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Creatine is a key regulator of brain energy homeostasis, and well-balanced creatine metabolism is central in healthy brain functioning. Still, the variability of brain creatine metabolism is largely unattended in magnetic resonance spectroscopy (MRS) research. In the human brain, marginal sex differences in creatine levels have been found in the prefrontal cortex. It is however not known to what degree these sex differences are stable or change with varying gonadal hormone levels. The current study therefore investigated creatine in the prefrontal cortex across the menstrual cycle. In addition, we explored cerebral asymmetries. Creatine, Choline (Cho), N-acetylaspartate (NAA), Myo inositol (mI), and glutamate + glutamine (Glx) were assessed three times in 15 women and 14 men using MRS. Women were tested in cycle phases of varying hormone levels (menstrual, follicular, and luteal phase). Prefrontal creatine was found to change across the menstrual cycle, in a hemisphere-specific manner. Women in the follicular phase showed increased left prefrontal creatine accompanied with reduced right prefrontal creatine, while this asymmetry was not present in the luteal phase. In men, the creatine levels remained stable across three testing sessions. In general, both men and women were found to have higher creatine levels in the left as compared to the right prefrontal cortex. Exploratory analyses of other metabolites showed similar asymmetries in NAA, Cho, and mI, while Cho also showed a menstrual cycle effect. This is the first time that sex hormone-related changes in creatine metabolism have been demonstrated in the human brain. These findings may have important methodological implications for MRS research, as it supports previous concerns against uncritical usage of creatine as a reference measure for other metabolites, assumed to be invariant across individuals and conditions., (Copyright © 2018 University of Bergen. Published by Elsevier Inc. All rights reserved.)

Dyslexia is a literacy disorder affecting the efficient acquisition of reading and writing skills. The disorder is neurobiological in origin. Due to its developmental nature, longitudinal studies of dyslexia are of essence. They are, however, relatively scarce. The present study took a longitudinal approach to cortical connectivity of brain imaging data in reading tasks in children with dyslexia and children with typical reading development. The participants were followed with repeated measurements through Pre-literacy (6 years old), Emergent Literacy (8 years old) and Literacy (12 years old) stages, using Dynamic Causal Modelling (DCM) when analysing functional magnetic resonance imaging (fMRI) data. Even though there are a few longitudinal studies on effective connectivity in typical reading, to our knowledge, no studies have previously investigated these issues in relation to dyslexia. We set up a model of a brain reading network involving five cortical regions (inferior frontal gyrus, precentral gyrus, superior temporal gyrus, inferior parietal lobule, and occipito-temporal cortex). Using DCM, connectivity measures were calculated for each connection in the model. These measures were further analysed using factorial ANOVA. The results showed that the difference between groups centred on connections going to and from the inferior frontal gyrus (two connections) and the occipito-temporal cortex (three connections). For all five connections, the typical group showed stable or decreasing connectivity measures. The dyslexia group, on the other hand, showed a marked up-regulation (occipito-temporal connections) or down-regulation (inferior frontal gyrus connections) from 6 years to 8 years, followed by normalization from 8 years to 12 years. We interpret this as a delay in the dyslexia group in developing into the Pre-literacy and Emergent literacy stages. This delay could possibly be detrimental to literacy development. By age 12, there was no statistically significant difference in connectivity between the groups, but differences in literacy skills were still present, and were in fact larger than when measured at younger ages., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Difficulties in left-right discrimination (LRD) are commonly experienced in everyday life situations. Here we investigate the neurocognitive mechanisms of LRD and the specific role of left angular gyrus. Given that previous behavioral research reported women to be more susceptible to left-right confusion, the current study focuses particularly on the neural basis of sex differences in LRD while controlling for potential menstrual cycle effects (repeated measures design). 16 women and 15 men were presented pictures of pointing hands in various orientations (rotated versus non-rotated) and were asked to identify them as left or right hands. Results revealed that LRD was particularly associated with activation in inferior parietal regions, extending into the right angular gyrus. Irrespective of menstrual cycle phase, women, relative to men, recruited more prefrontal areas, suggesting higher top-down control in LRD. For the subset of rotated stimuli as compared to the non-rotated, we found leftward asymmetry for both men and women, although women scored significantly lower. We conclude that there are sex differences in the neurocognitive mechanisms underlying LRD. Although the angular gyrus is involved in LRD, several other parietal areas are at least as critical. Moreover, the hypothesis that more left-right confusion is due to more bilateral activation (in women) can be rejected., (Copyright © 2015. Published by Elsevier Inc.)

Valuable stimuli are invariably localized in space. While our knowledge regarding the neural networks supporting value assignment and comparisons is considerable, we lack a basic understanding of how the human brain integrates motivational and spatial information. The amygdala is a key structure for learning and maintaining the value of sensory stimuli and a recent non-human primate study provided initial evidence that it also acts to integrate value with spatial location, a question we address here in a human setting. We measured haemodynamic responses (fMRI) in amygdala while manipulating the value and spatial configuration of stimuli in a simple stimulus-reward task. Subjects responded significantly faster and showed greater amygdala activation when a reward was dependent on a spatial specific response, compared to when a reward required less spatial specificity. Supplemental analysis supported this spatial specificity by demonstrating that the pattern of amygdala activity varied based on whether subjects responded to a motivational target presented in the ipsilateral or contralateral visual space. Our data show that the human amygdala integrates information about space and value, an integration of likely importance for assigning cognitive resources towards highly valuable stimuli in our environment., (Copyright © 2014. Published by Elsevier Inc.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Several reports of premotor cortex involvement in speech perception have been put forward. Still, the functional role of premotor cortex is under debate. In order to investigate the functional role of premotor cortex, we presented parametrically varied speech stimuli in both a behavioral and functional magnetic resonance imaging (fMRI) study. White noise was transformed over seven distinct steps into a speech sound and presented to the participants in a randomized order. As control condition served the same transformation from white noise into a music instrument sound. The fMRI data were modelled with Dynamic Causal Modeling (DCM) where the effective connectivity between Heschl's gyrus, planum temporale, superior temporal sulcus and premotor cortex were tested. The fMRI results revealed a graded increase in activation in the left superior temporal sulcus. Premotor cortex activity was only present at an intermediate step when the speech sounds became identifiable but were still distorted but was not present when the speech sounds were clearly perceivable. A Bayesian model selection procedure favored a model that contained significant interconnections between Heschl's gyrus, planum temporal, and superior temporal sulcus when processing speech sounds. In addition, bidirectional connections between premotor cortex and superior temporal sulcus and from planum temporale to premotor cortex were significant. Processing non-speech sounds initiated no significant connections to premotor cortex. Since the highest level of motor activity was observed only when processing identifiable sounds with incomplete phonological information, it is concluded that premotor cortex is not generally necessary for speech perception but may facilitate interpreting a sound as speech when the acoustic input is sparse., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Previous functional activation studies in patients with aphasia have mostly relied on standard group comparisons of aphasic patients with healthy controls, which are biased towards regions showing the most consistent effects and disregard variability within groups. Groups of aphasic patients, however, show considerable variability with respect to lesion localisation and extent. Here, we use a novel method, joint independent component analysis (jICA), which allowed us to investigate abnormal patterns of functional activation with O(15)-PET during lexical decision in aphasic patients after middle cerebral artery stroke and to directly relate them to lesion information from structural MRI. Our results demonstrate that with jICA we could detect a network of compensatory increases in activity within bilateral anterior inferior temporal areas (BA20), which was not revealed by standard group comparisons. In addition, both types of analyses, jICA and group comparison, showed increased activity in the right posterior superior temporal gyrus in aphasic patients. Further, whereas standard analyses revealed no decreases in activation, jICA identified that left perisylvian lesions were associated with decreased activation of left posterior inferior frontal cortex, damaged in most patients, and extralesional remote decreases of activity within polar parts of the inferior temporal gyrus (BA38/20) and the occipital cortex (BA19). Taken together, our results demonstrate that jICA may be superior in revealing complex patterns of functional reorganisation in aphasia.

In working memory (WM), functional imaging studies demonstrate cerebellar involvement indicating a cognitive role of the cerebellum. These cognitive contributions were predominantly interpreted as part of the phonological loop within the Baddeley model of WM. However, those underlying investigations were performed in the context of visual verbal WM which could pose a bias when interpreting the results. The aim of this fMRI study was to address the question of whether the cerebellum supports additional aspects of WM in the context of higher cognitive functions. Furthermore, laterality effects were investigated to further disentangle the cerebellar role in the context of the phonological loop and the visuospatial sketchpad. A direct comparison of verbal and abstract visual WM was performed in 17 young volunteers by applying a 2-back paradigm and extracting the % change in BOLD signal from the fMRI data. To minimize potential verbal strategies, Attneave and Arnoult shapes of non-nameable objects were chosen for the abstract condition. The analyses revealed no significant differences in verbal vs. abstract WM. Moreover, no laterality effects were demonstrated in both verbal and abstract WM. These results provide further evidence of a broader cognitive involvement of the cerebellum in WM that is not only confined to the phonological loop but also supports central executive subfunctions. The fact that no lateralization effects are found might be attributed to the characteristics of the n-back paradigm which emphasizes central executive subfunctions over the subsidiary slave systems.

In this work we introduce a new algorithm to correct the imaging artefacts in the EEG signal measured during fMRI acquisition. The correction techniques proposed so far cannot optimally represent transitions, i.e. when abrupt changes of the artefact properties due to head movements occur. The algorithm developed here takes the head movement parameters from the fMRI signal into account to calculate adequate EEG artefact templates and subsequently correct the distorted EEG data. The data reported in this work demonstrate that the realignment parameter-informed algorithm outperforms the commonly used moving average algorithm if head movements occur. The superiority is reflected by comparing the residual variance after artefact correction with either method. The residual variance is lower around head-movements that exceed head deflections of about 1 mm when applying the realignment parameter-informed algorithm. Additionally, the signal to noise ratio of a surrogate event-related potential (ERP) increased by 10-40% for head displacements larger than 1 mm. The algorithm developed here is particularly suited for studies where head movements of the subject cannot be prevented as in studies with patients, children, or during sleep. Furthermore, the enhanced signal to noise ratio of a single trial ERP indicates the power of the presented algorithm for single trial ERP-fMRI studies in which EEG signal quality is a critical factor.

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.

Dichotic listening (DL) is one of the most frequently used paradigms to study hemispheric asymmetry and has been employed in several neuroimaging studies. The classic behavioral DL paradigm requires the subject to give a verbal response on each trial, which may cause image artifacts due to head movements when applied to an imaging environment. In order to avoid such artifacts most studies have used modified versions of the classic DL paradigm, where no verbal response is required. The purpose of the present study was to test a new DL paradigm, specifically developed for the fMRI environment, which is based on collecting verbal responses and thus being as close as possible to the classic DL behavioral task. By employing a sparse-sampling EPI acquisition schema we attempted to limit the negative impact of overt speech on image quality. A 5-s 'silent gap' allowed for stimulus presentation and collection of a verbal response to occur between subsequent image acquisitions and served as a high-pass filter that was optimized to detect activations of interest. Hence, the contribution of response-related activations to the measured signal was reduced. Twelve healthy volunteers (six males and six females) participated in the study. In order to obtain a measure of reliability, all participants went through the classic DL paradigm three times. The results, based on the estimation of the intraclass correlation coefficient, functional probability maps as well as on laterality maps, showed consistent activation in the right and left superior temporal gyrus, left middle temporal gyrus, and right inferior temporal gyrus, thus replicating previous results with visual display and motor response DL paradigms. It is concluded that an fMRI DL paradigm based on overt verbal responses is feasible and could have general implications for future fMRI studies of speech perception and product in general.

The specific role of particular cerebral regions with regard to executive functions remains elusive. We conducted a functional magnetic resonance imaging (fMRI) study to segregate different network components underlying the Wisconsin Card Sorting Test (WCST), a test widely applied clinically to assess executive abilities. Three different test variants of the WCST, differing in task complexity (A > B > C), were contrasted with a high-level baseline condition (HLB). Cognitive subcomponents were extracted in a serial subtraction approach (A-C, A-B, B-C). Imaging data were further subjected to a correlational analysis with individual behavioral parameters. Contrasting A with the HLB revealed the entire neural network underlying WCST performance, including frontoparietal regions and the striatum. Further analysis showed that, within this network, right ventrolateral prefrontal cortex related to simple working memory operations, while right dorsolateral prefrontal cortex related to more complex/manipulative working memory operations. The rostral anterior cingulate cortex (ACC) and the temporoparietal junction bilaterally represented an attentional network for error detection. In contrast, activation of the caudal ACC and the right dorsolateral prefrontal cortex was associated with increased attentional control in the context of increasing demands of working memory and cognitive control. Non-frontal activations were found to be related to (uninstructed relative to instructed) set-shifting (cerebellum) and working memory representations (superior parietal cortex, retrosplenium). The data provide neural correlates for the different cognitive components involved in the WCST. They support a central role of the right dorsolateral prefrontal cortex in executive working memory operations and cognitive control functions but also suggest a functional dissociation of the rostral and caudal ACC in the implementation of attentional control.

Previous neuroimaging studies have consistently reported bilateral activation to speech stimuli in the superior temporal gyrus (STG) and have identified an anteroventral stream of speech processing along the superior temporal sulcus (STS). However, little attention has been devoted to the possible confound of individual differences in hemispheric dominance for speech. The present study was designed to test for speech-selective activation while controlling for inter-individual variance in auditory laterality, by using only subjects with at least 10% right ear advantage (REA) on the dichotic listening test. Eighteen right-handed, healthy male volunteers (median age 26) participated in the study. The stimuli were words, syllables, and sine wave tones (220-2600 Hz), presented in a block design. Comparing words > tones and syllables > tones yielded activation in the left posterior MTG and the lateral STG (upper bank of STS). In the right temporal lobe, the activation was located in the MTG/STS (lower bank). Comparing left and right temporal lobe cluster sizes from the words > tones and syllables > tones contrasts on single-subject level demonstrated a statistically significant left lateralization for speech sound processing in the STS/MTG area. The asymmetry analyses suggest that dichotic listening may be a suitable method for selecting a homogenous group of subjects with respect to left hemisphere language dominance.

Data on the development of the attentional systems remain scarce. We used structural and event-related functional magnetic resonance imaging to investigate differences in the neural mechanisms associated with alerting, reorienting, and executive control of attention between children (ages 8 to 12 years) and adults, while controlling for effects of performance and brain morphology. Behaviorally, children exhibited a numerically smaller alerting effect and significantly larger invalidity (reorienting) and interference (executive control of attention) effects. Neurally, children showed significantly reduced brain activation in a priori defined regions-of-interest in right-sided frontal-midbrain regions during alerting, in the right-sided temporo-parietal junction during reorienting of attention, and in the dorsolateral prefrontal cortex during executive control of attention. In addition, children activated significantly more brain regions outside the a priori defined regions-of-interest, such as the superior frontal gyrus during reorienting and the superior temporal gyrus during executive control of attention. Functional group differences overlapped with structural group differences in gray matter volume in particular within the frontopolar areas. The data suggest that there is a transition from functional yet immature systems supporting attentional functions in children to the more definitive adult networks and that the differences observed may reflect both developmental changes in cognitive strategies and morphology.

The objective of this study was to investigate phonological processing in the brain by using sub-syllabic speech units with rapidly changing frequency spectra. We used isolated stop consonants extracted from natural speech consonant-vowel (CV) syllables, which were digitized and presented through headphones in a functional magnetic resonance imaging (fMRI) paradigm. The stop consonants were contrasted with CV syllables. In order to control for general auditory activation, we used duration- and intensity-matched noise as a third stimulus category. The subjects were seventeen right-handed, healthy male volunteers. BOLD activation responses were acquired on a 1.5-T MR scanner. The auditory stimuli were presented through MR compatible headphones, using an fMRI paradigm with clustered volume acquisition and 12 s repetition time. The consonant vs. noise comparison resulted in unilateral left lateralized activation in the posterior part of the middle temporal gyrus and superior temporal sulcus (MTG/STS). The CV syllable vs. noise comparison resulted in bilateral activation in the same regions, with a leftward asymmetry. The reversed comparisons, i.e., noise vs. speech stimuli, resulted in right hemisphere activation in the supramarginal and superior temporal gyrus, as well as right prefrontal activation. Since the consonant stimuli are unlikely to have activated a semantic-lexical processing system, it seems reasonable to assume that the MTG/STS activation represents phonetic/phonological processing. This may involve the processing of both spectral and temporal features considered important for phonetic encoding.

Voxel-based relaxometry (VBR) is a novel morphometric method that analyses the relaxation rate R2 derived from multi-echo T2-weighted images on a voxel-by-voxel basis. We used VBR to study the brain morphology of 14 patients suffering from multiple-system atrophy of cerebellar type (MSA-C) and compared the results with those obtained by voxel-based morphometry (VBM) of T1-weighted images. VBR analysis revealed reduction of relaxation rate R2 in the cerebellum and brainstem reflecting infratentorial brain atrophy. The affected regions largely corresponded to those regions in which VBM showed reductions of grey and white matter. In addition, R2 was increased in the putamen, a region in which VBM did not show abnormalities. Our data show that the combination of VBR and VBM provided convergent and complimentary information about the brain morphology of MSA-C.

The present study used functional and structural MRI to investigate differences in neuronal substrates underlying shifts of attention in young and old subjects, studied with dichotic listening. Two different consonant-vowel syllables were presented and the subjects were instructed to attend to and report from either the left or right ear stimulus. Typically, a right-ear advantage is observed when attending to the right-ear stimulus, and a left-ear advantage when attending to the left-ear stimulus. The behavioral results showed that the old group had difficulties with attentional modulation of the right-ear advantage in the attend left condition. This is interpreted as a failure of an important aspect of attentional control; the top-down biasing of attention for selection of task-relevant stimulus. The fMRI results showed that an area in the left middle frontal gyrus was more activated in the young group compared to the old group in the attend left condition. The structural MRI data showed reduced gray matter density of the same area in the old group. Based on these converging findings, we suggest that the left middle frontal gyrus plays an important role in top-down biasing of selecting task-relevant stimuli, and to inhibit processing of task-irrelevant stimuli. To our knowledge, this is one of the first studies addressing the question on how age-related changes in attentional processing is reflected in both functional and structural differences in the brain.