Cognitive, affective, & social neuroscience
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1 Cognitive, affective, & social neuroscience Time: Wed, 10:15 to 11:45 Prof. Dr. Björn Rasch, Division of Cognitive Biopsychology University of Fribourg 1
2 Content } Introduction to imaging genetics } } } The endophenotype concept Heritability and reproducibility of fmri Imaging genetics of emotion and emotional memory } Sleep and memory } } Sleep and the moon Exam 2
3 Literature } Article } Flint & Munafo 2007, Psychological Medicine } The endophenotype concept } Pschychological Medicine } Hariri et al., 2002, Science } The serotonin transporter polymorphism and the response of the human amygdala 3
4 Polymorphism } Genetic mutation that occurs in more than 1% of the population } } Single-nulecotide polymorphism (SNP) } } } Substitution Deletion Insertion Copy-number variation (CNV) } May fall into } } } Coding sequence of genes Non-coding-regions of genes Intergenic regions } May cause } } Changes in the gene-encoded polypeptide (non-synonymous) No changes (synonymous, sient mutation) 4
5 Imaging genetics 5
6 Imaging Genetics 6
7 5-HTTLPR & Amygdala 7
8 5-HTTLPR & Amygdala 8
9 5-HTTLPR & Amygdala 9
10 5-HTTLPR & depression 10
11 Caspi et al.,
12 Caspi et al.,
13 Genotypes & phenotypes } Genotype } genetic constitution of an organism } specific combination of alleles } Allele: form of a gene } Phenotype } observable characteristic or trait of the organism 13
14 Genotypes & phenotypes 14
15 Selection of genes } Genetic variability: } Single nucleotide polymorphisms (SNPs) } Copy number variations (CNVs) } } Approaches } Candidate gene studies } Genome wide association analysis } Problems: } Allele frequency } Population stratification } Functionality 15
16 Selection of genes } Minor allele frequency: } Min > 5% } Imaging genetics: > 30% } Population stratification } Problem: Inhomogenic populations } Differences in allele frequences plus difference in prevalence of phenotype } Possible causes: Migration Non-random mating } Violation increases Type I and Type II errors } Overestimation of association between polymorphismus and trait 16
17 Selection of genes } Functionality: } Within gene } Affect structure of protein } Exp.: COMT } Outside coding sequence } Influence expression } Exp.: Serotonin transporter (5-HTT) } Problem: } Unkown functionality } Possible both inside and outside gene coding sequence 17
18 Selection of phenotype } Types } Phenotype } Visible characteristics Exp.: Height, eye color, psychiatric desease (e.g. schizophrenia) } Endophenotype } Not directly observable Exp.: Psychological construct (e.g. working memory), brain activity } Selection criteria } High validity } High reliability } High heritability 18
19 Selection of phenotype } Validity } Does the test measure what it is supposed to measure? } Construct validity } Operationalization of theoretical construct } Convergent vs. divergent validity } Criterion validity } Predictive validity between criterion and predicted } Classical test theory: Upper limit = reliability(single measures) 19
20 Selection of phenotype } Reliability } Does the test measure consistently? } Test-retest reliability } Correlation between two assesments of the same test } r tt } Split have consistency } Correlation between test halfs } Internal consistency } Cronbach s alpha } Mean of all split half possiblities } Intra Class Coefficient (ICC) 20
21 Heritability } Statistical Model: } Phenotype (P) = Genotype (G) + Environment (E) } Heritability (broad sense) } H 2 = Var(G) / Var(P) } Var(G) includes: Allelic variation (additive variance) Multi-genetic interactions Maternal / Paternal effects } Heritability (narrow sense) } h 2 = Var (A) / Var (P) } Var(A) includes: Additive (allelic) variance 21
22 Twin studies 22
23 Twin studies } Monozygotic twins (Mz) } 100% identical genes } Dizygotic twins (DZ) } 50% identical genes } similar environments } Rough estimate of heritability: } Double distance between concordance rates } Degree of similarity between two persons 23
24 Schizophrenia } Mental disorder } often characterized by abnormal social behavior and failure to recognize what is real } Lifetime prevalence: 0.3% - 0.7% } High heritability (> 80%) } Hypothesis: Decreased dopamine activity in in prefrontal cortex } Medication: Dopamine-related } Some diagnostic criteria (DSM-5) 24
25 COMT } Catechol-O-methyl transferase (COMT) } Enzyme } Involved in degradation of dopamine, epinephrine and norepinephrine } COMT most important regulator of prefrontal dopamine function in humans } Polymorphism in COMT-gene } Val 158/108 Met polymorphism (rs4680) } Valine-to-methionine (Val/Met) substitution at position 158 (long form, membrane-bound) at position 108 (short form, soluble) } Val-variant degrades 4 times more dopamine than Met variant Val-variant associated with less prefrontal dopamine } Candidate polymorphism for schizophrenia 25
26 COMT and schizophrenia } Extensively studies in large samples sizes } No consistent evidence for an association } See meta-analysis } Munafo et al., 2005, Molecular Psychiatry 26
27 COMT and schizophrenia } Possible reasons for lack of association } Schizophrenia has complex genetic architecture } Multiple genes involved, complicated interactions } Diagnostic of schizophrenia difficult } Only qualitative distinction (yes / no) } Diagnostic criteria appropriate? } Several subtypes, different underlying mechanisms? } Alternative: } Endophenotypes 27
28 Endophenotype } Internal process (not-directly observable) } Can be reliably and objectively measured } Criteria: Endophenotypes need to be } Heritable } Co-segregate with a psychiatric disease } Present when the disease is not } Present in non-affected family members at a higher rate than in the general population } Should be involved in a biological plausible mechanism of pathogenesis of the disease 28
29 Endophenotype } Examples 29
30 Endophenotypes } Advantages } Endophenotypes represent more defined and quantifiable measures than diagnostic categories } Involve probably fewer genes / less complex } Should have higher chance to detect genetic underpinnings } Example: Prefrontal functions } Endophenotype for Schizophrenia } Wisonsin Card Sorting Test E.g. learning and changing rules 30
31 Endophenotypes } Association between COMT and Wisconsin Card Sorting Test } More perseveration errors in Val/Met + Val/Val as compared to Met/Met (see Flint & Munafo, 2006) } Small and inconsistent effect 31
32 Endophenotypes } Most endophenotypes do not have a better chance to detect genetic influences } Similar effect sizes, large sample sizes needed for replication } Inconsistent results } Null-effects in meta-analyses } Are neurophysiologcal endophenotypes better? } Brain Imaging 32
33 5-HTTLPR & Amygdala 33
34 5-HTTLPR & Amygdala 34
35 Overview cognitive genetics Imaging genetics Human psychiatric genetics Translational bottleneck Mouse molecular genetics 35
36 Imaging genetics 36
37 37
38 38
39 Brain Imaging 39
40 Brain Imaging Method Type Invasive Brain property used: } EEG / ERP Recording No Electrical } Single cell / Multi unit recordings } } } } TMS MEG PET fmri Recording Stimulation Recording Recording Recording Yes No No Yes No Electrical Electromagnetic Magnetic Haemodynamic Haemodynamic 40
41 fmri 41
42 Neurovascular coupling Sensoric stimulation Neuronal response? Vascular response Brain imaging 42
43 Hemodynamic response function (HRF) 43
44 HRF 44
45 HRF Logothetis et al., 2001, Nature 45
46 Block Design 46
47 Imaging genetics } Is brain activity measured by fmri a good endophenotype? } Criteria for endophenotypes: } Internal process (not-directly observable) } Can be reliably and objectively measured } Heritable } Co-segregate with a psychiatric disease } Present when the disease is not } Present in non-affected family members at a higher rate than in the general population } Should be involved in a biological plausible mechanism of pathogenesis of the disease 47
48 Homework } Please read } Blockland et al., 2011, J. Neurosci. } Heritability of Working Memory Brain Activation 48
49 Thank you for your attention. 49
50 EEG
51 MEG 51
52 PET 52
53 PET 53
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