Final Exam

Pick’s Disease

Frontotemporal lobe dementia; one of the less common types of dementia. Early symptoms include behavioural changes.

Neurons

Cells in the CNS which are much more vulnerable than other tissue cells. They use glucose as their primary carbon source and are not replaced in significant numbers.

\~25%, 50% if necessary

The brain consumes _____% of total oxygen and glucose in the bloodstream, up to…

Glial Cells

Cells in the CNS involved in regulating the health and survival of other cells in the CNS. Dysfunction in these cells is implicated in disease and injury to the CNS.

Developmental Die-Off

During development more neurons are created than are necessary in adulthood, so fine tuning is required and orchestrated by interactions with the environment. Cell death during this process occurs without tissue inflammation or disruption of the surrounding cells/

2 Kinds of Cell Death

Non-programmed and programmed.

Glutamate-Induced Neuron Death

Excessive stimulation through the receptors for glutamate caused by excessive release, failure of the re-uptake mechanisms, exposure to toxic agonists, etc. Too much activity can cause imbalance of ions such as calcium and sodium, causing DNA programmed and necrotic cell death.

Reactive Oxygen Species

Can damage cell membrane and intracellular organelles and will activate DNA programmed cell death mechanisms.

Hypoglycemia

Loss of glucose leads to rapid depletion of cellular energy reserves and will activate DNA programmed cell death mechanisms.

Ischemic Cascade of Events

Ischemia → decreased oxygen and glucose → decreased ATP → depolarization → glutamate release → NMDA receptor activation → increase in calcium ion concentration → neuronal injury or death

Necrosis

Dramatic and rapid form of cell death in which every compartment of the cell disintegrates. Characterised by marked dysregulation of ion homeostasis causing cell swelling, dilation of the mitochondria and ER, formation of vacuoles in the cytoplasm, and activation of proteases that degrade cellular components.

chromatin clumps, the nuclear membrane is disrupted, and gene transcription and thus protein synthesis stops. ATP rapidly depletes, cells lyse and spill their contents into the extracellular space which can cause an inflammatory response.

During necrotic death processes…

Type 1 Programmed Cell Death (PCD)

Apoptosis; occurs in both “appropriate” and “inappropriate” cell death and is essential for development. Has intrinsic (signals arise from within the cell) and extrinsic (death activators bind receptors at the cell surface) pathways.

Intrinsic Apoptosis Pathway Steps

Mitochondrial pathway: intracelluar stress promotes the release of cytochrome c from the mitochondria → cytochrome c binds APAF-1 and induces the creation of the apoptosome → APAF-1 and cytochrome c capture and bind caspase-9 which completes the apoptosome → apoptosome activates caspase-3

Pro-Apoptotic Proteins

Bax, Bak, Bad, Bid

Anti-Apoptotic Proteins

Bcl-2, Bcl-xl, Bcl-w

Fas and TNF Receptor Function

Integral membrane proteins with exposed receptor domains at the cellular surface. Fas is bound by FasL which causes recruitment of FADD which recruits caspase-8 to form the death-induced signalling complex (DISC) - this causes the subsequent action of caspase-3 or caspase-7.

Caspase-Independent Pathway

Apoptosis-inducing factor (AIF) is released from the mitochondria when the cell receives signals to die → AIF migrates to the cell nucleus → AIF binds to the DNA and triggers its destruction and cell death

Apoptosis Characteristics

Cell shrinks and fragments, cell membrane “blebs” but integrity is maintained, mitochondria have increased membrane permeability, chromatin is clumped and fragmented in the nuclei, DNA appears in the cell cytosol, process requires DNA programmed cascade/protein synthesis/RNA transcription/ATP

Necrosis Characteristics

Cell swells, membrane becomes smooth and is lysed, mitochondria swell and become disordered, nuclei swell and membrane becomes disrupted, DNA diffuses randomly, does not require protein synthesis/RNA transcription and is energy independent

How to Detect Apoptosis

Presence of cytomorphological changes, DNA fragmentation, caspases, cleaved substrates, membrane alterations, or mitochondrial assays

Tunel Staining

Terminal deoxynucleotidyl transferase mediated dUTP nick end labelling which allows incorporation of nucleotide labels into fragmented DNA

Seizure

Excessive hypersynchronous neuronal cortical discharge. Is a transient occurence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain, usually less than 2 minutes in duration.

Focal Seizure

Seizures which affect a specific area of the brain, also referred to as partial seizures.

Generalized Seizures

Seizures which affect both sides of the brain, including: absence, atonic, tonic, clonic, tonic-clonic, myoclonic, and febrile seizures.

Epilepsy

Two or more unprovoked or reflex seizures less than 24 hours apart OR a single unprovoked or reflex seizure and a greater than 60% risk of having another seizure over the next 10 years OR an epilepsy syndrome.

Seizure Electrograph

A clear ictal even compromising of a sudden, repetitive, evolving stereotyped waveform with a definite start, middle, and end.

Frontal Sleep-Related Hypermotor Epilepsy

Occurs during NREM sleep, and is brief and highly stereotyped. May overlap with parasomnias.

Dementia

Global deterioration of intellectual function in the face of unimpaired consciousness.

Bedside Dementia Tests

Mini mental status examination (MMSE), Montreal objective cognitive assessment (MOCA); test the patient’s level of consciousness, orientation, memory, attention and concentration, knowledge, and language

Pout Reflex

If the lip is tapped with a tendon hammer, a pout response is observed. Abnormal in frontal lobe dementia.

Glabellar Reflex

When tapped between the eyes, patient should be able to inhibit blinking. Abnormal in frontal lobe dementia.

Anterior Lobe Dementia

Dementia in the frontal pre-motor cortex; patient exhibits behavioural changes and loss of inhibition, antisocial behaviour, is facile and irresponsible. E.g. Pick’s disease, Huntington’s disease.

Posterior Lobe Dementia

Dementia in the parietal or temporal lobes; patient exhibits disturbances in cognitive function without marked changes in behaviour. E.g. Alzheimer’s disease.

Degenerative Causes of Dementia

Alzheimer’s disease, Lewy body dementia, tauopathies (i.e. Pick’s disease, progressive supranuclear palsy), Huntington’s disease, Parkinson’s disease, Wilson’s disease

Cerebrovascular Causes of Dementia

Multi-infarct dementia, CNS vasculitis

Structural Causes of Dementia

Normal pressure hydrocephalus, brain tumours, head injuries, subdural hematomas

Infectious Causes of Dementia

Creutzfeld-Jakob disease, neurosyphilis, HIV, viral encephalitis

Toxic/Metabolic Causes of Dementia

Drugs, alcohol, heavy metals, carbon monoxide, vitamin deficiencies (e.g. B12, thiamine, folate), hypothyroidism, uremia, hepatic encephalopathy

Lab Investigations for Dementia

Complete blood count, thyroid function tests, B12 level test, folate level test, serum electrolytes, glucose level tests, toxicity screens, tests for syphilis or HIV, neuroimaging, EEG, cerebrospinal fluid exam

Neurodegenerative Dementia Themes

Age-dependent regression, some brain regions are more susceptible, misfolded and abnormally deposited proteins, unknown precise cause

Alzheimer’s Disease

An irreversible, progressive brain disease that slowly deteriorates memory and thinking skills and is the most common cause of dementia. Symptoms include impairment in memory, attention, language and communication, abstract thinking, judgement, and changes in personality, depression, visuospatial disorientation. Signs include motor and gait disturbances, poverty of movement and slowness, falls, bowel and bladder control issues, and seizures.

Neuropathology of Alzheimer’s Disease

Cortical atrophy, synaptic and neuronal loss, neurofibrillary tangles with paired helical fragments, abnormally hyperphosphorylated microtubule-associated proteins, tau deposition, neuritic plaques with an amyloid core

Drugs to Treat Alzheimer’s Symptoms

Cholinergic agents such as donepezil, rivastigmine, or galantamine and non-cholinergic agents such as memantine.

75

The chance of seizures being controlled by medications is ___%.

25

__% of patients who have seizures that are not able to be controlled by medication are eligible for epilepsy surgery.

Superior temporal gyrus, medial temporal gyrus, inferior temporal gyrus, fusiform gyrus, parahippocampal gyrus, hippocampus, and amygdala

Temporal Lobe Anatomy

CA 1, CA 2, CA 3, CA 4, granule cell layer

Internal Architecture of the Temporal Lobe

Invasive Monitoring Techniques

Depth and grid electrodes

Surgeries for Epilepsy

Temporal lobectomy or resection, selective amygdalohippocampectomy, extra temoral resection, awake craniotomy, vagal nerve stimulation, laser interstitial thermo therapy (LiTT), multiple subpial resection

Temporal Lobectomy

The most common type of surgery for people with temporal lobe epilepsy in which the anterior temporal lobe, amygdala, and hippocampus are removed.

Awake Craniotomy

Intraoperative stimulation under local anaesthesia.

3 Basic States of Sleep

Awake (presence of the alpha rhythm), nREM sleep (N1 = alpha drop-out, N2 = sleep spindles and K complexes, N3 = slow wave sleep), and REM sleep (no muscle tone, rapid eye movements)

reticular neuron activity, GABA-B receptors

In REM sleep there is an increase in __________ activity which hyperpolarises relay neurons via…

T-type calcium channels, sleep spindles

Hyperpolarization of relay neurons activates _______ which allows low threshold depolarization burst mode thalamo-cortical activation that generates…

increased stage N2 sleep and increased spindle activity.

Benzodiazepines are associated with…

REM Sleep

Characterized by rapid eye movements, lack of EMG muscle activity, and “awake” looking EEG.

parabrachial/precoeruleus nuclei (pons) and the supramammillary nuclei (midbrain).

In wakefulness, glutamate is secreted by…

brain stem nuclei, caudally to the motor neurons in the spinal cord and rostrally to neurons throughout the cortex.

Wakefulness is supported by excitatory transmission from…

Other Important NTs Involved in Sleep

Hypocretin, adenosine, and melatonin

Hypocretin

Produced by cells in the hypothalamus and is thought to provide inputs to various nuclei important in sleep to support these and stabilize sleep states. Functions in promoting wakefulness, stabilizing sleep and wake episodes, and maintenance of skeletal muscle tone during wakefulness.

Adenosine

Mediator of sleepiness after prolonged wakefulness; thought to promote the transition to SWS by inhibiting basal forebrain neurons.

Insufficient Sleep Syndrome

Most common cause of sleepiness. Chronic sleep deprivation can lead to weight gain, high blood pressure, and diabetes.

Obstructive Sleep Apnea Syndrome

Second most common cause of sleepiness. Characterized by temporary pauses in breathing while sleeping occurring due to diminished muscle tone during sleep and airway collapse. Patient tries to breath with closed airway and eventually wakes up with the effort; associated with obesity, snoring, and increased risk of heart attack or stroke. Best treated with a CPAP machine.

Narcolepsy

Symptoms include excessive daytime sleepiness with sleep attacks, cataplexy (temporary loss of muscle tone with no loss of awareness), sleep paralysis, and hallucinations. Associated with low levels of hypocretin.

Hypnogogic Hallucinations

Hallucinations upon falling asleep.

Hypnopompic Hallucinations

Hallucinations upon waking up.

Restless Legs Syndrome

Uncomfortable sensation in the legs with an urge to move the legs while attempting to fall asleep. Can be associated with iron-deficiency anemia and be treated with iron supplementation, gabapentin, or dopamine agonists

Parasomnias

Abnormal movements or behaviours intruding into sleep, classified based on what stage of sleep they originate from. When arousing from nREM: confusional arousals, sleep terrors, sleepwalking. REM: REM sleep behaviour disorder.

Sleep Terrors

Arise out of slow-wave sleep and is more common in kids. Can be brought on by stress, sleep deprivation, alcohol, and fevers. Associated with sleep walking and confusional arousals.

REM Sleep Behaviour Disorder

Loss of REM atonia where the patient acts out dreams (e.g. kicking and yelling in sleep). More common in the elderly and is associated with Parkinson’s disease and Lewy body dementia.

Substance Abuse Disorder

Addiction; chronic relapsing disorder characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state when access to the drug is prevented.

biopsychological

Addiction is a ______ disease; risky drug use can be correlated with biological factors, socioeconomic status, homelessness, social isolation, and early life trauma.

Cycle of Addiction

Initial drug use → continued drug use → drug withdrawal < - > compulsive drug use

genetics and mood

Initial drug use can be determined by…

positive reinforcement

Continued drug use is driven by…

Incentive Salience

Motivation for rewards that is learned by previously learned associations about a reward.

Drug Withdrawal

Has the opposite effects of acute drug use (e.g. dysphoria, increased pain, anxiety) and unpleasant symptoms can drive craving and relapse. Symptoms get worse with chronic drug use.

alcohol

Certain drugs, such as ____, can induce lethal withdrawal symptoms.

Compulsive Drug Use

Characterised by a shift from impulse to compulsive drug use and a shift from positive reinforcement to negative reinforcement.

Neural Circuits Involved in Drug Use

Mesolimbic dopamine system, prefrontal cortex, central amygdala

Mesolimbic Dopamine System

Dopamine containing neurons in the ventral tegmental area project to the ventral striatum and prefrontal cortex. Dopamine release occurs following a salient stimuli and promotes motivated behaviour.

depression and anhedonia.

Deficits in dopamine signalling are associated with…

salience

Phasic dopamine signals ______ of reward cues, but not does necessarily signal the reward itself.

All

____ drugs of abuse evoke dopamine release, although they do so via different mechanisms.

Heroin Mechanism

Binds to mu opioid receptors located o inhibitory GABAergic interneurons in the VTA. Mu opioid receptors are inhibitory G-protein coupled receptors (which inhibit neurons) and cause disinhibition leading to dopamine release.

Psychostimulants Mechanism

E.g. cocaine; blocks the dopamine transporter, inhibiting reuptake of the dopamine from the synaptic cleft into the presynaptic axon terminal which increases synaptic levels of dopamine.

psychostimulant, opioid reward.

Midbrain dopamine is required for ________ reward, but not…

Incentive Sensitization

Amplification of drug wanting triggered by drug cues, driven by sensitization of the mesolimbic dopamine system.

Prefrontal Cortex in Addiction

Glutamate afferents project from the cortex into the striatum and increase dopamine release. Drug cues activate orbital frontal cortex in addicted individuals but not non-addicted individuals. Glutamate release increases AMPA expression and LTP at dopamine in the striatum, increasing dopamine signalling.

Central Amygdala in Addiction

A nucleus in the limbic brain associated with fear and anxiety; neuropeptide release in the central amygdala causes anxiety. Withdrawal is associated with increased CRF levels here.

Partial Dopamine Agonists

Normalize sensitized drug-evoked phasic release and decreased tonic levels during withdrawal to bring dopamine back to the homeostatic level.

Agonist Replacement Therapy

A comprehensive treatment approach including maintenance on an opioid agonist and cognitive behavioural therapy. The agonist therapy blunts the symptoms of withdrawal and the replacement agonist has a longer half-life so there is avoidance of a repeated high/crash cycle.

Advantages of Agonist Replacement Therapy

Reduces drug cravings, better participation in addiction treatment since withdrawal symptoms aren’t distracting, improved social functioning, reduction in infectious disease/death associated with illicit drug use

Psychiatrist

A physician who specialises in the diagnosis and treatment of mental disorders. They treat patients through psychotherapy, psychopharmacology, somatic therapies, and lifestyle modification.

Psychotherapy

Involves addressing a patient’s thoughts, behaviours, emotions, and relationships through developing insight, changing cognitions, and changing behaviours.

Pharmacotherapy

The prescription of drugs to aid in the management of a mental disorder.

Somatic Therapy

Involve stimulating neural circuits, e.g. electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, vagal nerve stimulation, and phototherapy.

Course of Major Depressive Disorder

Average onset is 25-30 years of age, which may be sudden or gradual. Is recurrent and after one episode the likelihood of a second episode is 50%. After two episodes, the likelihood of a third episode is 80%.