INTRODUTION
Catechol-O-methyl transferase (COMT) is an enzyme that plays a significant role in the metabolism of dopamine (DA) and amounts to approximately 60% or more of DA breakdown in the frontal cortex . The gene expressing the COMT enzyme could affect cognition and functioning of the brain via its action on dopaminergic function. A polymorphic variation occurs in the coding area of the COMT gene (a Guanine to Adenine replacement), changing the amino acid from valine (Val) to methionine (Met) at the codon position 158 (Val158Met) and consequently influencing the thermal tolerance and stability of the enzyme. Allelic discrepancies in enzyme function lead to lower DA activity in Val carriers. The homozygous variation Methionine allele causes production of an enzyme with low activity, leading to higher DA concentrations relative to individuals harboring the homozygous variation in amino acid Valine or the heterozygous Val/Met variation. These studies demonstrate that this variation contributes to majority of the discrepancies in COMT activity . In humans, a lot of attention from the scientific community has been steered towards COMT, with regards to the genetic vulnerability to disorders such as depression, anxiety, schizophrenia and deficiencies in cognitive roles in the brain. Many studies have targeted COMT gene, since the protein is produced at a high a levels in sections of the brain that play a role in cognitive functioning and emotional processing, such as limbic regions and prefrontal cortical region .
The influence of the COMT genetic profile on EEG recording in postmenopausal normal women is not clear . Women older than 50 years display a substantial reduction in serum concentrations of estrogens that generate considerable physiological action. The dopaminergic system exerts its influence on the striatum estrogen activities and functions as a multifaceted chemical messenger in the brain, which can communicate with the neurotransmitter molecules in the crucial brain nuclei and enhance the neuronal role in the brain, as mediated through expression of genes and ion channels guarded by transmitters . It has been demonstrated that estrogen controls the COMT promoter function. The COMT promoter comprises of two estrogen response elements occurring in the promoter and physiological levels, estrogen suppresses COMT expression levels in cells presenting the estrogen receptors . The estrogen-controlled reduction in COMT expression is supplemented by a reduction in COMT activity). This negative control by estrogens is agreement with the data in literature that women possessing high estrogen levels exhibit a higher level of COMT functioning relative to those women possessing low concentrations of estrogens. Relative to men, women present a higher intensity of fluorodopa uptake [18F] in the striatum, indicating a large amount of presynaptic DA production and a lesser affinity for D2 receptor that represents increased DA concentrations and greater level of internalization of the DA carrier . However, EEG research studies on COMT function have failed to take into consideration, the estrogenic condition that includes or menstrual cycle or menopausal status and may be an important contributing factor. DA processes may especially make sense in the prefrontal role in middle aged women that exhibit lower concentrations of estrogen.
Owing to the variable regional expression profile of COMT in human brain autopsies, the Val158Met polymorphic variation is considered to regulate dopaminergic neurotransmission, predominantly in the prefrontal cortex . However, it is relatively unclear, if the variable production of COMT alters the resting-condition EEG regional influence in case of postmenopausal normal women. The aim of this study was to investigate into the actions of the Val158Met substitution in COMT on EEG functioning in the frontal area of the brain, which is linked to primary physiological roles such as logical reasoning, self-control, planning, abstract emotions and memory. Another objective of the researchers was to evaluate whether the COMT gene profile also influences the EEG activity in other regions of the brain such as the parietal region, related to, sensory, attention, verbal and visual mechanisms, and the midline area, which plays a considerable role in cognitive growth and attention. This study proposed that the resting-condition EEG power bands in the various regions in the shut eyes and open eyes conditions would vary based on the COMT genetic make-up in postmenopausal normal women .
METHODS
Subjects
This study enrolled 24 normal and normal postmenopausal women volunteers in the age group of 48 to 65 years of age, with healthy uteruses, of which 11 were homozygous for Met/Met variation and 13 were homozygous for Val/Val polymorphism. The subjects were examined in one single session of one hour by a trained individual .
Genetic Profiling
Genomic DNA was derived from blood leukocytes with the help of standard methods. A polymorphic site occurring in a small region of exon 4 was augmented by PCR. The PCR yield products were treated for digestion at 37°C overnight and electrophoresed on an agarose gel of composition 4%, and stained using the ethidium bromide dye. The two anticipated digestion products; a 114 bp in length of Val/Val genetic profile, and a 96 bp in length of Met/Met genetic profile were analyzed .
EEG Data
All EEG analysis was performed during one hour and participants were asked to rest securely and rest chin on a given platform. The period of response comprised of a 3 min phase each with shut and open eyes. EEG reactions and movements of the eye were documented by appropriately implanting electrodes. All bands of resting EEG power in the various areas of frontal, parietal and midline cortical regions, were analyzed to determine whether there were any genotype-based differences between homozygous Valine and Methionine carriers .
Statistical Analysis
STATISTICA was utilized for statistical analyses. The statistical confidence of the analysis was validated using a specific mode in STATISTICA. Two-tailed tests with were performed to examine a standardized action size of 10% between the two categories of subjects .
Prior to statistical analysis, the data was examined for a normal distribution by employing the Levene’s test . A Mann-Whitney U-test was utilized to comparatively analyze the demographic properties between the homozygous Val genotype and homozygous Met genotype in COMT genotypes, since these variables did not follow the normal distribution. The factorial ANOVA 2 × 3 design was employed to study group variations and discrepancies in the shut and open eyes situations. Substantial interactions were recorded using separate ANOVAs and supplement contradictions were quantified to justify the properties of significant effects. η2 values were documented in every ANOVA test. as the extent of effect and the level of significance established, was at p less than 0.05 .
RESULTS
Properties of participants
COMT genetic profile did not digress from Hardy-Weinberg equilibrium . The subjects with Val/Val and Met/Met profiles did not vary significantly in terms of parameters such as level of education, height, body mass index (BMI), age at menarche, years of menopause, pregnancy-associated factors, systolic and diastolic arterial tensions. Age was inclined to be on the higher side in the Met/Met category of patients.
Interactions
The communication between genotypes and bands was considerably significant. Univariate findings showed that Met homozygous subjects presented higher values of certain waves relative to the individuals that possessed the Val/Val genotype, while certain bands did not substantially vary across genotypes. The interaction of between genotype and region was not significant, suggesting that the EEG strength in the different areas was not influenced by interactions between genotypes, as reflected by the interaction between genotypes and region .
DISCUSSION
The results of this study reveal the repercussions of the polymorphism in COMT at Val158Met location on resting-state EEG status in both shut and open eyes conditions in normal women . The primary result of this study was a statistically significant association amid COMT genotypes and EEG spectrum. The characterization of this interaction indicated that Met homozygous women presented higher intensities of delta, theta and beta1 activity relative to homozygous Val/Val women, revealing a considerable effect of genotypes. Further analysis revealed that women harboring the Met/Met profile, who had higher DA at the synaptic location presented amplified power in spectrum: delta was elevated in the eyes-shut status, theta value elevated in both open and shut eye situations, and alpha1 was raised in the open eyes status.
Intriguingly, no Genotype by Region interaction was detected suggesting that EEG regulation in the resting condition in the various regions of the human brain was not influenced by communications between genotypes . The absence of these COMT actions on EEG regional control may be attributed to owing to the of lack of sensitivity or statistical control to diagnose an action. The findings of this study are partially in accordance to the study that evaluated the consequence of the COMT genotypic profiles on activation of BOLD in the process of execution of a working memory assignment that included male and female normal participants .
The EEG in resting condition is an ever-changing indicator of cortical stimulation and is, hence, regarded as a transitional profile for many actions wherein arousal is concerned . Some critical associations could be derived from the possible effects of resting- condition EEG status on the behavioral, psychological and cognitive modifications and entail further investigation. For instance, larger absolute control of bands has been linked to cortical inhibitory mechanisms and increased theta and alpha bands have been shown in Met genetic form individuals with schizophrenia and in patients suffering from attention-deficit/hyperactivity disorder relative to healthy subjects. High intensity of fast activity has been linked to arousal, anxiety and emotional activity and depression in females. Although the situation of the participants was not quantified, the authors noted a substantial increase in observed alpha2 and beta1waves control in subjects with the homozygous Met profile relative to women that harbored Val/Val profile, which may represent arousal. Prospective studies on the COMT genotype and EEG activity should take into consider the results in the context of emotional condition of the participants .
References
Ortiz, S. (2015). Modulation of the COMT Val158Met polymorphism on resting-state EEG power. Frontiers in Human Neuroscience, 9 (136): 1-8.
Stokes, P. R. (2011). The effects of the COMT Val108/158Met polymorphism on BOLD activation during working memory, planning and response inhibition: a role for the posterior cingulate cortex? Neuropsychopharmacology, 36, 763–771.
