Neurometabolic patterns of an "at risk for mental disorders" syndrome involve abnormalities in the thalamus and anterior midcingulate cortex.

BACKGROUND: The ultra-high risk (UHR) paradigm allows the investigation of individuals at increased risk of developing psychotic or other mental disorders with the aim of making prevention and early intervention as specific as possible in terms of the individual outcome. METHODS: Single-session 1H-/31P-Chemical Shift Imaging of thalamus, prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices was applied to 69 UHR patients for psychosis and 61 matched healthy controls. N-acetylaspartate (NAA), glutamate/glutamine complex (Glx), energy (PCr, ATP) and phospholipid metabolites were assessed, analysed by ANOVA (or ANCOVA [with covariates]) and correlated with symptomatology (SCL-90R). RESULTS: The thalamus showed decreased NAA, inversely correlated with self-rated aggressiveness, as well as increased PCr, and altered phospholipid breakdown. While the aMCC showed a pattern of NAA decrease and PCr increase, the DLPFC showed PCr increase only in the close-to-psychosis patient subgroup. There were no specific findings in transition patients. CONCLUSION: The results do not support the notion of a specific pre-psychotic neurometabolic pattern, but likely reflect correlates of an "at risk for mental disorders syndrome". This includes disturbed neuronal (mitochondrial) metabolism in the thalamus and aMCC, with emphasis on left-sided structures, and altered PL remodeling across structures.

Alterations of neurometabolism in the dorsolateral prefrontal cortex and thalamus in transition to psychosis patients change under treatment as usual - A two years follow-up 1H/31P-MR-spectroscopy study.

BACKGROUND: The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology. METHODS: 29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwent 1H-/31P-MR spectroscopy of the prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices and the thalamus. N-acetylaspartate (NAA), glutamate (Glu, Glx), energy (PCr, ATP) and phospholipid metabolites (PME, PDE) were compared to 27 healthy controls by ANCOVA and correlated with patients' symptom ratings (BPRS-E, SCL-90R). For longitudinal analysis, linear mixed model (LMM) and ANCOVA for repeated measures were used. RESULTS: DLPFC: In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus: In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC: In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up. CONCLUSION: Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Interrelations between dopamine and serotonin producing sites and regions of the default mode network.

Recent functional magnetic resonance imaging (fMRI) studies showed that blood oxygenation level-dependent (BOLD) signal fluctuations in the default mode network (DMN) are functionally tightly connected to those in monoaminergic nuclei, producing dopamine (DA), and serotonin (5-HT) transmitters, in the midbrain/brainstem. We combined accelerated fMRI acquisition with spectral Granger causality and coherence analysis to investigate causal relationships between these areas. Both methods independently lead to similar results and confirm the existence of a top-down information flow in the resting-state condition, where activity in core DMN areas influences activity in the neuromodulatory centers producing DA/5-HT. We found that latencies range from milliseconds to seconds with high inter-subject variability, likely attributable to the resting condition. Our novel findings provide new insights into the functional organization of the human brain.

Establishment and effects of allograft and synthetic bone graft substitute treatment of a critical size metaphyseal bone defect model in the sheep femur.

Assessment of bone graft material efficacy is difficult in humans, since invasive methods like staged CT scans or biopsies are ethically unjustifiable. Therefore, we developed a novel large animal model for the verification of a potential transformation of synthetic bone graft substitutes into vital bone. The model combines multiple imaging methods with corresponding histology in standardized critical sized cancellous bone defect. Cylindrical bone voids (10 ml) were created in the medial femoral condyles of both hind legs (first surgery at right hind leg, second surgery 3 months later at left hind leg) in three merino-wool sheep and either (i) left empty, filled with (ii) cancellous allograft bone or (iii) a synthetic, gentamicin eluting bone graft substitute. All samples were analysed with radiographs, MRI, µCT, DEXA and histology after sacrifice at 6 months. Unfilled defects only showed ingrowth of fibrous tissue, whereas good integration of the cancellous graft was seen in the allograft group. The bone graft substitute showed centripetal biodegradation and new trabecular bone formation in the periphery of the void as early as 3 months. µCT gave excellent insight into the structural changes within the defects, particularly progressive allograft incorporation and the bone graft substitute biodegradation process. MRI completed the picture by clearly visualizing soft tissue ingrowth into unfilled bone voids and presence of fluid collections. Histology was essential for verification of trabecular bone and osteoid formation. Conventional radiographs and DEXA could not differentiate details of the ongoing transformation process. This model appears well suited for detailed in vivo and ex vivo evaluation of bone graft substitute behaviour within large bone defects.

Comparison of metabolic adaptations between endurance- and sprint-trained athletes after an exhaustive exercise in two different calf muscles using a multi-slice 31 P-MR spectroscopic sequence.

Measurements of exercise-induced metabolic changes, such as oxygen consumption, carbon dioxide exhalation or lactate concentration, are important indicators for assessing the current performance level of athletes in training science. With exercise-limiting metabolic processes occurring in loaded muscles, 31 P-MRS represents a particularly powerful modality to identify and analyze corresponding training-induced alterations. Against this background, the current study aimed to analyze metabolic adaptations after an exhaustive exercise in two calf muscles (m. soleus - SOL - and m. gastrocnemius medialis - GM) of sprinters and endurance athletes by using localized dynamic 31 P-MRS. In addition, the respiratory parameters VO2 and VCO2 , as well as blood lactate concentrations, were monitored simultaneously to assess the effects of local metabolic adjustments in the loaded muscles on global physiological parameters. Besides noting obvious differences between the SOL and the GM muscles, we were also able to identify distinct physiological strategies in dealing with the exhaustive exercise by recruiting two athlete groups with opposing metabolic profiles. Endurance athletes tended to use the aerobic pathway in the metabolism of glucose, whereas sprinters produced a significantly higher peak concentration of lactate. These global findings go along with locally measured differences, especially in the main performer GM, with sprinters revealing a higher degree of acidification at the end of exercise (pH 6.29 ± 0.20 vs. 6.57 ± 0.21). Endurance athletes were able to partially recover their PCr stores during the exhaustive exercise and seemed to distribute their metabolic activity more consistently over both investigated muscles. In contrast, sprinters mainly stressed Type II muscle fibers, which corresponds more to their training orientation preferring the glycolytic energy supply pathway. In conclusion, we were able to analyze the relation between specific local metabolic processes in loaded muscles and typical global adaptation parameters, conventionally used to monitor the training status of athletes, in two cohorts with different sports orientations.

Assessment of intra- and inter-regional interrelations between GABA+, Glx and BOLD during pain perception in the human brain - A combined 1H fMRS and fMRI study.

To explore brain activity and the related neurochemical processes, current research focuses increasingly on the combined acquisition of 1H MR spectra and fMRI data to investigate potential associations between local metabolite resting state levels and stimulus-induced BOLD signal changes. In this study, whole-brain fMRI measurements and localized functional 1H MEGA-PRESS MRS scans were conducted at 3T in healthy subjects prior to and during acute pain stimulation to quantify resting state GABA+/tCr and Glx/tCr levels in the insular cortex together with their stimulus-induced changes and to explore associations between these neurochemical parameters with intra-regional but also inter-regional BOLD responses. Inter-regionally, a significant negative correlation between the BOLD signal of a cluster in the supplementary motor area with overlap to the mid-cingulate cortex (R = -0.56, p = 0.004) and the insular resting state GABA+/tCr was obtained. Furthermore, pain induced insular ΔGlx was significantly positively associated with the BOLD signal in the left superior frontal gyrus, left and right inferior frontal gyrus, left inferior parietal lobe, left superior temporal gyrus, left anterior insula and right posterior insula, with R values ranging from 0.59 to 0.73 (p < 0.005). No intra-regional association was observed between BOLD and metabolite measures. These findings point toward interactions between metabolite levels and stimulus-induced BOLD responses in brain regions belonging to the pain processing network. The combination of fMRS and fMRI provides a powerful tool to improve our understanding about the complex system of neurochemical processes and brain activity within brain networks.

Difference optimization: Automatic correction of relative frequency and phase for mean non-edited and edited GABA 1H MEGA-PRESS spectra.

Phase and frequency corrections of magnetic resonance spectroscopic data are of major importance to obtain reliable and unambiguous metabolite estimates as validated in recent research for single-shot scans with the same spectral fingerprint. However, when using the J-difference editing technique 1H MEGA-PRESS, misalignment between mean edited (ON‾) and non-edited (OFF‾) spectra that may remain even after correction of the corresponding individual single-shot scans results in subtraction artefacts compromising reliable GABA quantitation. We present a fully automatic routine that iteratively optimizes simultaneously relative frequencies and phases between the mean ON‾ and OFF‾1H MEGA-PRESS spectra while minimizing the sum of the magnitude of the difference spectrum (L1 norm). The proposed method was applied to simulated spectra at different SNR levels with deliberately preset frequency and phase errors. Difference optimization proved to be more sensitive to small signal fluctuations, as e.g. arising from subtraction artefacts, and outperformed the alternative spectral registration approach, that, in contrast to our proposed linear approach, uses a nonlinear least squares minimization (L2 norm), at all investigated levels of SNR. Moreover, the proposed method was applied to 47 MEGA-PRESS datasets acquired in vivo at 3T. The results of the alignment between the mean OFF‾ and ON‾ spectra were compared by applying (a) no correction, (b) difference optimization or (c) spectral registration. Since the true frequency and phase errors are not known for in vivo data, manually corrected spectra were used as the gold standard reference (d). Automatically corrected data applying both, method (b) or method (c), showed distinct improvements of spectra quality as revealed by the mean Pearson correlation coefficient between corresponding real part mean DIFF‾ spectra of Rbd=0.997±0.003 (method (b) vs. (d)), compared to Rad=0.764±0.220 (method (a) vs. (d)) with no alignment between OFF‾ and ON‾. Method (c) revealed a slightly lower correlation coefficient of Rcd=0.972±0.028 compared to Rbd, that can be ascribed to small remaining subtraction artefacts in the final DIFF‾ spectrum. In conclusion, difference optimization performs robustly with no restrictions regarding the input data range or user intervention and represents a complementary tool to optimize the final DIFF‾ spectrum following the mandatory frequency and phase corrections of single ON and OFF scans prior to averaging.

Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naïve ultra-high-risk subjects and first-episode schizophrenia.

Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both (1)H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder.

Glutamate receptor δ 1 (GRID1) genetic variation and brain structure in schizophrenia.

Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group × genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning.

[Interventional MR-mammography: manipulator-assisted large core biopsy and interstitial laser therapy of tumors of the female breast]]. / Interventionelle MR-Mammographie: Manipulatorgestützte Biopsie und interstitielle Lasertherapie von Tumoren der weiblichen Brust.

The present study investigated the clinical application of magnetic resonance (MR)-guided breast interventions, such as manipulator-assisted large core breast biopsy (LCBB) inside a 1.5 T whole-body magnet and MR-guided interstitial laser therapy (ILT). Sixteen patients underwent LCBB and 1 additional patient underwent 4 sessions of ILT of a recurrent undifferentiated lymph node metastasis in the axilla using a Nd-YAG laser (1064 nm). Temperature changes of the tumor tissue during ILT were monitored using phase images of a gradient echo sequence (GRE) (TR/TE/FA = 25/12/30). In 5 patients the biopsy findings were histopathologically confirmed after open surgery. In 3 patients, the biopsy missed one tubular and one ductal carcinoma; one invasive carcinoma was underestimated. Eight patients with benign findings are still in the follow-up period. The heating zone during ILT was well delineated on subtracted phase images. No severe adverse events were observed with LCBB or ILT. MR-guided breast biopsies are feasible with the manipulator system inside a whole-body 1.5 Tesla MR scanner. GRE information is suitable for therapy monitoring during ILT within the tumor. Further studies are necessary to evaluate the accuracy of the manipulator system and the efficacy of ILT in the treatment of breast lesions.