**8. Conclusion**

364 Neuroimaging for Clinicians – Combining Research and Practice

The involved sites included areas harbouring NF-KB genes, which are proneuroinflammatory factors (Fig 2). Several studies indicate that the nuclear factor-kappa B (NF-kappaB) -activation cascade plays a crucial role not only in immune esponses, inflammation, and apoptosis but also in the development and processing of pathological pain (Niederberger & Geisslinger, 2008). This could represent one aspect of a FMS

Fig. 2. Examples of induced chromosomal fragile sites in regions harbouring NF-KB genes.

Chronic fatigue syndrome (CFS) and Persian Gulf War Ilness (PGI)/Persian Gulf War Syndrome (PGWS) and Fibromyalgia syndrome (FMS) are overlapping symptom complexes without objective markers or known pathophysiology according to the literature. When the cerebrospinal fluid proteome was examined to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids were identified in two independent cohorts of subjects with overlapping CFS, PGWS and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) appear to be shared (Baraniuk et al., 2005). PGWS may be a syndrome especially occurring in FMS susceptible genotypes when exposed to specific genotoxicants or the stress of warfare. Of the 130 veterans who were evaluated clinically, 103 had unexplained fatigue, and 44 veterans met the 1994 U.S. Centers for Disease Control criteria for CFS (Mc Cauley et al., 2002). The number of Gulf War veterans who have developed the so-called Gulf War syndrome has risen to about one-third of the 800,000 U.S. forces deployed, and unknown proportions of those involved in the subsequent wars. Uncounted civilians and personnel of other nations that fought in Iraq and other wars since 1991 have also been afflicted (Bertell, 2006). Particulate depleted uranium (DU), widely suspected as one of the prime causes of PGWS associated pathologies, compounds were demonstrated to induce time and concentration-dependent cytotoxic (producing a toxic

**7.2 A diseasome overlap with Persian Gulf War syndrome?** 

diseasome.

Garcia-Campayo and co-workers (2009) took the optimistic view that imaging can take advantage of developments straight from routine individual biomarkers to multiple-scale biomarker profiles. "Imaging should predict treatment response, look at stratification for specific treatment modalities, and look at the characterization of an individual patient" (Garcia-Campayo et al., 2009). Browning et al., 2011 recently reviewed the debate about the nature of somatoform disorders (such as fibromyalgia) and posed the question: "Is there evidence of altered neural function or structure that is specifically associated with somatoform disorders?" These authors described studies reporting neuroimaging findings in patients with a somatoform disorder or a functional somatic syndrome (such as fibromyalgia) and found a "relatively mature literature on symptoms of pain" (and less developed literatures on conversion and fatigue symptoms). (Browning et al., 2011). Both the hippocampus (Emad et al., 2008; Wood et al., 2009; Fayed et al., 2010) and amygdala (Lutz et al., 2008; Burgmer et al., 2009; Valdés et al., 2010) have been implicated in FMS. To summarize, the literature suggests that early life is a period of increased vulnerability, although the effects of stress may be difficult to detect for years (as seems to be the case with

Stress Shaping Brains: Higher Order DNA/Chromosome

exceeded and pathological processes start appearing.

*Bioessays* 26(12):1299–306.

Genet 23(1):8-10.

14(3):283–91.

5:22

*them"* (Hawkins et al., 2010).

**9. Acknowledgement** 

earlier research.

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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 effects of early experiences on the developing human brain.

#### **8.1 Genetic and clinical implications**

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 contribute significantly to imaging of programmed stress disorders.

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 outcomes.

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 stress pathways of an interface system (hormones, antibodies and fragile sites) during physiological learning and memory processes, how such stress shapes the developing brain, and what spectrum of disorders may result when physiological activity thresholds are exceeded and pathological processes start appearing.

*"Data integration itself is not an end: it is designed to generate novel hypotheses and help to test them"* (Hawkins et al., 2010).
