CSAII Flashcards
Give 6 Sensations of pain
Burning Radiating Stabbing Deep Ache Freezing Itch
3 Reasons for Pain
Warning signs:
- avoidance of harmful stimuli
- prevents further injury
- Rest following injury
3 Classifications of Pain
Nociceptive
Inflammatory
Neuropathic
What are Nociceptors?
Primary sensory (1st order) neurons Pain detection found in: -skin -muscle -viscera -meninges
3 Types of afferent nerve fibre
Aβ - Myelinated, 100m/s, light touch
Aẟ- Thinly myelinated, 30-75m/s, light touch, instant sharp pain
C Fibre- unmyelinated, 1m/s, nociception
5 Afferent nerve endings
Free nerve endings (Aẟ, C- arbourised) Meissner's corpuscles (Aβ, light touch) Pacinian corpuscles (Aβ, vibration) Merkel Discs (Aβ, pressure) Ruffini (Aβ, stretching)
Aẟ fibres features
Sharp pricking pain
Well localised
Reflex arcs
first pain, before C fibres
C Fibres features
Slow, dull ache, burning
persistent
poorly localised
second pain, after Aẟ
5 ways to activate nociceptors
pressure heat cold chemical ie H+ Tissue damage/inflammation
What is polymodality?
C fibres responding to multiple stimuli
eg pressure temperature and chemical
decoding within CNS determines which modality is being encoded
Pressure transduction in nociceptors?
Mechanically gated ICs
TRP channels
Temperature transduction in nociceptors?
TRPV1 channels (vanilloid) heat
TRPM cold
TRPA1 v cold
CNS pain pathway:
SPINOTHALAMIC TRACT Nociceptor -> SC via DRG Dorsal horn Forms tract of lissauer 1st Order Synapse in substantia gelatinosa 2nd order excited by Glu + sub P Crossing over to anterolateral column To thalamus
What is referred pain?
Convergence of Visceral and Cutaneous pain
synapsing onto same 2nd order neuron in SC
Brain perceives pain as cutaneous
eg angina perceived as pain in chest wall + left arm
Path of 3rd order neurons
Thalamus to somatosensory cortex
HAL homunculus
Projections to insula + cingulate cortex (emotional aspect of pain)
Descending regulation of pain
- Stress induced analgesia: torn muscle in race and keeps running, battle victims
- Behaviour, emotions at time, past experiences
- Higher cortical regions activate descending modulatory pathways
PERIAQUADUCTAL GREY MATTER (PGM)
ROSTRAL VENTROMEDIAL MEDULLA (RVM)
Cortex - PAG - RVM - Dorsal Horn
Modulates Spinothalamic tract activity
Descending inhibition of pain factors
- PAG, RVM-> ST tract
- 5-HT projections act on inhibitory interneurons in Dorsal Horn
- Endogenous Opiods, eg endorphins, enkephalins
- stress induced analgesia
Chemicals released following tissue injury?
ATP, H+, Serotonin (platelets), Histamine (mast cells), Bradykinin, Prostaglandin, NGF
Which chemicals directly bind to nociceptors in inflammatory responses?
ATP binds to purinergic receptors (P2X)
H+ binds to acid-gated ion channels eg lactic acid buildup
Serotonin binds to 5-HT3 receptors
What is Neurogenic inflammation and what does it cause?
Activation of one nociceptor branch triggers release of Substance P and CGRP from another
causes:
- vasodilation
- increased permeability
- mast cells release histamine
- More inflammation
What benefits does inflammation hold?
Pain hypersensitivity
- makes pain more painful
- prevents contact with injury site to promote healing
What is allodynia?
A painful response from a non-noxious stimulus
What is hyperalgesia?
an exaggerated response from a noxious stimulus
What is peripheral sensitisation?
increase in the responsiveness of nociceptors
Bradykinin reduces TRPV1 threshold
PG reduces Na+ threshold
Increased pain, eg sunburn
Timescales for acute/chronic pain?
Acute <3 months
chronic >3 months
Treatments for acute pain
Local anaethetics:
- lidocaine/lignocaine (Na+ blockers)
Topical capsaicin (chili peppers) - repeated use reduces nociceptor firing (Ca2+ excitotoxicity?)
NSAIDs
- inhibits PG synthesis (COX inhibition), prevents peripheral sensitisation
Paracetamol
- unknown mechanism
Opioids
- morphine, codeine, tramadol
- effective but addictive + SEs
- endogenous opioid system agonists
- BS, SC, periphery
Gate control
- simultaneous activation of Aβ eg rubbing
- activates inhibitory interneuron cancelling C fibre response
Chronic pain epidemiology
20-50% of population
11 causes of chronic pain?
chronic back pain cancer carpal tunnel syndrome arthritis fibromyalgia diabetes migraine post-surgery MS trigeminal Neuralgia phantom limb
2 types of chronic pain
Inflammatory
- persistent tissue inflammation eg arthritis
Neuropathic
- NS injury eg compression, traction, sever, hypoxia, demyelination, tumour
Neuropathic Pain Symptoms
Burning pain Stabbing pain Aching Electrocution pain Radiating pain Hypersensitivity
Neuropathic pain mechanisms
V complex
Peripheral sensitisation
spontaneous nociceptor firing
accumulation of ICs at site of injury, causes hypersensitivity
What is central sensitisation?
Increase in responsiveness of nociceptive Ns in CNS
normal inputs -> abnormal OPs
Reduced threshold for activation of 2nd Order Neurons
- Similar process to LTP (sustained Glu, Ca2+ through NMDA, kinase cascades)
What is CNS hyperalgesia?
Follows central sensitisation
activation of nociceptors results in amplified SC activation
Central Allodynia mechanism?
non noxious Aβ fibres also synapse onto 2nd order spinothalamic Ns
- usually inactive as incapable of reaching threshold
- central sensitisation causes AP firing
Chronic Pain treatments?
Difficult to treat
Tricyclic antidepressants eg Amytriptyline
anticonvulsants eg pregabalin, gabapentin
NMDA antagonists eg ketamine
CBT
SC stimulator, gate control
Placebos
What is the hierarchy of motor control?
Low level- execution, BS, SC
Middle- Tactics, motor cortex, cerebellum
High- strategy, association areas of neocortex, BG
Basal ganglia anatomical features?
Caudate Nucleus Putamen Globus Pallidus (int&ext) Thalamus Hypothalamus Substantia Nigra Subthalamic Nucleus
Lentiform Nucleus: putamen+pallidum
Corpus Striatum: CN+LN
Neostriatum (dorsal, motor): CN+putamen
What are Basal Ganglia Loops?
Processing pattern for motor activity
Cortical IP-Striatum-GPi-Thalamus-Cortex
3 Key Pathways of basal ganglia?
Direct (exc) promote movement
Indirect (inh) withhold movement: GPe, STN
Hyperdirect pause movement: STN
Thalamus inhibition prevents movement
What is the role of the substantia Nigra?
DA release
Interacts with Striatum Ns
DA/ACh balance, DA promotes movement, ACh prevents
D1 & D2 receptors
2 categories of movement disorders and their associated conditions?
Hyperkinetic movement hemiballismus Tics Chorea Myoclonus
Hypokinetic Movement
Parkinsonian conditions
Ataxia
Apraxia
Define Hemiballismus
high amplitude flailing of limbs
unilateral
Impaired STN activity
Cause: stroke
Define Tic Disorders
brief repetitive movements with premonitory urge
blinking, coughing, limb movements
Tourettes + coprolalia (swearing) severe tic expressions
worse with anxiety
high comorbidity (50% ADHD, 33% OCD, 50% Anxiety)
Define Chorea
jerky, brief, irregular movement
Appears to flow from limb to limb
causes:
Huntington’s disease
Neuroleptics
Define Huntington’s Disease
Motor/cognition deficits
- cognitive: poor decision making, multitasking
- behavioural: irritability, depression, apathy, anxiety, delusions
- Physical: chorea, motor persistence, dystonia, eye movements
Genetics:
Autosomal Dominant, complete penetrance
Trinucleotide repeat on C4
Longer repeat sequence= earlier onset
Define Myoclonus
Brief movement with rapid onset & offset
+ve (muscular contractions)
-ve (muscular inhibitions)
Causes:
Juvenile myoclonic epilepsy
Hypoxia
Prion disease
Treatment: antiepileptics
Define Dystonia
Abnormal twisting posture
facial, axial, truncal
Jerky tremor
Causes:
Stroke, trauma, encephalitis, PD, HD
Impaired DA activity in BG
Define Tremor
Involuntary, rhythmic sinosoidal alternating movements of part of the body
limbs, head, chin, soft palate
Pathophysiology:
Postulated theory: increased activity in cerebellothalamocortical tract
PD: DA dysfunction in pallidum
Essential Tremor: GABAergic dysfunction in cerebellum
What are treatments for Hyperkinetic movement disorders?
Tics/Chorea/Ballismus
- D2 antagonists: haloperidol, chlorpromazine, risperidone
- Dopamine depleting agents: tetrapenazine
- Atypical antipsychotics: Clozapine, olanzapine, ariprazole
Define oculogyric crisis
Acute response to certain drugs
fixed upward stare
neck+trunk extension
Jaw spasms, tongue protrusion
Define Neuroleptic Malignant Syndrome (NMS)
acute medical emergency develops over hours/days response to D2 antagonists rigidity, muscle breakdown raised CPK (creatine protein kinase) fever, confusion autonomic instability
Define tardive Dyskinesia
choreic oral-facial movements, dystonic trunk posturing
DA hypersensitivity, synaptic plasticity
treatment: gradual withdrawal from offending drug
Define parkinsonism (akinetic rigid syndrome)
slowness of movement/thought
stiffness
shaking
bradykinesia (loss of facial exp, arm swing, fine movement)
Akinesia (voluntary movement dysfunction)
rigidity
rest tremor
Depression, anxiety, autonomic involvement, sleep disturbance
Define Parkinson’s Disease
Neurodegenerative DA cells in substantia Nigra 70% of cells lost when symptoms present idiopathic in 80% of cases Diffuse lewi body disease Atypical parkinsonianism - MSA (multiple system atrophy) - PSP (progressive supranuclear palsy) - CBD (corticobasal degeneration)
Early PD treatments?
Amantadine: glutamate agonist
Anti-cholinergics: helps BG ACh/DA balance
MAOis: prevents breakdown of 5-HT, NA, DA
selegiline, rasagiline
L-DOPA: crosses BBB and then promotes DA synthesis
- Entacapone/Tolcapone prevents peripheral metabolism
Advanced PD treatments?
Duodopa
Levodopa administered to duodenum via infusion pump
narrow therapeutic range, unpredictable bioavailability
DA agonists Bypasses SN when cells are dead peroglide (ergot; no longer used due to fibromyalgia) promipexole (non ergot) apomorphine (subcutaneous infusion)
Define Neurosis (5 disorders, 1 treatment)
Anxiety disorders Depression OCD Adjustment Disorders Somatisation Disorders
Treatment: antidepressants
Define Psychosis (definition, 4 disorders, treatment)
detachment from reality, no insight, delusions+hallucinations, psychotic episode if presented for a week
organic
schizophrenia
Bipolar disorder
Depressive psychosis
Treatment: antipsychotics
Define Delusion
Firmly held belief
inadequate grounds
doesn’t change mind following contradictory evidence
Primary: delusional perception Secondary: incorrect perception but based off understandable grounds Persecutory Grandiose Responsibility for world tragedy
Define Hallucinations
Perceptions without external stimulus
any sensory modality
Schneider’s first rank symptoms? (Schizophrenia)
Schneider’s first rank symptoms:
- Auditory hallucinations
- somatic hallucinations
- thought withdrawal, thinking out loud
- delusional perception
Signs of Schizophrenia
Appearance: unkempt, weight gain/loss
Behaviour: social withdrawal
Medication side effects:
- Parkinsonian symptoms
- Tardive dyskinesia
- Skin discolouration
- Severe weight gain- olanzapine
What are the aspects of the Mental State Examination?
A Small Majority Thought Parents Created Infants
Appearance/behaviour Mood Thought Perception Cognition Insight
Epidemiology of Schz?
0.2-0.7%, 50% in monoxygotic twins
AoO: men= 21-26, women= 25-32
social drift, urban drift, household stability
Prognosis of Schz?
~20% full recovery, off medication
~25% steady decline, persistent symptoms
~50% relapsing remitting, some functional impairment
Suicide in 5-10%
Pathophysiology of Schz?
Ventricular enlargement
Reduced grey matter
cytoarchitectural changes
hallucinations: paracingulate sulcus morphology
Neurophysiology of Schz?
Hypofrontality: decreased blood flow to PFC bilaterally
Wisconsin Card sorting: unable to detect rule changes
Auditory Cortex activation during hallucinations
Stroop test difficulties
Psychopharmacology of Schz? (3 types)
1) Typical Antipsychotics
- Haloperidol, Chlorpromazine
- D2 antagonists, prevent acute (+ve) symptoms
- Parkinsonian Symptoms, TD
2) Atypical Antipsychotics
- Clozapine, Olanzapine
- Lowered D2 activity, fewer extrapyramidal SEs
- Mainly D4, but affects all Ds + 5HT
- improves +ve & -ve symptoms
- SEs: severe weight gain, sedation, salivation
- Increased PFC DA activity, Decreased DA in NAcc
3) DA agonists
- cocaine, amphetamine, OD of L-DOPA
- Drug-induced psychosis
- treated by drugs in (1)
Glutamate Hypothesis in Schz?
1)PCP causes +ve, -ve, cog symptoms
NMDAR antagonists
2) lower NMDAR count in mice model
- schz symptoms, social withdrawal
3) NMDA antagonists model Schz
- PFC: less Glu firing to VTA GABAergic Ns
- Less GABAergic inhib. of VTA-NAcc DA Ns
- Greater DA release in NAcc
- Less activation of VTA-NAcc DA Ns: less Glu - hypofrontality
DA antagonists: psychotic or antipsychotic?
Antipsychotic
DA agonists: psychotic or antipsychotic?
Psychotic
DSM-V
Diagnostic & Statistical Manual for Mental Disorders
ICD-10
International Classification of Diseases
Major Depressive Episode Criteria/Symptoms
5 or more symptoms for 2w constant depressed mood diminished interest weight loss/gain insomnia/hypersomnia psychomotor agitation/retardation fatigue/loss of energy feeling of worthlessness/guilt impaired concentration/decision making recurrent suicidal thoughts, plans, attempts
Mania
Constantly, abnormally elevated mood functional impairment heightened self esteem grandiose racing thoughts no need to sleep
Mixed affective Disorders
meets full criteria for mania/hypomania/depression
and 3 criteria for the opposite polarity
Major Depressive Disorder
AoO: 25-35y/o Females>males 7% prevalence 1/5 lifetime prevalence 8-19% die by suicide
Bipolar Disorder
BPI: mania
BP2: hypomania and depression
AoO: 15-24
Prevalence: 0.6-2.4%
30-50% attempt suicide
symptomatic for half their lives
Aetiology of Major Depressive Disorder (MDD)
HPA axis function, affected by stress, childhood trauma, genetic factors
Hypothalamus, Pituitary, Adrenal
CRH. ACTH. Cortisol
Monoamine Dysfunction
1st Gen antidepressants
1) MAOi phenelzine, tranylcypromine nonselective inhibition of MAOs -retention of 5HT, DA, NA SEs: dry mouth, GI disturbances, headache, drowsiness, food interactions
2) Tricyclic Antidepressants amitriptyline, clomipraline Nonselective inhibition of MA reuptake - retention of 5HT, NA, DA SEs: constipation, dry mouth, orthostatic hypotension, cardiac/pulmonary fibrosis, drowsiness
2nd Gen antidepressants
1) SSRIs sertraline, citalopram, fluoxetine Equal efficacy to tricyclics broad spectrum: OCD, PTSD, Panic, GAD, Social Anxiety low toxicity
2) SNRIs
serotonin-NE reuptake inhibitors
venlafaxine, duloxetine
Neural systems involved in depression
increased activity:
- amygdala, vestibulospinal tract, PFC
Decreased activity:
- VST
Bipolar Disorder Treatment
Antipsychotics
- D2/D3 antagonists: haloperidol, olanzapine, risperidone
- DA partial agonists: ariprazole
- Rapid antimanic effect
Lithium
- multiple mechanisms, antisuicide
- prevention of relapse
Anticonvulsants
- Valproate, lamotrigine, carbamezapine
- GABA activity
What is an Acute Stress Reaction?
hours-3 days following catastrophic event
-numbness, daze, insomnia, restless, anger/anx/dep
What is Adjustment Disorder?
wide range of symptoms
stressor not necessarily life threatening
out-of-proportion to stressor
lasts upto 6 months
what is PTSD?
Response to exceptionally catastrophic event
witness/experienced event involving torture/death
intense fear/helplessness/horror
Flashbacks with full emotional intensity
immediate onset
GAD
persistent symptoms, no particular stimulus
worry, apprehension, autonomic hyperactivity
fearful anticipation, sleep disturbances, sadness
prevalence 9%
women>men
70% comorbidity
Genetic & environmental roles
HPA axis
Treatment: SSRIs, BZD
Panic Disorder
Fear of losing control, going mad, fainting, dying etc
Palpitations, tachycardia, chest pain, sweating, trembling, dyspnoea, faintness, nausea, paraesthesia, chills
prevalence: 7-9%
AoO: 15-24, 45-54
Genetic and environmental roles
locus coeruleus
SSRIs, BZD, CBT
Agoraphobia
Scenarios one cannot easily escape
Avoidance, stays at home etc
Specific Phobias
Inappropriate response to object/situation
eg spiders, heights
genetic role, past experience, preparedness (marks), classical conditioning, observational learning
Social Phobia
Fear of being judged, observed
avoidance of trigger situations
lifetime risk: 2.4-13.3%
81% of sufferers will at some point meet be comorbid
AoO: <5yo, 11-15yo
Treatment: Beta Blockers, MAOi
OCD
Obsessional thoughts/urges
compulsions reduce anxiety
contamination, order, sexual, violence
prevalence: 2-3%
67% comorbidity
5HT dysregulation, DA dysfunction
Amygdala Fear pathway?
Sensory-Amygdala-hypothalamus-locus coeruleus-acute stress response
Acute stress response= hpa axis
Chronic stress physiology
Chronic activation of glucocorticoid Rs in hippocampus
-increased Ca2+ influxes, excitotoxicity
Therefore some anxiety disorders can result from diminished hippocampal activity
Amygdala+HC receive highly processed info from cortex
-diffuse modulatory systems: NE (FoF), 5HT (mood/emotion)
GABAergic dysfunction: fewer BZD binding sites: inability to suppress inappropriate fear responses
