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ADC apparent diffusion coefficient (mm2/s) BOLD blood oxygen-level dependent (contrast) f tissue perfusion (in ml/s/g tissue or ml/min/100 g tissue) FA fractional anisotropy

MTR magnetization transfer ratio is the ratio between the equilibrium magnetization and the steady-state magnetization under saturation conditions

Rj relaxation rate (s_1) T relaxation time (s)

ADC apparent diffusion coefficient (mm2/s) BOLD blood oxygen-level dependent (contrast) f tissue perfusion (in ml/s/g tissue or ml/min/100 g tissue) FA fractional anisotropy

MTR magnetization transfer ratio is the ratio between the equilibrium magnetization and the steady-state magnetization under saturation conditions

Rj relaxation rate (s_1) T relaxation time (s)

of choice for structural neuroimaging. A weak point of the method is its inherent low sensitivity, which has a negative impact on spatial resolution. Correspondingly, identifying small brain structures or assessing subtle/minor pathological alterations, putting high demands on spatial resolution, is challenging. Substantial efforts have been made in recent years to increase MR sensitivity by either moving to higher static magnetic field strengths or by refining RF detection devices, such as the cryogenic detection technology. State-of-the-art MR systems for routine clinical neuroimaging (Konarski et al. 2007) operate at 3 T allowing for spatial resolutions in the order of 1 mm3 (Fig. 1a), while clinical research systems up to 7.0 T have been constructed. In contrast, the high spatial resolution required in rodent brain imaging led to the development of MR systems operating at up to 17.6 T. For example, the combination of high magnetic field strength (9.4 T) with cryogenic RF detection devices enabled the routine recording of high-resolution (52 x 52 x 170 m3)

mouse brain images (Fig. 1b) in a measurement time of 10 min (Baltes et al. 2009).

In structural MRI, usually morphometric comparisons between groups are performed using hypothesis-based selection of regions of interest (ROIs), which is a lengthy process and prone to evaluation errors. More recently, voxel-based morphometry (VBM) has been developed as a fully automated comparison of whole brains on a voxel-by-voxel basis. After spatial normalization of the brains to a stereotactic standard space, brain regions are compared with respect to differences in residual tissue concentrations rather than differences in shape. Clinical application of structural readouts using MRI cover a broad range of disorders from neurodegenerative (i.e., stroke and dementia) to neuropsychiatric diseases (American Psychiatric Association (APA) 2000) (e.g., ► schizophrenia, ► posttraumatic stress disorder (PTSD), or mood disorders, such as ► bipolar affective disorders). For example, VBM studies in schizophrenia generally confirmed and

Magnetic Resonance Imaging. Fig. 1. Visualization of neuroanatomical structures in the human (a) and in the mouse brain (b) put different demands on spatial resolution. While an in-plane resolution of 0.9 x 0.9 mm2 in human subjects is sufficient for gray vs. white matter discrimination, a resolution of 52 x 52 m2 is required in mouse brain to depict cortical structures, such as subfields of the hippocampus. For comparison of the dimensions, the mouse brain image (b) is depicted as inset in the human brain image (a) using the same scale. (Courtesy of R. Luechinger, PhD, University and ETH Zurich, Switzerland.)

extended ROI-based studies showing less gray matter concentration in multiple cortical and subcortical regions (Pearlson and Calhoun 2007). In patients suffering, e.g., from bipolar disorders, structural MRI has been applied to assess neuroanatomical abnormalities between healthy subjects and patients. While overall brain volumes appeared to be normal, regional differences have been observed in prefrontal cortex, and subcortical and medial temporal structures involved in the behavioral network, which is known to be affected in bipolar disorders (Stra-kowski et al. 2005). Similarly, in preclinical MRI, mor-phometric readouts hold promise to phenotype rodent models of central nervous system (CNS) diseases with applications in mouse models of neurological disorders such as ► Alzheimer's disease (AD) or ► Huntington's disease or in rat models of schizophrenia. Its value for detection of subtle or diffuse morphometric abnormalities, i.e., in neuropsychiatric models that are predictive for disease progression or can serve as surrogate markers for end-stage disease status has to be further validated in carefully planned and analyzed longitudinal studies.

While structural MRI provides information on neuroanatomical alterations preceding or accompanying psychiatric diseases, fMRI allows assessing changes in neuronal activation patterns between healthy subjects and patients, which might be more closely related to the disease progression or effects of drug administration.

Functional MRI

Underlying Biological Processes fMRI is widely applied in clinical and preclinical studies to assess brain function, keeping in mind that the MR method is sensitive to hemodynamic changes prompted by neuronal activity rather than the neuronal activation itself. Local neuronal activity leads to an increased consumption of oxygen and nutrients triggering an increase in local perfusion, i.e., regional cerebral blood flow (CBF) and cerebral blood volume (CBV) (Fig. 2). As the efficiency of oxygen extraction decreases with increasing flow rates, the venous blood contains more oxygenated hemoglobin in the activated state when compared with the resting state. The higher concentration of oxyhemoglobin, and correspondingly the lower concentration of paramagnetic deoxyhemoglobin during activation leads to a decrease in R2* relaxation rates, thus an increase in the MR signal. This mechanism, called blood oxygenation level dependent (► BOLD) contrast, has found widespread use in the neuroscience community to study brain function under physiological and pathological conditions. It is

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