Lecture 6a Outline
1.      Causes of Brain Damage
     a.      Tumors
     b.      Cerebrovascular Disorders
     c.      Closed-Head Injuries
     d.      Infections
     e.      Neurotoxins
     f.      Genetic Factors
2.      Epilepsy
     a.      Partial Seizures
     b.      Generalized Seizures
3.      Parkinson's Disease
4.      Huntington's Disease
5.      Multiple Sclerosis
6.      Alzheimer's Disease

Relevant Video Segments

Segment 18.             A Case of Phenylketonuria
Setment 19.             Down's Syndrome

Lecture 6a

1.      Causes and Effect of Brain Damage
a.      Tumors
-       a tumor (called a neoplasm) is a group of cells growing independently of the rest of the body;
     a tumor can be encapsulated or infiltrating;
     it can be benign or malignant
-       metastatic tumors are tumors that originate in one organ and spread to another;
     [symptoms of multiple cerebral tumors are often the first signs of lung cancer]

-       20% of brain tumors are meningiomas,  i.e.tumors that grow in the meninges;
     they are encapsulated and benign, but their growth can squeeze the brain

-     other 80% of brain tumors form from glia.

b.      Cerebrovascular Disorders

-       "stroke" is commonly used to refer to any cerebrovascular disorder of sudden onset
Two types:

     1.  intracerebral hemorrhage, which is  the bursting of aneurysms (balloon-like dilations of weak areas of blood vessels) is a major cause of intracerebral bleeding;
     blood around a neurons interfer with normal functioning and must be removed
     aneurysms can be congenital or they may be caused by infection or toxins

     2.cerebral ischemia is cell death caused by interruption of blood supply to the brain;
     cells die from a shortage of oxygen (hypoxia);
     the area of damage is called an infarct

Three main causes of cerebral ischemia:

     (1) in thrombosis a plug (a thrombus) becomes lodged at its site of formation; the plug may comprise hair, oil, cancerous cells, air bubbles, etc.;

     (2) in embolism a plug (an embolus) travels from its site of formation and becomes lodged in a smaller blood vessel;
     (3) in arteriosclerosis the thickening of a blood vessel wall, usually from the accumulation of fat, blocks blood flow

the role of excitatorv amino acids in stroke-produced brain damage is currently under investigation

Figure 6.5 in 4ed. text     (use Digital Image Archive Figure

The events following a stroke are believed to be as follows
     1. glutamate, the brain's most prevalent excitatory amino acid neurotransmitter is released in excessive quantities [when blood vessels are blocked they deprive neurons of nutrients]
     the excessive glutamate overactivates glutamate receptors on postsynaptic membrane sites,
     and too many Na+ and Ca+ ions are allowed to enter the postsynaptic neuron;      the over abundance of Na+ and Ca+ triggers either:
           (a) an excessive release of glutamate, causing a cascade of this toxic effect or            (b) triggers a sequence of reactions that kill the postsynaptic neuron

     in experimental animals, NMDA (N-methyl-D-aspartate) receptor blockers  administered directly after a stroke have been shown to reduce subsequent brain damage

c.      Closed-head Injuries
-       a brain contusion is an injury in which there is bleeding from the blow in the absence of a laceration;

     the bleeding results in a hematoma (a bruise or collection of clotted blood); contusions are caused by the brain hitting the skull, and they are often contre coup (on other side of brain from blow)

-       concussion is the diagnosis when a blow to the head disrupts consciousness, but no evidence of physical damage can be found;

     the punch-drunk syndrome is the accumulation of many concussions

d.      Infections
-       encephalitis is the general term for inflammation of brain resulting from infection
-       bacterial infections can be treated with antibiotics, but if left untreated they can cause meningitis (inflammation of meninges), brain abscesses (pockets of pus), and general paresis (from syphylis bacteria)
-       viral infections cannot as yet be successfully treated;

     neurotropic viral brain infections preferentially attack the nervous system (e.g., rabies virus);
     pantropic viral brain infections show no preference for the nervous system but they sometimes attack it (e.g., mumps and herpes viruses)
e.      Neurotoxins

-       brain damage can be produced by a variety of toxins in the environment;

     “mad Hatters" were the result of mercury poisoning;

     “crackpots" were originally those who drank tea from cracked ceramic pots with lead cores

-       exogenous vs. endogenous toxins;
in some disorders toxins appear to be created by the patient's own body; e.g., in MS (multiple sclerosis) the patient seems to manufacture antibodies to his or her own myelin

f.      Genetic Factors

-       some genetic disorders are accidents of cell division during fetal development;
e.g., in Down's syndrome an extra chromosome 21 is present in all cells; trisomy 21
-       more commonly, genetic disorders are inherited;
strong evidence that a disorder is inherited comes from twin studies (monozygotic vs. dizygotic) and from early-adoption studies

-       the situation is complex to unravel when what is inherited is a hypersusceptibility to some other agent (e.g., an infection or toxin); e.g., in PKU (phenylketonuria) the patient inherits no enzyme to metabolize the amino acid phenylalanine and is poisoned by phenylalanine-rich diets

-     genetic neuropsychologicl disorders are usually associated with recessive genes:
     otherwise, the organism would not survive to pass them on to its progeny.  

However, there are cses where a dominant gene is abnormal; the most notable is Huntington's disease, a motor disease that does not develop until a person is likely to have had children.

g.     Programmed Cell Death

-     Dysfunctional (including inactive) neurons and other cells are eliminated by activating genes that kill them;  
     This programmed cell death is called apoptosis
     This differs from necrosis, in which neurons die passively as a result of injury

2.      Epilepsy
     See fig. 6.9 in your text (Digital Image Archive Figure CH06F07.bmp)

-       epilepsy is any disorder in which epileptic seizures recur spontaneously

-       when convulsions (motor seizures) are present, epilepsy is easy to diagnose;      convulsions often involve clonus (tremor), tonus (rigidity), loss of balance, and/or loss of consciousness
-       however, many seizures involve subtle changes in thought, mood, and/or behavior with no convulsive sumptoms whatsoever

-        the observation of epileptic spikes in the EEG is incontrovertible evidence of epilepsy;
     however, failure to observe them does not prove that the person is not epileptic

-       there are two main classes of seizures: partial seizures and generalized seizures

a.      Partial Seizures
-       partial seizures are those that do not involve the entire brain
-       simple partial seizures are partial seizures whose symptoms are primarily sensory and/or motor; usually the symptoms start in one part of the body and spread through it as discharges spread through the sensory and motor areas of the brain
-       complex partial seizures are characterized by psychological and behavioral symptoms that look much like normal behaviors;
     they often begin with a complex psychological symptom called an aura (an idea, a memory, a hallucination, an emotion, etc.), which may or may not develop into motor symptoms;
     the motor symptoms of complex partial seizures vary in complexity from automatisms (simple, compulsive, repeated behaviors such as tugging on a piece of hair)      to psychomotor attacks (long sequences of behavior that are out of context and slightly peculiar but are, for the most part, normal-appearing);
     epileptics typically have no memory for the events of a complex partial seizure

b.      Generalized Seizures
-       generalized seizures are those that involve the entire brain;
     they may start from a focus and gradually spread across the brain,
     or they may begin almost simultaneously throughout the entire brain;
     for example, grand mal seizures (means “big trouble”) include tonic-clonic, loss of balance and consciousness, tongue biting, incontinence, turning blue from hypoxia) and
     petit mal (“little trouble”) seizures (petit mal absence, 3-per-second spike-and-wave)
     See fig. 6.10 in your text (Digital Image Archive Figure CH06F09.bmp)

3.     Parkinson's Disease

-       Parkinson's disease attacks 1% of the population;
     it usually develops in people in their 50s or 60s;
     the first symptom is often a tremor or stiffness of the fingers

-       symptoms of the full-blown disorder are tremor at rest, muscular rigidity, cruel restlessness, bradykinesia (poverty and slowness of movement), and a shuffling wide-based gait; there is no intellectual deterioration (no dementia)

-       its cause is not known (pesticides are suspected),

     but it is associated with degeneration in the dopamine pathway projecting from the substantia nigra to the striatum;

it is treated with L-DOPA (a precursor of dopamine) because dopamine does not readily penetrate the blood-brain barrier; Deprenyl, an MAO (mono-amine oxidase) inhibitor and dopamine agonist, slows the development of the disorder

4.      Huntington's Disease
-       like Parkinson's disease, it is a motor disorder;
     unlike Parkinson's disease, it is extremely rare,
     its cause is understood, and it is always associated with dementia
-       its main symptoms are complex jerky movements of entire limbs;
     because the movements in some cases are dance-like, it was called Huntington's chorea
-       Huntington's disease is caused by a single dominant gene;
     50% of all offspring of a Huntington's parent will get it;
     the reason why the disease has not disappeared is that the first symptoms do not appear until after the age of reproduction (at 45 or 50 years of age);
     the patient dies about 15 years after the first symptoms are apparent
-       it is now possible to test the sons and daughters of a Huntington's parent to determine which have inherited the lethal gene; would you want such a test if you were in such a situation?

5.      Multiple Sclerosis
MS is a auto-immune disease of CNS myelin; it leads to the development of areas of hard scar tissue throughout the CNS; "sclerosis" means "hardening"

-       the symptoms depend on the location of the scars;

     but common symptoms are ataxia (loss of motor coordination), weakness, numbness, tremor, and poor vision
-       it attacks people in early adulthood; there are often periods of partial recovery, but there are no exceptions to the generally worsening progression of the disorder
-       it is more common in cool climates; it is rare among orientals;

     the concordance rate is 36% in monozygotic twins and 12% in dizygotic twins

-       because a similar disorder (experimental allergic encephalomyelitis) can be produced in animals by injecting them with myelin and a substance that stimulates the body's immune reaction, it is believed that MS results from a faulty immune reaction against the body's own myelin, perhaps resulting from an early infection or toxin

6.     Alzheimer's Disease

     See fig. 6.12 and 6.13 in your text (Digital Image Archive Figure CH06F12.bmp)

-       5% of people over 65 years old suffer from Alzheimer's disease;

     the first signs are anosmia (loss of olfactory sensitivity), a decline in cognitive ability (e.g., forgetfulness) and
     emotional instability (e.g., depression); eventually there is total dementia and an inability to perform even the most simple responses (e.g., swallowing); it is terminal
-       autopsy reveals:
     (1) loss of neurons (particularly cholinergic neurons),
     (2) amyloid plaques (clumps of degenerating neurons next to an abnormal protein called amyloid), and
     (3) tangles of neurofibrils within neurons
-       in one study of a form of Alzheimer's disease that runs through families, the abnormal gene was identified; it was on chromosome 21, the same chromosome involved in Down's syndrome;
     Down's patients that survive until adulthood almost always develop Alzheimer's disease.

     And I see men become mad and demented from no manifest cause, and at the same time doing many things out of place... some jumping up and fleeing out of doors, and deprived of reason..., and afterwards becoming well rational as before, although they be pale and weak; and this will happen not once but frequently.
     Hippocrates's description of psychomotor epilepsy translated from The Sacred Disease

Suggested Websites for Lecture 6a:

Brain Trauma:
     From the Neurosurgeon site maintained by Michael Lusk, MD, a collection of pages and links related to head trauma and surgery. Includes a glossary of neurosurgical terms as well as images and brief text of various sorts of cerebral trauma, with links to many other sites related to stroke, traumatic head injury, aneurysms, and other cerebral disorders. See also:
     for the Whole Brain Atlas site and some excellent images and time-lapse movies of various brain trauma, including stroke, Alzheimer's disease, Huntington's disease, and MS.

Huntington's Disease:
From the Huntington's Disease Society of America, a good resource for those interested in the etiolgy andcause of HD.

Parkinson's Disease:
     An abysmally long URL, but a great site from the Department of Clinical Neurosciences at the University of Birmingham, England; note the references to James Parkinson's original monograph, the links to the anatomical correlates of Parkinson's Disease, and the QuickTime movies of patients displaying the symptoms of Parkinson's Disease.

Lecture 6b


1.   What is an animal model?
2.   Kindling Model of Epilepsy
3.   Transgenic Mouse Model of Alzheimer's Disease
4.   MPTP Model of Parkinson's Disease

Lecture Notes

a.  What is an animal model?

-      it is rare that the type of experiments necessary to understand a human neuro-psychological disorder can be conducted on human patients;

quasi-experimental studies may  be possible, but not experiments;

thus it is difficult to study the causal factors in human neuropsychological disorders

-      accordingly, the study of animal models has contributed much to the understanding of some neuropsychological disorders

-      the decision to induce a neuropsychological disorder in a laboratory animal is not a decision  made lightly;

     the medical researcher must make difficult decisions such as to engage in research that involves the induction of pathological states in laboratory animals,
     or to potentially contribute to the suffering and death of untold thousands of humans by refusing to engage in a line of research that might eventually lead to an effective new treatments

-      There are three kinds of animal models:

     1)  homologous animal models are animal disorders that duplicate the human disorder in every significant respect: underlying pathology, symptoms, and prognosis)

     2)  isomorphic animal models are animal disorders that duplicate the human disorder in every significant respect, but are induced in the laboratory in a way that does not resemble the etiology of the human disorder

     3)  predictive animal models do not closely resemble the human disorder in any obvious way, but there is something about the model that allows the researcher to make predictions about the human disorder or its response to treatment
-      to use an animal model one must appreciate what kind of model it is;
     e.g., etiology cannot be studied with isomorphic and predictive models, and the      underlying physiological pathology cannot be identified with a predictive model;      truly homologous models of nervous system disorders are rare;
     at best animal models reflect only some aspects of a disorder

-      the problem in developing an animal model is that it is often not possible to tell how well an animal model equates to the human disorder because we don't have a complete understanding of the human disorder;

     this is a classic "Catch 22" situation

2.  Kindling Model of Epilepsy  (kindling is a small bits of wood used to start a fire)

- in the typical kindling experiment, an animal (usually a rat) receives one mild brief (usually 1 second) electrical stimulation (usually to the amygdala) at regular intervals (usually once per day)

- the first stimulation has no behavioral effect;
     however, after a few stimulations a mild convulsion involving clonic jaw movements is elicited;
     with further stimulation the convulsions elicited by each stimulation become longer and longer and more and more generalized;
     after about 15 amygdala stimulations, each stimulation produces a fully generalized convulsion (characterized in sequence by jaw clonus, head nodding, forelimb clonus, rearing up, and falling over)

-     kindling can be produced by the periodic stimulation of many brain sites other than the amygdala, and it can also be produced by the periodic injection of initially subconvulsive doses of convulsive drugs--although the form of the convulsions is different for different agents

-      kindling has been reported in many species other than rats (e.g., frogs, rabbits, mice, cats, dogs, monkeys,

-      kindling does not occur at all at short interstimulation intervals (less than 20 minutes or so);
and it takes many more stimulations to kindle if the intervals are less than an hour or so

- the most interesting and important aspect of kindling is its permanence;
     if an animal is kindled and then left unstimulated for several weeks, the next stimulation often elicits a generalized convulsion;
thus the change in the brain that underlies kindling does not go away when the series of stimulations is curtailed

-      the kindling paradigm has been used as a model in two ways:

1) kindling has been used as a model of epileptogenesis (the development of epilepsy);      many researchers feel that if they discover the mechanism of kindling, they will discover changes that turn a healthy human into an epileptic;
     drugs that block kindling, may prove to be effective prophylactically
against the development of epilepsy (e.g., against the epilepsy that sometimes develops after a blow to the head)

2) the convulsions elicited in kindled rats by stimulation of various areas have been used as models of clinical convulsions;
     many studies have used kindled convulsions to test the effectiveness of
anticonvulsant drugs;
     for example, Racine et al., (1975) found that diphenylhydantoin (Dilantin) blocked kindled convulsions elicited by neocortical stimulation but not those elicited by amygdala stimulation;
     diazepam (Valium) did not block cortical convulsions but did block amygdalar

-      kindled convulsions as studied in most labs are not isomorphic models of epilepsy;
     in epilepsy, convulsions recur spontaneously, whereas kindled convulsions are elicited;
     however, experiments on rats by Pinel and on monkeys, baboons, and cats by Wada have shown that if animals are kindled long enough (e.g., 300 stimulations in rats), they will eventually become truly epileptic;
     they will have convulsions that recur spontaneously even after the stimulations have been curtailed

3.   Transgenic Mouse Model of Alzheimer's Disease

-      This is the most exciting advance in Alheimer's disease research in many years, as this area has suffered for lack of a good animal model

-      in the most promising transgenic mouse model, genes that accelerate human amyloid development are injected into fertilized mouse embryos
     as these mice mature, their brains develop amyloid plaques with a distribution similar to that seen in human patients.
more importantly, these transgenic mice also display deficits on various tasks of learning and memory, much like their human counterparts.

4.   MPTP Model of Parkinson's Disease

     We discussed Parkinson's disease last section; the symptoms are tremor at rest, muscular rigidity, cruel restlessness, poverty and slowness of movement, and shuffling wide-based gait;

     Parkinson patients are typically intellectually normal

     - in 1982, several young people were admitted to hospital in San Francisco, California with severe Parkinson's symptoms;
     this was surprising because severe cases are not usually seen before the age of 50

-       it was discovered that all were opiate addicts who had recently used an illicit synthetic opiate made by the same person;

     some of the batch was obtained, and it was found to contain l-methyl-4phenyl-l,2,3,6- tetrahydropyridine or MPTP

-      the similarity between the MPTP syndrome and Parkinson's disease was remarkable;      even minor symptoms of Parkinson's disease such as seborrhea (oily skin) and micrographia (very small handwriting) were present

-      this suggested that Parkinson's disease might be effectively studied in an MPTP animal model;
     it was quickly established that laboratory primates exposed to MPTP reacted similarly;
     they displayed similar behavioral symptoms and similar neural pathology;
     there was cell loss in the substantia nigra and a reduction in dopamine

-      curiously, the behavioral effects of MPTP on laboratory rodents proved to be mild, unreliable, and temporary;
     also, some MPTP monkeys do not develop the parkinsonian symptoms even though their dopamine is depleted

-      you will learn in Chapter 15 that the MPTP animal model has played a major role in the development of the exciting new neurotransplantation treatment for Parkinson's disease

-      MPTP animal modeling has also led to the discovery that deprenyl. a monoamine agonist and monoamine oxidase (MAO) inhibitor acts to block the effects of MPTP by increasing the level of dopamine via the inhibition of monoamine oxidase;

     deprenyl administration in early Parkinson's patients greatly slows the progression of the disease

Suggested Websites for Lecture 6b:

Animal Models of Parkinson's Disease:

     News on a genetically engineered mouse that resists the pathology associated with Parkinson's Disease.

Squirrels and Strokes:
     http:/ 97/bob1.htm
     Insights that hibernating squirrels are giving stroke researchers about cerebral blood flow and brain function.