Decision-Making in Health and Disease III PDF

Decision-Making in Health and Disease III Irina Baetu Repetitive behaviours or thoughts Graybiel (2008) Annual Review of Neuroscience  Repetitive behaviours or thoughts Tourette syndrome: urge to perform vocal or motor tics Autism: repetitive behaviours and...

Decision-Making in Health and Disease III Irina Baetu Repetitive behaviours or thoughts Graybiel (2008) Annual Review of Neuroscience  Repetitive behaviours or thoughts Tourette syndrome: urge to perform vocal or motor tics Autism: repetitive behaviours and narrow interests Obsessive compulsive disorder (OCD): obsessions cause anxiety, compulsions (rituals) seem to be driven by the presence of obsessions and seem to reduce anxiety  Repetitive behaviours or thoughts as extreme habits Habits are triggered by particular stimuli Habits can have both motor and cognitive components: - Graybiel (2008) refers to obsessions as ‘habits of thought’ - Williams et al. (2011) describe repetitive thoughts as behaviours that were not completely expressed - e.g., OCD is not always characterized by repetitive behviours, there are many cases of ego-dystonic repetitive thoughts (obsessions such as the fear of doing terrible things and the inability to stop having these unpleasant thoughts) Difficult to ‘break the cycle’ (i.e., difficult to stop the habit/thought in the presence of the trigger)  Evidence for the involvement of dopamine in repetitive behaviours or thoughts Tourette syndrome, autism and OCD are comorbid and are associated with excessive midbrain dopamine levels. Dopamine antagonist medications for Tourette syndrome and OCD reduce repetitive behaviours. Parkinson’s patients on dopaminergic medication: up to 25% develop compulsions or repetitive behaviours.  Evidence for the involvement of dopamine in repetitive behaviours or thoughts Amphetamine or cocaine administration (both drugs increase dopamine release) causes hyperactivity and compulsive and stereotypical behaviours in humans and in other species. In animals, these effects depend on the striatum (i.e., administering a drug that increases dopamine release induces stereotypical behaviours only if the striatum is intact). This suggests that such behaviours depend on dopamine release in the basal ganglia. The role of the basal ganglia  Classical basal ganglia model Direct ‘Go’ pathway Indirect ‘No-Go’ pathway Cortex Cortex STN GPe Striatum STN GPe Striatum GPi and SNr GPi and SNr Weak inhibition Strong inhibition Thalamus Thalamus Select motor command Inhibit motor command  Hyperdopaminergic state: Direct > Indirect Direct ‘Go’ pathway Indirect ‘No-Go’ pathway Cortex Cortex STN GPe Striatum STN GPe Striatum GPi and SNr GPi and SNr Weak inhibition Strong inhibition Thalamus Thalamus Select motor command Inhibit motor command  Normal action selection Cortex The cortex initiates many action plans Striatum  Normal action selection Cortex The cortex initiates many action plans Striatum Many of these action plans are inhibited by the indirect pathway (and hence are never performed), and only a few activate the direct pathway enough to disinhibit the thalamus. Thalamus  Normal action selection Cortex Striatum Once completed, the selected action plan is also inhibited by the indirect pathway Thalamus to ensure it isn’t repeated. Imbalance: Direct > Indirect (e.g., due to excess dopamine) Cortex The cortex initiates many action plans Striatum Fewer of these action plans are inhibited by the indirect pathway so more are performed (some of which might be completely irrelevant or useless in the current context). Thalamus Imbalance: Direct > Indirect (e.g., due to excess dopamine) Cortex Striatum Performed action plans are also meant to end (be performed once only) and a weaker Thalamus indirect pathway might not be able to terminate a motor program and stop its repetition. Animal studies  Stereotypical behaviour in (non-human) animals Excessive grooming: - paw licking, which can cause blisters - biting fingers, nails Excessive lever pressing in a Skinner box, wheel running, platform jumping  Disrupting the indirect pathway in monkeys Stereotypical behaviours (e.g., finger biting in monkeys) can be induced by injecting a GABA antagonist in the GPe and hence disrupting the functioning of the indirect pathway. Direct ‘Go’ pathway Indirect ‘No-Go’ pathway Cortex Cortex STN GPe Striatum STN GPe Striatum GABA GPi and SNr GPi and SNr antagonist W eak inhibition Strong inhibition Thalamus Thalamus Select motor command Inhibit motor command Grabli et al. (2004) Brain  The Indirect ‘No-Go’ Pathway Cortex STN GPe Striatum Legend Glutamate – excitatory connection GABA – inhibitory connection STN = subthalamic nucleus GPi and SNr SNr = substantia nigra pars reticulata GPi = globus pallidus internal segment Strong inhibition (thalamus is even more inhibited GPe = globus pallidus external segment than usual) Thalamus Inhibit motor command  Normal functioning of the Indirect Pathway Cortex STN GPe Striatum Legend Glutamate – excitatory connection GABA – inhibitory connection STN = subthalamic nucleus GPi and SNr SNr = substantia nigra pars reticulata GPi = globus pallidus internal segment Strong inhibition (thalamus is even more inhibited GPe = globus pallidus external segment than usual) Thalamus Inhibit motor command  Disrupting the Indirect Pathway Cortex STN GPe Striatum Legend Glutamate – excitatory connection GABA GABA – inhibitory connection antagonist STN = subthalamic nucleus GPi and SNr SNr = substantia nigra pars reticulata GPi = globus pallidus internal segment Strong inhibition (thalamus is not as inhibited) GPe = globus pallidus external segment Thalamus Less inhibition of the motor command  Disrupting the indirect pathway in monkeys Stereotypical behaviours (e.g., finger biting in monkeys) can be induced by injecting a GABA antagonist in the GPe and hence disrupting the functioning of the indirect pathway. Direct ‘Go’ pathway Indirect ‘No-Go’ pathway Cortex Cortex STN GPe Striatum STN GPe Striatum GABA GPi and SNr GPi and SNr antagonist W eak inhibition Strong inhibition Thalamus Thalamus Select motor command Inhibit motor command Grabli et al. (2004) Brain These graphs show the proportion of time the monkeys spend doing these behaviours Grabli et al. (2004) Brain Before being injected, the monkeys mostly like to rest or observe their own hands (they do this in two separate experiments, that’s why there are two graphs). Grabli et al. (2004) Brain  GABA antagonist injection in the anterior GPe caused persistent repetition of a grooming behaviour Lick/bite fingers Grabli et al. (2004) Brain  GABA antagonist injection in the dorsal GPe caused hyperactivity (increased all behaviours and Lick/bite fingers exploration). Their performance on a food retrieving task was also worse, as if they weren’t paying attention to what they were doing… Grabli et al. (2004) Brain  Disrupting the indirect pathway in monkeys Interfering with different parts of the GPe resulted in different inhibition deficits: - repeatedly performing the same behaviour Anterior GPe (unable to ‘exit a loop’) - akin to tics, compulsions in humans Posterior - allowing all behaviours to be performed despite their irrelevance + what looks GPe like disrupted attention (monkeys made many errors on the food retrieval task repeatedly going back to locations where they had already collected food and were now empty) So the basal ganglia are not only involved in selecting actions to perform while inhibiting others, but perhaps also selecting and inhibiting patterns or thought or things we focus on…  Naturally-occurring individual differences in stereotypical behaviour in (non-human) animals Animals also show individual differences (like humans do…). So not all members of a species are the same and some individuals show these behaviours to a greater extent than others: - stereotypical behaviours - signs of anxiety - anti-social behaviours, etc. Some studies also investigated why some of these animals show more stereotypical behaviours than others, and whether this is related to basal ganglia functioning.  Naturally-occurring individual differences in stereotypical behaviour in (non-human) animals Some mice show excessive spontaneous stereotypic jumping. The high stereotypy mice seemed to have naturally lower activity in the indirect pathway. Presti & Lewis (2005) Behavioural Brain Research lower indirect Dynorphin concentration in pathway striatum reflects direct functioning pathway activity. Enkephalin concentration in striatum reflects indirect pathway activity. Mice that exhibit more stereotypical behaviour show higher a direct > indirect pathway direct/indirect imbalance, mainly driven by ratio lower activity in the indirect pathway. Presti & Lewis (2005) Behavioural Brain Research And what about humans?  Dopaminergic hyperactivity in OCD and Tourette Individuals with Tourette syndrome or OCD show enhanced dopaminergic activity (or reduced D2 receptor density) in the striatum. Denys et al. (2013) European Neuropsychopharmacology; Perani et al. (2008) NeuroImage In Tourette syndrome, striatal dopaminergic activity correlates with the increase in tic severity induced by amphetamine. Denys et al. (2013) European Neuropsychopharmacology Antipsychotics (which block dopamine receptors) can alleviate OCD symptoms. Hollander et al. (2002) Journal of Clinical Psychiatry  Deficient punishment learning in OCD and Tourette We’ve seen in the last lecture that Tourette syndrome is associated with a tendency to learn less from punishment and more from reward in an unmedicated state. A similar pattern has been reported for OCD. Marzuki et al. (2021) JAMA Network Open  Decision-making (action selection) vs learning Excessive dopamine release (and hence a direct > indirect imbalance) can have two effects: 1. Action selection: It’s easier to select an already learnt habit and it’s harder to inhibit it (or to select an alternative action). 2. Learning: If the compulsive behaviour (or habit) is performed and if it generates some temporary relief, it’s easier to learn to repeat it again (it’s easy to further strengthen direct pathway connections). But if the compulsive behaviour is directly followed by some negative consequence, the weaker indirect pathway will not learn as much from this negative feedback. This enhanced learning from reward than from punishment might contribute to the maintenance of the habit.  The role of anxiety An acute state of anxiety seems to increase the likelihood of behaving in a habit-like manner and to decrease our ability to control impulses or habits (i.e., it decreases our goal-directed behaviour). Though anxiety might not necessarily contribute to learning, it might affect the expression of learnt habits by making it even easier for a learnt habit to be selected by the basal ganglia. Stress or acute anxiety: - increase compulsions in OCD - increase repetitive behaviours in autism - increase tics in Tourette  Implications for treatment Classic cognitive behavioural theory proposes that OCD is characterized by irrational, intrusive, beliefs that there might be future harm to oneself or others, and compulsions are a reaction to these obsessions in an attempt to reduce distress and prevent the perceived threat (Salkovskis, 1985). This implies that compulsions are under the control of the person (they willingly perform these behaviours with the aim of preventing possible harm – so this theory assumes these compulsions are goal-directed). BUT, individuals with OCD are actually impaired on tasks that measure goal-directed behaviour, or the ability to overcome or control habitual responding. So although this might explain how compulsions start, it doesn’t explain how they are maintained.  Implications for treatment Habit hypothesis of compulsivity (Gillan et al., 2016): OCD is characterized by excessive habit learning at the expense of more flexible goal-directed behaviour. This theory would imply that rather than convincing a person that their behaviour is unhelpful, therapy should aim at extinguishing these habits via new learning, including extinguishing habits of thought.  Extinction treatments Cognitive behavioural therapy (CBT) that incorporates exposure with response prevention (ERP) therapy relies on extinction. This involves repeatedly exposing the patient to triggers and preventing the response – or compulsion – until the habit weakens. Habit reversal therapy (HRT) involves extinguishing the habit by teaching a different habit that competes with it – counterconditioning of a competing response can speed up extinction of the unwanted habit. Extinction can take a while as it requires slow rewiring of basal ganglia circuits, so consistency and patience are crucial!  Extinction treatments Extinction might also be difficult to learn in these individuals because of basal ganglia dopaminergic imbalance, so this learning could be ‘boosted’ pharmacologically by restoring direct-indirect pathway balance: - SSRI (selective serotonin reuptake inhibitors) increase serotonin levels, which dampen dopamine release. - Antipsychotics (for more difficult OCD and Tourette cases) directly or indirectly dampen dopamine release.  Extinction treatments Final thoughts: Drugs alone won’t solve the problem: they may restore some imbalance, but they won’t make tics/obsessions/compulsions go away: extinguishing these habits is still a necessary behavioural intervention. However, drugs can enhance extinction learning, so in many cases a combination of behavioural and pharmacological interventions is probably most helpful.  Mind your habits! Indirect pathway: Direct pathway: DON’T eat the donuts! EAT the donuts!!!