Neuropsychiatric disorders

• Stroke

• Epilepsy

• Headache

• Schizophrenia

• Depression

• Multiple sclerosis

• Autism

• Parkinson´s disease

• Alzheimer´s disease

Contents

• STROKE (BRAIN ATTACK) = poor blood flow to the brain cause cell death • focal • global ischemia There are two main types of strokes: 1. Ischemic – interruption of blood flow in a cerebral vessels

(80% of all strokes) – mortality 20%

2. Hemorrhagic (20%) - bleeding into brain tissue (blood vessel ruptures) hypertension, aneurysms, arteriovenous malformations, head injury – mortality 80%

Silent stroke – without any symptoms, but the brain is damaged Transient ischemic attack – deficit lasting less than 1 hour - a

zone of penumbra without central infarction

Umbra – central infarct area surrounded by a penumbra of ischemic tissue that may recover

Causes

thrombosis (50%)

embolism (30%)

cerebral hypoperfusion

cerebral venous thrombosis

intracerebral hemorrhage

Ischemic

Hemorrhagic

CT scan of an intraparenchymal bleed

(bottom arrow) with surrounding

edema (top)

CT scan of the brain showing a

right-hemispheric ischemic

stroke

start suddenly (seconds to minutes)

face weakness

arm weakness

speech difficulties

vision, smell, taste, hearing impairment

headache + vomiting + loss of consciousness – mainly in hemorrhagic stroke

Symptoms

Etiology

blood pressure!

atherosclerosis

smoking

diabetes

atrial fibrillation

obesity, physical inactivity

alcohol consumption

drugs (cocaine, amphetamines)

age, sex, race, family history

M > F

Stroke – animal models

• Endothelin-1 induced vasoconstriction

• Middle cerebral artery (MCA) occlusion (injecting particles to carotid artery)

• Permanent transcranial middle cerebral artery occlusion - introducing a suture directly into the internal carotid artery (ICA), and advancing the suture until it interrupts the blood supply to the MCA

Epilepsy

= group of neurological disorders characterized by recurrent seizures (predisposition 1-3% of population)

Seizure – abnormal behavior caused by an electrical discharge from neurons in the cerebral cortex

I. Partial seizures

- small group of neurons in one hemisphere with secondary spread of seizure activity to other parts of the brain.

1. simple partial (no loss of consciousness, symptoms on the contralateral side, motor or sensory, ANS – hypo or hypertension, tachycardia may occur)

2. complex partial (impaired consciousness, from temporal lobe/psychomotor seizures, automatism – repetitive, non-purposeful actions – lips smacking, grimacing, patting, rubbing clothing)

3. secondarily generalized partial (discharges in deeper structures of the brain, such as the thalamus - progression to tonic-clonic seizure activity)

aura (visual changes, hearing voices, strange smells, anxiety, fear) – several seconds up to 60 minutes before a seizure.

II. Generalized seizures

Absence (disturbance in consciousness; blank stare, motionless, unresposibility)

Atonic = akinetic (slackening of the jaw, drooping of limbs, falling to the ground, „drop attacks“)

Tonic (constant contractions of the muscles. A person often turns blue)

Clonic (shaking of the limbs, ,,postictal phase,, loss of bowel or bladder control)

Tonic-clonic (contraction of the limbs followed by their extension along with arching of the back which lasts 10–30 seconds (the tonic phase). A cry may be heard due to contraction of the chest muscles, followed by a shaking of the limbs in unison (clonic phase).

Myoclonic seizures (spasms of muscles in either a few areas or all over – bilateral jerking of the muscles).

Etiology

• unprovoked (primary or idiopathic) - no identifiable cause - genetic

• provoked (secondary or acute symptomatic) - include febrile seizures, seizures precipitated by systemic metabolic conditions (e.g. hypoglycemia, hypoxia, hypocalcemia, uremia, alkalosis, and rapid withdrawal and febrile seizures in children)

Cause:

unknown... brain injury, stroke, brian tumors, infections, birth defects

Difference between epilepsy and seizure

• Epilepsy is a disorder characterized by recurring seizures

• Seizure is a brief, temporary disturbance in the electrical activity of the brain

Animal models

• Models of epileptic seizures rather than epilepsy

• Maximal electroshock seizure

• NMDA model - homework

Headache

• Pain is a distressing feeling often caused by intense or damaging stimuli.

• Brain lacks pain receptors • Several areas of head and neck do have pain receptors: • Extracranial arteries, middle meningeal artery, large veins, venous

sinuses, cranial and spinal nerves, head and neck muscles, eyes, ears, teeth and lining of the mouth

Headache • secondary vs primary (90%)

• Tension-type headache - non-pulsing "bandlike" pressure on both sides of the head, no other symptoms

• Migraine - pulsing head pain, nausea, photophobia and phonophobia

• Cluster headache - short episodes (15–180 minutes) of severe pain, usually around one eye, with autonomic symptoms (tearing, red eye, nasal congestion), occurs at the same time every day

• Chronic daily headache – 15 days or more/ month

Tension type headache

• most common type

• usually not sufficiently severe to interact with daily activities

• Dull, aching, diffuse, nondescript, hatband distribution

• Infrequent, episodic or chronic

• Unknown cause – theory: sustained tension of the muscles of the scalp and neck; psychogenic stress, anxiety, depression, muscular stress, overuse of analgesics or caffeine overuse (or lack of caffeine in addicts )

• Treatment: more responsive to nonpharmacologic techniques (massage, acupuncture, relaxation, imagery, and physical therapy)

Migraine

• Without aura (85%)

pulsatile, throbbing unilateral headache, 1-2 days, nausea & vomiting, sensitivity to light & sound, visual disturbances hallucinations

• With aura (15%) similar but + visual or neurologic symptoms that precede the

headache (aura - within 5 – 20 minutes , lasting 1 hour)

• Gender differences in occurance

Causes of migraine

• result from a primary disorder in the brain related to episodic changes in neural hyperexcitability → dilation of blood vessels → pain and further nerve activation.

Treatment:

Non-pharmacological:

• the avoidance of migraine triggers (maintaining regular eating and sleeping habits, control of the stress, retire to a quiet, darkened room).

Pharmacological:

• acetylsalicylic acid;

• analgesics (e.g., naproxen sodium, ibuprofen);

• serotonin receptor agonists (e.g., sumatriptan, naratriptan, rizatriptan, zolmitriptan);

• ergotamine derivatives (e.g., dihydroergotamine);

• antiemetic medications (e.g., prochlorperazine, metoclopramide).

Chronic daily headache

• 15 or more days a month

• Unknown cause, theories:

transformed migraine headache,

new daily persistent headache,

postraumatic headache

• Manifestations: from migraine to chronic tension-like headache

• Treatment: combination of pharmacologic and non-pharmacologic and behavioral interventions

Cluster headache

• Relatively uncommon

• Occur in clusters over weeks or months followed by a long, headache free remission phase

• Primary neurovascular headache with rapid onset (duration 15-180 min)

• Severe unrelented unilateral pain located in orbital, retroorbital, temporal, supraorbital and infraorbital region

• Symptoms: restlessness conjunctival redness, lacrimation, nasal congestion, rhinorrhea, ptosis (drooping or falling of the upper eyelid), eyelid edema.

• More common in men

• Treatment: quickly acting medications

Headache – animal models

• Activation of pain-producing cranial structures (dura mater, venous sinuses, meningeal and pial arteries) - innervated by afferent sensory branches of the trigeminocervical nerves

• Trigeminal autonomic cephalalgia – homework

Parkinson‘s disease

• Degenerative disorder of the CNS, mainly affecting the motor system

• Degradation of dopaminergic neurons in substantia nigra (↓ dopamine) Lewy

bodies

Symptoms:

shaking

rigidity

bradykinesis (slowness of movement)

postural instability

Later: dementia, depression, anxiety

• Treatment

no cure

treatment directed to improve the symptoms

Pharmacologic:

levodopa = L-DOPA (early) (antiparkinson medication)

dopamine agonists (later)

Non-pharmacologic:

education, daily exercise, and adequate nutrition

• Etiology

cause – unknown

genetic and environmental factors

pesticides

Tobacco smoke, coffe or tea - protective?

Parkinson‘s disease – animal models

• Toxin-based models: • rotenone (pesticide)

• paraquat (herbicide)

• maneb (fungicide)

• commonly used in primates

• 6-hydroxydopamine (neurotoxin) – destroys dopaminergic neurons in the nigrostriatal pathway when it is injected into the substantia nigra of the rats

Alzheimer’s disease • chronic neurodegenerative disease • cortical atrophy and loss of neurons – parietal and

temporal lobes → ventricular enlargement (i.e., hydrocephalus) from the loss of brain tissue

FIGURE 53-6 Alzheimer’s disease. (A) Normal brain. (B) The brain of a patient with Alzheimer’s disease shows cortical atrophy, characterized by slender gyri and prominent sulci.

Alzheimer‘s disease

1. Pre-dementia stage: short-term memory loss (difficulty in remembering recently learned facts and inability to acquire new information) + apathy

2. Early stage: aphasia, apraxia, agnosia

3. Moderate stage: hindered independence, paraphasias, long-term memory impairement

4. Advanced stage: completely dependent upon caregivers, apathy, exhaustion

Cause:

inherited (genetic): AD mutations in 1 of 3 genes: amyloid precursor protein

(APP) presenilins 1 presenilins 2 → ↑ amyloid β – senile

plaques

sporadic: not AD mutations - risk factor: mutations in apolipoprotein E (APOE) – metabolism of the fat

Cholinergic hypothesis

• the disease is caused by reduced synthesis of the neurotransmitter acetylcholine.

• has not maintained widespread support - medications intended to treat acetylcholine deficiency have not been very effective

Amyloid hypothesis – pieces of beta amyloid forms clusters = oligomers, after chains of clusters = fibrils and ,,mats,, of fibrils = beta sheets → plaque → disruption of cell to cell communication → activation of IS → inflammation → brain cells die

Tau hypothesis (hyperphosphorylated tau – neurofibrillary tangles)

Other hypothesis

• Neurovascular hypothesis – poor function of BBB

• Smoking

• Air pollution

• Infections (viruses)

• trauma

• low level of education

Alzheimer‘s disease

Treatment

- No cure

- Medications (for cognitive problems):

- acetylcholinesterase inhibitors

- NMDA receptor antagonists

- Small benefit – just slowing the progress of the disease

Animal models

• Scopalamine

• APP and PSEN mutants

• double-Tg mice - over-express human mutant APP and tau (Tg line APPsw-tauvlw ) - deposition of Aβ, hyperphosphorylation of Tau – memory impairment

Schizophrenia

Mental disorder characterized by abnormal social behavior and failure to understand reality

Disorder of thought and language

Onset: 17 – 25 years of age •Men: 18 – 25 years of age •Women: 25 – 35 years of age

Positive Disorganized,

incomprehensible speech Delusion Hallucinations (mostly

auditory) Disorganized catatonic

behavior Impaired ability to respond to

environment Ehancement or blunting of

senses in the early stage

Negative Alogia Avolition (lack of

motivation) Apathy Affective flattening Anhedonia

Subtypes of Schizophrenia

Paranoid schizophrenia • Persecutory or grandiose

delusions • Auditory hallucinations • Negative symptoms not

prominent • Better prognosis, less

disturbance in brain anatomy

Disorganized schizophrenia • Disintergration of personality • Predominance of negativve

symptoms • Socially withdrawn and inept • Personal grooming neglected • Daily activities disturbed • Prognosis not good

Catatonic schizophrenia • rare • Psychomotor disturbance (retardation or excitement) • Extreme negativism • Peculiar voluntary movements (grimacing, posuring, echolalia or

echopraxia)

• Etiology - unknown

Abnormalities in brain anatomy at the onset

Combination of environmental and genetic factors

Genetic factors: variety of common and rare genetic variants

Environmental factors: being rised in a city, cannabis use, parental age, poor nutrition during pregnancy, certain infections

High rate of substance abuse

Schizophrenia

Diagnostic criteria

• At least two of the following symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior must be present.

Treatment

• Goals: Induce remission, prevent recurrence, restore behavior, cognitive or psychosocial functions

• Pharmacological & non-pharmacological

Schizophrenia – animal models

• Developmental models

• Pharmacological models: drug – induced (amphetamine)

• Lesion models – neonatal lesion in hippocampus

• Genetic models

Depression

• Mood disorder

• Disorder of emotions rather than a disturbance of thought

• Common & underdiagnosed & undertreated

• Major depressiom: 20 % of population

unipolar (persistant unpleasant mood) F>M

bipolar (alternating periods of depressions and mania) F=M

Etiology

• Genetic predispozition

• Life events – physical abuse, sexual abuse, unequal parental treatment of siblings

• Medical treatments – drug induced depression

• Substance induced – alcohol, sedatives, opioids, hallucinogens

• Non-psychiatric illnesses – result of other diseases (e.g. hypoandrogenism) or nutritional deficiences

Depression - manifestation

• Depressed mood

• Anhedonia

• Feeling of worthlessness or excessive guilt

• Decreased concentration

• Psychomotor agitation or retardation

• Insomnia or hypersomnia

• Decreased libido

• Change in weight or appetite

• Thoughts of death or suicidal ideation

melancholic – depression is worse in the morning, insomnia with early morning awakening, anorexia with significant weight loss, psychomotor retardation or agitation, excessive or inappropriate guilt, loss of interest in activity, inability to respond to pleasurable stimuli, and a complete loss of capacity for joy.

atypical - becomes worse as the day progresses, overeating, and hypersomnia (excessive sleep).

depression with psychotic features - presence of delusions or hallucinations that may or may not be mood congruent

depression with catatonic features - excessive mobility or motoric immobility, extreme negativism, repetitive speech, and peculiar voluntary movements

Unipolar depression

Bipolar depression

• Manic – depressive illness

• periods of elation or irritability (mania) with or without (unipolar mania) episodes of depression

• Unipolar mania is rare

• Manifestations of mania: decreased need for food and sleep, labile mood, irritability, racing thoughts, high distractibility, rapid and pressured speech, inflated self-esteem, and excessive involvement with pleasurable activities, some of which may be high risk.

• subjective experience of mania can be quite pleasurable to the individual, with a heightened sense of wellbeing and increased alertness

• Rapid cycling – four or more mood shifts during 1 year F>M

chronic specifier - if symptoms persist more than 2 years

postpartum specifier - if the onset is within 4 weeks of childbirth

dysthymic disorder - a persistent but mild depression that lasts longer than 2 years

Depression

Depression – diagnostic criteria

• Simultaneous presence of five or more aforementioned symptoms during a 2-week period and these must represent a change of previous functioning

• Must be differentiated from grief reactions, medication side effects and sequelae of medical illnesses.

• Bipolar - basis of the pattern of occurrence of manic, hypomanic, and depressed episodes over time that are not due to medications or other therapies.

• The frequency, duration, and severity of the manic or depressive periods are unique to each individual

Depression - treatment

• antidepressant drugs, electroconvulsive therapy, lithium, anticonvulsants

• psychotherapy

Depression – animal models

Multiple sclerosis

• Demyelinating disease of CNS

• Demyelination of neurons in the white matter of the brain, spinal cord and optic nerve => conduction abnormality

• Destruction by IS or fail to produce myelin

• The most common non-traumatic neurologic disability

• First symptoms 20-40 years, F>M

• Exacerbations and remissions (80%) over many years

Etiology

• Prevalence – varies around the world

• F>M

• Not directly inherited – familiar predisposition is there

• Combination of genetic and environmental factors such as infectious agents

• Infections

• Smoking

• Stress …

Symptoms

depends on the location and extent of the lesion

The course of the MS • Relapsing- remitting course = unpredictable

relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity.

• Secondary progressive course = initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission

• Primary progressive course = with no remission after the initial symptoms

• Progressive relapsing course = gradual neurologic deterioration from the onset of symptoms but with subsequent superimposed relapses.

MS - Treatment

• to treat acute symptoms of the disease – corticosteroids

• those used to modify the course of the disease - interferon-beta

• those used to interrupt progressive disease – cyclosporine

• those used to treat the symptoms of the disorder - diazepam

Multiple sclerosis – animal models

• Myelin basic protein mutant

• Proteolipid protein mutant

• Myelin associated protein mutant

• Murine encephalomyelitis virus (TMEV)

• Experimental allergic encephalomyelitis (EAE)

Autism

• Autism spectrum disorders (ASD)

• Presence of abnormal or impaired development

• Onset of symptoms: before 3 years of age

• ♂ : ♀ = 2.5 - 4:1

>

(ADDM Network: 2000 – 2012) Surveillence year Number of ADDM

sites reporting Prevalence/

10 000 children

This is about 1 in X children [date of publication of the

results]

2000 6 67 1 z 150 [2007]

2002 14 66 1 z 150 [2007]

2004 8 80 1 z 125 [2009]

2006 11 90 1 z 110 [2009]

2008 14 113 1 z 88 [2012]

2010 11 147 1 z 68 [2014]

2012 11 146 1 z 68 [2014]

Autism and Developmental Disabilities Monitoring (ADDM) Network

Autism - prevalence

Autism - prevalence

1 z 45

Etiology

• still unknown

• multiple factors:

– genetic (200-1000 candidate genes)

– environmental (non-genetic) – environmental chemicals, maternal factors, drugs

– advanced age

?

Symptoms

Communication deficit

• development of spoken language is delayed

• qualitative impairments both in verbal and nonverbal communication

• characteristic features of their ,,speech,,:

– echolalia,

– verbal chunks,

– pop-up words,

– giant words,

– neologism

Autism – social deficits

• Lack of non-verbal behavior (eye-to-eye gaze, facial expression, gestures, body postures)

• Lack of appropriate peer relationships

• Absence of social-emotional reciprocity

• Less eye contact

• Less interest in human voices and faces

• Lack of strong emotional relationships to mothers

• Frequent absence of responding to own name

• Less interest in social interaction or social stimuli

• Less interest in social play with peers

Autism – repetitive behavior Type of repetitive behavior Description

Motoric stereotypes repeated non-purposeful movements – hand flapping,

head rolling, body rocking

Compulsive behavior repeated forms of behavior performed according to

rules – the arrangement of objects in stacks or lines

Sameness behavior insistence on sameness – insistence on the position of

objects e.g. lining up the toys in a certain order

Ritualistic behavior performing daily activities in the same manner – e.g. a

dressing ritual

Restricted behavior

limited range of focus, interest, or activity –

preoccupation with a single television program, toy, or

game

Self-injurious behavior self-oriented movements causing injuries – eye-poking,

skin-picking, hand-biting, head-banging

Autism - treatment

• Only symptomatic

• Pharmacological: psychoactive drugs, anticonvulsants – antidepressants, antipsychotics

• Support of the family members

Autism – animal models

• Animal models based on lesions in specific areas of the brain - lesions induced chemically, surgically and by viruses

• Animal models based on modifications of the genome – oxytocin KO mice, mutations in serototnin systems, OXTR KO mice

• Microtine model - Montane vole model – this interesting animal model naturally displays an inability to form normal social attachments.

Date of the exams

• 18.12. – PPT (5 min)

• 21.12. (13:00) – Faculty of Medicine

• 12.1. (9:00) SAV

• 19.1. (9:00) SAV

• 26.1. (9:00) SAV

• 2.2. (9:00) SAV