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Biopsych - Brain injury and neurodegeneration (Y2) - Coggle Diagram
Biopsych - Brain injury and neurodegeneration
(Y2)
Hippocampal lesions and the role of the hippocampus in memory formation
Clive Wearing - intact procedural memory
HM - hippocampal lesion; remained normal intelligence and had no psychological illness, but the surgery caused anterograde amnesia
-> Not affected - working memory, old and new procedural memory and facts and events following damage
-> Affected - new facts and events and severe anterograde amnesia
The hippocampal formation - high-level brain region -
Huge amount of visual processing until any sensory information reaches the hippocampus
In other senses (auditory and somatosensory) there is similarly complex processing upstream of the hippocampus - except olfactory inputs that reach the hippocampus more directly
Olfactory bulb -> entorinhal cortex
Such high level brain areas are expected to be notoriously difficult to understand - responses must be complex
Place cells - O'Keefe and Dostrovosky (1971) -
-> Place cells fire when the animal is in a specific region of space
-> Multi-electrode recording shows that the place fields of these cells 'tile' the environment to provide a spatial map
-> Dorsal hippocampal lesions impair spatial navigation
-> Place cells provide the spatial context for memory
In humans -
Maguire's taxi drivers - larger posterior hippocampus in taxi drivers - the more experienced, the larger it was
Hippocampus and binding
Hippocampus binds together different aspects (items and context) of an event to support recollection (Diana et al, 2007)
Hippocampus binds together information from the perirhinal cortex (items - the what) and the parahippocampal cortex (context - the where) through the entorhinal cortex
The relational theory of hippocampus function (Cohen and Eichenbaum, 1993):
To form a memory (episode) the hippocampus supports the binding together of all perceptually and conceptually distinct aspects and elements that make up the memory
What does hippocampal damage tell us about memory?
There are dissociable systems (not affected; short term memory and implicit memory)
Hippocampus is crucial for memory formation but not recall of older memories (anterograde but not retrograde amnesia)
Memories must become consolidated and hippocampal-independent over time
The thalamus is thought to be critical - relay station - located near the centre of the brain:
Nerve fibres project out of the thalamus in all directions, allowing it to act like a hub
It has several functions, such as the relaying of sensory signals
The thalamus has many connections to the hippocampus
The thalamus is densely connected to the cerebral cortex
It is thought to be critical for the transfer of information from hippocampus to cortex
Korsakoff's syndrome - caused by thiamine deficiency due to alcoholism
Results in damage to the thalamus (and general cortical atrophy)
Severe anterograde but also some retrograde amnesia
Suggests thalamus is important for forming memories (and also recalling memories)
But, earlier memories are better preserved (temporal gradient in retrograde amnesia, Rensen et al, 2017)
Suggests that, over a long time, memories get stored in a way that does not require the thalamus
System consolidation of memories
Sensory information is bound together in the hippocampal formation to form a memory episode
This information is slowly transferred to cortex, via the thalamus
Over time - memories become consolidated in the cortex, and eventually can be retrieved without the thalamus / hippocampus structures (Squire, 2006)
Alternative view - over time, memories become semantic and are stored based on meaning
Semantic memories without a hippocampus - Bayley et al, 2008
Some evidence that the cortex can learn semantic information, independent of hippocampus
Two patients with large lesions of hippocampus and surrounding regions were given 4 tests of semantic knowledge
Earlier knowledge recall confirmed to be intact
Both patients exhibited some capacity for new learning of words, names and faces, although performance was low
Limitations of understanding around hippocampal damage -
These patient studies have provided useful information and insight into how memory is organised in the brain
But case studies have limitations - damage is usually not confined to a single brain structure, and lots of variation in damage pattern between cases
Cases are often rare/unique - makes it hard to draw conclusions generalisable to the healthy brain
Also the brain responds to damage, as we see in relation to stroke
Memory systems - two forms of long term memory -
Explicit (Declarative) -> Facts (semantic) and events (episodic) -> medial temporal lobe and hippocampus
Implicit (nondeclarative) ->
Priming -> neocortex
Procedural (skills and habits) -> striatum
Associative learning - conditioning -> emotional responses = amygdala, skeletal muscles = cerebellum
Nonassociative learning (habituation and sensitisation) -> reflex pathways
Stroke damage and neural function
What is a stroke -
Disruption of blood supply and subsequent brain damage
-> Ischemic strokes due to blood clots are the most common (8.5%) - constriction blockage of blood vessels leaves the brain starved of oxygen
-> Haemorrhagic stroke - rupture of blood vessels (toxic for cells)
-> Symptoms of an ischemic stroke occur suddenly as death of brain tissue occurs within minutes - cells surrounding stroke location deprived of blood and oxygen
Doctors can usually identify where damage occurred based on symptoms e.g. weakness of the left leg points to damage to right motor cortex
Brain imaging (e.g. MRI) can be used to show the extent of damage
After a stroke -
-> The brain responds physically to stroke damage by repair processes - creates new blood vessels, axonal growth and remyelination and creating new synapses and neurons
-> The brain responds functionally to stroke damage through reorganisation - surrounding brain region (or opposite hemisphere) takes on function that was lost and recovery of function is therefore possible
Rehabilitation of motor function - most recover after stroke occurs over the first 3 months
Rehabilitation is most important during this time period
Even after a serious stroke, motor function can recover nearly completely within the first few months (Ward et al, 2003)
Rehabilitation of cognitive functions - Turunen et al, 2018 -
Most common impairments are in psychomotor speed (34%) and executive function (27%)
Over 6 months, some recovery of function is possible - particularly in executive function and visual memory
From 6 months onwards, limited scope for improvement
Cognitive deficits after stroke -
Stroke can cause a diverse range of cognitive problems, depending on which brain regions have been affected
As many as two-thirds of patients experience cognitive impairment or decline following stroke and approximately one third go on to develop dementia
Risk for developing dementia may be up to 10 times greater among individuals with stroke than for those without
If we know which regions have been damaged (using MRI) this can inform our knowledge of which regions link to specific cognitive functions
Language deficits after stroke - stroke can cause a range of language problems
Aphasia
-> Common consequence - problems of speech production
-> Includes Broca's and Wernicke's aphasias
Difficulties with accessing word meanings (semantics) are frequently observed in stroke aphasia
-> These deficits are associated with damage to temporoparietal and prefrontal regions of the left hemisphere
-> These patients tell us temporoparietal regions are important for storing word meanings
-> Also - left prefrontal (cognitive control) regions are important for controlling access to word meanings, in a task-appropriate fashion
Other language deficits following stroke -
Agraphia - problems spelling and writing
Alexia - word blindness / visual aphasia - damage to visual/temporal regions in left hemisphere and problems with reading
Dementia pathology and symptoms
Dementia = loss of cognitive functioning that interferes with a person's daily life and activities - globally affects around 4.6 million people (2015) and increases as populations age
Types of dementia -
Alzheimer's disease - most common = 50-70% of cases
Vascular (multi-infarct) dementia
Posterior cortical atrophy
Also - Lewy body dementia and frontotemporal dementia
https://www.sciencedaily.com/releases/2025/12/251224032354.htm
- challenging idea that it is irreversible
Prevalence of Alzheimer's disease -
Age is the biggest risk factor - 0.5% prevalence at 55 years
Risk doubles every 5 years
About 7.7 million new cases of AD each year, with someone being diagnosed every 4 seconds globally
Early onset familial Alzheimer's disease (EOFAD) shows a clear inheritance pattern
Minority of cases (1%) but studies have identified specific genes responsible
Symptoms of dementia -
Preceded by mild cognitive impairment phase (high risk of transition)
Initial symptoms are in the memory domain
These progress to other cognitive domains - also mood and behavioural disturbances, in later stages
Progression from mild to severe AD can take up to 10 years - varies by patient
Mild AD -
Forgetfulness
Word finding
Difficulty
Apathy
Poor attention
Difficulty with complex tasks
Depression
Work trouble
Moderate AD -
Disorientation
Memory loss increases
Confusion
Insomnia
Wandering
Speech difficulty
Restlessness
Difficulty with IADLs
Severe AD -
Agnosia
Apraxia
Aggression
Agitation
Incontinence
Poor basic ADLs
Gait disturbance
Current treatment options -
Main drugs therapies are cholinesterase inhibitors which increase the levels of acetylcholine in the brain
ACh has an established role in learning and memory
In the synapse, it is broken down by acetylcholinesterase
By blocking that enzyme, acetylcholinesterase inhibitors increase ACh, improving memory
Cholinergic hypothesis of Alzheimer's - Arendt et al, 2015
Loss of cholinergic neurons -
Post-mortem studies found reduced levels of the enzyme responsible for ACh synthesis in the cortex of AD patients
Acetylcholinesterase inhibitors compensate for this by boosting ACh
No longer a favoured explanation - treatment is limited in effect and ACh is not the only neurotransmitter affected by AD, and AD is not the only neurodegenerative disorder that shows cholinergic dysfunction
-> Cholinergic system failure could be from another pathology
AChEIs for AD treatment -
These drugs offer improvement of symptoms in about 50% of cases
Improvements in cognition are sustained for about 2 years on average
They are not disease modifying - only modest or temporary improvement of symptoms - course of disease is not slowed
Long term effects of combining memantine with AChE inhibitors in Alzheimer's disease have demonstrated the combination slowed cognitive and functional decline compared with monotherapy or no treatment
Neural markers for AD
Amyloid-beta plaques -
Amyloid beta is a fragment of a larger protein called APP found in healthy neurons
In AD, abnormal cleavage of APP leads to higher levels of Amyloid Beta
Amyloid Beta 42 (insoluble) aggregates into clumps - plaques
Plaques trigger inflammatory response, making them toxic
Leads to synaptic dysfunction and neuronal death
Progression of amyloid plaques in AD - PET brain imaging can detect plaques
Follow a characteristic pattern as AD develops
Begin in hippocampal regions, spreads to temporal and frontal, eventually impacts whole cortex
Tau pathology similar to that seen with amyloid, but appears to build up after
Detectable early in disease process
Amyloid-cascade hypothesis -
States that this initiates the AD, triggering symptoms and other pathology such as NFTs and loss of brain volume
Has been the dominant AD theory of pathogenesis since the 90s
Familial AD implicates genes involved in the production of the precursor of beta-amyloid protein or its processing
But - amyloid load does not link well to symptom severity in AD - NFT levels correlate better
-> B-APP mutations - more AB pepties
-> Presenilin 1 mutation - more AB 42 peptides
-> Presenilin 2 mutation - more AB 42 peptides
-> TREM2 - higher density of AB plaques
Predictive utility - up to 30% of cognitively normal controls show elevated amyloid, measured by PET scanes - Seo et al, 2017
-> But - high amyloid does increase risk of later cognitive decline and predicts conversion from MCI to AD
Anti-amyloid drugs -
Strategies include -
Block / inhibit the overproduction or aggregation of AB - inhibit the enzymes which break down APP into AB
Promote clearance of AB from brain
Limited effect on symptoms so far - high cost and side effects risk
But drug trials are in patients - symptoms might be a signal it is too late, should start treatment earlier in life or target NFTs
Neurofibrillary tangles -
Tau protein is an intracellular protein which stabilises the microtubules that transport nutrients and molecules from the cell body to the axon and dendrites
In AD, abnormal chemical changes cause tau to become hyper phosphorylated and clump together, which then leads to formation of neurofibrillary tangles (NFT)
These impair microtubule function, preventing nutrients to axons and dendrites and impacting function
Brain shrinkage - begins in hippocampal formation - consistent with symptoms
Other dementias
Vascular (multi-infarct) dementia - second most common type
Loss of cognitive functioning due to a series of small 'silent' strokes
Symptoms -
-> Progressive cognitive impairment that occurs step-wise, after each stroke
-> Some improvement between events possible
Risk factors for vascular dementia includes age, hypertension, smoking, high cholesterol and diabetes
Early detection is essential - treatment involves reducing these risk factors, but diagnosis can be difficult since features overlap with other dementias
Posterior cortical atrophy - atypical variant of AD -
Focal, affecting posterior parietal cortex
Alzheimer-like pathology (amyloid plaques and neurofibrillary tangles)
Symptoms -
-> Blurred vision and light sensitivity
-> Progressive inability to recognise faces and objects (agnosia)
-> Problems with spatial skills such as dressing or driving
-> Impaired reading and writing
-> Memory, spoken language and reasoning better preserved until later stages