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Definitions of human pain acknowledge at least two dimensions of pain, affective and sensory, described as separable and thus potentially differentially modifiable. Using electroencephalography, we investigated perceptual and neural changes of emotional pain modulation in healthy individuals. Painful electrical stimuli were applied after presentation of priming emotional pictures (negative, neutral, positive) and followed by pain intensity and unpleasantness ratings. We found that perceptual and neural event-related potential responses to painful stimulation were significantly modulated by emotional valence. Specifically, pain unpleasantness but not pain intensity ratings were increased when pain was preceded by negative compared to neutral or positive pictures. Amplitudes of N2 were higher when pain was preceded by neutral compared to negative and positive pictures, and P2 amplitudes were higher for negative compared to neutral and positive pictures. In addition, a hierarchical regression analysis revealed that P2 alone and not N2, predicted pain perception. Finally, source analysis showed the anterior cingulate cortex and the thalamus as main spatial clusters accounting for the neural changes in pain processing. These findings provide evidence for a separation of the sensory and affective dimensions of pain and open new perspectives for mechanisms of pain modulation., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus-response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20-59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus-response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus-response learning under non-stressful environmental conditions., (© 2024. The Author(s).)

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ., Competing Interests: Conflict of interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks., (© 2022. The Author(s).)

Continuous real-time functional magnetic resonance imaging (fMRI) neurofeedback is gaining increasing scientific attention in clinical neuroscience and may benefit from the short repetition times of modern multiband echoplanar imaging sequences. However, minimizing feedback delay can result in technical challenges. Here, we report a technical problem we experienced during continuous fMRI neurofeedback with multiband echoplanar imaging and short repetition times. We identify the possible origins of this problem, describe our current interim solution and provide openly available workflows and code to other researchers in case they wish to use a similar approach., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The importance of effective research data management (RDM) strategies to support the generation of Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience data grows with each advance in data acquisition techniques and research methods. To maximize the impact of diverse research strategies, multidisciplinary, large-scale neuroscience research consortia face a number of unsolved challenges in RDM. While open science principles are largely accepted, it is practically difficult for researchers to prioritize RDM over other pressing demands. The implementation of a coherent, executable RDM plan for consortia spanning animal, human, and clinical studies is becoming increasingly challenging. Here, we present an RDM strategy implemented for the Heidelberg Collaborative Research Consortium. Our consortium combines basic and clinical research in diverse populations (animals and humans) and produces highly heterogeneous and multimodal research data (e.g., neurophysiology, neuroimaging, genetics, behavior). We present a concrete strategy for initiating early-stage RDM and FAIR data generation for large-scale collaborative research consortia, with a focus on sustainable solutions that incentivize incremental RDM while respecting research-specific requirements., (© The Author(s) 2023. Published by Oxford University Press GigaScience.)

Real-time fMRI (rt-fMRI) enables self-regulation of neural activity in localized brain regions through neurofeedback. Previous studies showed successful up- and down-regulation of neural activity in the anterior cingulate cortex (ACC) and the insula (Ins) during nociceptive stimulation. Such self-regulation capacity is, however, variable across subjects, possibly related to the ability of cognitive top-down control of pain. Moreover, how specific brain areas interact to enable successful regulation of nociceptive processing and neurofeedback-based brain modulation is not well understood. A connectivity analysis framework in the frequency domain was used to examine the up- or down-regulation in the ACC and Ins and pain intensity and unpleasantness ratings were assessed. We found that successful up- and down-regulation was mediated by the ACC and by its functional connectivity with the Ins and secondary somatosensory cortex. There was no significant relationship between successful up- or downregulation and pain ratings. These findings demonstrate functional interactions between brain areas involved in nociceptive processing during regulation of ACC and Ins activity, and the relevance of the frequency domain connectivity analysis for real-time fMRI. Moreover, despite successful neural regulation, there was no change in pain ratings, suggesting that pain is a complex perception, which may be more difficult to modify than other sensory or emotional processes., 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 Bucolo, Rance, Nees, Ruttorf, Stella, Monarca, Andoh and Flor.)

Pain is a multidimensional process, which can be modulated by emotions; however, the mechanisms underlying this modulation are unknown. We used pictures with different emotional valence (negative, positive, and neutral) as primes and applied electrical painful stimuli as targets to healthy participants. We assessed pain intensity and unpleasantness ratings and recorded electroencephalograms (EEGs). We found that pain unpleasantness and not pain intensity ratings were modulated by emotion, with increased ratings for negative and decreased ratings for positive pictures. We also found two consecutive gamma band oscillations (GBOs) related to pain processing from time frequency analyses of the EEG signals. The early GBO had a cortical distribution contralateral to the painful stimulus and its amplitude was positively correlated with intensity and unpleasantness ratings, but not with prime valence. The late GBO had a centroparietal distribution and its amplitude was larger for negative compared to neutral and positive pictures. The emotional modulation effect (negative vs. positive) of the late GBO amplitude was positively correlated with pain unpleasantness. The early GBO might reflect the overall pain perception, possibly involving the thalamocortical circuit, while the late GBO might be related to the affective dimension of pain and top-down-related processes., 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., (Copyright © 2022 Lyu, Zidda, Radev, Liu, Guo, Tong, Flor and Andoh.)

Background: The mechanisms underlying chronic phantom limb pain (PLP) are complex and insufficiently understood. Altered sensory thresholds are often associated with chronic pain but quantitative sensory testing (QST) in PLP has so far been inconclusive due to large methodological variation between studies and small sample sizes., Methods: In this study, we applied QST in 37 unilateral upper-limb amputees (23 with and 14 without PLP) and 19 healthy controls. We assessed heat pain (HPT), pressure pain, warmth detection and two-point discrimination thresholds at the residual limb, a homologous point and the thenar of the intact limb as well as both corners of the mouth., Results: We did not find significant differences in any of the thresholds between the groups. However, PLP intensity was negatively associated with HPT at all measured body sites except for the residual limb, indicating lower pain thresholds with higher PLP levels. Correlations between HPT and PLP were strongest in the contralateral face (r = -0.65, p < 0.001). Facial HPT were specifically associated with PLP, independent of residual limb pain (RLP) and various other covariates. HPT at the residual limb, however, were significantly associated with RLP, but not with PLP., Conclusion: We conclude that the association between PLP and, especially facial, HPT could be related to central mechanisms., Significance: Phantom limb pain (PLP) is still poorly understood. We show that PLP intensity is associated with lower heat pain thresholds, especially in the face. This finding could be related to central nervous changes in PLP., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed., 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., (Copyright © 2021 Kandić, Moliadze, Andoh, Flor and Nees.)

Phantom limb pain (PLP) may be relieved using a visual representation of an intact limb. However, patients with distorted (telescoped) phantoms seem unable to associate with visualizations of intact limbs. A virtual arm visualization was matched to the individual's phantom perception and controlled in an augmented reality (AR) intervention. Seven PLP participants with telescoped phantoms performed 8 supervised home-based AR-training sessions (45 minutes each) within 2 weeks. The virtual arm was superimposed in AR onto their residual limb and controlled using electromyography from the residual limb. AR-training sessions included 3 AR tasks aimed at reengaging the neural circuits related to the lost limb. Agency (Rubber hand illusion questionnaire) and telescoping (proprioceptive drift and felt telescoping) were monitored after individual training sessions. fMRI during lip pursing was assessed before and after intervention. Pain rating index scores were reduced by 52% (mean change = -1.884, P = .032, d = 1.135). Numerical rating scale scores of PLP severity (0-6) in patients benefitting from the intervention were reduced by 41% (mean change = .93 P = .022, d = 1.334). The lip pursing task illustrated decreased cortical activity in the primary somatosensory cortex, which correlated to the reduced numerical rating scale scores of PLP severity. PERSPECTIVE: Two weeks of novel AR interventions in patients with telescoped phantoms demonstrated reduced PLP and reversal of cortical reorganization. This research highlights the potential of individualized AR interventions for PLP and indicate the importance of agency in this type of treatments., (Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Following amputation, nearly all amputees report nonpainful phantom phenomena and many of them suffer from chronic phantom limb pain (PLP) and residual limb pain (RLP). The aetiology of PLP remains elusive and there is an ongoing debate on the role of peripheral and central mechanisms. Few studies have examined the entire somatosensory pathway from the truncated nerves to the cortex in amputees with PLP compared to those without PLP. The relationship among afferent input, somatosensory responses and the change in PLP remains unclear., Methods: Transcutaneous electrical nerve stimulation was applied on the truncated median nerve, the skin of the residual limb and the contralateral homologous nerve in 22 traumatic upper-limb amputees (12 with and 10 without PLP). Using somatosensory event-related potentials, the ascending volley was monitored from the brachial plexus, the spinal cord, the brainstem and the thalamus to the primary somatosensory cortex., Results: Peripheral input could evoke PLP in amputees with chronic PLP (7/12), but not in amputees without a history of PLP (0/10). The amplitudes of the somatosensory components were comparable between amputees with and without PLP. In addition, evoked potentials from the periphery through the spinal, subcortical and cortical segments were not significantly associated with PLP., Conclusions: Peripheral input can modulate PLP but seems insufficient to cause PLP. These findings suggest the multifactorial complexity of PLP and different mechanisms for PLP and RLP., Significance: Peripheral afferent input plays a role in PLP and has been assumed to be sufficient to generate PLP. In this study we found no significant differences in the electrical potentials generated by peripheral stimulation from the truncated nerve and the skin of the residual limb in amputees with and without PLP. Peripheral input could enhance existing PLP but could not cause it. These findings indicate the multifactorial complexity of PLP and an important role of central processes in PLP., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation -EFIC®.)

Phantom limb pain (PLP) has been associated with reorganization in primary somatosensory cortex (S1) and preserved S1 function. Here we examined if methodological differences in the assessment of cortical representations might explain these findings. We used functional magnetic resonance imaging during a virtual reality movement task, analogous to the classical mirror box task, in twenty amputees with and without PLP and twenty matched healthy controls. We assessed the relationship between task-related activation maxima and PLP intensity in S1 and motor cortex (M1) in individually-defined or group-conjoint regions of interest (ROI) (overlap of task-related activation between the groups). We also measured cortical distances between both locations and correlated them with PLP intensity. Amputees compared to controls showed significantly increased activation in M1, S1 and S1M1 unrelated to PLP. Neural activity in M1 was positively related to PLP intensity in amputees with PLP when a group-conjoint ROI was chosen. The location of activation maxima differed between groups in S1 and M1. Cortical distance measures were unrelated to PLP. These findings suggest that sensory and motor maps differentially relate to PLP and that methodological differences might explain discrepant findings in the literature.

Many studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays an important role in top-down cognitive control over intentional and deliberate behavior. However, recent studies have reported that DLPFC-mediated top-down control interferes with implicit forms of learning. Here we used continuous theta-burst stimulation (cTBS) combined with electroencephalography to investigate the causal role of DLPFC in implicit contextual memory-guided attention. We aimed to test whether transient disruption of the DLPFC would interfere with implicit learning performance and related electrical brain activity. We applied neuronavigation-guided cTBS to the DLPFC or to the vertex as a control region prior to the performance of an implicit contextual learning task. We found that cTBS applied over the DLPFC significantly improved performance during implicit contextual learning. We also noted that beta-band (13-19 Hz) oscillatory power was reduced at fronto-central channels about 140 to 370 ms after visual stimulus onset in cTBS DLPFC compared with cTBS vertex. Taken together, our results provide evidence that DLPFC-mediated top-down control interferes with contextual memory-guided attention and beta-band oscillatory activity., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Phantom limb (PLP) as well as residual limb pain (RLP) are still a very significant problem after amputation and their causes are only partially known. Here we tested whether the predisposition for the frequency, duration and intensity of PLP and RLP is shared with other prior chronic pains and/or the presence of postamputation subacute pain. A week preoperatively we collected data using validated questionnaires, a pain diary and interviews on past chronic pain conditions, acute pain, depression, anxiety, pain interference, life control, social support and affective distress and pain ratings one day before the amputation in 52 patients scheduled for limb amputation. In the week postamputation and again three and 12 months thereafter, we collected data on postoperative wound pain, PLP, RLP and non-painful phantom sensation (PLS). Phantom and residual limb pain indices were calculated per patient, integrating the intensity, frequency and duration of past chronic pain, PLP, RLP and PLS into a single value to index the overall burden of pain. We report that acute and chronic pain long before but not on the day before the amputation and subacute pain postamputation significantly predicted up to half of the variance in the incidence and severity of PLP, RLP and PLS 12 months postamputation. Moreover, the severity of these painful sensations at 12 months postamputation was partially predicted by preamputation scores of depression and anxiety. These findings corroborate the hypothesis that chronic pain and non-painful sensations following limb amputation are strongly related to longstanding preoperative chronic pain and to subacute postoperative pain as well as to psychological factors before the amputation that may be inherited and/or acquired (learning- and memory-related). Furthermore, we also confirm that subacute pain postamputation comprises an additional risk factor for long-term painful sensations postamputation. Our results suggest that timely interventions might prevent the development of chronic pain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cerebral small vessel disease in deep penetrating arteries is a major cause of lacunar infarcts, white matter lesions and vascular cognitive impairment. Local cerebral blood flow in these small vessels is controlled by endothelial-derived nitric oxide, which exerts a primary vasodilator stimulus on vascular myocytes, via cytoplasmic cyclic GMP. Here, we investigated whether the cGMP-degrading enzyme phosphodiesterase-5 (PDE5) is present in small penetrating arteries in the deep subcortical white matter of older people. Frontal cortical tissue blocks were examined from donated brains of older people (n = 42, 24 male: 18 female, median age 81, range: 59-100 years). PDE5, detected by immunohistochemical labeling, was graded as absent, sparse, or abundant in vascular cells within small arteries in subcortical white matter (vessel outer diameter: 20-100 µm). PDE5 labeling within arterial myocytes was detected in all cases. Degree of PDE5 expression (absent, sparse, or abundant) was not associated with age or with neuropathological diagnosis of small vessel disease. In conclusion, PDE5 is present in vascular myocytes within small penetrating arteries in older people. This is a potential molecular target for pharmacological interventions.

While the pathophysiology of transient global amnesia (TGA) is not understood, due to the specific nature of the clinical deficits, transient dysfunction in the medial temporal lobe, especially in the hippocampus, is assumed; however, concomitant disturbances in other brain regions and in executive function have been postulated. In this study, a cohort of 16 patients was prospectively recruited from the emergency department for resting-state functional MRI (fMRI) during the acute stage of TGA, as confirmed by a standardized neuropsychological assessment. Twenty age- and sex-matched controls, as well as twenty patients with a history of TGA, were recruited for comparison. Functional data were processed using independent component analysis (ICA), allowing the complete automatic (data-driven) identification of spontaneous network dynamics. We documented a severe disturbance in anterograde episodic long-term memory in all patients. Group-based ICA of resting-state data in acute TGA patients versus that of controls and patients with a past TGA episode demonstrated reduced FC mainly of structures belonging to the executive network (EN), but also the hippocampus, confirming its pathophysiological involvement in the disorder, as well as areas belonging to the salience network and other subcortical regions. No significant differences were found when comparing connectivity in patients with a history of TGA and controls. Our findings strengthen previous empirical and theoretical accounts of hippocampal and executive dysfunction in TGA. The disruption of frontal, parietal and insular control regions, together with disruption in the hippocampus, provides a new interpretation for the pathophysiology and neuropsychological profile of this neurological disorder on a large-scale network level., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cortical reorganization has been proposed as a major factor involved in phantom pain with prior nociceptive input to the deafferented region and input from the non-deafferented cortex creating neuronal activity that is perceived as phantom pain. There is substantial evidence that these processes play a role in neuropathic pain, although causal evidence is lacking. Recently it has been suggested that a maintenance of the cortical representation of the former hand area is related to phantom pain. Although interesting, evidence for this process is so far scarce. In addition, peripheral factors have been proposed as important for phantom limb pain. Although often introduced as contradictory, we suggest that cortical reorganization, preserved limb function and peripheral factors interact to create the various painful and nonpainful aspects of the phantom limb experience. In addition, the type of task (sensory versus motor), the interaction of injury- and use-dependent plasticity, the type of data analysis, contextual factors such as the body representation and psychological variables determine the outcome and need to be considered in models of phantom limb pain. Longitudinal studies are needed to determine the formation of the phantom pain experience., (Copyright © 2017 IBRO. All rights reserved.)

Non-invasive brain stimulation (NIBS) has been widely used as a research tool to modulate cortical excitability of motor as well as non-motor areas, including auditory or language-related areas. NIBS, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, have also been used in clinical settings, with however variable therapeutic outcome, highlighting the need to better understand the mechanisms underlying NIBS techniques. TMS was initially used to address causality between specific brain areas and related behavior, such as language production, providing non-invasive alternatives to lesion studies. Recent literature however suggests that the relationship is not as straightforward as originally thought, and that TMS can show both linear and non-linear modulation of brain responses, highlighting complex network dynamics. In particular, in the last decade, NIBS studies have enabled further advances in our understanding of auditory processing and its underlying functional organization. For instance, NIBS studies showed that even when only one auditory cortex is stimulated unilaterally, bilateral modulation may result, thereby highlighting the influence of functional connectivity between auditory cortices. Additional neuromodulation techniques such as transcranial alternating current stimulation or transcranial random noise stimulation have been used to target frequency-specific neural oscillations of the auditory cortex, thereby providing further insight into modulation of auditory functions. All these NIBS techniques offer different perspectives into the function and organization of auditory cortex. However, further research should be carried out to assess the mode of action and long-term effects of NIBS to optimize their use in clinical settings.

Classical fear conditioning is an important mechanism to adequately respond and adapt to environmental threats and has been related to the development of fear and anxiety. Both cue and context conditioning have been studied but little is known about their relation to relevant resting state networks. The default mode network (DMN) has been reported to be involved in affective learning and described as facilitating a state of readiness in responding to environmental changes. We examined resting state brain connectivity patterns of the default mode network (DMN) in 119 healthy volunteers. Specifically, we carried out correlation analyses between the DMN and skin conductance responses (SCRs) as well as arousal, valence and contingency ratings during learning. In addition, we examined the role of trait anxiety. Two different DMN patterns were identified in which stronger connectivity was linked to lower differential SCRs during fear and anxiety learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. These results were replicated in an independent sample. Functional connectivity of the DMN with these key regions at rest was also predictive of trait anxiety but this association could not be replicated in the second sample. We showed that DMN connectivity is differently associated with cued versus contextual learning mechanisms. Uncovering individual differences in baseline network connectivity of the DMN with these key regions might lead to a better understanding of fear and anxiety. Such findings could indeed help to identify vulnerability factors linked to network alterations at rest with dysregulation of learning processes involved in the pathophysiology of stress and anxiety disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study)., Methods: Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T 2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1)., Results: Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P =0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P =0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P =0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P =0.007)., Conclusions: Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers., (© 2017 American Heart Association, Inc.)

Previous work showed the existence of changes in the topographic organization within the somatosensory cortex (SI) in amputees with phantom limb pain, however, the link between nonpainful phantom sensations such as cramping or tingling or the percept of the limb and cortical changes is less clear. We used functional magnetic resonance imaging (fMRI) in a highly selective group of limb amputees who experienced inducible and reproducible nonpainful phantom sensations. A standardized procedure was used to locate body sites eliciting phantom sensations in each amputee. Selected body sites that could systematically evoke phantom sensations were stimulated using electrical pulses in order to induce phasic phantom sensations. Homologous body parts were also stimulated in a group of matched controls. Activations related to evoked phantom sensations were found bilaterally in SI and the intraparietal sulci (IPS), which significantly correlated with the intensity of evoked phantom sensations. In addition, we found differences in intra- and interhemispheric interaction between amputees and controls during evoked phantom sensations. We assume that phantom sensations might be associated with a functional decoupling between bilateral SI and IPS, possibly resulting from transcallosal reorganization mechanisms following amputation., (Copyright © 2017. Published by Elsevier B.V.)

Objective: Repetitive transcranial magnetic stimulation (rTMS) over the left temporo-parietal region has been proposed as a treatment for resistant auditory verbal hallucinations (AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology., Method: Twenty-seven patients with schizophrenia and medication-resistant AVH participated to a randomized, double-blind, placebo-controlled, add-on rTMS study. The stimulation targeted a language-perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms (SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales., Results: A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo-treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities., Conclusions: A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non-magnetic stimulation of the auditory cortex are suggested., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Resting-state fMRI studies have become very important in cognitive neuroscience because they are able to identify BOLD fluctuations in brain circuits involved in motor, cognitive, or perceptual processes without the use of an explicit task. Such approaches have been fruitful when applied to various disordered populations, or to children or the elderly. However, insufficient attention has been paid to the consequences of the loud acoustic scanner noise associated with conventional fMRI acquisition, which could be an important confounding factor affecting auditory and/or cognitive networks in resting-state fMRI. Several approaches have been developed to mitigate the effects of acoustic noise on fMRI signals, including sparse sampling protocols and interleaved silent steady state (ISSS) acquisition methods, the latter being used only for task-based fMRI. Here, we developed an ISSS protocol for resting-state fMRI (rs-ISSS) consisting of rapid acquisition of a set of echo planar imaging volumes following each silent period, during which the steady state longitudinal magnetization was maintained with a train of relatively silent slice-selective excitation pulses. We evaluated the test-retest reliability of intensity and spatial extent of connectivity networks of fMRI BOLD signal across three different days for rs-ISSS and compared it with a standard resting-state fMRI (rs-STD). We also compared the strength and distribution of connectivity networks between rs-ISSS and rs-STD. We found that both rs-ISSS and rs-STD showed high reproducibility of fMRI signal across days. In addition, rs-ISSS showed a more robust pattern of functional connectivity within the somatosensory and motor networks, as well as an auditory network compared with rs-STD. An increased connectivity between the default mode network and the language network and with the anterior cingulate cortex (ACC) network was also found for rs-ISSS compared with rs-STD. Finally, region of interest analysis showed higher interhemispheric connectivity in Heschl's gyri in rs-ISSS compared with rs-STD, with lower variability across days. The present findings suggest that rs-ISSS may be advantageous for detecting network connectivity in a less noisy environment, and that resting-state studies carried out with standard scanning protocols should consider the potential effects of loud noise on the measured networks., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pain can be modulated by contextual stimuli, such as emotions, social factors, or specific bodily perceptions. We presented painful laser stimuli together with body-related masochistic visual stimuli to persons with and without preferred masochistic sexual behavior and used neutral, positive, and negative pictures with and without painful stimuli as control. Masochists reported substantially reduced pain intensity and unpleasantness in the masochistic context compared with controls but had unaltered pain perception in the other conditions. Functional magnetic resonance imaging revealed that masochists activated brain areas involved in sensory-discriminative processing rather than affective pain processing when they received painful stimuli on a masochistic background. The masochists compared with the controls displayed attenuated functional connectivity of the parietal operculum with the left and right insulae, the central operculum, and the supramarginal gyrus. Masochists additionally showed negative correlations between the duration of interest in masochistic activities and activation of areas involved in motor activity and affective processing. We propose that the parietal operculum serves as an important relay station that attenuates the affective-motivational aspects of pain in masochists. This novel mechanism of pain modulation might be related to multisensory integration and has important implications for the assessment and treatment of pain.

Hemispheric asymmetries in human auditory cortical function and structure are still highly debated. Brain stimulation approaches can complement correlational techniques by uncovering causal influences. Previous studies have shown asymmetrical effects of transcranial magnetic stimulation (TMS) on task performance, but it is unclear whether these effects are task-specific or reflect intrinsic network properties. To test how modulation of auditory cortex (AC) influences functional networks and whether this influence is asymmetrical, the present study measured resting-state fMRI connectivity networks in 17 healthy volunteers before and immediately after TMS (continuous theta burst stimulation) to the left or right AC, and the vertex as a control. We also examined the relationship between TMS-induced interhemispheric signal propagation and anatomical properties of callosal auditory fibers as measured with diffusion-weighted MRI. We found that TMS to the right AC, but not the left, resulted in widespread connectivity decreases in auditory- and motor-related networks in the resting state. Individual differences in the degree of change in functional connectivity between auditory cortices after TMS applied over the right AC were negatively related to the volume of callosal auditory fibers. The findings show that TMS-induced network modulation occurs, even in the absence of an explicit task, and that the magnitude of the effect differs across individuals as a function of callosal structure, supporting a role for the corpus callosum in mediating functional asymmetry. The findings support theoretical models emphasizing hemispheric differences in network organization and are of practical significance in showing that brain stimulation studies need to take network-level effects into account., (Copyright © 2015 the authors 0270-6474/15/3514603-10$15.00/0.)

Transcranial direct current stimulation (tDCS) is attracting increasing interest because of its potential for therapeutic use. While its effects have been investigated mainly with motor and visual tasks, less is known in the auditory domain. Past tDCS studies with auditory tasks demonstrated various behavioral outcomes, possibly due to differences in stimulation parameters, task-induced brain activity, or task measurements used in each study. Further research, using well-validated tasks is therefore required for clarification of behavioral effects of tDCS on the auditory system. Here, we took advantage of findings from a prior functional magnetic resonance imaging study, which demonstrated that the right auditory cortex is modulated during fine-grained pitch learning of microtonal melodic patterns. Targeting the right auditory cortex with tDCS using this same task thus allowed us to test the hypothesis that this region is causally involved in pitch learning. Participants in the current study were trained for 3 days while we measured pitch discrimination thresholds using microtonal melodies on each day using a psychophysical staircase procedure. We administered anodal, cathodal, or sham tDCS to three groups of participants over the right auditory cortex on the second day of training during performance of the task. Both the sham and the cathodal groups showed the expected significant learning effect (decreased pitch threshold) over the 3 days of training; in contrast we observed a blocking effect of anodal tDCS on auditory pitch learning, such that this group showed no significant change in thresholds over the 3 days. The results support a causal role for the right auditory cortex in pitch discrimination learning.

Current functional MRI (fMRI) approaches assess underlying neuronal activity through monitoring the related local variations in cerebral blood oxygenation, blood volume and blood flow. This vascular response is likely to vary across brain regions and across individuals, depending on the composition of the local vascular bed and on the vascular capacity to dilate. The most widely used technique uses the blood oxygen level dependent (BOLD) fMRI signal, which arises from a complex combination of all of these factors. The model of handedness provides a case where one brain region (dominant motor cortex) is known to have a stronger BOLD response over another (non-dominant motor cortex) during hand motor task performance. We predict that this is accompanied by a higher vascular reactivity in the dominant motor cortex, when compared with the non-dominant motor cortex. Precise measurement of end-tidal CO2 and a novel sinusoidal CO2 respiratory challenge were combined with the high sensitivity and finer spatial resolution available for fMRI at 7 T to measure BOLD cerebrovascular reactivity (CVR) in eight healthy male participants. BOLD CVR was compared between the left (dominant) and right (non-dominant) primary motor cortices of right-handed adults. Hemispheric asymmetry in vascular reactivity was predicted and observed in the primary motor cortex (left CVR = 0.60 ± 0.15%/mm Hg; right CVR = 0.47 ± 0.08%/mm Hg; left CVR > right CVR, P = 0.04), the first reported evidence of such a vascular difference. These findings demonstrate a cerebral vascular asymmetry between the left and right primary motor cortex. The origin of this asymmetry largely arises from the contribution of large draining veins. This work has implications for future motor laterality studies that use BOLD, and it is also suggestive of a vascular plasticity in the human primary motor cortex., (Copyright © 2015 John Wiley & Sons, Ltd.)

The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD.

Objective: Analysis of hospitalization data can help elucidate the pattern of morbidity and mortality in any given area. Little data exist on critically ill children admitted to hospitals in the resource-limited nation of Nepal. We sought to characterize the profile, management, and mortality of children admitted to one PICU., Design: Retrospective analysis., Setting: A newly established PICU in Nepal., Patients: All patients between the ages of 0 to 16 years admitted to the PICU from July 2009 to July 2010., Interventions: None., Measurements and Results: In 12 months, 126 children were admitted to the PICU including 43% female patients. Sixty-three percent were under 5 years. Twenty-nine percent came from tertiary care hospitals and 38% from rural areas outside Kathmandu. Only 18% were transported by ambulance. Median distance travelled to be admitted was 30 km (interquartile range, 10-193). Highest number of admissions were in spring (40%) followed by summer (25%). Almost half were admitted for shock (45%), particularly septic shock (30%). The second commonest reason for admission was neurologic etiologies (15%). Neonatal admissions were also significant (19%). Mortality was 26% and was significantly associated with septic shock (p < 0.01), mechanical ventilation (p < 0.01), and multiple organ dysfunction (< 0.05). Almost one third of patients required mechanical ventilation; median duration was 4 days (interquartile range, 2-8). Mean length of stay in the hospital was 6.2 days (± 5.3) and median 4 (interquartile range, 2.5-9.0). Median Pediatric Risk of Mortality II score for nonsurvivors was 12 (interquartile range, 7-21), and median Pediatric Index of Mortality II for nonsurvivors was 10 (interquartile range, 3-32)., Conclusions: Within a short time of opening, the PICU has been seeing significant numbers of critically ill children. Despite adverse conditions and limited resources, survival of 75% is similar to many units in developing nations. Sepsis was the most common reason for PICU admission and mortality.

Objective: This study aims to describe the effect of 0.9% saline (NS) versus 0.45% saline (half NS) when used during recovery phase of diabetic ketoacidosis (DKA) in children., Methods: A retrospective analysis of all children (1-18 years old) with DKA admitted in the pediatric intensive care unit (PICU) from 2005 to 2009 was undertaken. The primary end point was effect on serum electrolytes and acidosis., Results: Compared to 47 patients who received only NS (group A) throughout the recovery period and 33 patients who received NS but were switched to half NS (group B) at some point during recovery, 41 who received only half NS (group C) had a significant decrease in corrected serum sodium (P < .01). Hyperchloremia leading to nonanion gap acidosis was significantly greater in NS groups A and B than in half NS group C (P < .01). This led to increased duration of insulin infusion and length of stay in the PICU in the NS groups., Conclusions: Hyperchloremia resulting in nonanion gap acidosis can occur and may prolong the duration of insulin infusion and length of PICU stay in patients receiving NS as post-bolus rehydration fluid. Alternatively, the use of half NS may result in a decrease in serum-corrected sodium. Providers need to be vigilant toward this while using higher or lower sodium chloride when managing children with DKA. Larger trials are required to study the clinical significance of the results of this study.

Unlabelled: Aim Mortality, predominantly due to cardiovascular events, is high in patients with chronic kidney disease (CKD) and left ventricular hypertrophy (LVH) is a strong risk factor. Vascular endothelial dysfunction (ED) is common in CKD, but its potential contribution to LVH in non-dialysis CKD is unknown. This study investigated the association of ED with LVH in non-dialysis CKD patients., Methods and Results: We studied 30 CKD patients (17 pre-dialysis and 13 renal transplant recipients) and 29 age-gender-matched controls. In both groups, high-sensitivity C-reactive protein (hsCRP) levels, systemic ED (brachial artery flow-mediated dilatation, FMD), and LVH using two-dimensional echocardiography were measured. LV mass index (LVMI) was calculated using Penn formula and indexed by height. CKD patients had higher CRP levels (3.9 ± 2.8 vs. 1.0 ± 0.7 mg/L; P < 0.001), reduced FMD (3.2 ± 2.1 vs. 6.1 ± 1.9%; P < 0.001), and increased LVMI (146.1 ± 40.2 vs. 105.3 ± 26.2 g/m; P < 0.001), compared with controls. In CKD patients, LVMI increased with decreasing FMD (r = -0.371; P = 0.043) and FMD decreased with increasing CRP (r = -0.741; P < 0.001). Patients with low FMD <2.3% had higher CRP and LVMI (161.9 ± 48.9 vs. 130.4 ± 20.7 g/m; P = 0.033), compared with CKD patients with FMD ≥2.3%. There was no significant difference in age, blood pressure, cholesterol, FMD, and LVMI between pre-dialysis and post-renal transplant CKD patients. In multivariate regression, the relationship between LVMI and FMD remained significant after adjusting for age, diabetes, and smoking (adjacent beta = -0.396; P = 0.004)., Conclusion: This pilot study demonstrates for the first time a relationship of ED with LVH in non-dialysis CKD patients; suggesting but not proving a cause-effect relationship.

Interhemispheric interactions can be important in transcranial magnetic stimulation (TMS) studies investigating motor or cognitive brain functions, but their role in predicting the outcome of TMS is not clear. Previously, we showed that individual differences in interhemispheric functional connectivity of auditory cortices influenced the behavioral effect of repetitive TMS (rTMS) applied over auditory cortex in a melody discrimination task. Here, functional magnetic resonance imaging (fMRI) scanning with the same task was carried out before and after rTMS applied over auditory cortex to determine how rTMS affects both behavior and neural function. After rTMS applied over the right auditory cortex, we found mean increases in activation in the contralateral auditory cortex. The degree and direction of modulation of the fMRI response were correlated with behavior: the higher the contralateral increase after stimulation, the faster the response times, whereas individuals with reduced contralateral activity showed no behavioral facilitation. We also found that higher interhemispheric connectivity between auditory cortices before TMS was associated with faster response times. This study shows directly the role of functional connectivity in the auditory network on TMS-induced modulation, which could explain its often variable effects on behavior. Combined TMS and fMRI is particularly useful to promote plastic reorganization in the auditory network and has implications for research on auditory-related disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Carotid artery disease is a widespread cause of morbidity and mortality. Porcine models of vascular disease are well established in vivo, but existing endothelial systems in vitro (e.g. human umbilical vein endothelial cells, rat aortic endothelial cultures) poorly reflect carotid endothelium. A reliable in vitro assay would improve design of in vivo experiments and allow reduction and refinement of animal use. This study aimed (1) to develop ex vivo endothelial cultures from porcine carotid and (2) to test whether these were suitable for lentivector-mediated transgene delivery. Surplus carotid arteries were harvested from young adult female Large White pigs within 10 min post-mortem. Small sectors of carotid artery wall (approximately 4 mm×4 mm squares) were immobilised in a stable gel matrix. Cultures were exposed to HIV-derived lentivector (LV) encoding a reporter transgene or the equivalent integration-deficient vector (IDLV). After 7-14 days in vitro, cultures were fixed and labelled histochemically. Thread-like multicellular outgrowths were observed that were positive for endothelial cell markers (CD31, VEGFR2, von Willebrand factor). A minority of cells co-labelled for smooth muscle markers. Sensitivity to cytotoxic agents (paclitaxel, cycloheximide, staurosporine) was comparable to that in cell cultures, indicating that the gel matrix permits diffusive access of small pharmacological molecules. Transgene-expressing cells were more abundant following exposure to LV than IDLV (4.7, 0.1% of cells, respectively). In conclusion, ex vivo adult porcine carotid artery produced endothelial cell outgrowths that were effectively transduced by LV. This system will facilitate translation of novel therapies to clinical trials, with reduction and refinement of in vivo experiments.

A recent study suggests that brain changes in amputees may be pain-induced, questioning maladaptive plasticity as a neural basis of phantom pain. These findings add valuable information on cortical reorganization after amputation. We suggest further lines of research to clarify the mechanisms that underlie phantom pain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Weaning is a high-risk phase in the life of infants around the world, because poorly managed, it raises protein-energy malnutrition to levels causing crucial problems to the health of infants., Aims: The purpose is to estimate the knowledge and the practices of the mothers regarding the conduct of food weaning of their children aged 6 to 18 months., Materials and Methods: We conducted a descriptive cross-sectional survey at the general hospital of Marcory in Abidjan-CI on a sample of 100 mother-child pairs who came to consult., Results: It emerges from this survey that., The mothers are young, with 94% younger than 35 years old. 88% of the mothers were of a low socioeconomic level. Dietary restrictions still remained a real obstacle to a better practice of weaning., The vast majority of the mothers (74%) ignore the notion of weaning and 40% of them had no information regarding this process. Food weaning was not conventional with an early weaning at 1 to 6 months in 38% of the cases and a late weaning (30%) after 13 months., Conclusion: It is necessary to set up a program focusing on the adequate conduct of weaning in infants to improve mothers' knowledge and the practices., (Le comitée de rédaction se réserve le droit de revoyer aux auteurs avant toute soumission à l'avis des lecteurs les manuscrits qui ne seraient pas conformes à ces modalités de présentation. En outre il leur conseille de sonserver un examplaire du manuscrit, des figures et des tableaux.)

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function. An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity. Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex, premotor cortex, primary somatosensory cortex and language-related areas, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task. We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.

Objectives: Although noninvasive positive pressure ventilation is increasingly used for respiratory distress, there is not much data supporting its use in children with status asthmaticus. The objective of this study was to determine safety, tolerability, and efficacy of early initiation of noninvasive positive pressure ventilation in addition to standard of care in the management of children admitted with status asthmaticus., Study Design: A prospective, randomized, controlled, clinical trial., Patients: Twenty patients (1-18 yrs old) admitted to the pediatric intensive care unit with status asthmaticus., Methods and Main Results: Children were randomized to receive either noninvasive positive pressure ventilation plus standard of care (noninvasive positive pressure ventilation group) or standard of care alone (standard group). Improvement in clinical asthma score was significantly greater in noninvasive positive pressure ventilation group compared to standard group at 2 hrs, 4-8 hrs, 12-16 hrs, and 24 hrs after initiation of interventions (p < .01). A significant decrease in respiratory rate at ≥ 24 hrs oxygen requirement after 2 hrs was noted in noninvasive positive pressure ventilation group as compared to standard group (p = .01 and p = .03, respectively). Although statistically not significant, fewer children in the noninvasive positive pressure ventilation group required adjunct therapy compared to standard group (11% vs. 50%; p = .07). There were no major adverse events related to noninvasive positive pressure ventilation. Nine out of ten patients tolerated noninvasive positive pressure ventilation through the duration of the study; noninvasive positive pressure ventilation had to be discontinued in one patient because of persistent cough., Conclusions: Early initiation of noninvasive positive pressure ventilation, along with short acting β-agonists and systemic steroids, can be safe, well-tolerated, and effective in the management of children with status asthmaticus.

Background: The pathophysiology of microvascular angina (cardiac syndrome X, CSX), (effort-induced angina, a positive response to exercise stress testing and angiographically normal coronary arteries) has not been fully elucidated. Various pathogenic mechanisms have been proposed, amongst which coronary microvascular dysfunction features prominently. Management of patients with microvascular angina is often challenging as a substantial number of patients does not respond to conventional anti-anginal therapy. In this study, we sought to assess the association between brachial artery FMD, high-sensitive C-reactive protein (hs-CRP) and cardiovascular risk factors including obesity in patients with cardiac syndrome X., Methods and Results: Thirty-four consecutive CSX patients (29 female, mean age 60 ± 9 years) were recruited from a specialised CSX clinic. Twelve asymptomatic subjects (10 female, mean age 51 ± 12 years) with comparable cardiovascular risk factor profile served as controls. All participants underwent standardized computer-assisted FMD measurements and assessment of hs-CRP concentrations at study entry. Body mass index (BMI), used as a general measure of obesity was calculated as weight (kilograms) divided by height (meters squared). Compared to controls, CSX patients had significantly higher hs-CRP concentrations (p = 0.003) and impaired FMD (p < 0.01). Moreover, among the CSX patients, a correlation between FMD and hs-CRP (r = -0.66, p < 0.01), FMD and BMI (r = 0.377, p = 0.028), and hs-CRP and BMI (r = -0.372, p = 0.030) was found., Conclusion: Impaired brachial artery FMD is significantly associated with elevated hs-CRP concentrations and BMI in patients with CSX. The results support the concept that low-grade inflammation and obesity may promote vascular dysfunction in these patients representing therapeutic targets for future research investigations.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to interfere with many components of language processing, including semantic, syntactic, and phonologic. However, not much is known about its effects on nonlinguistic auditory processing, especially its action on Heschl's gyrus (HG). We aimed to investigate the behavioral and neural basis of rTMS during a melody processing task, while targeting the left HG, the right HG, and the Vertex as a control site. Response times (RT) were normalized relative to the baseline-rTMS (Vertex) and expressed as percentage change from baseline (%RT change). We also looked at sex differences in rTMS-induced response as well as in functional connectivity during melody processing using rTMS and functional magnetic resonance imaging (fMRI). fMRI results showed an increase in the right HG compared with the left HG during the melody task, as well as sex differences in functional connectivity indicating a greater interhemispheric connectivity between left and right HG in females compared with males. TMS results showed that 10 Hz-rTMS targeting the right HG induced differential effects according to sex, with a facilitation of performance in females and an impairment of performance in males. We also found a differential correlation between the %RT change after 10 Hz-rTMS targeting the right HG and the interhemispheric functional connectivity between right and left HG, indicating that an increase in interhemispheric functional connectivity was associated with a facilitation of performance. This is the first study to report a differential rTMS-induced interference with melody processing depending on sex. In addition, we showed a relationship between the interference induced by rTMS on behavioral performance and the neural activity in the network connecting left and right HG, suggesting that the interhemispheric functional connectivity could determine the degree of modulation of behavioral performance.

Repetitive TMS (rTMS) provides a noninvasive tool for modulating neural activity in the human brain. In healthy participants, rTMS applied over the language-related areas in the left hemisphere, including the left posterior temporal area of Wernicke (LTMP) and inferior frontal area of Broca, have been shown to affect performance on word recognition tasks. To investigate the neural substrate of these behavioral effects, off-line rTMS was combined with fMRI acquired during the performance of a word recognition task. Twenty right-handed healthy men underwent fMRI scans before and after a session of 10-Hz rTMS applied outside the magnetic resonance scanner. Functional magnetic resonance images were acquired during the performance of a word recognition task that used English or foreign-language words. rTMS was applied over the LTMP in one group of 10 participants (LTMP group), whereas the homologue region in the right hemisphere was stimulated in another group of 10 participants (RTMP group). Changes in task-related fMRI response (English minus foreign languages) and task performances (response time and accuracy) were measured in both groups and compared between pre-rTMS and post-rTMS. Our results showed that rTMS increased task-related fMRI response in the homologue areas contralateral to the stimulated sites. We also found an effect of rTMS on response time for the LTMP group only. These findings provide insights into changes in neural activity in cortical regions connected to the stimulated site and are consistent with a hypothesis raised in a previous review about the role of the homologue areas in the contralateral hemisphere for preserving behavior after neural interference.

Auditory verbal hallucinations are a cardinal symptom of schizophrenia. Bleuler and Kraepelin distinguished 2 main classes of hallucinations: hallucinations heard outside the head (outer space, or external, hallucinations) and hallucinations heard inside the head (inner space, or internal, hallucinations). This distinction has been confirmed by recent phenomenological studies that identified 3 independent dimensions in auditory hallucinations: language complexity, self-other misattribution, and spatial location. Brain imaging studies in schizophrenia patients with auditory hallucinations have already investigated language complexity and self-other misattribution, but the neural substrate of hallucination spatial location remains unknown. Magnetic resonance images of 45 right-handed patients with schizophrenia and persistent auditory hallucinations and 20 healthy right-handed subjects were acquired. Two homogeneous subgroups of patients were defined based on the hallucination spatial location: patients with only outer space hallucinations (N=12) and patients with only inner space hallucinations (N=15). Between-group differences were then assessed using 2 complementary brain morphometry approaches: voxel-based morphometry and sulcus-based morphometry. Convergent anatomical differences were detected between the patient subgroups in the right temporoparietal junction (rTPJ). In comparison to healthy subjects, opposite deviations in white matter volumes and sulcus displacements were found in patients with inner space hallucination and patients with outer space hallucination. The current results indicate that spatial location of auditory hallucinations is associated with the rTPJ anatomy, a key region of the "where" auditory pathway. The detected tilt in the sulcal junction suggests deviations during early brain maturation, when the superior temporal sulcus and its anterior terminal branch appear and merge.

The patient was a 50-year-old woman with a palpable tumor and pain in the right breast in May of 2008. The tumor was then diagnosed as an atheroma. The tumor enlarged rapidly in June, and the pain and the redness had worsened. The patient was then referred to our hospital. The tumor was in the upper inner quadrant of the right breast with surface redness, measuring about 3 cm. In the mammographic (MMG) findings, the tumor shadow was in the upper inner quadrant of the right breast and was observed to be circular and have a high density with a plain boundary and slightly roughed edges. In the ultrasonographic (US) findings, an oval-shaped high echoic region was found subcutaneously in the right breast. Because the high echoic area was subdivided in the partition of the low echoic string, it looked like a pebbled wall. Upon core needle biopsy, this case was diagnosed as malignant lymphoma. After comparing the histopathology and the US image, it was determined that the pebbled wall-shaped image was due to lymphocyte infiltration of the tissue. The US image was peculiar and we report this case as a peculiar example of malignant lymphoma.

Background: Reactive telephone helplines for smoking cessation (where all calls to counselors are smoker initiated) are increasingly used in the United States. However, limited data from randomized controlled trials are available on their effectiveness. The study objective was to evaluate the real-world effectiveness of reactive telephone counseling for smoking cessation using a randomized controlled trial study design., Methods: The study was implemented during a period from 2003 to 2006 to evaluate a reactive telephone helpline run by the American Lung Association chapter of Illinois-Iowa. The 990 new callers, all adult current smokers who called the helpline, were randomized on their first call into one of the two following groups: a control group that received only mailed self-help literature (n = 496); and a study group that received supplemental live reactive telephone counseling (n = 494). Telephone follow-up was completed at 1, 3, 6, and 12 months after study enrollment by interviewers blinded to group assignment. Seven-day point prevalence rates of self-reported abstinence at follow-up evaluations were compared between the two groups using an intent-to-treat design., Results: The two groups did not differ significantly in baseline demographics and smoking-related behavior. The abstinence rates (ranging between 0.09 and 0.15) were not significantly different between the two groups at 1-, 3-, 6-, and 12-month follow-up evaluations. Post hoc subgroup analysis showed that black callers had lower abstinence rates at the 3- and 12-month follow-up evaluations as compared with white callers., Conclusion: Supplemental live, reactive telephone counseling does not provide greater success in smoking cessation than self-help educational materials alone.

Transcranial magnetic stimulation (TMS) is currently used for cognitive studies and investigated as a treatment for psychiatric disorders. Because of the cortex variability, the coil positioning stage is difficult and should be improved by using individual neuroimaging data. Sophisticated and expensive neuronavigation systems have been developed to guide the coil to selected regions on the patient's magnetic resonance images (MRI). Our objective was to develop a triangulation-based MRI-guided method to position manually the TMS coil over the subject's head, using a cortical target derived from individual MR data. We evaluated both the spatial accuracy and the reproducibility of the method using functional MR activations of two different targets in the motor and parietal cortices. The accuracy of the MRI-guided method, assessed from the Euclidean distance (D(m)) between the thumb motor target and the coil position eliciting reproducible thumb motor-evoked potentials with TMS, was D(m) = 10 +/- 3 mm. The reproducibility of the method, evaluated across two different operators, was D(m) = 6.7 +/- 1.4 mm for the repositioning in the motor cortex and D(m) = 6.0 +/- 3.2 mm in the parietal cortex. This novel method could be used clinically to assist positioning of the TMS coil.

Background: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC-D) as first-line chemotherapy in metastatic breast cancer (MBC)., Patients and Methods: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40 mg/m2 plus cyclophosphamide 500 mg/m2), D (60 mg/m2), or alternating treatment with AC-D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks., Results: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC-D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P = 0.13 for AC versus D, P = 0.14 for AC versus AC-D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P = 0.09 for AC versus D, P = 0.13 for AC versus AC-D) in the AC, D, and AC-D, respectively., Conclusion: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.