Important Points!

Important Points! • Website: http://play.psych.mun.ca • Course outline • Course lectures • Study questions • Course info (i.e. change of exam date, class cancelled, assignment info, etc) • Not time in class to cover all material in text, but students are responsible for text and class material for midterms and exams. • Students are responsible for all material covered in class (but not in text).

Chapter 15: Neurological Disorders

Preview Tumors Seizure Disorders Cerebrovascular Accidents Disorders of Development Degenerative Disorders Disorders Caused by Infectious Diseases

Tumors Introduction Tumor – a mass of cells whose growth is uncontrolled and that serves no useful function. Malignant Tumor – a cancerous tumor; lacks distinct border and may metastasize. Benign Tumor – a noncancerous tumor; has a distinct border and cannot metastasize. Metastasis – process by which cells break off of a tumor, travel through the vascular system, and grow elsewhere in the body.

Metastatic Tumor

Tumors (Continued) Glioma – a cancerous brain tumor composed of one of several types of glial cells. Malignant gliomas contain tumor initiating cells which originate from transformations of neural stem cells Rapidly proliferate and give rise to a glioma Meningioma – a benign brain tumor composed of the cells that constitute the meninges.

Malignant Glioma Meningioma Malignant Meningioma

Tumors • Tumors can damage brain tissue by 2 means: • Compression • Directly • Indirectly - blocking flow of CSF, hydrocephalus • Infiltration

Seizure Disorders • Epilepsy - Primary symptom is seizures, but not all who have seizures have epilepsy • Affects about 1% of the population • Difficult to diagnose due to the diversity and complexity of epileptic seizures

Seizures • Seizures often preceded by an aura, such as a smell, hallucination, or feeling • Aura’s nature suggests the epileptic focus • Warns epileptic of an impending seizure

Seizures • Partial seizures– does not involve the whole brain, has a definite focus, or source of irritation • Scarred region caused by old injury or developmental abnormality (malformed blood vessel) • Generalized epilepsy– involves the entire brain, widespread. • Often grow from a focus (may be unknown)

Partial Seizures • Simple • Symptoms are primarily sensory or motor or both • Symptoms spread as epileptic discharge spreads • Not associated with a loss of consciousness • Complex • Often restricted to the temporal lobes (temporal lobe epilepsy) • Patient engages in compulsive and repetitive simple behaviors (automatisms) • Lead to loss of consciousness

Figure 15.6 Primary Motor Cortex and Seizures

Generalized Seizures • Grand mal • Loss of consciousness • Tonic-clonic convulsions • Rigidity (tonus) • ~15 s • All muscles contract, arms are rigidly outstretched • Tremors (clonus) ~ 30 s • Muscles begin trembling, jerking – quick at first, then slower, eyes roll, face is contorted, tongue may be bitten, sweating, salivation. • Firing begins at focus spreads to other regions • Corpus callosum • Resulting hypoxia may cause brain damage

Generalized Seizures • Absence (Petit mal) • Common in children • Not associated with convulsions • A disruption of consciousness associated with a cessation of ongoing behavior • Unresponsive, usually do not notice their attacks • Can occur several hundred times/day

Seizures • Can cause brain damage • ~ 50% of patients with seizure disorders show damage to the hippocampus • Amount of damage – correlated with the number and severity of seizures • Status Epilepticus– a condition in which a patient undergoes a series of seizures without regaining consciousness • May cause significant hippocampal damage • Caused by excessive release of glutamate during seizure

Causes of seizures • Injury, stroke, developmental abnormality, effect of a growing tumor • Febrile seizures • Infantile fever • ~3% of children under 5 • Alcohol or barbiturate withdrawal • Sudden release of the inhibiting effects of alcohol or barbiturate leaves the brain in a hyper-excitable condition (can be fatal)

Causes of seizures • Alcohol effects (during intoxication) • GABA activation • NMDA blocked • Alcohol Withdrawal • Glutamate rebound • NMDA receptors

Causes of Seizures • Genetic factors (not common cause) • 70 genes (as of now) associated with seizure disorders • Nearly all genes identified control the production of ion channels

Treatments • Anticonvulsant drugs (increasing effectiveness of inhibitory synapses) • Brain surgery – remove region of the brain surrounding the focus (usually located in MTL)

Kindling Model of Epilepsy • A series of alternating bilateral brain stimulations eventually elicits convulsions – the kindling phenomenon • Typically amygdala or hippocampus • Neural changes are permanent • Produced by stimulation distributed over time • Convulsions are similar to those seen in some forms of human epilepsy – but they only occur spontaneously if kindled for a very long time • Kindling phenomenon is comparable to the development of epilepsy (epileptogenesis) seen following a head injury Ronald J Racine McMaster University

Stoke • 3rd leading cause of death • Most common cause of adult disability • Common consequences of stroke • Amnesia, aphasia, paralysis, coma • Infarct – area of dead or dying tissue produced by the stroke • Penumbra – dysfunctional area surrounding the infarct • Goal of treatment following stroke is to save the penumbra

Cerebrovascular Accidents • Incidence in US – 750,000/year • 1-2% by 75 • 2 major causes: • Hemorrhagic • ischemic

Cerebrovascular Accidents • Hemorrhagic Strokes Cerebrovascular accident caused by the rupture of a cerebral blood vessel • Malformed blood vessel • Weakened blood vessel from high blood pressure • Blood seeps out and accumulates within the brain, putting pressure on the surrounding tissue Fig. 15.7

Cerebral Hemorrhage Bleeding in the brain • Cerebral blood vessel ruptures and blood seeps into the surrounding neural tissue • Cause • bursting aneurysm • Aneurysm • pathological balloon-like dilation that forms in the wall of an artery at a point where the elasticity of the artery wall is defective • Congenital • Vascular poisons or infection • Weakened blood vessel from high blood pressure

Cerebrovascular Accidents • Ischemic Stroke – cerebrovascular accident caused by occlusion of a blood vessel • Thrombus – blood clot that forms within a blood vessel, which may occlude it. • Embolus – piece of material that forms in one part of the vascular system, breaks off, carried by blood stream until it reaches a smaller artery Ischemia – interruption of the blood supply to a region of the body. Fig. 15.7

Damage Due to Cerebral Ischemia • Does not develop immediately • Most damage is a consequence of excess neurotransmitter release – especially glutamate • Blood-deprived neurons become overactive and release glutamate • Ischemia-induced brain damage • takes time • does not occur equally in all parts of the brain • mechanisms of damage vary with the brain structure affected “Cerebral Penumbra” Nature Medicine (2008) 14:497-500

Blood supply interrupted • Oxygen, glucose and glycogen depleted • Na+/K+ transporters stop working • Depolarizes the cell • lnflux of Na+ and Ca2+ triggers • the release of still more glutamate • a sequence of internal reactions that ultimately kill the neuron • Causes cell to swell • Inflammatory responses • Microglia- phagocytosis • Astrocytes- scarring • Generation of free radicals • Toxic substances • Destroy nucleic acids, proteins and fatty acids

Treatment for Ischemic injury • Clot dissolving drugs • Tissue plasminogen activator (tPA) – within 3 hrs • Can have neurotoxic effects • Desmoteplase (anticoagulant; vampire bats) • Not toxic, up to 9 hrs • Hypothermia • Animal models show that hypothermia has neuroprotective effects • Corbett (MUN) • Slow to catch on in human treatment

Treatment for Ischemic injury • Animal models of stroke and ischemic injury • Gerbil, rat • Biernaskie and Corbett (2001) Enriched environment and post-ischemic training • Animals housed in enriched environments and subjected to training with affected limb showed enhanced dendritic complexity andlength • Motor assessment: EE plus training rats were indistinguishable from control 4 and 9 weeks after ischemia Enriched environment : Corbett (MUN)

Treatment for Ischemic injury • Physical therapy • Human studies • Taub et al (2006) • Constraint-induced movement therapy • Researchers put the good arm into a sling for 2 weeks after ischemic injury • Forced patients use the affected arm • Controls: relaxation and fitness exercise • CI therapy – changes in connections of primary motor cortex See Fig. 15.11

Preview Tumors Seizure Disorders Cerebrovascular Accidents Disorders of Development Toxic chemicals Inherited metabolic disorders Down Syndrome Degenerative Disorders Disorders Caused by Infectious Diseases

Toxic Chemicals • During pregnancy, impairs fetal development • Mother contracts rubella (German measles) • Toxin produced by virus • Mental retardation • Mother ingests alcohol during pregnancy • Mental retardation • Babies are smaller, and develop more slowly • Fetal alcohol syndrome – abnormal facial development, deficient brain development • Neural adhesion protein – protein that helps guide the growth of neurons in developing brain • Decreased plasticity in rats (decreased LTP) • Alters development of neuronal stem cells

Inherited Metabolic Disorders • At least 100 • Phenylketonuria (PKU) • Lack of enzyme that converts phenylalanine into tyrosine • XS phenylalanine in blood interferes with myelinization of neurons in CNS • Given food with phenylalanine, accumulates, severe mental retardation • Treatment • Low-phenylalanine diet

Inherited Metabolic Disorders • Tay-Sachs disease • Causes brain to swell and damage itself against the inside of the skull and dura mater • Metabolic “storage” disease • 1 or more enzymes are missing, waste products cannot be destroyed by lysosomes, accumulation • Lysosomes get larger, cells get larger, brain swells • Symptoms begin around 4 months • Exaggerated startle response, listlessness, irritability, spasticity, seizures, dementia, death

Down Syndrome • Genetic accident • ~0.15% of births • Usually occurs during ovulation • Extra chromosome 21 is created in the egg • 3 chromosome 21s in the zygote

Down Syndrome • Probability increases with advancing maternal age

Genetics of DS • Trisomy 21 • Caused by a nondisjunction event. • a gamete (a sperm or egg cell) is produced with an extra copy of chromosome 21 • Cause of approximately 95% • 88% from nondisjunction in the maternal gamete • 8% from nondisjunction in the paternal gamete. Nondisjunction is the failure of chromosome pairs to separate properly during cell division • The result of this error is a cell with an imbalance of chromosomes

Down Syndrome Mosaicism • When some of the cells in the body are normal and other cells have trisomy 21 • This can occur in one of two ways: • Nondisjunction event during early cell division in a normal embryo leads to a fraction of the cells with trisomy 21 • Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement. • Variability in the fraction of trisomy 21, both as a whole and among tissues. • Cause of 1–2%

Down Syndrome Robertsonian translocation • The long arm of chromosome 21 is attached to another chromosome, often chromosome 14 or itself (called an isochromosome) • A person with such a translocation is phenotypically normal. • During reproduction, there is a significant chance of creating a gamete with an extra chromosome 21 • Cause of 2–3% of observed cases of Down syndrome. • No maternal age effect, and is just as likely to have come from fathers as mothers.

Down Syndrome Duplication of a portion of chromosome 21 • Region of chromosome 21 will undergo a duplication (rare) • Leads to extra copies of some, but not all, of the genes on chromosome 21 • If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics • Very rare

Down Syndrome • Consequences • Disfigurement • Flattened skull and nose • Folds of skin over the inner corners of the eyes • Short fingers • Retarded intellectual development • Often serious medical complications

Preview Seizure Disorders CerebrovascularAccidents Disorders of Development Degenerative Disorders variant Creutzfeldt-Jackob (BSE) Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Multiple Sclerosis Disorders Caused by Infectious Diseases

Degenerative Disorders: vCJD • Transmissible Spongiform Encephalopathies • Contagious brain disease whose degenerative process gives the brain a sponge-like appearance. • Bovine Spongiform Encephalopathy (BSE) • Creutzfeldt-Jakob Disease (CJD) • Fatal familial insomnia • Kuru (humans) • Scrapie (sheep) • Prions– protein that can exist in two forms that differ only in their 3-D shape. • Stanley Prusiner (discovered 1986) • Nobel Prize (1997) • Normal prion protein (synaptic protein) • Development and learning and memory • Accumulation of misfoldedprion protein is responsible for TSE.

PRION DISEASES • PrPc (normal) and PrPsc (prion infected) • PrPSC-protease-resistant (prion protein also heat resistant) • Abnormal protein taken up into neuron by retrograde transport PrPSC PrPC

Transmissible Spongiform Encephalopathies • Encephalopathies • Encephalopathy gives the brain a ‘swiss cheese’-like appearance • Once introduced into the cell thePrPsc can cause the PrPc (normal) to become misfolded • APOPTOSIS: programmed cell death • Caspases: enzymes generated by the cell initiating cell death • BSE: caspase 12

Transmissable Spongiform Encephalopathy

Creutzfeldt-Jakob (and vCJD) • Fatal familial insomnia • Autosomal dominant • 40 families; affecting ~100 people • Kuru • Fore people of Papa New Guinea; cannabalism HUMAN PRION DISEASES

Important Points!