Author summaryThe neurovascular coupling (NVC) is the basis for functional magnetic resonance imaging (fMRI), since the NVC connects neural activity with the observed hemodynamic changes. This connection is highly complex, which warrants a model-based analysis. However, even though NVC-data from several species and many relevant variables are available, a mathematical model for all these data is still missing. Herein, we combine experimental data from mice, monkeys, and humans, to develop a comprehensive model for NVC. Importantly, our new approach to modelling propagates the qualitative insights from each species to the subsequent analysis of data from other species. In mice, we unravel the role of different neuronal sub-populations when producing a biphasic response to prolonged sensory stimulations. The qualitative role of these sub-populations is preserved when analysing primate data. These primate data add knowledge on the interplay between local field potential (LFP) and vascular changes. Similarly, these pre-clinical qualitative insights are propagated to analysis of human data, which contain additional insights regarding blood flow and volume in arterioles and venules, during both positive and negative responses. This work illustrates how data with complementary information from different species can be combined, so that qualitative insights from animals are preserved in the quantitative analysis of human data. Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied both experimentally and using mathematical models; various combinations of blood volume and flow, local field potential (LFP), hemoglobin level, blood oxygenation level-dependent response (BOLD), and optogenetics have been measured and modeled in rodents, primates, or humans. However, these data have not been brought together into a unified quantitative model. We now present a mathematical model that describes all such data types and that preserves mechanistic behaviors between experiments. For instance, from modeling of optogenetics and microscopy data in mice, we learn cell-specific contributions; the first rapid dilation in the vascular response is caused by NO-interneurons, the main part of the dilation during longer stimuli is caused by pyramidal neurons, and the post-peak undershoot is caused by NPY-interneurons. These insights are translated and preserved in all subsequent analyses, together with other insights regarding hemoglobin dynamics and the LFP/BOLD-interplay, obtained from other experiments on rodents and primates. The model can predict independent validation-data not used for training. By bringing together data with complementary information from different species, we both understand each dataset better, and have a basis for a new type of integrative analysis of human data.

Objectives As meditation is increasingly employed for the promotion of good health, there is a growing interest in using neuroimaging methods to investigate the neural mechanisms by which meditation acts. In the wake of this rising interest, criticism regarding the lack of clarity concerning theory, definitions, and taxonomy, as well as deficient or poorly reported methodology, has arisen. The aim of this study was to investigate trends in current neuroimaging research on meditation and to provide guidelines for future studies. Methods We made a literature search for articles published during 2016-2019 using the search phrases "meditation" and "functional magnetic resonance imaging or fMRI". Inclusion criteria were limited to meditation studies using resting-state fMRI or such task-based fMRI examinations that were specifically targeting meditative states in healthy participants. Text analysis was performed using Nvivo 12 Mac (QSR International). Results Twenty-eight articles were included from which we identified four different intention-based dimensions of meditation practice: The present moment, Wholesome qualities to cultivate, Unwholesome qualities to avoid, and Attitudes. Half of the studies do not make assessments of subjective experience. The results were related to networks and brain regions describing cognitive, affective, somatic, and self domains of brain function. Most studies describe meditation-related brain function in terms of "processes". Conclusions We defined five areas of potential improvement regarding research methodology: (1) Provide clear and unambiguous definitions of constructs and practices, (2) Include measures of subjective experience, (3) Perform correct assessment of processes, (4) Combine methodologies for more substantiated conclusions, (5) Avoid the risk of overinterpretation.

Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by disturbed interactions between the gut and the brain with depression as a common comorbidity. In both IBS and depression, structural brain alterations of the insular cortices, key structures for pain processing and interoception, have been demonstrated but the specificity of these findings remains unclear. We compared the gray matter volume (GMV) of insular cortex (IC) subregions in IBS women and healthy controls (HC) and examined relations to gastrointestinal (GI) symptoms and glutamate + glutamine (Glx) concentrations. We further analyzed GMV of IC subregions in women with major depression (MDD) compared to HC and addressed possible differences between depression, IBS, IBS with depression and HC.

The neurovascular and neurometabolic couplings (NVC and NMC) connect cerebral activity, blood flow, and metabolism. This interconnection is used in for instance functional imaging, which analyses the blood-oxygen-dependent (BOLD) signal. The mechanisms underlying the NVC are complex, which warrants a model-based analysis of data. We have previously developed a mechanistically detailed model for the NVC, and others have proposed detailed models for cerebral metabolism. However, existing metabolic models are still not fully utilizing available magnetic resonance spectroscopy (MRS) data and are not connected to detailed models for NVC. Therefore, we herein present a new model that integrates mechanistic modelling of both MRS and BOLD data. The metabolic model covers central metabolism, using a minimal set of interactions, and can describe time-series data for glucose, lactate, aspartate, and glutamate, measured after visual stimuli. Statistical tests confirm that the model can describe both estimation data and predict independent validation data, not used for model training. The interconnected NVC model can simultaneously describe BOLD data and can be used to predict expected metabolic responses in experiments where metabolism has not been measured. This model is a step towards a useful and mechanistically detailed model for cerebral blood flow and metabolism, with potential applications in both basic research and clinical applications. Author summary The neurovascular and neurometabolic couplings are highly central for several clinical imaging techniques since these frequently use blood oxygenation (the BOLD signal) as a proxy for neuronal activity. This relationship is described by the highly complex neurovascular and neurometabolic couplings, which describe the balancing between increased metabolic demand and blood flow, and which involve several cell types and regulatory systems, which all change dynamically over time. While there are previous works that describe the neurovascular coupling in detail, neither we nor others have developed connections to corresponding mechanistic models for the third aspect, the metabolic aspect. Furthermore, magnetic resonance spectroscopy (MRS) data for such modelling readily is available. In this paper we present a minimal mechanistic model that can describe the metabolic response to visual stimuli. The model is trained to describe experimental data for the relative change in metabolic concentrations of several metabolites in the visual cortex during stimulation. The model is also validated against independent validation data, that was not used for model training. Finally, we also connect this metabolic model to a detailed mechanistic model of the neurovascular coupling. Showing that the model can describe both the metabolic response and a neurovascular response simultaneously.

Introduction: Cognitive impairments in epilepsy are not well-understood. In addition, long-term emotional, interpersonal, and social consequences of the underlying disturbances are important to evaluate.

Purpose: To compare cognitive function including language in young adults with focal or generalized epilepsy. In addition, quality of life and self-esteem were investigated.

Patients and Methods: Young adults with no primary intellectual disability, 17 with focal epilepsy and 11 with generalized epilepsy participated and were compared to 28 healthy controls. Groups were matched on age (mean = 26 years), sex, and education. Participants were administered a battery of neuropsychological tasks and carried out self-ratings of quality of life, self-esteem, and psychological problems.

Results: Similar impairments regarding cognitive function were noted in focal and generalized epilepsy. The cognitive domains tested were episodic long-term memory, executive functions, attention, working memory, visuospatial functions, and language. Both epilepsy groups had lower results compared to controls (effect sizes 0.24-1.07). The total number of convulsive seizures was predictive of episodic long-term memory function. Participants with focal epilepsy reported lower quality of life than participants with generalized epilepsy. Lowered self-esteem values were seen in both epilepsy groups and particularly in those with focal epilepsy. Along with measures of cognitive speed and depression, the total number of seizures explained more than 50% of variation in quality of life.

Conclusion: Interestingly, similarities rather than differences characterized the widespread cognitive deficits that were seen in focal and generalized epilepsy, ranging from mild to moderate. These similarities were modified by quality of life and self-esteem. This study confirms the notion that epilepsy is a network disorder.

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.

Magnetotactic bacteria (MTB), ubiquitous in soil and fresh and saltwater sources have been identified in the microbiome of humans and many animals. MTB endogenously produce magnetic nanocrystals enabling them to orient and navigate along geomagnetic fields. Similar magnetite deposits have been found throughout the tissues of the human brain, including brain regions associated with orientation such as the cerebellum and hippocampus, the origins of which remain unknown. Speculation over the role and source of MTB in humans, as well as any association with the brain, remain unanswered. We performed a metagenomic analysis of the gut microbiome of 34 healthy females as well as grey matter volume analysis in magnetite-rich brain regions associated with orientation and navigation with the goal of identifying specific MTB that could be associated with brain structure in orientation and navigation regions. We identified seven MTB in the human gut microbiome: Magnetococcus marinus, Magnetospira sp. QH-2, Magnetospirillum magneticum, Magnetospirillum sp. ME-1, Magnetospirillum sp. XM-1, Magnetospirillum gryphiswaldense, and Desulfovibrio magneticus. Our preliminary results show significant negative associations between multiple MTB with bilateral flocculonodular lobes of the cerebellum and hippocampus (adjusted for total intracranial volume, uncorrected P<0.05). These findings indicate that MTB in the gut are associated with grey matter volume in magnetite-rich brain regions related to orientation and navigation. These preliminary findings support MTB as a potential biogenic source for brain magnetite in humans. Further studies will be necessary to validate and elucidate the relationship between these bacteria, magnetite concentrations, and brain function.

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood-brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r=- 0.44, p=0.002) and depression (r=- 0.50, p=0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t((33))=3.1, p(FDR)=0.02) and right lateral orbitofrontal cortex (OFC; t((33))=2.9, p(FDR)=0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r=0.28, p=0.007) and left lateral OFC (r=0.29, p=0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

The neurovascular coupling (NVC) connects neuronal activity to hemodynamic responses in the brain. This connection is the basis for the interpretation of functional magnetic resonance imaging data. Despite the central role of this coupling, we lack detailed knowledge about cell-specific contributions and our knowledge about NVC is mainly based on animal experiments performed during anesthesia. Anesthetics are known to affect neuronal excitability, but how this affects the vessel diameters is not known. Due to the high complexity of NVC data, mathematical modeling is needed for a meaningful analysis. However, neither the relevant neuronal subtypes nor the effects of anesthetics are covered by current models. Here, we present a mathematical model including GABAergic interneurons and pyramidal neurons, as well as the effect of an anesthetic agent. The model is consistent with data from optogenetic experiments from both awake and anesthetized animals, and it correctly predicts data from experiments with different pharmacological modulators. The analysis suggests that no downstream anesthetic effects are necessary if one of the GABAergic interneuron signaling pathways include a Michaelis-Menten expression. This is the first example of a quantitative model that includes both the cell-specific contributions and the effect of an anesthetic agent on the NVC.

Advances in neuroimaging open up the possibility for new powerful tools to be developed that potentially can be applied to clinical populations to improve the diagnosis of neurological disorders, including sleep disorders. At present, the diagnosis of narcolepsy and primary hypersomnias is largely limited to subjective assessments and objective measurements of behavior and sleep physiology. In this review, we focus on recent neuroimaging findings that provide insight into the neural basis of narcolepsy and the primary hypersomnias Kleine-Levin syndrome and idiopathic hypersomnia. We describe the role of neuroimaging in confirming previous genetic, neurochemical, and neurophysiological findings and highlight studies that permit a greater understanding of the symptoms of these sleep disorders. We conclude by considering some of the remaining challenges to overcome, the existing knowledge gaps, and the potential role for neuroimaging in understanding the pathogenesis and clinical features of narcolepsy and primary hypersomnias.

We present an application, and its development process, for interactive visual analysis of brain imaging data and clinical measurements. The application targets neuroscientists interested in understanding the correlations between active brain regions and physiological or psychological factors. The application has been developed in a participatory design process and has subsequently been released as the free software VisualNeuro. From initial observations of the neuroscientists workflow, we concluded that while existing tools provide powerful analysis options, they lack effective interactive exploration requiring the use of many tools side by side. Consequently, our application has been designed to simplify the workflow combining statistical analysis with interactive visual exploration. The resulting environment comprises parallel coordinates for effective overview and selection, Welchs t-test to filter out brain regions with statistically significant differences and multiple visualizations for comparison between brain regions and clinical parameters. These exploration concepts enable neuroscientists to interactively explore the complex bidirectional interplay between clinical and brain measurements and easily compare different patient groups. A qualitative user study has been performed with three neuroscientists from different domains. The study shows that the developed environment supports simultaneous analysis of more parameters, provides rapid pathways to insights and is an effective tool for hypothesis formation.

Olfactory dysfunction is an early manifestation of Parkinsons disease (PD). The present study aimed to illustrate potential differences between PD patients and healthy controls in terms of neural activity and functional connectivity within the olfactory brain network. Twenty PD patients and twenty healthy controls were examined with olfactory fMRI and resting-state fMRI. Data analysis of olfactory fMRI included data-driven tensorial independent component (ICA) and task-driven general linear model (GLM) analyses. Data analysis of resting-state fMRI included probabilistic ICA based on temporal concatenation and functional connectivity analysis within the olfactory network. ICA of olfactory fMRI identified an olfactory network consisting of the posterior piriform cortex, insula, right orbitofrontal cortex and thalamus. Recruitment of this network was less significant for PD patients. GLM analysis revealed significantly lower activity in the insula bilaterally and the right orbitofrontal cortex in PD compared to healthy controls but no significant differences in the olfactory cortex itself. Analysis of resting-state fMRI did not reveal any differences in the functional connectivity within the olfactory, default mode, salience or central executive networks between the two groups. In conclusion, olfactory dysfunction in PD is associated with less significant recruitment of the olfactory brain network. ICA could demonstrate differences in both the olfactory cortex and its main projections, compared to GLM that revealed differences only on the latter. Resting-state fMRI did not reveal any significant differences in functional connectivity within the olfactory, default mode, salience and central executive networks in this cohort.

We present an interactive visual environment for linked analysis of brain imaging and clinical measurements. The environment is developed in an iterative participatory design process involving neuroscientists investigating the causes of brain-related complex diseases. The hypotheses formation process about correlations between active brain regions and physiological or psychological factors in studies with hundreds of subjects is a central part of the investigation. Observing the reasoning patterns during hypotheses formation, we concluded that while existing tools provide powerful analysis options, they lack effective interactive exploration, thus limiting the scientific scope and preventing extraction of knowledge from available data.Based on these observations, we designed methods that support neuroscientists by integrating their existing statistical analysis of multivariate subject data with interactive visual explorationto enable them to better understand differences between patient groups and the complex bidirectional interplay between clinical measurement and the brain. These exploration concepts enable neuroscientists, for the first time during their investigations, to interactively move between and reason about questions such as ‘which clinical measurements are correlated with a specific brain region?’ or ‘are there differences in brain activity between depressed young and old subjects?’. The environment uses parallel coordinates for effective overview and selection of subject groups, Welch's t-test to filter out brain regions with statistically significant differences, and multiple visualizations of Pearson correlations between brain regions and clinical parameters to facilitate correlation analysis. A qualitative user study was performed with three neuroscientists from different domains. The study shows that the developed environment supports simultaneous analysis of more parameters, provides rapid pathways to insights, and is an effective support tool for hypothesis formation.

Purpose: The remodeling of functional neuronal connectivity in chronic widespread pain (CWP) patients remains largely unexplored. This study aimed to investigate functional connectivity in CWP patients in brain networks related to chronic pain for changes related to pain sensitivity, psychological strain, and experienced pain.

Patients and methods: Functional connectivity strength of the default mode network (DMN) and the salience network (SN) was assessed with functional magnetic resonance imaging. Between-group differences were investigated with an independent component analysis for altered connectivity within the whole DMN and SN. Then, changes in connectivity between nodes of the DMN and SN were investigated with the use of a seed-target analysis in relation to the covariates clinical pain intensity, pressure pain sensitivity, psychological strain, and as an effect of experienced experimental cuff-pressure pain.

Results: CWP patients showed decreased connectivity in the inferior posterior cingulate cortex (PCC) in the DMN and increased connectivity in the left anterior insula/superior temporal gyrus in the SN when compared to controls. Moreover, higher pain sensitivity in CWP when compared to controls was related to increased connectivity within the SN (between left and right insula) and between SN and DMN (between right insula and left lateral parietal cortex).

Conclusion: This study shows that connectivity within the DMN was decreased and connectivity within the SN was increased for CWP. Furthermore, we present a novel finding of interaction of pain sensitivity with SN and DMN-SN functional connectivity in CWP.

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Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions.

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BackgroundThere is insufficient knowledge of pathophysiological parameters to understand the mechanism behind prolonged whiplash associated disorders (WAD), and it is not known whether or not changes can be restored by rehabilitation. The aims of the projects are to investigate imaging and molecular biomarkers, cervical kinaesthesia, postural sway and the association with pain, disability and other outcomes in individuals with longstanding WAD, before and after a neck-specific exercise intervention. Another aim is to compare individuals with WAD with healthy controls.MethodsParticipants are a sub-group (n=30) of individuals recruited from an ongoing randomized controlled study (RCT). Measurements in this experimental prospective study will be carried out at baseline (before intervention) and at a three month follow-up (end of physiotherapy intervention), and will include muscle structure and inflammation using magnetic resonance imaging (MRI), brain structure and function related to pain using functional MRI (fMRI), muscle function using ultrasonography, biomarkers using samples of blood and saliva, cervical kinaesthesia using the butterfly test and static balance test using an iPhone app. Association with other measures (self-reported and clinical measures) obtained in the RCT (e.g. background data, pain, disability, satisfaction with care, work ability, quality of life) may be investigated. Healthy volunteers matched for age and gender will be recruited as controls (n=30).DiscussionThe study results may contribute to the development of improved diagnostics and improved rehabilitation methods for WAD.Trial registrationClinicaltrial.gov Protocol ID: NCT03664934, initial release 09/11/2018.

Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

The aim of this study was to investigate structural changes in the brain stem of adolescents with narcolepsy, a disorder characterized by excessive daytime sleepiness, fragmented night-time sleep, and cataplexy. For this purpose, we used quantitative magnetic resonance imaging to obtain R1 and R2 relaxation rates, proton density, and myelin maps in adolescents with narcolepsy (n = 14) and healthy controls (n = 14). We also acquired resting state functional magnetic resonance imaging (fMRI) for brainstem connectivity analysis. We found a significantly lower R2 in the rostral reticular formation near the superior cerebellar peduncle in narcolepsy patients, family wise error corrected p = .010. Narcolepsy patients had a mean R2 value of 1.17 s(-1) whereas healthy controls had a mean R2 of 1.31 s(-1), which was a large effect size with Cohen d = 4.14. We did not observe any significant differences in R1 relaxation, proton density, or myelin content. The sensitivity of R2 to metal ions in tissue and the transition metal ion chelating property of neuromelanin indicate that the R2 deviant area is one of the neuromelanin containing nuclei of the brain stem. The close proximity and its demonstrated involvement in sleep-maintenance, specifically through orexin projections from the hypothalamus regulating sleep stability, as well as the results from the connectivity analysis, suggest that the observed deviant area could be the locus coeruleus or other neuromelanin containing nuclei in the proximity of the superior cerebellar peduncle. Hypothetically, the R2 differences described in this paper could be due to lower levels of neuromelanin in this area of narcolepsy patients.

The cause of irritable bowel syndrome (IBS), a chronic disorder characterized by abdominal pain and disturbed bowel habits, is largely unknown. It is believed to be related to physical properties in the gut, central mechanisms in the brain, psychological factors, or a combination of these. To understand the relationships within the gut-brain axis with respect to IBS, large numbers of measurements ranging from stool samples to functional magnetic resonance imaging are collected from patients with IBS and healthy controls. As such, IBS is a typical example in medical research where research turns into a big data analysis challenge. In this chapter we demonstrate the power of interactive visual data analysis and exploration to generate an environment for scientific reasoning and hypothesis formulation for data from multiple sources with different character. Three case studies are presented to show the utility of the presented work.

The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy.

The purpose was to review the most recent literature on neuroimaging in the Kleine-Levin syndrome (KLS). We aimed to investigate if frontotemporal and thalamic dysfunction are key KLS signatures, and if recent research indicates other brain networks of interest that elucidate KLS symptomatology and aetiology. In a comprehensive literature search, we found 12 original articles published 2013-2018. Most studies report deviations related to cerebral perfusion, glucose metabolism, or blood-oxygen-level-dependent responses in frontotemporal areas and/or the thalamus. Studies also report dysfunction in the temporoparietal junction and the oculomotor network that also were related to clinical parameters. We discuss these findings based on recent research on thalamocortical networks and brain stem white matter tracts. The hypothesis of frontotemporal and thalamic involvement in KLS was confirmed, and additional findings in the temporoparietal junction and the oculomotor system suggest a broader network involvement, which can be investigated by future high-resolution and multimodal imaging.

Studying olfaction with functional magnetic resonance imaging (fMRI) poses various methodological challenges. This study aimed to investigate the effects of stimulation length and repetition time (TR) on the activation pattern of 4 olfactory brain regions: the anterior and the posterior piriform cortex, the orbitofrontal cortex, and the insula. Twenty-two healthy participants with normal olfaction were examined with fMRI, with 2 stimulation lengths (6 s and 15 s) and 2 TRs (0.901 s and 1.34 s). Data were analyzed using General Linear Model (GLM), Tensorial Independent Component Analysis (TICA), and by plotting the event-related time course of brain activation in the 4 olfactory regions of interest. The statistical analysis of the time courses revealed that short TR was associated with more pronounced signal increase and short stimulation was associated with shorter time to peak signal. Additionally, both long stimulation and short TR were associated with oscillatory time courses, whereas both short stimulation and short TR resulted in more typical time courses. GLM analysis showed that the combination of short stimulation and short TR could result in visually larger activation within these olfactory areas. TICA validated that the tested paradigm was spatially and temporally associated with a functionally connected network that included all 4 olfactory regions. In conclusion, the combination of short stimulation and short TR is associated with higher signal increase and shorter time to peak, making it more amenable to standard GLM-type analyses than long stimulation and long TR, and it should, thus, be preferable for olfactory fMRI.

Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease.

Increased perception of visceral stimuli is a key feature of Irritable Bowel Syndrome (IBS). While altered resting-state functional connectivity (rsFC) has been also reported in IBS, the relationship between visceral hypersensitivity and aberrant rsFC is unknown. We therefore assessed rsFC within the salience, sensorimotor and default mode networks in patients with and without visceral hypersensitivity and in healthy controls (HCs). An exploratory resting-state functional magnetic resonance imaging study was performed in 41 women with IBS and 20 HCs. Group independent component analysis was used to derive intrinsic brain networks. Rectal thresholds were determined and patients were subdivided into groups with increased (hypersensitive IBS, N = 21) or normal (normosensitive IBS, N= 20) visceral sensitivity. Between-group comparisons of rsFC were carried-out using region-of-interest analyses and peak rsFC values were extracted for correlational analyses. Relative to normosensitive IBS, hypersensitive patients showed increased positive rsFC of pregenual anterior cingulate cortex and thalamus within the salience network and of posterior insula within the sensorimotor network. When compared to both hypersensitive IBS and HCs, normosensitive IBS showed decreased positive rsFC of amygdala and decreased negative rsFC in dorsal anterior insula within the DMN. DMN and sensorimotor network rsFC were associated with rectal perception thresholds, and rsFC in posterior insula was correlated with reported symptom severity in IBS. Our exploratory findings suggest that visceral sensitivity in IBS is related to changes in FC within resting-state networks associated with interoception, salience and sensory processing. These alterations may play an important role in hypervigilance and hyperalgesia in IBS.

Within the field of neuroimaging, the discovery of a constellation of brain regions silently active when we are “resting” has provided a new view into the elusive effects of meditative practice. This network, called the default mode network (DMN), has been shown by functional neuroimaging to be active when an individual is at rest. Meta-analyses of the fMRI neurocorrelates of meditation have shown that across diverse practices, the most common general effect appears to be modulation of regions within the DMN. The specific ...

Functional magnetic resonance imaging (fMRI) of hemodynamic changes captured in the blood oxygen level-dependent (BOLD) response contains information of brain activity. The BOLD response is the result of a complex neurovascular coupling and comes in at least two fundamentally different forms: a positive and a negative deflection. Because of the complexity of the signaling, mathematical modelling can provide vital help in the data analysis. For the positive BOLD response, there are plenty of mathematical models, both physiological and phenomenological. However, for the negative BOLD response, no physiologically based model exists. Here, we expand our previously developed physiological model with the most prominent mechanistic hypothesis for the negative BOLD response: the neural inhibition hypothesis. The model was trained and tested on experimental data containing both negative and positive BOLD responses from two studies: 1) a visual-motor task and 2) a workin-gmemory task in conjunction with administration of the tranquilizer diazepam. Our model was able to predict independent validation data not used for training and provides a mechanistic underpinning for previously observed effects of diazepam. The new model moves our understanding of the negative BOLD response from qualitative reasoning to a quantitative systems-biology level, which can be useful both in basic research and in clinical use.

In preterm children with very low birth weight (VLBW amp;lt;= 1500 g), reading problems are often observed. Reading comprehension is dependent on word decoding and language comprehension. We investigated neural activation-within brain regions important for reading-related to components of reading comprehension in young VLBW adolescents in direct comparison to normal birth weight (NBW) term-born peers, with the use of functional magnetic resonance imaging (fMRI). We hypothesized that the decoding mechanisms will be affected by VLBW, and expect to see increased neural activity for VLBW which may be modulated by task performance and cognitive ability. The study investigated 13 (11 included in fMRI) young adolescents (ages 12 to 14 years) born preterm with VLBW and in 13 NBW controls (ages 12-14 years) for performance on the Block Design and Vocabulary subtests of the Wechsler Intelligence Scale for Children; and for semantic, orthographic, and phonological processing during an fMRI paradigm. The VLBW group showed increased phonological activation in left inferior frontal gyrus, decreased orthographic activation in right supramarginal gyrus, and decreased semantic activation in left inferior frontal gyrus. Block Design was related to altered right-hemispheric activation, and VLBW showed lower WISC Block Design scores. Left angular gyrus showed activation increase specific for VLBW with high accuracy on the semantic test. Young VLBW adolescents showed no accuracy and reaction time performance differences on our fMRI language tasks, but they did exhibit altered neural activation during these tasks. This altered activation for VLBW was observed as increased activation during phonological decoding, and as mainly decreased activation during orthographic and semantic processing. Correlations of neural activation with accuracy on the semantic fMRI task and with decreased WISC Block Design performance were specific for the VLBW group. Together, results suggest compensatory mechanisms by recruiting additional brain regions upon altered neural development of decoding for VLBW.

Background: Olfactory impairment is an early manifestation of Parkinsons disease (PD). Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) are two imaging techniques that allow noninvasive detection of microstructural changes in the cerebral white matter. Objective: To assess white matter alterations associated with olfactory impairment in PD, using a binary imaging approach with DTI and MT. Methods: 22 PD patients and 13 healthy controls were examined with DTI, MT and an odor discrimination test. DTI data were first analyzed with tract-based spatial statistics (TBSS) in order to detect differences in fractional anisotropy, mean, radial and axial diffusivity between PD patients and controls. Voxelwise randomized permutation was employed for the MT analysis, after spatial and intensity normalization. Additionally, ROI analysis was performed on both the DTI and MT data, focused on the white matter adjacent to olfactory brain regions. Results: Whole brain voxelwise analysis revealed decreased axial diffusivity in the left uncinate fasciculus and the white matter adjacent to the left olfactory sulcus of PD patients. ROI analysis demonstrated decreased axial diffusivity in the right orbitofrontal cortex, as well as decreased mean diffusivity and axial diffusivity in the white matter of the left entorhinal cortex of PD patients. There were no significant differences regarding fractional anisotropy, radial diffusivity or MT between patients and controls. Conclusions: ROI analysis of DTI could detect microstructural changes in the white matter adjacent to olfactory areas in PD patients, whereas MT imaging could not.

Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional fMRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics.

ObjectivesTo describe individual BF responses in a nursing home resident population for one-hour periods of bed rest. MethodsBF was measured for one hour over the sacrum in 0 degrees supine position and 30 degrees supine tilt position in 25 individuals aged 65 y or older while lying on a pressure-redistributing mattress. Measurements were made at three tissue depths (1, 2, and 10 mm) using the noninvasive optical techniques, LDF and PPG. ResultsEleven participants had a PIV response at 1mm depth in both positions and seven participants had a lack of this response at this depth and positions. The BF response at 1mm depth appeared immediately and remained over, or below, baseline for the entire 60min of loading in both positions. These BF patterns were also seen in deeper tissue layers. ConclusionsThe cutaneous BF response among the nursing home residents was distinct, appeared early, and remained during the one hour of loading.

This study investigates the relation between individual language ability and neural semantic processing abilities. Our aim was to explore whether high-level language ability would correlate to decreased activation in language-specific regions or rather increased activation in supporting language regions during processing of sentences. Moreover, we were interested if observed neural activation patterns are modulated by semantic incongruency similarly to previously observed changes upon syntactic congruency modulation. We investigated 27 healthy adults with a sentence reading task which tapped language comprehension and inference, and modulated sentence congruency employing functional magnetic resonance imaging (fMRI). We assessed the relation between neural activation, congruency modulation, and test performance on a high-level language ability assessment with multiple regression analysis. Our results showed increased activation in the left-hemispheric angular gyrus extending to the temporal lobe related to high language ability. This effect was independent of semantic congruency, and no significant relation between language ability and incongruency modulation was observed. Furthermore, there was a significant increase of activation in the inferior frontal gyrus (IFG) bilaterally when the sentences were incongruent, indicating that processing incongruent sentences was more demanding than processing congruent sentences and required increased activation in language regions. The correlation of high-level language ability with increased rather than decreased activation in the left angular gyrus, a region specific for language processing, is opposed to what the neural efficiency hypothesis would predict. We can conclude that no evidence is found for an interaction between semantic congruency related brain activation and highlevel language performance, even though the semantic incongruent condition shows to be more demanding and evoking more neural activation.

There is growing evidence as to the benefits of collecting BOLD fMRI data with increased sampling rates. However, many of the newly developed acquisition techniques developed to collect BOLD data with ultra-short TRs require hardware, software, and non-standard analytic pipelines that may not be accessible to all researchers. We propose to incorporate the method of shifted echo into a standard multi-slice, gradient echo EPI sequence to achieve a higher sampling rate with a TR of amp;lt; 1 s with acceptable spatial resolution. We further propose to incorporate temporal averaging of consecutively acquired EPI volumes to both ameliorate the reduced temporal signal-to-noise inherent in ultra-fast EPI sequences and reduce the data burden. BOLD data were collected from 11 healthy subjects performing a simple, event-related visual-motor task with four different EPI sequences: (1) reference EP/sequence with TR = 1440 ms, (2) shifted echo EP/sequence with TR = 700 ms, (3) shifted echo EPI sequence with every two consecutively acquired EPI volumes averaged and effective TR = 1400 ms, and (4) shifted echo EPI sequence with every four consecutively acquired EPI volumes averaged and effective TR = 2800 ms. Both the temporally averaged sequences exhibited increased temporal signal-to-noise over the shifted echo EPI sequence. The shifted echo sequence with every two EPI volumes averaged also had significantly increased BOLD signal change compared with the other three sequences, while the shifted echo sequence with every four EPI volumes averaged had significantly decreased BOLD signal change compared with the other three sequences. The results indicated that incorporating the method of shifted echo into a standard multi-slice EPI sequence is a viable method for achieving increased sampling rate for collecting event-related BOLD data. Further, consecutively averaging every two consecutively acquired EPI volumes significantly increased the measured BOLD signal change and the subsequently calculated activation map statistics.

Peripheral nerve injuries result in reorganization within the contralateral hemisphere. Furthermore, recent animal and human studies have suggested that the plastic changes in response to peripheral nerve injury also include several areas of the ipsilateral hemisphere. The objective of this study was to map the inter-hemispheric plasticity in response to median nerve injury, to investigate normal differences in contra- and ipsilateral activation, and to study the impact of event-related or blocked functional magnetic resonance imaging (fMRI) design on ipsilateral activation. Four patients with median nerve injury at the wrist (injured and epineurally sutured amp;gt;2 years earlier) and ten healthy volunteers were included. 3T fMRI was used to map the hemodynamic response to brain activity during tactile stimulation of the fingers, and a laterality index (LI) was calculated. Stimulation of Digits II-III of the injured hand resulted in a reduction in contralateral activation in the somatosensory area SI. Patients had a lower LI (0.21 +/- 0.15) compared to healthy controls (0.60 +/- 0.26) indicating greater ipsilateral activation of the primary somatosensory cortex. The spatial dispersion of the coordinates for areas SI and SII was larger in the ipsilateral than in the contralateral hemisphere in the healthy controls, and was increased in the contralateral hemisphere of the patients compared to the healthy controls. There was no difference in LI between the event-related and blocked paradigms. In conclusion, patients with median nerve injury have increased ipsilateral SI area activation, and spatially more dispersed contralateral SI activation during tactile stimulation of their injured hand. In normal subjects ipsilateral activation has larger spatial distribution than the contralateral. Previous findings in patients performed with the blocked fMRI paradigm were confirmed. The increase in ipsilateral SI activation may be due to an interhemispheric disinhibition associated with changes in the afferent signal inflow to the contralateral primary somatosensory cortex.

Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.

The aim of this study was to present a model that uses multi-parametric quantitative MRI to estimate the presence of myelin and edema in the brain. The model relates simultaneous measurement of R-1 and R-2 relaxation rates and proton density to four partial volume compartments, consisting of myelin partial volume, cellular partial volume, free water partial volume, and excess parenchymal water partial volume. The model parameters were obtained using spatially normalized brain images of a group of 20 healthy controls. The pathological brain was modeled in terms of the reduction of myelin content and presence of excess parenchymal water, which indicates the degree of edema. The method was tested on spatially normalized brain images of a group of 20 age-matched multiple sclerosis (MS) patients. Clear differences were observed with respect to the healthy controls: the MS group had a 79 mL smaller brain volume (1069 vs. 1148 mL), a 38 mL smaller myelin volume (119 vs. 157 mL), and a 21 mL larger excess parenchymal water volume (78 vs. 57 mL). Template regions of interest of various brain structures indicated that the myelin partial volume in the MS group was 1.6 +/- 1.5% lower for gray matter (GM) structures and 2.8 +/- 1.0% lower for white matter (WM) structures. The excess parenchymal water partial volume was 9 +/- 10% larger for GM and 5 +/- 2% larger for WM. Manually placed ROls indicated that the results using the template ROls may have suffered from loss of anatomical detail due to the spatial normalization process. Examples of the application of the method on high-resolution images are provided for three individual subjects: a 45-year-old healthy subject, a 72-year-old healthy subject, and a 45-year-old MS patient. The observed results agreed with the expected behavior considering both age and disease. In conclusion, the proposed model may provide clinically important parameters, such as the total brain volume, degree of myelination, and degree of edema, based on a single qMRI acquisition with a clinically acceptable scan time.

Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine-Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome.

The aim of this study was to investigate nursing staff induced repositionings and the patients' spontaneous movements during the day and night among older immobile patients in nursing care. Furthermore, the aim was to identify factors associated with the nursing staff induced repositionings and the patients' spontaneous movement frequency. An observational cross-sectional design was used. Spontaneous movements among patients (n = 52) were registered continuously using the MovinSense monitoring system. The nursing staff documented each time they repositioned the patient. Patients spontaneous movements were compared with nursing staff induced repositionings. There were large variations in the patients' spontaneous repositioning frequency during both days and nights, which shows that, although immobilised, some patients frequently reposition themselves. Analgesics were positively related to the movement frequency and psycholeptics were negatively related. The nursing staff more often repositioned the patients who were assessed as high risk than those assessed as low risk, but the patients' spontaneous movement frequency was not correlated to the risk score. This may be important when planning repositioning schedules. A monitoring system may be useful in decision making with regard to planning repositioning and positions used in the prevention of pressure ulcers among elderly immobile patients.

Background: Chronic widespread pain (CWP) such as fibromyalgia or is characterized by altered neural functional connectivity (fc) [1,2]. We investigated short-term neural plasticity in CWP by observing whether fc would change during resting state after a pressure-pain experience, and mainly expected changes in pain processing pathways.

Methods: Resting state fMRI was obtained from 38 CWP and 36 controls pre and post pain-stimulation session (10 min rest, 20 min pain, 10 min rest) at a Philips 3T Ingenia, SENSE coil, single-shot EPI gradient echo, TR/TE/FA/resolution = 2.2s/35ms/77°/3mm3, cerebrum coverage. Preprocessing in SPM12 for realigned, normalized and smoothed images (8mm FWHM). A ROI-to-ROI fc analysis (with CONN-toolbox [3]) was employed to test for Pre-/PostPain and group effects, at p<0.05 FDR corrected.

Results: Group-independent Pre- vs PostPain fc disruptions were seen between thalamus and temporal regions, right hippocampus, left amygdala. PostPain fc disruptions specific to CWP were observed between left nucleus accumbens (NAc) and bilateral thalamus, cuneus and intercalcarine sulcus.

Conclusions: PostPain fc showed changed thalamic connections. The thalamus modulates pain information and shows decreased blood flow in fibromyalgia [4]. Specific to CWP was a PostPain fc decrease between NAcc and thalamus as well as occipital lobe. The NAc is part of the cortical-basal ganglia-thalamic loop, and affected in fibromyalgia in the form of a decrease in mu-opioid receptor availability [5]. Aberrant functioning of NAc in a mouse model of chronic pain was linked to decreased motivation [6], in line with the NAc role in integrating cognitive and affective information for action selection [7]. Depression is also associated with disrupted fc with the cuneus [8], alterations in thalamic fc have also been related to persisting depression [9] The results indicate that CWP experience enhanced negative effects of pain on affective processing pathways, spurring further analysis of the impact of depression and anxiety symptoms in CWP.

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

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Background Irritable bowel syndrome (IBS) patients show evidence of altered central processing of visceral signals. One of the proposed alterations in sensory processing is an altered engagement of endogenous pain modulation mechanisms. The aim was to test the hypothesis that IBS patients with (IBS-S) and without visceral hypersensitivity (IBS-N) differ in their ability to engage endogenous pain modulation mechanism during habituation to repeated visceral stimuli.

Methods Brain blood oxygen level dependent (BOLD) response was measured during repeated rectal distension and its anticipation in 33 IBS patients with and without visceral hypersensitivity and 18 healthy controls (HCs). BOLD response to early and late phase of the distension series was compared within and between groups.

Key Results While BOLD response was similar during the early phase of the experiment, IBS-S showed greater BOLD response than IBS-N and HCs during the late phase of the distension series. IBS-S showed increasing BOLD response both to the anticipation and delivery of low intensity rectal distensions in brain regions including insula, anterior and mid cingulate cortex. IBS-N showed decreasing BOLD response to repeated rectal distensions in brain regions including insula, prefrontal cortex and amygdala.

Conclusions & Inferences These findings are consistent with compromised ability of IBS-S to respond to repeated delivery of rectal stimuli, both in terms of sensitization of sensory pathways and habituation of emotional arousal. The fact that both IBS subgroups met Rome criteria, and did not differ in terms of reported symptom severity demonstrates that similar symptom patterns can result from different underlying neurobiological mechanisms.

The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).

This work serves as a basis for a new type of fMRI analysis, which is based on a mechanistic interpretation of the hemodynamic response to synaptic activity. Activation was measured in the visual cortex of 12 healthy controls and ordinary differential equation models were fitted to the time series of the hemodynamic response. This allowed us to reject or refine previously proposed mechanistic hypotheses. This is the first attempt to describe the hemodynamic response quantitatively based on recent neurobiological findings. This mechanistic approach stands in contrast to the standard phenomenological description using the gamma variate function.

Objective: The aim of this study was to explore the interaction between interface pressure and pressure-induced vasodilation and reactive hyperemia with different pressureredistribution mattresses.

Method: A cross-sectional study was performed with a convenience sample of 42 healthy individuals between 18 and 64 years of age, 38 healthy individuals 65 years or older, and 35 inpatients 65 years or older at a university hospital in Sweden. Blood flow was measured at depths of 1 mm, 2 mm, and 10 mm using a combined system of laser Doppler flowmetry and photoplethysmography. The blood flow, interface pressure and skin temperature were measured in the sacral tissue before, during, and after load while lying on one standard hospital mattress and three different pressure-redistribution mattresses.

Results: There were significant differences between the three foam mattresses with regard to average sacral pressure, peak sacral pressure, and local probe pressure with the lowest values at the visco-elastic foam/air mattress (23.5 ± 2.5 mmHg, 49.3 ± 11.1 mmHg, 29.2 ± 14.0 mmHg respectively). A greater proportion of subjects had affected blood flow in terms of lack of pressure-induced vasodilation on the visco-elastic foam/air mattress compared to the alternating pressure mattress at tissue depths of 2 mm (39.0% vs. 20.0%, respectively) and 10 mm (56.9 % vs. 35.1%, respectively). Eleven individuals, including subjects in all three subject groups were identified with no pressure-induced vasodilation or reactive hyperemia in any mattress, and this was considered a high-risk blood flow response.

Conclusion: Interface pressure magnitudes considered not harmful during pressure-exposure lying on different pressure-redistribution mattresses can affect the microcirculation in different tissue structures. Despite having the lowest pressure values compared to the other mattresses, the visco-elastic foam/air mattress had the highest proportion of subjects with decreased blood flow indicating a more affected blood flow. Three young healthy individuals were identified with the high-risk blood flow response, indicating an innate vulnerability to pressure exposure and may not benefit from pressure-redistribution mattresses. Finally it was shown that the evaluation of pressure-redistribution support surfaces in terms of mean blood flow during and after tissue exposure is not feasible but assessment of pressure-induced vasodilation and reactive hyperemia could be a new possibility to assess individualized physiological measurements of mechanisms known to be related to pressure ulcer development.

Background. Pressure induced vasodilation (PIV) protects the skin from pressure induced ischemia. PIV responses at individual level during a long-term measurement period have not previously been described in an elderly population in a clinically relevant situation.

Aim. To describe individual PIV responses in a nursing home resident population for 1-hour periods of bed rest.

Method. From May 2011 to August 2012, blood flow at three tissue depths was measured for one hour over the sacrum in 0° supine position and 30° supine tilt position in 25 individuals aged 65 years or older while lying on a pressure redistributing mattress. Measurements were made using the non-invasive optical techniques Laser Doppler Flowmetry (LDF) and photoplethysmography. The individuals were divided into a PIV group and a non-PIV group based upon the LDF data.

Results. In the PIV group, the blood flow in almost all cases increased immediately and remained over baseline for the entire 60 minutes of loading in both positions, while the blood flow decreased immediately and remained below baseline in the non-PIV group. These blood flow patterns were also seen in deeper tissue layers although a PIV response was most common in the underlying tissue in both groups.

Conclusion. The cutaneous blood flow response among the nursing home residents was distinct, appeared early and remained during the one hour of loading in both the PIV and non-PIV group. The non-PIV group may be more vulnerable to pressure and thus may be at risk for pressure ulcer development. More research is needed in order to verify the results.

The default mode network (DMN) is a group of anatomically separate regions in the brain found to have synchronized patterns of activation in functional magnetic resonance imaging (fMRI). Mentation associated with the DMN includes processes such as mind wandering, autobiographical memory, self-reflective thought, envisioning the future, and considering the perspective of others. Abnormalities in the DMN have been linked to symptom severity in a variety of mental disorders indicating that the DMN could be used as a biomarker for diagnosis. These correlations have also led to the use of DMN modulation as a biomarker for assessing pharmacological treatments. Concurrent research investigating the neural correlates of meditation, have associated DMN modulation with practice. Furthermore, meditative practice is increasingly understood to have a beneficial role in the treatment of mental disorders. Therefore we propose the use of DMN measures as a biomarker for monitoring the therapeutic effects of meditation practices in mental disorders. Recent findings support this perspective, and indicate the utility of DMN monitoring in understanding and developing meditative treatments for these debilitating conditions.

The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinsons disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand I-123-FP-CIT (DaTSCAN (R)) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75 %) had visually predominant dopamine depletion in putamen, while most APS patients (56 %) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.