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Heidi J Silver1, E Brian Welch2, Malcolm J Avison2, Kevin D Niswender1,31Department of Medicine, 2Department of Radiology and Radiological Sciences, Institute of Imaging Sciences, Vanderbilt University, Nashville, TN, USA; 3Tennessee Valley Healthcare System, Nashville, TN, USAAbstract: Obesity is a threat to public health worldwide primarily due to the comorbidities related to visceral adiposity, inflammation, and insulin resistance that increase risk for type 2 diabetes and cardiovascular disease. The translational research portfolio that originally described these risk factors was significantly enhanced by imaging techniques, such as dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI). In this article, we briefly review the important contributions of these techniques to understand the role of body composition in the pathogenesis of obesity-related complications. Notably, these imaging techniques have contributed greatly to recent findings identifying gender and racial differences in body composition and patterns of body composition change during weight loss. Although these techniques have the ability to generate good-quality body composition data, each possesses limitations. For example, DEXA is unable to differentiate type of fat, CT has better resolution but provides greater ionizing radiation exposure, and MRI tends to require longer imaging times and specialized equipment for acquisition and analysis. With the serious need for efficacious and cost-effective therapies to appropriately identify and treat at-risk obese individuals, there is greater need for translational tools that can further elucidate the interplay between body composition and the metabolic aberrations associated with obesity. In conclusion, we will offer our perspective on the evolution toward an ideal imaging method for body composition assessment in obesity and weight loss, and the challenges remaining to achieve this goal.Keywords: obesity, imaging, body composition, visceral fat

Objective: We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH)., Methods: We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET)., Results: We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals., Conclusion: These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.

Central insulin resistance (IR) influences striatal dopamine (DA) tone, an important determinant of behavioral self-regulation. We hypothesized that an association exists between the degree of peripheral IR and impulse control, mediated by the impact of IR on brain circuits controlling the speed of executing "go" and/or "stop" responses. We measured brain activation and associated performance on a stop signal task (SST) in obese adults with type 2 diabetes (age, 48.1 ± 6.9 yrs (mean ± SD); BMI, 36.5 ± 4.0 kg/m2; HOMA-IR, 7.2 ± 4.1; 12 male, 18 female). Increasing IR, but not BMI, was a predictor of shorter critical stop signal delay (cSSD), a measure of the time window during which a go response can be successfully countermanded (R2 = 0.12). This decline was explained by an IR-associated increase in go speed (R2 = 0.13) with little impact of IR or BMI on stop speed. Greater striatal fMRI activation contrast in stop error (SE) compared with stop success (SS) trials (CONSE>SS) was a significant predictor of faster go speeds (R2 = 0.33, p = 0.002), and was itself predicted by greater IR (CONSE>SS vs HOMA-IR: R2 = 0.10, p = 0.04). Furthermore, this impact of IR on striatal activation was a significant mediator of the faster go speeds and greater impulsivity observed with greater IR. These findings suggest a neural mechanism by which IR may increase impulsivity and degrade behavioral self-regulation.

After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution cerebral blood volume-based functional magnetic resonance imaging (CBV-fMRI) mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6weeks after a mid-cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with individual differences in damage to and recovery of DC and spinocuneate pathways, and possibly the potentiation of spinothalamic pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES., Competing Interests: The authors declare no competing financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.

Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in humans. Detecting BAT is typically confirmed by the uptake of the injected radioactive tracer 18F-Fluorodeoxyglucose (18F-FDG) into adipose tissue depots, as measured by positron emission tomography/computed tomography (PET-CT) scans after exposing the subject to cold stimulus. Fat-water separated magnetic resonance imaging (MRI) has the ability to distinguish BAT without the use of a radioactive tracer. To date, MRI of BAT in adult humans has not been co-registered with cold-activated PET-CT. Therefore, this protocol uses 18F-FDG PET-CT scans to automatically generate a BAT mask, which is then applied to co-registered MRI scans of the same subject. This approach enables measurement of quantitative MRI properties of BAT without manual segmentation. BAT masks are created from two PET-CT scans: after exposure for 2 hr to either thermoneutral (TN) (24 °C) or cold-activated (CA) (17 °C) conditions. The TN and CA PET-CT scans are registered, and the PET standardized uptake and CT Hounsfield values are used to create a mask containing only BAT. CA and TN MRI scans are also acquired on the same subject and registered to the PET-CT scans in order to establish quantitative MRI properties within the automatically defined BAT mask. An advantage of this approach is that the segmentation is completely automated and is based on widely accepted methods for identification of activated BAT (PET-CT). The quantitative MRI properties of BAT established using this protocol can serve as the basis for an MRI-only BAT examination that avoids the radiation associated with PET-CT.

Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

Background: Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo (1) H magnetic resonance spectroscopy (MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region., Methods: MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa., Results: Increased maternal alcohol consumption around time of conception was associated with lower N-Acetylaspartate (NAA) levels in the deep nuclei (r = -0.33, p < 0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites (r = -0.37, p < 0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception (r = 0.35, p < 0.01) and during pregnancy (r = 0.38, p < 0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders., Conclusions: The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission., (Copyright © 2014 by the Research Society on Alcoholism.)

Independent component analysis (ICA) has been successfully utilized for analysis of functional MRI (fMRI) data for task related as well as resting state studies. Although it holds the promise of becoming an unbiased data-driven analysis technique, a few choices have to be made prior to performing ICA, selection of a method for determining the number of independent components (nIC) being one of them. Choice of nIC has been shown to influence the ICA maps, and various approaches (mostly relying on information theoretic criteria) have been proposed and implemented in commonly used ICA analysis packages, such as MELODIC and GIFT. However, there has been no consensus on the optimal method for nIC selection, and many studies utilize arbitrarily chosen values for nIC. Accurate and reliable determination of true nIC is especially important in the setting where the signals of interest contribute only a small fraction of the total variance, i.e. very low contrast-to-noise ratio (CNR), and/or very focal response. In this study, we evaluate the performance of different model order selection criteria and demonstrate that the model order selected based upon bootstrap stability of principal components yields more reliable and accurate estimates of model order. We then demonstrate the utility of this fully data-driven approach to detect weak and focal stimulus-driven responses in real data. Finally, we compare the performance of different multi-run ICA approaches using pseudo-real data.

Purpose: To test the hypothesis that a whole-body fat-water MRI (FWMRI) protocol acquired at 3 Tesla combined with semi-automated image analysis techniques enables precise volume and mass quantification of adipose, lean, and bone tissue depots that agree with static scale mass and scale mass changes in the context of a longitudinal study of large-breed dogs placed on an obesogenic high-fat, high-fructose diet., Materials and Methods: Six healthy adult male dogs were scanned twice, at weeks 0 (baseline) and 4, of the dietary regiment. FWMRI-derived volumes of adipose tissue (total, visceral, and subcutaneous), lean tissue, and cortical bone were quantified using a semi-automated approach. Volumes were converted to masses using published tissue densities., Results: FWMRI-derived total mass corresponds with scale mass with a concordance correlation coefficient of 0.931 (95% confidence interval = [0.813, 0.975]), and slope and intercept values of 1.12 and -2.23 kg, respectively. Visceral, subcutaneous and total adipose tissue masses increased significantly from weeks 0 to 4, while neither cortical bone nor lean tissue masses changed significantly. This is evidenced by a mean percent change of 70.2% for visceral, 67.0% for subcutaneous, and 67.1% for total adipose tissue., Conclusion: FWMRI can precisely quantify and map body composition with respect to adipose, lean, and bone tissue depots. The described approach provides a valuable tool to examine the role of distinct tissue depots in an established animal model of human metabolic disease., (Copyright © 2013 Wiley Periodicals, Inc.)

Diffusion tensor imaging (DTI) tractography provides noninvasive measures of structural cortico-cortical connectivity of the brain. However, the agreement between DTI-tractography-based measures and histological 'ground truth' has not been quantified. In this study, we reconstructed the 3D density distribution maps (DDM) of fibers labeled with an anatomical tracer, biotinylated dextran amine (BDA), as well as DTI tractography-derived streamlines connecting the primary motor (M1) cortex to other cortical regions in the squirrel monkey brain. We evaluated the agreement in M1-cortical connectivity between the fibers labeled in the brain tissue and DTI streamlines on a regional and voxel-by-voxel basis. We found that DTI tractography is capable of providing inter-regional connectivity comparable to the neuroanatomical connectivity, but is less reliable measuring voxel-to-voxel variations within regions.

Objective: Improved understanding of how depot-specific adipose tissue mass predisposes to obesity-related comorbidities could yield new insights into the pathogenesis and treatment of obesity as well as metabolic benefits of weight loss. We hypothesized that three-dimensional (3D) contiguous "fat-water" MR imaging (FWMRI) covering the majority of a whole-body field of view (FOV) acquired at 3 Tesla (3T) and coupled with automated segmentation and quantification of amount, type, and distribution of adipose and lean soft tissue would show great promise in body composition methodology., Design and Methods: Precision of adipose and lean soft tissue measurements in body and trunk regions were assessed for 3T FWMRI and compared to dual-energy X-ray absorptiometry (DXA). Anthropometric, FWMRI, and DXA measurements were obtained in 12 women with BMI 30-39.9 kg/m(2) ., Results: Test-retest results found coefficients of variation (CV) for FWMRI that were all under 3%: gross body adipose tissue (GBAT) 0.80%, total trunk adipose tissue (TTAT) 2.08%, visceral adipose tissue (VAT) 2.62%, subcutaneous adipose tissue (SAT) 2.11%, gross body lean soft tissue (GBLST) 0.60%, and total trunk lean soft tissue (TTLST) 2.43%. Concordance correlation coefficients between FWMRI and DXA were 0.978, 0.802, 0.629, and 0.400 for GBAT, TTAT, GBLST, and TTLST, respectively., Conclusions: While Bland-Altman plots demonstrated agreement between FWMRI and DXA for GBAT and TTAT, a negative bias existed for GBLST and TTLST measurements. Differences may be explained by the FWMRI FOV length and potential for DXA to overestimate lean soft tissue. While more development is necessary, the described 3T FWMRI method combined with fully-automated segmentation is fast (<30-min total scan and post-processing time), noninvasive, repeatable, and cost-effective., (Copyright © 2012 The Obesity Society.)

Background: Fetal alcohol-related growth restriction persists through infancy, but its impact later in life is less clear. Animal studies have demonstrated important roles for maternal nutrition in fetal alcohol spectrum disorders, but the impact of prenatal maternal body composition has not been studied in humans. This study examined the effects of prenatal alcohol exposure on longitudinal growth from birth through young adulthood and the degree to which maternal weight and body mass index (BMI) moderate these effects., Methods: Nearly 480 mothers were recruited at their first prenatal clinic visit to overrepresent moderate-to-heavy use of alcohol during pregnancy, including a 5% random sample of low-level drinkers and abstainers. They were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach. Their children were examined for weight, length/height, and head circumference at birth, 6.5 and 13 months, and 7.5, 14, and 19 years., Results: In multiple regression models with repeated measures (adjusted for confounders), prenatal alcohol exposure was associated with longitudinal reductions in weight, height, and weight-for-length/BMI that were largely determined at birth. At low-to-moderate levels of exposure, these effects were more severe in infancy than in later childhood. By contrast, effects persisted among children whose mothers drank at least monthly and among those born to women with alcohol abuse and/or dependence who had consumed ≥ 4 drinks/occasion. In addition, effects on weight, height, and head circumference were markedly stronger among children born to mothers with lower prepregnancy weight., Conclusions: These findings confirm prior studies demonstrating alcohol-related reductions in weight, height, weight-for-height/BMI, and head circumference that persist through young adulthood. Stronger effects were seen among children born to mothers with smaller prepregnancy weight, which may have been because of attainment of higher blood alcohol concentrations in smaller mothers for a given amount of alcohol intake or to increased vulnerability in infants born to women with poorer nutrition., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown., Methods: Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed (n = 11, age 19.5 ± 0.3 years) and control (n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range., Results: There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses., Conclusions: These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood., (Copyright © 2012 by the Research Society on Alcoholism.)

The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.

Functional magnetic resonance imaging (fMRI) at high magnetic field strength can suffer from serious degradation of image quality because of motion and physiological noise, as well as spatial distortions and signal losses due to susceptibility effects. Overcoming such limitations is essential for sensitive detection and reliable interpretation of fMRI data. These issues are particularly problematic in studies of awake animals. As part of our initial efforts to study functional brain activations in awake, behaving monkeys using fMRI at 4.7 T, we have developed acquisition and analysis procedures to improve image quality with encouraging results. We evaluated the influence of two main variables on image quality. First, we show how important the level of behavioral training is for obtaining good data stability and high temporal signal-to-noise ratios. In initial sessions, our typical scan session lasted 1.5 h, partitioned into short (<10 min) runs. During reward periods and breaks between runs, the monkey exhibited movements resulting in considerable image misregistrations. After a few months of extensive behavioral training, we were able to increase the length of individual runs and the total length of each session. The monkey learned to wait until the end of a block for fluid reward, resulting in longer periods of continuous acquisition. Each additional 60 training sessions extended the duration of each session by 60 min, culminating, after about 140 training sessions, in sessions that last about 4 h. As a result, the average translational movement decreased from over 500 μm to less than 80 μm, a displacement close to that observed in anesthetized monkeys scanned in a 7-T horizontal scanner. Another major source of distortion at high fields arises from susceptibility variations. To reduce such artifacts, we used segmented gradient-echo echo-planar imaging (EPI) sequences. Increasing the number of segments significantly decreased susceptibility artifacts and image distortion. Comparisons of images from functional runs using four segments with those using a single-shot EPI sequence revealed a roughly twofold improvement in functional signal-to-noise-ratio and 50% decrease in distortion. These methods enabled reliable detection of neural activation and permitted blood-oxygenation-level-dependent-based mapping of early visual areas in monkeys using a volume coil. In summary, both extensive behavioral training of monkeys and application of segmented gradient-echo EPI sequence improved signal-to-noise ratio and image quality. Understanding the effects these factors have is important for the application of high field imaging methods to the detection of submillimeter functional structures in the awake monkey brain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Across species, the brain evolved to respond to natural rewards such as food and sex. These physiological responses are important for survival, reproduction and evolutionary processes. It is no surprise, therefore, that many of the neural circuits and signaling pathways supporting reward processes are conserved from Caenorhabditis elegans to Drosophilae, to rats, monkeys and humans. The central role of dopamine (DA) in encoding reward and in attaching salience to external environmental cues is well recognized. Less widely recognized is the role of reporters of the "internal environment", particularly insulin, in the modulation of reward. Insulin has traditionally been considered an important signaling molecule in regulating energy homeostasis and feeding behavior rather than a major component of neural reward circuits. However, research over recent decades has revealed that DA and insulin systems do not operate in isolation from each other, but instead, work together to orchestrate both the motivation to engage in consummatory behavior and to calibrate the associated level of reward. Insulin signaling has been found to regulate DA neurotransmission and to affect the ability of drugs that target the DA system to exert their neurochemical and behavioral effects. Given that many abused drugs target the DA system, the elucidation of how dopaminergic, as well as other brain reward systems, are regulated by insulin will create opportunities to develop therapies for drug and potentially food addiction. Moreover, a more complete understanding of the relationship between DA neurotransmission and insulin may help to uncover etiological bases for "food addiction" and the growing epidemic of obesity. This review focuses on the role of insulin signaling in regulating DA homeostasis and DA signaling, and the potential impact of impaired insulin signaling in obesity and psychostimulant abuse., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Accurate anatomic co-registration is a prerequisite for identifying structural and functional changes in longitudinal studies of brain plasticity. Current MRI methods permit collection of brain images across multiple scales, ranging from whole brain at relatively low resolution (≥1 mm), to local brain areas at the level of cortical layers and columns (∼100 μm) in the same session, allowing detection of subtle structural changes on a similar spatial scale. To measure these changes reliably, high resolution structural and functional images of local brain regions must be registered accurately across imaging sessions. The present study describes a robust fully automated strategy for the registration of high resolution structural images of brain sub-volumes to lower resolution whole brain images collected within a session, and the registration of partially overlapping high resolution MRI sub-volumes ("slabs") across imaging sessions. In high field (9.4 T) reduced field-of-view high resolution structural imaging studies using a surface coil in an anesthetized non-human primate model, this fully automated coregistration pipeline was robust in the face of significant inhomogeneities in image intensity and tissue contrast arising from the spatially inhomogeneous transmit and receive properties of the surface coil, achieving a registration accuracy of 30±15 μm between sessions., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Dynamic B(0) shimming (DS) can produce better field homogeneity than static global shimming by dynamically updating slicewise shim values in a multislice acquisition. The performance of DS however is limited by eddy current fields produced by the switching of 2nd and 3rd order unshielded shims. In this work, we present a novel method of eddy field compensation (EFC) applied to higher order shim induced eddy current fields in multislice DS. This method does not require shim shielding, extra hardware for eddy current compensation or subject specific prescanning. The interactions between shim harmonics are modeled assuming steady state of the medium and long time constant, cross and self term eddy fields in a DS experiment and 'correction factors' characterizing the entire set of shim interactions are derived. The correction factors for a given time between shim switches are shown to be invariable with object scanned, shim switching pattern and actual shim values, allowing for their generalized prospective use. Phantom and human head, 2nd and 3rd order DS experiments performed without any hardware eddy current compensation using the technique show large reductions in field gradients and offsets leading to significant improvements in image quality. This method holds promise as an alternative to expensive hardware based eddy current compensation required in 2nd and 3rd order DS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dynamic slice-wise shimming improves B0 field homogeneity by updating shim coil currents for every slice in a multislice acquisition, producing better field homogeneity over a volume than can be obtained by a single static global shim. The first aim of this work was to evaluate the performance of slice-wise field-map-based second-order dynamic shimming in a human high-field 7 T clinical scanner vis-à-vis image based second order static global shimming. Another goal was to characterize eddy currents induced by second and third order shim switching. A final aim was to compare global and dynamic shimming through shim orders to elucidate the relative benefits of going to higher orders and to dynamic shim updating from a static shimming regime. An external hardware module was used to store and dynamically update slice-optimized shim values during multislice data acquisition. High-bandwidth multislice gradient echo scans with B0 field mapping and low-bandwidth single-shot echo planar scans were performed on phantoms and humans using second-order dynamic and static global shims. For the measurement of second and third order shim induced eddy currents, step response temporal phase changes of individual shims were measured and fit to shim harmonics spatially and to multiexponential decay functions temporally. Finally, an order-wise field-map-based comparison was performed with first, second and third order global static shimming, first and second order dynamic shimming, as well as combined second or third order global and first order dynamic shim. Dynamic shimming considerably improved B0 homogeneity compared to static global shimming both in phantoms and in human subjects, reducing image distortion and signal dropout. The unshielded second and third order shims generated strong B0 and self and cross-term eddy fields, with multiple time constants ranging from milliseconds to seconds. Field homogeneity improved with increasing order of shim, with dynamic shimming performing better than global shimming. Hybrid global and dynamic shimming approach yielded field homogeneity better than global static shims but worse than dynamic shims., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study mapped the fine-scale functional representation of tactile and noxious heat stimuli in cortical areas around the central sulcus of anesthetized squirrel monkeys by using high-resolution blood oxygen level-dependent (BOLD) fMRI at 9.4T. Noxious heat (47.5°C) stimulation of digits evoked multiple spatially distinct and focal BOLD activations. Consistent activations were observed in areas 3a, 3b, 1, and 2, whereas less frequent activation was present in M1. Compared with tactile activations, thermal nociceptive activations covered more area and formed multiple foci within each functional area. In general, noxious heat activations in area 3b did not colocalize with tactile responses. The spatial relationships of heat and tactile activations in areas 3a and 1/2 varied across animals. Subsequent electrophysiological mapping confirmed that the evoked heat and tactile BOLD signals were somatotopically appropriate. The magnitude and temporal profiles of the BOLD signals to noxious heat stimuli differed across cortical areas. Comparatively late-peaking but stronger signals were observed in areas 3b and 2, whereas earlier-peaking but weaker signals were observed in areas 3a, 1, and M1. In sum, this study not only confirmed the involvement of somatosensory areas of 3a, 3b, and 1, but also identified the engagements of area 2 and M1 in the processing of heat nociceptive inputs. Differential BOLD response profiles of the individual cortical areas along the central sulcus suggest that these areas play different roles in the encoding of nociceptive inputs. Thermal nociceptive and tactile inputs may be processed by different clusters of neurons in different areas. To critically bridge animal and human pain studies, human fMRI was related to primate fMRI and electrophysiology of nociceptive processing, examining the functional role of the primary somatosensory cortex in heat nociception and demonstrating that subregion areas 3a, 3b, 1, 2, and M1 are responsive to noxious heat stimuli., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We consider 3-D brain structures as continuous parameterized surfaces and present a metric for their comparisons that is invariant to the way they are parameterized. Past comparisons of such surfaces involve either volume deformations or nonrigid matching under fixed parameterizations of surfaces. We propose a new mathematical representation of surfaces, called q-maps, such that L² distances between such maps are invariant to re-parameterizations. This property allows for removing the parameterization variability by optimizing over the re-parameterization group, resulting in a proper parameterization-invariant distance between shapes of surfaces. We demonstrate this method in shape analysis of multiple brain structures, for 34 subjects in the Detroit Fetal Alcohol and Drug Exposure Cohort study, which results in a 91% classification rate for attention deficit hyperactivity disorder cases and controls. This method outperforms some existing techniques such as spherical harmonic point distribution model (SPHARM-PDM) or iterative closest point (ICP).

Manganese (Mn) is an essential metal required for normal homeostasis. Humans chronically exposed to high Mn levels, however, may exhibit psychomotor signs secondary to increased brain Mn. As Mn and iron (Fe) share several cellular membrane transporters, decreased Fe levels resulting from Fe deficiency or anemia lead to increased brain Mn deposition. Conversely, decreased Mn levels are associated with abnormal brain Fe accumulation. To reduce potential Mn toxicity resulting from brain Mn accumulation, we proposed that increased dietary Fe would attenuate brain Mn deposition. To test this hypothesis, three groups of Sprague-Dawley rats were injected weekly (14 weeks) with Mn (3 mg/kg) and fed normal Fe (TX), Fe-supplemented (FeS), or Fe-deficient (FeD) chow. Control (CN) rats received normal dietary Fe and saline injections. Using magnetic resonance imaging, rats were imaged biweekly for 14 weeks to qualitatively monitor brain Mn and Fe accumulation. Both FeS and FeD had greater brain Mn deposition than TX rats. By week 3, R(1) values, which correlate with Mn deposition, were statistically significantly increased (p < 0.05) in brain stem, cerebellum, cortex, midbrain, and striatum compared with CN or TX animals. By week 14, R(1) values for all brain regions in FeS and FeD animals were statistically significantly increased (p < 0.05). By the end of the study, similar results were obtained for R(2) values, a marker of Fe accumulation. These data suggest that Fe supplementation does not effectively protect and may even exacerbate brain Mn accumulation in mammals subchronically exposed to Mn.

Dynamic structural and functional remodeling of the Central Nervous System occurs throughout the lifespan of the organism from the molecular to the systems level. MRI offers several advantages to observe this phenomenon: it is non-invasive and non-destructive, the contrast can be tuned to interrogate different tissue properties and imaging resolution can range from cortical columns to whole brain networks in the same session. To measure these changes reliably, functional maps generated over time with high resolution fMRI need to be registered accurately. This article presents a new method for the automatic registration of thin cortical MR volumes that are aligned with the functional maps. These acquisitions focus on the primary somato-sensory cortex, a region in the anterior parietal part of the brain, responsible for fine touch and proprioception. Currently, these slabs are acquired in approximately the same orientation from acquisition to acquisition and then registered by hand. Because they only cover a small portion of the cortex, their direct automatic registration is difficult. To address this issue, we propose a method relying on an intermediate image, acquired with a surface coil that covers a larger portion of the head to which the slabs can be registered. Because images acquired with surface coils suffer from severe intensity attenuation artifact, we also propose a method to register these. The results from data sets obtained with 3 squirrel monkeys show a registration accuracy of 30 micrometers.).

Models of addiction include abnormalities in parts of the brain involving executive function/inhibitory control. Although previous studies have reported evidence of structural abnormalities in cocaine-dependent individuals, none have specifically targeted the homeless. The present preliminary study investigated brain structure in such an understudied group, homeless, crack-cocaine-dependent African American men (n = 9), comparing it to that in healthy controls (n = 8). Structural data were analyzed using voxel based morphometry (VBM) and a regions of interest (ROI) analysis. Homeless cocaine-dependent individuals had smaller gray matter volume in dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, insula, and superior temporal gyrus. Most of these areas subserve executive function or inhibitory control. These results are similar to those found in most previous studies of non-homeless cocaine-dependent individuals. Reduced gray matter in executive function/inhibitory control regions of the brain in cocaine-dependent individuals may be a preexisting risk factor for the development of addiction and/or a consequence of drug abuse.

Gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, normalized to total creatine (tCr), were measured in the anterior cingulate and cerebellar vermis in healthy adults (n=19, age=24.6±6.4 years) using ¹H MRS at 3 T, and metabolite correlations across regions and subjects were determined. Mean anterior cingulate and cerebellar GABA/tCr ratios were 0.31 (0.08) and 0.23 (0.06), respectively, while corresponding Glu levels were 1.16 (0.10) and 0.70 (0.07), respectively. Anterior cingulate and cerebellar glutamate levels were correlated (r=0.6103, P=.0140), although it is noted that when adjusted for multiple comparisons, all correlations reported here cluster to a P value of .0583. It is unlikely that this correlation is driven by correlations in tCr, since interregional correlations were not observed for other metabolites referenced to tCr. Correlations were also observed among metabolites in both the anterior cingulate and cerebellar vermis. In the former, N-acetylasparate was linearly dependent on glutamate (r=0.6577, P=.0063) and, at or below this significance threshold, four metabolites were correlated in the cerebellar vermis (Ins/tCh: r=0.6261, P=.0109. NAA/tCh: r=0.6426, P=.0082. NAA/Glu: r=0.6412, P=.0085. tCh/Glu: r=0.6193, P=0.0122)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We consider the task of computing shape statistics and classification of 3D anatomical structures (as continuous, parameterized surfaces). This requires a Riemannian metric that allows re-parameterizations of surfaces by isometries, and computations of geodesics. This allows computing Karcher means and covariances of surfaces, which involves optimal re-parameterizations of surfaces and results in a superior alignment of geometric features across surfaces. The resulting means and covariances are better representatives of the original data and lead to parsimonious shape models. These two moments specify a normal probability model on shape classes, which are used for classifying test shapes into control and disease groups. We demonstrate the success of this model through improved random sampling and a higher classification performance. We study brain structures and present classification results for Attention Deficit Hyperactivity Disorder. Using the mean and covariance structure of the data, we are able to attain an 88% classification rate.

In the visual and auditory systems specialized neural pathways use motion cues to track object motion and self-motion, and use differential motion cues for figure-ground segregation. To examine the neural circuits that encode motion in the somatosensory system, we have developed neuroimaging methods to study motion processing in human and nonhuman primates. We have implemented stimulus presentation paradigms to examine neural encoding of apparent motion percepts. These paradigms are designed to be compatible with fMRI, optical imaging, and electrophysiological methods, thereby permitting direct comparison of data derived across neurofunctional scales. An additional motivation for using a common tactile motion stimulation paradigm is to bridge two disparate bodies of work, that derived from neuroimaging studies in humans and another from neuroimaging, neurophysiological and neuroanatomical studies in monkeys. Here, we demonstrate that such an approach through the use of optical imaging and 9.4 Tesla fMRI experiments in monkeys, and 7 Tesla fMRI experiments in humans is effective in revealing neural regions activated by tactile motion stimuli. These methods span spatial scales capable of detecting 100 μm sized domains to those that would reveal global whole brain circuits. Armed with such capabilities, our long-term goals are to identify directionally selective areas and directionally se-lective functional domains and understand the global pathways within which they reside. Such knowledge would have great impact on our thinking regarding not only tactile motion processing, but also general strategies underlying somatosensory cortical processing.

Sparse-spokes pulses are 2D slice-selective pulses that effectively mitigate inhomogeneities in the transmitted RF field and reduce unwanted RF artifacts in MR images. Here we consider the practical design of such pulses for high-field MRI and demonstrate limitations of the technique. We analyze the performance of pulses considering input noise as well as other effects such as saturation and T2( *) relaxation. We discuss in detail the correspondence between the reduction of RF inhomogeneities and the fidelity of the input parameters, such as the transmit B1+ field map and combined phase of the main B0 field and eddy-currents. Results include simulations, utilizing 7 T field maps acquired in phantoms and in-vivo, as well as in-vivo experiments. The necessary performance of system hardware components to achieve significant improvements is described., (2010 Elsevier Inc. All rights reserved.)

Background: The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes., Methods: We recorded event-related potentials (ERPs) during a Go/No-go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD., Results: Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level., Conclusion: This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD.

The parkinsonian symptoms and increased Mn accumulation in dopaminergic (DAergic) neurons of the basal ganglia implicate impaired dopamine signaling in the neurotoxic effects of chronic manganese overexposure. Using blood oxygenation level-dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), we mapped brain responses to acute amphetamine (AMPH; 3 mg/kg, ip), which stimulates midbrain DAergic systems, in male Sprague-Dawley rats following 6 weeks of chronic MnCl(2) (5 mg Mn/kg, one per week, iv) or saline treatment. Plasma Mn content, measured immediately following phMRI, was elevated twofold in Mn-treated animals (p < 0.05), but the twofold increase in mean striatal Mn content did not reach significance. In saline-treated animals, AMPH stimulated robust positive BOLD responses throughout the basal ganglia and their reciprocally innervated connections. In contrast, acute AMPH stimulated a negative BOLD response in many of these structures in the Mn-treated group, resulting in significant differences between saline- and Mn-treated AMPH-evoked BOLD responses within caudate putamen, globus pallidus, substantia nigra, mediodorsal thalamic nucleus, and somatosensory cortex. These results demonstrate the utility of AMPH-evoked phMRI as readout of the DAergic signaling in vivo and confirm the vulnerability of DAergic systems to Mn.

This study evaluates the intra- and inter-subject variability of digit maps in area 3b of anesthetized squirrel monkeys. Maps were collected using high field blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). BOLD responses to individual digit stimulations were mapped and their response properties (location, area of activation, % signal change, time to peak response) were compared within and across imaging sessions separated by up to 20 months. During single digit stimulation using a block design, the spatiotemporal response of the BOLD signal for individual runs within and across sessions and animals was well conserved, with a time to peak BOLD response of 20+/-4 s. The variability in the center of BOLD activation in area 3b was 0.41+/-0.24 mm (mean+/-SD) across individual 5-7 min runs within a scanning session and 0.55+/-0.15 mm across sessions. The average signal change across all animals, runs and sessions was 0.62+/-0.38%, and varied 32% within and 40% across sessions. In a comparison of the stability and reproducibility of the area of single digit activation obtained using three approaches, use of a fixed statistical threshold (P<10(-5)) yielded an average area of 4.8+/-3.5 mm(2) (mean+/-SD), adaptive statistical thresholding 1.32+/-1.259 mm(2) (mean+/-SD), and combined fixed statistical and adaptive BOLD signal amplitude 4.4+/-2.5 mm(2) (mean+/-SD) across image runs and sessions. The somatotopic organization was stable within animals across sessions, while across animals, there was some variation in overall activation pattern and inter-digit distances. These results confirm that BOLD activation maps of single digits in area 3b as characterized by activation center, signal amplitudes, and temporal profile are very stable. The activation sizes determined by various criteria are the most variable measure in this preparation, but adaptive statistical thresholding appears to yield the most stable and reproducible maps. This study serves as a baseline assessment of the limits imposed on the detection of plastic changes by experimental variations of the digit BOLD fMRI activation maps in normal animals, and as an indicator of the likely performance limits in human studies.

Background: Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults., Methods: In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation., Results: In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (> or =5 standard drinks) during pregnancy than if she drank regularly (M > or = 1 drink/day) without binge drinking., Conclusions: These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.

The limitations on the sensitivity for detecting small changes in MRI, CT, and ultrasound pulse-echo images are used to estimate the practical requirements for molecular imaging and targeted contrast enhancement for these modalities. These types of imaging are highly unlikely to approach the sensitivity for detecting molecular processes of radionuclear methods, and the prospects for achieving sufficient concentrations of appropriate agents in vivo are poor for several types of applications such as small-molecule targeting of specific receptors. However, using relatively large carrier systems such as particles and liposomes, sufficient concentrations of paramagnetic agents may be delivered to achieve MR-signal changes adequate for detection. The use of higher-resolution MR images will aid the prospects for molecular imaging in small animals. Theoretic considerations also predict that a similar approach, using rather large particles or carriers of materials with a high atomic number, may also be successful for CT, especially with additional developments such as the use of monochromatic x-rays. The prospects of molecular imaging by x-ray imaging may not be as bleak as has been predicted. For ultrasound detection, gas-filled bubbles can provide a sufficient backscattered sound intensity to be detectable at concentrations and sizes not much different from agents designed for these other modalities.

We report studies of the nonlinear nature of blood oxygen level-dependent (BOLD) responses to short transient deactivations in human visual cortex. Both functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) have been used to compare and contrast the hemodynamic response functions (HRFs) associated with transient activation and deactivation in primary visual cortex. We show that signal decreases for short duration deactivations are smaller than corresponding signal increases in activation studies. Moreover, the standard balloon model of BOLD effects may be modified to account for the observed nonlinear nature of deactivations by appropriate changes to simple hemodynamic parameters without recourse to new assumptions about the nature of the coupling between activity and oxygen use.

Manganese (Mn) and iron (Fe) are both paramagnetic species that can affect magnetic resonance relaxation rates. They also share common transport systems in vivo and thus in experimental models of metal exposure their effects on relaxation rates may interact in a complex fashion. Here we present a novel model to interpret the combined effects of Mn and Fe on MRI relaxation rates. To achieve varying levels of both metals, adult rats were separated into four groups; a control group and three groups treated with weekly intravenous injections of 3 mg Mn/kg body for 14 weeks. The three treated groups were fed either a normal diet, Fe deficient or Fe enriched diet. All rats were scanned using MRI at the 14th week to measure regional water relaxation rates. Rat brains were removed at the end of the study (14th week) and dissected into regions for measurement of Mn and Fe by atomic absorption spectroscopy. For the normal diet groups, R(1) was strongly correlated with tissue Mn concentrations. However, the slopes of the linear regression fits varied significantly among different brain regions, and a simple linear model failed to explain the changes in relaxation rate when both Mn and Fe contents changed. We propose a competition model, which is based on the ability of Mn and Fe to compete in vivo for common binding sites. The combined effect of Mn and Fe on the relaxation rates is complicated and additional studies will be necessary to explain how MRI signals are affected when the levels of both metals are varied.

Purpose: To describe an initial experience imaging the human hippocampus in vivo using a 7T magnetic resonance (MR) scanner and a protocol developed for very high field neuroimaging., Materials and Methods: Six normal subjects were scanned on a 7T whole body MR scanner equipped with a 16-channel head coil. Sequences included a full field of view T1-weighted 3D turbo field echo (T1W 3D TFE: time of acquisition (TA)=08:58), T2*-weighted 2D fast field echo (T2*W 2D FFE: TA=05:20), and susceptibility-weighted imaging (SWI: TA=04:20). SWI data were postprocessed using a minimum intensity projection (minIP) algorithm. Total imaging time was 23 minutes., Results: T1W 3D TFE images with 700 microm isotropic voxels provided excellent anatomic depiction of macroscopic hippocampal structures. T2*W 2D FFE images with 0.5 mm in-plane resolution and 2.5 mm slice thickness provided clear discrimination of the Cornu Ammonis and the compilation of adjacent sublayers of the hippocampus. SWI images (0.5 mm in-plane resolution, 1.0 mm slice thickness) delineated microvenous anatomy of the hippocampus., Conclusion: In vivo 7T MR imaging can take advantage of higher signal-to-noise and novel contrast mechanisms to provide increased conspicuity of hippocampal anatomy., (Copyright (c) 2008 Wiley-Liss, Inc.)

Background: Manganism is a central nervous system disorder caused by toxic exposure to manganese. Manganism has been related to occupational exposures, liver diseases, prolonged parenteral nutrition, and abuse of illicit drugs. Initially manifested by a reversible neuropsychiatric syndrome (locura manganica), the main symptoms and signs of manganism are emotional lability, compulsive behavior and visual hallucinations. Locura manganica is followed by an irreversible extrapyramidal syndrome, the onset of which occurs years after chronic exposure., Objectives: To characterize the regional distribution of Mn in the rat brain after subchronic exposure to Mn. This animal model holds special clinical relevance, reflecting the earlier clinical stages of manganism before chronic exposure to Mn exerts its irreversible effects., Methods: Sprague-Dawley rats were intravenously injected with MnCl2 weekly, for a total of 14 weeks - approximately 1/10 of the lifetime of the rat. T1-weighted magnetic resonance imaging was used to detect the distribution of Mn deposition in brain tissues, as evidenced by areas of T1-weighted hyperintense signals., Results: A consistent region-specific pattern of T1-weighted hyperintensities was observed in the brains of Mn-treated rats. Cortical hyperintensities were prominent in the hippocampus and dentate gyrus. Hyperintensities were also observed in the olfactory bulbs, pituitary gland, optic nerves and chiasma, pons, midbrain tegmentum, habenula, lentiform and caudate nuclei, thalamus, chorioid plexus and cerebellar hemispheres., Conclusions: Prominent Mn depositions, evidenced by T1-weighted hyperintensities in the hippocampus after subacute exposure to Mn, are compatible with the clinical picture of manganism during its early stages, and may explain its pathophysiology.

Chronic exposure to manganese (Mn) may lead to a movement disorder due to preferential Mn accumulation in the globus pallidus and other basal ganglia nuclei. Iron (Fe) deficiency also results in increased brain Mn levels, as well as dysregulation of other trace metals. The relationship between Mn and Fe transport has been attributed to the fact that both metals can be transported via the same molecular mechanisms. It is not known, however, whether brain Mn distribution patterns due to increased Mn exposure vs. Fe deficiency are the same, or whether Fe supplementation would reverse or inhibit Mn deposition. To address these questions, we utilized four distinct experimental populations. Three separate groups of male Sprague-Dawley rats on different diets (control diet [MnT], Fe deficient [FeD], or Fe supplemented [FeS]) were given weekly intravenous Mn injections (3 mg Mn/kg body mass) for 14 weeks, whereas control (CN) rats were fed the control diet and received sterile saline injections. At the conclusion of the study, both blood and brain Mn and Fe levels were determined by atomic absorption spectroscopy and magnetic resonance imaging. The data indicate that changes in dietary Fe levels (either increased or decreased) result in regionally specific increases in brain Mn levels compared with CN or MnT animals. Furthermore, there was no difference in either Fe or Mn accumulation between FeS or FeD animals. These data suggest that dietary Fe manipulation, whether increased or decreased, may contribute to brain Mn deposition in populations vulnerable to increased Mn exposure.

Functional magnetic resonance imaging (fMRI) has become the method of choice for mapping brain activity in human subjects and detects changes in regional blood oxygenation and volume associated with local changes in neuronal activity. While imaging based on blood oxygenation level dependent (BOLD) contrast has good spatial resolution and sensitivity, the hemodynamic signal develops relatively slowly and is only indirectly related to neuronal activity. An alternative approach termed magnetic source magnetic resonance imaging (msMRI) is based on the premise that neural activity may be mapped by magnetic resonance imaging (MRI) with greater temporal resolution by detecting the local magnetic field perturbations associated with local neuronal electric currents. We used a hybrid ms/BOLD MRI method to investigate whether msMRI could detect signal changes that occur simultaneously at the time of the production of well-defined event-related potentials, the P300 and N170, in regions that previously have been identified as generators of these electrical signals. Robust BOLD activations occurred after some seconds, but we were unable to detect any significant changes in the T2*-weighted signal in these locations that correlated temporally with the timings of the evoked response potentials (ERPs).

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level-dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

Background: HIV-associated dementia (HIV-D) is a subcortical dementia consisting of cognitive and motor symptoms that ultimately affects as many as 20% of patients with AIDS and is associated with significant morbidity and mortality. With the advent of highly active antiretroviral therapy (HAART), the use of sensitive and efficient screening tests for HIV-D continue to be needed for identifying individuals who develop this disorder., Objective: The objective of this study was to compare the HIV Dementia Scale (HDS) with comprehensive neuropsychological procedures in detecting both minor cognitive and motor disorder (MCMD) and HIV-D in a population of patients with varying durations of HAART., Methods: Forty-six HIV-seropositive patients completed both the HDS and a battery of neuropsychological tests as they enrolled in a MRI study. Each person was also assigned a MSK score based on clinical neurological examination. HDS score of 10 were considered cognitively unimpaired. Two separate sensitivity analyses were performed. Global Z scores (NPZ8) averaged from eight individual neuropsychological subtests were compared to the HDS score for each subject. An NPZ8 score -2.0 standard deviations (S.D.) below the mean was used to define HIV-D. Additionally, HIV-D, defined as -2.0 S.D. below the mean on one test or -1.0 S.D. below the mean on two or more tests from the NPZ8, were also compared to the HDS. Finally, performance on these cognitive measures was used to predict duration of HAART in this sample., Results: Using the average NPZ8 score based on American Academy of Neurology consensus criteria yielded a test sensitivity of 30%, a specificity of 0%, a positive predictive value of 0%, and a negative predictive value of 58% when compared to clinical MSK ratings. Comparison of the number of impaired tests with MSK severity yielded a test sensitivity of 43%, a specificity of 91%, a positive predictive value of 83%, and a negative predictive value of 61%. HDS scores were less efficient in predicting the presence of subtle and mild HIV-D in this sample., Conclusion: While the HDS is a useful bedside test that a physician may quickly administer to HIV seropositive patients to assist in diagnosing suspected cases of frank HIV-D, the HDS, as a screen, is not as accurate in detecting HIV-D as a more thorough neuropsychological examination. With an increasing prevalence of HIV-D and minor cognitive/motor disorder (MCMD) following the introduction of HAART, the development of more sensitive bedside measures is essential in order to identify individuals with these disorders and monitor treatment regimens.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human brain and has been implicated in several neuropsychiatric disorders. In vivo human brain GABA concentrations are near the detection limit for magnetic resonance spectroscopy ( approximately 1 mM), and because of overlap with more abundant compounds, spectral editing is generally necessary to detect GABA. In previous reports, GABA spectra edited by J-difference spectroscopy vary considerably in appearance. We have evaluated the factors that affect GABA spectra and the conditions necessary for robust acquisition of J-difference spectra from arbitrary brain regions. In particular, we demonstrate that variations in spectral quality can be explained in part by the incoherent addition of transients that results from shot to shot frequency and phase variations. An automated time-domain spectral alignment strategy that enables reproducible acquisition of high-quality GABA spectra at 3 T with a standard 30-cm T/R volume coil is presented. Representative GABA spectra from human frontal lobe, an area where susceptibility-induced frequency and phase variations are especially troublesome, that demonstrate the robustness of the acquisition and data handling strategy used in this study are presented.

Although blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to explore human brain function, questions remain regarding the ultimate spatial resolution of positive BOLD fMRI, and indeed the extent to which functional maps revealed by positive BOLD correlate spatially with maps obtained with other high-spatial-resolution mapping techniques commonly used in animals, such as optical imaging of intrinsic signal (OIS) and single-unit electrophysiology. Here, we demonstrate that the positive BOLD signal at 9.4T can reveal the fine topography of individual fingerpads in single-condition activation maps in nonhuman primates. These digit maps are similar to maps obtained from the same animal using intrinsic optical imaging. Furthermore, BOLD fMRI reliably resolved submillimeter spatial shifts in activation in area 3b previously identified with OIS (Chen et al., 2003) as neural correlates of the "funneling illusion." These data demonstrate that at high field, high-spatial-resolution topographic maps can be achieved using the positive BOLD signal, weakening previous notions regarding the spatial specificity of the positive BOLD signal.

Recently, we have demonstrated that the fine-digit topography (millimeter sized) previously identified in the primary somatosensory cortex (SI), using electrophysiology and intrinsic signal optical imaging, can also be mapped with submillimeter resolution using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging at high field. In the present study, we have examined the dependence of BOLD signal response on stimulus intensity in two subregions of SI, Areas 3b and 1. In a region(s)-of-interest (ROI) analysis of Area 3b, BOLD signal amplitude increased linearly with increasing amplitude of an 8-Hz vibrotactile stimulus, and BOLD signal was sustained throughout the stimulation period. In contrast, in Area 1, a significant BOLD signal response was only observed with more intense stimuli, and ROI analysis of the dependence of BOLD response showed no significant dependence on stimulus intensity. In addition, activation was not sustained throughout the period of stimulation. Differing responses of Areas 3b and 1 suggest potentially divergent roles for subregions of SI cortices in vibrotactile intensity encoding. Moreover, this study underscores the importance of imaging at small spatial scales. In this case, such high-resolution imaging allows differentiation between area-specific roles in intensity encoding and identifies anatomic targets for detailed electrophysiological studies of somatosensory neuronal populations with different coding properties. These experiments illustrate the value of nonhuman primates for characterizing the dependence of the BOLD signal response on stimulus parameters and on underlying neural response properties.

Conventional single-voxel localization for MR spectroscopy (MRS) is restricted to selecting only rectangular-shaped regions of interest (ROIs). The complexity of tissue shapes of interest and the desire to maximize the signal-to-noise ratio (SNR) while minimizing partial-volume effects require more sophisticated localization techniques. A group of spatially selective RF pulses are proposed in this work for the measurement of spectra from regions of arbitrary shape based on using a radial trajectory in k-space. Utilizing a single k-line per excitation results in a broad spectroscopic bandwidth. However, spatial localization accuracy is compromised for nutation angles > 10 degrees because of the small-tip-angle approximation of the Bloch equations. By interleaving multiple radial k-lines per excitation with nonselective refocusing pulses, one can achieve accurate localization for nutation angles up to 90 degrees while simultaneously maintaining the spectral bandwidth. The technique is described and compared with existing localization methods, and in vivo results are demonstrated., ((c) 2007 Wiley-Liss, Inc.)

Activation of 5-hydroxytryptamine2C (5-HT(2C)) receptors by the 5-HT(2) receptor agonist m-chlorophenylpiperazine (m-CPP) elicits anxiety in humans and anxiety-like behavior in animals. We compared the effects of m-CPP with the anxiogenic GABA(A) receptor inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142) on both anxiety-like behavior and regional brain activation using functional magnetic resonance imaging (fMRI) in the rat. We also determined whether the selective 5-HT(2C) receptor antagonist SB 242084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] would blunt m-CPP or FG-7142-induced neuronal activation. Both m-CPP (3 mg/kg i.p.) and FG-7142 (10 mg/kg i.p.) elicited anxiety-like behavior when measured in the social interaction test, and pretreatment with SB 242084 (1 mg/kg i.p.) completely blocked the behavioral effects of both anxiogenic drugs. Regional brain activation in vivo in response to anxiogenic drug challenge was determined by blood oxygen level-dependent (BOLD) fMRI using a powerful 9.4T magnet. Region of interest analyses revealed that m-CPP and FG-7142 significantly increased BOLD signals in brain regions that have been linked to anxiety, including the amygdala, dorsal hippocampus, and medial hypothalamus. These BOLD signal increases were blocked by pretreatment with SB 242084. In contrast, injection of m-CPP and FG-7142 resulted in BOLD signal decreases in the medial prefrontal cortex that were not blocked by SB 242084. In conclusion, the brain activation signals produced by anxiogenic doses of both m-CPP and FG-7142 are mediated at least partially by the 5-HT(2C) receptor, indicating that this receptor is a key component in anxiogenic neural circuitry.