Schizophrenia: Symptoms, Pathophysiology, and Behavioral Mechanisms, Study notes of Communication

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Schizophrenia Clinical Presentation of Schizophrenia General

1. Schizophrenia is a chronic disorder of thought and affects التاثير , causing a significant disturbance in the individual’s ability to function vocationall y مهنرثand interpersonally. A. People with schizophrenia may appear uncooperative غرا ممتااث , suspicious شاوك , hostile عُد ْ انِي , anxious مُشَكَّشُمالذِّهْن , or aggressive حثدُّمالطَّبْع due to their misinterpretation تَح ْ ِيف of reality.

B. They may have poor hygiene and appear dirty unkempt (^) َثأشْع , stained crumple clothes as psychosis

as well as depressive symptoms, may lead to impaired self-care. C. Sleep and appetite are often disturbed. D. People with schizophrenia often have difficulty living independently in the community and have difficulty forming close relationships with others. E. They have problems with initiating or maintaining employment. F. Comorbid medical disorders, such as type 2 diabetes and chronic obstructive pulmonary disease, are prevalent in schizophrenia due to sedentary lifestyles, poor dietary habits leading to obesity, and/or heavy cigarette smoking. Approximately 85% of people with schizophrenia smoke, and approximately 50% use drugs and alcohol, rates that are much higher than in the general population.

2. The onset of symptoms in most cases is insidious غاثدم , usually preceded by a prodromal الباثد phase characterized by gradual social withdrawal, diminished interests, changes in appearance and hygiene, changes in cognition, and bizarre or odd behaviors. Symptoms Hallmark symptoms include psychotic symptoms, negative symptoms, and cognitive impairments that last for at least 6 months. A. Psychotic symptoms: These symptoms are sometimes called positive symptoms, as they are “added on to” or “Behaviors that are present that should not present” a person’s normal experience. They may include:
3. Hallucinations (distortions or exaggeration of perception) Hallucinations are false or distorted sensory experiences that appear to be real perceptions. These sensory impressions are generated by the mind rather than by any external stimuli, and may be seen, heard, felt, and even smelled or tasted. They can include: Auditory hallucinations: voices” are the most common type of hallucination. The voices may a. talk to the person about their behavior,

b. commanding (i.e., commanding the person to perform a particular action). c. threatening or warn them of apparent danger. Patients may feel compelled to perform the commanded task or may experience much anxiety when they do not. visual hallucinations (e.g., recognizable objects or unformed lights or shadows) olfactory hallucinations (e.g. unpleasant odors) tactile hallucinations (e.g., feeling that someone is touching you when no one is near by)

2. Delusionsاالوهام (fixed false beliefs) Delusions frequently involve fixed false beliefs despite invalidating evidence, and may be bizarre in nature. delusions of control (e.g., believing one's thoughts and movements are controlled by someone else) delusions of reference (e.g., believing someone on TV is talking specifically to you) erotomanic delusions (e.g., believing Brad Pitt or Angelina Jolie is in love with you) grandiose delusions (e.g., believing one is a billionaire who owns all hotels in the city) persecutory delusions (e.g., believing ones is being followed or try to hurt them or harassed by CIA) somatic delusions (e.g., believing ones nose is infested by worms)
3. Disorganized (or illogical) speech/thinking , also described as “thought disorder” or “loosening of associations,” is a key aspect of schizophrenia. Disorganized thinking is usually assessed primarily based on the person’s speech. Thought disorders - illogical thought & speech that can include: alogia/poverty of content - impoverished speech م اكالت قلت& thinking (very little information conveyed by speech) thought blocking - a sudden losing train of thought, abrupt interruption in speech word salad - words strung together nonsensically perseveration - repeating words or ideas persistently Thinking and speech may be incomprehensible غتاض and illogical, silliness and laughter that is not related to content of speech Subtle ةر ُ اكبَدِيهَت حاضِت, (^) ِِ فتا disturbances in associative thinking may develop years before disorganized thinking (formal thought disorder). 4. Grossly disorganized behavior includes difficulty in goal-directed behavior (leading to difficulties in activities in daily living), unpredictable agitation or silliness, social disinhibition, or behaviors that are bizarre to onlookers. Their purposelessness distinguishes them from unusual behavior prompted by delusional beliefs.

PATHOPHYSIOLOGY

A. Dopamine hypothesis of schizophrenia: First-generation antipsychotics are also known as: typical, conventional تقليدد, dopamine antagonists, neuroleptics and classic antipsychotics. The oldest theory associated with the patho-physiology of schizophrenia is the dopamine hypothesis, which proposes that psychosis is due to excessive dopamine in the brain. Evidence with the theory: Basis of classical dopamine hypothesis of schizophrenia Dopamine-releasing drugs (amphetamine, mescaline, L-dopa, cocaine) can induce state closely resembling paranoid schizophrenia in normal persons and low dose of them worse schizophrenia symptoms due to increase dopamine. Typical antipsychotics that are effective in the treatment of schizophrenia have in common the ability to inhibit the dopaminergic system by blocking action of dopamine in the brain. The four pathways relevant to the pharmacology of antipsychotics in the treatment of schizophrenia are:  The mesolimbic pathway over activity: The mesolimbic pathway originates (cell body) in the ventral tegmental area (midbrain) and innervates several structures of the limbic system (axon terminate), including the nucleus accumbens in the ventral striatium. The mesolimbic pathway is associated with the reward circuit.

The mesolimbic pathway plays a key and complex role in motivation, emotions, reward, and positive symptoms of schizophrenia; where there is increase in dopamine release (or increase dopamine receptors (D2) or loss of upper inhibitory neurons). D2 antagonists reduce positive symptoms of schizophrenia. All antipsychotic drugs have the ability to reduce dopaminergic neurotransmission.  The mesocortical pathway decrease activity (dysfunction): Meso-cortical pathway: From Ventral tagmental area to prefrontal cortex which are: a. dorsolateral responsible for Cognition and executive function in normal b. ventromedial responsible for Emotions and affect in normal Hypofunction (decrease dopamine or due to decrease number of dopamine receptor (D1) of the mesocortical pathway might be related to cognitive and negative symptoms of schizophrenia

The nigrostriatal system The nigrostriatal system contains about 80% of the brain’s dopamine. The nigrostriatal system projects from cell bodies in the pars compacta of the substantia nigra to terminals that innervate the striatum (caudate and putamen).The nigrostriatal system is involved in motor planning, dopaminergic neurons stimulate purposeful movement.

For atypical antipsychotic drugs it will attached to  5HT 2 A auto-receptors preventing auto-inhibitory effect of serotonin ►↑ serotonin release ►↑dopamine in the mesocortical pathway that might be related to cognitive and negative symptoms of schizophrenia  Dopamine (D 2 ) receptor ►↓dopamine effect ►↓ positive symptoms of schizophrenia in the mesolimbic pathway. Note: Atypical antipsychotic drugs attached to D 2 receptor loose and rapidly dissociated this is why it has lower side effect on  Nigrostriatal system so has lower extra-pyramidal symptoms (psudoParkinsonian) and tardive dyskinesia because: a. less affinity to dopamine receptors so cause less sever dopamine deficiency b. 5HT 2A receptors is found in striatum and substantia nigra that will be blocked by the drug  tuberoinfundibular pathway so has lower hyperprolactinemia effect if D2 receptors in the mesolimbic system are blocked completely as in typical antipsychotic drugs, this may not only reduce positive symptoms of schizophrenia, but a block reward mechanisms “neuroleptic- induced deficit syndrome”, leaving patients apathetic, anhedonic, lacking motivation, interest, and joy from social interactions a state very similar to that of negative symptoms of schizophrenia, and this may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia, besides it may worsen negative and cognitive symptoms B. Glutamate (or N-methyl-D-aspartate (NMDA) receptor hypo-function) hypothesis of schizophrenia Phencyclidine does this by blocking a type of glutamate receptor known as N-methyl-D-aspartate named for the agonist that binds there selectively. This observation has led to the notion that N-methyl- D-aspartate receptors may be pathologically hypo-functional in untreated schizophrenia, much like the condition produced by the ingestion of phencyclidine. An important descending glutamatergic pathway projects from cortical pyramidal neurons to dopamine neurons in the ventral tegemental area.

A. Positive symptoms of schizophrenia in the mesolimbic pathway: May be the result of a. No initial glutamate b. hypo-functional NMDA receptors on GABA interneurons in the cerebral cortex. Normally: GLU-GABA-GLU-DA: (+) – (-) – (+) ►↓ dopamine

Schizophrenia: GLU-zero-GLU-DA: (+) – (zero) – (+) ►↑ dopamine This hypofunction may lead to over activation of downstream glutamate signaling to the ventral tegmental area. Over activation of this pathway may result in turn in excess dopamine in the ventral striatum via the mesolimbic pathway ►↑ positive symptoms of schizophrenia in the mesolimbic pathway B. Negative symptoms of schizophrenia in the mesocortical pathway: The circuit has changed from GLU-GABA-GLU-DA to one of GLU-GABA-GLU-GABA-DA and it has an extra step. May be the result of First: a. No initial glutamate, b. hypo-functional NMDA receptors on GABA interneurons in the cerebral cortex. Second: Extra GABA interneurons Normally: GLU-GABA-GLU-DA: (+) – (-) – (+) ►↓ dopamine

Schizophrenia: GLU-zero-GLU-GABA-DA: (+) – (zero) – (+) – (-) ►↓ dopamine Low activation of this pathway may result in turn in low dopamine in the ventral striatum via the mesocortical pathway ►↑ negative symptoms of schizophrenia in the mesocortical pathway

Behavioral and Motivational Mechanisms of the Brain (The Limbic System and the Hypothalamus) Hypothalamus: Hypothalamic input:  nucleus of the solitary tract This nucleus collects all of the visceral sensory information from the vagus and relays it to the hypothalamus and other targets. Information includes blood pressure and gut distension.  reticular formation This catch all nucleus in the brainstem receives a variety of inputs from the spinal cord. Among them is information about skin temperature, which is relayed to the hypothalamus.  retina Some fibers from the optic nerve go directly to a small nucleus within the hypothalamus called the suprachiasmatic nucleus. This nucleus regulates circadian rhythms, and couples the rhythms to the light/dark cycles.  circumventricular organs Examples The Organum vasculosum laminae terminalis ( OVLT ) , which is sensitive to changes in osmolarity The area postrema , which is sensitive to toxins in the blood and can induce vomiting and angiotesin II.  limbic and olfactory systems Structures such as the amygdala, the hippocampus, and the olfactory cortex project to the hypothalamus, and probably help to regulate behaviors such as eating and reproduction. The hypothalamus also has some intrinsic receptors, including thermoreceptors and osmoreceptors to monitor temperature and ionic balance, respectively. Hypothalamic output:  neural signals to the autonomic system - the (lateral) hypothalamus projects to the (lateral) medulla, where the cells that drive the autonomic systems are located (the parasympathetic and the sympathetic system). With access to these systems, the hypothalamus can control heart rate, vasoconstriction, digestion, sweating, etc.  endocrine signals to/through the pituitary Hypothalamic functions are: The internal functions are collectively called vegetative functions of the brain, and their control is closely related to behavior I. Control of pituitary gland (anterior and posterior lobe). II. Control of autonomic functions: The single most important hypothalamic nucleus of the central autonomic network is the paraventricular nucleus (PVN).The paraventricular nucleus (PVN) has two morphological classes of neurons that fall into three functional categories. a.The magnacellular (big) neurons cells control posterior pititury gland secretion b. The parvocellular (small) neurons

1. neuroendocrine-related functional control anterior pituitary hormone secretion
2. central autonomic control.

the dorsal longitudinal fasciculus (DLF) ► the brainstem and lateral to Lamina X of the spinal cord  the medial forebrain bundle: joins the limbic system and the hypothalamus  the mammillotegmental tract: originate in the mammillary nuclei and project to the reticular formation of the pons and medulla The paraventricular nucleus (PVN) receives direct sympathetic and parasympathetic afferent inputs therefore is the only brain site in a closed efferent-afferent reflex loop with both the sympathetic and parasympathetic nervous systems.

angiotensin II. Dryness of the mouth and mucous membranes of the esophagus Visceral osmoreceptros Gastrointestinal and pharyngeal stimuli influence thirst (distension of stomach inhibit thirst). The central controller for water balance is the hypothalamus but there is no single anatomically defined center which is solely responsible for producing an integrated response to changes in water balance. The osmoreceptors are located in the area known as the AV3V (anteroventral 3 rd^ ventricle) in hypothalamus where the organum vasculosum of the lamina terminalis is part of it. organum vasculosum of the lamina terminalis are sites for angiotensin II action The thirst center is located in the lateral hypothalamus. ADH is formed predominantly in the neurons of the supraoptic and paraventricular nuclei. These nuclei receive input from the osmoreceptors and also from ascending adrenergic pathways from A. the low pressure baroreceptors  Large systemic veins  Pulmonary vessels  The walls of the right atrium and ventricles of the heart (the atrial volume receptors) B. the high pressure baroreceptors  Transverse aortic arch  Carotid sinuses of the left and right internal carotid arteries  Juxta-glomerular-apparatus (renal afferent arteriole)

Neural Mechanisms of Thirst Sensory information from the baroreceptors located in the atria of the heart is sent to a nucleus in the medulla: the nucleus of the solitary tract. This nucleus sends efferent axons to many parts of the brain, including the region around the AV3V.

The second signal for volumetric thirst is provided by angiotensin, located in one of the circumventricular organs. The subfornical organ (SFO), is the site at which blood angiotensin acts to produce thirst. Subfornical organ (SFO) contains neurons that detect the presence of angiotensin in the blood and excite neural circuits that initiate drinking. Neuron in the subfornical organ send their axons to the median preoptic nucleus The median preoptic nucleus receives information from angiotensin-sensitive neurons in the SFO. In addition, this nucleus receives information from the OVLT (which contains osmoreceptors) and from the nucleus of the solitary tract (which receives information from the atrial baroreceptors). OVLT will send information to thirst center located at lateral hypothalamus. The sensation of thirst will decrease with age , this is why old people are prone to dehydration easily IV. Relation to thermal regulation: The normal body functions depend upon a relatively constant body temperature Because the speed of chemical reactions varies with the temperature the enzyme systems of the body have narrow temperature ranges in which their function is optimal Oral, morning temperature is (36.3 to 37.1 C) Heat production and heat loss: A. Heat production: Heat production is increased by ingestion of food contraction of skeletal muscle. Heat production can be varied by endocrine mechanisms as it will be increased by catecholamine, thyroid hormones and sympathetic stimulation. B. Heat loss: Methods of heat loss:  radiation and conduction (70%)  vaporization of sweat( 27%)  respiration (2% )  urination and defecation (1%)

1. Mechanisms activated by cold: A. increase heat production: Shivering, hunger, increase voluntary activity, increase secretion of nor- epinephrine and epinephrine. B. decrease heat loss: Cutaneous vasoconstriction, curling up and horripilation.
2. Mechanisms activated by heat: a. Increase heat loss: Cutaneous vasodilatation, sweating, increase respiration. b. Decrease heat production:Anorexia, apathy and inertia. Hypothalamic role in controlling body temperature: typically 36.7–37.1°C body temperature level is crucial temperature level which is called the “set-point” Posterior hypothalamus

Posterior hypothalamus destruction causes hypothermia

This is why aspirin act as antipyretic through the block of Prostaglandins.Blocking Prostoglandin will decrease set point which is below the actual body temperature; and this will stimulate heat losing mechanism to lower body temperature.

Hypothermia: Human tolerate body temperature of 21 C to 24 C with permanent ill effect, and induced hypothermia has been extensively used in surgery (as in open heart surgery). In hypothermic patients, the circulation can be stopped for relatively long period because the oxygen need of the tissue is greatly reduced. Blood pressure is low, and bleeding is minimal. Limbic system: The word “limbic” means “border.” The hypothalamus, the primary output node for the limbic system The limbic lobe consists of the hippocampal gyrus, cingulate gyrus, subcollasal gyrus, and septal region.. Main Components of the Limbic System limbic cortex functions as a two-way communication and association linkage between the neocortex and the lower limbic structures An important route of communication between the limbic system and the brain stem is the medial forebrain bundle

Functions of limbic system: Most of limbic system is related to hypothalamus

1. Autonomic function: Stimulation of many parts of limbic system, especially that of amygdala, produce autonomic responses (CVS , respiratory, GI through hypothalamus). Such changes are also observed during emotion.
2. Regulation of body feeding behavior: It is mainly through hypothalamus
3. Regulation of sexual behavior and reproduction Sexual behavior ,the basic sex derive (urge to couple)is the function of limbic system and hypothalamus, which in turn are influenced by gonadal hormones and cerebral cortex
4. Maternal behavior: In general maternal behaviors concerned with the nursing and protection of offspring by the mother
5. Emotion behavior
6. Motivation behavior: The last two are one of the most important function. Diseases of the Limbic System: 1.Schizophrenia 2.Depression Reward مكافئةand punishment عقابfunction of limbic system It is already clear that several limbic structures are particularly concerned with( a. the sensations are pleasant (reward or satisfactionرضا) b. the sensations are unpleasant (punishment or نفورaversion) Reward center or pleasure center ان المتعة هو جزء اساسي من غريزة حب البقاء هي اماغريزية موروثة مثل غريزة الطعام و الجنس(التكاثر) او مكتسبة مثل غريزة حب التملك او المال The ventral tegmental area (VTA: is found in mid brain) and through the Medial forebrain bundle (MFB) is connected to Nucleus accumbens forms (reward circuit or mesolimbic pathway) is also called ventral striatum is part of limbic system is most associated with pleasure and reward is a dopaminergic neurons. Dopamine rewards us with a pleasant sensation. is important for memory and for motivating behaviors. By blocking this pathway, antipsychotic drugs reduce the intense emotions caused by conditions such as schizophrenia

It is particularly interesting that stimulation in the punishment centers can frequently inhibit the reward and pleasure centers completely, demonstrating that punishment and fear can take precedenceاالولويدة over pleasure and reward Strong stimulation of the punishment centers of the brain, especially in the periventricular zone of the hypothalamus and in the lateral hypothalamus causes an emotional pattern (the rage الغضب) Fortunately, in the normal animal, the rage phenomenon is held in check mainly by inhibitory signals from the ventromedial nuclei of the hypothalamus. In addition, portions of the hippocampi and anterior limbic cortex, especially in the anterior cingulate gyri and subcallosal gyri, help suppress the rage phenomenon. Placidity رباطة الجأش هدوء and Tamenessترويض. Exactly the opposite emotional behavior patterns occur when the reward centers are stimulated: placidity and tameness. If no reward and punishment effect, repletion of stimuli will causes habituation and therfore will cause the animal to ignore it. If got reward and punshment effect, stimuli will be reinforced and animal will build up strong memory trace; so this two effects are important in learning and memory

Effects of Stimulating the Amygdala. A. Effects of Stimulating the Amygdala similar to hypothalamus stimulation: (1) increases or decreases in arterial pressure; heart rate; gastrointestinal motility and secretion; (2) defecation or micturition; (3) pupillary dilation or, rarely, constriction; (4) piloerection (5) secretion of various anterior pituitary hormones, especially the gonadotropins and adreno- corticotropic hormone. B. amygdala stimulation can cause several types of involuntary movement. (1)tonic movements, such as raising the head or bending the body; (2) circling movements; (3) occasionally clonic, rhythmical movements (4) different types of movements associated with olfaction and eating, such as licking, chewing, and swallowing. C. amygdala stimulation can cause several types of emotions:

1. rage, escape, punishment, severe pain, and fear similar to the rage pattern
2. reward and pleasure.
3. sexual activities that include erection, copulatory Effects of Bilateral Ablation of the Amygdala (The Klüver-Bucy Syndrome). When the anterior parts of both temporal lobes are destroyed in a monkey, this procedure removes not only portions of temporal cortex but also of the amygdalas that lie inside these parts of the temporal lobes. This removal causes changes in behavior called the Klüver-Bucy syndrome, which is demonstrated by an animal that (1) Tameness (loss of fear) (2) has extreme curiosity about everything, has a tendency to place everything in its mouth (3) forgets rapidly (Anterograde amnesia) (4) Visual agnosia (cannot recognize objects visually), Psychic blindness (objects in visual field are treated inappropriatly as inability to recognize facial expression) (5) Hypersexuality(autoerection): often has a sex drive so strong that it attempts to copulate with immature animals, animals of the wrong sex, or even animals of a different species. Although similar lesions in human beings are rare, afflicted people respond in a manner not too different from that of the monkey. Hippocampus: Short term memory is lost on removal of bilateral hippocampus Stimulation of part of hippocampus can elicit pleasure, rage, passivity, or excessive sex drive Functions of Hippocampus:
4. memory (dorsal region): a. store and processes memories (translation of short into long term memory i.e. sore new memory i.e consolidation of memory) b. help to find memories c. encode memories, and then helps to find them when you want to remembered something d. main relay station that determines whether a new memory should go to long-term memory or be deleted after short-term usefulness is over
5. Comparing sensory information what the brain expect about the world
6. Enable us to form spatial memories for navigation the environment Papez circuit Papez (1937)was the first to identify is not function of any specific brain center but 4 basic structure form a circuit is one of the major pathways of the limbic system is chiefly involved in the cortical control of emotion and storing memory.