Clinical Neuropsychiatry (2014) 11, 2, 61-67

Psychiatric effects of ionizing radiation Donatella Marazziti, Stefano Baroni, Amedeo Lombardi, Valentina Falaschi, Stefano Silvestri, Armando Piccinni, Federico Mucci, Liliana Dell’Osso

Abstract Radiation exposure leads to an increased risk for cancer and also atherosclerotic, cardiovascular, cerebro-vascular and neurodegenerative effects. Different data would indicate that radiation-induced neurodegeneration is a multifactorial process involving several all types with oxidatively-stressed mitochondria being a recurring element. With the present paper we aim to present a comprehensive review on brain effects of radiation exposure, with a special focus on their possible role in the pathophysiology of different psychiatric disorders. Key words: ionizing radiation, neurogenesis, hippocampus, brain areas, psychiatric disorders Declaration of interest: none Donatella Marazziti, Stefano Baroni, Amedeo Lombardi, Valentina Falaschi, Stefano Silvestri, Armando Piccinni, Federico Mucci, Liliana Dell’Osso Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa Corresponding author Donatella Marazziti, MD Phone: +39 050 2219879; Fax: +39 0502219787 e-mail: [email protected]

Introduction Ionizing radiation (IR) is a radiation with enough energy so that during an interaction with an atom, it can remove tightly bound electrons from the orbit of an atom, causing the atom to become charged or ionized. The fact that these radiations are ionizing allows them to be detected and discriminated from other forms of radiation (such as infra-red or radiowaves). Ionizing radiation is present in three varieties: α (alpha) particles, β (beta) particles, and γ (gamma) rays. All these forms of radiation are energetic enough to remove electrons from atoms. Alpha particles are strongly ionizing, but can be stopped by paper or skin. They have a strong positive charge (+2) and a mass of 4. One alpha particle can ionize 10,000 atoms. However, because it puts all its energy into ionizing others, it very quickly runs out of energy itself. Hence, alpha particles cannot penetrate through much. Beta particles are electrons, but they are called beta particles to identify that they come from the nucleus of the atom; these particles are also strongly ionizing (perhaps 1 beta particle will cause 100 ionizations). Gamma rays are very poor at ionizing (about 1 to 1), but they are very difficult to stop and are very penetrating. Therefore, gamma emission accompanies most emissions of beta or alpha particles. In eukaryotic cells, ionizing radiation induces damages to proteins, lipids and DNA, directly or indirectly, as a result of free radical formation. Cell signaling events in response to IR depend on environmental conditions occurring during DNA repair, besides genetic and physiological features of the biological systems (United Nations Scientific Committee on the Effects of Atomic Radiation 2008; Food and Drug Administration 2010). Submitted February 2014, Accepted March 2014 © 2014 Giovanni Fioriti Editore s.r.l.

Medical radiation from x-rays and nuclear medicine is the largest manmade source of radiation exposure in Western countries, accounting for a mean effective dose of 3.0 mSv per capita per year, similar to the radiologic risk of 150 chest x-rays (Picano 2004; President’s Cancer Panel 2010). About 30 million workers are professionally exposed to radiation, and of these the interventional fluoroscopists (cardiologists and radiologists) are amongst the most exposed. In fact, their annual exposure is equivalent to 5 mSv per year which would lead to a projected lifetime attributable excess cancer risk of 1 in 100 (United Nations Scientific Committee on the Effects of Atomic Radiation 2008; Venneri et al. 2009). This explains the increasing interest of scientific community on cancer and noncancer, including brain effects of radiation exposure. The effects can be clustered in low dose effects (1 Sv or 1 Gy) exposures, of particular interest in radiotherapy (Annals of the Institute for International Research on Criminal Policy 2012). Currently, the majority of the data are those regarding radiotherapy dose range, while just a few information is available on the moderate-to-low dose range, that probably is where we need them most (Picano and Vano 2011). Therefore, there is a great need for exploring what and if low/moderate doses may provoke any dangerous effect, especially on the brain which is now recognized one of the main dose-limiting organs in radiotherapy (Tofilon and Fike 2000).  Given the high number of

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occupationally exposed workers and the high and rising number of interventional radiology and CT procedures, totalling millions each year, this subject becomes of key scientific and social relevance (Komasa et al. 2013). Therefore, the aim of the present paper was to review the main literature on psychiatric effects of IR, while highlighting the special needs in the field, especially in terms of data gathering and possible prevention of detrimental effects.

Psychiatric effects of high doses of IR In the studies evaluating the effects of total cranial irradiation on cognition and emotions, IR was demonstrated to provoke cognitive deficits in exposed individuals, especially during childhood and adolescence. However, the relatively short follow-up time ( 500 mGy groups. Another study described that an increased proportion of white female radiologic technicians experience death from AD, as compared with workers in other occupations (Schulte et al. 1996). In a study of female workers from 12 US nuclear weapon plants, an unexpected increased mortality from mental disorders was detected (Wilkinson et al. 2000). The most common diagnosis was dementia, which accounted for 91, out of the total of 166 deaths from mental disorders. In a nested case-control study within a pooled cohort of 67,976 female nuclear workers, the total lifetime radiation doses (consistently less than 100 mSv, and often in the 10 mSv range) were associated with an odds ratio of 2.1 (95% CI=1.02, 4.29) for death from dementia (Sibley et al. 2003). These results are consistent with Russian reports of cognitive impairments following occupational radiation exposures in clean-up workers following the accident at Chernobyl (Zhavoronkova et al. 1997, Ponomarenko et al. 1999, Loganovsky and Loganovskaja 2013). Associations between occupation and neurodegenerative diseases was also reported, with the highest mortality odds ratio for presenile dementia in dentists, for Parkinson’s disease (PD) in biological scientists, and for motor neuron diseases in veterinarians – all categories exposed to various environmental toxicants, including IR (Park et al. 2005). Non significant increased risks were reported for health diagnostic practitioners, and decreased for radiological technicians (Park et al. 2005). Children are a particular target group with high sensitivity for the correlation of radiation and neurodegenerative diseases: they have still an immature brain and a long-life expectancy allowing radiationinduced effects with a prolonged latency to develop. A further group available to study the long-term effects of moderate doses of IR and its effects on the central nervous system is represented by children who received X radiation to treat ringworm on the scalp (Tinea capitis) (Schulz and Albert 1968). Recently, a mortality analysis was published gathered from amongst 11,311 former US flight attendants, exposed to cosmic radiation, including IR, up to 10 mSv per year (Pinkerton et al. 2011). Cosmic radiation is quantitatively different from terrestrial IR and consists primarily of charged particles and neutrons, with neutrons contributing 40-60% of the dose equivalent at average flight altitude (Goldhagen 2000). The ensuing findings showed an elevated mortality for alcoholism, drowning and interventional self-harm among women and an increased, albeit non significantly, mortality for mental psychoneurotic and personality disorders (Standardized mortality ratio=1.39; 95% CI, 0.88-2.08). Amongst female flight attendants, a non significantly 19% increase in mortality from suicide was also observed (Zeeb et al. 2010). Taken together, these data all collected for a cumulative, documented or estimated, dose exposure in the low-to-moderate dose range (from 10 to 500 mSv) are not reassuring, especially in view of the already-mentioned data suggesting that moderate dose (500 mSv) in adult mice can substantially impair hippocampal neurogenesis, which is important for memory, learning, stress response and mood regulation (Silasi et al. 2004). Neural stem cells are highly sensitive to radiation even at chronic, moderate doses. Moreover, repetitive fractionated exposure (more closely mirroring the model of professional exposure) seems to provoke several more pronounced effects on cellular signalling and neurogenesis than acute exposure. Clinical Neuropsychiatry (2014) 11, 2

Pathophysiology The IR-related brain injury does not occur as a single, immediate event. It is considered a dynamic and multiphasic process occurring over time, characterized by pathological changes of vessels and myelin, resulting in vascular damage, white matter injury and coagulation necrosis (Calvo et al. 1988, Reinhold et al. 1990, Van Der Maazen et al. 1993, Hopewell and Van Der Kogel 1999, Tofilon and Fike 2000, Belka et al. 2001, Brown et al. 2007). In terms of pathophysiology, in vitro findings showed that IR can lead to neuronal death (Enokido et al. 1996, Gobbel et al. 1998). Moreover, in vivo studies, carried out in animals, reported significant brain damage following IR. Histological changes, as well as cognitive functions, were investigated in the brain of 20 Fischer 344 rats aged 6 months treated with whole brain irradiation. In parallel to cognitive functions impairment, as revealed by the water maze task and the passive avoidance task, a relevant brain damage was reported, in particular demyelination, in some cases accompanied by necrosis in the corpus callosum and the parietal white matter close to the corpus callosum. The brain areas without necrosis were, however, characterized by decreased myelin basic proteins, alterations of neurofilaments and increased glial fibrillary acidic proteins with gliosis. These histological alterations of the brain structures after IR were similar to those found in neurodegenerative conditions such as Alzheimer’s disease, Binswanger’s disease and multiple sclerosis (Akiyama et al. 2001). The occurrence of neuroinflammation has been found to be a significant component of the brain response to IR (Tofilon and Fike 2000, Monje and Palmer 2003). In fact, an increased number of activated CD68-expressing microglia has been reported after IR, so that it has been hypothesized that this might contribute to the alteration of the neurogenesis and to the hippocampal damage often described in animal models. The hippocampal granule cell layer, which are those capable to regenerate, has been found to be injured by RT, even at lower doses than those believed to damage glial cells or neurons (Monje 2002, Monje and Palmer 2003, Hartung et al. 2011). There is now convincing evidence that inhibition of adult neurogenesis in the dentate gyrus of the hippocampus affects learning and memory. In particular, the memory linking past events to the context seems to be very sensitive to a reduction of the neurogenesis (Winocur et al. 2006, Wojtowicz et al. 2008, Hernandez-Rabaza et al. 2009). In some studies, the negative effect of RT on hippocampal neurogenesis was irreversible (Wojtowicz 2006), while in others a recovery was observed, possibly related to the replication of the neural precursors (Monje et al. 2003, Rola et al. 2004, Ben Abdallah et al. 2007). Significant increase in the incidence of cerebrovascular disease have been demonstrated in a cohort study of nuclear workers employed at the Mayak Production Association (Mayak PA), among workers who received cumulative doses higher than 0.2 Gy, compared with those who received 100 mGy before 18 months”.The crucial point is that, with no doubt, we need more data, especially outside the RT model, as well as in the low-to-moderate dose range. This is particularly relevant for both the scientific and social side due to the high number of patients and professionals involved, taking into account also that the downside of IR is magnified by the relative lack of awareness by doctors and patients of doses and effects of diagnostic IR (Malone et al. 2011). In particular, a challenging model is represented by contemporary interventional cardiologists and radiologists, who may receive a whole body exposure after a professional lifetime around 100 to 200 mSv and a head dose in the range of 1 to 3 Gy, falling well within the range of possible psychological and psychiatric effects. In studying this population of catheterization laboratory professionals, we also need to be aware of the substantial limitations of the epidemiological approach, which requires very large populations followed-up for decades to detect clinically overt risks that can be even of moderate entity (Land 1980). Rather, as suggested by United Nations Scientific Committee on the Effects of Atomic Radiation (2008), we should focus on subclinical endpoints, as well as biomarkers, since this information is more likely to lead to insight. The ideal biomarker is a proximal sign of disease and a long-term predictor of clinical events. In case of psychological disease, the brain-derived neurotrophic factor is directly linked to hippocampal neurogenesis and is reduced in pre-depressive and degenerative conditions (Piccinni et al. 2008, 2008b, 2009; Zuccato and Cattaneo 2009). In Italy, this approach will be used in the Healthy Cath Lab study, promoted by the Italian National Research Council with endorsement of Italian Society of Invasive Cardiologist, and designed by interventional cardiologists for interventional cardiologists. Similar studies are being organized in US and sponsored by National Institute of Health and National Cancer Society (Food and Drug Administration 2010, President’s Cancer Panel 2010). These studies will hopefully produce in the forthcoming years the necessary evidence-base required to answer the unresolved issue of the psychiatric effects of lowto-moderate IR exposure.

References Akiyama K, Tanaka R, Sato M, Takeda N (2001). Cognitive dysfunction and histological findings in adult rats one year after whole brain irradiation. Neurologia Medico Chirurgica (Tokyo) 41, 12, 590-8. Annals of the Institute for International Research on Criminal Policy (IRCP) (2012). Early and late effects of radiation in normal tissues and organs: threshold doses for tissue Clinical Neuropsychiatry (2014) 11, 2

Psychiatric effects of ionizing radiation reactions and other non-cancer effects of radiation in a radiation protection context. (published at ICRP website: www.icrp.org) Arduino DM, Esteves AR, Cardoso SM (2011). Mitochondrial fusion/ fission, transport and autophagy in Parkinson’s disease: when mitochondria get nasty. Parkinson’s Disease 767230. Armstrong C, Ruffer J, Corn B, DeVries K, Mollman J (1995). Biphasic patterns of memory deficits following moderatedose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms. Journal of Clinical Oncology 13, 9, 2263-2271. Armstrong CL, Corn BW, Ruffer JE, Pruit AA, Mollman JE, Phillips PC (2000). Radiotherapeutic effects on brain function: double dissociation of memory systems. Neuropsychiatry Neuropsychology & Behavioral Neurology 13, 101-111. Armstrong CL, Hunter JV, Ledakis GE, Cohen B, Tallent EM, Goldstein BH, Tochner Z, Lustig R, Judy KD, Pruitt A, Mollman JE, Stanczak EM, Jo MY, Than TL, Phillips P (2002). Late cognitive and radiographic changes related to radiotherapy: initial prospective findings. Neurology 59, 40-48. Azimzadeh O, Scherthan H, Sarioglu H, Barjaktarovic Z, Conrad M, Vogt A, Calzada-Wack J, Neff F, Aubele M, Buske C, Atkinson MJ, Tapio S (2011). Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation. Proteomics 11, 3299-3311. Azizova TV, Muirhead CR, Moseeva MB, Grigoryeva ES, Sumina MV, O’Hagan J, Zhang W, Haylock RJ, Hunter N (2011). Cerebrovascular diseases in nuclear workers first employed at the Mayak PA in 1948-1972. Radiatiation and Environmental Biophysics 50, 539-552. Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dorr W, Sarioglu H, Schafer A, Atkinson MJ, Zischka H, Tapio S (2011). Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One 6, e27811. Belka C, Budach W, Kortmann RD, Bamberg M (2001). Radiation induced CNS toxicity-- molecular and cellular mechanisms. British Journal of Cancer 85, 1233-1239. Ben Abdallah NMB, Slomianka L, Lipp HP (2007). A reversible effect of X-irradiation on proliferation, neurogenesis and cell death in the dentate gyrus of adult mice. Hippocampus 17, 1230-1240. Brown WR, Blair RM, Moody DM, Thore CR, Ahmed S, Robbins ME, Wheeler KT (2007). Capillary loss precedes the cognitive impairment induced by fractionated wholebrain irradiation: a potential rat model of vascular dementia. Journal of the Neurological Sciences 257, 6771. Bueler H (2009). Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Experimental Neurology 218, 235-246. Butterfield DA, Reed T, Newman SF, Sultana R (2007). Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radical Biology & Medicine 43, 658-677. Calvo W, Hopewell JW, Reinhold HS, Yeung TK (1988). Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. British Journal of Radiology 61, 1043-1052. DeAngelis LM, Delattre JY, Posner JB (1989). Radiationinduced dementia in patients cured of brain metastases. Neurology 39, 6, 789-796. Duman RS, Heninger GR, Nestler EJ (1997). A molecular and cellular theory of depression. Archives of General Psychiatry 54, 7, 597-606. Eckert A, Schulz KL, Rhein V, Gotz J (2010). Convergence of amyloid-beta and tau pathologies on mitochondria in Clinical Neuropsychiatry (2014) 11, 2

vivo. Molecular Neurobiology 41, 107-114. Elsworth JD, Roth RH (1997a). Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson’s disease. Experimental Neurology 144, 4-9. Elsworth JD, Roth RH (1997b) Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson’s disease. Experimental Neurology 144, 4-9. Enokido Y, Araki T, Tanaka K, Aizawa S, Hatanaka H (1996). Involvement of p53 in DNA strand break-induced apoptosis in postmitotic CNS neurons. European Journal of Neuroscience 8, 1812-1821. Food and Drug Administration (FDA) (2010). Unveils initiative to reduce unnecessary radiation exposure from medical imaging. White paper 9. Fuller Torrey E (1995). Prevalence of psychosis among the Hutterites: A reanalysis of the 1950–53 study. Schizophrenia Research 16, 2, 167-170. Gobbel GT, Bellinzona M, Vogt AR, Gupta N, Fike JR, Chan PH (1998). Response of postmitotic neurons to X-irradiation: implications for the role of DNA damage in neuronal apoptosis. Journal of Neuroscience 18, 147-155. Goldhagen P (2000). Overview of aircraft radiation exposure and recent ER-2 measurements. Health Physics 79, 526544. Greenamyre JT, Hastings TG (2004). Biomedicine Parkinson’s-divergent causes, convergent mechanisms. Science 304, 1120-1122. Hartung H, Tan SK, Steinbusch HM, Temel Y, Sharp T (2011). High-frequency stimulation of the subthalamic nucleus inhibits the firing of juxtacellular labelled 5-HTcontaining neurons. Neuroscience 186, 135-145. Hernandez-Rabaza V, Llorens-Martin MV, Ferragud A, Velazquez-Sanches C, Arcusa A, Gomez-Pinedo U, Perez-Villalba A, Rosello J, Trejo JL Barcia JA, Canales JJ (2009). Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal. Neuroscience 159, 59-68 Hirsch EC (1993). Does oxidative stress participate in nerve cell death in Parkinson’s disease? European Neurolology 33, 52-59. Hopewell JW, Van Der Kogel AJ (1999). Pathophysiological mechanisms leading to the development of late radiationinduced damage to the central nervous system. Frontiers of Radiation Therapy and Oncology 33, 265-275. Iwata Y, Suzuki K, Wakuda T, Seki N, Thanseem I, Matsuzaki H, Mamiya T, Ueki T, Mikawa S, Sasaki T, Suda S, Yamamoto S, Tsuchiya KJ, Sugihara G, Nakamura K, Sato K, Takei N, Hashimoto K, Mori N (2008). Irradiation in adulthood as a new model of schizophrenia. PLoS One e2283. Jenner P (1998). Oxidative mechanisms in nigral cell death in Parkinson’s disease. Movement Disorders 13, Suppl 1, 24-34. Komasa Y, Hasebe AK, Tsuboi M, Jimba M, Kimura S (2013). Prioritizing mental health issues of community residents affected by Fukushima Daiichi nuclear power plant accident. Clinical Neuropsychiatry 10, 6, 241-244. Knott C, Stern G, Wilkin GP (2000). Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Molecular and Cellular Neuroscience 16, 724-739. Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y, Abe K (2011). Progressive neurovascular disturbances in the cerebral cortex of Alzheimer’s disease-model mice: protection by atorvastatin and pitavastatin. Neuroscience 197, 358–368. Land CE (1980). Estimating cancer risks from low doses of ionizing radiation. Science 209, 1197-1203 Licker V, Kovari E, Hochstrasser DF, Burkhard PR (2009). Proteomics in human Parkinson’s disease research. 65

Donatella Marazziti et al. Journal of Proteomics 73, 10-29. Loganovsky KN, Loganovskaja TK (2000). Schizophrenia spectrum disorders in persons exposed to ionizing radiation as a result of the Chernobyl accident. Schizophrenia Bulletin 26, 751-773. Loganovsky KN, Loganovskaja TK (2013). Cortical-limbic neurogenesis asymmetry as possible cerebral basis of brain laterality following exposure to ionizing radiation. Clinical Neuropsychiatry 10, 3/4, 174. Loganovsky KN, Volovik SV, Manton KG, Bazyka DA, FlorHenry P (2005). Whether ionizing radiation is a risk factor for schizophrenia spectrum disorders? The World Journal of Biological Psychiatry 6, 212–230. Malone J, Guleria R, Craven C, Horton P, Järvinen H, Mayo J, O’reilly G, Picano E, Remedios D, Leheron J, Rehani M, Holmberg O, Czarwinski R (2012). Justification of diagnostic medical exposures, some practical issues: report of an International Atomic Energy Agency Consultation. British Journal of Radiology 85, 523-538. Manji HK, Quiroz JA, Payne JL, Singh J, Lopes BP, Viegas JS, Zarate CA (2003). The underlying neurobiology of bipolar disorder. World Psychiatry 2, 3, 136-146. McGeer PL, McGeer EG (2004). Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism & Related Disorders 10, Suppl 1, S3-S7. Mirza B, Hadberg H, Thomsen P, Moos T (2000). The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95, 425-432. Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002). Irradiation induces neural precursor-cell dysfunction. Nature Medicine 8, 955-962. Monje ML, Palmer T (2003). Radiation injury and neurogenesis. Current Opinion in Neurology 16, 129-134. Monje ML, Toda H, Palmer TD (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science 5, 1760-1765. Mrak RE, Griffin WS (2007). Common inflammatory mechanisms in Lewy body disease and Alzheimer disease. Journal of Neuropathology & Experimental Neurology 66, 683-686. Nakane Y, Ohta Y (1986). An example from the Japanese Register: Some long-term consequences of the A-bomb for its survivors in Nagasaki. In: Giel R, Gulbinat WH, Henderson JH, editors. Psychiatric case registers in public health. Amsterdam: Elsevier Science Publishers B.V. pp 26 -27. Nyagu AI, Loganovsky KN, Loganovskaja TK (1998). Psychophysiologic aftereffects of prenatal irradiation. International Journal of Psychophysiology 30, 303-311. Park RM, Schulte PA, Bowman JD, Walker JT, Bondy SC, Yost MG, Mouchstone JA, Dosemeci M (2005). Potential occupational risks for neurodegenerative diseases. American Journal of Industrial Medicine 48, 1, 63-77. Peper M, Steinvorth S, Schraube P, Fruehauf S, Haas R, Kimmig BN, Lohr F, Wenz F, Wannenmacher M (2000). Neurobehavioral toxicity of total body irradiation: a follow-up in long-term survivors. International Journal of Radiation Oncology Biology Physics 46, 2, 303-311. Picano E (2004). Sustainability of medical imaging. Education and debate. British Medical Journal 328, 578-580. Picano E, Vano E (2011). The radiation issue in cardiology: the time for action is now. Cardiovascolar Ultrasound 9, 35. Piccinni A, Marazziti D, Del Debbio A, Bianchi C, Roncaglia I, Mannari C, Origlia N, Catena Dell’Osso M, Massimetti G, Domenici L, Dell’Osso L (2008a). Diurnal variation of plasma brain-derived neurotrophic factor (BDNF) in humans: an analysis of sex differences. Chronobiology International 25, 5, 819-826. Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio 66

A, Bianchi C, Mannari C, Martini, C, Da Pozzo E, Schiavi E, Mariotti A, Roncaglia I, Palla A, Consoli G, Giovannini L, Massimetti G, Dell’Osso L (2008b). Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. Journal of Affective Disorders 105 (1-3), 279-283. Piccinni A, Del Debbio A, Medda P, Bianchi C, Roncaglia I, Veltri A, Zanello S, Massimetti E, Origlia N, Domenici L, Marazziti D, Dell’Osso L (2009). Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving electroconvulsive therapy. European Neuropsychopharmacology 19, 5, 349-355. Pinkerton LE, Waters MA, Hein MJ, Zivkovich Z, SchubauerBerigan MK, Grajewski B (2012). Cause-specific mortality among a cohort of U.S. flight attendants. American Journal of Industrial Medicine 55, 1, 25-36. Ponomarenko VM, Nahorna AM, Osnach HV, Proklina TL (1999). An epidemiological analysis of the health status of the participants in the cleanup of the aftermath of the accident at the Chernobyl atomic electric power station. Lik Sprava 8, 39-41. Popoli M, Gennarelli M, Racagni G (2002). Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disorder 4, 3, 166-182. President’s Cancer Panel (2010). Environmental cancer risk underestimated. (deainfo.nci.nih.gov/advisory/pcp/pcp. htm) Prithivirajsingh S, Story MD, Bergh SA, Geara FB, Ang KK, Ismail SM, Stevens CW, Buchholz TA, Brock WA (2004). Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation. FEBS Letters 571, 227-232. Reinhold HS, Calvo W, Hopewell JW, Van Der Berg AP (1990). Development of blood vessel-related radiation damage in the fimbria of the central nervous system. International Journal of Radiation Oncology Biology Physics 18, 37-42. Rola R, Fishman K, Baure J, Rosi S, Lamborn KR, Obenaus A, Nelson GA, Fike JR (2008). Hippocampal neurogenesis and neuroinflammation after cranial irradiation with (56) Fe particles. Radiation Research 169, 626-632. Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR (2004). Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Experimental Neurology 188, 316-330. Roman DD, Sperduto PW (1995). Neuropsychological effects of cranial radiation: current knowledge and future directions. International Journal of Radiation Oncology Biology Physics 31, 983–998. Sadetzki S, Chetrit A, Mandelzweig L, Nahon D, Freedman L, Susser E, Gross R (2011). Childhood exposure to ionizing radiation to the head and risk of schizophrenia. Radiation Research 176, 670-677. Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nöthen MM, Cichon S (2005). Evidence for a relationship between genetic variants at the brainderived neurotrophic factor (BDNF) locus and major depression. Biological Psychiatry 58, 4, 307-314. Schulte PA, Burnett CA, Boeniger MF, Johnson J (1996). Neurodegenerative diseases: occupational occurrence and potential risk factors, 1982 through 1991. American Journal of Public Health 86, 1281-1288. Schulz RJ, Albert RE (1968). Follow-up study of patients treated by X-ray epilation for tinea capitis. 3. Dose to organs of the head from the X-ray treatment of tinea capitis. Archives of Environmental Health 17, 935-950. Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nöthen MM, Cichon S (2005). Evidence for a relationship Clinical Neuropsychiatry (2014) 11, 2

Psychiatric effects of ionizing radiation between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biological Psychiatry 58, 4, 307-314. Shore JH, Tatum EL, Vollmer WM (1986). Psychiatric reactions to disaster: the Mount St. Helens experience. The American Journal of Psychiatry 143, 5, 590-595. Sibley RF, Moscato BS, Wilkinson GS, Natarajan N (2003). Nested case-control study of external ionizing radiation dose and mortality from dementia within a pooled cohort of female nuclear weapons workers. American Journal of Industrial Medicine 44, 351-358. Silasi G, Diaz-Heijtz R, Besplug J, Rodriguez-Juarez R, Titov V, Kolb B, Kovalchuk O (2004). Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females. Biochemical and Biophysical Research Communications 325, 1223-1235. Tofilon PJ, Fike JR (2000). The radioresponse of the central nervous system: a dynamic process. Radiation Research 153, 357-370. Tong XK, Lecrux C, Hamel E (2012). Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. Journal of Neuroscience 32, 47054715. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (2008). Sources and effects of ionizing radiation. United Nations Scientific Committee on the Effects of Atomic Radiation. Van Der Maazen RW, Kleiboer BJ, Verhagen I, Van Der Kogel AJ (1993). Repair capacity of adult rat glial progenitor cells determined by an in vitro clonogenic assay after in vitro or in vivo fractionated irradiation. International Journal of Radiation Biology 63, 661-666. Venneri L, Rossi F, Botto N, Andreassi MG, Salcone N, Emad A, Lazzeri M, Gori C, Vano E, Picano E (2009). Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council’s Biological Effects of Ionizing Radiation VII Report. American Heart Journal 157, 118124.

Clinical Neuropsychiatry (2014) 11, 2

Viticchi G, Falsetti L, Vernieri F, Altamura C, Bartolini M, Luzzi S, Provinciali L, Silvestrini M (2012). Vascular predictors of cognitive decline in patients with mild cognitive impairment. Neurobiology of Aging 33, 1127, 1-9. Wilkinson GS, Trieff N, Graham R, Priore RL (2000). Study of mortality among female nuclear weapons workers. Final report: NIOSH Grant Nos. 1RO1 OHO3274, RO1/ CCR214546, RO1/CCR61, 2000, 2934-01. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S (2006). Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16, 3, 296-304. Wojtowicz JM (2006). Irradiation as an experimental tool in studies of adult neurogenesis. Hippocampus 16, 261-266. Wojtowicz JM, Askew ML, Winocur G (2008). The effects of running and inhibiting adult neurogenesis on learning and memory in rats. European Journal of Neuroscience 27, 1494-1502. Yamada M, Sasaki H, Mimori Y, Kasagi F, Sudoh S, Ikeda J, Hosada Y, Nakamura S, Kodama K (1999). Prevalence and risks of dementia in the Japanese population: RERF’s adult health study Hiroshima subjects. Radiation effects research foundation. Journal of The American Geriatric Society 47, 189-195. Zeeb H, Hammer GP, Langner I, Schafft T, Bennack S, Blettner M (2010). Cancer mortality among German aircrew: second follow-up. Radiation and Environmental Biophysics 49, 187-194. Zhavoronkova LA, Gogitidze NV, Kholodova NB (1997). The characteristics of the late reaction of the human brain to radiation exposure: the EEG and neuropsychological study (the sequelae of the accident at the Chernobyl atomic electric power station). Zhurnal Vysshei Nervnoi Deiatelnosti Imeni IP Pavlova 46, 699-711. Zlokovic BV (2008). The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201. Zuccato C, Cattaneo E (2009). Brain-derived neurotrophic factor in neurodegenerative diseases. Nature Reviews Neurology 5, 311-322.

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