Neurological Disorders

A brain disorder that has a clear pathological correlate

Disorders associated with developmental or degenerative mechanisms that are likely to have strong genetic factors

Disorders resulting from non genetic trauma, like tumours, injury or vascular disease, and infection

• Overly synchronous brain activity
• Too much stuff happening at the same time

• Both 
• At least 30% of epileptic disorders have known genetic antecedents
• At least 25% have known acquired antecedents - head trauma, severe perinatal injury, stroke, developmental lesions, post-infectious lesions and tumours

• They are excitable
• Too much excitement can cause them to pop due to too much stuff moving in or out, or through programmed cell death, or apoptosis 
• Neurons are also rarely replaced, meaning damage is often permanent
• In addition, neurons require substantial energy to retain functionality, even small disruptions of energy supply leads to dysfunction and cell death. These two attributes are minimised in healthy brains because neurons form recurrent circuits in which excitation and inhibition are in exquisite balance, but it is all too easy to disturb this balance.
• Finally, treatment is difficult - neural circuits are refined over years of experience and it is not easy to replicate this.

• Rhythmic or repetitive neural activity (the firing of action potentials, and the movement of ions in and out of axons)
• In simple systems, these rhythms are often set up by pacemaker activity in individual neurons, by current flow that resonates in specific frequency bands (for example, the brainstem neurons that control the diaphragm and thus breathing).
• In more complex systems, oscillations are usually realised by specific microcircuits in which inhibition plays a prominent role (for example, the ‘gamma’ rhythm in the cerebral cortex reflects interaction between excitatory and inhibitory neurons).

• A type of seizure that impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain
• Generalised seizures have a lot of different causes, but appear to appear to reflect abnormal activation of thalamocortical circuits, and thus widespread synchronisation of the brain.

• Lapses of awareness, sometimes with staring
• Absence seizures often last for 10s or so, are not preceded or followed by incident, and do not result in convulsions; they are characterised by loss of motor activity and consciousness.

• Seizures which affect initially only one hemisphere of the brain
• Start from a focus, usually in the cerebral cortex
• Partial seizures start in small groups of neurons that show exaggerated response to normal inputs, generating a large ‘burst of spiking activity that is then dampened by inhibition.
• In some cases, the inhibition is not strong enough and sets up a propagating wave of excitation through the local circuit and beyond. This wave also feeds back, causing the rhythmic cycles

• Simple seizures cause no interruption to consciousness (although they may cause sensory distortions or other sensations), whereas complex seizures interrupt consciousness to varying degrees.
• This does not necessarily mean that the person experiencing this sort of seizure will fall unconscious (like fainting).
• For example, a complex partial seizure may involve the unconscious repetition of simple actions, gestures or verbal utterances, or simply a blank stare and apparent unawareness of the occurrence of the seizure, followed by no memory of the seizure.

• In rare families, epilepsy appears to be associated with mutations in single genes.
• In most cases, these mutations affect ion channels, particularly the sodium or potassium channels that are so associated with excitability

• Seizures triggered by flickering or flashing light, sometimes spatial patterns, like checkerboards, are sufficient
• Thus brain rhythms can be entrained by external stimuli, and in turn bias
• Generally triggered by lights that flicker at 15-25 Hz (cycles per second) ceiling fans, strobe and christmas lights

• A progressive disorder marked by memory failures, personality changes, and impaired reasoning
• Overall, a 65 year old has about 1/5 chance of getting dementia before they die.

• A chronic neurodegenerative disease that usually starts slowly and gets worse over time
• The most common early symptom is difficulty in remembering recent events (short-term memory loss).
• As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss ofmotivation, not managing self care, and behavioural issues
• Occurs due to the buildup of plaque (protein bundles) causing tangles and disruption to neuronal networks

• Dementia resulting from a series of small strokes or changes in the brain's blood supply. Sudden onset of symptoms may be a sign of this dementia.
• Vascular dementia severely impacts memory and cognitive functioning.

• Fronto-temporal dementia: affects language, semantic memory and executive function
• Pick's Disease: affects personality, orientation and behaviour. It may be more common in women and occurs at an early age.
• Creutzfeldt-Jakob Disease: The disease progresses rapidly along with mental deterioration and involuntary movements.
• Huntington's Disease: Huntington's is an inherited, degenerative disease. The disease causes involuntary movement and usually begins during mid-life.
• Parkinson's Dementia: Parkinson's is a progressive disorder of the central nervous system. In later stages of Parkinson's
• disease, some patients develop dementia.
• Lewy Body Disease: This disease causes symptoms similar to Alzheimer's disease. Individuals with Lewy Body Disease experience hallucinations and can become fearful.

• At a macroscopic level, an Alzheimer’s brain is severely atrophied, with enlargement of the ventricles, and shrinkage of the neural circuitry. The cortex becomes thinner and the hippocampus shrinks.
• At a microscopic level, these are preceded and accompanied by progressively widespread formation of ‘tangles’ and ‘plaques’
• These begin in the entorhinal cortex, through the hippocampus, and thence cerebral cortex. These predict the psychological changes of patients- initially mild cognitive impairment (MCI) is primarily associated with degradation of memory function, and topographical disorientation (presumably hippocampal function) and ultimately praxis, the inability to plan and execute movements.

• The staging of decay aligns with the developmentof abilities and Alzheimer’s dementia may be considered development in reverse
• This is retrogenesis: degenerative mechanisms reverse the normal order of acquisition during development

• 1: Mild memory decline 
• 2: Decline of language & memory 
• 3: Decline of language, visuospatial function & memory 
• 4: Decline of language, visuospatial function, memory & abstract reasoning

• Acetylcholine levels are reduced in most AD patients, at early stages of the disease, and this is important in learning and memory
• Hypothesis is that reduced cholinergic signalling leads to reduced activity, increased pathological tau, and increased ß-amyloid
• Potentiating cholinergic function should reduce the effects of Alzheimer’s disease.
• Inhibitors of enzymes that break down acetylcholine have been trialled in >300,000 patients, but there are substantial side-effects, and still unknown efficacy

• The neurons that first show deposition of the protein aggregates are those which possess long and thin axons, and those that myelinate later during development. 
• This might explain why AD seems to be a uniquely human disease (extremely protracted myelination period in humans), the non-random topographic distribution pattern of protein aggregates (tangles) and the fact that AD resembles development in reverse (reverse myelination)

• The deposition of the amyloid-β peptide in the brain parenchyma is a crucial step that ultimately leads to Alzheimer's disease.
• This leads to inflammatory response, activating microglia and astrocytes, and causing plaque buildup 
• This causes progressive synaptic injury, and altered homeostasis
• This causes widespread disruption in ion movement and neurotransmitter release 
• This leads to dementia, plaques and tangles

• Early onset Alzheimer’s (<65 years old) tends to be familial - known mutations include APP (amyloid precursor protein), PS1/PS2 (presenilin)
• Late onset Alzheimer’s (>65 years old) is more common, but inheritance is more complex - one variant of the APOE (apolipoprotein E) gene is associated with substantially higher risk

• Consistently, immunisation against B amyloid and reduce the onset of cognitive decline in patients.
• Very recent work also suggests that the accretion of plaques and tangles can be reduced by physical disruption with ultrasound, potentially pointing to new treatments (Leinenga and Gotz, 2015)