CENTRAL NERVOUS

SYSTEM DISORDERS

PARIKH RIMA A.
Asst. Professor - Pharmacology
SPTM, NMiMS
Shirpur
NERVOUS SYSTEM

 Major division - Central

vs. Peripheral
 Central or CNS - brain
and spinal cord
 Peripheral- nerves
connecting CNS to
muscles and organs
Central Nervous System
Peripheral Nervous System
Peripheral Nervous System
 3 kinds of neurons Brain
Spinal
connect CNS to the body Cord
 sensory
 motor
 interneurons Nerves
 Motor - CNS to muscles
and organs
 Sensory - sensory
receptors to CNS
 Interneurons:
Connections Within CNS
Central Nervous System
Brain
Spinal
 The Central Nervous Cord

System controls all

of the body’s
activities.
 Brain and Spinal
Cord = 2 main
organs of CNS.
 The brain is the control center of the body
 It is about 2% of your body weight and uses 20% of
your body’s oxygen
 Spinal Cord - Link between brain and rest of body
(PNS)
 31 pairs of spinal nerves
 Reflexes processed directly by spinal cord
 Reflex – quick, automatic, unconscious responses
 Result of reflex arcs – shortest nerve pathways
The Brain has three main parts… Cerebrum,
Cerebellum, Brain Stem
Cerebrum –
 Largest part of the brain
– Learning and Senses
 2 hemispheres- Right and Left
 Connected by the Corpus Callosum
 Right side controls- left side
 Left side controls – right side of body
 Four sections - LOBES
1. Frontal Lobe 2. Parietal Lobe
3. Occipital Lobe 4.Temporal Lobe
Brain has 2 Hemispheres

 Left & Right sides are

Corpus Callosum
separate Right
Hemisphere
 Corpus Callosum - major
pathway between
hemispheres
 Some functions are
‘lateralized’
 language on left
 math, music on right
 Lateralization is never Left
100% Hemisphere
Each hemisphere is
divided into 4 lobes

Frontal

Parietal

Occipital

Temporal
Cerebellum -
 Second largest
 located below the cerebrum at back of skull
 This part is responsible for the balance and
muscle coordination
Brain Stem -
 Connects the brain to spinal cord
 The Two Regions act as “switchboard”
 Medulla Oblongata – Controls
heart rate, breathing rate, and
flow of blood through the blood
vessels.
 Pons – Relays signals between
the cerebrum and the cerebellum
Other Structures inside the
Brain
 Thalamus – receives messages from sensory
receptors; relays information to proper
regions of cerebrum
 Hypothalamus - Regulates hunger, thirst,
fatigue, anger, etc…
 Control of pituitary for endocrine function
Sensory Information sent
to opposite hemisphere
Left visual Right visual
 Principle is Contralateral field field

Organization
 Sensory data crosses over
in pathways leading to the
cortex
Optic
 Visual Crossover nerves

 left visual field to right

hemisphere
 right field to left
 Other senses similar

Left Visual Corpus Right Visual

Cortex Callosum Cortex
Contralateral Motor
Control
 Movements
controled by motor Motor Cortex Somatosensory Cortex

area
 Right hemisphere
controls left side of
body
 Left hemisphere
controls right side
 Motor nerves cross
sides in spinal cord
Gray & White matter -
 Gray Matter – Absence of myelin in masses of
neurons accounts for the gray matter of the
brain – Cerebral Cortex
 White Matter - Myelinated neurons gives
neurons a white appearance – inner layer of
cerebrum
CNS Disorders…
1. Mental illness is widespread in society but remains the
object of considerable stigma and a great deal of
misconception.
2. Psychiatric disorders like Anxiety, Depression, Mania and
Manic depression and Schizophrenia are on the rise globally.
3. Neurological disorders constitute Epilepsy, Parkinsonism,
Dementia, Migraine. Neurological disease is assuming
greater importance in ageing population as the prevalence of
Parkinsons disease and Dementia rises inexorably.
Psychiatric Disorder
Disorder of mood, thought,
behaviour and perception
Primarily Functional in
origin
Psychological treatment
Drugs commonly used
Ex: anxiety, depression,
mania, schizophrenia
Neurological Disorder
Disorder of movement,
intellect and sensation
Primarily Organic
Surgery sometimes
effective
Drug therapy- essential
Ex: epilepsy, stroke, brain
tumor, migraine and
Parkinsonism

 Some conditions have both components.

 Ex: Mood changes occur in epilepsy , intellectual and motor defects
occur in schizophrenia
Classes of Psychiatric
Disorders
Neurosis Psychosis
Insight Present Absent
Grasp of reality Present Absent
Hallucinations & Absent Present
Delusions

Symptoms resemble Yes No

Normal personality
Treatment options Non invasive Invasive often
necessary
Examples Anxiety, obsession, Schizophrenia,
mild depression mania, Severe
depression
 Medical Causes of Psychosis -
 Temporal lobe epilepsy
 Brain tumor, stroke, brain trauma
 CNS infections (AIDS, neurosyphilis)
 Dementia (Alzheimer's, Lewy's body, vascular)
 Wilson's disease
 Huntington's disease
 Vitamin deficiency (B12)
 Endocrine disorders (Cushing's syndrome)
 Autoimmune disorders (systemic lupus)
 Metabolic disorders (porphyria)
 V will study..
 Schizophrenia
 Anxiety and
depression
 Epilepsy
 Alzheimer’s Disease
 Parkinsonism   
SCHIZOPHRENIA -
 Mental disorder characterised by loss of contact with reality
(Psychosis), hallucination (false perception), delusions (false beliefs),
abnormal thinking , flattened effect (restricted range of emotions)
diminished motivation, disturbed work and social functioning
 Schizophrenia is a chronic, severe, and disabling brain disease.
 Split – Mind
 Hear voice that other don’t
 Believe that other people try to control their mind
 It is mental disorder characterized by abnormalities of perception or
expression of reality.
 Much misunderstood disease, nothing to do with split
personality.
 Split is between different components of the same personality
- between mood and action or behavior and belief for
example.
 The personality becomes fragmented or literally disintegrated
 Symptoms
 Positive Symptoms -
 Hallucinations – visual,
auditory, olfactory,
sensory.
 Delusions
 Thought disorder
 Movement disorder
 Trouble focusing / paying
attention.
 Problems with working
memory.
 Negative Symptoms -
 Flat affect
 Lack of pleasure
 Lack of ability to begin and
sustain planned activities.
 Too little speaking.
 Cognitive Symptoms -
 Poor executive functioning.
 Social Isolation
 Odd Behavior and Ideas
 Poor Hygiene
 Blunted Affect
Subtypes -
 Paranoid type - Where delusions and hallucinations are
present but thought disorder, disorganized behavior, and
affective flattening are absent.
 Disorganized type - Named hebephrenic schizophrenia in the
ICD. Where thought disorder and flat affect are present
together.
 Catatonic type - The subject may be almost immobile or
exhibit agitated, purposeless movement. Symptoms can
include catatonic stupor and waxy flexibility.
Chances of
development of
Schizophrenia
Causes -
 The causes of Schizophrenia are unknown
 Many theories and models have been put forward to explain the
Pathophysiology of Schizophrenia
 Both genetic predisposition and environmental factors are
important- as confirmed by studies on twins borne to
schizophrenic parents.
 Biological causes -
o Autoimmune or viral encephalitis
o Abnormally large brain ventricles (reduced brain size)
o Imbalance between the right and left hemispheres
Twin studies
 Why does one twin become schizophrenic
and the other does not?
 Lower birth weight
 More physiological distress
 More submissive, tearful, sensitive
 Impaired motor coordination
Structural changes in brain
 Increased loss of gray matter in adolescence
 Shrinkage of cerebellar vermis
 Thicker corpus callosum
 Frontal lobes
 Abnormal neuronal migration in one study
 Dendrites have fewer spines
 But no major structural abnormalities
 Measures of frontal function impaired
Etiology and Pathophysiology -

 Common condition - about 1% of the population likely to

have atleast one episode during their life - although not all of
them will become permanently ill.
 Uniform global prevalence.
 In terms of personal and economic costs, schizophrenia has
been described as among the worst disease afflicting mankind
 In the United States, about 2.5% of total annual health care
expenditures are spent on schizophrenia management
Etiology and
Pathophysiology -
 The disease shows a strong, but incomplete, hereditary tendency.
 In first-degree relatives - the risk = 10%; even in monozygotic twins, one
of whom has schizophrenia, the probability of the other being affected is
only about 50%.
 Genetic linkage studies aimed at identifying schizophrenia susceptibility
genes have identified likely chromosomes, but not yet any specific genes.
 Some environmental influences early in development have been identified
as possible predisposing factors, including maternal virus infections and
high blood pressure during pregnancy.
 This and other evidence suggests that schizophrenia is associated with a
neurodevelopmental disorder, affecting mainly the cerebral cortex, and
occurring in the first few months of prenatal development.
 This view is supported by brain imaging studies showing cortical atrophy,
with enlargement of the cerebral ventricles.
 These structural changes are present in schizophrenic patients presenting for
the first time and are probably not progressive, suggesting that they represent
an early irreversible aberration in brain development rather than a gradual
neurodegeneration.
 Studies of postmortem schizophrenic brains show evidence of misplaced
cortical neurons with abnormal morphology.
 Psychological factors, such as stress, may precipitate acute episodes but are
not the underlying cause.
 Recently, Research has focused on neuro-developmental
abnormalities arising at a very early age.
 Another avenue - new non invasive imaging techniques -
PET and MRI - used to visualize the living brain and monitor
changes in its activity with far greater precision than the
relatively crude EEG.
 Still unknown, whether there are structural abnormalities in
various brain centers or defective interconnections between
key centers.
 Functional theories - involve ideas of incomplete adjustment
to society, esp: family
 Vulnerability model - According to this model Schizophrenic
episode occurs when the subject gets vulnerable to a condition
which triggers the schizophrenic episode. This condition could
be either a social network or environment. Manipulation or
avoidance of such a condition can abort a schizophrenic
episode
 Developmental model - Abnormality in the development of
neuronal cells during foetal development may result in Schizo.
 Ecological model - external factors (social, cultural & physical
forces in environment, such as population density , individual space,
socio-economic status and racial status.
 Genetic model - genetic component to Schizo with a higher
incidence in the siblings of Schizophrenics
 Transmitter abnormality model - primarily by abnormality of
dopamine, D2 receptors ( v.imp - serotonin involvement – receptor
mediation)
 Recent research Supports the role of Serotonin as well and also
altered NMDA receptor mediated neurotransmission contributes to
the Pathophysiology of Schizophrenia.
Functional changes in
brain -
 Identified by CT and Cerebral Blood Flow Studies
 Some Patients have one or more of the following –
 Reduction of blood flow to the left Globus Pallidus
 Problems in the frontal lobes
 Medial temporal lobe is thinner
 Anterior Hypothalamus is smaller (especially left side)
 Lateral and third ventricles are enlarged
 Sulci are also enlarged (especially in the temporal and frontal lobes
 Indicated reduced numbers of neurons.
 Hypofrontality hypothesis
 Discordant twins: low frontal blood flow only in affected
twin
 Wisconsin card sorting task
 Schizophrenics can’t shift attn. to other criterion
 Functional imaging: frontal lobe activity lower at rest, esp. in
right hemisphere, does not increase during task.
 Drug treatment increased activation of frontal lobes
Neurochemical changes -
 Neurochemical mechanisms in schizophrenia came from analysing the effects
of antipsychotic and propsychotic drugs.
 Instead of neurochemical theory providing the basis for rational drug
treatment, the opposite occurred - drugs found by chance to be effective have
provided the main clues about the nature of the disorder.
 Indeed, an intensive search for neurochemical abnormalities in schizophrenia
proved frustrating for many years, no biochemical markers being found either
in postmortem brain material or in other samples from living patients.
 Only recently have imaging studies proved more successful in detecting
neurochemical abnormalities.
 The main neurochemical theories centre on dopamine and glutamate,
though other mediators, particularly 5-HT, are also receiving attention.
 Dopamine hypothesis -
 Amphetamine releases dopamine in the brain and can produce in
humans a behavioural syndrome indistinguishable from an acute
schizophrenic episode - very familiar to doctors who treat drug users.
 In animals, dopamine release causes a specific pattern of stereotyped
behaviour, which resembles the repetitive behaviours sometimes seen
in schizophrenic patients.
 Potent D2-receptor agonists (e.g. apomorphine and bromocriptine)
produce similar effects in animals, and these drugs, like amphetamine,
exacerbate the symptoms of schizophrenic patients.
 Furthermore, dopamine antagonists and drugs that block
neuronal dopamine storage (e.g. reserpine) are effective in
controlling the positive symptoms of schizophrenia, and in
preventing amphetamine-induced behavioural changes.
 There is a strong correlation between clinical antipsychotic
potency and activity in blocking D2-receptors and receptor
imaging studies have shown that clinical efficacy of
antipsychotic drugs is consistently achieved when D2-receptor
occupancy reaches about 80%.
 There is no consistent biochemical evidence for excessive dopamine
synthesis or release.
 Furthermore, the production of prolactin, which might be expected to
be abnormally low if dopaminergic transmission was facilitated, is
normal in schizophrenic patients.
 One difficulty in interpreting such studies is that nearly all
schizophrenic patients are treated with drugs that are known to affect
dopamine metabolism, whereas the non-schizophrenic control group
are not.
 A well-controlled study showed a raised dopamine content
postmortem in the amygdala of schizophrenic subjects, the
noradrenaline content being normal.
 The best evidence for increased dopamine release in schizophrenic patients comes from
imaging studies.
 A radioligand imaging technique was used to measure binding of a specific antagonist
(raclopride) to D2-receptors in the striatum. Injection of amphetamine caused
dopamine release, and thus displacement of raclopride, measured as a reduction of the
signal intensity.
 This reduction was greater by a factor of two or more in schizophrenic compared with
control subjects, implying a greater amphetamine-induced release of dopamine.
 The effect was greatest in schizophrenics during acute attacks, and absent during
spontaneous remissions - clear evidence linking dopamine release to the
symptomatology.
 An increase in dopamine receptor density in schizophrenia has been reported in some
studies, but not consistently, and the interpretation is complicated by the fact that
antipsychotic drug treatment is known to increase dopamine receptor expression.
Glutamate theory
 Another transmitter - glutamate.
 The glutamate NMDA (N-methyl-D-asparate) receptor antagonists, such
as phencyclidine, ketamine and dizocilpine, produce psychotic
symptoms (e.g. hallucinations, thought disorder) in humans, and reduced
glutamate concentrations and glutamate receptor densities.
 Though schizophrenia is difficult to diagnose in a mouse, transgenic
mice in which NMDA receptor expression is reduced (not abolished,
since this is fatal) show stereotypic behaviours and reduced social
interaction that are suggestive of schizophrenia, and which respond to
antipsychotic drugs-evidence which supports the glutamate hypothesis.
 According to this view, glutamate and dopamine exert
excitatory and inhibitory effects, respectively, on GABA-ergic
striatal neurons, which project to the thalamus and constitute a
sensory 'gate' (see below).
 Too little glutamate, or too much dopamine, disables the gate,
allowing uninhibited sensory input to reach the cortex.
Other theories
 Other transmitters - 5-HT and noradrenaline.
 The idea that 5-HT dysfunction could be involved – based on the fact that LSD produces
schizophrenia - like symptoms, and this idea has drifted in and out of favour many times.
 Many effective antipsychotic drugs, in addition to blocking dopamine receptors, also act
as 5-HT receptor antagonists.
 5-HT has a modulatory effect on dopamine pathways, so the two theories are not
incompatible.
 Affinity for 5-HT2A-receptors is a feature of many of the recently developed 'atypical'
antipsychotic drugs, which produce fewer extrapyramidal side-effects than the earlier
dopamine-selective compounds,
 Controversy exists as to whether the 5-HT2-receptor block contributes to the
antipsychotic effect or merely reduces the undesirable side-effects associated with D 2-
receptor antagonists.
Serotonin -Dopamine Interactions
Serotonin-Dopamine
Prefrontal Cortex Dopamine (DA)

GABA Serotonin (5-

(5-HT)
Glutamate Striatum
GABA/ACh Motor Outputs
Limbic
System Blockade of D2 receptors
by conventional APDs
causes EPS

Ventral Tegmental Area Substantia Nigra

(A10) (A9)

5-HT2A antagonists
Median Dorsal release dopamine from
Raphe Raphe inhibition
and decrease EPS
 Serotonin -Glutamate-Dopamine Interactions
Serotonin-Glutamate-Dopamine
NMDA antagonists elevate extracellular brain 5-HT2A antagonists restore dopaminergic
levels of 5-
5-HT in the prefrontal cortex function in the prefrontal cortex

Prefrontal
Cortex Dopamine
(DA)
NMDA Striatum
antagonists Glutamate
increase the Limbic
System Serotonin
firing of DA in
(5-
(5-HT)
limbic areas
GABA

Ventral Tegmental Area Substantia Nigra

(A10) (A9)

NMDA antagonists reduce burst

firing of VTA DA neurons
Median Dorsal
Raphe Raphe
5-HT2 antagonists block the
effects of NMDA antagonists
An Integrative Model of Schizophrenia
Serotonin Dopamine
5-HT2A D1, D2

Prefrontal
Prefrontal
Cortex
Cortex
5-HT2A Glutamate
Glutamate
selectively
targets A10

Limbic
System

A9/A10
Thalamus
Thalamus

Striatal Complex
SN/VTA Dopamine
Sense
Organs
 Schizophrenia Pathophysiology and Pharmacologic
Profile of Antipsychotic Drugs ((APDs)
APDs)

S c hizo phrenia Pathophys io

hizophrenia lo
iolo
logg y and Pharmac oolo
loggic Profile
lo gic Pro file of
of
Antips yc ho tic Drugs
Drug s ((APDs
APDs )
Schizophrenia Pharmacologic
Pathophysiology Profile of APDs
Past Excess dopaminergic Dopamine D22--receptor
receptor
activity antagonists
Present Renewed interest in the Combined 55-HT
-HT22/D22
role of serotonin (5 -HT)
(5-HT) antagonists
Future Imbalance in cortical More selective antagonists
communication and Mixed agonist/antagonists
cortical -midbrain
cortical-midbrain Neuropeptide analogs
integration, involving
multiple neurotransmitters
 Clinical features –
Positive features (Type 1)

Thought Distorted or irrational reasoning, reduced

insight
a.Loosened associations,
b.private language
Belief Delusions
Paranoia , external control, thought broadcast,
thought insertion, grandeur, ideas of reference,
Delusional perception
Perception Hallucinations
Auditory, visual, less common: gustatory, olfactory

Mood Inappropriate emotional responses

Behaviour Bizarre, Irrational, occasionally aggressive, rarely
violent
 Clinical features –
Negative features (Type2)

Mood Blunting (flattening) of affect

Behavior Withdrawn, antisocial, apathetic, poor self- care,
poverty of speech, anhedonia, avolition

Note:
 Patients in early acute stages have Type 1 with positive symptoms .
 Type 2 features, negative , usually seen in chronic schizophrenia
 Diagnosis -
 Must be continuously ill for at least 6 months.
 First eliminate any primary underlying cause such as iatrogenic psychosis (corticosteroids),
drug misuse (Amphetamines), brain tumor or infection, head injury, certain rare forms of
epilepsy, hyperthyroidism etc.
 The symptoms must have been present for at least a month with evidence of deterioration of
social functioning
 Distinguish between borderline schizophrenia and other psychoses (mania, depression) –
sometimes difficult.
 Presence of at least 2 symptoms from the list or Just one First rank symptom- positive-
forms of delusion
 Need to have one psychotic phase where you have -
 Delusions
 Hallucinations
 Disordered thoughts, incoherence, or other symptoms.
 V will
study..
 Schizophrenia
 Anxiety and
depression
 Epilepsy
 Alzheimer’s Disease
 Parkinsonism   
Are you afraid of ?
 small insect
 animal, reptile
 speaking to a large audience
 speaking in front of a small group of familiar people
 meeting new people
 attending social gatherings
 Anxiety –
Normal v/s Abnormal Response

 Some amount of anxiety is

“normal” and is associated
with optimal levels of
functioning.
 Only when anxiety begins to
interfere with social or
occupational functioning is
it considered “abnormal.”
 ANXIETY -
 Anxiety is a feeling of apprehension or fear.
 Anxiety - unpleasant emotional state often accompanied by
physiologic changes and behavior similar to those caused by fear.
 The source of this uneasiness is not always known or recognized,
which can add to the distress you feel.
 Anxiety disorders are a group of psychiatric conditions that
involve excessive anxiety.
 Anxiety is a normal reaction to threatening situations, and serves
a physiological protective function.
 Anxiety- desirable or not ?
 Anxiety disorders include not only generalized anxiety
disorder (GAD), social anxiety disorder (SAD, also known as
social phobia, specific phobia and panic disorder (PD), with
and without agoraphobia, but also obsessive-compulsive
disorder (OCD) and post-traumatic stress disorder (PTSD).
 Anxiety disorders are a group of illnesses that have in
common persistent feelings of apprehension, tension or
uneasiness, and are accompanied by physical symptoms such
as sweating, palpitations, and feelings of generalized stress.
What is anxiety ?
 It is a mood-state with Marked Negative effects
 Bodily symptoms of tension
 Apprehensions about future
 Its consequence is ‘worry’
Physiological
worry ?
 Worry is a normal response
to stressful situations limited
to particular situations
 Should not exceed the
duration of event
 Should not spread to other
topics
 Excessive worry should not
be seen as a normal response,
as part of one’s personality.
Pathological
worry ?
 It is a component of anxiety
 Negative emotional
thoughts, images
 Uncontrollable and they
occur in sequence
 Concern about future threats
and danger
 Their frequency and
intensity are more
What do people worry
about ?
 Real problems that could be potentially solved, but are not
acted on
 Real problems that probably cannot be solved (at least not by
the individual), but can be coped with
 “Imagined problems” that do not yet exist and probably will
never exist
 Worry about worry and its consequences
Pathological v/s normal
anxiety
 Autonomous responses
 Greater intensity
 Longer duration
 Behavior significantly affected
 Stressor may be minimal or absent
Origin of anxiety
 Protective response
 Normal/protective anxiety
 Fear and pathological anxiety
 Common underlying neuro-physiology
 Two categories of fear/anxiety
 Acute and
 Chronic
Negative effects of worry

1. Unreasonable fear
2. Anxiety Disorder
3. Panic Disorder
4. Substance abuse
5. Depression
What cause Anxiety
Disorders ?
 No single cause
 Several possible causes -
 genetics, other biological factors
 physiology, infection, injury, trauma
 temperament, life experiences
 upbringing, family, school, peers,
 society in general, Doctors in particular
 stress - chronic or acute
What cause Anxiety
Disorders ?
Importance of Anxiety
Disorders -
 Accurate Dx and Rx of anxiety disorders is essential
 Reduction of secondary psychiatric conditions -
 Depression
 Substance abuse problems
Sex differences in Anxiety
Disorders
What is Gen. Anxiety
Disorder ?
 Anxiety Disorders are characterized by persistent fear and
anxiety that occurs too often, is too severe, is triggered too
easily or lasts too long.
 The “What if?” disorder
 Compared with others with anxiety disorders, persons with
GAD have a better ability to maintain normal work and social
relationships in spite of their distress.
Generalized Anxiety
Disorder -GAD
 Pathological anxiety, which 1. Restlessness or feeling
is excessive, chronic and keyed up or on edge,
typically interferes with 2. Being easily fatigued,
their ability to function in
3. Difficulty concentrating or
normal daily activities.
mind going blank,
 GAD is distinguished from
4. Irritability,
Phobic anxiety – as it is
not triggered by a 5. Muscle tension,
specific object 6. Sleep disturbance
 Excessive anxiety and worry occurring more days than not for
at least 6 months, about a number of events. The person finds
it difficult to control the anxiety and worry and has associated
three (or more) of the above six symptoms
GAD – Mr. Fisc
Worry that is -
 Excessive, uncontrollable
 Frequent, multiple topics (not only onetime)
 More than one day out of two
3 out of 6 other associated physical symptoms
 Muscle tension, Restlessness
 Fatigued easily, Irritability
 Sleep disturbance, Concentration difficulty
Types of Anxiety Disorders
 Panic Disorder
 Obsessive-Compulsive Disorder
 Post-Traumatic Stress Disorder
 Phobias
 Generalized Anxiety Disorder
 Panic Disorder -
 The abrupt onset of an episode of intense fear or discomfort,
which peaks in approximately 10 minutes, and includes at least
four of the following symptoms:

• A feeling of imminent danger or doom • Nausea or abdominal discomfort

• The need to escape • Dizziness or lightheadedness
• Palpitations • A sense of things being unreal,
• Sweating depersonalization
• Trembling • A fear of losing control or "going
• Shortness of breath or a smothering crazy"
feeling • A fear of dying
• A feeling of choking • Tingling sensations
• Chest pain or discomfort • Chills or hot flushes
Panic Disorder -
There are three types of Panic Attacks -
1. Unexpected - the attack "comes out of the blue" without
warning and for no discernable reason.

2. Situational - situations in which an individual always has an

attack, for example, upon entering a tunnel.

3. Situationally Predisposed - situations in which an individual is

likely to have a Panic Attack, but does not always have one. An
example of this would be an individual who sometimes has
attacks while driving.
Obsessive-Compulsive Disorder
Characterized by uncontrollable obsessions and compulsions which the
sufferer usually recognizes as being excessive or unreasonable.
Obsessions are recurring thoughts or impulses that are intrusive or
inappropriate and cause the sufferer anxiety -
 Thoughts about contamination, for example, when an individual fears
coming into contact with dirt, germs or "unclean" objects;
 Persistent doubts, for example, whether or not one has turned off the
iron or stove, locked the door or turned on the answering machine;
 Extreme need for orderliness;
 Aggressive impulses or thoughts, for example, being overcome with the
urge to yell 'fire' in a crowded theater.
Obsessive-Compulsive Disorder
 Compulsions are repetitive behaviors or rituals performed by the OCD
sufferer, performance of these rituals neutralize the anxiety caused by
obsessive thoughts, relief is only temporary.
 Cleaning
 Checking
 Repeating
 Slowness
 Hoarding - Hoarders are unable to throw away useless items, such as old
newspapers, junk mail, even broken appliances
 In order for OCD to be diagnosed, the obsessions and/or compulsions must
take up a considerable amount of the sufferers time, at least one hour every
day, and interfere with normal routines.
Post-Traumatic Stress
Disorder
 Exposure to traumas such as a serious accident, a natural disaster, or criminal
assault can result in PTSD.
 When the aftermath of a traumatic experience interferes with normal
functioning, the person may be suffering from PTSD.
 Symptoms of PTSD are:
 Re-experiencing the event, which can take the form of intrusive thoughts and
recollections, or recurrent dreams;
 Avoidance behavior in which the sufferer avoids activities, situations, people
and/or conversations which he/she associates with the trauma;
 A general numbness and loss of interest in surroundings;
 Hypersensitivity, including - inability to sleep, anxious feelings, overactive startle
response, hypervigilance, irritability and outbursts of anger.
Social Phobia/Anxiety
 Social anxiety disorder, also known as social phobia, is an
intense fear of social situations.
 This fear arises when the individual believes that they may be
judged, scrutinized or humiliated by others.
 Individuals with the disorder are acutely aware of the physical
signs of their anxiety and fear that others will notice, judge
them, and think poorly of them.
 In extreme cases this intense uneasiness can progress into a full
blown panic attack.
Social Phobia/Anxiety
 Common anxiety provoking social situations include:
 public speaking
 talking with people in authority
 dating and developing close relationships
 making a phone call or answering the phone
 interviewing
 attending and participating in class
 speaking with strangers
 meeting new people
 eating, drinking, or writing in public
 using public bathrooms
 driving
 Shopping
Generalized Anxiety
Disorder
 Excessive uncontrollable worry about everyday things.
 This constant worry affects daily functioning and can cause
physical symptoms.
 GAD can occur with other anxiety disorders, depressive
disorders, or substance abuse.
 The focus of GAD worry can shift, usually focusing on issues
like job, finances, health of both self and family; but it can also
include more mundane issues such as, chores, car repairs and
being late for appointments.
 The intensity, duration and frequency of the worry are
disproportionate to the issue.
Specific Disorder Facts
 Generalized Anxiety Disorder
 Women are twice as likely to be afflicted than men.
 Very likely to exist along with other disorders.
 Obsessive Compulsive Disorder
 It is equally common among men and women.
 One third of afflicted adults had their first symptoms in childhood.
 Panic Disorder
 Women are twice as likely to be afflicted than men.
 Occurs with major depression in very high rates.
Specific Disorder Facts
 Posttraumatic Stress Disorder
 Women are more likely to be afflicted than men.
 Rape is the most likely trigger of PTSD, 65% of men and 45.9% of
women who are raped will develop the disorder.
 Childhood sexual abuse is a strong predictor of lifetime likelihood for
developing PTSD.
 Social Anxiety Disorder
 It is equally common among men and women.
 Specific Phobia affects
 Women are twice as likely to be afflicted as men.
Domains of anxiety

 Physical
 Affective
 Cognitive
 Behavioral
 Physical domain

 Anorexia  Hyperventilation
 Butterflies in stomach  Light-headedness
 Chest pain/tightness  Muscle tension
 Diaphoresis  Nausea, Vomiting
 Dry mouth  Pallor
 Dyspnoea  Palpitations
 Faintness  Paresthesias
 Flushing  Sexual dysfunction
 Headache
 Shortness of breath
 Stomach pain
 Tachycardia
 Tremulousness
 Urinary frequency
 Diarrhea
Affective domain

 Edginess
 Uneasiness
 Terror
 Panic
Behavioral domain

 Triggers many responses

 Behavioral in nature
 Concerned with diminishing
 And even avoiding the distress
Regulation of locus
ceruleus
 Alpha-noradrenergic auto receptors
 Serotonin receptors
 GABA-benzodiazepine receptors
 Opiate receptors
 Dopamine receptors
The amygdala and locus ceruleus
Pathophysiology of Anxiety
Disorder

 Pharmacocentric approach.
 Based on actions of diazepam like drugs.
 Believed to be disorder associated to GABA A receptor
/chloride ion channel complex.
 Stress response  cascade hormonal events including release
of corticotrophin rereleasing factor (CRF)  release
corticotropin  glucocorticoids, epinephrin  negative feed
back to hypothalamus  decreased release of CRF 
Homeostasis.
 Amygdala -10 modulator for response to fear or anxiety
stimuli. – Conscious / subconscious.
 When stimulated amygdala causes autonomic hyperactivity –
related to physical changes.
 Thus stress response involves activation of the
hypothalamic-pituitary – adrenal axis.
 Thus CRF appears to be anxiogenic, depressogenic and leads
to increased pain perception.
 GABA inhibits CRF release.
 Glucocorticoids activate locus cereleus which sends a powerfully
activating projection to amygdala  Increased CRF  more
glucocorticoids
 Prolonged exposure to glucocorticoids depletes NE  loss of attention,
vigilance, activity etc.  depression.
 Role of Serotonin: -
Agents enhancing serotonin neurotransmission may stimulate
hippocampal 5 HT receptors neuroprotection  anxiolytic.
Acute fear state
 Response to life-threatening danger
 Terror, helplessness,
 Sense of impending disaster/doom
 Urgency to flee or seek safety
 Sympathetic/Nor-adrenergic activation
 Located in locus ceruleus
 Corresponds to panic attacks
Agoraphobia
 Anxiety in situations where escape might be difficult (or
embarrassing) or help might not be available in the event of
having a panic attack or panic-like symptoms
 Situations are avoided or endured with marked distress
 May not leave home or may need a companion
 Can occur with and without panic disorder
Agoraphobia
Social Phobia
 Marked, persistent fear of social or performance situations
where a person is exposed to unfamiliar situations or people or
possible scrutiny by others.
 The individual fears acting in an embarrassing or humiliating
way.
 The Person recognizes fear as excessive.
 Exposure causes anxiety symptoms or panic
 Situations are avoided or endured with anxiety.
Specific Phobias
 Marked and persistent fear that is excessive or unreasonable,
cued by the presence or anticipation of a specific object or
situation (e.g., flying, heights, animals, receiving an injection,
seeing blood).
 Exposure to the phobic stimulus almost invariably provokes
an immediate anxiety response, which may take the form of a
Panic Attack.
 The person recognizes that his/her fear is excessive or
unreasonable. The phobic situation is avoided or else is
endured with intense anxiety or distress
 Acrophobia fear of heights
 Agoraphobia fear of open places
 Claustrophobia fear of enclosed places
 Ailurophobia fear of cats
 Cynophobia fear of dogs
 Pathophobia fear of disease
 Mysophobia fear of dirt and germs
 Arachnophobia fear of spiders
 Hematophobia fear of blood
 Xenophobia fear of strangers
 Panic Attack – DSM IV

1. Palpitations 8. Feeling dizzy, fainty

2. Sweating 9. Derealization (feelings of
unreality)
3. Trembling or shaking
10. Fear of going crazy
4. Shortness of breath
11. Fear of dying
5. Feeling of choking
12. Paresthesias
6. Chest pain or discomfort
13. Chills or hot flushes
7. Nausea or abd. distress
A discrete period of intense fear or discomfort in which 4 (or
more) of the above 13 symptoms develop abruptly and reach a
peak within 10 minutes
Panic Disorder with
Agoraphobia

 Recurrent unexpected panic attacks: anxiety

associated with at least four physical and/or
cognitive symptoms cognitive symptoms
 At least 1 month of worry about having additional
attacks or the consequences of an attack (losing
control, having a heart attack, “going crazy”).
 Agoraphobia
Medical conditions causing
anxiety

 Endocrine conditions
 Cardiovascular conditions
 Respiratory conditions
 Metabolic conditions
 Neurological conditions
Substances causing anxiety -

 Alcohol Substances that cause

 Amphetamines anxiety (withdrawal)
 Caffeine  Alcohol
 Cannabis  Cocaine
 Cocaine  Sedatives
 Hallucinogens  Hypnotics
 Inhalants  Anxiolytics
 Phencyclidine
Medications causing anxiety -

 Anesthetics  Oral contraceptives

 Analgesics  Antihistamines
 Sympathomimetics  Anti-parkinsonians
 Bronchodilators  Corticosteroids
 Anti-cholinergics  Antihypertensives
 Insulin  Cardiovascular drugs
 Thyroid hormones  Anticonvulsants
Epidemiology -
 All of these disorders are relatively common, with lifetime
prevalence ranging from about 2% for panic disorder and
OCD to over 5% for the others
 Except for OCD, all are more common in women.
 Except for panic disorder, childhood and adolescent onsets are
likely.
Etiology
Psychodynamic perspective
 realistic, neurotic, moral anxiety
 defense mechanisms
 origins in early parent-child relationships
 neurotic paradox – contradicts pleasure principle
 Neurotic styles – Shapiro
 inhibition of assertion/aggression
 inhibition of responsibility/independence
 inhibition of compliance/submission
 inhibition of trust/intimacy
 Biological perspective - Genetics
 family studies show up to 25% have an immediate family
member with an anxiety disorder
 twin studies - higher concordance rates for MZ than DZ twins
 genetics may operate through behavioural inhibition
 Biological perspective - Neuroanatomy
 locus ceruleus
 amygdala
 one form of peptide (combo of amino acids), CCK4, related to
panic; CCK4 is found in amygdala, hippocampus, cerebral
cortex, brain stem
 Biological perspective - Neurotransmitters
 norepinephrine (NE) – concentrated in locus ceruleus
 serotonin
 dopamine in social phobia and OCD
 interactions – serotonin affects locus ceruleus (where NE is
produced) and may also influence GABA
 Rachman’s revised theory
 classical conditioning
 modelling
 informational or instructional transmission
 Biological preparedness theory
 Seligman – evolutionary significance of stimuli that are easily
conditioned
 Bandura – properties of stimuli themselves (unpredictability
and uncontrollability) and the cognitive processing that
defines their threatening nature
 Cognitive theories
 Bandura – low perceived self-efficacy
 Beck – experiences, beliefs, appraisals
 Ellis – irrational beliefs, catastrophization
 Biopsychosocial perspective
 emotion
 biology
 environment
 behaviour
 cognition
DEPRESSION

 Mental state characterized by feeling of sadness,

loneliness, despair, low self-esteem, and self-reproach;
accompanying signs include psychomotor retardation or
at times agitation, withdrawal from interpersonal contact,
and vegetative symptoms such as insomnia and anorexia.

 The term refers to either a mood that is so characterized

or a mood disorder.
Depression is not just unhappiness

1. A potentially life-threatening disorder (suicide +

infanticide)
2. Destruction of family relationships
• Divorce - It is estimated that ~ 10 % of couples
choose to terminate their relationship during
pregnancy
• Loss of custody – due to abuse and/or neglect
3. Increased risk of psychosocial disorders in
children/partner
• Depression
• Child abuse/neglect
• Social/emotional development in children
 Difference Between “Normal” and
“Real” Depression

“Normal Depression” “Clinical Depression”

 Normal reaction to life events  Mood described as “black”
(e.g. death of loved one, major
 Many symptoms
changes)
 Longer duration (weeks –
 Mood described as “blue”
months)
 Few symptoms
 Significant impairment in
 Short duration
functioning (can be
 Little, if any, impairment in debilitating)
functioning
Depression - It’s not only a state of
mind.

Physical Symptoms Include - Emotional Symptoms Include -

Vague aches and pains Sadness

Headache Loss of interest or pleasure

Sleep disturbances Overwhelmed

Fatigue Anxiety

Diminished ability to think or concentrate,

Back pain indecisiveness

Significant change in appetite resulting in

weight loss or gain Excessive or inappropriate guilt
Common Symptoms of
Depression
 Sad mood
 Feeling worthless or guilty
 Fatigue / lack of energy
 Low motivation / difficulty starting activities
 Loss of interest or pleasure in activities
 Problems concentrating and thinking
 Increased or decreased appetite & weight
 Changes in pattern of sleep
 Suicidal thoughts or plans
Symptoms of depression -

 Concentration is often impaired

 Inability to experience pleasure
 Increase in self-critical thoughts, with a voice in the back of one's
mind providing a constant barrage of harsh, negative statements
 Sleep disturbance or unable to fall back to sleep
 Feeling fatigued after 12 hours of sleep
 Decrease in appetite or food loses its taste
 Feelings of guilt, helplessness and/or hopelessness
 Thoughts of suicide
 Increased isolation
 Missing deadlines or a drop in standards
 Change in personality
 Increased sexual promiscuity
 Increased alcohol/drug use
Causes of Depression
 Environmental Factors
 Stressful life events
 Death, Move, New Job, Relationship
 Psychological Factors
 Negative belief systems
 About self, world, future
 Biological Factors
 Genetic predisposition (i.e. familial link)
 Neurotransmitter abnormalities
Depression – the physical
presentation

• In primary care, physical

symptoms are often the chief
complaint in depressed
patients
• In a New England Journal of
Medicine study, 69% of
diagnosed depressed
patients reported
unexplained physical
symptoms as their chief
compliant.
N = 1146 Primary care patients
with major depression
Pathology of Depression
 The biogenic Amine Theory / Catecholamine
Theory of Depression…
 Suggests that depression is due to deficiency of
excitatory influence of biogenic amines – at
postsynaptic sites in brain.

 Depression is associated with a catecholamine

deficiency in the brain
 Mania is associated with a catecholamine excess in the
brain.
 The nigrostriatal system
runs from the
substantia nigra (A9)
forwards to the caudate,
putamen, and globus
pallidus, these 3
structures are called the
corpus striatum.
 The
mesolimbicocortical
sytem run from the
ventral tegmental area
(A10) forwards to the
nucleus accumbens,
amydala, septum,
olfactory nuclei.
Serotonin5HT and NorepinephrineNE
in the brain

Limbic
System
Prefrontal
Cortex

Raphe Locus
Nuclei (5- Ceruleus (NE
HT Source)
source)
Serotonin and Norepinephrine
in Depression -

 Serotonin and norepinephrine are believed to be key

neurotransmitters in the etiology of depression
 From the raphe nuclei and locus ceruleus, 5-HT and NE,
respectively, send projections up to the prefrontal cortex
and limbic system where emotional depressive
symptoms are thought to be mediated.
 Additionally, there are also 5-HT and NE-rich tracts into
the spinal cord, which are thought to modulate pain
perception.
 There are at least two sides to the
neurotransmitter story -
Functional domains of Serotonin and Norepinephrine1-4

Serotonin (5-HT) Depressed

Norepinephrine (NE)
Mood

Sex Anxiety Concentration

Vague Aches
Appetite Interest
and pain

Aggression Irritability Motivation

Thought
process

• Both serotonin and norepinephrine mediate a broad

spectrum of depressive symptoms
 Some symptoms (e.g. appetite, attention) seem to be
mediated more by one neurotransmitter than the other.
 Some other symptoms (e.g. anxiety) seem to be
mediated by either.
 There are other symptoms (e.g. aches and pain) that
seem to be mediated more consistently by a combination
of both the neurotransmitters.
The neurotransmitter
pathway story
 Dysregulation of Serotonin
(5HT) and Norepinephrine
(NE) in the brain are
strongly associated with
depression
Descending Pathway
 Dysregulation of 5HT and Descending
NE in the spinal cord may Pathway Ascending
explain an increased pain Pathway
perception among
depressed patients
 Imbalances of 5HT and NE
Ascending
may explain the presence of Pathway
both emotional and physical
symptoms of depression.
Common Types of Depression

 Major Depression
 Dysthymia
 Bipolar Disorder
 Seasonal Affective Disorder (SAD)
Major Depression

 This type causes symptoms that may:

 Begin suddenly, possibly triggered by a loss,
crisis or change
 Interfere with normal functioning
 Continue for months or years
 It is possible for a person to have only one
episode of major depression. It is more
common for episodes to be long lasting or to
occur several times during a person’s life
Dysthymia

 People with this illness are mildly depressed for

years.
 They function fairly well on a daily basis but
their relationships suffer over time.
Bipolar Disorder

 People with this type of illness change back and forth

between periods of depression and periods of mania (an
extreme high).
 Symptoms of mania may include:
 Less need for sleep
 Overconfidence
 Racing thoughts
 Reckless behavior
 Increased energy
 Mood changes are usually gradual, but can be
sudden
Season Affective Disorder
 This is a depression that results from changes in the
season.
 Most cases begin in the fall or winter, or when there is a
decrease in sunlight.
Professional
treatment is
necessary for
all these
types of
depression.
 V will study..
 Schizophrenia
 Anxiety and
depression
 Epilepsy
 Alzheimer’s Disease
 Parkinsonism   
 Periodic and unpredictable seizures caused by
the rhythmic firing of large groups of neurons.
 May range from mild twitching to loss of
consciousness and uncontrollable convulsions.
EPILEPSY
 A disorder of the brain characterized by an
enduring predisposition to generate epileptic
seizures and by the neurobiologic, cognitive,
psychological, and social consequences of this
condition.
 The definition of epilepsy requires the
occurrence of at least one epileptic seizure.
 They are characterized by paroxysmal cerebral
dysrhythmia, manifesting as episodes (seizures) of loss
or disturbance of consciousness, with or without
characteristic body movements, sensory or psychiatric
phenomena.
 It has a focal origin in brain, manifestations depend on
site of focus, regions into which discharge spreads and
postictal depression of these regions.
What is an epileptic seizure?
 A transient occurrence
of signs and/or
symptoms due to
abnormal excessive or
synchronous neuronal
activity in the brain.
 Commonly generated
in cortex and
hippocampus, may
also be subcortical.
CAUSES OF EPILEPSY
 ACUTE
 CONGENITAL
CAUSES OF ACUTE EPILEPSY -

 Cortical damage
 Trauma
 Stroke
 Neoplasm
 Autoimmune effects (Rasmussen’s encephalitis)
CAUSES OF CONGENITAL
EPILEPSY

 Dysgenesis (failure of cortex to grow properly)

 Vascular malformations
 At least eight single locus genetic defects are associated
with epilepsy.
 Most forms involve inheriting more than one locus.
(Examples: juvenile myoclonic, petit mal)
What causes the seizure?
Neuro - pathophysiology of Epilepsy:
Occasional, sudden, excessive, rapid, local
discharges of gray matter.

 Hyperexcitability in a critical mass of neurons

 Hypersynchrony
 Propagation -
 Normal pathways
 Pathologic pathways
What causes neuronal
hyperexcitability?

 Changes in ion channels

 Changes in receptors
Resting membrane potential

-70 mV
2
Action Potential
Paroxysmal Depolarization
Shifts
 Protracted bursts of action potentials typical of neurons
in an epileptic neuronal aggregate produces local
synchonization
 How might these shifts be produced?
Na Channels -

 Essential for depolarization during action potential

 Blocking fast channel inactivation leads to increased
excitability
 Induces paroxysmal depolarization shifts
 Increasing synchrony
Na Channels

 Role of Na channels in epilepsy suggested based on

observed effect of AEDs on Na currents
 There are genetic changes in molecular structure of Na
channels in some familial epilepsies
 Changes in Na channels have been observed in surgically
resected seizure foci
K Channels
 Important for post-excitatory membrane re-polarization
 M current controls sub-threshold membrane excitability
 K Channel blockade produces epileptiform discharges
invitro
 M current defect identified in benign neonatal familial
convulsions
Ca Channels
 Different types of channels (T, N, L, P, Q)
 Ca currents contribute to the paroxysmal depolarization
shift
 May be responsible for long-term structural changes
affecting excitability and synaptic efficacy
 Participate in cytotoxicity
 Activation of T-type channels is thought to underlie the
abnormal thalamocortical rhythmicity associated with 3-
Hz spike-and-wave in absence
What causes neuronal
hyperexcitability?

 Changes in ion channels

 Changes in receptors -
 Excitatory amino acid receptors
 GABA-A receptor
Excitatory amino acid (EAA)
receptors
 EAA: glutamate and aspartate
 Two main receptor types: AMPA/kainate and NMDA
NMDA receptor
 Sustains long-lasting
depolarization events
 NMDA agonists induce
epilepsies in animals
 Structural changes have
been seen in surgical
specimens
 Involved in long term
potentiation
GABA receptors
 Activation leads to
membrane
hyperpolarization via
inflow of Cl and
outflow K
 Decreased neuronal
firing
Epileptogenesis
 What causes the changes in ion channels and
receptors that lead to hyperexcitability and the
generation of seizures?
 Genetic
 Acquired
Epileptogenesis -

Inciting event

Epileptogenic
cascade

Changes in neuronal
network stability

Seizures
Inciting Events
 Stroke
 Tumor
 Infection
 Trauma
Epileptogenic cascade
 Exact mechanism unknown
 May involve alteration in gene expression
EPILEPTIC SEIZURE FOCI
 Motor Cortex - Cause movements on
contralateral side according to the somatotopic
location of the seizure focus.
 Somatosensory cortex - Cause an epileptic aura
in which a sensation is experienced. Also
depends on which part of somatotopic
representation holds the focus.
 Visual cortex - Cause a visual aura
(scintillations, colors).
 Auditory cortex - cause an auditory aura
(humming, buzzing, and ringing).
 Vestibular cortex - cause a feeling of spinning.
 Temporal lobe - cause complex behaviors.
 Olifactory cortex - cause malodorous aura.
 Hippocampus - particularly susceptible and a
frequent source of epileptic activity.
Classification of epileptic
seizures…

 PARTIAL –  GENERAL –
1. Simple partial 1. Generalised tonic-
seizures clonic
2. Complex partial 2. Absence seizures
seizures 3. Atonic seizures
3. Simple partial or 4. Myoclonic seizures
complex partial 5. Infantile spasm
seizures secondarily
generalized.
PARTIAL SEIZURES -
1. Simple partial seizures – lasts for 0.5 – 1 min, often
secondary. Convulsions are confined to group of muscles or
localised sensory disturbance depending on the area of cortex
involved in seizure without loss of consciousness.
2. Complex partial seizures – attacks of bizarre and confused
behaviour and purposeless movements, emotional changes
lasting 1 – 2 min along with impairement of consciousness. An
aura often proceeds. The seizure focus is located on temporal
lobe.
3. Simple partial or complex partial seizures secondarily
generalized – The partial seizures occur first and evolves into
generalised tonic – clonic seizures with loss of consciousness.
GENERALIZED SEIZURES -
 Involve wide areas of the brain and loss of
consciousness
 Petit mal - consciousness is transiently lost and
the EEG displays spike and wave activity.
 Grand mal - consciousness lost for a longer
period and the individual will fall if standing
when seizure starts.
 Tonic phase: generalized increased muscle tone.
 Clonic phase: series of jerky movements. Bowel and
bladder may evacuate.
1. Generalised tonic-clonic – commonest, lasts 1 – 2
min. The usual sequence is aura – cry –
unconsciousness – tonic spasm of all body muscles –
clonic jerking followed by prolonged sleep and
depression of all CNS function.
2. Absence seizures – minor epilepsy, prevelant in
children, lasts about 0.5 min. Momentary loss of
consciousness, patient apparently freezes and stares in
one direction, no muscular component or little bilateral
jerking. EEG showa characteristic 3 cycles per second
spike and wave paattern.
3. Atonic seizures – Akinetic epilepsy, Unconsciousness
with relaxation of all muscles due to excessive
inhibitory discharge. Patient may fall.
4. Myoclonic seizures – shock like momentary
contraction of muscles of a limb or the whole body.
5. Infantile spasm – (Hypsarrhythmia) seen in infents.
Probably not a form of epilepsy. Intermittent muscles
spasm and progressive mental deterioration. Diffuse
changes in interseizure EEG are noted.
ELECTROPHYSIOLOGICAL
CORRELATES OF SEIZURE ACTIVITY

 EEG spikes that occur between full-blown

seizures are called interictal spikes.
 These arise from long-lasting
depolarizations called depolarization shifts.
EEG TRACING OF EPILEPTIC
SIEZURE
DEPOLARIZATION SHIFTS
 Trigger repetitive action potentials in cortical neurons
 Regenerative calcium mediated dendridic potentials in
cortical neurons
 Reduction of inhibitory interactions in cortical circuits
 Release of potassium and excitatory amino acids from
hyperactive neurons
 Excitation of NMDA- type glutamate receptors [n-methyl-
d-aspartate, glutamate analog]. (Calcium entry and long
term potentiation [ltp]).
 Seizures activate NMDA receptors and strengthen
connections between excited neurons.
TREATMENTS FOR EPILEPSY

 No effective preventions or cures known.

 Surgical methods
 Seizure inhibiting drugs
 V will study..
 Schizophrenia
 Anxiety and
depression
 Epilepsy
 Alzheimer’s Disease
 Parkinsonism   
ALZHEIMER'S DISEASE (AD)

 A disorder involving
loss of mental functions
resulting from brain
tissue changes.
 Defined - “Acquired
deterioration in
cognitive abilities that
impairs successful
performance of
activities of daily living”
 A condition that damages several parts of the brain
 Accounts for the majority of dementia cases -
 Alzheimer’s Type Dementia (50-75 % of cases)
 Vascular dementia (10 to 20 %)
 Dementia with Lewy bodies (10 to 15 %)
 Frontotemporal dementia (5 to 15 %)
How the Brain and Nerve Cells Change during Alzheimer's disease
 Dementia…
 Memory is most common cognitive
ability lost in dementia.
 + language, visiospatial ability,
calculation, judgment & problem
solving.
 + Neuropsychiatric & social deficits –
depression, withdrawal, hallucinations,
delusions, insomnia, agitation,
disinhibition.
 Functional Anatomy of
Dementia… Dementia results from
disorders of cerebral neuronal circuits
and is a result of total quantity of
neuronal loss combined with the specific
location of such loss.
What are the forms of Dementia?
 There are over 100 causes of Dementia
 The Commonest is Alzheimer’s Disease - 50-70%
 Vascular Dementia (VaD) and Multi-infarct Dementia
(MID) account for 15-20%
 Lewy Body Disease (DLB) for 10-20%
 Mixed Dementias
 Alcohol related cognitive loss
 Fronto-temporal dementias
 Presenile Dementias
 Is it Forgetfulness or a Dementia?
 Forgetfulness involves DETAILS of events, etc. Dementia involves
whole segments of events.
 Forgetfulness can often be COMPENSATED by special techniques,
reminders, writing things down etc. Dementia impairs new
learning.
 Dementia affects more than just memory. It involves many aspects
of daily life causing disruptions in occupational, social and
relational functions.
 In Dementia loss of ability to abstract thinking, judgment and loss
of social graces leading to isolation from normal society.
 Visuospatial problems, poor judgment can lead to dangerous
driving, poor financial and legal decisions.
Alzheimer's disease
 The commonest cause of dementia.
 The disorder rarely occurs under the age of 45 years.
 The incidence increases with age.
 The cause of AD is not known (neurodegenerative)
 Up to 30% of cases are familial (the loci were found on
chromosome 21 and 19).
 Pathology – the presence of senile plaques and neurofibrillary
tangles in the brain.
 Diagnosis of AD may be established during life by early
memory failure, slow progression and exclusion of other
causes.
Typical Clinical Syndrome of
AD

1. Amnestic type of memory defect -

 difficulty learning and recalling new information
2. Progressive language disorder -
 beginning with anomia and progressing to fluent
aphasia
3. Disturbances of visuospatial skills -
 manifested by environmental disorientation and
 difficulty copying figures in the course of mental
status examination
4. There are usually deficits in executive function
 Planning
 Insight
 Judgment
5. The patient is typically unaware of memory or
cognitive compromise.
6. All cognitive deficits progressively worsen.
Epidemiology

 Most common cause of dementia amongst the elderly

 Alzheimer’s patients occupy 20% of psychiatric
institutions
 Affects -
 5% of individuals in their 60s
 20% of individuals in their 70s
Characteristics
 Progressive form of dementia that is caused due to
neuronal loss.
 Micro -
 Neurofibrillary tangles (tau protein aggregates)
 Senile plaques (Amyloid-b sheets)
 Macro -
 Severely shrunken hippocampus
 Thin cerebral cortex
 Gross, diffuse atrophy in affected areas
Symptoms
 Stage 2: Very Mild Cognitive Decline
 Memory lapses, forgetting familiar words, names,
etc.
 Not evident during a medical examination or to
family or friends
 Stage 3: Mild
 decreased ability to remember names when
introduced to new people
 Losing/misplacing objects frequently
 Decline in ability to plan/organize tasks
 Stage 4: Moderate
 Decreased knowledge of recent activities/events
 Impaired ability to perform mentally challenging
tasks
 Decline in the ability to plan/organize
 Stage 5: Moderately Severe
 Major gaps in memory/cognitive function
 Confused about time/date
 Declined ability performing less challenging mental
tasks
 Stage 6: Severe
 Major gaps in memory widen
 Most awareness of recent experiences is lost
 Recollect personal history improperly
 Forget names but can usually distinguish between
familiar and unfamiliar faces
 Personality/behavioral changes
 Delusions
 Hallucinations
 Tend to wander/become lost
 *

 Stage 7: Very Severe

 Final stage
 Lose ability to
 Respond to environment
 Speak
 Ultimately, control movement
 Reflexes become abnormal
 Muscles grow rigid
 Swallowing is impaired
Types of AD
 Early Onset (Familial) AD
 Genetic
 Large proportion of cases include mutations -
 PS1 or PS2 (Chromosomes 14 & 1, respectively)
 APP (Chromosome 21)
 Both lead to an increase of Amyloid-b-42
 Sporadic (most common)
 no heritable component
 Tau and amyloid-b dysfunction
 Atypical Features that Suggest a Diagnosis
Other than Alzheimer's Disease:
Diagnostic consideration
Feature
Abrupt onset Vascular dementia

Stepwise deterioration Vascular dementia

Prominent behavior changes Frontotemporal dementia

Profound apathy Frontotemporal dementia

Prominent aphasia Frontotemporal dementia, vascular dementia

Progressive gait disorder Vascular dementia, hydrocephalus
Prominent fluctuations in levels of Delirium due to infection, medications, or
consciousness or cognitive abilities other causes; dementia with Lewy bodies;
seizures
Hallucinations or delusions Delirium due to infection, medications, or
other causes; dementia with Lewy bodies
Extrapyramidal signs or gait Parkinsonian syndromes, vascular dementia
Eye-movement abnormalities Progressive supranuclear palsy, Wernicke's
encephalopathy
 Figure 1 - Scans of Patients with Probable Alzheimer's Disease.
 In Panel A, a magnetic resonance image shows cortical atrophy and
ventricular enlargement.
 In Panel B, a positron-emission tomographic scan shows reduced
glucose metabolism in the parietal lobes bilaterally (blue-green) as
compared with more normal metabolism in other cortical areas
(yellow).
Pathophysiology of AD -

 Gross, diffuse atrophy of the brain -

 Loss of neurons and synapses
 MRI’s show -
 Severe atrophy in the cerebral cortex
 Extreme widening of the sulci
 Enlargement of the ventricular system
 Hippocampus -
 Key role in the formation of new memories
 Atrophy is especially severe here
 Among the first few areas of brain to be affected
 Occipitotemporal function -
 Damage to area 37
 Inability to read and write
 Damage to temporal polar region
 Failure to recognize friends and family
 Decrease in frontal lobe function -
 Occurs within 3 years of onset
 ‘spaced out’: seemingly unaware of surroundings
 Lasts about 5 to 6 years before death
 Dementia is observed when NFD reaches the association
cortical areas
NORMAL ALZHEIMER’S

Enlarged Ventricles

Widening Sulcus

Atrophied
Hippocampus
Amyloid Cascade Hypothesis -
 Proposed in 1991 by Hardy & Allsop
 A ‘mismetabolism’ of APP is the initiating event in AD
pathogenesis
 Leads to aggregation of Ab42 (extracellular)
 Plaque formation leads to
 Disruption of synaptic connections
 Potential drop in available neurotransmitters
• Acetylcholine
• Glutamate
 Tangle formation is secondary (intracellular)
β - Amyloid Plaques -
 Composed of β-Amyloid protein (Aβ)
 Most common forms vary from 40-42 aa’s
• Ab40 & Ab42
 Amyloid Precursor Protein (APP)
 Found in all cell types of all species
• Function still unknown
• Triple APP KO mice (and both homologues APLP1
& APLP2) result in abnormal layering of the
cerebral cortex
 Undergoes proteolytic cleavage to form Ab via 2
different pathways.
 α-secretase -Prevents
formation of Aβ (cuts
within Aβ sequence) --
eventually yields p3
 γ-secretase cleaves
membrane bound
portion (C99) and
releases Aβ
-- PS1 & PS2 are
essential for proper
function,
-- cleaves @ variable
points.
 Accumulation of A occurs
extracellularly
 Located in the neuropil
 Dense core of A filaments
arranged in a -sheet
conformation
 Surrounded by microglia
and dystrophic neurites
 Mechanism of toxicity in brain
still unclear…
 Aberrant microglial
activation?
 Induction of apoptosis?
 Hydrogen peroxide
production?  -amyloid plaques via
fluorescent staining
 Tau (τ) Proteins -
 Primarily expressed in neurons.
 Promote microtubule assembly.
 Stabilize cellular microtubules -
 Modulates rate of polymerization
 Essential in axon development -
 Axonal localization is conserved
through species (quail, xenopus,
etc.)
 6 isoforms present in human
brain -
 Differ in number of tubulin
binding domains
Neurofibrillary Tangles -

 Found INTRAcellularly
 Intracellular tangles are an accumulation of paired
-helical filaments (PHF)
 1988: hyperphosphorylated tau was found to be the
main constituent of PHF’s
 All 6 isoforms exist hyperphosphorylated
 Reduced ability to properly bind to microtubules
Neurofibrillary Tangles -

 Level of HP tau is 4~8 fold higher in AD brains than in

age-matched normal brains
 Inevitable degenerating process as a result of aging
brain.
 Study showed that ~100% of non-AD brains exhibited
some level of tau pathology in the entorohinal cortex
 Some in hippocampus
 Theoretical ‘threshold’ for dementia exists around about
when the inferior temporal cortex is affected.
Morphology and Distribution of Neuritic Plaques and Neurofibrillary Tangles
Pathologic diagnosis of AD
require the presence of both
neuritic plaques and
neurofibrillary tangles in excess
of the abundance anticipated
for age-matched healthy
controls.
Neuritic plaques consist of a
central core of amyloid protein
surrounded by astrocytes,
microglia, and dystrophic
neurites often containing paired
helical filaments.
Neurofibrillary tangles are the
second major histopathological
feature of AD. They contain
paired helical filaments of
abnormally phosphorylated tau
protein that occupy the cell
body and extend into the
dendrites.
Paired Helical Filaments
(PHF)

100 nm
 Tangle

Plaque
Neurofibrillary Degeneration
Pathway -
 Follows from limbic structures to neocortical association
areas -
 Starts in transentorhinal cortex
 Continues into hippocampus
 Ends in the neocortical areas
 Heiko Braak
 Used large tissue sections of brains and with silver
staining was able to determine overall pathway of
degeneration
 Observed in all AD brains
Risk Factors
 Age, Female sex
 Most potent risk factor - presence of the apolipoprotein
e4 (APOE e4) allele.
 Lifetime risk of AD for an individual
 without the e4 allele is approximately 9%
 carrying at least 1 e4 allele is 29%
 e4 genotype is not sufficiently specific or sensitive for
the diagnosis of AD to allow its use as a diagnostic test
Other Risk Factors
 Head injury
 Low serum levels of folate and vitamin B12
 Elevated plasma and total homocysteine levels
 Family history of AD or dementia
 Fewer years of formal education
 Lower income
 Lower occupational status
Diagnostic Criteria
 Cognitive impairment severe enough to cause social or
occupational disability in at least two domains -
 Memory
 Language
 Calculations
 Orientation
 Judgment
 V will study..
 Schizophrenia
 Anxiety and
depression
 Epilepsy
 Alzheimer’s Disease
 Parkinsonism
Definition -
 Described by Dr. James Parkinson in 1817.
 Parkinson's syndrome, is a neurological syndrome
characterized by tremor, hypokinesia, rigidity, and
postural instability.
 The underlying causes of parkinsonism are numerous,
and diagnosis can be complex.
 Characterized by masked face, stooped posture,
slowness of voluntary movements, festinating gait,
rigidity and tremors.
 Parkinsonism is a clinical syndrome consisting of 4
cardinal features:
1) Bradykinesia (slowness of movement) and, in extreme
cases, a loss of physical movement (akinesia)
2) muscular rigidity
3) resting tremor (which usually disappears during
voluntary movement)
4) impairment of postural balance leading to disturbances
of gait and falling.
Causes of parkinsonism -
1) Idiopathic PD:
• Due to loss of dopaminergic neurons of the substantia
nigra.
• Progressive loss of dopamine-containing neurons is a
feature of normal aging; however, most people do not lose
the 70% to 80% of dopaminergic neurons required to cause
symptomatic PD.
• Death frequently results from complications of immobility,
including aspiration pneumonia or pulmonary embolism
2) Secondary PD:
• E.g., following stroke, and intoxication with dopamine-
receptor antagonists as antipsychotics and antiemetics.
Epidemiology and course -
 Overall prevalence is 1-2 per 1000, but it is 5- to 10 times more
common among the elderly, the prevalence among people aged
over 65 yrs being about 3%.
 Nevertheless PD can affect people as young as 40.
 Prevalence in Europe, N.America is twice that of China and Japan
 PD has insidious onset, with slowly progressive non –specific
signs such as muscle pain, stiffness, mild depression and general
slowing down.
 Over 80% of Nigrostriatal dopamine must be lost before
symptoms become apparent.—This PRODROMAL phase may last
for 5 yrs.
PD – proceed through 5 stages
1. Prodromal phase - asymptomatic
2. Early symptomatic phase - little disabilty ,drugs may
not be needed
3. Main treatable phase(5-7 yrs) - Levodopa effectve
4. Late phase-declining levodopa effectiveness
5. Terminal Phase- disease extremely difficult to control
Disease vs Syndrome

 Disease = a morbid process having characteristic

symptoms; pathology, etiology, and prognosis may be
known

 Syndrome = a set of symptoms occurring together;

different etiologies but similar presentation
Parkinson’s Syndromes -

Metabolic causes – Structural Causes –

 Hypothyroidism  Strokes
 Hypoparathyroidism  Tumors
 Alcohol withdrawl  Chronic subdurals
(pseudoparkinsonism)  NPH (Normal
 Chronic liver failure Pressure
 Wilson’s disease Hydrocephalus)
Medications/chemicals —
 neuroleptics (typicals more than the atypicals),
 SSRI (selective serotonin reuptake inhibitors),
 metoclopromide/maxeran,
 Reserpine,
 MPTP,
 in Methcathinone (ephedrone) users – high plasma
Manganese levels (NEJM Mar 6, 2008)
 CO, cyanide, organic solvents, carbon disulfide
 Lewy Body spectrum PSP (progressive
of Diseases (DLB = supranuclear palsy) or
Dementia with LB) – Steeles Richardson
 early onset visual (or Olszewski Syndrome
other) hallucinations  gaze abnormalities
 fluctuating cognitive  postural instability, early
abilities unexplained falls
 bulbar features—dysphonia,
 sleep disorders
dysarthria, dysphagia
 neuroleptic sensitivity,  rapidly progressive---median
even to atypicals 6 yrs.
 CBD (cortico basal
degeneration) –
 Asymmetric parkinsonism
 postural instability
 ideomotor apraxia
 Aphasia
 alien limb phenomenon
 impaired cortical
sensations
Multi System Atrophy
(alpha- synuclein + glial
cytoplasmic inclusions,
autonomic dysfunction,
pyramidal signs)
 Shy Drager Syndrome,
 Olivopontocerebellar
atrophy,
 Striatonigral
degeneration
 Other Infections –
Neurodegenerative  Encephalitis
Disorders —  HIV/AIDS
 Alzheimer’s Disease, later
stages
 Neurosyphilis
 Huntington’s Disease (rigid  Toxoplasmosis
form)  CJD (Creuzfeld Jakob)--
 Frontotemporal Dementia with prion disease
Parkinsonism, Chromosome-  Progressive multifocal
17 linked (FTDP-17) leukoencephalopathy
 Spinocerebellar ataxias
 STAGES OF PARKINSON'S DISEASE

DOPAMINE
(% control)
100

80

ADAPTIVE 60
CAPACITY

40 COMPENSATION
-no symptoms
20
MILD SYMPTOMS
DECOMPENSATION
MARKED SYMPTOMS
0
Pathophysiology of Parkinsonism
 10 affects basal ganglia which consists of interconnection
between – forebrain, diencephalon and mesencephalon.
 Degeneration of these dopaminergic nigro striatal
neurons result in diminished dopamine release allowing
cholinergic transmission to predominate in basal
ganglia.
 Dopamine deficiency – Akinesia –
 Cholinergic hyperactivation – tremors and rigidity.
 Normally high conc. of Dopamine in the Basal ganglia of
the brain is reduced.
 Alternative cause for pathophysiology basis in idiopathic
parkinsonism is…
 the loss of dopaminergic neuron in the substantia nigra -
that normally inhibit the output of GABA ergic cells in
the corpous striatum, where as cholinergic neurons exert
a excitatory effect.
 Various studies showed – high risk of PA associated with
occupational exposure to herbicides, insecticides, and
neurotoxins.
 Whether caused by toxin exposure or genetic susceptibility,
subsequent oxidant stress and Apoptosis play a major role in
promoting neurodegeneration.
 In PA – degenerataion of cells with loss of pigmented
neurons in the pars compacta of s.n.
 The degenerating pigmenting neurons contain eosinophilic
inclusion bodies (Lewy bodies) - characteristic of PA.
 Origin is unclear.
 In PA- brain conc. of protective reductants (glutathione0
are reduced and reactive oxidants(O2,OH,Fe+3) are
elevated.
 Also defects of mitochondrial respiration and xenobiotic
metabolizing enzymes (Glutathione transferase,CYP-450
2D6,N-acetyl transferase) may contribute to free radical
generation and oxidant stress.
 In PD dopaminergic and other cells die due to…
 Genetic vulnerability
 Oxidative stress
 Proteosomal dysfunction
 Environmental factors
 Oxidative stress – free radicals, toxins (MPTP), defects
in mitochondrial complex I of oxidative
phosphorylation,
 Proteosomal dysfunction in substentia nigra.
 Other factors are – microglial activation, low grade
inflamation, and apoptosis.
Morphology
 A neurodegenerative disorder.
 Gross examination reveals mild frontal atrophy with loss
of normal dark melanin pigment in mid brain.
 Microscopically – degeneration of dopaminergic cells
with presence of Lewy bodies (Lewy bodies are abnormal
aggregates of protein that develop inside nerve cells) in
the remaining neurons and substentia nigra (SN).
 These Lewy bodies have a high concentration of alpha
Synuclein and are pathologic hall mark of disease.
 Consequence of dopaminergic cell loss in SN is gradual
denervation of striatum leading to motor symptoms of
PD.
 Symptoms develop when striatal dopamine depletion
reaches 50 – 70% of normal.
Role of alpha Synuclein -
 The cause in idiopathic Parkinson’s disease is unknown,
but it is not accelerated aging.
 Rarely is Parkinson’s disease inherited as a dominant
disorder.
 Mutation of Alpha synuclein gene (chromosome 4q) has
been identified in one large Italian family, the Contursi
family, and in five Greek families.
 Mutation of the parkin gene has been identified as the
cause of autosomal-recessive juvenile parkinsonism.
 In the overwhelming majority of familial cases of
Parkinson’s disease, no genetic abnormality has been
identified.
 In the majority of cases the disease is believed to be
caused by environmental factors.
 The place of birth and residence seem to play a greater
role than the race.
What is alpha Synuclein
 Alpha Synuclein (SNCA) is a protein of unknown
function 10 found in neural tissues.
 Lewy bodies are found to have high concentration of
alpha synuclein.
 Mutations in alpha synuclein gene can cause familial PD
by promoting the formation of alpha synuclein - positive
filaments that aggregate in Lewy bodies.
 This pathology involves various nuclei (centers) in brain
viz. olfactory, glassopharyangial, vagal nerve nuclei.
 Involvement of these nuclei may play a role in non-
motor and refractory motor aspects of PD.
 Refractory motor symptoms - postural instability, gait
and bulbar disturbances.
 Non-motor symptoms - autonomic disturbances, sleep,
emotional and cognitive aspects.