Effect of spinal anesthesia-induced deafferentation on pain processing in healthy male volunteers: A task-related fMRI study.

Background: Spinal anesthesia causes short-term deafferentation and alters the crosstalk among brain regions involved in pain perception and pain modulation. In the current study, we examined the effect of spinal anesthesia on pain response to noxious thermal stimuli in non-deafferented skin areas using a functional magnetic resonance imaging (fMRI) paradigm. Methods: Twenty-two healthy subjects participated in the study. We performed a task-based fMRI study using a randomized crossover design. Subjects were scanned under two conditions (spinal anesthesia or control) at two-time points: before and after spinal anesthesia. Spinal anesthesia resulted in sensory loss up to dermatome Th6. Calibrated heat-pain stimuli were administered to the right forearm (C8-Th1) using a box-car design (blocks of 10s on/25s off) during MRI scanning. Pain perception was measured using a visual analogue scale (1-100) at the beginning and the end of each session. Generalized estimating equations were used to examine the effect of intervention by time by order on pain scores. Similarly, higher-level effects were tested with appropriate general linear models (accounting for within-subject variations in session and time) to examine: (1) Differences in BOLD response to pain stimulus under spinal anesthesia versus control; and (2) Effects of spinal anesthesia on pain-related modulation of the cerebral activation. Results: Complete fMRI data was available for eighteen participants. Spinal anesthesia was associated with moderate pain score increase. Significant differences in brain response to noxious thermal stimuli were present in comparison of spinal versus control condition (post-pre). Spinal condition was associated with higher BOLD signal in the bilateral inferior parietal lobule and lower BOLD signal in bilateral postcentral and precentral gyrus. Within the angular regions, we observed a positive correlation between pain scores and BOLD signal. These observations were independent from order effect (whether the spinal anesthesia was administered in the first or the second visit). However, we did observe order effect on brain regions including medial prefrontal regions, possibly related to anticipation of the experience of spinal anesthesia. Conclusions: The loss of sensory and motor activity caused by spinal anesthesia has a significant impact on brain regions involved in the sensorimotor and cognitive processing of noxious heat pain stimuli. Our results indicate that the anticipation or experience of a strong somatosensory response to the spinal intervention might confound and contribute to increased sensitivity to cognitive pain processing. Future studies must account for individual differences in subjective experience of pain sensation within the experimental context.

The photobiology of the human circadian clock.

SignificanceThe function of our biological clock is dependent on environmental light. Rodent studies have shown that there are multiple colors that affect the clock, but indirect measures in humans suggest blue light is key. We performed functional MRI studies in human subjects with unprecedented spatial resolution to investigate color sensitivity of our clock. Here, we show that narrowband blue, green, and orange light were all effective in changing neuronal activity of the clock. While the clock of nocturnal rodents is excited by light, the human clock responds with a decrease in neuronal activity as indicated by a negative BOLD response. The sensitivity of the clock to multiple colors should be integrated in light therapy aimed to strengthen our 24-h rhythms.

Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.

Ketamine is a promising treatment option for patients with Major Depressive Disorder (MDD) and has become an important research tool to investigate antidepressant mechanisms of action. However, imaging studies attempting to characterise ketamine's mechanism of action using blood oxygen level-dependent signal (BOLD) imaging have yielded inconsistent results- at least partly due to intrinsic properties of the BOLD contrast, which measures a complex signal related to neural activity. To circumvent the limitations associated with the BOLD signal, we used arterial spin labelling (ASL) as an unambiguous marker of neuronal activity-related changes in cerebral blood flow (CBF). We measured CBF in 21 MDD patients at baseline and 24 h after receiving a single intravenous infusion of subanesthetic ketamine and examined relationships with clinical outcomes. Our findings demonstrate that increase in thalamus perfusion 24 h after ketamine administration is associated with greater improvement of depressive symptoms. Furthermore, lower thalamus perfusion at baseline is associated both with larger increases in perfusion 24 h after ketamine administration and with stronger reduction of depressive symptoms. These findings indicate that ASL is not only a useful tool to broaden our understanding of ketamine's mechanism of action but might also have the potential to inform treatment decisions based on CBF-defined regional disruptions.

Resting-state functional MRI shows altered default-mode network functional connectivity in Duchenne muscular dystrophy patients.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by absence of dystrophin protein. Dystrophin is expressed in muscle, but also in the brain. Difficulties with attention/inhibition, working memory and information processing are well described in DMD patients but their origin is poorly understood. The default mode network (DMN) is one of the networks involved in these processes. Therefore we aimed to assess DMN connectivity in DMD patients compared to matched controls, to better understand the cognitive profile in DMD. T1-weighted and resting state functional MRI scans were acquired from 33 DMD and 24 male age-matched controls at two clinical sites. Scans were analysed using FMRIB Software Library (FSL). Differences in the DMN were assessed using FSL RANDOMISE, with age as covariate and threshold-free cluster enhancement including multiple comparison correction. Post-hoc analyses were performed on the visual network, executive control network and fronto-parietal network with the same methods. In DMD patients, the level of connectivity was higher in areas within the control DMN (hyperconnectivity) and significant connectivity was found in areas outside the control DMN. No hypoconnectivity was found and no differences in the visual network, executive control network and fronto-parietal network. We showed differences both within and in areas outside the DMN in DMD. The specificity of our findings to the DMN can help provide a better understanding of the attention/inhibition, working memory and information processing difficulties in DMD.

Hyperalgesia and Reduced Offset Analgesia During Spinal Anesthesia.

INTRODUCTION: Spinal anesthesia induces short-term deafferentation and causes connectivity changes in brain areas involved in endogenous pain modulation. We determined whether spinal anesthesia alters pain sensitivity and offset analgesia. Offset analgesia is a manifestation of endogenous pain modulation and characterized by profound analgesia upon a small decrease in noxious stimulation. METHODS: In this randomized controlled crossover trial, static thermal pain responses and offset analgesia were obtained in 22 healthy male volunteers during spinal anesthesia and control conditions (absence of spinal anesthesia). Pain responses and offset analgesia were measured on a remote skin area above the upper level of anesthesia (C8/Th1). RESULTS: Following spinal injection of the local anesthetic, the average maximum anesthesia level was Th6. Static pain scores at C8/Th1 were higher during spinal anesthesia compared to control: 59.1 ± 15.0 mm (spinal anesthesia) versus 51.7 ± 19.7 mm (control; p = 0.03). Offset analgesia responses were decreased during spinal analgesia: pain score decrease 79 ± 27% (spinal anesthesia) versus 90 ± 17% (control; p = 0.016). DISCUSSION: We confirmed that spinal anesthesia-induced deafferentation causes hyperalgesic responses to noxious thermal stimulation and reduced offset analgesia at dermatomes remote and above the level of deafferentation. While these data suggest that the reduction of offset analgesia has a central origin, related to alterations in brain areas involved in inhibitory pain control, we cannot exclude alternative (peripheral) mechanisms. TRIAL REGISTRATION: Dutch Cochrane Center under identifier (www.trialregister.nl) NL3874.

Effects of oxytocin administration and conditioned oxytocin on brain activity: An fMRI study.

It has been demonstrated that secretion of several hormones can be classically conditioned, however, the underlying brain responses of such conditioning have never been investigated before. In this study we aimed to investigate how oxytocin administration and classically conditioned oxytocin influence brain responses. In total, 88 females were allocated to one of three groups: oxytocin administration, conditioned oxytocin, or placebo, and underwent an experiment consisting of three acquisition and three evocation days. Participants in the conditioned group received 24 IU of oxytocin together with a conditioned stimulus (CS) during three acquisition days and placebo with the CS on three evocation days. The oxytocin administration group received 24 IU of oxytocin and the placebo group received placebo during all days. On the last evocation day, fMRI scanning was performed for all participants during three tasks previously shown to be affected by oxytocin: presentation of emotional faces, crying baby sounds and heat pain. Region of interest analysis revealed that there was significantly lower activation in the right amygdala and in two clusters in the left superior temporal gyrus in the oxytocin administration group compared to the placebo group in response to observing fearful faces. The activation in the conditioned oxytocin group was in between the other two groups for these clusters but did not significantly differ from either group. No group differences were found in the other tasks. Preliminary evidence was found for brain activation of a conditioned oxytocin response; however, despite this trend in the expected direction, the conditioned group did not significantly differ from other groups. Future research should, therefore, investigate the optimal timing of conditioned endocrine responses and study whether the findings generalize to other hormones as well.

Electroencephalography theta/beta ratio covaries with mind wandering and functional connectivity in the executive control network.

The ratio between frontal resting-state electroencephalography (EEG) theta and beta frequency power (theta/beta ratio, TBR) is negatively related to cognitive control. It is unknown which psychological processes during resting state account for this. Increased theta and reduced beta power are observed during mind wandering (MW), and MW is related to decreased connectivity in the executive control network (ECN) and increased connectivity in the default mode network (DMN). The goal of this study was to test if MW-related fluctuations in TBR covary with such functional variation in ECN and DMN connectivity and if this functional variation is related to resting-state TBR. Data were analyzed for 26 participants who performed a 40-min breath-counting task and reported the occurrence of MW episodes while EEG was measured and again during magnetic resonance imaging. Frontal TBR was higher during MW than controlled thought and this was marginally related to resting-state TBR. DMN connectivity was higher and ECN connectivity was lower during MW. Greater ECN connectivity during focus than MW was correlated to lower TBR during focus than MW. These results provide the first evidence of the neural correlates of TBR and its functional dynamics and further establish TBR's usefulness for the study of executive control, in normal and potentially abnormal psychology.

Connectivity of the hippocampus and Broca's area during acquisition of a novel grammar.

Following Opitz and Friederici (2003) suggesting interactions of the hippocampal system and the prefrontal cortex as the neural mechanism underlying novel grammar learning, the present fMRI study investigated functional connectivity of bilateral BA 44/45 and the hippocampus during an artificial grammar learning (AGL) task. Our results, contrary to the previously reported interactions, demonstrated parallel (but separate) contributions of both regions, each with their own interactions, to the process of novel grammar acquisition. The functional connectivity pattern of Broca's area pointed to the importance of coherent activity of left frontal areas around the core language processing region for successful grammar learning. Furthermore, connectivity patterns of left and right hippocampi (predominantly with occipital areas) were found to be a strong predictor of high performance on the task. Finally, increasing functional connectivity over time of both left and right BA 44/45 with the right posterior cingulate cortex and the right temporo-parietal areas points to the importance of multimodal and attentional processes supporting novel grammar acquisition. Moreover, it highlights the right-hemispheric involvement in initial stages of L2 learning. These latter interactions were found to operate irrespective of the task performance, making them an obligatory mechanism accompanying novel grammar learning.

Oral contraceptives positively affect mood in healthy PMS-free women: A longitudinal study.

OBJECTIVE: Menstrual cycle phase and oral contraceptives (OC) use influence mood and cognition and these effects may be moderated by the mineralocorticoid receptor (MR) genotype. The effect of menstrual cycle phase on mood may be increased if participants know that this is the focus of study. We assessed aspects associated with reproductive depression such as mood, interpersonal sensitivity, affect lability and depressive cognitions in MR-genotyped OC-users and naturally cycling (NC) women in a carefully masked design. METHODS: A homogenous sample of healthy, PMS-free, pre-menopausal MR-genotyped women (n=92) completed online questionnaires eight times during two consecutive cycles. RESULTS: The masking of the research question was successful. OC-users did not differ significantly from NC women in positive and negative affect at the time of assessment, personality characteristics (e.g. neuroticism) or mental and physical health. Both groups reported more shifts in anger in the first cycle week (p<0.001; ηp2=0.08). Compared to NC women, OC-users reported fewer mood-shifts between depression and elation in the mid-luteal phase of the menstrual cycle (p=0.002; ηp2=0.10) and had fewer ruminating thoughts at all phases (p=0.003; ηp2=0.11). Effects of MR-genotype were not significant after correction for multiple comparisons. CONCLUSION: OC users scored more favorably on measures associated with reproductive depression. OC users also showed a decreased affect variability possibly indicating an emotional blunting effect, which is in line with previous reports on affect-stabilizing effects of OC. Limitations were loss of cases due to irregularities in the menstrual cycle length and possible confounding by the 'survivor effect', since almost all OC-users took OC for more than a year.

In vivo visualization of the locus coeruleus in humans: quantifying the test-retest reliability.

The locus coeruleus (LC) is a brainstem nucleus involved in important cognitive functions. Recent developments in neuroimaging methods and scanning protocols have made it possible to visualize the human LC in vivo by utilizing a T1-weighted turbo spin echo (TSE) scan. Despite its frequent use and its application as a biomarker for tracking the progress of monoaminergic-related neurodegenerative diseases, no study to date has investigated the reproducibility and inter-observer variability of LC identification using this TSE scan sequence. In this paper, we aim to quantify the test-retest reliability of LC imaging by assessing stability of the TSE contrast of the LC across two independent scan sessions and by quantifying the intra- and inter-rater reliability of the TSE scan. Additionally, we created a probabilistic LC atlas which can facilitate the spatial localization of the LC in standardized (MNI) space. Seventeen healthy volunteers participated in two scanning sessions with a mean intersession interval of 2.8 months. We found that for intra-rater reliability the mean Dice coefficient ranged between 0.65 and 0.74, and inter-rater reliability ranged between 0.54 and 0.64, showing moderate reproducibility. The mean LC contrast was 13.9% (SD 3.8) and showed scan-rescan stability (ROI approach: ICC = 0.63; maximum intensity approach: ICC = 0.53). We conclude that localization and segmentation of the LC in vivo are a challenging but reliable enterprise although clinical or longitudinal studies should be carried out carefully.

On neural correlates of individual differences in novel grammar learning: An fMRI study.

We examine the role of language analytical ability, one of the components of language aptitude - a specific ability for learning languages - during acquisition of a novel grammar. We investigated whether the neural basis of Artificial Grammar Learning (AGL) differs between populations of highly and moderately skilled learners. Participants performed an AGL task during an fMRI scan and data from task's test phases were analysed. Highly skilled learners performed better than moderately skilled ones and engaged during the task more neural resources in the right hemisphere, i.e. in the right angular/supramarginal gyrus and superior frontal and middle frontal gyrus and in the posterior cingulate gyrus. Additional analyses investigating the temporal dynamics of brain activity during learning revealed lateralisation differences in the modulation of activity in the parietal and temporal cortex. In particular, the left angular gyrus BOLD activity was coupled with high performance on the AGL task and with a steep learning curve.

Whole-brain functional connectivity during acquisition of novel grammar: Distinct functional networks depend on language learning abilities.

In an effort to advance the understanding of brain function and organisation accompanying second language learning, we investigate the neural substrates of novel grammar learning in a group of healthy adults, consisting of participants with high and average language analytical abilities (LAA). By means of an Independent Components Analysis, a data-driven approach to functional connectivity of the brain, the fMRI data collected during a grammar-learning task were decomposed into maps representing separate cognitive processes. These included the default mode, task-positive, working memory, visual, cerebellar and emotional networks. We further tested for differences within the components, representing individual differences between the High and Average LAA learners. We found high analytical abilities to be coupled with stronger contributions to the task-positive network from areas adjacent to bilateral Broca's region, stronger connectivity within the working memory network and within the emotional network. Average LAA participants displayed stronger engagement within the task-positive network from areas adjacent to the right-hemisphere homologue of Broca's region and typical to lower level processing (visual word recognition), and increased connectivity within the default mode network. The significance of each of the identified networks for the grammar learning process is presented next to a discussion on the established markers of inter-individual learners' differences. We conclude that in terms of functional connectivity, the engagement of brain's networks during grammar acquisition is coupled with one's language learning abilities.

Beta receptor-mediated modulation of the oddball P3 but not error-related ERP components in humans.

RATIONALE: The P3 is a ubiquitous component of stimulus-driven neural activity that can be observed in scalp electrophysiological recordings. Multiple lines of evidence suggest an important role for the noradrenergic system in the generation of the P3. However, pharmacological studies of the P3 using noradrenergic manipulations have so far been limited to agents that affect α2-receptor signaling. OBJECTIVES: The present study investigated whether ß-adrenergic receptors are involved in the generation of the P3 and the error positivity (Pe), a component of the event-related potential that is elicited by errors and that bears many similarities to the P3. METHODS: We used a double-blind, placebo-controlled, crossover design in which we examined in human participants (N = 16) the effect of a single dose of propranolol (80 mg) on the amplitudes of the P3 observed in visual and auditory oddball tasks and the Pe observed in a flanker task. RESULTS: We found that P3s to auditory stimuli were increased in amplitude following treatment with propranolol. Propranolol also modulated the P3 to visual stimuli, but in a direction dependent on participants' level of trait anxiety: In participants with lower trait anxiety, propranolol resulted in a (non-significant) decrease in P3 amplitudes; in participants with higher trait anxiety, propranolol significantly enhanced P3 amplitude. Propranolol did not modulate the amplitude of the Pe or behavioral measures of conflict/error-related performance adjustments. CONCLUSIONS: These results provide the first evidence for involvement of ß-adrenergic receptors in P3 generation. We speculate that propranolol affected the P3 through actions at ß2-receptors in the locus coeruleus.

Oral contraceptives may alter the detection of emotions in facial expressions.

A possible effect of oral contraceptives on emotion recognition was observed in the context of a clinical trial with a corticosteroid. Users of oral contraceptives detected significantly fewer facial expressions of sadness, anger and disgust than non-users. This was true for trial participants overall as well as for those randomized to placebo. Although it is uncertain whether this is an effect of oral contraceptives or a pre-existing difference, future studies on the effect of interventions should control for the effects of oral contraceptives on emotional and cognitive outcomes.

Effect of deafferentation from spinal anesthesia on pain sensitivity and resting-state functional brain connectivity in healthy male volunteers.

Patients may perceive paradoxical heat sensation during spinal anesthesia. This could be due to deafferentation-related functional changes at cortical, subcortical, or spinal levels. In the current study, the effect of spinal deafferentation on sensory (pain) sensitivity was studied and linked to whole-brain functional connectivity as assessed by resting-state functional magnetic resonance imaging (RS-fMRI) imaging. Deafferentation was induced by sham or spinal anesthesia (15 mg bupivacaine injected at L3-4) in 12 male volunteers. RS-fMRI brain connectivity was determined in relation to eight predefined and seven thalamic resting-state networks (RSNs) and measured before, and 1 and 2 h after spinal/sham injection. To measure the effect of deafferentation on pain sensitivity, responses to heat pain were measured at 15-min intervals on nondeafferented skin and correlated to RS-fMRI connectivity data. Spinal anesthesia altered functional brain connectivity within brain regions involved in the sensory discriminative (i.e., pain intensity related) and affective dimensions of pain perception in relation to somatosensory and thalamic RSNs. A significant enhancement of pain sensitivity on nondeafferented skin was observed after spinal anesthesia compared to sham (area-under-the-curve [mean (SEM)]: 190.4 [33.8] versus 13.7 [7.2]; p<0.001), which significantly correlated to functional connectivity changes observed within the thalamus in relation to the thalamo-prefrontal network, and in the anterior cingulate cortex and insula in relation to the thalamo-parietal network. Enhanced pain sensitivity from spinal deafferentation correlated with functional connectivity changes within brain regions involved in affective and sensory pain processing and areas involved in descending control of pain.

The neural correlates of in-group and self-face perception: is there overlap for high identifiers?

Social identity, the part of the self-concept derived from group membership, is a key explanatory construct for a wide variety of behaviors, ranging from organizational commitment to discrimination toward out-groups. Using functional magnetic resonance imaging (fMRI), we examined the neural basis of social identity through a comparison with the neural correlates of self-face perception. Participants viewed a series of pictures, one at a time, of themselves, a familiar other, in-group members, and out-group members. We created a contrast for self-face perception by subtracting brain activation in response to the familiar other from brain activation in response to the self face, and a contrast for social identity by subtracting brain activation in response to out-group faces from brain activation in response to in-group faces. In line with previous research, for the self-familiar other contrast we found activation in several right-hemisphere regions (inferior frontal gyrus, inferior and superior parietal lobules). In addition, we found activation in closely-adjacent brain areas for the social identity contrast. Importantly, significant clusters of activation in this in-group-out-group contrast only emerged to the extent that participants reported high identification with the in-group. These results suggest that self-perception and social identity depend on partly similar neural processes.

Genetic marker of norepinephrine synthesis predicts individual differences in post-error slowing: a pilot study.

When our brain detects the commission of an error, we slow down immediately thereafter: a phenomenon called post-error slowing (PES). Some researchers have speculated that slowing after unexpected errors or negative feedback is related to the activity of the neuromodulatory locus coeruleus-norepinephrine system. In the present pilot study, we tested whether individual differences in the size of PES are related to differences in genetic predisposition related to norepinephrine synthesis. In a sample of 100 healthy adults, we studied the dependency of an individual's size of PES on the DBH5'-ins/del polymorphism-a variation in the DBH gene associated with the production of the enzyme dopamine ß-hydroxylase, which catalyzes the conversion of dopamine to norepinephrine. DBH5'-ins/del heterozygotes, who have intermediate levels of plasma DßH activity, showed increased PES in a Simon task compared to del/del homozygotes and ins/ins homozygotes, who have low and high levels of plasma DßH activity, respectively. This outcome pattern presents preliminary evidence that the size of PES varies with DßH activity and, presumably, NE release according to an inverted U-shape: intermediate levels of DßH activity and NE release are associated with larger post-error adjustments.

Brain networks subserving fixed versus performance-adjusted delay stop trials in a stop signal task.

The stop signal task is a widely used tool for assessing inhibitory motor control. Two main task variants exist: (1) a fixed delay version, where all volunteers complete the same trials, resulting in performance differences due to individual variation in inhibitory capacity, and (2) a performance-adjusted version that uses a tracking algorithm to equate performance and task difficulty across subjects, leading to ∼50% successful inhibition for every participant. Our aim was to investigate commonalities, mean differences and between-subject variability in brain activation for successful response inhibition between the performance-adjusted and fixed delay version. We conducted a functional magnetic resonance imaging (fMRI) study in 18 healthy individuals, using a within-subject, within-task design where both adjusting and fixed delay trials were analysed separately. Conjunction analyses identified a network of areas involved in successful response inhibition in both task versions. In comparing the fixed and performance-adjusted versions, we found no significant differences between delay conditions during successful inhibition. While activation measures in the inhibitory networks of both delay variants were highly comparable, the neural responses to fixed delay trials were more variable across participants. This suggests that performance-adjusted stop signal tasks may be more suitable for studies in which the performance differences need to be controlled for, such as for developmental or clinical studies. Fixed delay stop signal tasks may be more appropriate in studies assessing the neural basis of individual differences in performance, such as studies of personality traits or genetic associations.

Functional significance of the emotion-related late positive potential.

The late positive potential (LPP) is an event-related potential (ERP) component over visual cortical areas that is modulated by the emotional intensity of a stimulus. However, the functional significance of this neural modulation remains elusive. We conducted two experiments in which we studied the relation between LPP amplitude, subsequent perceptual sensitivity to a non-emotional stimulus (Experiment 1) and visual cortical excitability, as reflected by P1/N1 components evoked by this stimulus (Experiment 2). During the LPP modulation elicited by unpleasant stimuli, perceptual sensitivity was not affected. In contrast, we found some evidence for a decreased N1 amplitude during the LPP modulation, a decreased P1 amplitude on trials with a relatively large LPP, and consistent negative (but non-significant) across-subject correlations between the magnitudes of the LPP modulation and corresponding changes in d-prime or P1/N1 amplitude. The results provide preliminary evidence that the LPP reflects a global inhibition of activity in visual cortex, resulting in the selective survival of activity associated with the processing of the emotional stimulus.