Rövid történelmi bevezetés

Joan of Arc (Jeanne d'Arc) born: kb. 1412. 1429. Free Orleans. 1430: captured by burgunds, sold to the English, charged by witchcraftry 1431:burned to death 1415-1429   Territories controlled by Henry VI of Englandpink   Territories controlled by Philip III of Burgundy lilac  Territories controlled by Charles VII of France blue wikipedia 

Auditory hallucinations (religional) obsession Bizarre thinking Bizarre ideas, misconseptions Significant suggestion ability Giniality (knowing things without learning) Unbreakeble devotion to misconseptions

Classification of the symptoms of schizophrenia Timothy Crow és Nancy Andreasen (1991) Two cathegories Pozitíve (pszichotic) symptoms: hallucinations, misconseptions, bizarre behavior and speech. „Healthy” subjects have no symptoms, and they react well to medical treatment. Dezorganization symptoms: a disturbance of thinking, dezorganizing speech, behavior, attention. Negative symptoms (absence symptoms): Primer negative symptoms : loss of emotion andkommunication, arrest of thinking, lack of motivation, anergia, apathy, anhedony, a decrease of social and és szexual activity, disturbed attention. Secunder negative symptoms : not connected to the disease directly. Anxiety, depression). A negative symptoms hardly react to medical treatment . DSM IV: Diagnostic and statistical manual of mental disorders http://hu.wikipedia.org/wiki/Skizofr%C3%A9nia

Schizofrenia – spektrum disease Etiology genetic, disturbance in neuronal development or biochemical disturbance of the nervous system, psychosocial difficulties (e.g. infectious, viral illness during pregnancy, or social isolation) Risk factors Drug abuse, family relationship (both parents are affected: 34-40%, monozygotic twins: 50%[1]) Main Symptoms Disturbed emotions, thinking, behavior. Disturbance in separation of objective and subjective events. Disturbed communication, hallucinations (auditory, mainly). Misconseptions, bizarre behavior, disintegration of personality. -> LOSS of social connections!!! Marginalization, homeless people Diagnostic klinical psychodiagnostic, scales for estimation of the symptoms Prison, immigrants effect! Schizophrenia is not multiple personality! Schizophrenia is a spectrum disorder! Illness of young adults.

MR image of twins, aleft is healthy, the right has Schizophrenia. The affected twin has dilatated ventricules, less brain tissue. Other changes: decrease of grey matter in temporal lobe, frontal lobe and hippocampus. Rita Carter: The human brain book left right

A DSM-IV a skizofréniát öt alosztályba sorolja Paranoid (DSM kód 295 A DSM-IV a skizofréniát öt alosztályba sorolja Paranoid (DSM kód 295.3/BNO kód F20.0): vonatkoztatásos, üldöztetéses, nagyzásos téveszmék, gyakran hallucinációk jellemzik, de kevésbé jellemzők a gondolkodási zavarok, a dezorganizált viselkedés, vagy az affektív zavarok (az érzelmi élet elsivárosodása). Gyakori a düh, szorongás, zárkózottság, emellett előfordulhatnak egyéb motívumok is, például féltékenység, vallásosság, vagy szomatikus paranoiák. Általában 30 éves kor után kezdődik, így az érettebb személyiségstruktúra következtében a szociális és érzelmi válaszkészség jobban megmarad. Dezorganizált/ hebefrén (DSM kód 295.1/BNO kód F20.1): A gondolkodási zavar és az affektív zavar együttes jelenléte: inkoherens, szétesett gondolkodás, elszegényedett, oda nem illő emócionális válasz, bizarr, általában a környezeti hatásokat figyelmen kívül hagyó viselkedés, a realitásérzékelés súlyos károsodása. A téveszmék, hallucinációk általában szétesettek. A skizofréniának ez a fajtája általában serdülőkorban kezdődik. Kataton (DSM kód 295.2/BNO kód F20.2): alapvetően a pszichomotoriumot érinti. A mozgás intenzitásában megmutatkozó változás szélsőséges lehet, melyek hirtelen váltakozhatnak. Jellemző lehet motoros gátoltság, mutizmus, szélsőséges esetben stupor (megmerevedettség), katalepszia vagy a flexibilitas cerea, amikor egy-egy kényelmetlen helyzetet vesznek fel a betegek, és akár órákon keresztül megtartják azt. Más esetekben céltalan aktivitásfokozódás, nyugtalanság, izgalmi állapot tapasztalható, ez szélsőséges esetben mozgásviharrá fokozódhat. Elemei: jellegzetes pózok, sztereotip mozdulatok vagy grimaszok, modorosság, grimaszok, echolalia (a hallott szavak kényszeres, visszhangszerű ismétlése), echopraxia (a látott mozgás gépies utánzása), negativizmus (a beteg és a környezet közötti kapcsolat megszakadása). Nem-differenciált (DSM kód 295.9/BNO kód F20.3): a pszichotikus tünetek megjelennek, de a paranoid, hebefrén vagy kataton kategóriákba nem sorolható be, vagy ezek közül többe is besorolható. Reziduális (DSM kód 295.6/BNO kód F20.5): a kórlefolyás sajátosságaira vonatkozó kategória. Legalább egy pszichotikus epizód után pszichotikus tünetek nélkül, a negatív tünetek dominanciája, míg a pozitív tünetek csak csökkent intenzitással vannak jelen. Jellemző még az érzelmi elsivárosodás, a szociális visszahúzódás, az excentrikus viselkedés, a logikátlan gondolkodás és az asszociációk lazulása.

Decreased funtionality of the frontal cortex

Limbic cortex ( amygdala occasionally): fMRI image, right hemisphere of a schizophrenia patient. During normal speech the same areas of the left hemispheres are activated. Brodmann 44-45. It can be an explanation for auditory hallucinations? Therefore patients think that other speak to them, or somone „planted a radio” into their head?. MRI images showed large alterations in: Prefrontal cortex, temporal cortex, Limbic cortex ( amygdala occasionally): Wi Hoon Jung1,2, Joon Hwan Jang3, Min Soo Byun3, Suk Kyoon An4, and Jun Soo Kwon1,2,3,5 Structural Brain Alterations in Individuals at Ultra-high Risk for Psychosis: A Review of Magnetic Resonance Imaging Studies and Future Directions, DOI: 10.3346/jkms.2010.25.12.1700 • J Korean Med Sci 2010; 25: 1700-1709

Schizofrenia and amygdala: fMRI: increased activity for scary or emotionally negative pictures No or decreased activity for emotionally positive pictures Cause of anhedonia, no joy, no reaction for love, etc. Cognitive neuroscience of emotional memory Kevin S. LaBar and Roberto Cabeza NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 55

Dopamin-theory: dopamin has a stronger effect on schizophrenia patients, there is more dopamin and DA receptor (Amphetamin-effect, PCP treatment – animal modell J. Hirvonen and J. Hietala Neurotransmitters and Genetics of Schizophrenia Figure 2 Increased caudate dopamine D2 receptors (top row) and increased cortical dopamine D1 receptors (bottom row) in unaffected cotwins of patients with schizophrenia. Results from a voxel-based receptor mapping analysis are visualized on a magnetic resonance imaging template

Glutamate- theory, GABA-theory The dopamin level is not elevated originally, but the glutamate regulation is decreased on DA cells, resulting in higher amount of DA release; Isr J Psychiatry Relat Sci - Vol 47 - No. 1 (2010) Glutamatergic theories of schizophrenia Daniel C. Javitt, MD, PhD The GABA innervation of the pyramidal cells is decreased, they misfunctioned, and therefore there is loww amount of glutamate Proc. Natl. Acad. Sci. USAVol. 95, pp. 5341–5346, April 1998 Neurobiology A subclass of prefrontal g-aminobutyric acid axon terminals areselectively altered in schizophrenia TSUNG-UNG WOO*, RICHARD E. WHITEHEAD*, DARLENE S. MELCHITZKY*, AND DAVID A. LEWIS*†‡ Glutamate-input is decreased on inhibitory neurons, therefore the GABA level is decreased. Schizophrenia Research 73 (2005) 159– 172, Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons S.L. Eastwood*, P.J. Harrison Brain Res. 2008 July 7; 1218: 267–277. doi:10.1016/j.brainres.2008.03.092. There is abnormally low level of certain GLU receptors (mGluR2)

Proc. Natl. Acad. Sci. USA. 95, pp Proc. Natl. Acad. Sci. USA. 95, pp. 5341–5346, April 1998 A subclass of prefrontal g-aminobutyric acid axon terminals are selectively altered in schizophrenia FIG. 1. Laminar distribution and overall intensity of GAT-1 immunoreactivity in area 46 is similar in matched normal control (A) and schizophrenic (B) subjects (see Table 1, triad 3). Hash marks indicate the layer 1–2 and 3–4 borders. At higher magnification (C), GAT-1-labeled axon cartridges (open arrows) are readily identified amid the diffuse punctate immunoreactivity. Solid arrow indicates the same blood vessel in A and C. Individual GAT-1-immunoreactive axon cartridges are located below the unlabeled cell bodies of pyramidal neurons (P) in normal control (D) and schizophrenic (E) subjects. [Bars 5 500 mm (A and B), 50 mm (C), and 10 mm (D and E).]

Cannabis receptor 1 theory Neuropsychopharmacology. 2010 September ; 35(10): 2060–2071. doi:10.1038/npp.2010.75. Neuropsychopharmacology. 2010 September ; 35(10): 2060–2071. doi:10.1038/npp.2010.75. Cannabinoid CB1 Receptor Immunoreactivity in the Prefrontal Cortex: Comparison of Schizophrenia and Major Depressive Disorder Stephen M. Eggan, PhD1, Samuel R. Stoyak, BS2, Christopher D Verrico, PhD1, and David A.Lewis, MD1,2 Abnormally low level of CB1-R in prefrontal cortex Warning! Antipsychotic treatment may decrease it as well. And marijuana consumption may cause decrease of it as well. It may cause schizofrenia (symptoms) as well, even after years without consumption. -> Kompenzation? Amount of CB1-R is low, BECAUSE the level of GLU and GABA is low? Autoimmun theory: „Suspicious” relationship with infectious disease. (if mother has viral infection during pregnancy, may increase the risk. No juvenile diabetes, no rheumatoid artritis (Bánki M. Csaba: Az agy évtizedében)

The perisynaptic signaling machinery (PSM) may have evolved to translate anterograde transmission to retrograde communication Katona and Freund (2008) Nature Medicine 14:923-930

SCHIZOPHRENIA AND CANNABIS A recent human study found that smoking higher potency cannabis (sinsemilla or ‘skunk’) leads to an increase in the risk of developing psychosis (Di forti et al., 2009). This is consistent with the hypothesis that THC exposure increases the risk of psychosis. In addition, the concentration of other cannabinoids in cannabis preparations may be important in terms of whether a person develops schizophrenia following cannabis use. Epidemiological evidence suggests that cannabis use is a risk factor for schizophrenia, while cannabis use in individuals with a predisposition for schizophrenia results in an exacerbation of symptoms and worsening of the schizophrenic prognosis. The neurodevelopmental characteristic of adolescence probably creates a more vulnerable circumstance for cannabis to produce psychotic-like symptoms and possibly cause schizophrenia. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental modelsbph_721 511..522 Daniel T Malone1, Matthew N Hill2 and Tiziana Rubino3, British Journal of Pharmacology (2010), 160, 511–522

The neuropathology of schizophrenia Disturbed Neurodevelopment, disturbed neuron migration theory: Abnormally large number of neurons in the white matter Abnormal glial cells Possible effects of synaptic imbalances on oligodendrocyte– axonic interactions in schizophrenia: a hypothetical model Bernhard J. Mitterauer1 and Birgitta Kofler-Westergren2* Abnormal grey matter Abnormal transmitter-system Dialogues Clin Neurosci. 2009 ; 11(3): 269–280.Neuroplasticity of Excitatory and Inhibitory Cortical Circuits inSchizophrenia David A. Lewis, MD Abnormal cell size? Brain (1999), 122, 593–624 The neuropathology of schizophrenia A critical review of the data and their interpretation Paul J. Harrison Fig. 1 Schematic cartoon exaggerating the putative cytoarchitectural features of schizophrenia. The grey matter contains an unchanged number of neurons, but the pyramidal neurons (black triangles) are smaller and more densely packed. The cortex is thinner, especially in laminae II and III. The reduced neuron size and increased neuron density are both correlates of a reduced neuropil volume, which in turn reflects abnormalities affecting the axonal (green) and dendritic (red) arborizations of some neurons. For example, there may be less extensive, or otherwise aberrant, synaptic connections formed by incoming corticocortical fibres (hollow green lines, shown as having restricted terminations on dendritic spines, denoted by thin red lines) and by axon collaterals (solid green lines, shown as being shorter and in a different position) of efferent pyramidal neurons. Glia (grey filled circles) are unaffected. Although the figure illustrates the situation in the prefrontal neocortex, a similar diagram could be drawn for the hippocampus. For clarity, possible differences in the distribution and synaptic organization of interneuron subpopulations (blue and brown) and white matter (wm) neurons (purple), as well as the pattern of changes in the cingulate gyrus and subcortical structures, are omitted.

Disturbed Neurodevelopment, disturbed neuron migration theory : In hippocampus, a significant decrease of Reelin-ir was found in patients with schizophrenia, bipolar disorders and major depression (Fatemi et al., 2000, 2001). Reelin expression is reduced in a variety of psychiatric disorders, and it has been proposed that abnormalities of the reelin gene represent putative vulnerability factors for psychosis and cortical pathology in schizophrenia (Impagnatiello et al., 1998; Guidotti et al., 2000a,b; Chen et al., 2002). Hippocampal Cajal-Retzius cells and Reelin are essential for neuronal positioning and formation of layer-specific connections (Del Rio et al., 1997; Frotscher, 1997; Deller et al., 1999; Drakew et al., 2002). Neocortical and archicortical Cajal-Retzius cells disappear after the period of cortical migration (Del Rio et al., 1996; Meyer and Goffinet, 1998; Meyer et al., 2002). whereas decreased expression of Reelin mRNA correlates with the extent of migration defects in the dentate gyrus of patients with temporal lobe epilepsy (Haas et al., 2002).

Summary: Most likely we have to find something smaller than the cell The disorder is caused by multiple factors, Whole genom + environment Synapse is affected: input-output, receptors, ion channels, transmitter synthesis, decay, realise, reuptake, etc. Secunder messanger system is afffected as well, most likely: genexpression and regulation, epigenetic factors Prefrontal cortex and temporal cortec might be specially affected

Köszönöm a figyelmet!

Az agyi jutalmazó rendszer Sültkrumpli + Cukor függés!! Rita Carter: The human brain book