Biological Foundations of Mental Health Week 5 Reward, emotion & action PDF

Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 3 The reward system of the brain Dr Sylvane Desrivieres Department of Social Genetic and Development Psychiatry Lecture transcript Slide 1 In this lecture, I will describe the reward system of the brain. But before...

Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 3 The reward system of the brain Dr Sylvane Desrivieres Department of Social Genetic and Development Psychiatry Lecture transcript Slide 1 In this lecture, I will describe the reward system of the brain. But before I go into details about the reward pathway, let us define the notions of reward and positive reinforcement. Slide 2 Humans, as well as other organisms, engage spontaneously in behaviours that are rewarding. And they do so because the pleasurable feelings that are associated with the reward provide positive reinforcement, which means that the behaviour is repeated. So we can say that a reward is an appetitive stimulus, that when given to a human or another animal, alters its behaviour by producing positive reinforcement. Now rewards can be classified into two categories-- natural rewards and artificial rewards, such as drugs of abuse. Slide 3 Examples of natural rewards include food, water, sex, and nurturing. All of these reinforce behaviours that are necessary for our survival. With such a role of the reward pathway in motivation and reinforcement, it is important to note that this hedonic system can be deregulated in people suffering from various psychiatric orders, for example, people suffering from eating and affecting disorders, and hedonia-- that is, a lack of pleasure-- or dysphoria, a negative affect-- and also in people abusing drugs. I will show examples of this later in the lecture. And there is a pathway in the brain that is responsible for our responses to rewards, which you can see in the next slide. Slide 4 Responses to rewards are mediated primarily by the ascending mesolimbic dopamine pathway, that plays a primary role in the reward system. The mesolimbic dopamine pathway connects the ventral tegmental area, VTA, one of the principal dopamine-producing areas in the brain, with the nucleus accumbens. That is an area found in the ventral striatum, that is strongly associated with motivation and reward. Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. Another major dopamine pathway, the mesocortical pathway, travels from the VTA to the prefrontal cortex, and is also considered part of the reward system. So the reward system is generally considered to be made up of the main dopamine pathways of the brain, and especially of the mesolimbic pathway, and also formed by structures like the VTA in the nucleus accumbens, which are connected by these dopamine pathways. As the structures that are associated with the reward system are found along the major dopamine pathways in the brain, it is not surprising that the brain responds by increasing the release of a neurotransmitter, dopamine, when it is exposed to a rewarding stimulus. So because this pathway is a key detector of a rewarding stimulus, it is an important determinant of motivation and incentive drive. So in simplistic terms, activation of this pathway tells the individuals to repeat what it did to get that reward. Not surprisingly, it is a very old pathway from an evolutionary point of view. For example, the use of dopamine neurons to mediate behavioural responses to natural rewards is seen in worms and flies which have evolved one to two billion years ago. Slide 5 But how was this brain reward pathway discovered? Its discovery came from pioneering experiences by two scientists, James Olds and Peter Milner, who performed intracranial self-simulation experiments in rats, in 1954. These experiments consisted in implanting electrodes in the brains of rats and allowing the animals to self-stimulate by pressing a lever that delivered a mild burst of electrical current to stimulate the neurons. What they discovered is that electrical stimulation in certain parts of the brain, particularly in the septal area, which lies close to the nucleus accumbens, would produce the strongest effects, making rats to self-stimulate repeatedly. Olds and Milner’s experiments were significant, because they appeared to verify the existence of brain structures that were responsible for rewarding experiences. Because if the rats pressed the lever repeatedly to receive stimulation to these areas, it suggested that the experience was rewarding. Various rewards sites have been identified in the brain since these initial experiments. And it was discovered that some of the most sensitive areas are situated along the length of the medial forebrain bundle. That is a large collection of nerve fibres that travels between the VTA and the lateral hypothalamus, and towards the nucleus accumbens. Some areas of a medial forebrain bundle were found to be so sensitive, that rats would choose receiving stimulation to them over food or sex. Eventually, it was recognised that dopamine neurons are activated during this type of rewarding brain stimulation, and researchers found that they could cause rats to stop press a lever by administering a dopamine antagonist, that is a drug that blocks the effect of dopamine. In other words, without the activity of dopamine, the rats were less likely to find brain stimulation reinforcing, and so they stopped pressing the lever altogether. Now it is important to notice that like with self-stimulation, the reward pathway is strongly activated by drugs of abuse, who all induce release of dopamine at dopamine terminals, including the nucleus accumbens. Slide 6 The drugs induced the release of dopamine in the nucleus accumbens was demonstrated with experiments in which a small microdialysis probe was implanted into the brains of freely moving rats. And this allowed to measure the amount of dopamine that is released into the extrasynaptic space. Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. You can see on this figure, that injection of rats with drugs such as ethanol and morphine, resulted in strong release of dopamine in the nucleus accumbens, and also, but to a lesser extent, to some release in the dorsal caudate nucleus. That is a part of the dorsal striatum. You can also note that both the magnitude that is the amount of dopamine released and the duration of the effect increase with the dose of the drug. Although it is not shown on this figure, most drugs abused by humans, which include opiates, ethanol, nicotine, amphetamine, and cocaine, can activate the reward pathway by inducing the release of dopamine in the nucleus accumbens, and have the same dose dependent effect. The very strong effect of drugs on dopamine release explains why drugs are more addictive than natural rewards. When some drugs are taken, they can release 2 to 10 times the amount of dopamine than natural rewards do. This can occur almost immediately, when drugs are smoked or injected. And the effects can last much longer than those produced by natural rewards. The resulting effects on the brain’s reward pathway dwarf those produced by natural rewards, and the effect of such a powerful reward strongly motivates people to take drugs again and again. Moreover, this deregulated dopamine release affects all the brain circuits, alerting all the brain regions of novel rewarding experience, and recruiting other neurotransmitter systems. But how does simulation of the brain’s reward circuits can teach one to keep taking drugs? Our brains are wired to ensure that we will repeat life sustaining activities by associating those activities with pleasure or reward. So whenever the reward circuit is activated, the brain notes that something important is happening that needs to be remembered, and teaches us to do it again and again and again without thinking about it. Because drugs of abuse stimulate the same circuit, we learn to abuse drugs in the same way, and this is why scientists sometimes say that drug abuse is something we learn to do very, very well. Slide 7 But what if the reward pathway becomes persistently activated? Such persistent activation of the reward pathway occurs in the case of chronic drug abusers or even in individuals consuming unusually large quantity of food. To answer this question, scientists have quantified dopamine neurotransmission in the brains of addicted or obese individuals, using positron emission tomography-- PET. They have found that compared to non-addicted or non-obese control subjects, individuals that were addicted or obese had reduced levels of dopamine D2 and D3 receptors in their striatum. This reduction of dopamine D2 and D3 receptors in the striatum is evidenced by the decreased intensity of the red signal in this figure. This shows that new adaptations occur in the brain following over activation with a reward pathway, and that the brain adjusts to the overwhelming surges in dopamine and other neurotransmitters by producing less dopamine, or by reducing the number of receptors that can receive signals. Slide 8 So what could be the consequences of such neural adaptations? A current hypothesis is that dopamine’s impact on the reward circuit could become abnormally low, considerably reducing that person’s ability to experience any pleasure. This would then explain why the chronic drug abuser eventually feels flat, depressed, and unable to enjoy things that previously brought pleasure. So such drug abusers need to take drugs just to try and bring their dopamine function back up to normal. This could also explain why tolerance develop, requiring large amounts of the drug to create the dopamine high. Transcripts by 3Playmedia Week 5 © King’s College London 2017 3. Slide 9 All reinforcing drugs induce the release of dopamine in the nucleus accumbens, but they use distinct mechanisms to do so. But before looking at how drugs interfere with the mesolimbic reward pathway, let us analyse the major types of neurons that are part of this pathway. We have already seen that dopamine neurons in the ventral tegmental area project to the nucleus accumbens where they release dopamine when activated. What is also important is to know that VTA neurons are under the inhibitory control of local GABAergic interneurons. So activation of those GABAergic VTA neurons would prevent release of dopamine in the nucleus accumbens by inhibiting VTA dopamine neurons. So how do different drugs act? They control the activity of these neural mechanisms by various means. For example, nicotine activates VTA dopamine cells directly by banding to nicotinic acetylcholine receptors that are expressed on their surface, which causes dopamine to be released in the nucleus accumbens. Psychomotor stimulants like cocaine and amphetamine, increase the concentration of dopamine in the synaptic cleft in the nucleus accumbens, through direct actions on dopamine transporters at dopamine terminals. The rewarding properties of opiates are mediated by their binding to mu-opioid receptors that are found in two locations in the brain reward circuits. Mu-opioid receptors are expressed on the GABAergic VTA interneurons, and opioids accurately inhibit these interneurons, causing disinhibition of the dopamine VTA neurons, and consequently release of dopamine in the nucleus accumbens and other terminal fields. Mu-opioid receptors are also expressed on the nucleus accumbens and on dorsal striatal neurons. Opiates can stimulate these receptors directly, and therefore, produce reward in a dopamine independent manner. As for alcohol, it facilitates the release of dopamine in the nucleus accumbens by indirectly activating dopamine neurons. Alcohol inhibits GABAergic VTA interneurons by binding to gamma aminobutyric acid A receptors on those neurons, and by facilitating the release of opioid peptides in the VTA. In addition, alcohol-induced release of opioid peptides in the nucleus accumbens could also produce reward in a dopamine independent manner. Slide 10 We have, so far, detailed the fundamental role of dopamine and the mesolimbic dopamine system in reward. But it is important to note that since the earliest research on the reward system, our perspective on dopamine’s role in reward has changed slightly. At one time, dopamine was considered to be the neurotransmitter responsible for causing the experience of pleasure. But it is now thought to be involved in aspects of reward other than the direct experience of pleasure. Likewise, the mesolimbic dopamine system clearly plays an important role in reward, but that role may not be as hedonic as previously thought. This slide shows experimental examples suggesting that dopamine is not a hedonic signal, which means not a pleasure signal, but a signal for motivated behaviour. A more current view, either dopamine does not cause hedonic reactions or pleasure, but rather more specifically increases the motivation components of reward, such as incentive salients, producing wanting or seeking without causing liking or show hedonic impact. Another major alternative hypothesis is that dopamine causes learning about rewards. Transcripts by 3Playmedia Week 5 © King’s College London 2017 4. Slide 11 Not only does the reward system involve more than dopamine, but brain circuitries other than the mesolimbic dopamine pathway are critically involved in mediating the effects of reinforcement. One has to remember that the mesolimbic pathway does not act in isolation, but is part of a series of integrated circuits which involve several other key brain regions-- at the centre of this network, the cortical basal ganglia circuit. This circuit involves cortical areas, such as the orbital frontal cortex and the interior cingulate cortex, that work in concert with basal ganglia structures like the ventral striatum, the ventral pallidum, and the mid-brain dopamine neurons, to execute motivated, well-planned behaviours. For example, the ventral striatum receives major cortical input for the orbital frontal cortex and the interior single cortex, and substantial dopaminergic input from the ventral tegmental area and the substantia nigra. On the other hand, the ventral striatum sends projections through the ventral tegmental area and substantia nigra, and to the ventral pallidum, which in turn, via the medial dorsal nucleus of the thalamus, project back to the prefrontal cortex. Other circuits work in tandem with elements of the reward system to develop appropriate goaldirected actions, which relies on the combined interplay of sensory inputs, emotional informations, and memories of prior outcomes. For example, a reward pathway tells the memory centres in the brain, which involve the hippocampus and the amygdala, to pay particular attention to all features of this rewarding experience so that it can be repeated in the future. In this respect, the amygdala, which is particularly important for conditioned forms of learning, interacts with the VTA nucleus accumbens pathway to determine the rewarding or aversive value of an environmental stimulus. By doing so, it helps an organism establish associations between environmental cues and whether or not that particular experience was rewarding or aversive-- for example, remembering what was associated with finding food or fleeing a predator. On the other hand, the hippocampus is critical for declarative memory-- the memory of persons, places, or things. Along with the amygdala, it establishes memories of drug experiences, for example, which are important mediators of relapse. Slide 12 Various behavioural mechanisms of reward can be measured nowadays thanks to advances in neuroimaging technologies. For example, a functional neuroimaging task called the monitory incentive delay task, or MID task, can be used to measure brain activation patterns that are associated with specific aspects of reward in humans. In this test, subject lay under an MRI scanner that will cause brain activation patterns, while they play repeated trials in which they win or lose money, or any equivalent incentive, depending on their ability to pay attention and react quickly. This task is the reaction time task, which means that it tests how quickly the subject can react and pull the trigger to hit a target that only appears for a short time on the screen. If the subject can hit the target, they will score points. Subject can tell where the target will appear and how many points it can win by the symbol they see on the screen before each trial. For example, a circle with three lines, as in this picture, means 10 points. Responding too early or too late will result in a loss. The subjects receive one incentive-- money or equivalent-- for points to enhance motivation during the task. Patterns of brain activity are recorded when a reward is anticipated, that is, after the cue is given, but before the subject hits the target, or when receiving the outcome. In this task, regions of the reward system, such as the nucleus accumbens, are activated when a reward is anticipated. Transcripts by 3Playmedia Week 5 © King’s College London 2017 5. Slide 13 We use the MID task to study the reward system in our group. One of our aims is to understand how deficits in reward processing is implicated in mental disorders, such as attention deficit hyperactivity disorder, ADHD, and addictions. First, we have analysed a large sample of 13-year-old adolescents, trying to define clusters of brain activation patterns in their whole brain, while they anticipated a reward in the MID task. In this way, we found that not only structure that are associated with the reward pathway were activated during a reward anticipation in this task, but several of the clusters were also identified. You can see on this figure the location of these clusters. One cluster consisted of the caudate, putamen, and nucleus accumbens, that all form part of the striatum. And this is a cluster that we named the Reward Cluster. Another cluster that we labelled the Attention Cluster, included areas of the occipital cortex involved in early visual processing. Third cluster, the Response Preparation Cluster, including cortical somatosensory and motor areas. We then explored the relation of these ephemeral clusters with behavioural outcomes that are relevant for ADHD and addictive behaviours. We observed that a low activation in the reward cluster is associated with high ADHD related hyperactivity in boys. On the other hand, the Attention Cluster and the Response Preparation cluster, showed significant negative association with lifetime alcohol consumption. Overall, our results indicate that specific reward-related brain processes relate to distinct and clinically relevant behaviours. They also indicate that functional collections related to reward anticipation, such as reward processing, attention processing, and response preparation, are differentially associated with adolescent ADHD symptoms and alcohol consumption. Slide 14 In summary, we have seen that the reward system refers to a group of structures that is involved in mediating rewarding experiences. But while it is evident that the mesolimbic dopamine pathway is implicated in pleasurable and potentially addictive behaviours, the substrates of pleasure are not confined to this system. We have also seen that dopamine is not the only neurotransmitter involved. In fact, we have seen that the actual network dedicated to creating the feelings we associate with rewarding or aversive experiences is more complex. Finally, I have shown you that current research using neuroimaging approaches aims at better understanding the distinct contribution of components of the reward system in psychiatric disorders, such as drug addiction, ADHD, and depression. Transcripts by 3Playmedia Week 5 © King’s College London 2017 6. Module: Biological Foundations of Mental Health Week 5 Biological basis of learning, memory & cognition Topic 1 Cerebral cortex and mental health - Part 1 of 3 Professor Francesca Happé Professor of Cognitive Neuroscience, Institute of Psychiatry, Psychology and Neuroscience Lecture transcript Slide 4 In previous topics, you have learned about the structure of the brain and the sensory and motor areas of the cortex. In this topic, we will look at the function of the association cortex and specifically the frontal lobes. You will learn about the high-order control functions that allow us to deal with new situations and the vital role of the frontal lobes in this behavioural and cognitive flexibility. We will also look at what happens when the frontal lobes are affected by acquired or developmental disorders. Slide 5 The brain is traditionally divided into different areas. The cortex can be divided into primary sensory and motor areas, secondary sensorimotor areas, and association cortices. This topic will focus on the functions of the association cortex and the relevance of this part of the brain for understanding acquired, developmental, and psychiatric disorders. The association cortex takes information from primary and secondary sensory and motor cortices as well as the brain stem and thalamus. It sends information to the cerebellum, basal ganglia, and hippocampus. And information also flows between the different association cortices. Slide 6 We often think about information flowing from lower to higher-level areas in the brain-- for example, from primary visual cortex to regions where objects are recognised and named. However, information also flows top-down from higher-level areas to modulate activity in primary sensory cortex. In this way, our expectations from context or prior experience can influence how we interpret ambiguous stimuli. This top-down influence is responsible for some interesting perceptual effects. For example, take a look at these blobs. Can you see anything meaningful in them? Now have a look at this picture. Here are those blobs again. Do you see what they are now? The blobs haven’t changed, but the topdown information in your brain has. Now your knowledge from the picture helped you complete the perception of the blobs and see them as a face. The association cortex integrates sensory and motor information to produce meaningful perception of the world around us. But it does more than this. It allows abstract representation and supports flexible behaviour. Transcripts by 3Playmedia Week 5 © King’s College London 2019 1. Slide 7 The association cortex can be divided into three-- the posterior or parietal association area, the limbic or temporal association area, and the anterior or frontal association area. These association areas have different but interconnected functions. The posterior association area is important for attention and the convergence of sensory information. Here, the visual, auditory, and somatosensory information meets. The limbic association area is involved in forming long-term memories and emotional responses which will, in turn, affect how we behave. The anterior association area-- the frontal lobes, including the prefrontal cortex-- is vital for planning, decision making, and working memory. The frontal association area is particularly important for mental health. Many psychiatric and neurodevelopmental conditions are believed to involve abnormal functioning of the frontal lobes, and especially the prefrontal cortex. Slide 8 The frontal cortex plays a vital role in a set of higher-order cognitive processes termed executive functions. What are executive functions? This is a term that covers lots of different control functions that allow flexible behaviour. These include generating, planning, monitoring, switching, and inhibiting behaviour. All these are especially important when we are faced with novel situations or challenges. Think about a time when you have had to cope with change-- for example, if you have a bathroom redecorated and maybe have a light switch where you used to have a pull cord. You might find you reach up automatically to where the light pull used to be. Your frontal lobes need to kick in to help you inhibit that now-irrelevant action. Let’s take a closer look at some executive functions and how they are typically tested or measured. Transcripts by 3Playmedia Week 5 © King’s College London 2019 2. Module: Biological Foundations of Mental Health Week 5 Biological basis of learning, memory & cognition Topic 1 Cerebral cortex and mental health - Part 2 of 3 Professor Francesca Happé Professor of Cognitive Neuroscience, Institute of Psychiatry, Psychology and Neuroscience Lecture transcript Slide 3 In 1948, Grant and Berg published their now very famous Wisconsin Card Sorting Test. It is a test of cognitive reasoning. In the Wisconsin Cart Sort Test, you have to classify cards according to different criteria. You have three ways to classify a card, and the only feedback you get is whether you are doing it correctly or not. Cards can be classified according to the colour of its symbols, the shape of the symbols, or the number of the shapes on each card. Let’s watch as someone plays the game. Our player chooses blue squares first. She’s lucky, because the first rule needs her to classify the cards by colour. She continues to follow the colour rule. Then suddenly the rule changes. Our player now has to decide on which rule to try out. She can choose either shape or number. She chooses number, and again, she is lucky. As you will notice later when you try the game yourself, after the rule changes, you are prone to making more mistakes. The task measures how well people can adapt to the changing rules. Slide 4 The Tower of Hanoi was designed to test your cognitive abilities. The rules of the game are straightforward. You are presented with three pegs and a number of discs stacked up on one of the pegs in order of size, with the biggest disc at the bottom. Your task is to transfer the whole tower onto a different peg disc by disc, but you are not ever allowed to place the larger disc onto a smaller one. To do this task, you have to think ahead several moves to make the best decisions. The task tests your ability to plan. Let’s watch as someone plays the game. Slide 5 In this task, you are presented with a number of coloured shapes and are then asked to name the colours as fast as you can from left to right. Once you have completed this task, you are given a similar list. But this time, you are not presented with shapes but rather with coloured words. The trick is that the actual word red, for example, is not necessarily coloured red but blue or some other colour. You are then asked to name the colour the word is printed in as opposed to the colour the word spells out. Why not try it for yourself? Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. You will notice that it is much harder to get the colour right when reading the words, because the printed word distracts you. Reading is automatic, and it takes effort to suppress the meaning it generates. So the Stroop task measures inhibitory control. Slide 6 The final task we look at is commonly used as an assessment in cognitive neuroscience to measure attention and working memory. In the task, you are asked to look at a sequence of objects. In the two-back test, you are asked to respond when you see an object repeated after a sequence of two images have been displayed. In a three-back test, you have to wait until you see the same image after a sequence of three images have been displayed, and so on. Let’s have a look at someone playing the two-back game. The sequence starts, and when our player notices that the fish appears again after the pencil, she clicks. And the same happens when she sees the image of the cheese repeated. The game will get harder as the player has to hold longer intervals in mind. Recalling three-back is harder than two, and so on. The n-back game tests working memory. That’s the ability to hold information in mind while you manipulate it. Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. Module: Biological Foundations of Mental Health Week 5 Biological basis of learning, memory & cognition Topic 1 Cerebral cortex and mental health - Part 3 of 3 Professor Francesca Happé Professor of Cognitive Neuroscience, Institute of Psychiatry, Psychology and Neuroscience Lecture transcript Slide 3 How do we know that the frontal cortex is important for executive functions? There are at least two sorts of evidence, neuroimaging and neuropsychological cases of acquired frontal lobe damage. Slide 4 fMRI studies show prefrontal regions are active when volunteers engage in tasks, like those you just tried, the Wisconsin card sorting test, the Tower of Hanoi, the Stroop task, and the N-back task. Slide 5 Interestingly, frontal regions seem to be particularly important when we’re learning new skills. Once a skill is well established, fMRI studies show less frontal involvement. So to respond flexibly to our environment, frontal regions are essential. This is illustrated in a study by Hampshire, et al., 2015. See how the activation in the frontal regions decreases across the blocks of an inhibition task as the volunteers become more practised at the test. Slide 6 The second source of evidence for the importance of the frontal lobes in executive functions comes from neuropsychological cases of acquired brain damage. When previously healthy people have a head injury or a stroke that damages their frontal lobes, they typically show impairments in judgement and decision-making. Slide 7 A range of psychiatric and neurodevelopmental conditions are also associated with impairments in executive functions and frontal lobe integrity. Autism spectrum disorder, schizophrenia, bipolar disorder, and major depression have all been linked to executive function deficits. Slide 8 Let’s look more closely at autism as an example of a neurodevelopmental disorder where the frontal lobes are implicated. Transcripts by 3Playmedia Week 5 © King’s College London 2019 1. Autism spectrum disorder, or ASD, is a neurodevelopmental condition characterised by impaired social and communicative development, with rigid and repetitive behaviours and interests. Children and adults with ASD show impairment in executive functions, particularly on planning tasks, like the Tower of Hanoi, and set-shifting, like the Wisconsin card sorting test. Most children and adults with ASD dislike change and have a strong preference for narrow routines and repetition. This is thought to reflect impairments in frontal functions that are necessary for adaptive response to change and novelty. Slide 9 What about the social and communication problems that define ASD? These are thought to result from an impairment in recognising what others are thinking, so-called “theory of mind.” Because people with ASD find it hard to recognise what others might think or mean, they are often confused by social situations and struggle with communication. Think how confusing it would be to be told to “paint the child next to you” if you couldn’t guess what the teacher meant. Slide 10 Theory of mind can be tested with a variety of tasks. Watch the following short animation. Slide 11 What does the small triangle want? What is the big triangle trying to do? Let’s look at some more examples. Slide 12 Using animations like these, or static cartoons or written stories that also cause healthy volunteers to think about other people’s thoughts, fMRI studies show activation of medial prefrontal cortex, as well as temporal poles and superior temporal sulcus. People with ASD often simply see triangles moving around and don’t attribute thoughts to them. Asked what was going on in the animations, they might say the red one moved right and then the blue one turned 90 degrees. The brain activity of volunteers with ASD doing theory of mind tests is also different, even when they can answer the test questions correctly. Slide 13 Reduced top-down effects have also been suggested to be important in understanding autism. Remember how seeing the picture of the face helped you see the blobs as a face? People with ASD don’t show that strong top-down effect, especially when they’re looking at faces versus other objects. Slide 14 Unlike acquired frontal lobe patients, people with ASD do not have circumscribed lesions. Instead, it seems the connectivity of different brain regions is atypical. Slide 15 In this session we have looked at the association cortex and focused especially on the frontal lobes and their role in executive functions. Acquired or developmental abnormalities in these regions impair the ability to respond flexibly to novel situations. Because of the importance of these functions, frontal involvement is hypothesised to underlie many psychiatric and neurodevelopmental symptoms. Transcripts by 3Playmedia Week 5 © King’s College London 2019 2. Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 2 The structure and function of the Basal Ganglia - part 1 of 5 Dr Frank Hirth Department of Basic and Clinical Neuroscience Lecture transcript Slide 1 In the following lecture, we will address the basal ganglia. We will go through anatomy to connectivity and functionality, and then we’ll later look at how this function of the basal ganglia relates to specific diseases. We will look at examples of diseases and then we will also look into what the basal ganglia may have to do with free will, and whether their structure is evolutionary conserved. Slide 2 The basal ganglia are located in the basal forebrain. You can see on the left a picture of a human head, where the basal ganglia are located. And on the right side, you can see the basal ganglia anatomy. We have, on the top left-hand side, the caudate nucleus, and on the right-hand side, the putamen. Those together form the striatum. We then have the globus pallidus, which we will see later, comes as an external and an internal segment. We then have the subthalamic nucleus and the substantia nigra. Slide 3 Here again, you can see, from a side view, those components, and then the names of those nuclei. Again the striatum, which in primates consist of caudate, putanem, and the ventral striatum, including the nucleus accumbens. We then have the globus pallidus, which consists of the internal and external domains of the globus pallidus. The subthalamic nucleus and the substantia nigra pars reticulata. Slide 4 Here again on the left-hand side, you see a side-view of the basal ganglia and their location within the brain. And now on the right-hand side, you see a cross-section, like you see when you have postmortem sections of the human brain. Again, you see the caudate nucleus and the putamen, which together form the striatum. The globus pallidus, the internal and external segment, the substantia nigra, and the subthalamic nucleus. Slide 5 The connectivity of the basal ganglia. As you can see on the left-hand side, we have, again, the cross-section where we see the parts of the basal ganglia. And on the right-hand side, you see the connectivity through which those parts of the basal ganglia are connected to other parts in the Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. brain. At the top, you see that cortical input actually projects directly on the striatum, but also on the subthalamic nucleus. The subthalamic nucleus is connected to the external segment of the globus pallidus as well as to the substantia nigra reticulata and the internal segment of the globus pallidus. The striatum has direct connections to the substantia nigra reticulata and the globus pallidus internal segment, as well as to the globus pallidus external segment. You can also see what is called the SNC, that is the substantia nigra pars compacta, where dopaminergic connections project onto the striatum. Importantly, as you can see, the SNR and GPI have a projection to the thalamus and they have a projection to the tectum and thereby influence motor programmes. Slide 6 Here, we see the connectivity of the basal ganglia, but now highlighted are various so-called loops. The connectivity that I just described is repeated several times, and we call them so-called reentrant loops. And they can be categorised because of the functions they are involved in. So we have the sensorimotor loop, we have the associative loop, and the ventral loop. Highlighted are different parts of the cortex, as you can see on the top. And those have connections to various parts of the basal ganglia, such as the putamen, the caudate, the globus pallidus external and internal segments, the substantia nigra, reticulata, and the subthalamic nucleus, and then of course the thalamus, which is a central element as we will see later. Now if you compare the sensorimotor with the associative loop, you can see that different cortical areas are involved. But also, the different connections among the basal ganglia are involved. Slide 7 In the next slide now, we look more at the functional connectivity. Again, as you can see on the lefthand side, we have a cross-section of the brain, which highlights the different nuclei of the basal ganglia. And now on the right side, we have a very, very simple scheme of connectivity. At the top, you see the cortex, you see the striatum, you see the two parts of the globus pallidus, the external GPE and the internal segment at GPI. You see the STN, which is the subthalamic nucleus. You also see, together with the GPI, the substantia nigra pars reticulata and you also see the thalamus. Now what is important are three features. First of all, you see connections that are in green. Those are excitatory connections, that is, they are activating regions that are connected to it. You also see red connections. Those are inhibitory connections. So those activities inhibit the target region. In addition, you can also see that the striatum has two different ways to reach the GPI and SNR, as we will outline in the next slide. Slide 8 Next slide illustrates the functional connectivity of the basal ganglia, and it’s an animated slide where I will guide you through the various parts, their connections, and we will later see why they are important. So again, on the right hand side, you see a cross-section through the brain, with the main parts of the basal ganglia. And on the left-hand side, again, you see the scheme, which highlights the various parts of the basal ganglia, how they are connected with the cortex, with each other, and the thalamus. Now important is the input nuclei of the basal ganglia are the caudate and to putamen, which together form the striatum. Note the red dots on the right-hand cross-section, the caudate nucleus and the putamen. And on the left-hand side, striatum in the scheme. The intrinsic nuclei are the subthalamic nucleus, STN, and the external segment of the globus pallidus. As you can see, the striatum has an inhibitory reconnection onto the globus pallidus external segment, and the GPE itself has also an inhibitory connection to the STN. Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. Next, we look at the output nuclei, which on the right-hand side, you can see with the red dots, is the globus pallidus and a substantia nigra reticulata. On the left-hand side in the scheme, you can see they come together. They are the GPI and the SNR. They receive inhibitory connections from the striatum and excitatory connection from the subthalamic nucleus. This is important. The output nuclei, GPI and SNR, also project inhibitory connections to the thalamus. That is, the basal ganglia nuclei inhibit the thalamus, whereas the thalamus has excitatory connections to the cortex again. Finally, we have neur0modulatory input to the striatum, which comes from the substantia nigra pars compacta, SNC, which are dopaminergic innovations into the striatum. We will later see why they are important. Slide 9 Having established the functional connectivity between the parts of the basal ganglia, the cortex, and the thalamus, let me re-emphasize the parallel loops within the basal ganglia that subserve distinct functions. Remember in a previous slide, we looked at the sensory motor loop, the associative loop, and the ventral loop. Now here again in this scheme, you can see that basically, you can conceptualise these different loops as multiplications of existing connections. But of course, they subserve different functions, which is one of the very important features of the basal ganglia. The multiplication of parallel loops, which are reentrant loops that subserve different functions. Slide 10 Now in order to understand what the basal ganglia actually do, we shall focus on movement and how this is modulated. Now remember what I told you about the different connections within the basal ganglia. The green ones are the excitatory ones and the red ones are the inhibitory ones. Once again, the cortex has excitatory inputs to the striatum. The striatum has inhibitory connections to the output nuclei, the GPI and SNR, and it also has inhibitory connections to the internal nuclei, the GPE, which itself has inhibitory connection to the STN. Now what is important is that the output nuclei have inhibitory connections to the thalamus, and it is this output that is important to understand how movement is modulated through disinhibition. Slide 11 It is highlighted in this slide here, where it is now emphasised the inhibitory connection between GPI and SNR, which are the output nuclei to the thalamus, whereas the thalamus has an excitatory connection to the cortex. Slide 12 So keep in mind that the output nuclei of the basal ganglia are inhibitory, as emphasised by the red inhibitory connection from GPI SNR to the thalamus. Slide 13 The output nuclei maintain a high tonic level of discharge, as you can see in this speech circle, where those different lines represent action potentials. So what you can see is a high tonic activity of the output nuclei. Now because they have inhibitory connections to the thalamus, this high tonic activity suppresses the thalamus. Transcripts by 3Playmedia Week 5 © King’s College London 2017 3. Slide 14 This high tonic activity of the output nuclei and the inhibitory connection of the thalamus actually keeps the thalamus quiet, and hence, there cannot be any excitatory activity on the cortex, which is the absence of movement. Slide 15 Now movement modulation occurs through this inhibition of thalamocortical target regions. How is this achieved? As you can see in the illustration, you would need an impaired activity of the output nuclei, which in turn, as you can see in the animation, does disinhibit the thalamus, which then in turn can cause an excitatory activity towards the cortex. Just look at the speech circles. The tonic activity, the normally tonic activity of the GPI SNR is interrupted in the middle. You don’t see these bars, which represent action potentials. That means during this time, the normally inhibitory activity to the thalamus is interrupted, and this is shown in the speech circle for the thalamus. You see all of a sudden in this corresponding time frame, there is activity, which are these bars that represent action potentials. And because the thalamus has an excitatory connection to the cortex, you can see that there is cortical activity. And this is movement modulation through disinhibition. Slide 16 In the next slide, we can summarise what we have learned so far. So the basal ganglia mediate movement through disinhibition. Key to understand is that the output nuclei of the basal ganglia, the GPI and SNR are inhibitory. They maintain a high tonic level of discharge, thereby suppressing the activity in target regions such as the thalamus. The phasic decrease in firing rate transiently releases the target regions from inhibition. It thereby causes disinhibition, which then can lead to thalamocortical activity, and thereby promote movement. Transcripts by 3Playmedia Week 5 © King’s College London 2017 4. Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 2 The structure and function of the Basal Ganglia - part 2 of 5 Dr Frank Hirth Department of Basic and Clinical Neuroscience Lecture transcript Slide 2 Now we are able to look into another very, very important concept of the basal ganglia. And that is the direct and indirect pathways. Those are pathways that play a crucial role in understanding how the basal ganglia function, and why their dysfunction has such a wide range of disabilities as a consequence. What we are looking at now is the two ways the striatum innovates either the output nuclei or the indirect nuclei. Slide 3 So let’s first look at the direct pathway. The direct pathway is the direct connection from the striatum to the output nuclei. And as I said before, this is an inhibitory connection. So the direct pathway is the direct connection from the striatum to the GPi/SNr. Slide 4 The basal firing rates in the striatum are very low, and dependent upon cortical excitation. That means if the striatum is not activated by excitatory cortical connections, there’s not much activity. Hence, its inhibitory connection to the output nuclei is low. Slide 5 Under these conditions, striatal firing has little impact on the output nuclei, as you can see here. Remember, the output nuclei show a high rate of tonic firing, which is inhibitory on the thalamus. Now, because the striatum is not activated, its inhibitory connection to the GPi/SNr has no effect. Slide 6 Now, phasic cortical excitation drives excitatory discharge in the striatum. Again, you can see that animated by these little bars, which represent action potentials. Now, the cortex has excitatory connections to the striatum. This causes activation of the striatum. Now, because the striatum has an inhibitory connection to the GPi/SNr, it causes a transient inhibition of GPi/SNr firing. Slide 7 As a consequence, this activation of the direct pathway promotes action. Why? Because in that phase Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. where striatal inhibitory activity inhibits GPi/SNr activity, the output nuclei are not inhibitory on the thalamus. And this can promote action. So let me summarise. The activation of the direct pathway promotes action. And this is because the striatum has an inhibitory activity on the output nuclei, the GPi/SNr. And because it is inhibitory and the GPi is inhibitory in the thalamus, what you have is a disinhibition of thalamic activity, which thereby promotes action. Slide 8 Now let’s have a look at the indirect pathway. As mentioned beforehand, we are now looking at the connections from the striatum to the intrinsic nuclei, which is highlighted here. So the striatum has an inhibitory connection to the globus pallidus external segment, with the globus pallidus external segment having an inhibitory connection to the subthalamic nucleus. And the subthalamic nucleus in turn has an excitatory connection to the GPi/SNr, which are the output nuclei. Slide 9 Now again let’s consider that striatal neurons have low tonic firing rates. Again, dependent upon strong cortical inputs. So without cortical input, the striatum doesn’t have much activity. That is, in this case of the indirect pathway, it does not impose inhibitory activity on the GPe. Slide 10 Now, GPe neurons are similar to those in the internal segment. They have high tonic firing rates. Keep that in mind. The GPe, the external segment of the globus pallidus, has a high tonic firing rate. Slide 11 And because of inhibitory activity of the GPe neurons, the subthalamic nucleus activity is suppressed. Slide 12 Firing under these conditions causes high discharge in the output nuclei GPi/SNr because they are anyway tonically active, and they are inhibitory to the thalamus. So because the STN is not able to have excitatory activity to the GPi/SNr, their inhibitory activity is not suppressed. Slide 13 Now, what happens to the indirect pathway when we have strong phasic cortical excitation? Focus on the indirect pathway on the left-hand side. You have phasic cortical excitation. Slide 14 It now causes a transient inhibition of the external globus pallidus because the striatum has an inhibitory connection on the GPe, and because the GPe shows a high tonic firing rate. Slide 15 Now, because the GPe is inhibitory acting on the STN, this leads to the fact that, for a short transient disinhibition of the STN, this can be active, and thereby excite the output nuclei, GPi and SNr. Slide 16 Now, in contrast to the direct pathway, this activity of the STN onto the output nuclei increases the Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. discharge of the GPi and SNr. And because they are inhibitory, this causes a further inhibition of the thalamus and cortex, which causes the suppression of action because of the enhanced suppression of the thalamus. Slide 17 So here again you can see a summary of the indirect pathway and the direct pathway. Let’s focus first on the left-hand side, the indirect pathway. Phasic cortical activity activates the striatum, which acts inhibitory on the external segment of the globus pallidus. Now, because the external segment of the globus pallidus normally shows a high tonic rate of discharge, this phasic activity of the striatum causes an inhibition. Now, as you can see, this inhibition of the GPe causes a transient activation of the STN. Why? Because the GPe is inhibitory acting on the STN. Now, because it has no activity, this inhibitory activity on the STN is released, and the STN itself can fire excitatory to the output nuclei GPi and SNr. Now remember, the GPi and SNr also show a high rate of tonic activity. And because they are inhibitory to the thalamus, this activity of the STN onto those output nuclei causes a further inhibition of the thalamus. Now, on the right-hand side, you see the direct pathway, where we look again at phasic cortical activity. This phasic cortical activity activates the striatum. Now, because the striatum has an inhibitory connection to the output nuclei, the GPi and SNr, this causes a transient inactivity of the output nuclei. Now, because the output nuclei are inhibitory acting onto the thalamus, this causes a transient inactivity of the inhibition, and thereby action can be facilitated. Slide 18 So, once more, you see here a summary of the two major features. The indirect pathway suppresses action, whereas the direct pathway facilitates action. Now, interestingly, recent research has shown that they are both cooperatively active, and regulate motor output. This is very important to memorise. In old models, it was always thought that motor activity, for example, would rely on direct pathway activity, whereas the indirect pathway was silent, whereas when you had no activity, or stopped an activity, the indirect pathway was active and the direct pathway was silent. This old model is no longer valid. We now know from experiments that I will show you in a minute that it’s the cooperative activity of the direct and indirect pathway that regulates adaptive behaviour. We don’t know yet how this works, but we start to have an idea how they together can mediate adaptive behaviour. Transcripts by 3Playmedia Week 5 © King’s College London 2017 3. Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 2 The structure and function of the Basal Ganglia - part 3 of 5 Dr Frank Hirth Department of Basic and Clinical Neuroscience Lecture transcript Slide 2 Now let’s look at a very important modulator of the direct and indirect pathway. And this is dopamine. There are other neural modulators, but we are looking at dopamine now because we know most about it and it’s one of the most important neural modulators of basal ganglia activity. The dopamine input arises from another part of the substantia nigra, which is called pars compacta, here in this scheme, abbreviated SNC. As you can see, we have two connections to the striatum. One connecting to the direct pathway, and one connecting to the indirect pathway. Slide 3 It is now important to understand the modulatory activity of dopamine by looking at the dopamine receptors that are expressed and active in the direct versus indirect pathway. As you can see in the scheme, the direct pathway expresses D1 receptors, whereas the indirect pathway expresses D2 receptors. And it is because of the different nature of these D1 and D2 receptors that we have different responses to dopamine signalling. Slide 3 Now the D2 signalling suppresses the firing in indirect pathway neurons... Slide 5...which is outlined here. Now let’s look at D2 signalling. D2 signalling suppresses firing in the indirect pathway neurons. How is that achieved? Because of this peculiar activity of the D2 receptors. It results in the reduction of inward, depolarising currents, and the increase of hyperpolarising currents, and therefore diminishes the spiking in the indirect pathway. As a consequence, you have less activity of the GPI. That means dopamine signalling via D2 receptors diminishes indirect pathway activity, and as a result, dopamine acting on D2 reduces the indirect pathway inhibitory effect, and thus facilitates movement. Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. Slide 6 Now let’s look at D1 signalling pathway when it receives dopaminergic input. In contrast to the D2 dopamine receptor, the D1 receptor acts differently. Dopamine input enhances calcium currents and reduces potassium currents. The effect of this is to increase the spiking of the neurons in the striatum. That is, it facilitates striatal signalling on the output nuclei. Slide 7 That, of course, causes an inhibition of the output nuclei. And as shown here, dopamine acts on D1, and thereby facilitates the movement in the presence of strong cortical drive. Slide 8 So let’s summarise the dopamine effects on the direct and indirect pathway. Keep in mind that this is due to the fact that D1 and D2 receptors respond differently to dopamine. That is, the very same neurotransmitter can have opposite effects. Dopamine signalling through D2 receptors in the indirect pathway suppresses striatal inhibitory activity. Dopamine signalling through D1 receptors in the direct pathway facilitates strong phasic inputs, it suppresses weak inputs. Thus, dopamine modulates impact of direct and indirect pathway activity via different differential action of D1 and D2 receptors. Slide 9 This is once more illustrated in this slide here. Remember, the overall activity of the indirect pathway suppresses action. The overall activity of the direct pathway facilitates action. Now dopamine modulates their impact. And at the bottom, you can see very recent experiments, the results of very recent experiments, which illustrate that. In the lab of Anatol Kreitzer, they used optogenetics to activate either the D1, which is the direct pathway, or the D2, the indirect pathway. Now you will learn later about optogenetics, but for now, let’s summarise what optogenetic does. You can express a factor in a neuron that allows you to activate that neuron by a pulse of light. And you can see, on the left bottom side, there are two sources of light that shine onto the striatum, STR. Now in the middle, the circular line shows when the activity of D1, the direct pathway, has been modulated. Wherever you see a grey dot, the light was off. Wherever you see a red dot and connections between the red dot, the light was on. That means the light was switched on and hence the neurons of the direct pathway were activated. You can clearly see whenever the light was on, this mouse was running around in the arena, which clearly emphasises the role of the direct pathway in facilitating movement and thus action. Now on the right-hand side, you see a similar experimental set-up. But now, light activates the D2 receptor, which, as you know, is expressed in the indirect pathway. In grey, the light is off. In green, light is switched on, and thus, activates neurons of the indirect pathway. You can clearly see that when you switch the light on and thereby activate the neurons of the indirect pathway, you immediately stop movement and thus inhibit action. This study, which was published in 2010 by Anatol Kreitzer’s lab, is a very elegant demonstration of the major output of the direct and indirect pathway. Slide 10 And this work is beautifully illustrated in this video, which you can actually download yourself and have a look at. It illustrates what happens when you activate, via optogenetic activation, the indirect pathway. It suppresses action and thus inhibits motor behaviour. Now as you can see from this study, when you artificially activate the indirect pathway, you suppress action and thus inhibit motor behaviour. You can well imagine that any problems with the activity of the direct pathway or the indirect pathway can be related with disease, and this is indeed the case. Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 2 The structure and function of the Basal Ganglia - part 4 of 5 Dr Frank Hirth Department of Basic and Clinical Neuroscience Lecture transcript Slide 2 Here, you see a list of behavioural abnormalities that are seen in basal ganglia dysfunction. They include motor abnormalities, impaired memory formation, attention deficits, affective disorders, sleep disturbances. Now interestingly, those dysfunctions can be found either in isolation or sometimes together in a variety of basal ganglia-related disorders, such as Parkinson’s disease, Huntington’s disease, or even dystonia, abulia, dementia, but also attention deficit hyperactivity disorder or even schizophrenia. In case you know a little bit about these diseases, it is very interesting that the very same brain region can lead to so different behavioural outcomes. Slide 3 Let’s look into one of the diseases, which is Parkinson’s disease. This is characterised by the specific loss of dopaminergic input into the striatum. Here, you see the summary scheme, where you have dopaminergic input from the substantia nigra pars compacta, the SNC. Slide 4 Now what happens in Parkinson’s disease? On the left hand side, you see a cross-section through the human brain, where you can see where the substantial nigra pars compacta is located. On the righthand side, you see that SNC specifically innervates the putamen and the caudate, which constitute, as you now know, the striatum, and this connection is called the nigrostriatal pathway. Now what is important in Parkinson’s disease is that because of the specific loss of dopaminergic neurons in the pars compacta, you lose the nigrostriatal pathway. That is, dopamine does no longer have an impact onto the striatum. Slide 5 What is the consequence of that, if you no longer have dopaminergic modulatory input onto the striatum? That is, the direct pathway becomes less active, whereas the indirect pathway becomes more active. Remember, this is due to the fact that the D1 and D2 receptors respond differently to dopamine. Transcripts by 3Playmedia Week 5 © King’s College London 2017 1. Slide 6 Because of this absence of dopamine, action selection via the direct pathway is suppressed, whereas action inhibition via the indirect pathway is facilitated. Slide 7 And this causes the very typical symptoms of Parkinson’s disease, which is tremor, rigidity, bradykinesia. But please be also aware that Parkinson’s disease is characterised by non-motor symptoms that also can account for basal ganglial dysfunction. And one of the most important is sleep disturbances, which occur even before any motor symptoms are visible. Slide 8 But as mentioned, we also have other disorders that are related to the basal ganglial dysfunction, and I will illustrate it with another example. Slide 9 What you see here are MRI scans through the human brain. On the left-hand side, you can see highlighted the different regions, the caudate and the putamen, which together form the striatum. Then the globus pallidus, the nucleus accumbens, which also belongs to the striatum, and the anterior cingulate. On the right-hand side, you see the scan of a patient which has been diagnosed with abulia, also called Athymhormia. This is caused by lesions of the globus pallidus and the connections between the striatum and the globus pallidus. Remember, this is part of the indirect pathway where you have an inhibitory connection from the striatum to the external segment of the globus pallidus. Now what is interesting is that those patients have been characterised by a profound inertia. Action is impaired in its initiation and in maintenance as well. Action is also impaired in its progress, since it tends to stop unless kept up by external stimulation. Now this is intriguing. Those patients which have defects in the globus pallidus and the striatal pathway, they have great difficulties to initiate actions. And that, of course, directly relates to what we call voluntary actions or voluntariness. Now voluntariness, as you know, is a central point when we regard our freedom of activity, what we want to do and when we want to do it. Transcripts by 3Playmedia Week 5 © King’s College London 2017 2. Module: Biological Foundations of Mental Health Week 5 Reward, emotion & action Topic 2 The structure and function of the Basal Ganglia - part 5 of 5 Dr Frank Hirth Department of Basic and Clinical Neuroscience Lecture transcript Slide 2 Now let’s look at something that is more considered like a food for thoughts, and that is what basal ganglia might have to do with voluntariness and free will. Slide 3 Remember the experiments from that an Anatol Kreitzer’s lab where he used optogenetics to artificially activate the direct D1 pathway or the indirect D2 pathway, and remember when the indirect pathway was artificially activated, it suppressed activity of the mouse. Now, you could ask, does that mean that the mouse was deprived of her freedom to do what she wants? I’m well aware this is a very anthropocentric view, but nevertheless, isn’t voluntariness conceived as a key concept of free will? Slide 4 And in fact, it was the philosopher Kant who said that a person acts freely if he does of his own accord what must be done. Now, think of people with basal ganglia dysfunctions. They are impaired in their actions and, if you like, in a way they are deprived in expressing their free will. Slide 5 Now, according to Kant, we are on the one hand determined by natural law and on the other hand free because of our capacity to obey moral law. Now, think of people with basal ganglia dysfunctions who are impaired in their judgments. Slide 6 So with that, I would like to end this little thought experiments and I would like to ask you, so, what is free will, and has it anything to do with the basal ganglia? And just as a reminder, Stan Grillner, a researcher at the Karolinska Institute once said, “The only output of the nervous system is the motor system, whether in in cognition or action.” And without the functional basal ganglia, you inevitably have problems to express voluntariness. Transcripts by 3Playmedia Week © King’s College London 2018 1. Slide 7 Now, apart from the possible connection to free will, I would also give you a very brief introduction into another aspect, and that is where does the basal ganglia potentially come from? Where did it evolve from? We recently carried out a study where we compared the basal ganglia to a region in the insect brain which is called the central complex. So on the right hand side, you can see it. There is an insect head with a compound eye. When you look into the central brain, there is this ochre region which is called the central complex. It comes in various nucleides, the protocerebral bridge, the fan-shaped body, the ellipsoid body, and the noduli. And experiments quite similar to the one by Anatol Kreitzer’s group showed that, if you inactivate this central complex, you have problems with actions. Slide 8 And in most recent studies, we showed that also, the central complex and its sub-components are connected by so-called re-entrant loops. These are parallel projecting loops that integrate and convey sensory motor representations that select and maintain behavioural activity. Slide 9 Now, what is striking is, when you look at the behavioural manifestations that are regulated by the neural activity of the virtual basal ganglia in the insect’s central complex-- and in this table, they are shown next to each other-- you may appreciate that there is quite a substantial overlap, even though those brain regions look so different. But we now know that similar genetic programmes actually underlie their formation and function, and those behavioural manifestations can be regarded as shared action selections. Slide 10 This is also re-emphasised by the fact that, if you have a dysfunction of the basal ganglia and the central complex, you see homologous pathological manifestations such as motor abnormalities, impaired memory formation, attention deficits, affective disorders, and sleep disturbances. So once more, let me re-emphasize. Although these structures are so different, not only in size, but also in appearance, they seem to regulate similar behavioural manifestations and pathology. Slide 11 And the final slide shown here actually made us to suggest that there is a corresponding circuit organisation of the basal ganglia and the central complex. And indeed, there are new results which suggest that, also, the centre complex in insects is involved in, if you like, voluntariness. That is, with that region in the brain of a fly, for example, this is necessary to explore your environment and to look out for the new and open. Transcripts by 3Playmedia Week © King’s College London 2018 2.