A Henning

GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI

The human anterior cingulate cortex (ACC) is part of the default-mode network that shows predominant negative blood oxygen level–dependent (BOLD) responses in functional magnetic resonance imaging (fMRI). We combined fMRI during emotional processing and resting-state magnetic resonance spectroscopy measurements and observed that the concentration of GABA in the ACC specifically correlated with the amount of negative BOLD responses in the very same region. Our findings show that default-mode network negative BOLD responses during emotions are mediated by GABA.

The Relationship Between Aberrant Neuronal Activation in the Pregenual Anterior Cingulate, Altered Glutamatergic Metabolism, and Anhedonia in Major Depression

CONTEXT Major depressive disorder (MDD) is characterized by diverse metabolic and functional abnormalities that occur in, among other regions, the pregenual anterior cingulate cortex (pgACC), a cortical region linked to anhedonia. OBJECTIVES To contextualize metabolic, functional, and clinical parameters and thus to reveal cellular mechanisms related to anhedonia. DESIGN The pgACC was investigated using a combined functional magnetic resonance imaging and magnetic resonance spectroscopic approach. Negative blood oxygenation level-dependent (BOLD) activations in the pgACC were assessed during emotional stimulation. Quantitative J-resolved magnetic resonance spectroscopy in the pgACC enabled simultaneous determination of glutamine, glutamate, N-acetylaspartate, glucose, and gamma-aminobutyric acid concentrations. Subjective emotional intensity ratings as well as various clinical parameters were determined. SETTING The patients were recruited and evaluated in the Department of Psychiatry, University of Zurich, while the measurements were performed in the Institute of Biomedical Engineering, University of Zurich and the Technical University Zurich. PARTICIPANTS Nineteen unmedicated patients with MDD and 24 healthy subjects. MAIN OUTCOME MEASURES Reduced glutamine levels and lower functional responses in pgACC in anhedonic depressed patients were expected to be the predominant effect of abnormal glutamatergic transmission. It was further tested if, among patients, the ratings of emotional intensity on visual stimulation predicted the amount of metabolic and functional alterations in terms of reduced relative metabolite concentrations and BOLD changes. RESULTS Patients with highly anhedonic MDD show decreased glutamine but normal glutamate and gamma-aminobutyric acid concentrations, with glutamine concentrations being dissociated from glucose concentrations. Glutamate and N-acetylaspartate concentrations in pgACC correlate with negative BOLD responses induced by emotional stimulation in MDD; whereas in healthy subjects, negative BOLD responses correlate with gamma-aminobutyric acid instead. Negative BOLD responses as well as glutamate and N-acetylaspartate concentrations correlate with emotional intensity ratings, an anhedonia surrogate, in those with MDD but not in healthy subjects. CONCLUSION Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

Background— Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Methods and Results— Forty-six consecutive patients with symptomatic exercise limitation (peak &OV0312;o2 <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by 31P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak &OV0312;o2, symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to −0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak &OV0312;o2) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg−1 · min−1; P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). Conclusions— In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.

Heart Failure With Preserved Ejection Fraction Is Characterized by Dynamic Impairment of Active Relaxation and Contraction of the Left Ventricle on Exercise and Associated With Myocardial Energy Deficiency

OBJECTIVES We sought to evaluate the role of exercise-related changes in left ventricular (LV) relaxation and of LV contractile function and vasculoventricular coupling (VVC) in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and to assess myocardial energetic status in these patients. BACKGROUND To date, no studies have investigated exercise-related changes in LV relaxation and VVC as well as in vivo myocardial energetic status in patients with HFpEF. METHODS We studied 37 patients with HFpEF and 20 control subjects. The VVC and time to peak LV filling (nTTPF, a measure of LV active relaxation) were assessed while patients were at rest and during exercise by the use of radionuclide ventriculography. Cardiac energetic status (creatine phosphate/adenosine triphosphate ratio) was assessed by the use of (31)P magnetic resonance spectroscopy at 3-T. RESULTS When patients were at rest, nTTPF and VVC were similar in patients with HFpEF and control subjects. The cardiac creatine phosphate/adenosine triphosphate ratio was reduced in patients with HFpEF versus control subjects (1.57 +/- 0.52 vs. 2.14 +/- 0.63; p = 0.003), indicating reduced energy reserves. Peak maximal oxygen uptake and the increase in heart rate during maximal exercise were lower in patients with HFpEF versus control subjects (19 +/- 4 ml/kg/min vs. 36 +/- 8 ml/kg/min, p < 0.001, and 52 +/- 16 beats/min vs. 81 +/- 14 beats/min, p < 0.001). The relative changes in stroke volume and cardiac output during submaximal exercise were lower in patients with HFpEF versus control subjects (ratio exercise/rest: 0.99 +/- 0.34 vs. 1.25 +/- 0.47, p = 0.04, and 1.36 +/- 0.45 vs. 2.13 +/- 0.72, p < 0.001). The nTTPF decreased during exercise in control subjects but increased in patients with HFpEF (-0.03 +/- 12 s vs. +0.07 +/- 0.11 s; p = 0.005). The VVC decreased on exercise in control subjects but was unchanged in patients with HFpEF (-0.01 +/- 0.15 vs. -0.25 +/- 0.19; p < 0.001). CONCLUSIONS Patients with HFpEF have reduced cardiac energetic reserve that may underlie marked dynamic slowing of LV active relaxation and abnormal VVC during exercise.

Reduced field‐of‐view MRI using outer volume suppression for spinal cord diffusion imaging

A spin‐echo single‐shot echo‐planar imaging (SS‐EPI) technique with a reduced field of view (FOV) in the phase‐encoding direction is presented that simultaneously reduces susceptibility effects and motion artifacts in diffusion‐weighted (DW) imaging (DWI) of the spinal cord at a high field strength (3T). To minimize aliasing, an outer volume suppression (OVS) sequence was implemented. Effective fat suppression was achieved with the use of a slice‐selection gradient‐reversal technique. The OVS was optimized by numerical simulations with respect to T1 relaxation times and B1 variations. The optimized sequence was evaluated in vitro and in vivo. In simulations the optimized OVS showed suppression to <0.25% and ∼3% in an optimal and worst‐case scenario, respectively. In vitro measurements showed a mean residual signal of <0.95% ± 0.42 for all suppressed areas. In vivo acquisition with 0.9 × 1.05 mm2 in‐plane resolution resulted in artifact‐free images. The short imaging time of this technique makes it promising for clinical studies. Magn Reson Med 57:625–630, 2007.

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

Slice-selective FID acquisition, localized by outer volume suppression (FIDLOVS) for 1H-MRSI of the human brain at 7 T with minimal signal loss

In comparison to 1.5 and 3 T, MR spectroscopic imaging at 7 T benefits from signal‐to‐noise ratio (SNR) gain and increased spectral resolution and should enable mapping of a large number of metabolites at high spatial resolutions. However, to take full advantage of the ultra‐high field strength, severe technical challenges, e.g. related to very short T2 relaxation times and strict limitations on the maximum achievable B1 field strength, have to be resolved. The latter results in a considerable decrease in bandwidth for conventional amplitude modulated radio frequency pulses (RF‐pulses) and thus to an undesirably large chemical‐shift displacement artefact. Frequency‐modulated RF‐pulses can overcome this problem; but to achieve a sufficient bandwidth, long pulse durations are required that lead to undesirably long echo‐times in the presence of short T2 relaxation times. In this work, a new magnetic resonance spectroscopic imaging (MRSI) localization scheme (free induction decay acquisition localized by outer volume suppression, FIDLOVS) is introduced that enables MRSI data acquisition with minimal SNR loss due to T2 relaxation and thus for the first time mapping of an extended neurochemical profile in the human brain at 7 T. To overcome the contradictory problems of short T2 relaxation times and long pulse durations, the free induction decay (FID) is directly acquired after slice‐selective excitation. Localization in the second and third dimension and skull lipid suppression are based on a T1‐ and B1‐insensitive outer volume suppression (OVS) sequence. Broadband frequency‐modulated excitation and saturation pulses enable a minimization of the chemical‐shift displacement artefact in the presence of strict limits on the maximum B1 field strength. The variable power RF pulses with optimized relaxation delays (VAPOR) water suppression scheme, which is interleaved with OVS pulses, eliminates modulation side bands and strong baseline distortions. Third order shimming is based on the accelerated projection‐based automatic shimming routine (FASTERMAP) algorithm. The striking SNR and spectral resolution enable unambiguous quantification and mapping of 12 metabolites including glutamate (Glu), glutamine (Gln), N‐acetyl‐aspartatyl‐glutamate (NAAG), γ‐aminobutyric acid (GABA) and glutathione (GSH). The high SNR is also the basis for highly spatially resolved metabolite mapping. Copyright

Structure of the two most C-terminal RNA recognition motifs of PTB using segmental isotope labeling

The polypyrimidine tract binding protein (PTB) is a 58 kDa protein involved in many aspects of RNA metabolism. In this study, we focused our attention on the structure of the two C‐terminal RNA recognition motifs (RRM3 and RRM4) of PTB. In a previous study, it was found that the two RRMs are independent in the free state. We recently determined the structure of the same fragment in complex with RNA and found that the two RRMs interact extensively. This difference made us re‐evaluate in detail the free protein structure and in particular the interdomain interface. We used a combination of NMR spectroscopy and segmental isotopic labeling to unambiguously study and characterize the interdomain interactions. An improved segmental isotopic labeling protocol was used, enabling us to unambiguously identify 130 interdomain NOEs between the two RRMs and to calculate a very precise structure. The structure reveals a large interdomain interface, resulting in a very unusual positioning of the two RRM domains relative to one another.

Diffusion-weighted imaging of the entire spinal cord

In spite of their diagnostic potential, the poor quality of available diffusion‐weighted spinal cord images often restricts clinical application to cervical regions, and improved spatial resolution is highly desirable. To address these needs, a novel technique based on the combination of two recently presented reduced field‐of‐view approaches is proposed, enabling high‐resolution acquisition over the entire spinal cord. Field‐of‐view reduction is achieved by the application of non‐coplanar excitation and refocusing pulses combined with outer volume suppression for removal of unwanted transition zones. The non‐coplanar excitation is performed such that a gap‐less volume is acquired in a dedicated interleaved slice order within two repetition times. The resulting inner volume selectivity was evaluated in vitro. In vivo diffusion tensor imaging data on the cervical, thoracic and lumbar spinal cord were acquired in transverse orientation in each of four healthy subjects. An in‐plane resolution of 0.7 × 0.7 mm2 was achieved without notable aliasing, motion or susceptibility artifacts. The measured mean ± SD fractional anisotropy was 0.69 ± 0.11 in the thoracic spinal cord and 0.75 ± 0.07 and 0.63 ± 0.08 in cervical and lumbar white matter, respectively. Copyright