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The midbrain periaqueductal gray (PAG) region is organized into distinct subregions that coordinate survival-related responses during threat and stress [Bandler R, Keay KA, Floyd N, Price J (2000) Brain Res 53 (1): [95][96][97][98][99][100][101][102][103][104]. To examine PAG function in humans, researchers have relied primarily on functional MRI (fMRI), but technological and methodological limitations have prevented researchers from localizing responses to different PAG subregions. We used high-field strength (7-T) fMRI techniques to image the PAG at high resolution (0.75 mm isotropic), which was critical for dissociating the PAG from the greater signal variability in the aqueduct. Activation while participants were exposed to emotionally aversive images segregated into subregions of the PAG along both dorsal/ventral and rostral/caudal axes. In the rostral PAG, activity was localized to lateral and dorsomedial subregions. In caudal PAG, activity was localized to the ventrolateral region. This shifting pattern of activity from dorsal to ventral PAG along the rostrocaudal axis mirrors structural and functional neurobiological observations in nonhuman animals. Activity in lateral and ventrolateral subregions also grouped with distinct emotional experiences (e.g., anger and sadness) in a factor analysis, suggesting that each subregion participates in distinct functional circuitry. This study establishes the use of high-field strength fMRI as a promising technique for revealing the functional architecture of the PAG. The techniques developed here also may be extended to investigate the functional roles of other brainstem nuclei.brain stem | neuroimaging | emotion | high-resolution T he periaqueductal gray (PAG) is a small tube-shaped region of the midbrain involved in survival-related responses and homeostatic regulation important for affective responses and stress (1-3). Subregions of the PAG underlie distinct, coordinated behavioral responses to threat. For example, stimulation in the lateral/dorsolateral portion produces active-coping responses (e.g., "fight" or "flight") that involve increasing heart rate and arterial pressure, redistribution of the blood to the limbs, and a fast-acting, nonopioid-mediated analgesia. Stimulation in the ventrolateral portion produces passive-coping responses (i.e., disengagement, freezing) that involve reduced heart rate, decreased reactivity to the environment, and a longer-term, opioid-mediated analgesic response. These responses occur even when inputs to PAG from the cortex are severed (1, 4).The considerable animal literature on the critical role of the PAG in coordinating emotional responses has led to a surge of interest in studying the PAG in humans. The PAG plays a central role in neurobiologically inspired theories of human emotion (5), the neural circuitry underlying depression and anxiety (3, 6), autonomic regulation (7), and pain (8-11). To examine PAG function in humans, researchers have relied primarily on functional MRI (fMRI). To date, dozens of human neuroimaging...

These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.

The rapid development of transgenic mouse models of neurodegenerative diseases, in parallel with the rapidly expanding growth of MR techniques for assessing in vivo, non-invasive, neurochemistry, offers the potential to develop novel markers of disease progression and therapy. In this review we discuss the interpretation and utility of MRS for the study of these transgenic mouse and rodent models of neurodegenerative diseases such as Alzheimer's (AD), Huntington's (HD) and Parkinson's disease (PD). MRS studies can provide a wealth of information on various facets of in vivo neurochemistry, including neuronal health, gliosis, osmoregulation, energy metabolism, neuronal-glial cycling, and molecular synthesis rates. These data provide information on the etiology, natural history and therapy of these diseases. Mouse models enable longitudinal studies with useful time frames for evaluation of neuroprotection and therapeutic interventions using many of the potential MRS markers. In addition, the ability to manipulate the genome in these models allows better mechanistic understanding of the roles of the observable neurochemicals, such as N-acetylaspartate, in the brain. The argument is made that use of MRS, combined with correlative histology and other MRI techniques, will enable objective markers with which potential therapies can be followed in a quantitative fashion.

Sphingosine 1-phosphate (SP1) receptors may be attractive targets for modulation of inflammatory processes in neurodegenerative diseases. Recently fingolimod, a functional S1P1 receptor antagonist, was introduced for treatment of multiple sclerosis. We postulated that anti-inflammatory mechanisms of fingolimod might also be protective in Alzheimer’s disease (AD). Therefore, we treated a mouse model of AD, the 5xFAD model, with two doses of fingolimod (1 and 5 mg/kg/day) and measured the response of numerous markers of Aβ pathology as well as inflammatory markers and neurochemistry using biochemical, immunohistochemistry and high resolution magic angle spinning magnetic resonance spectroscopy (MRS). In mice at 3 months of age, we found that fingolimod decreased plaque density as well as soluble plus insoluble Aβ measured by ELISA. Fingolimod also decreased GFAP staining and the number of activated microglia. Taurine has been demonstrated to play a role as an endogenous anti-inflammatory molecule. Taurine levels, measured using MRS, showed a very strong inverse correlation with GFAP levels and ELISA measurements of Aβ, but not with plaque density or activated microglia levels. MRS also showed an effect of fingolimod on glutamate levels. Fingolimod at 1 mg/kg/day provided better neuroprotection than 5 mg/kg/day. Together, these data suggest a potential therapeutic role for fingolimod in AD.

Although previous studies of focal hand dystonia have detected cortical sensorimotor abnormalities, little is known about the role of the basal ganglia in this disorder. We report here that when focal hand dystonic patients performed finger-tapping tasks, functional magnetic resonance imaging showed persisting elevations of basal ganglia activity after the tasks ended. We posit that inhibitory control of the basal ganglia may be faulty in focal hand dystonia, and that the increases we observe in "resting" activity may mask basal ganglia abnormalities in standard imaging contrast analyses.

Relative to common clinical magnetic field strengths, higher fields benefit functional brain imaging both by providing additional signal for high-resolution applications and by improving the sensitivity of endogenous contrast due to the blood oxygen level dependent (BOLD) mechanism, which has limited detection power at low magnetic fields relative to the use of exogenous contrast agent. This study evaluates the utility of iron oxide contrast agent for gradient echo functional MRI at 9.4 T in rodents using cocaine and methylphenidate as stimuli. Relative to the BOLD method, the use of high iron doses and short echo times provided a roughly twofold global increase in functional sensitivity, while also suppressing large vessel signal and reducing susceptibility artifacts. MRI is widely used to assess brain function in humans and animals due to a powerful combination of capabilities, including high spatiotemporal resolution, volumetric coverage, and the potential for noninvasive, longitudinal studies. Many of the target applications for fMRI in animal models are inherently challenging in terms of sensitivity. For instance, functional signals often are attenuated in disease or recovery states, such as the evolution of neuronal plasticity during recovery from stroke (1-3). Pharmacological stimuli can produce widespread, graded, dosedependent changes in local brain function; low-field blood oxygen level dependent (BOLD) signal is simply inadequate for detecting changes in many brain regions without averaging results from a very large number of animals (4,5).High magnetic field strengths provide numerous advantages for fMRI, as well as challenges (6). Sample polarization increases with magnetic field, providing additional signal that can be traded for higher spatial resolution. Functional changes in the BOLD relaxation rate also increase with field strength (7), making BOLD detection power more competitive with that provided by an exogenous agent (8). Moreover, paramagnetic deoxyhemoglobin shortens blood relaxation times at high field strengths, which should decrease spatially nonspecific signal associated with draining vessels. However, the time scale for relaxation of transverse magnetization using gradient echoes (T 2 *) becomes progressively shorter and more heterogeneous, especially in regions near magnetic susceptibility interfaces that arise at air-tissue and bone-tissue interfaces. Signal dropout and image distortion reduce some of the theoretical advantages of BOLD fMRI at high fields by forcing a choice between increased image artifacts or the reduced sensitivity that accompanies short gradient echo times or spin echo methods.Because of the limitations of BOLD sensitivity, many fMRI applications in animal models have employed exogenous contrast agents (1-3,9 -11), which experimentally have been shown to markedly improve fMRI sensitivity at magnetic field strengths up to 4.7 T (4,5,8,12-14). The use of exogenous agents with very long blood half lives for fMRI has been termed IRON fMRI (5), to denote the increas...

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