Neuropsychology- Lectures 9-12 Flashcards
What is Evolution?
“Biological evolution is concerned with inherited changes in populations of organisms over time leading to differences among them.”
Or, change over time.
Darwin’s Theory of Evolution
Two central concepts:
Adaptation – the ability to adapt to changing environments.
Natural selection – process by which some species’ variations are passed on and others are not.
The Four Principals of Darwin’s Theory.
Plant and animal species are dynamic over time (change is inevitable)
Evolution is gradual and continuous (environment > species modification)
But, sudden dramatic changes to the environment can challenge species’ ability to adapt
Natural selection occurs with and without environmental change
Universal common ancestry
Survival of the fittest
Survival and Reproduction Process.
Fittest Means:
Fittest’ can refer to different traits and behaviours in different species.
Variation and competition influence reproductive success.
Variation
Variability in traits (e.g., colouration).
Genetic variation – mutations in DNA.
Competition
Overproduction of offspring – not all will survive/reach maturity.
The environment cannot support unlimited population growth.
Struggle for survival:
Competition between and within species for resources, predation, climate.
Selection – traits are passed on.
Universal Common Ancestry
“I should infer from analogy that probably all the organic beings which have ever lived on this earth have descended from some one primordial form, into which life was first breathed”
(Darwin, 1859, p. 484)
Evidence for universal common ancestry:
Brown et al. (2001):
Focused on 45 species of archaea, bacteria and eukaryotes
Identified 23 proteins conserved in all 45 species
Constructed a universal tree that provided a link between the three domains of life
Inferred from the tree = one species providing the genetic code for all later forms of life
Mendel and his pea plant experiments.
Dominant and recessive genes.
What is a gene?
DNA = molecule with a double helix Gene = section of DNA (~200 – 2 million base pair) Codon = 3 x nucleobase (unit of DNA code)
Gene Expression: From Genes to Proteins
Transcription: segment of DNA is copied into messenger ribonucleic acid (mRNA)
Translation: a process of protein synthesis
Transfer RNA (tRNA): carries an amino acid to the ribosome
Mendel Experiments
Gene for flower colour: 2 alternative versions.
An alternative version of a gene: Allele (inherit from each parent).
Gene for flower colour has a specific location on the chromosome.
If the alleles at a locus differ: Dominant allele will be expressed.
Mendel and his Laws of Heredity
The Law of Segregation:
Each inherited trait is defined by a gene pair.
Offspring inherit one genetic allele from each parent when sex cells unite in fertilization.
The Law of Independent Assortment:
Genes for different traits are sorted separately from one another.
Inheritance of one trait is not dependent on the inheritance of another.
The Law of Dominance:
If the alleles at a locus differ, the dominant allele will be expressed.
Evolution: Modern Synthesis (Huxley, 1942)
Darwin + Mendel = The Genetical Theory of Natural Selection (Fisher, 1918, cited in Moran & Smith, 1966; 1930)
Variation and competition → survival and reproduction
Genetic mutations = essential for natural selection
Genetic mutation:
Majority due to error in DNA replication.
Epigenetics: Study of Heritable Phenotypic Change
Epigenome:
Chemical compounds that can regulate the activity of genes (turn off / on)
Not part of the DNA sequence – attached or added to DNA.
Culture and Evolution: Role of Social Learning
Culture
Adaptation to the environment:
E.g., hunting strategies in killer whales (ecotype)
Gene variants linked with different strategies (Foote et al., 2016)
Can help survival and, therefore, the ability to reproduce
Behaviours learnt → over time → selection for these behaviours
Structure of Grey Matter
Cortical layers are regionally specific. Primary sensory cortex, association cortex and primary motor cortex.
Oligodendrocytes
Send projections that wrap axons with myelin to speed up signal conduction.
Microglia
Immune cells of the brain. Monitor cells for damage and clearance of cell debris.
Astrocytes
Monitor neural activity along axons at synapses and will signal to blood vessels to dilate blood vessels to increase blood flow to provide energy to the neurons.
How does the brain work?
Electrical activity allows for communication between neurons.
The brain is composed of 86 billion neuron.
What is an action potential?
A movement of electrical activity down the Axon.
- Membrane becomes depolarised
- Action potential and repolarisation
- Refractory period
Action potential: All or nothing response
Excitatory postsynaptic potential (EPSP)
EPSP ↑ likelihood of an AP
Positively charged ions flow into cell
Additive effect = depolarisation
Inhibitory postsynaptic potential (IPSP) IPSP ↓ likelihood of an AP Negatively charged ions flow into cell Or, positively charged ions flow out of cell Additive effect = hyperpolarisation
Glutamate and GABA
Cortical excitability:
Balance between excitation and inhibition
Glutamate (glutamic acid)
Major excitatory NT
Gamma-aminobutyric acid (GABA)
Major inhibitory NT (brain and spinal cord)
Linked with seizures:
↑ glutamate or
↓GABA or GABA receptor dysfunction
= neural hyperexcitability > seizures
But, synchronicity of neuronal populations also needed
Acetylcholine
Acetylcholine synthesis:
Acetylcholine (ACh) is made from choline and coenzyme acetyl (CoA)
Synaptic cleft – ACh is broken down by the enzyme acetylcholinesterase
Choline is transported back into the axon terminal and used to make more ACh
Cholinergic pathways in the brain:
Linked with arousal, attention, memory
↑ sensory perception on waking
Damage = memory deficits, AD
Dopamine
Dopamine synthesis:
L-Tyrosine (amino-acid) converted into L-DOPA converted to dopamine
Synaptic cleft – enzyme degradation monoamine oxidase (MAO), catechol-O-methyl transferase (COMT) > homovanillic acid (HVA)
Dopamine is transported back into the axon terminal via dopamine transporters (DAT)
Dopaminergic pathways in the brain:
Linked with reward motivated behaviour
↑Involved in motor control
Role in addiction, PD and ADHD
Norepinephrine (AKA noradrenaline)
Norepinephrine (NE) synthesis:
NE is converted from dopamine within the vesicle
NE pathways in the brain:
Mobilises brain and body for action (fight or flight)
Regulates arousal and alertness
Linked with memory and attention
Serotonin
Serotonergic pathways in the brain:
Predominantly linked with mood
Links with cognition and health outcomes?
Indirect effect(s) of mood?
Agonist and Antagonist Drug Mechanisms
Agonist Drugs:
Nicotine
↑ ACh activity
↑ attention
Opioids Analgesia (pain relief) Sedation Antagonist Drugs: Botulinum Toxin (Botox) Blocks acetylcholine release in PNS Prevents muscle contractions
Caffeine
Blocks adenosine receptors
↑ wakefulness
Indirect agonist = enhances action or release of neurotransmitter(s), but has no individual effect on receptors
Alcohol
↑ GABA (inhibitory neurotransmitter) > ↓ CNS activity
↑ dopamine, endogenous opioids = reward pathways in brain
Antidepressants:
Tricyclic antidepressants (TCAs): Developed 1950’s, common treatment until SSRIs
Side effects:
Sedation caused by histamine H1 receptor blockade;
Postural hypotension due to α adrenoreceptor blockade
Blurred vision, dry mouth and constipation due to muscarinic acetylcholine receptor blockade.
Antidepressants pt2:
Selective Serotonin Reuptake Inhibitors (SSRIs)
MDD, social anxiety disorder, panic disorder, OCD, eating disorders, PTSD
Controversy over efficacy: Mild to moderate depression (d = .11) Severe depression (d = .17) Very severe depression (d = .47) See Fournier et al. (2010)
Methodological issues relate to: Baseline assessment of depression Length of follow-up Attrition (drop-out) Relapse rates
Cipriani et al. (2018):
522 double blind studies
116, 477 participants
All drugs ↑ efficacious than placebo
Modest effect sizes in adults with MDD
Escitalopram, mirtazapine, paroxetine, agomelatine, and sertraline
= ↑ response and ↓ dropout rate than the other antidepressants
Reboxetine, trazodone, and fluvoxamine
= ↓ efficacy and acceptability profiles compared with the other antidepressants
Concerns with SSRIs
Serotonin Syndrome:
Serotonin toxicity = typically caused by taking 2+ serotonergic medications
Concern with OTC drugs
Concern of suicide risk in children and adolescents:
But, suicide is rare
Suicide rates ↓ with ↑ drug prescriptions
3,4-Methylenedioxymethamphetamine (MDMA)
MDMA targets specific neurons (monoamine)
Presynaptic releasing agent of specific neurotransmitters
Serotonin, dopamine, norepinephrine and release of hormones (e.g. oxytocin and cortisol)
Linked with mood, pleasure and energy
Oxytocin = ‘love hormone’, stress (arousal)
Subjective effects 30-45 minutes after oral ingestion
Dependent on dose, setting, user
Maximal concentration 1.5 to 3 hours after ingestion
Duration of action 4-6 hours (depletion of serotonin)
Positive Effects of MDMA
Euphoria
Increased energy
Feelings of belonging and closeness
Increased openness
Feelings of love and empathy
Bright, intense visual perceptions
Heightened sensations (touch, taste, smell, hearing)
Musical appreciation
Fear dissolution
“Profound” thought
Other Effects of MDMA
Appetite loss
Vertical nystagmus
Bruxism and trismus
Moderate increases in HR and BP
Mild visual hallucinations
Mind racing
Changes in thermoregulation
Restlessness, nervousness, shivering
Negative Effects of MDMA
Short-memory loss
Confusion
Vertigo
Muscle tension
Nausea & vomiting
Concentration difficulties
“Crash” - come down
Hangover lasting days to weeks
Depression and fatigue for up to a week
Psychological addiction
Panic attacks
Prevalence of MDMA use: EU
Most recent estimate = ~1.8 million young adults (aged 15–34) used MDMA/ecstasy in the last year (1.4 % of this age group).
EU national estimates = 0.3 % to 5.6 % (EMCDDA, 2015).
Prevalence of MDMA use: US
In 2014, more than 17 million people (12 years +) reported using MDMA at least once in their lifetime
Increased from 11 million people in 2004
660,000 people reported using MDMA in the last month
Increased from 450,000 in 2004
Hatzidimitriou et al. (1999):
10 squirrel monkeys used:
4 control
6 given 5 mg/kg twice daily for 4 consecutive days. Dosage selected as known to produce moderate to severe 5-HT lesions.
2/3 euthanized at 2 weeks and 6-7 years
2 weeks: 85-95% ↓ in neocortex
7 years: 34-56%
Evidence of long term damage, but not as bad as previously thought.
Fantegrossi et al. (2004):
No differences in 5-HT concentration in brain tissue in any brain region
7 adult rhesus monkeys used:
3 MDMA-naïve controls
4 self-administered MDMA (IV catheter; stimulus = red light)
PET scanned for VMAT binding after 2 months abstinence
Euthanized 7-10 days after scanning
Studies on MDMA with humans
Can’t make direct comparisons with animal research (e.g. toxic dosages)
Can’t assess 5-HT or axons in vivo, but can PET scan for SERT
SERT reductions in MDMA users compared to polydrug using controls (Roberts et al., 2016)
FC (+ DLPFC), TC, PC, OP limbic regions (thalamus, hippocampus, anterior cingulate, amygdala)
Medium sized effects in FC, limbic areas; large effects in TC, PC, OC, DLPFC
No differences in midbrain regions
What does this mean? Greater sensitivity for mood disorders - speculation
Issues with the literature:
Small sample sizes
Variable MDMA use and polydrug use
Variable abstinence (days, weeks, months)
Reliant on self-report of usage (unknown dosage (mg) of MDMA; tablets; episodes)
Structural and Functional Brain Changes
Moderate MDMA use
Average of <50 lifetime episodes of ecstasy use or
Average lifetime consumption of <100 ecstasy tablets
Abstinence assessed by urine drug screening
No evidence for structural (MRI) or functional (fMRI) differences between MDMA users and age-matched controls.
Issues with the literature:
Small sample sizes restricts generalizability
Controls not matched for other drug use
Some studies looked at amphetamine-like stimulants (not specifically MDMA)
MRI/fMRI scanning cannot determine neurotoxicity (GM, WM volumes and BOLD)
Heavy use = higher use of other drugs, other lifestyle and environmental factors
Effects of MDMA on cognition
Neurocognition: fMRI, fNIRS, EEG (Roberts et al., 2018)
Some evidence of increased brain activity in MDMA users
Equivalent cognitive task performance = brain is working harder
ERP components = amplitude ↓ in MDMA users (sensitive to post-synaptic voltage changes)
Variable results of cognitive deficits with MDMA use (Parrott, 2000):
Memory deficits – immediate and delayed recall, recognition and spatial recall
Controls: drug naïve and matched for other drug use
MDMA users report subjective memory impairments
Deficits in reasoning and planning (ToL and WCST)
More impulsive (self-report questionnaires)
Other information processing abilities (RT, Stroop, Trails) – not different to controls
Mixed results – not all studies find memory deficits
Deficits correlate with amount of MDMA consumed
Deficits can improve with abstinence
So how dangerous is MDMA?
Low dependence (psychological dependence) and low physical harm (see Nutt et al., 2007) Adverse events (see Nutt, 2009): Horse riding = 1 in 350 episodes MDMA = 1 in 10,000 episodes
Death (1994-2003 in UK; Schifano et al., 2006)
394 ecstasy mentioned
165 sole drug mentioned
Mainly caused by dehydration and increased body temperature
Confounded by other drug use and alcohol consumption, other risk behaviours
18th in harmfulness out of 20 recreational drugs
Can MDMA be beneficial?
Was used in psychotherapy/psychiatry before it was illegal
Potential as a treatment for PTSD (see Feduccia et al., 2018)
Evidence that MDMA can enhance positive emotional bias
Double blind repeated measures design (MDMA/placebo)
19 participants (5 female) with previous use of MDMA
Used participant provided best and worst autobiographical memories
After MDMA:
Best memories = more vivid, emotionally intense and more positive, increased brain activity
Worst memories = reported as less negative, reduced brain activity
See Carhart-Harris et al. (2014)
Electroencephalography
Electroencephalogram (EEG) records post-synaptic voltage changes.
The column-like organisation of pyramidal cells transmits electrical activity to the scalp.
Summation of large groups of neurons firing in synchrony.
Volume conductor:
Scalp, skull, brain, CSF
= unknown location of signal generation
Clinical Applications: Epilepsy
Neurological condition: Characterised by repeated seizures ↓ inhibition → excessive firing of neurons Hyper-excitation Range of seizure types
Clinical Applications: Sleep
Polysomnography (sleep EEG):
Narcolepsy (sudden falling asleep)
Sleep apnoea (breathing stops during sleep)
Insomnia (falling asleep / staying asleep)
Parasomnia (terrors; nightmares; sleep walking / paralysis)
EEG activity is used to characterise sleep stages:
Awake = alpha and beta (15–60 Hz; ~30 μV)
REM = beta (paradoxical sleep – high frequency, low voltage)
Stage 1 = theta (4–8 Hz; 50–100 μV)
Stage 2 = sleep spindles (10–15 Hz oscillations; 50–150 μV)
Stage 3 = delta (2–4 Hz; 100–150 μV)
Stage 4 = delta (0.5–2 Hz; 100–200 μV)
EEG Pros and Cons
Advantages:
Excellent temporal resolution (milliseconds) > ‘online’ functioning
Distinguish timing of different processes (sensory > cognitive)
Low cost
Mobile – but with limitations
Disadvantages: Poor spatial resolution Numbers of individual trials needed for averaging (40+ pp x condition) Fatigue and boredom Movement artifacts
Positron Emission Tomography (PET)
Fluorodeoxyglucose (FDG) = glucose analogue (isotope = Fluorine-18)
Absorbed by high glucose using cells (e.g., brain) > prevents glucose from leaving cell (until radioactive decay)
Intracellular concentration = glucose metabolism
Less ‘active’ cells = hypometabolism
11C-labeled benzothiazole Pittsburgh Compound B (11C-PiB)
11C-PiB is a fluorescent derivative of thioflavin T
Targets and binds to beta amyloid (Aβ40 and Aβ42 fibrils) and insoluble plaques containing Aβ40 and Aβ42 (high affinity)
Most commonly used radioligand used in Aβ deposition imaging
Klunk et al. (2004) – first study
Disease Progression: Imaging Evidence
Amyloid deposition = spectrum, need cut-off for meaningful burden
PiB- and PiB+ using the DVR (1.08; see Villeneuve et al., 2015. Brain)
DVR = Distribution Volume Ratio of a receptor-containing region to a non-receptor region
PET Pros and Cons
Advantages:
Widely used in oncology (diagnosis, staging and treatment)
Distinguish areas of hypometabolism / Aβ deposition in the brain (e.g., AD)
Identify areas of activity with cognitive processes
Examination of neurotransmitter systems
Dopamine, serotonin and opioid receptors (ligand binding to receptors)
Disadvantages:
Radiotracer is radioactive (109 minutes half-life)
Unable to be used in some populations (e.g., during pregnancy)
High cost:
Creation of isotopes and ligands
Medical team / environment needed
MRI Pros and Cons
Advantages:
Excellent spatial resolution
Calculation of GM and WM volumes; correlations with cognitive functions
Non-invasive and does not involve radiotracers
Disadvantages:
Only informs on structure, not function
Lengthy scanning time (40-60 minutes)
Expensive
Not suitable for young children, people with claustrophobia, pacemakers, metal implants etc.
Due to noise, bore (60cm), magnetisation of metal objects
fMRI Pros and Cons
Main advantage:
Excellent spatial resolution
Main disadvantage:
Poor temporal resolution (timing of the haemodynamic response)
Concerns over the multiple comparisons problem:
Compare vast numbers of voxels to assess if voxel is ‘activated’
Issues with false positives, need to correct for multiple comparisons
Dead salmon = brain and spinal cord activity
London Taxi Driver Study
Investigated spatial memory (navigation) in response to environmental challenges (e.g., learning)
Used London taxi drivers (n = 16)
Also found that ↑ experience
↑ posterior volumes
↓anterior volumes
Posterior hippocampus:
Supports spatial navigation
Can expand with experience
Case Studies: The Hippocampus
Clive Wearing (1938 - ) Viral encephalitis destroyed his hippocampus = anterograde and retrograde amnesia (inability to form or maintain new memories and the loss of previous memories)
Henry Molaison (1926-2008) H.M. - removal of hippocampus (for treatment of epilepsy)
Alcohol-Related Brain Disease (ARBD)
Umbrella term = caused by long-term alcohol misuse
Direct neurotoxic effects of alcohol
Thiamine (vitamin B1) deficiency:
Inadequate nutrition, malabsorption of thiamine (from gastro-intestinal tract), impaired utilisation of thiamine in cells
Wernicke Encephalopathy (WE):
Eye movement disorders
Ataxia – impaired coordination, balance
Confusion (+ other altered mental status)
UK prevalence 0.5% (Harper et al., 1995)
But, autopsy studies identified 75-80% more cases than clinical examination (undiagnosed)
Approx. 80-90% PwAUD with WE > develop KS (Victor et al., 1989)
Alcohol-Related Brain Disease
Korsakoff Syndrome (KS):
Severe retrograde and anterograde amnesia
Confabulation
Spatiotemporal disorientation
Executive dysfunction
25%: complete /significant / slight / no recovery (Smith & Hillman, 1999)
25% need long-term residential care (Kopelman et al., 2006)
Wernicke-Korsakoff Syndrome (WKS):
2 Stages: WE (acute, reversible stage) > KS (chronic, irreversible stage) / co-occurence
Brain abnormalities (lesions) characteristic of WKS present in ~13% of PwAUD (Harper et al., 1988) Clinical diagnosis, autopsy confirmation (~20% autopsy confirmed WKS had clinical diagnosis; Harper, 1998)
Functional Neuroanatomy
Visual Area:
Sight
Image perception
Image recognition
Temporal Area:
Memory
Limbic system - hippocampus
Motor Area:
Initiation of voluntary muscles
Broca’s Area:
Language – speech production
Auditory Area:
Hearing
Cingulate cortex:
Limbic system –
ACC = conflict monitoring
Parietal Area:
Integrates sensory information
Olfactory Area:
Smelling
Primary Somatosensory Area:
Inputs of touch and feeling
Somatosensory Association Area:
Integrates and analyses different somatic inputs
Wernicke’s Area:
Language – comprehension (written and spoken)
Supplementary Motor Area:
Preparation and initiation of goal-driven behaviour
Prefrontal Regions: Targeting attention Working memory processes Planning initiation of activity Initiation and control of deliberate action Decision making Problem solving and reasoning
Cerebellum:
Coordination of movement
Balance and equilibrium, posture
What is neuropsychology?
Neuropsychology is concerned with the relationships between brain and behaviour.
Research investigates how brain structure and function can influence affect, behaviour and cognition (ABC).
Clinical research focuses on the links between brain damage and changes in ABC.
The Heart vs. Brain Hypothesis
The Brain Hypothesis:
Aristotle – nonmaterial psyche > heart to produce action
Hippocrates – link between brain and behaviour
Brain = seat of intelligence
Galen – anatomist, clinical observations of gladiators, spinal nerves and treating wounds
Localisation of Function: Evidence against Heart Hypothesis
Renaissance and the Scientific Revolution > Biology and Anatomy
Gall – brain controlled mental functions, not the heart
Different parts of the brain are linked with specific functions
Localisation of Function
Gall (1758-1828) and Spurzheim (1776-1832):
Brain dissections identified the corticospinal tract:
Hemispheric control of contralateral movement
Brain sends messages to spinal cord to produce movement
Cortex is a distinctly functioning part of the brain
The corpus callosum connected the two hemispheres
Phrenology: bumps = personality
Scientifically inaccurate, but influential
Localisation and Lateralisation of Language
Clinical observations (19th C): Speech disorders linked with lesions in the left hemisphere.
Left hemisphere = dominant hemisphere. Speech and language are considered to be central to consciousness
Auburtin (1861): pressure on exposed frontal lobe = abolished speech production.
Broca: identified case studies (n = 8) = left frontal lesions and speech deficits.
Broca’s area = region linked with speech production
Broca’s aphasia = syndrome linked with damage to Broca’s area (a = not and phasia = speech)
Organisation of Language
Wernicke: hearing and speech = related
Cases: people with aphasia + lesions in auditory projection area
Fluent speech but impaired comprehension of spoken words and sentences
Wernicke’s area
Wernicke’s aphasia (fluent aphasia or receptive aphasia)
Model of Language Organisation:
Auditory information travels from ears to primary auditory area
Processed into sound representations in Wernicke’s area
Sound representations sent to Broca’s area (where representations of sound movements are stored)
Neural signals from Broca’s area to motor cortex = mouth movements to produce correct sounds
Case Study: Phineas Gage
Phineas Gage (1823-1860)
Railroad construction worker
Metal rod blasted through his frontal lobe (1848)
Post-injury changes:
Preserved memory and general intelligence
Linked damage to the prefrontal cortex (PFC) with personality changes
Challenges in establishing the extent and duration of post-injury changes
De Schotten et al. (2015) argue that white matter damage was more significant than grey matter damage
Evidence that functioning depends on the connectivity and coordination of different brain regions
Experimental Methods
Experiment: Cause and effect
Flourens (1794-1867) Surgical ablation (removal of brain tissue) = lesions in rabbits and pigeons Cortex = loss of perception, movement and judgement Cerebellum = loss of balance and motor coordination Brainstem (medulla oblongata) = death
Ferrier (1843-1928)
Electrical stimulation of cortex in dogs and monkeys
Ablation of specific brain regions > confirmed stimulation results
Mapping of cortical regions responsible for movement
Translated to humans = predicted regions damaged by tumours
