BMS 200 Schizophrenia Migraines & Microbiome PDF

BMS 200 Schizophrenia Migraines & Microbiome Outcomes Describe the basic epidemiology and clinical features of schizophrenia Discuss the dopaminergic hypothesis of schizophrenia and evidence that inflammation may contribute to the pathophysiology Describe the evidence linking inflammation and g...

BMS 200 Schizophrenia Migraines & Microbiome Outcomes Describe the basic epidemiology and clinical features of schizophrenia Discuss the dopaminergic hypothesis of schizophrenia and evidence that inflammation may contribute to the pathophysiology Describe the evidence linking inflammation and gut microbiome to the pathophysiology of migraines Common Psychiatric Presentations Definition for Delusion - REVIEW Delusion ▪ A belief that is clearly false and indicates an abnormality in content of thought ▪ False belief cannot be explained by the person’s cultural or religious background or intelligence level Belief is held despite being presented with * evidence against it (“fixed” – firmly maintained) Patient is convinced the delusion is real ▪ Can be due to: mental disorder, neurological or medical disorder ▪ Examples: schizophrenia, substance abuse, bipolar disorder, major depressive disorder (MDD), delirium and dementia Definition for Hallucination - REVIEW Hallucination ▪ “A sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs” Not under voluntary control Vivid, clear, with full force and impact of a non-hallucination perception Most common are visual, auditory, tactile, olfactory ▪ gustatory, nociceptive, thermoceptive, proprioceptive are possible Formed (i.e. voice making a command) or unformed (i.e. non- specific sound) With insight – px is aware that she is experiencing a hallucination - OR without insight – patient believes the perception is real ▪ Can occur in illness or during an adjustment disorder or without mental illness (i.e. grief) ▪ Can be due to: psychiatric, neurological or medical disorder Delirium, substance withdrawal, intoxication, CNS infection, seizures can all cause hallucinations Schizophrenia – DSM V criterial simplified two (or more) of the following signs or symptoms below. At least one of these must be (1), (2), or (3) 3 1. delusions 2. hallucinations 3. disorganized speech (e.g. frequent derailment or incoherence) 4. grossly disorganized or catatonic behaviour 5. negative symptoms (i.e. diminished emotional expression or avolition) Continuous signs of the disease must be present for at least 6 months, and 1 month must include active symptoms (1 – 4) ▪ Can be less than 1 month if successfully treated Level of functioning in work/school, social relationships, self- care is markedly decreased -Can’t be due to another condition Schizophrenia - definitions Disorganized speech, thoughts: ▪ Speech and thought – derailment, poverty of speech, tangentiality, lack of logic, perserveration, neologism, thought blocking, clanging, echolalia… these are part of - a phenomenon known as “thought disorders” Behaviour can be disorganized or catatonic ▪ Catatonia, as it relates to schizophrenia Psychomotor disturbances motor immobility Stupor, rigidity, strange postures, “waxy flexibility” ▪ excessive activity Echolalia, echopraxia ▪ Sometimes both can be present at different times Schizophrenia - definitions Derailment: Also known as "loose associations," this is when a person's thoughts shift abruptly from one topic to another unrelated topic, making their speech difficult to follow. There may be a lack of logical connection between ideas. Poverty of Speech: This refers to limited verbal output, where the person's speech is reduced in quantity or content. They might give brief or monosyllabic answers, which lack detail or elaboration, even when more is expected. Tangentiality: This occurs when a person goes off-topic or provides an irrelevant answer during conversation. The response is loosely related or completely unrelated to the question or topic at hand. Lack of Logic (Illogical Thinking): This involves making conclusions or statements that don’t follow a logical sequence or have faulty reasoning. The person may present ideas in a way that defies conventional logic. Schizophrenia - definitions Perseveration: Repetitive thoughts or speech, where a person repeats the same word, phrase, or idea over and over, often despite a change in the topic or context. Neologism: The creation of new, often nonsensical, words that only have meaning to the person using them. These made-up words are often unrecognizable and not based on any known language. Thought Blocking: This is when a person's thoughts are interrupted or stopped abruptly, often in the middle of speaking. The person may pause for an extended period or appear to lose their train of thought. Clanging: Speech characterized by the use of rhyming or alliteration, often with words linked together based on sound rather than meaning. The focus is on the phonetic aspects of words, which can make the content nonsensical. Echolalia: The repetition or mirroring of words or phrases spoken by someone else, often without understanding the meaning. This behavior can be seen in individuals with autism or certain types of psychosis. Examples of disorganized speech - FYI Clanging as a type of derailment: ▪ “I’m not trying to make noise. I’m trying to make sense. If you can make sense out of nonsense, well, have fun. I’m trying to make sense out of sense. I’m not making cents anymore. I have to make dollars.” ▪ Note that the reasoning follows how words rhyme, instead of their meaning ! clanging ▪ Derailment means jumping from thought to thought with poor links between them and inability to follow a coherent “story” or line of reasoning From: https://www.thenationalcouncil.org/wp-content/ uploads/2022/09/Disorganized-Symptoms-of- Psychosis-Slides.pdf Schizophrenia - Disorganized Behavior: Disorganized behavior involves a significant disruption in the ability to perform activities of daily living in an organized or functional manner. This can manifest as: Incoherent or erratic behavior: Individuals may engage in behavior that is bizarre or nonsensical, such as inappropriate dressing (e.g., wearing heavy coats in hot weather), aimless wandering, or difficulty initiating or completing tasks. Inappropriate emotional responses: The person might laugh or cry at inappropriate times, act unpredictably, or show sudden changes in mood. Difficulty in planning or sequencing: Tasks like making meals or managing personal hygiene might become impossible or disorganized due to cognitive fragmentation. Disorganized behavior often results in social and functional impairment, as the person loses the ability to engage in normal social interactions or maintain routine activities. Schizophrenia - Disorganized Behavior: Disorganized behavior involves a significant disruption in the ability to perform activities of daily living in an organized or functional manner. This can manifest as: Incoherent or erratic behavior: Individuals may engage in behavior that is bizarre or nonsensical, such as inappropriate dressing (e.g., wearing heavy coats in hot weather), aimless wandering, or difficulty initiating or completing tasks. Inappropriate emotional responses: The person might laugh or cry at inappropriate times, act unpredictably, or show sudden changes in mood. Difficulty in planning or sequencing: Tasks like making meals or managing personal hygiene might become impossible or disorganized due to cognitive fragmentation. Disorganized behavior often results in social and functional impairment, as the person loses the ability to engage in normal social interactions or maintain routine activities. Schizophrenia - Catatonia A complex psychomotor syndrome characterized by abnormal movements, behaviors, and reactions. Psychomotor disturbances can include the following: Motor Immobility: The most characteristic symptom of catatonia is * - a marked reduction in voluntary movement or a complete lack of movement. - Stupor: A profound unresponsiveness, where the person remains motionless and mute despite external stimuli. The person might appear awake but does not react to their environment. Rigidity: Muscular stiffness that does not allow movement, even when an external force is applied. Strange postures: The individual may adopt unusual, often uncomfortable or bizarre positions (called catalepsy) and hold them for extended periods. Schizophrenia - Catatonia Excessive Motor Activity: On the opposite end of the spectrum, catatonia can also present as excessive, purposeless activity that is not influenced by external stimuli. This hyperactivity is not goal-directed and can be erratic. Echolalia: The automatic repetition of words spoken by others. The person echoes what another person says, often without understanding or intent. Echopraxia: The imitation or mirroring of the movements or gestures of another person. Like echolalia, echopraxia is automatic and not voluntary or intentional. Schizophrenia – negative symptoms Communication – very little speech, limiting responses to 1-2 words even with extensive prodding, long pauses before responses Emotion/affect – very limited range of emotional experiences, reduced affective expressiveness, blunted expressions or monotonous speech Social activity – few friends, little desire for any social interaction Motivation – barely moving, spending a lot of time sitting or lying down, decreased basic activities such as hygiene, grooming. Little interest in world events, hobbies, goals Psychomotor activity – slowed movements, few expressive gestures, almost appears that moving spontaneously requires large amounts of effort Schizophrenia Onset usually between puberty and 3rd decade ▪ Affects 1% of the population Pathogenesis is not well-understood ▪ Psychosis and other positive symptoms thought to be associated with dysregulation in dopaminergic systems ▪ Neurological basis for cognitive symptoms are poorly understood ▪ Cognitive symptoms include: Problems with working memory and attention Executive functions, such as ability to organize information Social cognition – difficulty understanding/noticing subtle interpersonal cues, difficulty with forming relationships with others Dopamine and Schizophrenia There is a hyper-responsiveness of the dopaminergic system in schizophrenia: ▪ (1) Antipsychotic drugs block DA via D2 receptors ▪ (2) Drugs that increase DA (L-dopa, amphetamines) will cause increase in psychosis GABA interneurons: ▪ Last to be incorporated into the developing brain ▪ Most vulnerable to developmental insults Highly susceptible to damage from oxidative stress * * and glutamatergic drive – particularly in the early postnatal developmental period before puberty  Dopaminergic system What is the “dopaminergic system”? ▪ Diffusely-projecting monoamine systems (discussed in BMS 150) Monoamines = dopamine, norepinephrine, serotonin Diffuse projections = send long axons to various brain areas influencing many functions over different regions  Dopaminergic system ▪ Most of the neuronal cell bodies that release dopamine are located in the midbrain Midbrain areas = ventral tegmental area (VTA) and substantia nigra They release dopamine from their synaptic terminals (at the end of their axons), which project to a WIDE variety of targets Ventral tegmental area: project to many areas, such as nucleus accumbens, PFC, limbic system - Mesolimbic and mesocortical areas Primarily involved in reward, motivation, emotion - dopamine plays critical role in pleasure, addiction and reinforcing behaviours Substantia nigra: project primarily to striatum, key part of basal ganglia involved in motor control - nigrostriatal pathway Important for movement regulation - dysfunction strongly linked to Parkinson’s (death of DA producing neurons in this region) Dopaminergic system Projections: “reward/motivation”: ▪ VTA ! nucleus accumbens and ventral striatum (of the basal ganglia) Motor functions: ▪ Substantia nigra ! striatum (of basal ganglia) Executive functions: ▪ VTA/dorsal substantia nigra ! many cortical areas Dopaminergic system Projections: “reward/motivation”: ▪ VTA ! nucleus accumbens and ventral striatum (of the basal ganglia) Motor functions: ▪ Substantia nigra ! striatum (of basal ganglia) Executive functions: ▪ VTA/dorsal substantia nigra ! many cortical areas Dopaminergic system Projections: “reward/motivation”: ▪ VTA ! nucleus accumbens and ventral striatum (of the basal ganglia) Motor functions: ▪ Substantia nigra ! striatum (of basal ganglia) Executive functions: ▪ VTA/dorsal substantia nigra ! many cortical areas Dopaminergic system Dopaminergic (DA) neurons fire in a slow, pacemaker fashion “at rest” ▪ Known as tonic firing – the ventral pallidum (basal ganglia) slows down this activity via GABA release reticular activating system detects a stimulus ! glutamate release onto DA neurons ! rapid bursts of action potentials ▪ Phasic firing Activation of part of the hippocampus (subiculum) ! enhanced tonic firing ! “stronger” phasic firing in response to a stimulus ▪ Tends to occur with “interesting” stimuli or acutely stressful stimuli - - - Activation of the amygdala ! decreased tonic firing ! “weaker” phasic firing ▪ This is particularly notable during chronic stress - Dopaminergic system and schizophrenia All known antipsychotic medications block D2 receptors, and L- dopa (dopamine precursor) as well as amphetamines (cause “leak” of dopamine into synaptic cleft) worsen positive symptoms ▪ However, antipsychotics do not seem to help cognitive or negative symptoms In schizophrenia, there is evidence that the hippocampal areas that stimulate tonic activity are hyperfunctioning ! - inappropriately increased tonic activity ▪ VTA neurons that release dopamine do not seem to be abnormal ▪ Reduced inhibitory GABA-ergic neurons in the hippocampus Theory: hyperactive dopaminergic activity due to “hippocampal overdrive” ! all stimuli are seen as “important” or real ! delusions/hallucinations Dopaminergic system and schizophrenia The dopaminergic system projects to a wide variety of brain areas ▪ May explain some of the cognitive or negative symptoms of schizophrenia Stress, especially in childhood and adolescence, seems to be a risk factor for developing schizophrenia ▪ Stress early in life seem to lead to loss of inhibitory GABA-ergic neurons in the hippocampus ▪ (Over)activation of the amygdala may be linked to loss of these neurons Inflammation and Schizophrenia? General inflammation may be linked to schizophrenia, although “how” is poorly understood, and no theories have been clearly supported by the evidence ▪ Elevations in pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta) during psychosis, normalize with antipsychotic treatment (few studies) Pro-inflammatory cytokines --> kynureneic acid production (a metabolite of the amino acid tryptophan) Kynurenic acid blocks NMDA receptor, which can cause psychosis ▪ Activation of microglial cells ! Cognitive dysfunction and grey matter volume loss? Microglia are key in pruning synapses – possibility that “overactivated” microglia are involved in volume loss Migraine – pathophysiology - Involves trigeminal nerve & its connections to vascular structures in the meninges Review Pain signals initiated by activation of nociceptors in meningeal vessels; activated nociceptors project to trigemina ganglion which contain cell bodies of trigeminal sensory neurons The key pathway for pain in migraine ! trigeminovascular input from the meningeal vessels ! trigeminal ganglion ! synapses on second-order neurons in the trigeminocervical complex (TCC) in the brainstem TCC ! thalamus ! cortex & Important modulation of the trigeminovascular nociceptive (pain) input comes from midbrain nuclei ▪ dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus TCC is crucial for processing Problems with modulation of pain pain signals from head & neck sensation from these trigeminal afferents seems to be the cause ▪ Abnormal pain sensation related to vascular dilation and constriction? (vasomotion) Migraine – pathophysiology - Review Medications that act on this pathway: ▪ 5-HT1 receptors – important in the trigeminal nucleus and the thalamus, bind to serotonin - Blocked by drugs known as “-triptans” (i.e. sumatriptan) ▪ CGRP (calcitonin-gene- related peptide) seems to mediate neurotransmission at the trigeminal ganglion and at the vasoactive efferents (it’s a vasodilator and a pain modulator) Migraine – pathophysiology - Review A number of theories were suggested, but best accepted is a neurovascular one ▪ primary neural dysfunction – wave of “spreading depression” (slowly travelling wave of neural excitability) travels through the cortex and leads to activation of the trigeminal complex leads to vascular-generated pain spreading depression wave thought to be linked to other neurological findings may also be linked to modulation of nociceptor afferents by locus ceruleus and dorsal raphe nucleus  CNS becomes more sensitive to sensory input, particularly pain Central Sensitization - Review Pro-inflammatory cytokines ! release of nerve growth factor from mast cells ▪ NGF increases the release of BDNF from C fibres = ▪ This increases the excitability of “pro-pain” dorsal horn networks and C fibre transmission  Neurogenic Inflammation - Review Interestingly, action potentials can actually move BOTH ways down a pain fibre (in particular, a C fibre) E▪ From spinal cord ! * ▪ From periphery ! spinal cord = orthodromic periphery = antidromic 3 C fibres can release numerous substances, but in particular substance P and CGRP, from dendrites into peripheral tissues when action potentials move antidromically 3 ▪ Substance P can cause mast cell degranulation, S vasodilation, and edema ▪ CGRP can cause vasodilation ▪ These substances can increase inflammation – this is known as neurogenic inflammation Migraines and Gut Microbiome Is there any evidence of a connection? ▪ Eradication of H. pylori results in improvement (though not resolution) of migraine symptoms H. pylori triggers release of CGRP, and thus may be sensitizing the nerves ▪ Irritable bowel syndrome (IBS) – is characterized by visceral hypersensitivity. IBS is more common in migraine sufferers than general population (increased risk of migraine 40-80%) Food intolerances can trigger both IBS and migraine episodes Higher amount of circulating serotonin in IBS Pharmaceuticals modulating serotonin receptors are effectively used in both IBS and migraines Possible Mechanisms: Pro-inflammatory cytokines, IL-1Beta, IL-6, IL-8, TNF-alpha, IFN are increased in migraine suffers; sensitize afferent endings and can induce visceral pain Dysbiosis: & (Bacterial product) ▪ Increase gut permeability ! LPS leakage ! pro- inflammatory cytokine release ▪ Some bacterial strains can metabolize tryptophan thus may affect local gut serotonin metabolism Serotonin receptors are found on various immune cells (unclear if it is involved in modulating inflammation) References 1 Arzani M, Jahromi SR, Ghorbani Z, Vahabizad F, Martelletti P, Ghaemi A, et al; School of Advanced Studies of the European Headache Federation (EHF-SAS). Gut-brain Axis and migraine headache: a comprehensive review. J Headache Pain. 2020 Feb 13;21(1):15. doi: 10.1186/ s10194-020-1078-9. Including: "Introduction" - through to and including "Dietary approaches in migraine headache with a focus on the gut-brain Axis" Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016 Aug;17(8):524-32. doi: 10.1038/nrn.2016.57. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015 Mar;2(3):258-270. doi: 10.1016/S2215-0366(14)00122-9.