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Most research involving nutrition in ruminants focusses on the rumen. The ruminant intestine remains an area less studied, although a few studies have utilized the fetal ovine intestine for inflammation-based research [ , ]. Some research has suggested that the presence of Mycobacterium avium subspecies paratuberculosis Map , a bacterium that causes intestinal disease in cattle, can be associated with people with CD [ ].

Although most studies provide contradicting evidence regarding the presence of Map in CD patients, some researchers have suggested that this cattle enteric pathogen can contribute to the onset of CD in human tissue, and vice versa [ , ]. The bovine animal model has also been used to study non-typhoid enteric infection induced by S. A few studies have used sheep as comparative models for human studies, using intestinal loops in neonatal sheep to study mucosal immune function [ ].

Although this model is good for studying the impact of pathogens on intestinal injury Fig. The rabbit is another animal model that has been used to study colitis. Following muramyl dipeptide administration, mononuclear cell infiltration, lymphoid aggregation, and transmural inflammation were observed in the rabbit colon [ ]. Of late, preterm rabbit models have been used as a method to understand physiologic and biologic changes associated with intestinal dysfunction, neonatal necrotizing enterocolitis, and rectal-anal obstruction [ ].

Rabbits and guinea pigs have also been used to study intestinal lesions resulting from the administration of common chemical incitants to be discussed later in the review of intestinal inflammation [ 52 , 56 ]. Each animal model has an array of advantages and disadvantages to its use and therefore a comprehensive study examining multiple aspects of intestinal inflammation requires the use of two or more animal models. For instance, using an invertebrate model to study mechanisms involved in innate immunity in conjunction with a genetically engineered murine model could provide a broader understanding of the causes of intestinal inflammation with respect to both innate and adaptive immunity.

Alternatively, a mouse model can be used to determine the immunologic mechanisms of pathogen challenge on the intestine, and these observations paired with the effects of the pathogen on intestinal architecture and enterocyte function in the swine or NHP. In animal models of inflammation, chemicals are often used as fast, economic and effective strategies to induce intestinal tissue injury. The effectiveness of inducing tissue injury following treatment with chemical agents varies and depends on the molecular weight, concentration, manufacturer, and batch of the chemical [ ].

In addition, the species, gender [ 56 ], and the genetic background of the animal model being challenged influences the degree of tissue injury [ , ]. The method of administration also influences the induction and severity of disease, as some chemicals work well to induce inflammation after ingestion [ 56 ], while others function best when applied directly to the site of infection, such as the rectal administration of haptenating agents [ ]. Furthermore, microorganisms present in the intestine can interact with the chemical incitant and interfere with its ability to effectively incite tissue injury [ ].

In general, chemical incitants induce tissue damage that can effectively represent clinical cases of intestinal inflammation. Acknowledgements We thank the members of the Enteric Microbiology and Intestinal Health Research group at the University of Alberta and Lethbridge Research Centre for their research expertise, encouragement, and helpful discussions. Competing interests The authors declare that they have no competing interests.

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Dev Comp Immunol. Completion of the swine genome will simplify the production of swine as a large animal biomedical model. BMC Med Genom. The ethics of using transgenic non-human primates to study what makes us human. Nat Rev Genet. Different views on ethics: how animal ethics is situated in a committee culture. J Med Ethics. Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis. Association between nucleotide oligomerisation domain two Nod2 gene polymorphisms and canine inflammatory bowel disease.

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Academic Press; Immune networks in animal models of inflammatory bowel disease. Assessing inflammatory disease at mucosal surfaces in murine genetic models. In: Perl A, editor. Humana Press; Chronic experimental colitis induced by dextran sulphate sodium DSS is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. T cell transfer model of colitis: a great tool to assess the contribution of T cells in chronic intestinal inflammation. Methods Mol Biol.

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Drug Des Dev Ther. Species-specific regulation of Toll-like receptor 3 genes in men and mice. J Biol Chem. Differential expression and regulation of toll-like receptors TLR in human leukocytes: selective expression of TLR3 in dendritic cells. The laboratory mouse. Effect of intraperitoneal radiotelemetry instrumentation on voluntary wheel running and surgical recovery in mice. Optical coherence tomography for ultrahigh resolution in vivo imaging.

Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish. PLoS One. A new model of chronic hapten-induced colitis in young rats. J Pediatr Gastroenterol Nutr. Resistin-like molecule beta regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice. Resistant starch modulates in vivo colonic butyrate uptake and its oxidation in rats with dextran sulfate sodium-induced colitis.

J Nutr. Acute and chronic histological changes of the small bowel secondary to C. Dig Dis Sci. Diets enriched in oat bran or wheat bran temporally and differentially alter the composition of the fecal community of rats. Temporal change in the gut community of rats fed high amylose cornstarch is driven by endogenous urea rather than strictly on carbohydrate availability. J Appl Microbiol. Phylum level change in the cecal and fecal gut communities of rats fed diets containing different fermentable substrates supports a role for nitrogen as a factor contributing to community structure.

The utility of Apc-mutant rats in modeling human colon cancer. Laboratory mice and rats. Mater Methods. Google Scholar Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioallied Sci. Human, mouse, and rat genome large-scale rearrangements: stability versus speciation. Genome Res. Evolution of the innate immune system: the worm perspective. Immunol Rev. Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium.

Population dynamics and habitat sharing of natural populations of Caenorhabditis elegans and C. BMC Biol. Caenorhabditis elegans as a simple model to study phenotypic and genetic virulence determinants of extraintestinal pathogenic Escherichia coli. Microbes Infect. Caenorhabditis elegans as a model for intracellular pathogen infection. Cell Microbiol. Influence of planktonic and sessile Listeria monocytogenes on Caenorhabditis elegans. Arch Microbiol. OrthoList: a compendium of C. Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells. EMBO Rep.

Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Front Cell Infect Microbiol. Drosophila melanogaster as a model for human intestinal infection and pathology. The Drosophila larva as a tool to study gut-associated macrophages: PI3K regulates a discrete hemocyte population at the proventriculus.

Quantitative proteomics identifies ferritin in the innate immune response of C. The worm has turned—microbial virulence modeled in Caenorhabditis elegans. Trends Microbiol. Giardia duodenalis-induced alterations of commensal bacteria kill Caenorhabditis elegans : a new model to study microbial—microbial interactions in the gut. The insects: structure and function. Cambridge university press; From Zebrafish to human: modular medical models. Annu Rev Genom Hum Genet. Mutations affecting development of zebrafish digestive organs. Retinoic acid suppresses intestinal mucus production and exacerbates experimental enterocolitis.

Role of gut microbiota in a zebrafish model with chemically induced enterocolitis involving toll-like receptor signaling pathways. Chapter 4—Study of host—microbe interactions in zebrafish. Methods in Cell Biology. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. The pig as an experimental model for elucidating the mechanisms governing dietary influence on mineral absorption. Exp Biol Med Maywood.

A pig model of the human gastrointestinal tract. Immune development in jejunal mucosa after colonization with selected commensal gut bacteria: a study in germ-free pigs. Influence of a probiotic Enterococcus faecium strain on development of the immune system of sows and piglets. Rapid protection of gnotobiotic pigs against experimental Salmonellosis following induction of polymorphonuclear leukocytes by avirulent Salmonella enterica. Infect Immun. Genome-wide association study for T lymphocyte subpopulations in swine. BMC Genom. The evolutionary basis for differences between the immune systems of man, mouse, pig and ruminants.

Evolution of the V, D, and J gene segments used in the primate gammadelta T-cell receptor reveals a dichotomy of conservation and diversity. Control of immunoglobulin isotype production by porcine B-cells cultured with cytokines. Accessed 03 Dec Regulation of the gestation period in mice. J Reprod Fertil.

Sexual maturation of female house mice: social inhibition. Dev Psychobiol. Pathology of captive moustached tamarins Saguinus mystax. Comp Med. Spontaneous terminal ileitis resembling Crohn disease in captive tamarins. J Med Primatol. Macaque models of human infectious disease. Experimental models of inflammatory bowel disease. Review article: mechanisms of initiation and perpetuation of gut inflammation by stress. Aliment Pharmacol Ther. Evidence that colitis is initiated by environmental stress and sustained by fecal factors in the Cotton-Top Tamarin Saguinus oedipus.

Spontaneous pathology of the common marmoset Callithrix jacchus and tamarins Saguinus oedipus , Saguinus mystax. Visualizing cytokine-secreting cells in situ in the rhesus macaque model of chronic gut inflammation. Clin Diagn Lab Immunol. Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. J Pediatr. Characterization of the fecal microbiome from non-human wild primates reveals species specific microbial communities.

Microbial community analysis of rectal methanogens and sulfate reducing bacteria in two non-human primate species. Experimental Campylobacter jejuni infection in Macaca nemestrina. J Clin Microbiol. The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci. Brain—gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome. Lack of conservation effort rapidly increases African great ape extinction risk.

Conserv Lett. Effective feeding enrichment for non-human primates: a brief review. Anim Welf. B-virus Cercopithecine herpesvirus 1 infection in humans and macaques: potential for zoonotic disease. Emerg Infect Dis. Campylobacter jejuni colitis in gnotobiotic dogs. Can J Comp Med. Intestinal cytokine mRNA expression in canine inflammatory bowel disease: a meta-analysis with critical appraisal. Comparison of microbiological, histological, and immunomodulatory parameters in response to treatment with either combination therapy with prednisone and metronidazole or probiotic VSL 3 strains in dogs with idiopathic inflammatory bowel disease.

The rumen and its microbes. New York: Academic Press Inc; Gut inflammation and expression of ICC in a fetal lamb model of fetoscopic intervention for gastroschisis. Surg Endosc. Gut Pathog. An attenuated Salmonella enterica serovar Typhimurium strain lacking the ZnuABC transporter induces protection in a mouse intestinal model of Salmonella infection. J Immunol Methods. An animal model of necrotizing enterocolitis NEC in preterm rabbits. Fetal Pediatr Pathol. Cecectomy causes long-term reduction of colonization resistance in the mouse gastrointestinal tract.

The effect of caecectomy on the faecal concentrations of urobilinogen and active trypsin in mice. Microb Ecol Health Dis. Human intestine matures as nude mouse xenograft. Enterohemorrhagic Escherichia coli induce attaching and effacing lesions and hemorrhagic colitis in human and bovine intestinal xenograft models. Transplant of fetal intestine: survival and function in a subcutaneous in adult animals. Ann Surg. Human intestinal development in a severe-combined immunodeficient xenograft model.

Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. An intestinal xenograft model for Cryptosporidium parvum infection. Cryptosporidium parvum infection of human intestinal epithelial cells induces the polarized secretion of C-X-C chemokines. Cryptosporidium parvum infection of human intestinal xenografts in SCID mice induces production of human tumor necrosis factor alpha and interleukin Use of recombinant Entamoeba histolytica cysteine proteinase 1 to identify a potent inhibitor of amebic invasion in a human colonic model.

Eukaryot Cell. Human intestinal epithelial cells produce proinflammatory cytokines in response to infection in a SCID mouse-human intestinal xenograft model of amebiasis. Epithelial cell-initiated inflammation plays a crucial role in early tissue damage in amebic infection of human intestine. Tumor necrosis factor alpha is a key mediator of gut inflammation seen in amebic colitis in human intestine in the SCID mouse-human intestinal xenograft model of disease.

Development, characterization, and utilization of an intestinal xenograft model for infectious disease research. Lab Invest. Human embryonic gastric xenografts in nude mice: a new model of Helicobacter pylori infection. Mycobacterium avium paratuberculosis invades human small-intestinal goblet cells and elicits inflammation.

J Infect Dis. Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 ICAM -1 expression and neutrophil adhesion. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostaglandin h synthase-2 expression and prostaglandin E2 and F2alpha production.

Shigella infection in a SCID mouse-human intestinal xenograft model: role for neutrophils in containing bacterial dissemination in human intestine. Rumen cannulation: procedure and use of a cannulated bovine. Measurement of volatile fatty acid disappearance and fluid flux across the abomasum of cattle, using an improved omasal cannulation technique.

Am J Vet Res. Technical note: development of a duodenal cannula for sheep. These results were also verified as an independent predictor of patient survival using a multivariate Cox proportional hazards model. IMS has great potential in exploring biomolecular mechanisms underlying disorders. An IMS study developed a preliminary proteomic algorithm that could discriminate meningioma, glioma and non-tumor tissue, although the number of patients was very small In the present review, investigators used support vector machine models able to classify meningioma spectra using a training set built from: i a single brain tumor class that compared both glioma and meningioma with non-tumor tissue including blood ; ii a meningioma brain tumor class and non-tumor brain class; and iii a meningioma class, a glioma class, and a non-tumor brain class.

Training sets were built based on the gold standard of WHO histopathology classification of tumors of the central nervous system. Another group was able to discern glioblastoma and oligodendroglioma tumor biopsies by MS but not by IMS In conjunction with proteomic approaches to assess brain tumors, lipidomic signatures could also provide beneficial information regarding diagnosis, grading and the resection margins Furthermore, pharmacokinetics and pharmacodynamics studies have been performed.

Salphati et al visualized and compared the distribution of PI3K inhibitors in glioblastoma multiforme in mouse brain by IMS. Drug transit through the blood-brain barrier BBB is essential for therapeutic response in malignant glioma and was studied by IMS In this review, three examples of drug transit through the BBB were reported in mouse brain. In all cases, drugs were found to penetrate the BBB. Specifically, RAF and erlotininb were localized within tumor regions, whereas BKM distributed in the brain parenchyma.

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Notably, drugs distributed independently of the heme signal, indicating the escape of the drug molecules from the tumor vasculature. Additionally, other proteomic mass spectrometric techniques contributed to new insights into breast cancer pathogenesis and prognosis reviewed in ref. Dijda et al 63 used human breast tumor tissue for the optimization of the protocol for detection of peptides in FFPE sections.

Read Chapter 003 Small Animal Imaging as a Tool for Modeling CNS Disorders:Strengths and Weaknesses

Cornett et al 58 described an automated workflow integrating histopathology and breast tissue profiling of various components in breast cancer tissue. A further IMS analysis of human breast cancer sections revealed three proteins to be specifically localized in different regions of the cancer tissue IMS of metastatic breast cancer in a lymph node found protein signals specifically localized in histologically defined regions An IMS study comparing breast primary tumors from patients with or without lymph node involvement highlighted six differently expressed proteins that could predict lymph node status Besides efforts to elucidate prognostic biomarkers, also predictive profiles have been identified.

This is of special interest since at present HER2 amplification status is determined by immunohistochemistry or in situ hybridization or both. These methods suffer from subjective interpretation as well as from high costs and are time-consuming Dekker et al 73 were able to demonstrate mass signals for stromal activation in breast carcinoma. Furthermore, IMS has been utilized to assess the distribution of lipids in breast cancer showing that heterogeneity is not only restricted to the proteome , Since most metastases are adenocarcinomas it might be challenging for the pathologist to determine the origin of the primary tumor.

Ion density map of HSB 27 protein show an exclusive distribution to a subset of breast biopsies a—c , whereas SH3L1 is highly expressed in pancreas biopsies d—f. IMS was able to discern between the gastric cancer and the normal gastric mucosa Furthermore, protein profiles from early stage gastric cancer were significantly different from advanced stage gastric tumors Also, specific signals for poorly differentiated gastric cancer were found Choi et al identified proteins as negative regulators for lymph node metastasis in gastric adenocarcinoma.

A seven-protein signature was associated with unfavorable overall survival independent of major clinical covariates as demonstrated by MALDI IMS on frozen tissues Thomas et al applied IMS technique to detect lipids in human colorectal liver metastasis biopsies. With the help of a tissue based proteomic approach, a large panel of proteins that are associated with regional lymph node metastasis was identified The penetration and distribution of platinum-based metallodrugs was demonstrated in metastatic tissue of colon cancer by IMS Djidja et al 81 identified a glucose-regulated protein as a biomarke r within pancreatic tumor tissue sections.

Moreover, metastatic tissue from breast cancer could be discerned from pancreatic cancer with an overall accuracy of Investigation of large tissue sections of duodenal mucosa, normal pancreatic tissue and pancreatic carcinoma by MALDI IMS could clearly discern the various tissue compartments Fig. Pancreatic intraepithelial neoplasia PanIN is highlighted by a square. Le Faouder et al 75 were able to distinguish hepatocellular carcinoma from cirrhosis by IMS. Rahman et al and Yanagisawa et al 76 reported proteomic patterns specific for normal alveolar and bronchial tissues, pre-invasive lesions and invasive lung cancer.

Analysis of microarrays of biopsies from adenocarcinoma and squamous cell carcinoma was performed by Groseclose et al 67 and could clearly discern both tumor types without immunohistochemistry. Besides the proteomic profile, lung cancer could be subclassified also by lipid analysis Proteomic strategies in lung cancer diagnostics in tissue, blood and serum are described elsewhere in detail Notably, EGF-receptor antagonists as target drugs in lung cancer were characterized in lung cancer tissue Schwamborn et al could distinguish between classical Hodgkin lymphoma and lymphadenitis.

Hardesty et al found peptides that discriminate prognostic subgroups in melanoma patients. Additionally, this group identified signatures associated with favorable and poor survival. IMS has also been utilized to differentiate Spitz naevus and melanoma, which is important due to the completely different therapeutic consequences of both entities Sugihara et al introduced IMS to provide new information on one of the drugs vemurafenib currently used in the treatment of malignant melanoma.

IMS techniques have been used to discriminate thyroid cancer specific peptides from normal thyroid tissue The authors found a thyroid cancer specific protein, however, only five patients were included in the study. Other investigators 14 identified not only a specific proteomic pattern to discriminate non-metastatic from metastatic thyroid cancers but showed also a functional relationship between these proteins and a specific pathway. Pagni et al 66 were able to distinguish between different thyroid lesions applying IMS to fine needle aspiration smears.

With these results, investigators highlighted a potential role of MALDI IMS as a supporting tool to discriminate malignant from benign thyroid lesions as well as between different types of thyroid lesions. Oppenheimer et al 44 studied tumor margins of renal cell carcinoma by IMS. IMS has been used to identify and map specific peptides that accurately distinguished malignant from normal renal tissue Oezdemir et al reported improvement of grading of non-invasive papillary urothelial neoplasia applying IMS.

A recent report utilized IMS for the analysis of a bladder cancer tissue microarray to evaluate prognostically relevant molecules Lemaire et al not only discriminated between benign and malignant ovarian tumors, but identified a new candidate protein biomarker only present in ovarian carcinoma. Specific proteins in tumor interface zones associated with ovarian serous cancer tissues, were described by Kang et al Liu et al demonstrated that sulfatides are more abundant in ovarian cancer than control tissues. Drug distribution of platinum-based drugs was shown in peritoneal carcinomatosis of ovarian cancer Studies of prostate cancer have utilized IMS to aid diagnosis and for the discovery of proteins relevant to the underlying biology 41 , 82 , The first clinical study of human prostate cancer by IMS was performed by Schwambor et al A specific fragment of mitogen activated protein kinase could discriminate cancer from normal prostatic tissue Furthermore, a marker for early recurrence of prostate cancer has been identified by Steurer et al One report utilized IMS for the classification of myxoid sarcomas.

Willems et al 40 could discriminate myxofibrosarcoma and myxoid liposarcoma that may share a similar histology. Furthermore, intratumoral heterogeneity was demonstrated in myxofibrosarcomas. In human tissue and cells, tumor-associated alterations were studied in various entities.

MALDI IMS may improve exact determination of tumor margins, tumor typing, grading and prognosis and could have therapeutic implications. Diagnostic procedures in pathology are based on histology, histochemistry, immunohistochemistry and molecular pathology and will include proteomic techniques like MALDI IMS to improve diagnostic accuracy. Additionally, we foresee that immunohistochemical methods will be at least partly replaced by IMS. This is of great importance, especially if molecular testing is required for diagnostics and only small tissue biopsies are available for such tests.

In this regard, MALDI IMS requires only one tissue section for the analysis, thus adequate remaining tissue is available for additional molecular testing. In this scenario, elaborate molecular testing of DNA and RNA alterations will be performed either by next generation sequencing or by mass spectrometric techniques. Applications of IMS in the clinic are growing as this technology has proved its feasibility and versatility. The implementation of biocomputational tools combined with IMS will allow biostatistical evaluation for determination of molecular signals able to type or grade tumors and will provide information about prognosis.

Furthermore, drug distribution in different tissue types and cellular components may be monitored by IMS. To ensure similar sample preparation and processing, robust standard operating procedures need to be developed for the application of IMS in routine histopathology.

Quality control will be achieved by interlaboratory validation as well as by sharing large databases of MALDI signatures of tumors or other diseases. Clin Chem. View Article : Google Scholar.

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Clin Microbiol Rev. Curr Opin Microbiol. Kueger S, Steinhauser D, Willmitzer L and Giavalisco P: High-resolution plant metabolomics: from mass spectral features to metabolites and from whole-cell analysis to subcellular metabolite distributions.

Plant J. Mol Cell Proteomics. View Article : Google Scholar :. Anal Chem. Methods Mol Biol. Oral Oncol. Int J Mol Med. Scand J Rheumatol. Trends Biotechnol. J Proteome Res. J Mol Med. Anticancer Res. Morita Y, Ikegami K, Goto-Inoue N, et al: Imaging mass spectrometry of gastric carcinoma in formalin-fixed paraffin-embedded tissue microarray. Cancer Sci. Horn PJ and Chapman KD: Lipidomics in situ: insights into plant lipid metabolism from high resolution spatial maps of metabolites. Prog Lipid Res. Chem Phys Lipids. Mass Spectrom Rev. May 26— View Article : Google Scholar : Epub ahead of print.

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J Pathol. J Pharm Biomed Anal. Cancer Res. Angel PM and Caprioli RM: Matrix-assisted laser desorption ionization imaging mass spectrometry: in situ molecular mapping. Expert Rev Proteomics. Mass Spectrom. Histol Histopathol. Schwamborn K and Caprioli RM: Molecular imaging by mass spectrometry: looking beyond classical histology. Nat Rev Cancer. Chaurand P: Imaging mass spectrometry of thin tissue sections: a decade of collective efforts. Rompp A and Spengler B: Mass spectrometry imaging with high resolution in mass and space.

Histochem Cell Biol. Goodwin RJ: Sample preparation for mass spectrometry imaging: small mistakes can lead to big consequences. Nat Med. High field MRI scanners, operating in the range of 4. In comparison, standard clinical MRI scanners operate in the range of 0. There are two major advantages of using ultra-high magnetic field scanners for diffusion-weighted imaging.

High-field animal scanners are equipped with strong imaging gradients, essential for high spatial resolution and strong diffusion gradient pulses. However, increased sensitivity to artefacts demand careful optimization of MRI acquisition parameters to deliver highest quality images [ 13 ]. Many DWI studies of the mouse brain have been performed using ex vivo imaging because they provide high spatial resolution images and are free of motion artefacts compared to live imaging.

However, ex vivo imaging does not allow longitudinal monitoring of disease progression. In addition, ex vivo diffusion is affected by the fixation procedures, and therefore they may show a different specificity compared to in vivo DWI [ 14 ]. Preclinical rodent in vivo DWI data has predominantly been acquired using the spin-echo sequence SE-DWI [ 15 — 17 ] due to its greater immunity to magnetic susceptibility at high magnetic field.

This sequence, however, is time-consuming and allows a limited number of diffusion encoding directions 6—12 directions within a reasonable data acquisition time. These requirements for HARDI acquisition can be problematic for in vivo DWI, as high b-values result in lower overall SNR, and the increased number of diffusion encoding directions result in a longer acquisition time. The use of EPI readout provides several advantages: it reduces the susceptibility to bulk patient motion or physiological movements because the data is acquired in fractions of a second [ 21 , 22 ]; its short acquisition time allows HARDI acquisition with a large number of diffusion-encoding directions; it can provide a high SNR per unit of scanning time, an advantage for DWI [ 23 , 24 ].

Our optimization of the sequence parameters addressed technical challenges of DWI of the rodent brain in an ultra-high magnetic field, including the effect of relaxation times, magnetic susceptibility, motion and chemical shift artefacts. The Stjeskal-Tanner spin-echo DWI SE-DWI sequence is the preferred imaging technique for ex vivo mouse brains because it maximises signal-to-noise ratio and spatial resolution given no specific constraint on experiment time [ 5 , 7 , 10 ].

However, in vivo mouse brain imaging is time limited, requiring anaesthesia and consideration of animal wellbeing.

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SE-DWI is also more susceptible to motion artefacts due to relatively long acquisition times required, resulting in cumulative phase encoding errors [ 29 ]. The combination of phase errors and less time for signal averaging result in reduced SNR. To compensate for this limitation, images are often acquired with thicker slices resulting in increased adverse partial volume effects [ 5 , 30 ].

With such considerations, optimising SE-DWI acquisitions to achieve both high in-plane and slice resolution, as well as a high number of diffusion encoding-directions, is problematic. Therefore this sequence was not assessed in this study. Compared to the spin-echo sequence, EPI is more susceptible to a number of artefacts, such as increased sensitivity to magnetic field inhomogeneity, image blurring, Nyquist ghosting, chemical shift and eddy current artefacts [ 24 , 32 ]. The major cause of distortion at high magnetic field is local magnetic field inhomogeneity due to magnetic susceptibility differences between adjacent tissues [ 32 ].

EPI, consisting of a sequence of gradient echoes, suffers more severely from susceptibility effects compared to spin-echo sequences, especially with increasing length of echo train and echo spacing due to phase error accumulation [ 33 ]. These problems are more pronounced for in vivo mouse brain MRI than in human imaging because of the relatively small rodent brain size compared to the affected areas and because of the higher field strengths generally associated with small animal imaging.

Pronounced signal loss and distortion is observed around the air cavities of the jaw, ear canals and olfactory bulb, and to a lesser extent, the brain-skull interface [ 34 ]. Therefore, the imaging sequence echo time TE must be minimised to allow echo acquisition with sufficient SNR [ 35 ]. Nyquist ghosts are caused by EPI gradient readout errors. Any mismatch between the alternating gradients due to eddy current effects gives rise to phase errors causing ghosting in the phase-encoding direction [ 36 ].

Eddy currents are residual magnetic fields induced by gradient switching. They persist after the gradients are switched off, even in self-shielded gradients, causing image distortion through scaling, shifting and shearing in image slices [ 37 ]. The effect of eddy currents in DWI is magnified due to the large diffusion gradients employed. DWI sequences using bipolar diffusion gradients [ 1 , 32 ] can be used to minimize this problem. However, if high b-values are required, bipolar gradients may require longer echo times [ 38 , 39 ].


We have noted that image distortion due to eddy current artefacts is negligible in our scanner. Eddy current artefacts can be minimised with careful gradient eddy current compensation preemphasis adjustment. Chemical shift artefacts are more severe at higher magnetic field with the linear increase in resonance frequency separation of fat and water signals [ 36 ]. Nyquist ghosting also deteriorates image quality further in the presence of chemical shift artefacts. Chemical shift artefacts can be minimized using EPI with high receiver bandwidth to reduce the sampling time and consequently the echo spacing, but at the expense of lower SNR.

Fat suppression saturation techniques are therefore necessary for EPI sequences [ 40 ]. A combination of the segmented-EPI DWI sequence [ 41 ] with a partial Fourier acquisition and reconstruction [ 42 ] is preferred for imaging at high magnetic fields as the TE can be significantly shortened. Higher segmentation factors will result in increased accumulation of phase errors.

Bulk motion results in variations in phase shift between successive echoes resulting in image ghosting and the introduction of diffusion-weighting further complicates the correction of the introduced phase error [ 44 ]. Navigator echo correction utilises non-phase encoding echoes before or after the imaging echo to correct phase variations of the acquired imaging echoes. The echo position is used to determine the shifts in k-space so that the data can be re-gridded accordingly [ 28 , 45 — 47 ].

Immobilization of the subject is usually achieved with general anaesthesia and physical restraint head mask, tooth bar and tape. Administration of anaesthesia using isoflurane-oxygen mixture inhalation is preferred over intraperitoneal injection because it allows for continuous adjustment according to the condition of the animal throughout the duration of the experiment [ 48 , 49 ].

Respiratory monitoring and triggering during image acquisition reduces propagation of motion artefacts. Sharp inhalation or exhalation or irregular patterns should be avoided. Acquisition should be initiated during a plateau in the breathing cycle of the animal. Respiratory triggering, however, increases the experimental time by factor of approximately two [ 48 , 50 , 51 ].

MRI data were acquired on a To reduce geometrical distortion, the mouse brain was initially shimmed globally using a standard free-induction decay FID -based first order and Z 2 shimming procedure. Then a Bruker Mapshim protocol, which employs magnetic field-map information, was used to optimize the shimming of the whole head volume using the first and second order shims. Finally, a localized shim was performed on a rectangular voxel derived using the Point Resolved Spectroscopy PRESS method and placed in the centre and encompassing the entire brain to refine the first and second order shims [ 52 ].

The improvement obtained by localized field map shimming is shown in S1 Fig. Four dummy scans were employed to ensure steady state conditions. Sixty-four diffusion direction-encoding measurements were acquired within approximately 55 minutes without respiratory triggering and 2 hours with respiratory triggering. The respiratory triggering was required to minimize motion artefacts.

Two excitation averages NEX were used to increase the SNR, whilst maintaining a reasonable experimental time frame of 2 hours. Segmentation of the echo train is required to reduce off-resonance artefacts. RF radiofrequency , Gz slice gradient , Gy phase gradient , and Gx readout gradient. MRI data was acquired from 24 contiguous slices acquired at 0. Partial k-space data was acquired in the phase encoding dimension with a combination of partial Fourier transform FT and zero-fill acceleration factors of 1.

The encoding acceleration reduced the echo train length ETL to avoid acquisition at the late stage of the T 2 relaxation period Fig 2 and the total acquisition time. Encoding acceleration in the frequency-encoding dimension was not used, as it did not reduce TE or the acquisition time. This diagram shows the combination of zero filling and partial Fourier transformation and how they are applied to fill k-space. Zero filling reduces the echo train length and consequently avoids acquisition at late echo period with significant signal decay. Dashed lines represent K-space lines, which were not acquired by the combined zero-fill and partial Fourier accelerated acquisition.

The EPI echo train was segmented into 10, 8 and 4 segments to assess the optimal level of segmentation with respect to acquisition time, sensitivity to motion artefacts and reduction of the echo time. Four shot segmentation was found to be optimal. To reduce motion artefacts, diffusion images were registered to a single b 0 image image acquired without the application of diffusion gradients using 2D translation only rigid body registration using the program FSL FLIRT fsl.

The corpus callosum was divided into small segments, including forceps minor and major, rostral, middle and caudal. Other WM structures examined included the external capsule, right and left cerebral peduncles, optic tracts, internal capsule and optic nerve, segmented according to the histological atlas [ 54 ]. ROI were drawn manually on FA maps of each individual mouse.

This image sequence represents rostral top left to caudal bottom right brain slices. The following structures were analysed: Rt green and Lt brown optic nerve ON , forceps minor corpus callosum fmi navy , rostral corpus callosum R-cc red , middle corpus callosum M-cc green , external capsule ec yellow , fimbria fi dark blue , internal capsule ic green , caudal corpus callosum C-cc blue , Rt navy and Lt pink optic tract opt , Rt brown and Lt red cerebral peduncle cp and forceps major corpus callosum fmj dark red.

Partial Fourier k-space encoding acceleration was applied in both phase- and frequency-encoding dimensions using an acceleration factor of 1. These parameters resulted in an acquisition period of 4. Thus only sacrificed animals were imaged using these protocols. SNR measurements were obtained from images acquired with and without diffusion gradients.

Two ROIs were defined in the central slice package: 1 inside the brain tissue to measure the signal intensity and 2 outside the head to measure the background noise. SNR was calculated as the mean signal intensity of the brain tissue minus the mean signal intensity of the background, divided by the standard deviation of the background [ 55 ].

SE-DWI was tested to obtain diffusion measurements at On the other hand, in situ diffusivity parameters are generally smaller than those obtained in vivo , presumably due to the absence of blood flow and physiological motion during in situ acquisitions [ 14 ]. Increasing number of segments showed more motion artefacts due to more misalignment of k-space lines. Four-segmented ETL produced a good compromise between low image distortion, low sensitivity to motion and reasonable total acquisition time Fig 6C.

This can be observed in the anterior cingulate cortex adjacent to the corpus callosum. Most of the major WM structures can be easily identified, including the corpus callosum, external capsule, cerebral peduncles, optic tracts, optic nerve and fimbria. Fig 8 shows FA colour maps of the mouse brain from rostral to caudal slices wherein the WM structures were clearly visualized according to their expected fibre directions. The quality of the images was acceptable, even in regions that are problematic, such as the optic nerves Fig 9.