially here and then it goes down again so this is a really really important message the high is related to how quickly this dopamine burst happens and as I mentioned earlier being high is an important part of the addiction process without that pleasant feeling that high feeling you know there's going to be not really much point in using these substances so you can see here again Volkoff did this really really nice study where she looked at injecting an amount of methylphenidate versus a clinically therapeutic dose given orally and you can see the injection is pretty much like the cocaine it goes right in and starts to come down however the oral is really really slow and it builds up and it kind of stays now when you look at people's self reports of feeling high this is the injected one they're feeling high when you look at this there's no reported feelings of feeling high so that's a really critical point methylphenidate or any stimulant ADHD medication when effectively prescribed and taken the way it was prescribed doesn't make you feel high and it's not going to be abusable like you know snorting cocaine or injecting methamphetamine it's not the same thing there are two very different things so a number of people have looked at this now there's an animal literature which conflicts a lot with the human literature but when you look in humans which are maybe not really comparable to animals in some ways there's a couple of different findings no studies have found that it's actually increased the risk one study in 2010 actually found that it protected kids from future substance abuse so early in effective treatment medication treatment of ADHD in this study had a protective effect and it decreased the risk of future substance use subsequent studies have found that it neither protects nor increases the risk so that's a very very important message and again if you think about the theories that I spoke about earlier about how children with uncontrolled ADHD symptoms tend to do poorly in school, poorly socially they start going down this bad pathway and they start getting led into substance abuse this is a really really important message it's important to give them self esteem and good social interactions and healthy relationships and that will protect against substance abuse so there is no evidence that it actually increases the risk for substance abuse I just wanted to show you some interesting even though I said that caveat about the animal studies it may depend so we need a lot more research in this area it's the ADHD and substance abuse comorbidity is a very very controversial one in terms of treatment and a lot of medical professionals don't feel comfortable treating the two because they may not know enough about adult ADHD they may not know there are abusable drugs so you have to be very careful what you prescribe so a lot more research is needed in this area this is just anecdotal and I don't personally prescribe to the self medication hypothesis of ADHD and substance abuse but in all of the methamphetamine users that have come through my study it's almost to a diagnostic level the way they respond I ask them how did the methamphetamine make you feel when it was in your system and the people that don't have high flags for ADHD just say paranoid and whatever your classic picture is of people who do methamphetamine and people who have high ratings of ADHD say things like well I would organize my closet or I would do a crossword puzzle so I'm not saying that they actively seek this out because they have ADHD because I think they're not even aware of that but it's just another reason to continue using it once you use this it feels good hey it helps me organize my closet and I get to do things and I have lots of energy and I can focus a little bit more to keep using and for an addict you don't need any more reasons to keep using because there's plenty like I've shown you the drug itself does a good job of that so some studies suggest that earlier treatment of ADHD is critical so the earlier you can get the symptoms under control get the kid on a good path healthy social interactions a good tool performance that's going to ultimately benefit the child in a huge way there's a recent study that came out last year by Jordan Nadal and again this is an animal study so I'm not saying that this is absolutely true but I just thought it was interesting and just shows we need to research this more they looked at rats and cocaine use so what they did was they have these rat models of ADHD so they gave adolescent rats who had never been treated for ADHD prior to adolescence and they gave them either methylphenidate or dextramphetamine and they found in the adolescent rats that they did better when they were prescribed dextramphetamine in adolescence instead of methylphenidate so my point is the point at which we medicate may be important what we medicate with may be important at what stage and individual differences are really really important so a very careful thought as Dr. Pakirek said has to go into each individual case and we have to really pay attention to each individual again people with ADHD people with substance abuse they have these disruptions in the dopaminergic and reward system those with ADHD and those who abuse substances share common features like this cognitive control impairments, decision making impulsivity and there are elevated rates of substance abuse in ADHD there's no evidence that effective treatment of ADHD with stimulant medication leads to risk for substance abuse in humans in fact it may protect from addiction depending on whether you're medicated, how effectively you're treated etc that's a really important point, thank you we have time for questions from the audience because that seems to be a common occurrence yes there are and obviously there's a lot of so the question was about typically developing adolescents and young adults who are abusing stimulant medications so they're not they don't have ADHD they're using it for whatever reason to enhance their school performance or yes that does unfortunately that does happen and there are a lot of studies looking at this Marty Paulus when he was at San Diego he looked at college students abusing ADHD medication we don't really know definitively what effect that abusing stimulant medication has on the typically developing brain but if you look at inappropriate use of stimulants in the case of drug abuse how it affects your prefrontal cortex how it affects other brain regions that would be a warning sign I would say because you have not been prescribed this medication you know you don't know if you're taking the correct dosage you're not sure if you're taking it in the correct way so and there's no risk benefit trade off to you taking it people with ADHD need the medication if they don't they have all sorts of adverse effects on their brain and on their health due to these poor social interactions failing in school all these things so you don't have that as a typical person you're just trying to get better grades so it's not definitive yet how it affects the brain but I would say it's probably not a good idea to do it but it's unfortunate because it does create this controversy in the field about ADHD medication and people who are legitimately taking it and it also makes psychiatrists in academic institutions extremely reticent to prescribe ADHD medications which as we've talked about earlier is good you want to do a careful work up but you don't want to avoid giving somebody who really needs the medication the medication for these reasons so it's unfortunate but it certainly does occur quite frequently and we don't really fully understand it yet what about non-stimulant medication is there any relationship between that and substance abuse I don't know the answer to that I my main focus is on stimulants and stimulant abuse so I don't know I'm not sure what the answer to that is maybe Dr. Packereck or Dr. Schweitzer might know the answer to that at the table session so I was just thinking about how people with legitimate pain who take opiates it's the same kind of thing that you were describing previously it was mentioned in one of the presentations that clonidine is something that's used for ADHD I had only heard of clonidine being used previously in terms of treating opiate withdrawal so is there some kind of correlation between treating opiate withdrawal and treating ADHD I don't think so I think a lot of different medications have different uses but the opiate epidemic is a huge one and again as you've raised it's a really thorny issue because I work with Sacramento Drug Court that's where I'm currently conducting my study and the rate of heroin abuse has skyrocketed I mean you know this it's in the news everywhere and it's because of painkillers however you know people are in legitimate pain and need to be prescribed these medications so I think it's really really important for people for doctors to monitor their patients familial support is really really important and you know we need to really carefully look at each person and on an individual basis and see warning signs for opiate dependence but not you know stop medicating people who actually need it so you know the whole familial support aspect is really really important in treating substance abuse and ADHD as well recent studies have shown that because this comes up all the time with clinicians how do I treat somebody who has a history of substance abuse who has ADHD I'm terrified of giving them a stimulant it's possible that they may abuse it you can go with a non stimulant medication but that might not be effective for everyone so studies show that family support is critical psychotherapy all sorts of cognitive therapies all of these things used together and a lot of support for the patient and that's what will get them through so I think that's you know consistent message that we've had throughout all the talks is that support systems are really really important sorry I got off topic a little bit there Hi, how does trauma in either early childhood or early adulthood affect the neurology of brain development related to diagnosis of ADHD later in life and possible substance abuse you know there are factors that can happen in usual and also in early childhood that can manifest as ADHD like symptoms I think it's unclear as to the spectrum of ADHD where these things fit in is that different from having some sort of genetic predisposition that your brain just developed in a certain way I'm not sure of the correlation between early brain insult and substance abuse but I'm sure you're aware substance abuse is incredibly complex issue early traumas in childhood just traumatic experiences not necessarily brain traumas they can cause substance abuse issues in later life whether it be you know physical, emotional sexual abuse there's all sorts of factors that come into play when looking at substance abuse and then substance abuse at ADHD as well you might be more vulnerable to these things impacting you if you have poor decision making processes and poor cognitive control to start with so again you know it comes down to the individual and yeah we have to look at these things on an individual basis my research mainly focuses on you know the brain mechanisms and I do collect data on family support structure you know lifetime traumatic events past year traumatic events that have occurred in the past year but I mainly focus because all of these things are important but I mainly focus on looking at the brain itself and how it relates to substance use but there's so many factors that are involved in substance use it's a very very complicated issue I've noticed in adolescents that I've known as well as adults that I've known both with ADHD they tend to be really drawn to pot why is that? That's a very very good question so a lot of people with ADHD report that the pot calms their racing thoughts and they argue that it actually helps them to focus I think we really need a lot more research in this area we're not really sure how marijuana affects motivation, attention learning in people with ADHD so it may very well be that they have this subjective feeling that it's calming the racing thoughts and that it's helping some of their symptoms but we're not really sure how much it impacts attention, motivation learning, all of those things so I think that's maybe how they're drawn to it is because it does help them relax it helps them to get rid of these racing thoughts in their minds and focus somewhat but especially with the legalization of marijuana now this is a really critical area that we have to look at because we just don't know we know that it's marijuana may have impacts on the developing brain so I would imagine that in ADHD where you've already got impairments and certain compromising brain function in cognitive and reward systems that it could exacerbate the normal problem there is in typical development so these are all questions that we really need to look at but yes, a lot of people with ADHD do report that and some clinicians are actually prescribing pot for people with ADHD which I don't know I'm open, maybe it does help but I don't think there's enough research to know exactly what it does to the brain yet in ADHD for sure Hi, thanks I want to thank you Catherine and your peers for coming here today I think that's really great I have a question about mothers and pregnancy and the effect that methamphetamine or a heroin mother would have during and post-delivery on that infant and child being more susceptible to having ADHD and is there a way for us to intervene early to help these young infants and children be caught in time to get the support they need through their young lives, adolescence and into adulthood? Yes, that's a really good question as well I think there is evidence to suggest that drug use and alcohol use during pregnancy does have sometimes not so subtle effects on attention in children however it's a really delicate balance I'm not a medical professional but I think it's really really important not to stigmatize mothers who are addicts because a lot of the time mothers will perceive when they go in and they're addicts and they are pregnant they will perceive that they're being judged, they're frightened they think that they might be social services will be called on them and their child will be taken away which may or may not be appropriate but the point is they will avoid coming in and this has been shown in research they'll avoid coming in for prenatal care and as you know that also has an effect on the developing fetus so depending on the substance using and depending on how much support she has and how feasible it is to help her to stop using the substances that's really really critical and important because they have to come in for prenatal care first and they have to feel that they're not being judged and we recently published a study which showed that in a group of women who were coming in they had extremely negative experiences unfortunately going for a prenatal appointment and there were drug addicts so I think it's important to get them help it's important to get them off the drug if possible if not to sort of maintain them maybe some replacement therapy or something like that because if they just try to get off on their own it could have serious physical effects on themselves and their pregnancy too so it's a very very complicated issue for sure you know some children have shown to have cognitive impairments when their mothers have been abusing and again support is needed but I think the really important message is not to stigmatize people and to try to give them positive support and help throughout their pregnancy if that's maintaining them if that's helping them to get off the drugs in whatever fashion you mean ADHD medication there are studies that look I haven't done it myself but I have come across studies where they've looked at Parkinson's and shown that it's a separate I believe if I remember correctly that it's not there's no correlation between the two and that it's subtly different they do obviously have commonalities but I haven't done the research myself but I have come across a paper before where they looked at Parkinson's and it wasn't ADHD medication actually it was stimulant abuse but I'm not sure I'm aware of any studies that have looked at the long term effects of ADHD medication and correlation with Parkinson's I'm not aware that there is one but I I'm not sure I think it's similar to what Dr. Pacurek said some people do outgrow their ADHD and some people outgrow their need to take ADHD medication so again it comes down to effective treatment of a patient on an individual basis so some patients may need to be on stimulant medication for the rest of their lives and other people may only have to take it for a short while it really varies from person to person and ADHD itself is an extremely heterogeneous disorder so if that answers your question I don't suggest that people stay on medication for the rest of their lives if it's not necessary but I think some people do need to take medication for the rest of their lives and it's again it's a risk benefit calculation you know how damaging environment can damage your brain as well if you're not having healthy interactions if you're not able to hold down a job if you're not able to cope with life that's going to have negative effects on your brain as well so the key is how does your ADHD impact your life and how what can you be treated with that's going to help you navigate your life to the point where you can function and where you're happy thank you so much Dr. Fassbender thank you thank you these are all excellent questions and you're going to have an opportunity to ask many more questions at the next session after the break so please if you haven't filled these out fill these out and pop them in the boxes and we'll be able to get more dialogue going in the next session so we have 15 minutes please be back here at 2.30 with your questions thank you