Renate Grüner

Functional Relevance of Interindividual Differences in Temporal Lobe Callosal Pathways: A DTI Tractography Study

The midsagittal corpus callosum is topographically organized, that is, with regard to their cortical origin several subtracts can be distinguished within the corpus callosum that belong to specific functional brain networks. Recent diffusion tensor tractography studies have also revealed remarkable interindividual differences in the size and exact localization of these tracts. To examine the functional relevance of interindividual variability in callosal tracts, 17 right-handed male participants underwent structural and diffusion tensor magnetic resonance imaging. Probabilistic tractography was carried out to identify the callosal subregions that interconnect left and right temporal lobe auditory processing areas, and the midsagittal size of this tract was seen as indicator of the (anatomical) strength of this connection. Auditory information transfer was assessed applying an auditory speech perception task with dichotic presentations of consonant-vowel syllables (e.g., /ba-ga/). The frequency of correct left ear reports in this task served as a functional measure of interhemispheric transfer. Statistical analysis showed that a stronger anatomical connection between the superior temporal lobe areas supports a better information transfer. This specific structure-function association in the auditory modality supports the general notion that interindividual differences in callosal topography possess functional relevance.

Pancreatic Lipomatosis Is a Structural Marker in Nondiabetic Children With Mutations in Carboxyl-Ester Lipase

Both pancreatic volume reduction and lipomatosis have been observed in subjects with diabetes. The underlying molecular and pathological mechanisms are, however, poorly known, and it has been speculated that both features are secondary to diabetes. We have recently described pancreatic atrophy and lipomatosis in diabetic subjects of two Norwegian families with a novel syndrome of diabetes and exocrine pancreatic dysfunction caused by heterozygous carboxyl-ester lipase (CEL) mutations. To explore the early pathological events in this syndrome, we performed radiological examinations of the pancreas in nondiabetic mutation carriers with signs of exocrine dysfunction. In a case series study at a tertiary hospital, we evaluated 11 nondiabetic and mutation-positive children with fecal elastase deficiency and 11 age- and sex-matched control subjects using ultrasound and magnetic resonance imaging (MRI) to estimate pancreatic fat content. The pancreata of nondiabetic mutation carriers exhibited increased reflectivity on ultrasound and had MRI findings indicative of lipomatosis. Apparently, carriers of heterozygous CEL mutations accumulate fat in their pancreas before the anticipated development of diabetes. Our findings suggest that lipomatosis of the pancreas reflects early events involved in the pathogenesis of diabetes and exocrine pancreatic dysfunction syndrome.

Default-Mode Network Functional Connectivity is Closely Related to Metabolic Activity

Over the last decade, the brains default‐mode network (DMN) and its function has attracted a lot of attention in the field of neuroscience. However, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood‐oxygen level‐dependent (BOLD) signal, are still incompletely understood. In the present study, we combined 2‐deoxy‐2‐[18F]fluoroglucose positron emission tomography (FDG‐PET), proton magnetic resonance spectroscopy (1H‐MRS), and resting‐state functional magnetic resonance imaging (rs‐fMRI) to investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest. The results of the correlation analyzes using the dorsal posterior cingulate cortex (dPCC) as seed region showed spatial similarities between fluctuations in FDG‐uptake and fluctuations in BOLD signal. More specifically, in both modalities the same DMN areas in the inferior parietal lobe, angular gyrus, precuneus, middle, and medial frontal gyrus were positively correlated with the dPCC. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, PCC and left angular gyrus was associated with functional connectivity within the DMN. We did not, however, find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results lend further support for a close association between local metabolic activity and functional connectivity and provide further insights towards a better understanding of the underlying mechanism of the BOLD signal. Hum Brain Mapp 36:2027–2038, 2015.

A critical re-examination of sexual dimorphism in the corpus callosum microstructure.

Recent diffusion-tensor imaging (DTI) studies suggest sexual dimorphism in the micro-structural architecture of the corpus callosum. However, the corpus callosum is also found to be larger in males than in females, a fact that might introduce a systematic bias to the analysis of DTI parameters. Diffusion parameters obtained in the larger male corpus callosum could be less affected by partial-volume averaging with surrounding non-callosal tissue than respective parameters obtained in the smaller female corpus callosum, i.e. the sex of the subject and partial-volume effects would be confounded. The objective of the present DTI study was to re-examine microstructural sex differences in the corpus callosum, while controlling for corpus callosum size differences between sexes. We compared 41 female and 34 male participants using regional tract-based spatial statistics (TBSS) analysis. Clusters of significantly higher fractional anisotropy (FA) and lower diffusion strength in males compared to females were detected in the genu and truncus of the corpus callosum. However, only the sex difference located in the anterior genu subregions could be unequivocally interpreted. This was the only cluster where the diffusion parameters did not correlate with regional callosal size. The present results indicate a stronger inter-hemispheric connectivity between the frontal lobes in males than females, which might be related to sex differences in hemispheric asymmetry and brain size.

Separating the effects of alcohol and expectancy on brain activation: An fMRI working memory study ☆

The aim of this study was to use BOLD fMRI to evaluate the effect of alcohol intoxication on neuronal activation, when controlling for expectancy. Behavioural studies have shown that both alcohol intoxication and expectancy affect cognition, mood and behaviour. However, previous neuroimaging studies have not separated the effects of alcohol intoxication from the possible confounding effects of expectancy. Forty-five healthy male participants participated in the study. A balanced placebo design with four groups was used together with a working memory paradigm. Half of the participants consumed a soft-drink before the MR scanning session (half of them were correctly informed about the content of their drink, and half were incorrectly informed that they consumed an alcoholic beverage), and the other half consumed an alcoholic beverage before the MR scanning session (half of them were correctly informed about the content of their drink, and half were incorrectly informed that they consumed a soft-drink). A blood alcohol concentration (BAC) of 0.08% was used as the alcohol intoxication level. The most conspicuous result was that alcohol intoxication decreased neuronal activation especially in the dorsal anterior cingulate cortex (dACC) and in prefrontal areas, while expectancy increased neuronal activation in the same areas. This study shows that alcohol intoxication and expectancy have opposite effects on neuronal activation. The present results could have implications for pharmacological imaging studies.

Iterative blind deconvolution in magnetic resonance brain perfusion imaging

In first pass magnetic resonance brain perfusion imaging, arterial input functions are used in the deconvolution of the observed contrast concentrations to obtain quantitative hemodynamic parameters. Ideally, arterial input functions should be measured in each imaged voxel to eliminate the effects of delay and dispersion of the contrast agent from the injection site. An approach based on iterative blind deconvolution with the Richardson–Lucy algorithm is proposed for the simultaneous estimation of voxel‐specific arterial input functions and voxel‐specific tissue residue functions. An extended contrast concentration model was used to separate the first pass bolus from additional recirculation and leakage signals. The extended model was evaluated using in vivo data. Computer simulations examined the feasibility of iterative blind deconvolution in perfusion imaging. Preliminary in vivo results from a patient with fibromuscular dysplasia showed territories with delayed/dispersed arterial input functions that coincided with the location of territories supplied by collateral circulation as described from the complete radiologic examination. Higher flow values and shorter mean transit times compared to conventional methods were obtained in these areas, suggesting that the effects of dispersion were minimized. The in vivo estimated arterial input functions visualized the patients blood supply patterns as a function of time. Magn Reson Med, 2006.

A critical review of pro-cognitive drug targets in psychosis: convergence on myelination and inflammation

Antipsychotic drugs have thus far focused on dopaminergic antagonism at the D2 receptors, as counteracting the hyperdopaminergia in nigrostriatal and mesolimbic projections has been considered mandatory for the antipsychotic action of the drugs. Current drugs effectively target the positive symptoms of psychosis such as hallucinations and delusions in the majority of patients, whereas effect sizes are smaller for negative symptoms and cognitive dysfunctions. With the understanding that neurocognitive dysfunction associated with schizophrenia have a greater impact on functional outcome than the positive symptoms, the focus in pharmacotherapy for schizophrenia has shifted to the potential effect of future drugs on cognitive enhancement. A major obstacle is, however, that the biological underpinnings of cognitive dysfunction remain largely unknown. With the availability of increasingly sophisticated techniques in molecular biology and brain imaging, this situation is about to change with major advances being made in identifying the neuronal substrates underlying schizophrenia, and putative pro-cognitive drug targets may be revealed. In relation to cognitive effects, this review focuses on evidence from basic neuroscience and clinical studies, taking two separate perspectives. One perspective is the identification of previously under-recognized treatment targets for existing antipsychotic drugs, including myelination and mediators of inflammation. A second perspective is the development of new drugs or novel treatment targets for well-known drugs, which act on recently discovered treatment targets for cognitive enhancement, and which may complement the existing drugs. This might pave the way for personalized treatment regimens for patients with schizophrenia aimed at improved functional outcome. The review also aims at identifying major current constraints for pro-cognitive drug development for patients with schizophrenia.

Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas

Background:We aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and to explore the potential value of these markers to identify patients with poor outcome.Methods:In fifty-four surgically staged endometrial carcinoma patients, immunohistochemical staining with factor VIII and Ki67 allowed assessment of microvessel density (MVD) and microvascular proliferation reflecting tumour angiogenesis. In the same patients, preoperative pelvic DCE-MRI and DWI allowed the calculation of parameters describing tumour microvasculature and microstructure in vivo.Results:Microvascular proliferation was negatively correlated to tumour blood flow (Fb) (r=−0.36, P=0.008), capillary permeability surface area product (PS) (r=−0.39, P=0.004) and transfer from the blood to extravascular extracellular space (EES) (Ktrans) (r=−0.40, P=0.003), and was positively correlated to tumour volume (r=0.34; P=0.004). High-tumour microvascular proliferation, low Fb and low Ktrans were all significantly associated with reduced progression/recurrence-free survival (P<0.05).Conclusion:Disorganised angiogenesis with coexisting microvascular proliferation and low tumour blood flow is a poor prognostic factor supporting that hypoxia is associated with progression and metastatic spread in endometrial carcinomas.

Single-Channel Blind Estimation of Arterial Input Function and Tissue Impulse Response in DCE-MRI

Multipass dynamic MRI and pharmacokinetic modeling are used to estimate perfusion parameters of leaky capillaries. Curve fitting and nonblind deconvolution are the established methods to derive the perfusion estimates from the observed arterial input function (AIF) and tissue tracer concentration function. These nonblind methods are sensitive to errors in the AIF, measured in some nearby artery or estimated by multichannel blind deconvolution. Here, a single-channel blind deconvolution algorithm is presented, which only uses a single tissue tracer concentration function to estimate the corresponding AIF and tissue impulse response function. That way, many errors affecting these functions are reduced. The validity of the algorithm is supported by simulations and tests on real data from mouse. The corresponding nonblind and multichannel methods are also presented.

The Effects of Alcohol Intoxication on Neuronal Activation at Different Levels of Cognitive Load

The aim of this study was to investigate how alcohol intoxication at two blood alcohol concentrations (BAC) affected neuronal activation during increasing levels of cognitive load. For this purpose we used functional magnetic resonance imaging (fMRI) together with a working memory n-back paradigm with three levels of difficulty. Twenty-five healthy male participants were scanned twice on two separate days. Participants in the control group (N=13) were scanned after drinking a soft-drink at both scanning sessions, while participants in the alcohol group (N=12) were scanned once after drinking an alcoholic beverage resulting in a BAC of 0.02%, and once after drinking an alcoholic beverage resulting in a BAC of 0.08%. A decrease in neuronal activation was seen in the dorsal anterior cingulate cortex (dACC) and in the cerebellum in the alcohol group at the BAC of 0.08% when the participants performed the most demanding task. The dACC is important in cognitive control, working memory, response inhibition, decision making and in error monitoring. The results have revealed that the effect of alcohol intoxication on brain activity is dependent on BAC and of cognitive load.