Test-retest stability of spontaneous brain activity and functional connectivity in the core resting-state networks assessed with ultrahigh field 7-Tesla resting-state functional magnetic resonance imaging.

The growing demand for precise and reliable biomarkers in psychiatry is fueling research interest in the hope that identifying quantifiable indicators will improve diagnoses and treatment planning across a range of mental health conditions. The individual properties of brain networks at rest have been highlighted as a possible source for such biomarkers, with the added advantage that they are relatively straightforward to obtain. However, an important prerequisite for their consideration is their reproducibility. While the reliability of resting-state (RS) measurements has often been studied at standard field strengths, they have rarely been investigated using ultrahigh-field (UHF) magnetic resonance imaging (MRI) systems. We investigated the intersession stability of four functional MRI RS parameters-amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF; representing the spontaneous brain activity), regional homogeneity (ReHo; measure of local connectivity), and degree centrality (DC; measure of long-range connectivity)-in three RS networks, previously shown to play an important role in several psychiatric diseases-the default mode network (DMN), the central executive network (CEN), and the salience network (SN). Our investigation at individual subject space revealed a strong stability for ALFF, ReHo, and DC in all three networks, and a moderate level of stability in fALFF. Furthermore, the internetwork connectivity between each network pair was strongly stable between CEN/SN and moderately stable between DMN/SN and DMN/SN. The high degree of reliability and reproducibility in capturing the properties of the three major RS networks by means of UHF-MRI points to its applicability as a potentially useful tool in the search for disease-relevant biomarkers.

MR-PET head motion correction based on co-registration of multicontrast MR images.

Head motion is a major source of image artefacts in neuroimaging studies and can lead to degradation of the quantitative accuracy of reconstructed PET images. Simultaneous magnetic resonance-positron emission tomography (MR-PET) makes it possible to estimate head motion information from high-resolution MR images and then correct motion artefacts in PET images. In this article, we introduce a fully automated PET motion correction method, MR-guided MAF, based on the co-registration of multicontrast MR images. The performance of the MR-guided MAF method was evaluated using MR-PET data acquired from a cohort of ten healthy participants who received a slow infusion of fluorodeoxyglucose ([18-F]FDG). Compared with conventional methods, MR-guided PET image reconstruction can reduce head motion introduced artefacts and improve the image sharpness and quantitative accuracy of PET images acquired using simultaneous MR-PET scanners. The fully automated motion estimation method has been implemented as a publicly available web-service.

Sequential implementation of DSC-MR perfusion and dynamic [18F]FET PET allows efficient differentiation of glioma progression from treatment-related changes.

PURPOSE: Perfusion-weighted MRI (PWI) and O-(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18F]FET PET. METHODS: We evaluated 104 patients with WHO grade II-IV glioma and suspected TP on conventional MRI using PWI and dynamic [18F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax) and dynamic [18F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC). RESULTS: Across all patients, the differentiation of TP from TRC using rCBVmax or [18F]FET PET parameters was moderate (AUC = 0.69-0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18F]FET PET parameters (TBRmax, Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3). CONCLUSION: While marked hyperperfusion on PWI indicated TP, [18F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.

From simultaneous to synergistic MR-PET brain imaging: A review of hybrid MR-PET imaging methodologies.

Simultaneous Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scanning is a recent major development in biomedical imaging. The full integration of the PET detector ring and electronics within the MR system has been a technologically challenging design to develop but provides capacity for simultaneous imaging and the potential for new diagnostic and research capability. This article reviews state-of-the-art MR-PET hardware and software, and discusses future developments focusing on neuroimaging methodologies for MR-PET scanning. We particularly focus on the methodologies that lead to an improved synergy between MRI and PET, including optimal data acquisition, PET attenuation and motion correction, and joint image reconstruction and processing methods based on the underlying complementary and mutual information. We further review the current and potential future applications of simultaneous MR-PET in both systems neuroscience and clinical neuroimaging research. We demonstrate a simultaneous data acquisition protocol to highlight new applications of MR-PET neuroimaging research studies.

Accurate hybrid template-based and MR-based attenuation correction using UTE images for simultaneous PET/MR brain imaging applications.

BACKGROUND: Attenuation correction is one of the most crucial correction factors for accurate PET data quantitation in hybrid PET/MR scanners, and computing accurate attenuation coefficient maps from MR brain acquisitions is challenging. Here, we develop a method for accurate bone and air segmentation using MR ultrashort echo time (UTE) images. METHODS: MR UTE images from simultaneous MR and PET imaging of five healthy volunteers was used to generate a whole head, bone and air template image for inclusion into an improved MR derived attenuation correction map, and applied to PET image data for quantitative analysis. Bone, air and soft tissue were segmented based on Gaussian Mixture Models with probabilistic tissue maps as a priori information. We present results for two approaches for bone attenuation coefficient assignments: one using a constant attenuation correction value; and another using an estimated continuous attenuation value based on a calibration fit. Quantitative comparisons were performed to evaluate the accuracy of the reconstructed PET images, with respect to a reference image reconstructed with manually segmented attenuation maps. RESULTS: The DICE coefficient analysis for the air and bone regions in the images demonstrated improvements compared to the UTE approach, and other state-of-the-art techniques. The most accurate whole brain and regional brain analyses were obtained using constant bone attenuation coefficient values. CONCLUSIONS: A novel attenuation correction method for PET data reconstruction is proposed. Analyses show improvements in the quantitative accuracy of the reconstructed PET images compared to other state-of-the-art AC methods for simultaneous PET/MR scanners. Further evaluation is needed with radiopharmaceuticals other than FDG, and in larger cohorts of participants.

Dual-time-point O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for grading of cerebral gliomas.

OBJECTIVE: We aimed to evaluate the diagnostic potential of dual-time-point imaging with positron emission tomography (PET) using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) for non-invasive grading of cerebral gliomas compared with a dynamic approach. METHODS: Thirty-six patients with histologically confirmed cerebral gliomas (21 primary, 15 recurrent; 24 high-grade, 12 low-grade) underwent dynamic PET from 0 to 50 min post-injection (p.i.) of (18)F-FET, and additionally from 70 to 90 min p.i. Mean tumour-to-brain ratios (TBRmean) of (18)F-FET uptake were determined in early (20-40 min p.i.) and late (70-90 min p.i.) examinations. Time-activity curves (TAC) of the tumours from 0 to 50 min after injection were assigned to different patterns. The diagnostic accuracy of changes of (18)F-FET uptake between early and late examinations for tumour grading was compared to that of curve pattern analysis from 0 to 50 min p.i. of (18)F-FET. RESULTS: The diagnostic accuracy of changes of the TBRmean of (18)F-FET PET uptake between early and late examinations for the identification of HGG was 81% (sensitivity 83%; specificity 75%; cutoff - 8%; p < 0.001), and 83% for curve pattern analysis (sensitivity 88%; specificity 75%; p < 0.001). CONCLUSION: Dual-time-point imaging of (18)F-FET uptake in gliomas achieves diagnostic accuracy for tumour grading that is similar to the more time-consuming dynamic data acquisition protocol. KEY POINTS: • Dual-time-point imaging is equivalent to dynamic FET PET for grading of gliomas. • Dual-time-point imaging is less time consuming than dynamic FET PET. • Costs can be reduced due to higher patient throughput. • Reduced imaging time increases patient comfort and sedation might be avoided. • Quicker image interpretation is possible, as no curve evaluation is necessary.

Characterizing cerebral oxygen metabolism employing oxygen-17 MRI/MRS at high fields.

This article provides a comprehensive overview of oxygen ((17)O) magnetic resonance spectroscopy and imaging, including the advantages and challenges offered by the different methods developed thus far. The physiological role and relevance of oxygen, and its participation in aerobic metabolism, are addressed to emphasize the importance of the investigations and the efforts related to these developments. Furthermore, a number of methods employed in the determination of the cerebral metabolic rate of oxygen in neural cells will be presented, focusing primarily on methodologies enabling absolute quantification.

Hybrid PET/MRI in Cerebral Glioma: Current Status and Perspectives.

Advanced MRI methods and PET using radiolabelled amino acids provide valuable information, in addition to conventional MR imaging, for brain tumour diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumour progression from treatment-related changes, and the early assessment of responses to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing, and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other, leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods, but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumours. PET is only required in equivocal situations, and the spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumours compared with a single modality. This review focuses on studies investigating the diagnostic value of combined amino acid PET and 'advanced' MRI in patients with cerebral gliomas. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterisation of newly diagnosed tumours. Few data are available concerning the delineation of tumour extent. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumour recurrence from treatment-related changes. Here, the PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of cerebral gliomas, for which hybrid PET/MRI offers optimal conditions.

Human cortical connectome reconstruction from diffusion weighted MRI: the effect of tractography algorithm.

Reconstructing the macroscopic human cortical connectome by Diffusion Weighted Imaging (DWI) is a challenging research topic that has recently gained a lot of attention. In the present work, we investigate the effects of intra-voxel fiber direction modeling and tractography algorithm on derived structural network indices (e.g. density, small-worldness and global efficiency). The investigation is centered on three semi-independent distinctions within the large set of available diffusion models and tractography methods: i) single fiber direction versus multiple directions in the intra-voxel diffusion model, ii) deterministic versus probabilistic tractography and iii) local versus global measure-of-fit of the reconstructed fiber trajectories. The effect of algorithm and parameter choice has two components. First, there is the large effect of tractography algorithm and parameters on global network density, which is known to strongly affect graph indices. Second, and more importantly, there are remaining effects on graph indices which range in the tens of percent even when global density is controlled for. This is crucial for the sensitivity of any human structural network study and for the validity of study comparisons. We then investigate the effect of the choice of tractography algorithm on sensitivity and specificity of the resulting connections with a connectome dissection quality control (QC) approach. In this approach, evaluation of Tract Specific Density Coefficients (TSDCs) measures sensitivity while careful inspection of tractography path results assesses specificity. We use this to discuss interactions in the combined effects of these methods and implications for future studies.

Connectivity Patterns in the Core Resting-State Networks and Their Influence on Cognition.

Introduction: Three prominent resting-state networks (rsNW) (default mode network [DMN], salience network [SN], and central executive network [CEN]) are recognized for their important role in several neuropsychiatric conditions. However, our understanding of their relevance in terms of cognition remains insufficient. Materials and Methods: In response, this study aims at investigating the patterns of different network properties (resting-state activity [RSA] and short- and long-range functional connectivity [FC]) in these three core rsNWs, as well as the dynamics of age-associated changes and their relation to cognitive performance in a sample of healthy controls (N = 74) covering a large age span (20-79 years). Using a whole-network based approach, three measures were calculated from the functional magnetic resonance imaging (fMRI) data: amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and degree of network centrality (DC). The cognitive test battery covered the following domains: memory, executive functioning, processing speed, attention, and visual perception. Results: For all three fMRI measures (ALFF, ReHo, and DC), the highest values of spontaneous brain activity (ALFF), short- and long-range connectivity (ReHo, DC) were observed in the DMN and the lowest in the SN. Significant age-associated decrease was observed in the DMN for ALFF and DC, and in the SN for ALFF and ReHo. Significant negative partial correlations were observed for working memory and ALFF in all three networks, as well as for additional cognitive parameters and ALFF in CEN. Discussion: Our results show that higher RSA in the three core rsNWs may have an unfavorable effect on cognition. Conversely, the pattern of network properties in healthy subjects included low RSA and FC in the SN. This complements previous research related to the three core rsNW and shows that the chosen approach can provide additional insight into their function. Impact statement Using a whole network-based approach, our study characterizes the normal patterns (including resting-state activity [RSA], short- and long-range functional connectivity [FC]) of three prominent resting-state networks (rsNW) within the context of age-dependent changes and explores their relevance for different cognitive domains. Our results revealed a pattern with low RSA and FC in the salience network in healthy volunteers, whereas higher RSA, particularly in the central executive network, seemed to have a negative effect on cognition. These results increase the knowledge about the three core rsNWs and the understanding about their relevance for cognition.

Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Quantitative measurement of blood-brain barrier permeability in human using dynamic contrast-enhanced MRI with fast T1 mapping.

Breakdown of the blood-brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast-enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T(1) mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) from plasma into brain. A quarter of the standard Gd-DTPA dose for dynamic contrast-enhanced magnetic resonance imaging was found to give both sufficient contrast-to-noise and high T(1) sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T(1). Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10(-4) L/g min. MRI measurements were not [corrected] correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast-enhanced magnetic resonance imaging with low dose Gd-DTPA and fast T(1) imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes.

Combined 18F-FET PET and diffusion kurtosis MRI in posttreatment glioblastoma: differentiation of true progression from treatment-related changes.

BACKGROUND: Radiological differentiation of tumor progression (TPR) from treatment-related changes (TRC) in pretreated glioblastoma is crucial. This study aimed to explore the diagnostic value of diffusion kurtosis MRI combined with information derived from O-(2-[18F]-fluoroethyl)-l-tyrosine (18F-FET) PET for the differentiation of TPR from TRC in patients with pretreated glioblastoma. METHODS: Thirty-two patients with histomolecularly defined and pretreated glioblastoma suspected of having TPR were included in this retrospective study. Twenty-one patients were included in the TPR group, and 11 patients in the TRC group, as assessed by neuropathology or clinicoradiological follow-up. Three-dimensional (3D) regions of interest were generated based on increased 18F-FET uptake using a tumor-to-brain ratio of 1.6. Furthermore, diffusion MRI kurtosis maps were obtained from the same regions of interest using co-registered 18F-FET PET images, and advanced histogram analysis of diffusion kurtosis map parameters was applied to generated 3D regions of interest. Diagnostic accuracy was analyzed by receiver operating characteristic curve analysis and combinations of PET and MRI parameters using multivariate logistic regression. RESULTS: Parameters derived from diffusion MRI kurtosis maps show high diagnostic accuracy, up to 88%, for differentiating between TPR and TRC. Logistic regression revealed that the highest diagnostic accuracy of 94% (area under the curve, 0.97; sensitivity, 94%; specificity, 91%) was achieved by combining the maximum tumor-to-brain ratio of 18F-FET uptake and diffusion MRI kurtosis metrics. CONCLUSIONS: The combined use of 18F-FET PET and MRI diffusion kurtosis maps appears to be a promising approach to improve the differentiation of TPR from TRC in pretreated glioblastoma and warrants further investigation.

Cognitive levels of performance account for hemispheric lateralisation effects in dyslexic and normally reading children.

Recent theories of developmental dyslexia explain reading deficits in terms of deficient phonological awareness, attention, visual and auditory processing, or automaticity. Since dyslexia has a neurobiological basis, the question arises how the reader's proficiency in these cognitive variables affects the brain regions involved in visual word recognition. This question was addressed in two fMRI experiments with 19 normally reading children (Experiment 1) and 19 children with dyslexia (Experiment 2). First, reading-specific brain activation was assessed by contrasting the BOLD signal for reading aloud words vs. overtly naming pictures of real objects. Next, ANCOVAs with brain activation during reading the individuals' scores for all five cognitive variables assessed outside the scanner as covariates were performed. Whereas the normal readers' brain activation during reading showed co-variation effects predominantly in the right hemisphere, the reverse pattern was observed for the dyslexics. In particular, middle frontal gyrus, inferior parietal cortex, and precuneus showed contralateral effects for controls as compared to dyslexics. In line with earlier findings in the literature, these data hint at a global change in hemispheric asymmetry during cognitive processing in dyslexic readers, which, in turn, might affect reading proficiency.

The impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval.

Episodic memory impairment is a frequently reported symptom in schizophrenia. It has been shown to be associated with reduced neural activity of the hippocampus and prefrontal cortex. Given the high heritability of schizophrenia the question arises if alterations in brain activity are modulated by susceptibility genes and might be detectable in healthy risk allele carriers. The present study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 (P1578) of the dystrobrevin-binding protein 1 (DTNBP1) on brain activity in 84 healthy subjects assessed by functional magnetic resonance imaging (fMRI) while they performed an episodic memory task comprising encoding and retrieval of faces. During encoding, the group of risk allele carriers (n = 29) showed enhanced neural activity in the left middle frontal gyrus (BA 11) and bilaterally in the cuneus (BA 17, 7) when compared with the nonrisk carrier group (n = 55). During retrieval, the risk group (compared to the non risk group) showed increased right hemispheric neural activity comprising the medial frontal gyrus (BA 9), inferior frontal gyrus (BA 9), and inferior parietal lobule (BA 40). Since there were no behavioral performance differences, increased neural activity of the risk group might be interpreted as a correlate of higher effort or differing cognitive strategies in order to compensate for a genetically determined slight cognitive deficit. Interestingly, the laterality of increased prefrontal activity is in accordance with the well known hemispheric encoding/retrieval asymmetry (HERA) model of episodic memory.

Scatter Correction Based on GPU-Accelerated Full Monte Carlo Simulation for Brain PET/MRI.

Accurate scatter correction is essential for qualitative and quantitative PET imaging. Until now, scatter correction based on Monte Carlo simulation (MCS) has been recognized as the most accurate method of scatter correction for PET. However, the major disadvantage of MCS is its long computational time, which makes it unfeasible for clinical usage. Meanwhile, single scatter simulation (SSS) is the most widely used method for scatter correction. Nevertheless, SSS has the disadvantage of limited robustness for dynamic measurements and for the measurement of large objects. In this work, a newly developed implementation of MCS using graphics processing unit (GPU) acceleration is employed, allowing full MCS-based scatter correction in clinical 3D brain PET imaging. Starting from the generation of annihilation photons to their detection in the simulated PET scanner, all relevant physical interactions and transport phenomena of the photons were simulated on GPUs. This resulted in an expected distribution of scattered events, which was subsequently used to correct the measured emission data. The accuracy of the approach was validated with simulations using GATE (Geant4 Application for Tomography Emission), and its performance was compared to SSS. The comparison of the computation time between a GPU and a single-threaded CPU showed an acceleration factor of 776 for a voxelized brain phantom study. The speedup of the MCS implemented on the GPU represents a major step toward the application of the more accurate MCS-based scatter correction for PET imaging in clinical routine.

Disentangling the prefrontal network for rule selection by means of a non-verbal variant of the Wisconsin Card Sorting Test.

This study disentangles the prefrontal network underlying executive functions involved in the Wisconsin Card Sorting Test (WCST). During the WCST, subjects have to perform two key processes: first, they have to derive the correct sorting rule for each trial by trial-and-error, and, second, they have to detect when this sorting rule is changed by the investigator. Both cognitive processes constitute key components of the executive system, which is subserved by the prefrontal cortex. For the current fMRI experiment, we developed a non-verbal variant of the WCST. Subjects were instructed either to respond according to a given sorting rule or to detect the correct sorting rule, like in the original version of the WCST. Data were obtained from 14 healthy male volunteers and analysed using SPM and a random effects model. All conditions activated a fronto-parietal network, which was generally more active when subjects had to search for the correct sorting rule than when the rule was announced beforehand. Significant differences between these two conditions were seen in the dorsolateral prefrontal cortex (PFC) and the parietal lobe. In addition, the data provided new evidence for the assumption of differentiated roles of the left and right prefrontal cortex. Although the right PFC showed a general involvement in response selection and the execution of goal directed responses, based on given rules, the left PFC was only activated when inductive reasoning and feedback integration was required.

Genetic variation in the schizophrenia-risk gene neuregulin 1 correlates with brain activation and impaired speech production in a verbal fluency task in healthy individuals.

Impaired performance in verbal fluency tasks is an often replicated finding in schizophrenia. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and temporal areas. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes for the disorder, such as NRG1, modulate verbal fluency performance and its neural correlates. Four hundred twenty-nine healthy individuals performed a semantic and a lexical verbal fluency task. A subsample of 85 subjects performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (MRI). NRG1 (SNP8NRG221533; rs35753505) status was determined and correlated with verbal fluency performance and brain activation. For the behavioral measure, there was a linear effect of NRG1 status on semantic but not on lexical verbal fluency. Performance decreased with number of risk-alleles. In the fMRI experiment, decreased activation in the left inferior frontal and the right middle temporal gyri as well as the anterior cingulate gyrus was correlated with the number of risk-alleles in the semantic verbal fluency task. NRG1 genotype does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in schizophrenia and may explain some of the cognitive and brain activation variation found in the disorder. More generally, NRG1 might be one of several genes that influence semantic language capacities.

Muscarinic antagonist effects on executive control of attention.

Acetylcholine plays a major role in mediating attention processes. We investigated the muscarinic antagonist effect of scopolamine on functional neuro-anatomy of attention and cognition. We assessed 12 healthy volunteers while performing the Attention Network Task on 0.4 mg scopolamine and placebo in a single-blind randomized trial in a 1.5 T magnetic resonance scanner. Neurocognitive measures included verbal learning, verbal memory, verbal fluency, trail making, digit span, a continuous performance task and a planning task (Tower of London). When compared to placebo, scopolamine increased reaction times for conflicting stimulus processing, together with decreasing brain activation in the anterior cingulate cortex (a brain region involved in conflict processing) suggestive of a muscarinic antagonist effect on executive control of attention. Contrary to the notion of a predominantly right-hemispheric lateralization of cognitive processes associated with orienting attention, scopolamine reduced brain activity in left superior and left middle frontal brain areas. Our neuropsychological test data revealed a selective effect of scopolamine on verbal learning and memory while other cognitive domains, such as planning and working memory, were unaffected. These findings are consistent with muscarinic modulation of dopaminergic neurotransmission in frontal attention networks when processing conflicting information.

Nicotinic antagonist effects on functional attention networks.

Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.