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Elske Sitsen, Monique van Velzen, Mischa de Rover, Albert Dahan, Marieke Niesters Department of Anesthesiology, Leiden University Medical Center, Leiden, RC 2300, the NetherlandsCorrespondence: Marieke NiestersDepartment of Anesthesiology, Leiden University Medical Center, H5-022, Leiden, RC 2300, the NetherlandsEmail m.niesters@lumc.nlIntroduction: 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.Keywords: spinal anesthesia, analgesia, pain responses, hyperalgesia, deafferentation

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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Sitsen, Khalili-Mahani, de Rover, Dahan and Niesters.)

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.

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.

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., (© 2021. The Author(s).)

Introduction: Considering the transformation process that has been occurring in pharmacy education and the urgent need to address social health needs, proposals of teaching methods for the development of competences and skills in patient-centered care have become an issue worth discussing. The study describes and discusses the method that has been used for developing of these competencies through experiential learning in a university pharmacy in Brazil., Educational Activity: The Teaching and Learning of Pharmacy Services (TLPS) method encompasses 2 components: theoretical-reflexive one (developing protocols covering the patient care process) and practical-reflexive one (using the protocols with real patients). TLPS connects the 2 components in a way to enable students to acquire and apply theoretical knowledge for a comprehensive assessment of the patients' needs and understand how clinical reasoning and decision-making take place. The assessment process is performed, by the supervisor, which evaluates the behaviors necessary for good professional performance., Discussion: The active learning methodologies have been effectively used in the classroom as a way to stimulate critical thinking, problem-solving, and clinical reasoning. However, experiential learning is considered a central point in the learning process and essential for knowledge building. Thus, the method herein described is shown as an innovative tool to promote self-learning, consolidation and interrelation of the acquired knowledge, easier identification of patients' needs, normalization of behaviors, and improvement in the quality of care.

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 T 1 -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.

Aims: Furosemide is commonly prescribed for symptom relief in heart failure (HF) patients. Although few data support the continuous use of loop diuretics in apparently euvolemic HF patients with mild symptoms, there is concern about safety of diuretic withdrawal in these patients. The ReBIC-1 trial was designed to evaluate the safety and tolerability of withdrawing furosemide in stable, euvolemic, chronic HF outpatients. This multicenter initiative is part of the Brazilian Research Network in Heart Failure (ReBIC) created to develop clinical studies in HF and composed predominantly by university tertiary care hospitals., Methods: The ReBIC-1 trial is currently enrolling HF patients in NYHA functional class I-II, left ventricular ejection fraction ≤45%, without a HF-related hospital admission within the last 6 months, receiving a stable dose of furosemide (40 or 80 mg per day) for at least 6 months. Eligible patients will be randomized to maintain or withdraw furosemide in a double-blinded protocol. The trial has two co-primary outcomes: (1) dyspnea assessment using a visual-analogue scale evaluated at 4 time points and (2) the proportion of patients maintained without diuretics during the follow-up period. Total sample size was calculated to be 220 patients. Enrolled patients will be followed up to 90 days after randomization, and diuretic will be restarted if clinical deterioration or signs of congestion are detected. Pre-defined sub-group analysis based on NT-proBNP levels at baseline is planned., Perspective: Evidence-based strategies aiming to simplify HF pharmacotherapy are needed in clinical practice. The ReBIC-1 trial will determine the safety of withdrawing furosemide in stable chronic HF patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)