Cumulative lifetime stressor exposure impairs stimulus-response but not contextual learning.

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.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study.

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.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

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.

Practical challenges of continuous real-time functional magnetic resonance imaging neurofeedback with multiband accelerated echo-planar imaging and short repetition times.

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.

Cortical networks underlying successful control of nociceptive processing using real-time fMRI.

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.

Phantom limb pain after unilateral arm amputation is associated with decreased heat pain thresholds in the face.

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.

Data management strategy for a collaborative research center.

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.

Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation.

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.

Gamma Band Oscillations Reflect Sensory and Affective Dimensions of Pain.

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.

Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective.

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.

Individualized Augmented Reality Training Reduces Phantom Pain and Cortical Reorganization in Amputees: A Proof of Concept Study.

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.

Peripheral input and phantom limb pain: A somatosensory event-related potential study.

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.

Disruption of the Prefrontal Cortex Improves Implicit Contextual Memory-Guided Attention: Combined Behavioral and Electrophysiological Evidence.

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.

Resting-state connectivity alterations during transient global amnesia.

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.

Pre- and postoperative predictors of phantom limb pain.

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.

Insights Into Auditory Cortex Dynamics From Non-invasive Brain Stimulation.

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.

Default mode network connectivity of fear- and anxiety-related cue and context conditioning.

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.

Contextual modulation of pain in masochists: involvement of the parietal operculum and insula.

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.

Asymmetric Interhemispheric Transfer in the Auditory Network: Evidence from TMS, Resting-State fMRI, and Diffusion Imaging.

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.

Polarity-specific transcranial direct current stimulation disrupts auditory pitch learning.

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.