In this study, we used tract-based spatial statistics (TBSS) to analyze diffusion tensor MR imaging (DTI) data acquired from the rat brain, ex vivo, for the first time. The aim was to highlight potential changes in the whole brain anatomy in the kainic acid model of epilepsy, and further characterize the changes with histology. Increased FA was observed in dorsal endopiriform nucleus, external capsule, corpus callosum, dentate gyrus, thalamus, and optic tract. A decrease in FA was seen in the horizontal limb of the diagonal band, stria medullaris, habenula, entorhinal cortex, and superior colliculus. Some of the areas have been described in kainic acid model before. However, we also found regions that to our knowledge have not been previously reported to undergo structural changes, in this model, including stria medullaris, nucleus of diagonal band, habenula, superior colliculus, external capsule, corpus callosum, and optic tract. Four of the areas highlighted in TBSS (dentate gyrus, entorhinal cortex, thalamus and stria medullaris) were analyzed in more detail with Nissl, Timm, and myelin-stained histological sections, and with polarized light microscopy. TBSS together with targeted histology confirmed that DTI changes were associated with altered myelination, neurodegeneration, and/or calcification of the tissue. Our data demonstrate that DTI in combination with TBSS has a great potential to facilitate the discovery of previously undetected anatomical changes in animal models of brain diseases.
This is a preview of subscription content, log in to check access.
This work was supported by Academy of Finland and Sigrid Juselius Foundation. We thank Ms. Maarit Pulkkinen for assistance in histology, Dr. Jari Nissinen for technical assistance, MSc Kari Mauranen for consultation in statistical analysis, and MSc Nick Hayward for revising the language of the manuscript.
Conflict of interest
The authors declare no competing financial interests.
Basser PJ, Pierpaoli C (1998) A simplified method to measure the diffusion tensor from seven MR images. Magn Reson Med 39:928–934PubMedCrossRefGoogle Scholar
Douaud G, Smith S, Jenkinson M, Behrens T, Johansen-Berg H, Vickers J, James S, Voets N, Watkins K, Matthews PM, James A (2007) Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain 130:2375–2386PubMedCrossRefGoogle Scholar
Du F, Eid T, Lothman EW, Kohler C, Schwarcz R (1995) Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J.Neurosci 15:6301–6313PubMedGoogle Scholar
Garant DS, Gale K (1987) Substantia nigra-mediated anticonvulsant actions: role of nigral output pathways. Exp Neurol 97:143–159PubMedCrossRefGoogle Scholar
Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15:870–878PubMedCrossRefGoogle Scholar
Hirsch E, Snead OC, Vergnes M, Gilles F (1992) Corpus callosotomy in the lithium-pilocarpine model of seizures and status epilepticus. Epilepsy Res 11:183–191PubMedCrossRefGoogle Scholar
Hopkins KJ, Wang GJ, Schmued LC (2000) Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res 864(1):69–80PubMedCrossRefGoogle Scholar
Insausti R, Herrero MT, Witter MP (1997) Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 7:146–183PubMedCrossRefGoogle Scholar
Jenkinson M, Smith S (2001) A global optimisation method for robust affine registration of brain images. Med Image Anal 5:143–156PubMedCrossRefGoogle Scholar
Jenkinson M, Bannister P, Brady M, Smith S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17:825–841PubMedCrossRefGoogle Scholar
Laitinen T, Sierra A, Pitkanen A, Grohn O (2010) Diffusion tensor MRI of axonal plasticity in the rat hippocampus. Neuroimage 51:521–530PubMedCrossRefGoogle Scholar
Larsen L, Griffin LD, Grassel D, Witte OW, Axer H (2007) Polarized light imaging of white matter architecture. Microsc Res Tech 70:851–863PubMedCrossRefGoogle Scholar
Nairismagi J, Grohn OH, Kettunen MI, Nissinen J, Kauppinen RA, Pitkanen A (2004) Progression of brain damage after status epilepticus and its association with epileptogenesis: a quantitative MRI study in a rat model of temporal lobe epilepsy. Epilepsia 45:1024–1034PubMedCrossRefGoogle Scholar
Pajevic S, Pierpaoli C (1999) Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: application to white matter fiber tract mapping in the human brain. Magn Reson Med 42:526–540PubMedCrossRefGoogle Scholar
Puig J, Pedraza S, Blasco G, Daunis-I-Estadella J, Prats A, Prados F, Boada I, Castellanos M, Sanchez-Gonzalez J, Remollo S, Laguillo G, Quiles AM, Gomez E, Serena J (2010) Wallerian degeneration in the corticospinal tract evaluated by diffusion tensor imaging correlates with motor deficit 30 days after middle cerebral artery ischemic stroke. AJNR Am J Neuroradiol 31:1324–1330PubMedCrossRefGoogle Scholar
Rieppo J, Hallikainen J, Jurvelin JS, Kiviranta I, Helminen HJ, Hyttinen MM (2008) Practical considerations in the use of polarized light microscopy in the analysis of the collagen network in articular cartilage. Microsc Res Tech 71:279–287PubMedCrossRefGoogle Scholar
Risold PY, Swanson LW (1995) Cajal’s nucleus of the stria medullaris: characterization by in situ hybridization and immunohistochemistry for enkephalin. J Chem Neuroanat 9:235–240PubMedCrossRefGoogle Scholar
Schwob JE, Fuller T, Price JL, Olney JW (1980) Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: a histological study. Neuroscience 5(6):991–1014PubMedCrossRefGoogle Scholar
Shepherd TM, Ozarslan E, King MA, Mareci TH, Blackband SJ (2006) Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus. Neuroimage 32:1499–1509PubMedCrossRefGoogle Scholar
Sloviter RS (1982) A simplified Timm stain procedure compatible with formaldehyde fixation and routine paraffin embedding of rat brain. Brain Res Bull 8:771–774PubMedCrossRefGoogle Scholar
Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505PubMedCrossRefGoogle Scholar
Smith SM, Johansen-Berg H, Jenkinson M, Rueckert D, Nichols TE, Miller KL, Robson MD, Jones DK, Klein JC, Bartsch AJ, Behrens TE (2007) Acquisition and voxelwise analysis of multi-subject diffusion data with tract-based spatial statistics. Nat Protoc 2:499–503PubMedCrossRefGoogle Scholar
Tovar-Moll F, Evangelou IE, Chiu AW, Richert ND, Ostuni JL, Ohayon JM, Auh S, Ehrmantraut M, Talagala SL, McFarland HF, Bagnato F (2009) Thalamic involvement and its impact on clinical disability in patients with multiple sclerosis: a diffusion tensor imaging study at 3T. AJNR Am J Neuroradiol 30:1380–1386PubMedCrossRefGoogle Scholar
Zhang J, van Zijl PC, Mori S (2002) Three-dimensional diffusion tensor magnetic resonance microimaging of adult mouse brain and hippocampus. Neuroimage 15:892–901PubMedCrossRefGoogle Scholar