Insulin-stimulated brain glucose uptake correlates with brain metabolites in severe obesity: A combined neuroimaging study.

The human brain undergoes metabolic adaptations in obesity, but the underlying mechanisms have remained largely unknown. We compared concentrations of often reported brain metabolites measured with magnetic resonance spectroscopy (1H-MRS, 3 T MRI) in the occipital lobe in subjects with obesity and lean controls under different metabolic conditions (fasting, insulin clamp, following weight loss). Brain glucose uptake (BGU) quantified with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)) was also performed in a subset of subjects during clamp. In dataset A, 48 participants were studied during fasting with brain 1H-MRS, while in dataset B 21 participants underwent paired brain 1H-MRS acquisitions under fasting and clamp conditions. In dataset C 16 subjects underwent brain 18F-FDG-PET and 1H-MRS during clamp. In the fasting state, total N-acetylaspartate was lower in subjects with obesity, while brain myo-inositol increased in response to hyperinsulinemia similarly in both lean participants and subjects with obesity. During clamp, BGU correlated positively with brain glutamine/glutamate, total choline, and total creatine levels. Following weight loss, brain creatine levels were increased, whereas increases in other metabolites remained not significant. To conclude, insulin signaling and glucose metabolism are significantly coupled with several of the changes in brain metabolites that occur in obesity.

Impaired damping of cerebral blood flow velocity pulsatility is associated with the number of perivascular spaces as measured with 7T MRI.

Arterial walls stiffen with age, cardiovascular risk factors, and various vascular diseases, which may lead to less damping of the arterial blood flow pulse, subsequent microvascular damage, and enlarged perivascular spaces (PVS). However, the exact interplay between these processes is unclear. This study aimed to investigate the relation between blood flow velocity pulsatility in the small lenticulostriate arteries and their supplying middle cerebral artery and the respective damping factor (DF), with the number of MRI-visible PVS in elderly subjects. Blood flow velocity waveforms were obtained in 45 subjects (median age [range]: 64 [48-81] years, 47% male) using 7T MRI. PVS were scored in the basal ganglia (BG) and centrum semiovale (CSO). Spearman correlation analyses were used to determine associations of the blood flow pulsatility and the DF, with PVS score, adjusted for age and sex. We found a significant association between a lower DF and a higher number of PVS in the BG (rs = -0.352, P = 0.021), but not in the CSO. This finding supports the supposed pathophysiological mechanism in which excessive kinetic energy deposition leads to damage of small perforating arteries and contributes to the enlargement of PVS at the level of the BG, but possible other pathways might also be of influence.

The association of white matter connectivity with prevalence, incidence and course of depressive symptoms: The Maastricht Study.

BACKGROUND: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. METHODS: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. RESULTS: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05-1.39) and OR = 1.21 (1.02-1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94-1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95-1.17) and OR 1.08 (0.83-1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. CONCLUSIONS: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings.

Assessment of microvascular rarefaction in human brain disorders using physiological magnetic resonance imaging.

Cerebral microvascular rarefaction, the reduction in number of functional or structural small blood vessels in the brain, is thought to play an important role in the early stages of microvascular related brain disorders. A better understanding of its underlying pathophysiological mechanisms, and methods to measure microvascular density in the human brain are needed to develop biomarkers for early diagnosis and to identify targets for disease modifying treatments. Therefore, we provide an overview of the assumed main pathophysiological processes underlying cerebral microvascular rarefaction and the evidence for rarefaction in several microvascular related brain disorders. A number of advanced physiological MRI techniques can be used to measure the pathological alterations associated with microvascular rarefaction. Although more research is needed to explore and validate these MRI techniques in microvascular rarefaction in brain disorders, they provide a set of promising future tools to assess various features relevant for rarefaction, such as cerebral blood flow and volume, vessel density and radius and blood-brain barrier leakage.

The effects of multi-echo fMRI combination and rapid T2*-mapping on offline and real-time BOLD sensitivity.

A variety of strategies are used to combine multi-echo functional magnetic resonance imaging (fMRI) data, yet recent literature lacks a systematic comparison of the available options. Here we compare six different approaches derived from multi-echo data and evaluate their influences on BOLD sensitivity for offline and in particular real-time use cases: a single-echo time series (based on Echo 2), the real-time T2*-mapped time series (T2*FIT) and four combined time series (T2*-weighted, tSNR-weighted, TE-weighted, and a new combination scheme termed T2*FIT-weighted). We compare the influences of these six multi-echo derived time series on BOLD sensitivity using a healthy participant dataset (N = 28) with four task-based fMRI runs and two resting state runs. We show that the T2*FIT-weighted combination yields the largest increase in temporal signal-to-noise ratio across task and resting state runs. We demonstrate additionally for all tasks that the T2*FIT time series consistently yields the largest offline effect size measures and real-time region-of-interest based functional contrasts and temporal contrast-to-noise ratios. These improvements show the promising utility of multi-echo fMRI for studies employing real-time paradigms, while further work is advised to mitigate the decreased tSNR of the T2*FIT time series. We recommend the use and continued exploration of T2*FIT for offline task-based and real-time region-based fMRI analysis. Supporting information includes: a data repository (https://dataverse.nl/dataverse/rt-me-fmri), an interactive web-based application to explore the data (https://rt-me-fmri.herokuapp.com/), and further materials and code for reproducibility (https://github.com/jsheunis/rt-me-fMRI).

The association of markers of cerebral small vessel disease and brain atrophy with incidence and course of depressive symptoms - the maastricht study.

BACKGROUND: Cerebral small vessel disease (CSVD) and neurodegeneration may be involved in the development and persistence of late-life depressive symptoms, but longitudinal evidence is scarce. We investigated the longitudinal associations of markers of CSVD and brain atrophy with incident depressive symptoms and the course of depressive symptoms, above and below 60 years of age. METHODS: White matter hyperintensity volumes (WMH), presence of lacunar infarcts and cerebral microbleeds, and white matter, grey matter, and cerebral spinal fluid volumes were assessed at baseline by 3T MRI in The Maastricht Study (mean age 59.5±8.5 years, 49.6% women, n=4,347; 16,535 person-years of follow-up). Clinically relevant depressive symptoms (9-item Patient Health Questionnaire≥10) were assessed at baseline and annually over seven years. We used Cox regression and multinomial logistic regression analyses adjusted for demographic, cardiovascular, and lifestyle risk factors. RESULTS: Above 60 years of age, larger WMH volumes were associated with an increased risk for incident depressive symptoms (HR[95%CI]:1.24[1.04;1.48] per SD) and a persistent course of depressive symptoms (OR:1.44[1.04;2.00] per SD). Total CSVD burden was associated with persistent depressive symptoms irrespective of age (adjusted OR:1.58[1.03;2.43]), while no associations were found for general markers of brain atrophy. LIMITATIONSS: Our findings need replication in other large-scale population-based studies. CONCLUSIONS: Our findings may suggest a temporal association of larger WMH volume with the incidence and persistence of late-life depression in the general population and may provide a potential target for the prevention of chronic late-life depression.

Glutamatergic and GABAergic reactivity and cognition in 22q11.2 deletion syndrome and healthy volunteers: A randomized double-blind 7-Tesla pharmacological MRS study.

AIMS: 22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly 'shifting' the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge. METHODS: Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined. RESULTS: No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC (η2= 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations (η2= 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients. DISCUSSION: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Imaging markers associated with the development of post-stroke depression and apathy: Results of the Cognition and Affect after Stroke - a Prospective Evaluation of Risks study.

INTRODUCTION: It has been suggested that the development of post-stroke apathy (PSA) and depression (PSD) may be more strongly associated with generalised brain pathology, rather than the stroke lesion itself. The present study aimed to investigate associations between imaging markers of lesion-related and generalised brain pathology and the development of PSA and PSD during a one-year follow-up. PATIENTS AND METHODS: In a prospective cohort study, 188 stroke patients received 3-Tesla MRI at baseline (three months post-stroke) for evaluation of lesion-related, vascular, and degenerative brain pathology. Presence of lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces was summed to provide a measure of total cerebral small vessel disease (cSVD) burden (range 0-4). The Mini International Neuropsychiatric Interview and Apathy Evaluation Scale were administered at baseline and repeated at 6- and 12-month follow-up to define presence of PSD and PSA, respectively. RESULTS: Population-averaged logistic regression models showed that global brain atrophy and severe cSVD burden (score 3-4) were significantly associated with the odds of having PSA (ORGEE 5.33, 95% CI 1.99-14.25 and 3.04, 95% CI 1.20-7.69, respectively), independent of stroke lesion volume and co-morbid PSD. Medium cSVD burden (score 2) was significantly associated with the odds of having PSD (ORGEE 2.92, 95% CI 1.09-7.78), independent of stroke lesion volume, co-morbid PSA, and pre-stroke depression. No associations were found with lesion-related markers. CONCLUSIONS: The results suggest that generalised degenerative and vascular brain pathology, rather than lesion-related pathology, is an important predictor for the development of PSA, and less strongly for PSD.

Texture analysis on parametric maps derived from dynamic contrast-enhanced magnetic resonance imaging in head and neck cancer.

AIM: To investigate the merits of texture analysis on parametric maps derived from pharmacokinetic modeling with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as imaging biomarkers for the prediction of treatment response in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: In this retrospective study, 19 HNSCC patients underwent pre- and intra-treatment DCE-MRI scans at a 1.5T MRI scanner. All patients had chemo-radiation treatment. Pharmacokinetic modeling was performed on the acquired DCE-MRI images, generating maps of volume transfer rate (K(trans)) and volume fraction of the extravascular extracellular space (ve). Image texture analysis was then employed on maps of K(trans) and ve, generating two texture measures: Energy (E) and homogeneity. RESULTS: No significant changes were found for the mean and standard deviation for K(trans) and ve between pre- and intra-treatment (P > 0.09). Texture analysis revealed that the imaging biomarker E of ve was significantly higher in intra-treatment scans, relative to pretreatment scans (P < 0.04). CONCLUSION: Chemo-radiation treatment in HNSCC significantly reduces the heterogeneity of tumors.

Quantitative MR and cognitive impairment in cryptogenic localisation-related epilepsy.

For patients with chronic cryptogenic localisation-related epilepsy (CLRE), conventional MRI does not provide measures to discern between patients with or without cognitive complaints. We investigated, in a preliminary study, whether it is possible to detect cerebral biomarkers of cognitive impairment in patients with CLRE using sensitive quantitative MRI techniques. Neuropsychological assessment and quantitative 3.0 T MRI, comprising T2 relaxometry, diffusion tensor imaging, and spectroscopic imaging, were applied to 35 patients with CLRE and 21 healthy controls. Analysis included the left and right hippocampi, and frontal and temporal lobes. Differences between the groups and correlations with cognitive and clinical characteristics were assessed. Patients with epilepsy scored significantly worse on cognitive tasks compared to healthy controls. Significantly larger CSF fractions in the hippocampi and left temporal lobe, a longer T2 relaxation time in the left hippocampus, and a significantly higher concentration of glutamate/glutamine in the left frontal lobe were observed in patients with epilepsy. Moreover, poor memory performance was significantly correlated with larger CSF fractions in the right hippocampus and left temporal lobe in patients. In the temporal lobe, an association between subtle changes in morphology (indicative of atrophy) and memory performance was found, consistent with previous literature. These results may help to explain the alterations in brain functioning in patients with epilepsy.

Working memory deficits in high-functioning adolescents with autism spectrum disorders: neuropsychological and neuroimaging correlates.

Working memory is a temporary storage system under attentional control. It is believed to play a central role in online processing of complex cognitive information and may also play a role in social cognition and interpersonal interactions. Adolescents with a disorder on the autism spectrum display problems in precisely these domains. Social impairments, communication difficulties, and repetitive interests and activities are core domains of autism spectrum disorders (ASD), and executive function problems are often seen throughout the spectrum. As the main cognitive theories of ASD, including the theory of mind deficit hypotheses, weak central coherence account, and the executive dysfunction theory, still fail to explain the broad spectrum of symptoms, a new perspective on the etiology of ASD is needed. Deficits in working memory are central to many theories of psychopathology, and are generally linked to frontal-lobe dysfunction. This article will review neuropsychological and (functional) brain imaging studies on working memory in adolescents with ASD. Although still disputed, it is concluded that within the working memory system specific problems of spatial working memory are often seen in adolescents with ASD. These problems increase when information is more complex and greater demands on working memory are made. Neuroimaging studies indicate a more global working memory processing or connectivity deficiency, rather than a focused deficit in the prefrontal cortex. More research is needed to relate these working memory difficulties and neuroimaging results in ASD to the behavioral difficulties as seen in individuals with a disorder on the autism spectrum.

Functional MRI in chronic epilepsy: associations with cognitive impairment.

Chronic epilepsy is frequently accompanied by serious cognitive side-effects. Clinical factors are important, but cannot account entirely for this cognitive comorbidity. Therefore, research is focusing on the underlying cerebral mechanisms to understand the development of cognitive dysfunction. In the past two decades, functional MRI techniques have been applied extensively to the study of cognitive impairment in chronic epilepsy. However, because of wide variation in study designs, analysis methods, and data presentation, interpretation of these studies has become increasingly difficult for clinicians. In patients with localisation-related epilepsy, whether findings of functional MRI represent the underlying neuronal substrate for cognitive decline remains a subject of debate.