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Published: May 29, 2018, There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.

Congenital deafness is often compensated by early sign language use leading to typical language development with corresponding neural underpinnings. However, deaf individuals are frequently reported to have poorer numerical abilities than hearing individuals and it is not known whether the underlying neuronal networks differ between groups. In the present study, adult deaf signers and hearing nonsigners performed a digit and letter order tasks, during functional magnetic resonance imaging. We found the neuronal networks recruited in the two tasks to be generally similar across groups, with significant activation in the dorsal visual stream for the letter order task, suggesting letter identification and position encoding. For the digit order task, no significant activation was found for either of the two groups. Region of interest analyses on parietal numerical processing regions revealed different patterns of activation across groups. Importantly, deaf signers showed significant activation in the right horizontal portion of the intraparietal sulcus for the digit order task, suggesting engagement of magnitude manipulation during numerical order processing in this group., Funding Agencies|Swedish Research Council [2005-1353]

Sleep deprivation has been reported to affect intrinsic brain connectivity, notably reducing connectivity in the default mode network. Studies to date have however shown inconsistent effects, in many cases lacked monitoring of wakefulness, and largely included young participants. We investigated effects of sleep deprivation on intrinsic brain connectivity in young and older participants. Participants aged 20–30 (final n = 30) and 65–75 (final n = 23) years underwent partial sleep deprivation (3 h sleep) in a cross-over design, with two 8-minutes eyes-open resting state functional magnetic resonance imaging (fMRI) runs in each session, monitored by eye-tracking. We assessed intrinsic brain connectivity using independent components analysis (ICA) as well as seed-region analyses of functional connectivity, and also analysed global signal variability, regional homogeneity, and the amplitude of low-frequency fluctuations. Sleep deprivation caused increased global signal variability. Changes in investigated resting state networks and in regional homogeneity were not statistically significant. Younger participants had higher connectivity in most examined networks, as well as higher regional homogeneity in areas including anterior and posterior cingulate cortex. In conclusion, we found that sleep deprivation caused increased global signal variability, and we speculate that this may be caused by wake-state instability., This work was supported by Riksbankens Jubileumsfond, Fredrik and Ingrid Thuring’s Foundation, and the Karolinska Institutet Strategic Neuroscience Program.

Introduction: Sleep deprivation has been reported to affect intrinsic brain connectivity, notably in the default mode network, but studies to date have shown inconsistent effects and have largely included young participants. We therefore aimed to investigate effects of partial sleep deprivation on intrinsic brain connectivity in young and older participants. Methods: Participants aged 20-30 (n = 30) and 65-75 (n = 23) years underwent partial sleep deprivation (3 h sleep) in a cross-over design, with two eyes-open resting state functional magnetic resonance imaging (fMRI) runs in each session. We assessed intrinsic brain connectivity using independent components analysis (ICA) as well as seed-region analyses of functional connectivity, and also analysed global signal variability, regional homogeneity, and the amplitude of low-frequency fluctuations. Participants were monitored with eye-tracking to ensure they did not fall asleep during scanning. Results: Sleep deprivation caused increased global signal variability, defined as log-transformed standard deviation of average gray matter signal (0.16 [0.07, 0.24], p = 0.0004). In contrast to previous studies, sleep deprivation did not cause major changes in investigated resting state networks, nor did it cause changes in regional homogeneity. Younger participants had higher functional connectivity in most examined resting state networks, as well as higher regional homogeneity in brain areas including anterior and posterior cingulate cortex. Conclusions: We show for the first time that partial sleep deprivation caused increased global signal variability. This outcome should be examined as a potential biomarker for sleepiness using independent data. Unlike a few earlier studies, we did not find less default mode connectivity in the sleep deprived state, possibly because of stricter monitoring of participants' wakefulness.

Load-dependent position error and its compensation approach in a hybrid stepper motor has been studied in this paper. With stepper motor modelling and load angle concept, low position stiffness feature for a stepper motor with open loop operation has been explained. A specific field oriented control has been proposed to maximize stepper motor position stiffness. Experimental verification shows the effectiveness of the proposed method. Results also show that stepper motor efficiency can be improved significantly by the proposed method.

Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes

The Stockholm Sleepy Brain Study I is a functional brain imaging study of 48 younger (20-30 years) and 36 older (65-75 years) healthy participants, with magnetic resonance imaging after normal sleep and partial sleep deprivation in a crossover design. We performed experiments investigating emotional mimicry, empathy for pain, and cognitive reappraisal, as well as resting state functional magnetic resonance imaging (fMRI). We also acquired T1- and T2-weighted structural images and diffusion tensor images (DTI). On the night before imaging, participants were monitored with ambulatory polysomnography and were instructed to sleep either as usual or only three hours. Participants came to the scanner the following evening. Besides MRI scanning, participants underwent behavioral tests and contributed blood samples, which have been stored in a biobank and used for DNA analyses. Participants also completed a variety of self-report measures. The resulting multimodal dataset may be useful for hypothesis generation or independent validation of effects of sleep deprivation and aging, as well as investigation of cross-sectional associations between the different outcomes. V. 2 of this manuscript published 2017-10-12. Changes: new co-author (Claus Lamm), changed affiliations for Kristoffer Månsson, minor changes in the abstract, and revisions of the main text and figures.

BACKGROUND: Rheumatoid arthritis (RA) is commonly accompanied by pain that is discordant with the degree of peripheral pathology. Very little is known about the cerebral processes involved in pain processing in RA. Here we investigated resting-state brain connectivity associated with prolonged pain in RA. METHODS: 24 RA subjects and 19 matched controls were compared with regard to both behavioral measures of pain perception and resting-resting state fMRI data acquired subsequently to fMRI sessions involving pain stimuli. The resting-state fMRI brain connectivity was investigated using 159 seed regions located in cardinal pain processing brain regions. Additional principal component based multivariate pattern analysis of the whole brain connectivity pattern was carried out in a data driven analysis to localize group differences in functional connectivity. RESULTS: When RA patients were compared to controls, we observed significantly lower pain resilience for pressure on the affected finger joints (i.e., P50-joint) and an overall heightened level of perceived global pain in RA patients. Relative to controls, RA patients displayed increased brain connectivity predominately for the supplementary motor areas, mid-cingulate cortex, and the primary sensorimotor cortex. Additionally, we observed an increase in brain connectivity between the insula and prefrontal cortex as well as between anterior cingulate cortex and occipital areas for RA patients. None of the group differences in brain connectivity were significantly correlated with behavioral parameters. CONCLUSION: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in RA patients.

Evidence suggests that the lag reported in mathematics for deaf signers derives from difficulties related to verbal processing of numbers, whereas magnitude processing seems unaffected by deafness. Neuroimaging evidence from hearing individuals suggests that verbal processing of numbers engages primarily left angular gyrus (lAG), whereas magnitude processing engages primarily the horizontal portion of the right intraparietal sulcus (rHIP). In a ROI analysis of brain imaging data from 16 adult deaf signers and 16 adult hearing non-signers, who did not differ on sex, age or education, we examined if activity in lAG and rHIP changed as a result of task (multiplication vs subtraction) and group (deaf signers and hearing non-signers). We found a significant main effect of brain region (F(1,30) = 117.00, p < .001, η_p^2 = .80) and an interaction effect between region and group (F(1,30) = 20.70, p < .001, η_p^2 = .41). Further analyses showed that there were no significant differences in average activation between groups in lAG (F(1,30) = 0.16, p = .70). However, in rHIP deaf signers showed significantly greater average activation compared to non-signers (F(1,30) = 15.20, p < .001, η_p^2 = .34). There were no significant differences in activation between subtraction and multiplication (F(1,30) = 0.66, p = .42) and no behavioural differences between groups (F(1,30) = 1.70, p = .20). These results suggest that when engaging in arithmetic tasks deaf signers successfully make use of qualitatively difference processes, compared to hearing non-signers, with stronger emphasis on brain regions relating to magnitude manipulation.

Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.

The mechanisms causing cognitive problems in chronic pain patients are not well understood. We used the Stroop color word task (SCWT) to investigate distraction-induced analgesia, cognitive performance, and cerebral activation patterns in 29 fibromyalgia (FM) patients (mean age 49.8 years, range 25-64 years) and 31 healthy controls (HC) (mean age 46.3 years, range 20-63 years). In the first study, SCWT was used to investigate distraction-induced analgesia in FM patients. Two versions of the task were applied, one with only congruent color-word images and one with incongruent images. Pressure pain thresholds were assessed using a pressure algometer before, during, and following SCWT. In the second study, reaction times (RTs) were assessed and functional magnetic resonance imaging (fMRI) was used to investigate cerebral activation patterns in FM patients and HC during the SCWT. An event-related task mixing incongruent and congruent images was used. In study one, we found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, we found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, we found normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients.

UNLABELLED: Antidepressant drugs are commonly used to treat fibromyalgia, but there is little knowledge about their mechanisms of action. The aim of this study was to compare the cerebral and behavioral response to positive treatment effects of antidepressants or placebo. Ninety-two fibromyalgia patients participated in a 12-week, double-blind, placebo-controlled clinical trial with milnacipran, a serotonin-norepinephrine reuptake inhibitor. Before and after treatment, measures of cerebral pain processing were obtained using functional magnetic resonance imaging. Also, there were stimulus response assessments of pressure pain, measures of weekly pain, and fibromyalgia impact. Following treatment, milnacipran responders exhibited significantly higher activity in the posterior cingulum compared with placebo responders. The mere exposure to milnacipran did not explain our findings because milnacipran responders exhibited increased activity also in comparison to milnacipran nonresponders. Stimulus response assessments revealed specific antihyperalgesic effects in milnacipran responders, which was also correlated with reduced clinical pain and with increased activation of the posterior cingulum. A short history of pain predicted positive treatment response to milnacipran. We report segregated neural mechanisms for positive responses to treatment with milnacipran and placebo, reflected in the posterior cingulum. The increase of pain-evoked activation in the posterior cingulum may reflect a normalization of altered default mode network processing, an alteration implicated in fibromyalgia pathophysiology. PERSPECTIVE: This study presents neural and psychophysical correlates to positive treatment responses in patients with fibromyalgia, treated with either milnacipran or placebo. The comparison between placebo responders and milnacipran responders may shed light on the specific mechanisms involved in antidepressant treatment of chronic pain.

Fibromyalgia (FM) is a syndrome characterized by chronic pain without known peripheral causes. Previously, we have reported dysfunctional pain inhibitory mechanisms for FM patients during pain administration. In this study we employed a seed correlation analysis, independent component analysis (ICA), and an analysis of fractional amplitude of low frequency fluctuations (fALFF) to study differences between a cohort of female FM patients and an age- and sex-matched healthy control group during a resting-state condition. FM patients showed decreased connectivity between thalamus and premotor areas, between the right insula and primary sensorimotor areas, and between supramarginal and prefrontal areas. Individual sensitivity to painful pressure was associated with increased connectivity between pain-related regions (e.g., insula and thalamus) and midline regions of the default mode network (including posterior cingulate cortex and medial prefrontal cortex) among patients and controls. However, neither ICA nor fALFF revealed any group differences. Our findings suggest that abnormal connectivity patterns between pain-related regions and the remaining brain during rest reflect an impaired central mechanism of pain modulation in FM. Weaker coupling between pain regions and prefrontal- and sensorimotor areas might indicate a less efficient system level control of pain circuits. Moreover, our results show that multiple, complementary analytical approaches are valuable for obtaining a more comprehensive characterization of deviant resting-state activity. In conclusion, our findings show that FM primarily is associated with decreased connectivity, for example, between several pain-related areas and sensorimotor regions, which could reflect a deficiency in pain regulation.

Evidence suggests that the lag reported in mathematics for deaf signers derives from difficulties related to the verbal system of number processing as described in the triple code model. For hearing individuals the verbal system has been shown to be recruited for both arithmetic and language tasks. In the present study we investigate for the first time neuronal representations of arithmetic in deaf signers. We examine if the neural network supporting arithmetic and language, including the horizontal portion of the intraparietal sulcus (HIPS), the superior parietal lobule (SPL) bilaterally, the left angular gyrus (AG), pars opercularis (POPE) and pars triangularis (PTRI) of the left inferior frontal gyrus (IFG), is differently recruited for deaf and hearing individuals. Imaging data were collected from 16 deaf signers and 16 well-matched hearing nonsigners, using the same stimulus material for all tasks, but with different cues. During multiplication, deaf signers recruited rHIPS more than hearing non-signers, suggesting greater involvement of magnitude manipulation processes related to the quantity system, whereas there was no evidence that the verbal system was recruited. Further, there was no support for the notion of a common representation of phonology for sign and speech as previously suggested.

OBJECTIVE: There is vast evidence to support the presence of brain aberrations in patients with fibromyalgia (FM), and it is possible that central plasticity is critical for the transition from acute to chronic pain. The aim of the present study was to investigate the relationship between brain structure and function in patients with FM. METHODS: Functional connectivity of the brain during application of intermittent pressure-pain stimuli and measures of brain structure were compared between 26 patients with FM and 13 age- and sex-matched healthy controls. Magnetic resonance imaging (MRI) was performed to obtain high-resolution anatomic images and functional MRI scans of the brain, which were used for measurements of pain-evoked brain activity. RESULTS: FM patients displayed a distinct overlap between decreased cortical thickness, decreased brain volumes, and decreased functional regional coherence in the rostral anterior cingulate cortex. The morphometric changes were more pronounced with longer exposure to FM pain. In addition, there was evidence of an association between structural and functional changes in the mesolimbic areas of the brain and the severity of comorbid depression symptoms in FM patients. CONCLUSION: The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain. These data may lead to the identification of early structural and functional brain alterations in response to pain, which could be used to develop markers for predicting the development of FM and other pain disorders.

Profoundly deaf individuals sometimes have difficulty with arithmetic and phonological tasks. In the present study we investigate if these differences can be attributed to differences in recruitment of neurobiological networks. Seventeen hearing non-signers (HN) and sixteen deaf signers (DS) matched on age, gender and non-verbal intelligence took part in an fMRI study. In the scanner three digit/letter pairs were visually presented and the participants performed six different blocked tasks tapping processing of digit and letter order, multiplication, subtraction and phonological ability. Data were analysed using two 2x2x2 ANOVAs; process (arithmetic, language) x level (high, low) x group (DS, HN). A main effect of process revealed language networks in the left inferior frontal gryus, supramarginal gyrus, fusiform gyrus and insula. Arithmetic networks included left middle orbital gyrus and superior medial gyrus. A main effect of level revealed low level processing (digit/letter order) in the right middle occipital gyrus and the right precuneus and high level processing (subtraction/multiplication/phonological ability) in left inferior frontal gyrus. There was no main effect of group but a significant task x group interaction in the right temporal pole which in DS (but not HN) was activated more for arithmetic than language processing (pfwe = .022) when multiplication was included in the analysis. This region is implicated in conceptual representation. These results suggest that both arithmetic and language are processed similarly by DS and HN with possible between-group differences in the use of conceptual representation in arithmetic and language tasks.

BACKGROUND: There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus. RESULTS: FM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0-100 visual analogue scale (p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients. CONCLUSION: Patients with FM displayed less connectivity within the brain's pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the funct

In hearing individuals, multiplication relies mainly on the phonological loop while subtraction relies on the visuo-spatial sketchpad (VSSP; Lee & Kang, 2002). Little is known about arithmetic neural networks in deaf signers (DS). Since DS often perform worse than hearing non-signers (NH) on arithmetic in general and multiplication in particular (Traxler, 2000), we hypothesized that there are strategic differences between how groups recruit the phonological loop in multiplication, but not in subtraction, leading to differential activation of phonological processing areas in left inferior frontal gyrus (Broca’s area). We investigated this using a blocked fMRI-design in which nine DS and 17 HN matched on age, gender, education and non-verbal intelligence (Raven & Raven, 1998) were tested on tasks of multiplication, subtraction and phonology (rhyme). The contrasts rhyme versus multiplication and rhyme versus subtraction were examined across groups within the region of interest defined by a probability map of Broca’s area (Amunts, 1999). We observed a significant interaction between task (multiplication and rhyme) and group (F = 12.64, p = .034, FWE-corrected), where the HN showed higher activation for rhyme than for multiplication (T = 4.55, p = .001, FWE-corrected) whereas there were no differences in activations between tasks for DS. For subtraction versus rhyme no interaction with group was found. These results suggest that there are differences between DS and HN in the phonology dependent neural networks in Broca’s area used during multiplication, which may be part of the explanation for poorer performance in DS.

BACKGROUND: Perceptual illusions play an important role in untangling neural mechanisms underlying conscious phenomena. The thermal grill illusion (TGI) has been suggested as a promising model for exploring percepts involved in neuropathic pain, such as cold-allodynia (pain arising from contact with innocuous cold). The TGI is an unpleasant/painful sensation from touching juxtapositioned bars of cold and warm innocuous temperatures. AIM: To develop an MRI-compatible TGI-unit and explore the supraspinal correlates of the illusion, using fMRI, in a group of healthy volunteers. METHODS: We constructed a TGI-thermode allowing the rapid presentation of warm(41°C), cold(18°C) and interleaved(41°C+18°C = TGI) temperatures in an fMRI-environment. Twenty volunteers were tested. The affective-motivational ("unpleasantness") and sensory-disciminatory ("pain-intensity") dimensions of each respective stimulus were rated. Functional images were analyzed at a corrected α-level <0.05. RESULTS: The TGI was rated as significantly more unpleasant and painful than stimulation with each of its constituent temperatures. Also, the TGI was rated as significantly more unpleasant than painful. Thermal stimulation versus neutral baseline revealed bilateral activations of the anterior insulae and fronto-parietal regions. Unlike its constituent temperatures the TGI displayed a strong activation of the right (contralateral) thalamus. Exploratory contrasts at a slightly more liberal threshold-level also revealed a TGI-activation of the right mid/anterior insula, correlating with ratings of unpleasantness (rho = 0.31). CONCLUSION/SIGNIFICANCE: To the best of our knowledge, this is the first fMRI-study of the TGI. The activation of the anterior insula is consistent with this region's putative role in processing of homeostatically relevant feeling-states. Our results constitute the first neurophysiologic evidence of thalamic involvement in the TGI. Similar thalamic activity has previously been ob