**10. References**

366 Neuroimaging for Clinicians – Combining Research and Practice

the hippocampus); stress-induced changes in amygdala (initial increases in activity and growth) are apparent earlier in life and more robustly than the hippocampus (decreases in growth), and later in life, when hippocampal changes are finally apparent, the initial amygdala volume increases may ultimately change to volumetric decreases (although it may remain hyperactive). Thus, through a combination of connectivity and volumetric studies, it would be possible to, in children as young as two years old, and extending through adulthood, examine the structural and functional networks that underlie the embedding of adversity.These brain areas represent important neuroanatomical structural markers that could be linked to the proposed stress memory interface pathways modifying

The clinical hypothesis that needs to be investigated further is that foetal programming by intrauterine stress leads to stress hypersensitivity during later life insults in genetically susceptible individuals. The genetic susceptibility mechanism may be based on disruption of a stress hormone-immune recombination-brain fragilome 'interface' pathway together with modifying polymorphic variation in the more fixed associated genetic building bricks anywhere along this pathway (e.g. HPA axis and glucocorticoid genetic variation). Furthermore, such a complex set of changes should be analyzable according to modern integrative genetics analyses. The ability to correlate dynamic changes in cellular ROS levels with mitochondrial metabolism and neuronal network activity is already a promising step towards a detailed mechanistic understanding of redox- and ROS-mediated signalling in normal and diseased brain function (Funke et al., 2011), and this can be expected to

In order to gain further insight into human genomic flexibility and its role in individual neurodevelopment, as well as neurological and neurobehavioural disorder phenotypes, current cytogenetic information about fragile genomic regions needs to be augmented by techniques such as innovative next generation sequence variation data, transcriptomic data, epigenomic data and analysis of the interactome to circumvent previous problems in this regard. Assigning genes to context-dependent and potentially overlapping 'transcription modules' in fragile regions will provide functional predictions for numerous genes as had been done in yeast to identify relations between modules (Re et al., 2006) and present a global view on the proposed interface system transcriptional networks. CFS characteristics may underly many previous analytic dilemmas in assessing the neurogenetic response to the environment. For instance, megabase-long satellite sequences and CFS-associated contiguous segmental duplications hamper both physical and fine scale genetic mapping. Links with miRNA, altered methylation and the origin of copy number variation now indicate that CFS region characteristics may be part of chromatinomic mechanisms that are increasingly linked with neuroplasticity and memory. RNA is centrally involved in directing various epigenetic processes considered to occur in neurons, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. Changes in a small number of RNA regulatory proteins may thus generate a great diversity of biological

The stage is now set to integrate transgenerational psychological stress research with, *inter alia* fragilomic and epigenomic studies and the extensive amount of available neuroanatomic imaging findings in prototypical antenatally programmed stress disorders. The aim would be to initiate the research and design of suitable imaging biomarkers to elucidate the role of

the effects of early experiences on the developing human brain.

contribute significantly to imaging of programmed stress disorders.

**8.1 Genetic and clinical implications** 

outcomes.


Stress Shaping Brains: Higher Order DNA/Chromosome

*Chromosome Res* 14(1):117–26.

*Acad Sci* U S A. Jul 26;102(30):10604-9.

disorders. *Med Hypotheses* 50(4):319-26.

immunity. *Med Hypotheses* 74(5):911-8.

construction. *Brain Behav Evol* 59(1-2):10-20

5;141(1):67-70.

54(4):2590-602.

*Genet*.36(2):132-5.

66(1):92-9.

Mechanisms Underlying Epigenetic Programming of the Brain Transcriptome 369

Dillon, N. (2006). Gene regulation and large-scale chromatin organization in the nucleus.

Durand, CM., Kappeler, C., Betancur, C., Delorme, R., Quach, H., Goubran-Botros, H.,

Emad, Y., Ragab, Y., Zeinhom, F., El-Khouly, G., Abou-Zeid, A., & Rasker, JJ. (2008).

Fayed, N., Garcia-Campayo, J., Magallón, R., Andrés-Bergareche, H., Luciano, JV., Andres,

Funke, F., Gerich, FJ., & Müller M.(2011). Dynamic, semi-quantitative imaging of

García-Campayo, J; Fayed, N; Serrano-Blanco, I; & Roca, Miquel. (2009). Brain dysfunction

Garofalo, G., Ragusa, RM., Argiolas, A., Scavuzzo, C., Spina, E., & Barletta, C. (1993)

Gericke, GS., Simonic, I., Cloete, E., Buckle, C., & Becker, PJ. (1995). Increased chromosomal

Gericke, GS. (2006). Reactive oxygen species and related haem pathway components as

Gericke, GS. (2006). Chromosomal fragility, structural rearrangements and mobile element

Gericke, GS. (2010). Common chromosomal fragile sites (CFS) may be involved in normal

Gibson, KR. (2002). Evolution of human intelligence: the roles of brain size and mental

neurobehavioural genetics..*Med Hypotheses* 66(2):276-85.

*American Journal of Medical Genetics (Neuropsychiat Genet)* 60:444-447. Gericke, GS. (1998). Chromosomal fragility may be indicative of altered higher-order DNA

dissociative disorders. *Current Opinion in Psychiatry* 22: 224-231

inositol, choline, and N-acetylaspartate. *Arthritis Res Ther* 12(4):R134. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer,D., Cigudosa

Melke, J., Nygren, G., Chabane, N., Bellivier, F., Szoke, A., Schurhoff, F., Rastam, M., Anckarsäter, H., Gillberg, C., Leboyer, M., & Bourgeron, T. (2006). Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders. *Am J Med Genet B (Neuropsychiatr Genet)*

Hippocampus dysfunction may explain symptoms of fibromyalgia syndrome. A study with single-voxel magnetic resonance spectroscopy. *J Rheumatol* 35(7):1371-7.

E., & Beltrán, J. (2010). Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine,

JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, & Esteller M.(2005). Epigenetic differences arise during the lifetime of monozygotic twins. *Proc Natl* 

intracellular ROS levels and redox status in rat hippocampal neurons. *Neuroimage* 

behind functional symptoms: neuroimaging and somatoform, conversive, and

Evidence of chromosomal fragile sites in schizophrenic patients. *Ann* 

breakage in Tourette Syndrome predicts the possibility of variable multiple gene involvement in spectrum phenotypes: Preliminary findings and hypotheses.

organization as the underlying genetic diathesis in complex neurobehavioral

possible epigenetic modifiers in neurobehavioural pathology. *Med Hypotheses*

activity may reflect dynamic epigenetic mechanisms of importance in

and traumatic cognitive stress memory consolidation and altered nervous system


Burgmer, M., Gaubitz, M., Konrad, C., Wrenger, M., Hilgart, S., Heuft, G., & Pfleiderer, B.

Caspi, A., Sugden, K., Moffitt, TE., Taylor, A., Craig, I., Harrington, I., McClay, J., Mill, J.,

Champagne, FA. (2008). Epigenetic mechanisms and the transgenerational effects of

Chun, J. (1999). Developmental neurobiology: a genetic Cheshire cat? *Curr Biol. Ser* 

Corballis, MC. (1992). On the evolution of language and generativity. *Cognition* 44(3):197-26. Cordero, OX., Hogeweg, P. (2006). Feed-forward loop circuits as a side effect of genome

Cosgrove, MS., Wolberger, C. (2005). How does the histone code work? *Biochem Cell Biol* 

Costa, E., Grayson, DR., Veldic, M., & Guidotti, A. (2004). Neurochemical basis for an epigenetic vision of synaptic organization. *Int Rev Neurobiol* 59:73-91. Chatterji, M., Tsai, CL., & Schatz, DG. (2004). New concepts in the regulation of an ancient

Chung, WY., Albert, R., Albert, I., Nekrutenko, A., & Makova, KD. (2006). Rapid and

Chuzhanova, N., Chen, JM., Bacolla, A., Patrinos, GP., Férec, C., Wells, RD., & Cooper, DN.

Cleary, JD., Pearson, CE. (2003). The contribution of cis-elements to disease-associated

Crespi, EJ., Denver, RJ. (2005). Ancient origins of human developmental plasticity. *Am J* 

Crews, D. (2008). Epigenetics and its implications for behavioral neuroendocrinology. *Front* 

Cushman, J., Lo J., Huang, Z., Wasserfall, C., & Petitto, JM. (2003). Neurobehavioral changes

Dai, J,. Xie, W,. Brady, TL,. Gao, J,. & Voytas, DF. (2007). Phosphorylation regulates

Delcuve, GP., Rastegar, M., & Davie, JR. (2009). Epigenetic control. *J Cell Physiol* 219(2):243–

Dietert, RR., Dietert, JM. (2008).Potential for early-life immune insult including

asymmetric divergence of duplicate genes in the human gene coexpression

(2009). Gene conversion causing human inherited disease: evidence for involvement of non-B-DNA-forming sequences and recombination-promoting

repeat instability: clinical and experimental evidence. *Cytogenet Genome Res* 100(1–

resulting from recombinase activation gene 1 deletion. *Clin Diagn Lab Immunol*

integration of the yeast Ty5 retrotransposon into heterochromatin. *Mol Cell*

developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. *J Toxicol Environ Health B Crit Rev*

reaction: transposition by RAG1/RAG2. *Immunol Rev* 200:261–71.

motifs in DNA breakage and repair. *Hum Mutat* 30(8):1189-1198

Crepaldi, L., Riccio, A. (2009). Chromatin learns to behave. *Epigenetics* 4(1):23-6.

maternal care. *Front. Neuroendocrinol* 29:386–397.

evolution. *Mol Biol Evol* 23(10):1931–6.

network. *BMC Bioinformatics* 7:46.

amygdala in patients with fibromyalgia. *Psychosom Med* 71(5):566-73. Cantu-Paz, E., Goldberg, DE. (1999). On the scalability of parallel genetic algorithms. *Evol* 

*Comput* 7(4):429-49.

9;9(17):R651-4.

83(4):468-76.

4): 25–55.

10(1):13-8.

50.

20;27(2):289-99.

11(8):660–80.

*Hum Biol* 17(1):44-54.

*Neuroendocrinol* 29(3):344-57.

(2009). Decreased gray matter volumes in the cingulo-frontal cortex and the

Martin, I., Braithwaite, A., & Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene, *Science* 301:386–389.


Stress Shaping Brains: Higher Order DNA/Chromosome

circuitry. *Proc Natl Acad Sci* 102(17):6143-7.

cause of nervous system disorders. *Neuron* 52(1):103–21.

phylogeny: new perspectives. *Nat Rev Immunol* 11:866-79.

*Papers of Barbara McClintock*. Garland, New York

reorganization. *Cell Cycle* 8(19):3102-6.

genome. *Dialogues Clin. Neurosci* 7:103–123.

and -beta gene clusters. *Gene* 349:1-14.

11(6):402-16.

*Bot (Lond)* 94(4): 48 1–95.

*Health* 57:340-8.

*Biosci* 34(2):195-8.

*Genet* 70:101-41.

*MD Advis* 3(3):18-25.

Mechanisms Underlying Epigenetic Programming of the Brain Transcriptome 371

Kaushal, D., Contos, JJ., Treuner, K., Yang, AH., Kingsbury, MA., Rehen, SK., McConnell,

chromosome loss in the postnatal mouse brain. *J Neurosci* 23(13):5599-606. Karayiorgou, M., Simon, TJ., & Gogos, JA. (2010). 22q11.2 microdeletions: linking DNA

Kingsbury, MA., Friedman, B., McConnell, MJ., Rehen, SK., Yang, AH., Kaushal, D.,& Chun,

Lee, JA., Lupsk,i JR. (2006). Genomic rearrangements and gene copy-number alterations as a

Levenson, JM., Sweatt, JD. (2006). Epigenetic mechanisms: a common theme in vertebrate

Liebich, I., Bode, J., Reuter, I., & Wingender E. (2002). Evaluation of sequence motifs found

Lubin, FD., Sweatt, JD. (2007). The IkappaB kinase regulates chromatin structure during

Lutz, J., Jäger, L., de Quervain, D., Krauseneck, T., Padberg, F., Wichnalek, M., Beyer, A.,

McCauley, LA., Joos, SK., Barkhuizen, A., Shuell, T., Tyree, WA., & Bourdette, DN. (2002).

McClintock, B. (1987). *The Discovery and Characterization of Transposable Elements: the Collected* 

McFarlane, RJ., Whitehall, SK. (2009). tRNA genes in eukaryotic genome organization and

Meaney, MJ. (2001). Maternal care gene expression and the transmission of individual differences in stress reactivity across generations, *Ann. Rev. Neurosci* 24:161–192. Meaney, MJ., Syzf, M. (2005). Environmental programming of stress responses through

Miki, R., Hattori, K., Taguchi, Y., Tada, MN., Isosaka, T., Hidaka, Y., Hirabayashi, T.,

Miyata, S., Hatton, GI. (2002). Activity-related, dynamic neuron-glial interactions in the hypothalamo-neurohypophysial system. *Microsc Res Tech* 56(2):143-57. Morange, M. (2009), What history tells us XVII. Conrad Waddington and the nature of life. *J* 

Murr, R. (2010). Interplay between different epigenetic modifications and mechanisms. *Adv* 

Natelson, BH. (2010). Chronic fatigue syndrome and fibromyalgia: a status report in 2010.

and invertebrate memory formation. *Cell Mol Life Sci* 63(9):1009–16.

reconsolidation of conditioned fear memories. *Neuron* 55(6):942-57.

tensor and volumetric imaging study. *Arthritis Rheum* 58(12):3960-9. Madlung ,A., Comai L. (2004) The effect of stress on genome regulation and structure. *Ann* 

MJ., Okabe, M., Barlow, C., & Chun, J. (2003). Alteration of gene expression by

structural variation to brain dysfunction and schizophrenia. *Nat Rev Neurosci*

J. (2005). Aneuploid neurons are functionally active and integrated into brain

in scaffold/matrix-attached regions (S/MARs). *Nucleic Acids Res* 30(15):3433– 42.Litman, GW., Cannon, JP., & Dishaw LJ. (2005). Reconstructing immune

Stahl, R., Zirngibl, B., Morhard, D., Reiser, M., & Schelling, G. (2008). White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-

Chronic fatigue in a population-based study of Gulf War veterans. *Arch Environ* 

DNA methylation: life at the interface between a dynamic environment and a fixed

Hashimoto,R., Fukuzako, H., & Yagi, T. (2005). Identification and characterization of coding single-nucleotide polymorphisms within human protocadherin-alpha


Gilmore, EC., Nowakowski, RS., Caviness Jr, VS., & Herrup, K.. (2000). Cell birth, cell death,

Glover, TW., Arlt, MF., Casper, AM., & Durkin, SG. (2005). Mechanisms of common fragile

Goldschmidt, R. (1982). *The Material Basis of Evolution.* Yale University Press,

González, E., Elorza, J., & Failde, I. (2010). Fibromyalgia and psychiatric comorbidity: their effect on the quality of life patients. *Actas Esp Psiquiatr* 38(5):295-300. Gow, JW., Hagan, S., Herzyk, P., Cannon, C., Behan, PO., & Chaudhuri, A. (2009). A gene

Grandbastien, MA. (2004). Stress activation and genomic impact of plant retrotransposons. *J* 

Gupta, S., Kim, SY., Artis, S., Molfese, DL., Schumacher, A., Sweatt, JD., Paylor, RE., &

Guterman, A., Richter-Levin, G. (2006). Neuromodulators of LTP and NCAMs in the

Hawkins, RD., Hon, GC., & Ren, B. (2010). Next generation genomics: an integrative

Hayashi, MT., Masukata, H. (2011). Regulation of DNA replication by chromatin structures:

Hilschman, N., Barnikol, HU., Barnikol-Watanabe, S., Götz, H., Kratzin, H., & Thinnes, FP.

Hirayama, T., Yagi, T. (2006). The role and expression of the protocadherin-alpha clusters in

Holliday, KL., Nicholl, BI., Macfarlane, GJ., Thomson, W., Davies, KA., & McBeth, J. (2010).

Hsu, E, Pulham, N, Rumfelt, LL, & Flajnik, MF. (2006). The plasticity of immunoglobulin

Ishiwata, K. (2009). Strategy for development of imaging biomarkers. *Nihon Shinkei Seishin* 

Jablonka, E, Raz, G. (2009). Transgenerational epigenetic inheritance:Prevalence,

Jackson, JA, Trevino, AV, Herzig, MC, Herman, TS, & Woynarowski, JM.. (2003). Matrix

Jorgensen, RA. (2004). Restructuring the Genome in Response to Adaptive Challenge:

(2001). The immunoglobulin-like genetic predetermination of the brain: the protocadherins, blueprint of the neuronal network. *Naturwissenschaften* 88(1):2-12. Hinsch, H., Hannenhalli, S. (2006). Recurring genomic breaks in independent lineages

Genetic variation in the hypothalamic-pituitary-adrenal stress axis influences susceptibility to musculoskeletal pain: results from the EPIFUND study. *Ann* 

Mechanisms and Implications for the Study of Heredity and Evolution. *The* 

attachment region (MAR) properties and abnormal expansion of AT island minisatellites in FRA16B fragile sites in leukemic CEM cells. *Nucleic Acids Res*

McClintock's Bold Conjecture Revisited. *Cold Spring Harb Symp Quant Biol* 69: 349-

amygdala and hippocampus in response to stress. *EXS* 98:137–48.

accessibility and recruitment. *Chromosoma*. Feb;120(1):39-46.

approach. *Nature Reviews Genetics* 11, 476-486

support genomic fragility. *BMC Evol Biol* 6:90.

gene systems in evolution. *Immunol Rev* 210:8-26.

the CNS. *Curr Opin Neurobiol* 16(3):336-42.

*Rheum Dis* 69(3):556-60.

31(21):6354–64.

354

*Yakurigaku Zasshi* 29(2):67-71.

*Quarterly Review of Biology* 84: 131–176.

site instability. *Hum Mol Genet* 14 Spec No. 2:R197-205.

ISBN:9780300028232, New Haven.

*Soc Biol* 198(4):425-32.

30(10):3589-99.

23(3):100–5.

cell diversity and DNA breaks: how do they all fit together? *Trends Neurosci*

signature for post-infectious chronic fatigue syndrome. *BMC Med Genomics* 25;2:38.

Lubin, FD. (2010). Histone methylation regulates memory formation. *J Neurosci*


Stress Shaping Brains: Higher Order DNA/Chromosome

*Immunol* 16(4):245-56.

*Endocrinol Metab* (6):479-88.

*Cancer Res* 66(5):2616-20.

*Fertil Suppl*. 62:191-203.

*Lab Immunol* 6(3):330-5.

36.

1802: 819-839.

*Sci U S A* 104(47):18613-8.

periphery. *FEBS J* 274(6):1383–92.

schizophrenia genetics. *Schizophr Res* 20(1-2):235-7.

regulation of cell differentiation. *Genetika* 43(5):581–600.

inheritance. *Birth Defects Res C Embryo Today* 93(1):51-5.

and development. *Clin Genet* 65(6):435-40.

testable hypotheses. *Anat Rec* 253(4):105–12.

*Clin Endocrinol Metab* 21(3):403–14.

environment. *Genes Dev* 24(15):1571-3.

Mechanisms Underlying Epigenetic Programming of the Brain Transcriptome 373

Schatz, DG. (2004). Antigen receptor genes and the evolution of a recombinase. *Semin* 

Seckl, JR., Holmes, MC. (2007). Mechanisms of disease: glucocorticoids, their placental

Shaklai, S., Amariglio, N., Rechavi, G., & Simon, AJ. (2007). Gene silencing at the nuclear

Singh, SM., McDonald, P., Murphy, B., & O'Reilly, R. (2004). Incidental neurodevelopmental

Sjakste, NI., Sjakste, TG. (2007). Possible involvement of DNA breaks in epigenetic

Skinner, MK. (2011). Role of epigenetics in developmental biology and transgenerational

Stribinskis, V., Ramos, KS. (2006). Activation of human long interspersed nuclear element 1

Striedter, GF. (1998). Progress in the study of brain evolution: from speculative theories to

Sun, JG., Han, S., Ji, H., Zheng, Y., & Ling, SC. (2007). Expression of RAG-1 in brain during mouse development. *Zhejiang Da Xue Xue Bao Yi Xue Ban* 36(2):161-6. Trapman, J., Dubbink, HJ. (2007). The role of cofactors in sex steroid action. *Best Pract Res* 

Turner, JD., Pelascini, LP., Macedo, JA., & Muller, CP. (2008). Highly individual methylation

Urnovitz, HB., Tuite, JJ., Higashida, JM., & Murphy, WH. (1999). RNAs in the sera of Persian

Valdés, M., Collado, A., Bargalló, N., Vázquez, M., Rami, L., Gómez, E., & Salamero, M.

Wallace, DC. (2010). The epigenome and the mitochondrion: bioenergetics and the

Waerzeggers, Y., Monfared, P., Viel,T., Winkeler,A., & Jacobs, AH. (2010). Mouse models in

Wang, T., Zeng, J., Lowe, CB., Sellers, RG., Salama, SR., Yang, M., Burgess, SM., Brachmann,

Varmuza, S. (2003). Epigenetics and the renaissance of heresy. *Genome* 46: 963-957

epigenetic regulatory mechanisms. *Nucleic Acids Res* 36(22):7207-18. Turner, AI., Tilbrook, AJ. (2006). Stress, cortisol and reproduction in female pigs. *Soc Reprod* 

Simonic, I., Gericke, GS. (1996). The enigma of common fragile sites. *Hum Genet* 97:524-31. Simonic, I., Ott, J. (1996). Novel etiological hypotheses imply new analysis methods for

metabolism and fetal 'programming' of adult pathophysiology. *Nat Clin Pract* 

episodes in the etiology of schizophrenia: an expanded model involving epigenetics

retrotransposition by benzo(a)pyrene, an ubiquitous environmental carcinogen.

patterns of alternative glucocorticoid receptor promoters suggest individualized

Gulf War veterans have segments homologous to chromosome 22q11.2. *Clin Diagn* 

(2010). Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study. *Arthritis Rheum* 62(6):1829-

neurological disorders:applications of non-invasive imaging. *Biochim Biophys Acta* 

RK., & Haussler, D. (2007). Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. *Proc Natl Acad* 


Nakayama, T., Yamashita, M. (2008). Initiation and maintenance of Th2 cell identity. *Curr* 

Nelson, W., Luo, M., Ma, J., Estep, M., Estill, J., He, R., Talag, J., Sisneros, N., Kudrna,

Nelson, ED., Monteggia, LM. (2011). Epigenetics in the mature mammalian brain: Effects on

Niederberger, E., Geisslinger, G. (2008). The IKK-NF-kappaB pathway: a source for novel

Orozco, LD, Cokus, SJ, Ghazalpour, A, Ingram-Drake, L, Wang, S, van Nas, A, Che, N,

gene expression and metabolic traits in mice. *Hum Mol Genet* 18(21):4118-29. Pancer, Z., Cooper, MD. (2006). The evolution of adaptive immunity. *Annu Rev Immunol*

Pedrosa, E., Stefanescu, R., Margolis, B., Petruolo, O., Lo, Y., Nolan, K., Novak, T., Stopkova,

Puliti, A., Rizzato, C., Conti, V., Bedini, A., Gimelli, G., Barale, R., & Sbrana, I. (2010). Low-

Raghavan, SC., Kirsch, IR., & Lieber, MR. (2001). Analysis of the V(D)J recombination

Rajendran, RS., Zupanc, MM., Lösche, A., Westra, J., Chun, J., & Zupanc, GK. (2007).

Re, A., Cora, D., Puliti, AM., Caselle, M., & Sbrana I. (2006). Correlated fragile site

Roth, DB., Roth, SY. (2000). Unequal access: regulating V(D)J recombination through

Savelyeva, L., Sagulenko, E., Schmitt, JG., & Schwab, M. (2006). Low-frequency common fragile sites: link to neuropsychiatric disorders? *Cancer Lett* 232(1):58-69. Sbrana, I., Zavattari ,P., Barale, R., & Musio, A. (1998). Common fragile sites on human

immunity and associated with carcinogenesis. *BMC Bioinformatics* 7:413. Rehen, SK., Yung, YC., McCreight, MP., Kaushal, D., Yang, AH., Almeida, BS., Kingsbury,

pathway in lymphocyte development. *Immunol Rev* 200:115-31.

molecular drug targets in pain therapy? *FASEB J* 22(10):3432-42.

networks in schizophrenia. *Neuroimage* 53(3):839-847.

fragile sites. *Mutat Res* 1;686:74- 83.

of teleost fish. *Dev Neurobiol* 67(10):1334-47.

chromatin remodeling. *Cell* 103(5):699-702.

camptothecin. *Hum Genet* 102(4):409-14.

D.,Kim, H., Ammiraju, JS., Collura, K., Bharti, AK., Messing, J., Wing, RA., SanMiguel, P., Bennetzen, JL., & Soderlund, C. (2008). Methylation-sensitive linking libraries enhance gene-enriched sequencing of complex genomes and map DNA

behavior and synaptic transmission. *Neurobiol Learn Mem* Mar 30. [Epub ahead of

Araujo, JA, Pellegrini, M., & Lusis, AJ. (2009). Copy number variation influences

P., & Lachman, HM. (2008). Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia. *Schizophr Res* 102(1-3):210-9. Potkin, SG., Macciardi, F., Guffanti, G., Fallon, JH., Wang,Q., Turner,JA., Lakatos,A.,

Miles,MF.,Lander, A., Vawter,MP., & Xie,X. (2010). Identifying gene regulatory

copy repeats on chromosome 22q11.2 show replication timing switches, DNA flexibility peaks and stress inducible asynchrony, sharing instability features with

efficiency at lymphoid chromosomal translocation breakpoints. *J Biol Chem*

Numerical chromosome variation and mitotic segregation defects in the adult brain

expression allows the identification of candidate fragile genes involved in

MA.,Cabral, KM., McConnell, MJ., Anliker, B., Fontanoz ,M., & Chun, J. (2005). Constitutional aneuploidy in the normal human brain. *J Neurosci* 25(9):2176-80. Rooney, S., Chaudhuri, J., & Alt, FW. (2004). The role of the non-homologous end-joining

chromosomes represent transcriptionally active regions: evidence from

*Opin Immunol* 20(3):265-71.

print]

24:497-518.

276(31):29126–33.

methylation domains. *BMC Genomics* 9:621.


**18** 

**Abnormal Brain Density in Victims of Rape with** 

**Analysis of Magnetic Resonance Imaging Study** 

Posttraumatic stress disorder (PTSD) is a relatively common and predictable psychological syndrome (Miller, 1999). PTSD occurs in a proportion of individuals exposed to severe psychological trauma (Kasai et al., 2006) and in which the individual responds with fear, helplessness, or horror (Danckwerts & Leathem, 2003). Individuals with PTSD suffer from intrusive memories about the traumatic event, persistent avoidance of stimuli associated with the trauma, and persistent symptoms of increased arousal. These symptoms become uncontrollable and disabling (Bremner & Charney, 1994) that serious threaten human health and social function. Due to its debilitating nature, PTSD has emerged as an important public

In recent years, a great deal of research has been directed towards understanding the etiology, phenomenology, neurobiology, clinical characteristics and treatment of PTSD (Nemeroff et al., 2006). However, a number of core psychological processes underlying PTSD have yet to be elucidated (Shin et al., 2006; Liberzon & Sripada, 2008). Over the past decade, findings from neuroimaging studies have allowed for tremendous advances in our understanding of the experience of emotions in healthy individuals and the dysregulation of these processes associated with PTSD. These studies have been useful in both generating hypotheses on the neurobiology of normative human responses to trauma and complementing our understanding of the wide-ranging alterations in trauma survivors who

Structural neuroimaging studies have focused primarily on hippocampal volumetry (Geuze et al., 2005) as well as the prefrontal cortex (Geuze et al., 2008a) and other brain structures. Hippocampal morphology has been correlated with severity of PTSD symptomatology (Gilbertson et al., 2002; Villarreal & King, 2004). However, the results have been inconsistent, with studies reporting significant reductions or increases, as well as unchanged volumes. For example, studies have shown that patients with PTSD are associated with bilateral lower hippocampal volume (Bossini & Castrogiovanni, 2007; Bremner et al., 2003; Emdad et al., 2006; Lindauer et al., 2004a; Vythilingam et al., 2005; Li et al., 2006), which are

health problem in the general population (Sareen et al., 2007).

**1. Introduction** 

develop PTSD.

**PTSD in Mainland China: A Voxel-Based** 

*1Mental Health Institute, Second Xiangya Hospital, Central-South University* 

Shuang Ge Sui1, Ling Jiang Li1, Yan Zhang1,

*3Faculty of Education, The University of Hong Kong, HHSAR* 

Ming Xiang Wu2 and Mark E. King3

*2ShenZhen People's Hospital* 

*P. R. China* 

