Many studies of molecular, genetic and gene change inschizophrenia in the world [1], [2] have concerned of gene Catechol-O-methyltransferase and Zinc-finger protein 804A [13], [14], but
Trang 11 The necessity of this study
Schizophrenia is a group of severe psychosis, characterized bypsychotic symptoms such as delusions, hallucinations, catatonia,disorganized speech and behavior The symptoms of schizophrenia arevaried and they always change over time [1]
In the world, there are tens of millions of people withschizophrenia, accounting for about 1% of the world's population.Every year, this rate increases by 0.15% of the population Prevalence
of schizophrenia in Vietnam is 0.3-0.8%, and every year it increases
by 0.1-0.15% of the population[2]
For decades, many authors have focused on the etiology andpathogenesis of schizophrenia according to several trends such asgenetics [9], [10] neurotransmitters [21], [22] environmental factors[19], [20] Each schizophrenia theory is characterized by its advantagesand limitations
Although many studies on schizophrenia have been conducted inVietnam, most of them have just described the clinical symptoms,progression and treatment of schizophrenia Few studies have researched
on EEG, but they still restricted, especially about the feature of EEG inschizophrenia Many studies of molecular, genetic and gene change inschizophrenia in the world [1], [2] have concerned of gene Catechol-O-methyltransferase and Zinc-finger protein 804A) [13], [14], but number
of studies on nucleotide polymorphisms in schizophrenia has been limited
in Vietnam
In previous decades, studies on the etiology and pathogenesis ofschizophrenia, including EEG and schizophrenic genetic, have facedmany difficulties and hassles, both in terms of technical procedures andequipment, which are not suitable to the current situation in Vietnam.Nowadays, because of new techniques and methods in quantitativeelectroencephalography [49], [50] and new generation sequencing [15],in-depth studies of EEG and molecular genetic in schizophrenia become
available Therefore, the “Research on features of electroencephalogram and some polymorphisms of COMT, ZNF804A gene in patients with schizophrenia” has been launched with two objectives as follows:
1/ To describe EEG and relationship between EEG and clinical features in patients with schizophrenia.
Trang 22/ To assess the frequency of allele and genotypic distribution of ZNF804A gene polymorphism rs1344706 and COMT gene polymorphism rs165599 in patients with schizophrenia.
2 Practical significance and new contributions
- This has been the first systematic study on clinical features
which initially assessed on the EEG and ZNF804A gene rs1344706 polymorphism, COMT gene polymorphism rs165599 in patients with
schizophrenia in Vietnam
- The analysis of EEG was successfully applied by EEGLab
sofware running on Matlab in schizophrenic patients
- EEG changes in patients with schizophrenia were varied:Amplitude of alpha wave, delta wave and theta wave had statisticallysignificant differences between two groups and recording channels Theenergy property of alpha wave in schizophrenia group was significantlylower than in control group The energy property of delta wave and thetawave in schizophrenia group were significantly higher than in controlgroup EEG frequency did not change in schizophrenic patients,comparing to control group There was a correlation betweenhallucinations and EEG in patients with schizophrenia, including:increase of amplitude, energy properties of alpha, delta, and theta waves
- The frequency of allele rs1344706 polymorphism inschizophrenic patients was 53.30% (A) and 46.70% (C), and thedistribution of three genotypes AA, CC and AC in patients withschizophrenia was 28.19%, 21.59% and 50.22% Whereas, frequency ofallele A and G of rs165599 polymorphism in schizophrenia patients was51.32% and 48.68%; and the distribution of genotypes AA, GG and AGwere 22.75%, 25.11% and 47.14%, respectively There was no difference
in allele frequency and genotypic distribution of rs1344706 and rs165599polymorphism between schizophrenia and control group There was also
no difference in allele frequency and genotypic distribution between twogroups in both females and males
- This research opened a new direction for early diagnosis as well
as tools to support the diagnosis and evaluation of treatment results inpatients with schizophrenia
3 Structure of thesis
Thesis was written in 152 pages, tables and figures The contentincludes: Introduction (2 pages); Chapter 1: Over view (38 pages);Chapter 2: Objects and methods (18 pages); Chapter 3: Result (46 pages);Chapter 4: Discussion (26 pages) and conclusion (2 pages);
Trang 3Recommendation (1 page); List of research projects that publish results ofthe thesis page; References (18 page) (Vietnamese documents and foreignlanguages documents).
CHAPTER 1 OVERVIEW 1.1 Concept of schizophrenia
Schizophrenia is characterized by many disturbances such asthinking disorder, emotional and behavioral disorder These symptomsinclude: positive symptoms such as delusions, hallucinations, andcatatonia; negative symptoms such as: flat affect, asociality, avolition,
Trang 4anhedonia, and alogia [5].
1.2 Electroencephalogram in schizophrenia
Previous studies have shown the changes of alpha wave, deltawave and theta wave in schizophrenia in terms of amplitude, power,frequency, and reactivity Especially, there are the appearance of waveswith frequency 25-35 Hz and low amplitude, as called "choppy" EEGchanges in schizophrenia occur in 64% of patients
Nowadays, researches have been focusing on analyzing the EEG inschizophrenia in terms of energy and output property
1.3 Changes in ZNF804A and COMT gene, in schizophrenia
1.3.1 ZNF804A gene and schizophrenia
ZNF804 is a gene encoding the ZNF804A protein in humans,
located on chromosome 2 q32.1, consisting of 4 exons, encoding
proteins with 1210 amino acids In humans, ZNF804A is widely
expressed in the brain, particularly in the developing hippocampusand cortex, as well as the cerebellum in adults A study of GWAS
identified ZNF804A as a sensitive gene of schizophrenia From the
genealogical studies of schizophrenia, it is said that geneticcoefficient is nearly 80% The rs1344706 polymorphism in intron 2
of the ZNF804A gene has been identified as the single polymorphism
which is most closely associated with schizophrenia Recent
evidences also have shown that the ZNF804A gene may be one of the
most potential genes which relate in schizophrenia [1]
1.3.2 The rs1344706 Polymorphism and schizophrenia
The relationship between rs1344706 polymorphism andschizophrenia is widely recognized and reached a consensus [85] The
association between ZNF804A and schizophrenia, especially rs1344706
polymorphism, has been confirmed by many researches on Europeansamples However, these results have not been consistent among Asians[86]
1.3.3 COMT gene and schizophrenia
COMT gene has a schizophrenia-related region on chromosome 22;
contains important fragments 22q11.2; related to catecholaminemetabolism: group of neurotransmitters involved in mental disorders and
psychiatric treatment Relationship of the COMT gene rs4680
polymorphism related to females in schizophrenia was found in a study (p
= 0.02) [108], [109] Another studies of COMT gene also showed the
relationship between schizophrenia and environmental risk factors such
as marijuana stimulant use to schizophrenia [110], [111], [112]
Trang 51.3.4 The rs165599 polymorphism and schizophrenia
The rs165599 polymorphism, which has received much attention
in schizophrenia researches, suggests it has a role to play Thispolymorphism, which plays a role in increasing dopamine, has explainedsome of the features of schizophrenia, including delusions, hallucinations,disorganized speech and behavior This role is also shown in theassociation of alleles with schizophrenia at the age of onset and thedecrease in working productivity [116]
1.4 Research on Electroencephalogram and genes in schizophrenia in Vietnam
Schizophrenia is one of the leading causes of disability, often onset
at a young age, with severe consequences for patients, families andsociety In the world, researches on changing EEG and genetic features inschizophrenia have been interested in many respects However,schizophrenia has been highly concerned about epidemiology and clinicalfeatures in Vietnam There have also been some studies evaluating EEG
in schizophrenia, but these studies have just assessed through subjectiveevaluation Extensive and in-depth assessments of specific functionalareas related to high-level functional disorders as well as studies of
genetic and polymorphic traits, including ZNF804A and COMT gene in
Vietnamese, have been still unclear Researches on EEG and genes inschizophrenia in the world still have showed many different results.Therefore, research on these issues in Vietnamese population is new andnecessary
CHAPTER 2 OBJECT AND METHOD 2.1 Study objects
The schizophrenia group includes 230 patients with schizophreniadiagnosed according to criteria of World Health Organization in 1992(ICD-10F) These patients was treated at the Department of Psychiatry,Military Hospital 103, Vietnamese Military Medical University
The control group includes 94 healthy people who suitable for age,gender and some other conditions with above patients
2.2 Methods
2.2.1 Study design
A Cross-sectional follow-up study includes analysis of clinical
Trang 6symptoms of patients corresponding to COMT, ZNF804A gene and EEG
changes in the schizophrenia group
2.2.2 Clinical research method
Clinical research method is to directly interview with patients andtheir family members to collect information about the patient's history
2.2.3 Electroencephalogram analysing method
EEGLab v13.4.4b analysis software running on MatLab 2017software
Procedure of EEG analysis was conducted at Diagnostic ImagingDepartment-103 Military Hospital-Vietnam Military Medical University
2.2.4 Research method of genetic polymorphism
The ZNF804A gene polymorphism rs1433706 was determined by the direct sequencing method and the COMT gene polymorphism
rs165599 was determined by the polymerase chain reaction-restrictionfragment length polymorphism (PCR-RFLP) method
Process of conducting these techniques to determine thepolymorphisms: Military Pharmaceutical Research Centre-VietnamMilitary Medical University
Trang 7Chapter 3 RESULTS 3.1 General features of study subjects
Table 3.1 Distributon by age group of two groups Age group Schizophrenic group
Bảng 3.2 Distribution by sex of two groups Sex Schizophrenic group
Trang 83.2 Features of mental disorders in patients with schizophrenia 3.2.1 Personal and family history
Table 3.3 Distribution by personal history in patients with schizophrenia
Figure 3.1 Distribution by family history in patients with schizophreniaThe result in Figure 3.1 shows that the prevalence of patientswhose third-degree relative suffering from mental disorders was high,accounting for 11.74%
Trang 9Echoing thought 10 4.35
The result in Table 3.4 shows that the auditory hallucination withcommenting content accounted for the largest prevalence (79.13%), whilecontent of conversation accounted for the lowest prevalence (25.22%)
Table 3.5 Number of types of hallucinations in patients with
schizophrenia
Content of hallucinations Number (n) Percent (%) p
0.000
Three types of
The results in Table 3.5 shows the number of hallucinations inpatients with schizophrenia Patients experiencing one type ofhallucinations accounted for the highest prevalence (47.83%), followed
by patients experiencing two types of hallucinations (47.39%)
Table 3.6 Classification of the content of hallucinations in patients with
schizophrenia
Content of hallucinations Number
(n)
Percent (%)
p
Conversation PseudoTrue 499 84.4815.52 0.000
0.754
The results in Table 3.6 shows that the prevalence of hallucinations were higher true hallucinations, especially in content ofcomment (74.18% compared to 25.82%), conversation (84.48% compared
pseudo-to 15.52%), and inducement (77.63% compared pseudo-to 22.37%)
Table 3.7 Behavioral control in patients with schizophrenia due to
Trang 10Behavioral control Numbe
r (n)
Percent (%)
p
< 0.000
Delusion of being followed 154 66.96
The result in Table 3.8 shows the prevalence of types of delusions
in schizophrenia Persecutory delusion accounted for the highest ratewith 86.96% There was very few patients who experienced invention
Trang 11and jealous delusion (equally 0.43%).
Table 3.9 The number of types of delusions in patients with
schizophrenia
Number of types of delusions Number
(n)
Percent (%)
Table 3.10 Behavioral control of delusional types in patients with
Persecutory delusion YesNo 13961 30.5069.50 0.000
3.3 Electroencephalogram in patients with schizophrenia
3.3.1 Energy property of electroencephalogram
Trang 12Figure 3.2 Alpha wave energy property in baseline EEG
The result in Figure 3.2 shows the alpha wave energy property inthe baseline EEG was significantly different between two groups(p<0.001) In particular, the alpha wave energy property in theschizophrenia group was statistically significantly lower than in thecontrol group in most areas of the cerebral cortex
Figure 3.3 Delta wave energy property in baseline EEG
The result in figure 3.3 shows the difference of delta wave energyproperty in the background EEG between two groups (p<0.001) Inwhich, the most difference was figured out at frontal area on both sides
Trang 13Figure 3.4 Theta wave energy property in baseline EEG
The result in Figure 3.4 shows the diffenrence of theta wave energyproperty in the background EEG between two groups (p<0.001) Inwhich, the most difference was figured out in the pre-frontal region onboth sides, the left frontal region, the central region on both sides and theright occipital region
3.3.2 Electroencephalogram amplitude
Figure 3.5 Alpha wave amplitude in baseline EEG
The result in Figure 3.5 shows alpha wave amplitude in the EEGbetween two groups (p<0.001) In particular, alpha wave amplitude in theschizophrenia group was significantly lower than in control group inmost regions of brain cortex
Trang 14Figure 3.6 Delta wave amplitude in baseline EEG
The Table in Figure 3.6 shows the difference of delta waveamplitude in the background EEG between two groups (p<0.001) Themost differences of delta wave amplitude were in prefrontal, frontal,parietal, occipital, and temporal region
Figure 3.7 Theta wave amplitude in baseline EEG
Figure 3.7 shows the difference of theta wave amplitude in theEEG between two groups (p<0.001) The most differences of theta waveamplitude were in frontal and occipital region on both sides
3.3.3 Electroencephalogram frequency
Trang 15Figure 3.8 Alpha wave frequency in baseline EEG
The result in Figure 3.8 showed that there was no difference in thealpha wave frequency between two groups
Figure 3.9 Delta wave frequency in baseline EEG
The result in Figure 3.9 shows that there was no difference in deltawave frequency in background EEG between two groups
Trang 16Figure 3.10 Theta wave frequency in baseline EEG
The result in Figure 3.10 shows that there was no difference intheta frequency in background EEG between two groups
3.3.4 Relationship of energy property and hallucinations
Figure 3.11 Relationship between alpha wave energy property and
hallucinations in patients with schizophrenia
The result in Figure 3.11 shows that alpha wave energy property inschizophrenic patients with hallucinations was higher than inschizophrenic patients without hallucinations (p<0.001)
Figure 3.12 Relationship between delta wave energy property and
hallucinations in patients with schizophrenia
The result in Figure 3.12 shows that delta wave energy property inschizophrenic patients with hallucinations was higher than inschizophrenic patients without hallucinations (p<0.001)
Trang 17Figure 3.13 Relationship between theta wave energy property and
hallucinations in patients with schizophrenia
The result in Figure 3.13 shows that theta wave energy property inschizophrenic patients with hallucinations was higher than inschizophrenic patients without hallucinations (p<0.001)
3.3.5 The relationship between amplitude and hallucinations
Figure 3.14 Relationship between alpha wave amplitude and
hallucinations in patients with schizophrenia
The result in Figure 3.14 shows that alpha wave amplitude inschizophrenic patients with hallucinations was higher than inschizophrenic patients without hallucinations (p<0.001)