BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. Part І. THE CONSEQUENCES OF IRRADIATION OF THE PARTICIPANTS OF THE LIQUIDATION OF THE CHORNOBYL ACCIDENT. / GOLOVNYI MOZOK TA ORGAN ZORU IaK POTENTsIINI MIShENI DLIa VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa. Chastyna I. TsEREBROOFTAL'MOLOGIChNI EFEKTY OPROMINENNIa V UChASNYKIV LIKVIDATsIÏ NASLIDKIV AVARIÏ NA ChAES.

BACKGROUND: Exposure to ionizing radiation could affect the brain and eyes leading to cognitive and vision impairment, behavior disorders and performance decrement during professional irradiation at medical radiology, includinginterventional radiological procedures, long-term space flights, and radiation accidents. OBJECTIVE: The objective was to analyze the current experimental, epidemiological, and clinical data on the radiation cerebro-ophthalmic effects. MATERIALS AND METHODS: In our analytical review peer-reviewed publications via the bibliographic and scientometric bases PubMed / MEDLINE, Scopus, Web of Science, and selected papers from the library catalog of NRCRM - theleading institution in the field of studying the medical effects of ionizing radiation - were used. RESULTS: The probable radiation-induced cerebro-ophthalmic effects in human adults comprise radiation cataracts,radiation glaucoma, radiation-induced optic neuropathy, retinopathies, angiopathies as well as specific neurocognitive deficit in the various neuropsychiatric pathology including cerebrovascular pathology and neurodegenerativediseases. Specific attention is paid to the likely stochastic nature of many of those effects. Those prenatally and inchildhood exposed are a particular target group with a higher risk for possible radiation effects and neurodegenerative diseases. CONCLUSIONS: The experimental, clinical, epidemiological, anatomical and pathophysiological rationale for visualsystem and central nervous system (CNS) radiosensitivity is given. The necessity for further international studieswith adequate dosimetric support and the follow-up medical and biophysical monitoring of high radiation riskcohorts is justified. The first part of the study currently being published presents the results of the study of theeffects of irradiation in the participants of emergency works at the Chornobyl Nuclear Power Plant (ChNPP).

NEUROPSYCHOBIOLOGICAL MECHANISMS OF AFFECTIVE AND COGNITIVE DISORDERS IN THE CHORNOBYL CLEAN-UP WORKERS TAKING INTO ACCOUNT THE SPECIFIC GENE POLYMORPHISMS. / NEIROPSYKhOBIOLOGIChNI MEKhANIZMY AFEKTYVNYKh I KOGNITYVNYKh ROZLADIV V UChASNYKIV LIKVIDATsIÏ NASLIDKIV AVARIÏ NA ChORNOBYL'S'KII AES Z URAKhUVANNIaM POLIMORFIZMU GENIV.

Relevance of the present work is determined by the considerable prevalence of both affective and cognitive disor-ders in the victims due to the Chornobyl accident, the pathogenesis of which is insufficiently studied.Objective is to identify the neuropsychiobiological mechanisms of the formation of the remote affective and cog-nitive disorders following exposure to ionizing radiation taking into account the specific gene polymorphisms.Design, object and methods of research. The retrospective and prospective cohort study with the external andinternal control groups. The randomized sample of the male participants in liquidation of the consequences of theaccident (Chornobyl clean-up workers, liquidators) at the Chornobyl nuclear power plant (ChNPP) in 1986-1987(n = 198) recruited from the Clinico-epidemiological registry (CER) of NRCRM aged 39-87 (M ± SD: 60.0-8.5 years)with the external irradiation dose ranged 0.6-5900.0 mSv (M ± SD: 456.0 ± 760.0 mSv) was examined. The compar-ison group (n = 110) consisted of the unexposed patients of the Radiation Psychoneurology Department with thecorresponding age and sex (the external control group). The internal control group included the liquidators irradi-ated at doses < 50.0 mSv (n = 42). The standard diagnostic neuropsychiatric scales, psychodiagnostic questionnairesand tests, neuropsychological methods (including the Wechsler Adult Intelligence Scale (WAIS) with premorbid IQ(pre-IQ) assessment), neuropsychiatric and psychophysiological methods (quantitative EEG (qEEG) and the audito-ry cognitive evoked potentials (Event-Related Potentials, ERP) were applied. The genotypes of the serotonin trans-porter gene SLC6A4 were determined by the 5_HTTLPR and rs25531 polymorphisms. The methods of descriptive and vari-ation statistics, non-parametric criteria, regression-correlation analysis, survival analysis by Kaplan - Meier and riskanalysis were used.Results. Cerebrovascular diseases, organic mental and depressive disorders, mainly of radiation-stress-relatednature, prevail among the liquidators. The overall risk of neuropsychiatric pathology increases (Pv < 0.001) with theirradiation dose. The verbal memory and learning are impaired, as well as the full IQ is reduced at the expense of theverbal one. The frequency of both mild cognitive impairment and dementia is risen. The cognitive impairment atdoses > 0.3 Sv is dose-dependent (r = 0.4-0.7; p = 0.03-0.003). Affective disorders (depression) and neurocogni-tive deficit are more severe at higher doses of irradiation (> 50 mSv). In the left posterior temporal region(Wernicke's area) the qEEG indices changes become dose-dependent at doses greater than 0.25-0.3 Sv. The dis-turbed brain information processes lateralized to the Wernicke's area are observed even at doses > 50 mSv. The car-riers of intermediate and low-level genotypes (LА/S, LА/LG, LG/LG, LG/S, S/S) of the serotonin transporter gene SLC6A4have more depressive disorders, especially severe ones, and tend to have more frequent and severe cognitive andstress-related disorders.The debut of depressive disorders in the carriers of the intermediate and low-activity genotypes occurs much earli-er (Log-Rank Test = 4.43, p = 0.035) in comparison with the carriers of the high-performance genotype LА/ LА.Conclusions. The radiation-induced dysfunction of the cortico-limbic system in the left dominant hemisphere ofthe human brain with a specific involvement of the hippocampus is considered to be the key cerebral basis of post-radiation organic brain damage. The association of genotypes by 5_HTTLPR and rs25531 polymorphisms of the SLC6A4gene with affective and cognitive disorders suggests the presence of neuropsychobiological features of these dis-orders associated with ionizing radiation depending on the certain gene polymorphisms.

Social and psychological state of the Chornobyl clean up workers. Risk factors for negative changes. / SOTsIAL'NO PSYKhOLOGIChNYY̆ STAN UChASNYKIV LNA NA ChORNOBYL'S'KIY̆ AES. FAKTORY RYZYKU NEGATYVNYKh ZMIN.

It is generally recognized that the Chornobyl nuclear accident caused strong psychosocial stress affecting the entire population of Ukraine, primarily people involved in recovery operations. But what are the reasons? What is the struc ture of stressors? What are their social, medical and biological consequences, what are strategy and preventive meas ures? Issues that require special research and development. OBJECTIVE: To study social and psychological state of the Chornobyl cleanup workers 1986-1987, and to determine regularities of changes and dangerous risk factors. MATERIALS AND METHODS: On the basis of Polyclinic of Radiation Registry, NRCRM, we conducted sample epidemiolog ical study of social and psychological state of the Chornobyl clean up workers 1986-1987. We used method of inter viewing based on «questionnaire¼, specially developed for this purpose. The study was conducted in October 2013 - May 2015. The sample numbered 235 males aged 18-50 at the time of the accident. Their average age was (31.3 ± 5.3) years at the time of the accident and (58.9 ± 5.3) at the time of survey. RESULTS: The results revealed that the Chornobyl nuclear accident and its consequences caused strong social and psychological stress among clean up workers 1986-1987. We have identified a set of factors closely related to the Chornobyl accident, they have caused a sustainable development of mental syndrome - «Anxiety about their own health and the health of family members, especially children¼. The other set of stressors which are not closely relat ed to the Chornobyl accident but are the result of the social and economic, social and political situation in the coun try. However the former was found to be the cause of such a psychological state as «dissatisfaction with the com pleteness and quality of life¼. CONCLUSIONS: Social and psychological state of the Chornobyl clean up workers 1986-1987 is estimated as «poor¼ and it integrally can be characterized as a state of chronic psychosocial stress. Mental syndrome «Anxiety about per sonal health and the health of family members¼ and psychological syndrome «Dissatisfaction with living condi tions¼ are main consequences of this state. We identified the main stressors closely related to the consequences of the Chornobyl accident as well as those that are not related to the accident but affect profoundly the level of men tal, social and physical well being. Results of the research are of great importance in organization and provision of social, medical and antiradiation protection of population under emergency situations involving radiation exposure. Key words: Chornobyl accident, clean up workers, social and psychological state, risk factors.

TERF1 and TERF2 downregulate telomere length in cognitive deficit at the late period after low-dose exposure. / Negatyvna reguljacija dovzhyny telomer genamy TERF1 ta TERF2 pry kognityvnomu deficyti u viddalenomu periodi pislja oprominennja u malyh dozah.

Purpose - to explore the role of radiation dose on gene regulation of telomere length and its influence on the patho-genesis of cerebrovascular neurocognitive deficit at the remote period of low-dose irradiation as a result of the Chornobyl accident. Materials and methods. We performed a study of TERF1, TERF2 and TERT genes expression (GE) by RT-PCR, and relative telomere length (RTL) by flow-FISH in 258 clean-up workers of Chornobyl accident divided by radiation dose groups (range 22-2800 mSv) and 78 controls with vascular cognitive deficit. Detailed psychometric interviews were performed to obtain quantitative data on the stage of cognitive deficit. Results. Statistically significant telomere shortening was demonstrated in groups of clean-up workers with radiation doses in 100-250 mSv and 250-500 mSv range (subsequently M ± SD: 15.85 ± 0.27; p< 0.02; 15.89 ± 0,33; p< 0.02; control: 17.21 ± 0,23). A decrease in RTL was in parallel to radiation dose increase and overexpression of negative telomere length regulators: TERF2 genes and, to a lesser extent TERF1; the opposite tendency was demonstrated for TERT GE. In exposed over 500 mSv a significant TERT overexpression was combined with decreased TERF1 and TERF2 GE, and absence of significant RTL changes in comparison with clean-up workers exposed to lower doses indicating a certain independency between gene expression and telomere length changes and possible threshold effects at this dose range. Analysis of the group of exposed in comparison with non-exposed demonstrated a significant decrease (p = 0.03) both of the mean MMSE and RTL parameters suggesting influence of previous exposure. Conclusion. This study shows parallel changes in decline of cognitive function and telomere length and differences in TERF2, TERT and TERF1 gene regulation at the late period after low dose and over 500 mSv exposure.

Depression and ionizing radiation.

The objective of this at issue paper is the analysis of published data in correlation with the results of own research on the potential role of ionizing radiation in the genesis of depressive disorders. Depression is one of the most significant and long-term effect of the atomic bombings, nuclear testing and radiation emergences. The participants of the accident at the Chornobyl nuclear power plant increased prevalence of depression (18.0% and 13.1% in controls) and suicide rates. Depression is mainly observed in the structure of an organic mental disorder against cerebrovascular disease. The clinical pattern is dominated by asthenoadynamic and asthenoapathetic depression. Depressive disorders in radiation emergencies are multifactorial, that is the result of exposure to the complex psychogenic and radiological accident's factors, impact of traditional risk factors, somatic and neurological diseases, genetic predisposition, predisposition, etc. At the same time, exposure to ionizing radiation is a factor in the genesis of depression. This impact can be direct (to the Central Nervous System), and indirectly through the somatic and neurological abnormalities (multiorgan dysfunction) as well as by a variety of pathogenic mechanisms of ionizing radiation on the brain that have been discovered recently. It is strongly necessary analytical clinical and epidemiological studies with verification of depression and evidence-based establishment of the role of radiation and non-radiation risk factors.

EEG patterns in persons exposed to ionizing radiation as a result of the Chernobyl accident: part 1: conventional EEG analysis.

Prospective conventional EEG study was carried out 3-5 and 10-13 years after the Chernobyl accident (1986) in patients who had acute radiation sickness and in emergency workers in 1986 ("liquidators"). Control groups comprised healthy volunteers; veterans of the Afghanistan war with posttraumatic stress disorder; veterans with mild traumatic brain injury; and patients with dyscirculatory encephalopathy. In 3-5 years after irradiation, there were irritated EEG changes with paroxysmal activity shifted to the left frontotemporal region (cortical-limbic overactivation) that were transformed 10-13 years after irradiation toward a low-voltage EEG pattern with excess of fast (beta) and slow (delta) activity together with depression of alpha and theta activity (organic brain damage with inhibition of the cortical-limbic system). Quantitative EEG is likely to be very informative for investigation of dose-effect relationships.

Schizophrenia spectrum disorders in persons exposed to ionizing radiation as a result of the Chernobyl accident.

We studied schizophrenia spectrum disorders in Chernobyl accident survivors by analyzing Chernobyl exclusion zone (EZ) archives (1986-1997) and by conducting a psychophysiological examination of 100 patients with acute radiation sickness (ARS) and 100 workers of the Chernobyl EZ who had worked as "liquidators-volunteers" for 5 or more years since 1986-1987. Beginning in 1990, there has been a significant increase in the incidence of schizophrenia in EZ personnel in comparison to the general population (5.4 per 10,000 in the EZ versus 1.1 per 10,000 in the Ukraine in 1990). Those irradiated by moderate to high doses (more than 0.30 Sv or 30 rem), including ARS patients, had significantly more left frontotemporal limbic and schizophreniform syndromes. We hypothesized that ionizing radiation may be an environmental trigger that can actualize a predisposition to schizophrenia or indeed cause schizophrenia-like disorders. The development of schizophrenia spectrum disorders in overirradiated Chernobyl survivors may be due to radiation-induced left frontotemporal limbic dysfunction, which may be the neurophysiological basis of schizophrenia-like symptoms. Persons exposed to 0.30 Sv or more are at higher risk of schizophrenia spectrum disorders. An integration of international efforts to discuss and organize collaborative studies in this field is of great importance for both clinical medicine and neuroscience.

EEG, cognitive and psychopathological abnormalities in children irradiated in utero.

Computerised EEG, a clinical neuropsychiatric examination, and IQ tests were examined in 50 randomly selected prenatally irradiated 9-10-year-old children and compared with 50 randomly selected non-exposed control children of the same age. In the prenatally irradiated children a disorganised EEG-pattern with slow and paroxysmal activity (acute and high-voltage delta-waves, sometimes: spike-waves) in the left fronto-temporal region was disclosed. There was also a significant predominance of delta- and beta (dominant frequency: 20 Hz)-power in the frontal lobe, particularly, in the left fronto-temporal region, together with depressed spectral theta-power. The more disorganised EEG-patterns were observed in those children exposed at 8-15 weeks of prenatal development, while left-hemisphere abnormalities were more typical for those exposed later at 16-25 weeks of gestation. There was also a significant increase of borderline and low range (70-90) IQ scores and a significant decrease of high verbal (> 110) IQ scores. Disorders of psychological development, particularly specific developmental disorders of speech, language, and scholastic skills were more common and correlated with left-sided slow- and fast-wave activity. Behavioural and emotional disorders (social estrangement, exhaustion, emotional lability, tearfulness, apathy) were also more common and associated with a L > R imbalance in arousal. We hypothesise that the cerebral basis of mental disorders in the prenatally irradiated children is the malfunction of the left hemisphere limbic-reticular structures, particularly in those exposed at the most critical period of cerebrogenesis (16-25 weeks of gestation). We propose that the left hemisphere is more vulnerable to prenatal irradiation than the right.

Psychophysiologic aftereffects of prenatal irradiation.

Prenatally irradiated children (n = 544), who were born between 26 April 1986 and 26 February 1987, in regions of the Ukraine which were radioactively contaminated as a result of the Chernobyl disaster, their mothers and teachers have been examined with psychometric tests. The control group of relevant children (n = 759), their mothers and teachers, were living at the radioecological 'clear' regions (Kharkov and Kharkov Region). Further, we randomly selected 50 prenatally irradiated children whose mothers were evacuated from the Chernobyl exclusion zone and 50 age-and-gender-matched non-exposed children. At this phase clinical examinations, psychometric tests, computerized EEG, thyroid function assessment and dosimetric reconstruction were used. We found a significant increase in mental retardation (IQ < 70) and of borderline and low range IQ, as well as emotional and behavioral disorders and a decrease in high IQ (IQ > 110) in children irradiated in utero as a result of the Chernobyl disaster, in comparison with the controls. One important biological mechanism in the genesis of mental disorders in prenatally irradiated children is the radiation-induced malfunction of the thyroid-pituitary system with the effect threshold of 0.30 Sv of thyroid exposure dose. We hypothesize that the cerebral basis of mental disorders in the prenatally irradiated children is the malfunction of the left hemisphere limbic-reticular structures, particularly in those exposed at the most critical period of cerebrogenesis (8-25 weeks of gestation). The data obtained reveal mental disorders in prenatally irradiated children and obviously reflect developmental abnormalities of brain structure and function as a result of the interaction of prenatal and post-natal factors where it is possible to assume radiation effects on the developing brain. A follow-up study of the children irradiated in utero, who may be at risk for schizophrenia, is proposed because of its particular importance to clinical medicine and neuroscience.