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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Chronic pain, with a prevalence of 20-30 % is the major cause of human suffering worldwide, because effective, specific and safe therapies have yet to be developed. It is unevenly distributed among sexes, with women experiencing more pain and suffering. Chronic pain can be anatomically and phenomenologically dissected into three separable but interacting pathways, a lateral 'painfulness' pathway, a medial 'suffering' pathway and a descending pain inhibitory pathway. One may have pain(fullness) without suffering and suffering without pain(fullness). Pain sensation leads to suffering via a cognitive, emotional and autonomic processing, and is expressed as anger, fear, frustration, anxiety and depression. The medial pathway overlaps with the salience and stress networks, explaining that behavioural relevance or meaning determines the suffering associated with painfulness. Genetic and epigenetic influences trigger chronic neuroinflammatory changes which are involved in transitioning from acute to chronic pain. Based on the concept of the Bayesian brain, pain (and suffering) can be regarded as the consequence of an imbalance between the two ascending and the descending pain inhibitory pathways under control of the reward system. The therapeutic clinical implications of this simple pain model are obvious. After categorizing the working mechanisms of each of the available treatments (pain killers, psychopharmacology, psychotherapy, neuromodulation, psychosurgery, spinal cord stimulation) to 1 or more of the 3 pathways, a rational combination can be proposed of activating the descending pain inhibitory pathway in combination with inhibition of the medial and lateral pathway, so as to rebalance the pain (and suffering) pathways., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several studies have demonstrated the neural correlates of chronic tinnitus. However, we still do not understand what happens in the acute phase. Past studies have established Zwicker tone (ZT) illusions as a good human model for acute tinnitus. ZT illusions are perceived following the presentation of a notched noise stimulus, that is, broadband noise with a narrow band-stop filter (notch). In the current study, we compared the neural correlates of the reliable perception of a ZT illusion to that which is not. We observed changes in evoked and total theta power in wide-spread regions of the brain particularly in the temporal-parietal junction, pregenual anterior cingulate cortex/ventromedial prefrontal cortex (pgACC/vmPFC), parahippocampus during perception of the ZT illusion. Furthermore, we observe that increased theta power significantly predicts a gradual positive change in the intensity of the ZT illusion. Such changes may suggest a malfunction of the sensory gating system that enables habituation to redundant stimuli and suppresses hyperactivity. It could also suggest a successful retrieval of the memory of the missing frequencies, resulting in their conscious perception indicating the role of higher-order processing in the mechanism of action of ZT illusions. To establish a more concrete relationship between ZT illusion and chronic tinnitus, future longitudinal studies following up a much larger sample of participants who reliably perceive a ZT illusion to see if they develop tinnitus at a later stage is essential. This could inform us if the ZT illusion may be a precursor to chronic tinnitus., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Objective: Burst spinal cord stimulation (SCS) is a novel stimulation paradigm that seems to provide better pain relief compared to the classic tonic SCS with minimal paresthesia sensation. Based on source localized electroencephalography and clinical data, it has been proposed that burst stimulation as defined by Dirk De Ridder exerts this greater effect by not only modulating the lateral and the descending pain-inhibitory pathways (similar to tonic SCS) but also modulating the medial pain pathway, which encodes the affective, motivational aspects of pain., Material and Methods: The current study evaluates the supraspinal differences between burst and tonic stimulation with another functional imaging technique, namely fluorodeoxyglucose positron emission tomography (FGD-PET) scanning, in seven patients, who underwent both burst and tonic SCS, to confirm this notion of medial pain pathway modulation., Results: The results of the current FGD-PET study show that burst stimulation, in contrast to tonic stimulation, indeed modulates the dorsal anterior cingulate cortex (i.e., medial pain pathway) more than tonic stimulation., Discussion: Our data suggest an inherent difference in the central neural mechanisms during burst and tonic stimulation, which could potentially alter the patient's perception of pain., Conflict of Interest: Dr. Yearwood, Dr. De Ridder, Dr. Falowski, and Dr. Vanneste are the consultants of Abbott. Dr. Venkatesan is an employee of Abbott. Hye Bin Yoo and Dr. Wing Ting To have no conflicts of interest to report., (© 2019 International Neuromodulation Society.)

More than 150 years have passed since Helmholtz first described perception as a process of unconscious inference about the causes of sensations. His ideas have since inspired a wealth of literature investigating the mechanisms underlying these inferences. In recent years, much of this work has converged on the notion that the brain is a hierarchical generative model of its environment that predicts sensations and updates itself based on prediction errors. Here, we build a case for modeling tinnitus from this perspective, i.e. predictive coding. We emphasize two key claims: (1) acute tinnitus reflects an increase in sensory precision in related frequency channels and (2) chronic tinnitus reflects a change in the brain's default prediction. We further discuss specific neural biomarkers that would constitute evidence for or against these claims. Finally, we explore the implications of our model for clinical intervention strategies. We conclude that predictive coding offers the basis for a unifying theory of cognitive neuroscience, which we demonstrate with several examples linking tinnitus to other lines of brain research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation's ability to suppress pain in fibromyalgia patients., Materials and Methods: Seven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H 2 15 O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H 2 15 O PET scans were taken during both the "ON" (active stimulation) and "OFF" (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the "ON" and "OFF" conditions., Results: Relative to the "OFF" condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands., Conclusion: PET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment., Trial Registration: This study is registered with ClinicalTrials.gov , number NCT00917176 (June 10, 2009).

The posterior cingulate cortex (PCC) is involved in food craving in obese food addicted individuals. This randomised, double-blind, placebo-controlled parallel study explored the potential therapeutic effects of infraslow neurofeedback (ISF-NF) on food craving targeting the PCC in obese women with symptoms of food addiction. Participants received six sessions of either ISF-NF (n = 11) or placebo (n = 10) over a three-week period. There were no reported adverse effects. Electrophysiologically, there were significant increases in infraslow activity (p = 0.0002) and infraslow/beta nesting (p < 0.001) in the PCC in the ISF-NF group (mean r = 0.004 ± 0.002) compared to placebo (mean r = 0.02 ± 0.002) two days after the last intervention. Also, there was a significant decrease in different dimensions of state food craving compared to baseline and to placebo. Findings suggest that source localized IFS-NF results in electrophysiological changes and may be associated with reduced food craving. This trial is registered at www.anzctr.org.au , identifier, ACTRN12617000601336. This study was funded by the Otago Medical Research Grant: CT375.

As the COMT polymorphism is especially prominent in the prefrontal cortex and has been associated with auditory gating, we hypothesize that tinnitus patients with this polymorphism have altered activity in the ventromedial prefrontal/anterior cingulate areas that modulates the tinnitus percept. To test this, we recruited a total of 40 tinnitus subjects and 20 healthy controls for an EEG study. A comparison between tinnitus subjects and healthy controls and their frequency of being Val/Val genotype or Met carriers (including Val/Met and Met/Met genotype) shows no significant effect, suggesting that the distributions for the tinnitus and healthy groups are similar. Our results show that an interaction between the amount of hearing loss and the COMT Val 158 Met polymorphism can increase susceptibility to the clinical manifestation of tinnitus. We further demonstrate that the parahippocampus becomes involved in tinnitus in patients with hearing loss that are Met carriers. In these patients, the parahippocampus sends more tinnitus information to the pregenual anterior cingulate cortex and auditory cortex that is specifically related with increased loudness. At the same time, the pregenual anterior cingulate cortex, which normally functions as a gatekeeper, is not cancelling this auditory information, ultimately leading to increased tinnitus loudness., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Distress is a domain-general behavioral symptom whose neural correlates have been under investigation for a long time now. Although some studies suggest that distress is encoded by changes in alpha activity and functional connectivity between specific brain regions, no study that we know has delved into the whole brain temporal dynamics of the distress component. In the current study, we compare the changes in the mean and variance of functional connectivity and small-worldness parameter over 3 min of resting state EEG to analyze the fluctuation in transient stable states, and network structure. On comparing these measures between healthy controls and patients experiencing low and high levels of distress due to a continuous ringing in the ear (tinnitus), we observe an increase in fluctuation between transient stable states characterized by an increase in both variance of functional connectivity and the small-worldness parameter. This results in a possible increase in degrees of freedom leading to a paradoxical equilibrium of the network structure in highly distressed patients. This may also be interpreted as a maladaptive compensation to look for information in order to reduce the hyper-salience in highly distressed individuals. In addition, this is correlated with the amount of distress only in the high distress tinnitus group, suggesting a catastrophic breakdown of the brain's resilience. Distress not only accompanies tinnitus, but other disorders such as somatic disorders, fibromyalgia, post-traumatic stress disorder, etc. Since the current study focuses on a disorder-general distress symptom, the methods and results of the current study have a wide application in different neuropathologies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alcohol addiction is accompanied by aberrant neural activity. Previously, task-based fMRI and resting-state EEG studies have revealed that craving, a critical component of addiction, is linked to abnormal activity in cortical regions including the dorsal anterior cingulate cortex (dACC), nucleus accumbens (NAcc), posterior cingulate cortex (PCC) and pregenual anterior cingulate cortex (pgACC), etc. In this study, we combine these two imaging techniques to investigate a group of alcohol-addicted patients and provide convergent evidence for the neural correlates of craving not only in alcohol but substance abuse in general. We observe abnormal BOLD signal levels in the dACC, NAcc, pgACC, PCC, amygdala, and parahippocampus (PHC) in a cue-reactivity fMRI experiment. These findings are consistent with increased beta-band activity in the dACC and pgACC in resting-state EEG. We further observe desynchronization characterized by decreased functional connectivity in cue-based fMRI and hypersynchronization characterized by increased functional connectivity between these regions in the theta frequency band. The results of our study show a consistent pattern of alcohol craving elicited by external cues and internal desires. Given the advantage of superior spatial and temporal resolution, we hypothesize a "central craving network" that integrates the different aspects of alcohol addiction into a unified percept.

Recent studies have adopted the Bayesian brain model to explain the generation of tinnitus in subjects with auditory deafferentation. That is, as the human brain works in a Bayesian manner to reduce environmental uncertainty, missing auditory information due to hearing loss may cause auditory phantom percepts, i.e., tinnitus. This type of deafferentation-induced auditory phantom percept should be preceded by auditory experience because the fill-in phenomenon, namely tinnitus, is based upon auditory prediction and the resultant prediction error. For example, a recent animal study observed the absence of tinnitus in cats with congenital single-sided deafness (SSD; Eggermont and Kral, Hear Res 2016). However, no human studies have investigated the presence and characteristics of tinnitus in subjects with congenital SSD. Thus, the present study sought to reveal differences in the generation of tinnitus between subjects with congenital SSD and those with acquired SSD to evaluate the replicability of previous animal studies. This study enrolled 20 subjects with congenital SSD and 44 subjects with acquired SSD and examined the presence and characteristics of tinnitus in the groups. None of the 20 subjects with congenital SSD perceived tinnitus on the affected side, whereas 30 of 44 subjects with acquired SSD experienced tinnitus on the affected side. Additionally, there were significant positive correlations between tinnitus characteristics and the audiometric characteristics of the SSD. In accordance with the findings of the recent animal study, tinnitus was absent in subjects with congenital SSD, but relatively frequent in subjects with acquired SSD, which suggests that the development of tinnitus should be preceded by auditory experience. In other words, subjects with profound congenital peripheral deafferentation do not develop auditory phantom percepts because no auditory predictions are available from the Bayesian brain., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The exact mechanism underlying fibromyalgia is unknown, but increased facilitatory modulation and/or dysfunctional descending inhibitory pathway activity are posited as possible mechanisms contributing to sensitization of the central nervous system. The primary goal of this study is to identify a fibromyalgia neural circuit that can account for these abnormalities in central pain. The second goal is to gain a better understanding of the functional connectivity between the default and the executive attention network (salience network plus dorsal lateral prefrontal cortex) in fibromyalgia. We examine neural activity associated with fibromyalgia (N = 44) and compare these with healthy controls (N = 44) using resting state source localized EEG. Our data support an important role of the pregenual anterior cingulate cortex but also suggest that the degree of activation and the degree of integration between different brain areas is important. The inhibition of the connectivity between the dorsal lateral prefrontal cortex and the posterior cingulate cortex on the pain inhibitory pathway seems to be limited by decreased functional connectivity with the pregenual anterior cingulate cortex. Our data highlight the functional dynamics of brain regions integrated in brain networks in fibromyalgia patients.

It is suggested that the brain undergoes plastic changes in order to adapt to changing environmental needs. Sensory deprivation results in decreased input to the brain leading to adaptive or maladaptive changes. Although several theories hypothesize the mechanism of these adaptive and maladaptive changes, the course of action taken by the brain heavily depends on the age of incidence of damage. The growing body of literature on the topic proposes that maladaptive changes in the brain are instrumental in creating phantom percepts, defined as the perception of a sensory experience in the absence of a physical stimulus. The current article reviews the mechanisms of adaptive and maladaptive plasticity in the brain in congenital, early, and late-onset sensory deprivation in conjunction with the phantom percepts in the different sensory domains. We propose that the mechanisms of adaptive and maladaptive plasticity fall under a universal construct of updating hierarchical Bayesian prediction errors. This theory of the Bayesian brain hypothesizes that the brain constantly compares its internal milieu with changing environmental cues and either adjusts its predictions or discards the change, depending on the novelty or salience of the external stimulus. We propose that adaptive plasticity reflects both successful bottom-up compensation and top-down updating of the model while maladaptive plasticity reflects failure in one or both mechanisms, resulting in a constant prediction-error. Finally, we hypothesize that phantom percepts are generated by the brain as a solution to this prediction error and are thus a manifestation of unsuccessful adaptation to sensory deprivation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Occipital nerve field (OCF) stimulation with subcutaneously implanted electrodes is used to treat headaches, more generalized pain, and even failed back surgery syndrome via unknown mechanisms. Transcranial direct current stimulation (tDCS) can predict the efficacy of implanted electrodes. The purpose of this study is to unravel the neural mechanisms involved in global pain suppression, mediated by occipital nerve field stimulation, within the realm of fibromyalgia. Nineteen patients with fibromyalgia underwent a placebo-controlled OCF tDCS. Electroencephalograms were recorded at baseline after active and sham stimulation. In comparison with healthy controls, patients with fibromyalgia demonstrate increased dorsal anterior cingulate cortex, increased premotor/dorsolateral prefrontal cortex activity, and an imbalance between pain-detecting dorsal anterior cingulate cortex and pain-suppressing pregenual anterior cingulate cortex activity, which is normalized after active tDCS but not sham stimulation associated with increased pregenual anterior cingulate cortex activation. The imbalance improvement between the pregenual anterior cingulate cortex and the dorsal anterior cingulate cortex is related to clinical changes. An imbalance assumes these areas communicate and, indeed, abnormal functional connectivity between the dorsal anterior cingulate cortex and pregenual anterior cingulate cortex is noted to be caused by a dysfunctional effective connectivity from the pregenual anterior cingulate cortex to the dorsal anterior cingulate cortex, which improves and normalizes after real tDCS but not sham tDCS. In conclusion, OCF tDCS exerts its effect via activation of the descending pain inhibitory pathway and de-activation of the salience network, both of which are abnormal in fibromyalgia.

One of the most intriguing questions in neuroscience is to understand the mechanism of information transfer between different brain areas. Recently, network theory has gained traction and is at the forefront of providing a possible explanation to not only the mechanism of information transfer but also in the identification of different neuropathologies. The perception of a phantom ringing in the ear called tinnitus, similar to other neuropathologies, has been shown to be accompanied by aberrant functional connectivity between different brain areas. Although, there have been independent studies showing that specific groups of areas encode individual symptoms of tinnitus, there has not been one study to show that tinnitus is the unified percept of distinguishable subnetworks encoding different behavioral aspects. This study combines resting-state functional connectivity obtained from the source-localized electroencephalography of 311 tinnitus patients and 264 controls, and a k-fold cross-validation machine learning algorithm to develop a predictive model that verifies the presence of behaviorally specific, spatiotemporally overlapping subnetworks in tinnitus. This reorganization is found to be exclusive to tinnitus, even when compared to physiologically similar disorders such as chronic pain, with each behavioral symptom having a unique oscillatory signature. This frequency-specific transmission of information, called multiplexing, enables different types of information to be carried between two brain regions through the same anatomical connection. In addition to understanding the efficient compensation mechanism of the brain in the presence of multisymptom disorders, the exclusivity of the prediction model presents an encouraging possibility for an objective neural marker for tinnitus.

Homeostasis is the basis of modern medicine and allostasis, a further elaboration of homeostasis, has been defined as stability through change, which was later modified to predictive reference resetting. It has been suggested that pleasure is related to salience (behavioral relevance), and withdrawal has been linked to allostasis in addictive types. The question arises how the clinical and neural signatures of pleasure, salience, allostasis and withdrawal relate, both in a non-addicted and addicted state. Resting state EEGs were performed in 66 people, involving a food-addicted obese group, a non-food addicted obese group and a lean control group. Correlation analyses were performed on behavioral data, and correlation, comparative and conjunction analyses were performed to extract electrophysiological relationships between pleasure, salience, allostasis and withdrawal. Pleasure/liking seems to be the phenomenological expression that enough salient stimuli are obtained, and withdrawal can be seen as a motivational incentive because due to allostatic reference resetting, more stimuli are required. In addition, in contrast to non-addiction, a pathological, non-adaptive salience attached to food results in withdrawal mediated through persistent allostatic reference resetting.

Aging and sensorineural hearing loss are known to be involved in the development of chronic tinnitus. This study explores the structural changes of gray matter using surface base methods and focuses more specifically on changes in cortical thickness in 127 tinnitus patients. The linear relationships between cortical thickness and behavioral measures including aging, tinnitus loudness, tinnitus duration, tinnitus distress, and hearing loss were analyzed. Three dimensional T1-weighted MR images were acquired and cortical gray matter volumes were segmented using FreeSurfer on Talairach space. The results showed that cortical thickness and volume are negatively correlated to age in widespread regions of frontal cortices, and positively to bilateral entorhinal cortex and left rostral anterior cingulate cortex. The cortical thickness changes related to hearing loss overlap with those related to normal aging. The gray matter volumes of bilateral amygdalae, hippocampi, nuclei accumbens, and thalami are all significantly negatively correlated to age. Tinnitus-related distress level and subjective loudness were negatively correlated only to the thalamic volume. The results suggest that the primary factor of long-term structural changes in chronic tinnitus patients is age and age related hearing loss, rather than hearing loss per se. Tinnitus related factors such as subjective tinnitus loudness, tinnitus duration, and the level of chronic tinnitus related distress were not correlated to important morphometric changes in this study.

Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic symptoms of vertigo episodes. This suggests that these patients have a neural signature or trait that makes them prone to developing chronic balance problems.

Brain networks are small-world networks typically characterized by the presence of hubs, i.e. nodes that have significantly greater number of links in comparison to other nodes in the network. These hubs act as short cuts in the network and promote long-distance connectivity. Long-distance connections increase the efficiency of information transfer but also increase the cost of the network. Brain disorders are associated with an altered brain connectome which reflects either as a complete change in the network topology, as in, the replacement of hubs or as an alteration in the connectivity between the hubs while retaining network structure. The current study compares the network topology of binary and weighted networks in tinnitus patients and healthy controls by studying the hubs of the two networks in different oscillatory bands. The EEG of 311 tinnitus patients and 256 control subjects are recorded, pre-processed and source-localized using sLORETA. The hubs of the different binary and weighted networks are identified using different measures of network centrality. The results suggest that the tinnitus and control networks are distinct in all the frequency bands but substantially overlap in the gamma frequency band. The differences in network topology in the tinnitus and control groups in the delta, theta and the higher beta bands are driven by a change in hubs as well as network connectivity; in the alpha band by changes in hubs alone and in the gamma band by changes in network connectivity. Thus the brain seems to employ different frequency band-dependent adaptive mechanisms trying to compensate for auditory deafferentation.

Tinnitus is a phantom sound commonly thought of to be produced by the brain related to auditory deafferentation. The current study applies concepts from graph theory to investigate the differences in lagged phase functional connectivity using the average resting state EEG of 311 tinnitus patients and 256 healthy controls. The primary finding of the study was a significant increase in connectivity in beta and gamma oscillations and a significant reduction in connectivity in the lower frequencies for the tinnitus group. There also seems to be parallel processing of long-distance information between delta, theta, alpha1 and gamma frequency bands that is significantly stronger in the tinnitus group. While the network reorganizes into a more regular topology in the low frequency carrier oscillations, development of a more random topology is witnessed in the high frequency oscillations. In summary, tinnitus can be regarded as a maladaptive 'disconnection' syndrome, which tries to both stabilize into a regular topology and broadcast the presence of a deafferentation-based bottom-up prediction error as a result of a top-down prediction.

Objective: Spinal cord stimulation is commonly used to treat medically intractable pain. Different stimulation designs are used to obtain pain suppression such as tonic stimulation, high frequency stimulation, and burst stimulation. Preliminary analysis of the same data used in this study demonstrated that burst stimulation likely modulates the medial pain pathways in contrast to tonic stimulation. The question arises what different and common supraspinal mechanisms burst and tonic stimulation use., Materials and Methods: The clinical and electroencephalography (EEG) data of five patients undergoing tonic, burst, and sham stimulation were analyzed to look at the commonalities and differences between burst and tonic stimulation. A source-localized (sLORETA) EEG substraction and conjunction analysis is performed in each condition for both activity and functional connectivity. A ratio between the dorsal anterior cingulate cortex (dACC) and pregenual anterior cingulate cortex/ventromedial prefrontal cortex (pgACC/vmPFC) is calculated to reflect a balance between pain supporting and pain suppressing systems., Results: Differences are noted in the dACC, dorsolateral prefrontal cortex, the primary somatosensory cortex, and the posterior cingulate cortex (PCC). Burst and tonic stimulation share activation in the pgACC, inferior parietal area, which encompasses the inferior secondary somatosensory cortex, PCC, and the parahippocampus. Burst suppression normalizes the pain supporting/pain suppressing balance in contrast to tonic stimulation., Discussion and Conclusion: These data suggest that burst and tonic stimulation both modulate the descending pain inhibitory system (via pgACC), as well as a self-referential contextual (via PCC) aversive memory system (via parahippocampus). However, burst normalizes the pain supporting/suppressing balance in contrast to tonic mode by a greater effect on the dACC., (© 2015 International Neuromodulation Society.)

Introduction: A fundamental question in phantom perception is determining whether the brain creates a network that represents the sound intensity of the auditory phantom as measured by tinnitus matching (in dB), or whether the phantom perception is actually only a representation of the subjectively perceived loudness., Methods: In tinnitus patients, tinnitus loudness was tested in two ways, by a numeric rating scale for subjectively perceived loudness and a more objective tinnitus-matching test, albeit it is still a subjective measure., Results: Passively matched tinnitus does not correlate with subjective numeric rating scale, and has no electrophysiological correlates. Subjective loudness, in a whole-brain analysis, is correlated with activity in the left anterior insula (alpha), the rostral/dorsal anterior cingulate cortex (beta), and the left parahippocampus (gamma). A ROI analysis finds correlations with the auditory cortex (high beta and gamma) as well. The theta band links gamma band activity in the auditory cortex and parahippocampus via theta-gamma nesting., Conclusions: Apparently the brain generates a network that represents subjectively perceived tinnitus loudness only, which is context dependent. The subjective loudness network consists of the anterior cingulate/insula, the parahippocampus, and the auditory cortex. The gamma band activity in the parahippocampus and the auditory cortex is functionally linked via theta-gamma nested lagged phase synchronization.

Previous positron emission tomography (PET) studies have shown that various cortical areas are activated to process speech signal in cochlear implant (CI) users. Nonetheless, differences in task dimension among studies and low statistical power preclude from understanding sound processing mechanism in CI users. Hence, we performed activation likelihood estimation meta-analysis of PET studies in CI users and normal hearing (NH) controls to compare the two groups. Eight studies (58 CI subjects/92 peak coordinates; 45 NH subjects/40 peak coordinates) were included and analyzed, retrieving areas significantly activated by lexical and nonlexical stimuli. For lexical and nonlexical stimuli, both groups showed activations in the components of the dual-stream model such as bilateral superior temporal gyrus/sulcus, middle temporal gyrus, left posterior inferior frontal gyrus, and left insula. However, CI users displayed additional unique activation patterns by lexical and nonlexical stimuli. That is, for the lexical stimuli, significant activations were observed in areas comprising salience network (SN), also known as the intrinsic alertness network, such as the left dorsal anterior cingulate cortex (dACC), left insula, and right supplementary motor area in the CI user group. Also, for the nonlexical stimuli, CI users activated areas comprising SN such as the right insula and left dACC. Previous episodic observations on lexical stimuli processing using the dual auditory stream in CI users were reconfirmed in this study. However, this study also suggests that dual-stream auditory processing in CI users may need supports from the SN. In other words, CI users need to pay extra attention to cope with degraded auditory signal provided by the implant., (© 2015 Wiley Periodicals, Inc.)

The Prodigy is a new type of internal pulse generator that controls the delivery of electrical stimuli to nervous tissue. It is capable of delivering burst stimulation, which is a novel waveform that consists of closely spaced high-frequency electrical impulses delivered in packets riding on a plateau, and followed by a quiescent period. Its inception was based on mimicking burst firing in the nervous system and usually delivered by unmyelinated fibers that uniformly have a motivational affective homeostatic function. It thereby targets a multimodal salience network, even though the stimuli are delivered at the level of the spinal cord. As such, it is specifically capable of influencing the affective/attentional components of pain. Burst stimulation was initially safely applied off-label to the auditory cortex for tinnitus, and later also to the spinal cord, the somatosensory cortex for neuropathic pain, subcutaneously for failed back surgery syndrome, and cingulate cortex for addiction and tinnitus.

It has been suggested that an auditory phantom percept is the result of multiple, parallel but overlapping networks. One of those networks encodes tinnitus loudness and is electrophysiologically separable from a nonspecific distress network. The present study investigates how these networks anatomically overlap, what networks are involved, and how and when these networks interact. Electroencephalography data of 317 tinnitus patients and 256 healthy subjects were analyzed, using independent component analysis. Results demonstrate that tinnitus is characterized by at least 2 major brain networks, each consisting of multiple independent components. One network reflects tinnitus distress, while another network reflects the loudness of the tinnitus. The component coherence analysis shows that the independent components that make up the distress and loudness networks communicate within their respective network at several discrete frequencies in parallel. The distress and loudness networks do not intercommunicate for patients without distress, but do when patients are distressed by their tinnitus. The obtained data demonstrate that the components that build up these 2 separable networks communicate at discrete frequencies within the network, and only between the distress and loudness networks in those patients in whom the symptoms are also clinically linked., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Phantom perceptions arise almost universally in people who sustain sensory deafferentation, and in multiple sensory domains. The question arises 'why' the brain creates these false percepts in the absence of an external stimulus? The model proposed answers this question by stating that our brain works in a Bayesian way, and that its main function is to reduce environmental uncertainty, based on the free-energy principle, which has been proposed as a universal principle governing adaptive brain function and structure. The Bayesian brain can be conceptualized as a probability machine that constantly makes predictions about the world and then updates them based on what it receives from the senses. The free-energy principle states that the brain must minimize its Shannonian free-energy, i.e. must reduce by the process of perception its uncertainty (its prediction errors) about its environment. As completely predictable stimuli do not reduce uncertainty, they are not worthwhile of conscious processing. Unpredictable things on the other hand are not to be ignored, because it is crucial to experience them to update our understanding of the environment. Deafferentation leads to topographically restricted prediction errors based on temporal or spatial incongruity. This leads to an increase in topographically restricted uncertainty, which should be adaptively addressed by plastic repair mechanisms in the respective sensory cortex or via (para)hippocampal involvement. Neuroanatomically, filling in as a compensation for missing information also activates the anterior cingulate and insula, areas also involved in salience, stress and essential for stimulus detection. Associated with sensory cortex hyperactivity and decreased inhibition or map plasticity this will result in the perception of the false information created by the deafferented sensory areas, as a way to reduce increased topographically restricted uncertainty associated with the deafferentation. In conclusion, the Bayesian updating of knowledge via active sensory exploration of the environment, driven by the Shannonian free-energy principle, provides an explanation for the generation of phantom percepts, as a way to reduce uncertainty, to make sense of the world., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

An external auditory stimulus induces an auditory sensation which may lead to a conscious auditory perception. Although the sensory aspect is well known, it is still a question how an auditory stimulus results in an individual's conscious percept. To unravel the uncertainties concerning the neural correlates of a conscious auditory percept, event-related potentials may serve as a useful tool. In the current review we mainly wanted to shed light on the perceptual aspects of auditory processing and therefore we mainly focused on the auditory late-latency responses. Moreover, there is increasing evidence that perception is an active process in which the brain searches for the information it expects to be present, suggesting that auditory perception requires the presence of both bottom-up, i.e. sensory and top-down, i.e. prediction-driven processing. Therefore, the auditory evoked potentials will be interpreted in the context of the Bayesian brain model, in which the brain predicts which information it expects and when this will happen. The internal representation of the auditory environment will be verified by sensation samples of the environment (P50, N100). When this incoming information violates the expectation, it will induce the emission of a prediction error signal (Mismatch Negativity), activating higher-order neural networks and inducing the update of prior internal representations of the environment (P300)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

There are pathophysiological, clinical, and treatment analogies between phantom limb pain and phantom sound (i.e., tinnitus). Phantom limb pain commonly is absent in dreams, and the question arises whether this is also the case for tinnitus. A questionnaire was given to 78 consecutive tinnitus patients seen at a specialized tinnitus clinic. Seventy-six patients remembered their dreams and of these 74 claim not to perceive tinnitus during their dreams (97%). This can be most easily explained by a predictive Bayesian brain model. That is, during the awake state the brain constantly makes predictions about the environment. Tinnitus is hypothesized to be the result of a prediction error due to deafferentation, and missing input is filled in by the brain. The heuristic explanation then is that in the dream state there is no interaction with the environment and therefore no updating of the prediction error, resulting in the absence of tinnitus.

Objective: The aim of the current study is to investigate structural changes on brain MRI using voxel based morphometry (VBM) related to an eight-week mindfulness based intervention (MBI) in Parkinson's Disease (PD)., Methods: A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Fourteen patients participated in a structured eight-week program of MBI. Thirteen patients received usual care (UC) alone. MRI data sets of the brain were obtained at baseline and after eight weeks follow-up. VBM analysis was performed using DARTEL from the SPM8 software. The resulting difference maps were statistically compared to examine gray matter density (GMD) differences. Results were reported at p<0.001, uncorrected for multiple comparisons., Results: Increased GMD was found in the MBI compared to the UC group in the region of interest (ROI) analysis in the right amygdala, and bilaterally in the hippocampus. Whole brain analysis showed increased GMD in the left and right caudate nucleus, the left occipital lobe at the lingual gyrus and cuneus, the left thalamus, and bilaterally in the temporo-parietal junction. In contrast, GMD differences were found in the UC group in the left anterior lobe and dentate nucleus of the cerebellum., Conclusions: To the best of our knowledge this is the first quantitative analysis of neurobiological effects of MBI in PD. Increased GMD was found in the MBI group in the neural networks that have been postulated to play an important role in PD. These areas have also been implicated in the functional networks mediating the benefits of meditation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Recent findings regarding different characteristics according to the age of tinnitus onset prompted us to conduct a study on the differences in tinnitus-related neural correlates between late-onset tinnitus (LOT; mean onset age, 60.4 years) and early-onset tinnitus (EOT; mean onset age, 29.7 years) groups. Hence, we collected quantitative electroencephalography findings of 29 participants with LOT and 30 with EOT, and from 59 controls. We then compared the results between the 2 groups and between the tinnitus groups and age- and sex-matched control groups using resting state electroencephalography source-localized activity and connectivity analyses. Compared with the EOT and older control groups, the LOT group demonstrated increased localized activity and functional connectivity in components of previously described tinnitus distress networks, and the default mode and intrinsic alertness networks, such as the prefrontal cortices, dorsal anterior cingulate cortex, and insula. The current findings of intrinsic differences in tinnitus-related neural activity between the LOT and EOT groups might be applicable for planning individualized treatment modalities according to age of onset. Moreover, differences with regard to the age of tinnitus onset might be a milestone for future studies on onset-related differences in other similar pathologies, such as pain or depression., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Based on functional imaging of beauty appreciation in art and of beautiful faces, a heuristic model is presented that proposes that beauty appreciation in art is based on a sexual selection mechanism that led to the preference of beautiful faces. Beauty is linked to sexual selection as a sign of fitness. Beautiful traits, like the peacock's tail, are costly and thereby signal superior genetic quality. Mechanistically, beauty is a construct of the brain that links positive feedback of the reward system with hedonic experience, namely pleasure, which itself might be encoded in the orbito-frontal cortex. The context determines whether a stimulus should lead to further approach or withdrawal in order to maintain a hedonic homeostasis. The fact that aesthetic appreciation of art uses the same circuitry as the aesthetic appreciation of faces suggests that there is no special art circuitry in the brain, but that available networks are used for aesthetic appreciation of art.

Notwithstanding successful reduction of tinnitus after cochlear implantation (CI) in patients with single-sided deafness (SSD) in recent studies, neither the exact mechanism of suppression nor the predictors of the amount of improvement are fully understood yet. We collected quantitative electroencephalography (qEEG) data from nine SSD patients who underwent CI for tinnitus management. By correlating the degree of improvement in tinnitus intensity and tinnitus-related distress with preoperative source-localized qEEG findings and comparing qEEG findings of patients with marked improvement after CI with those with relatively slight improvement with regard to source-localized activity complimented by connectivity analysis, we attempted to find preoperative predictors of tinnitus improvement. Our results showed increased activities of the auditory cortex (AC), posterior cingulate cortex (PCC) and increased functional connectivity between the AC and PCC as negative prognostic factors for the reduction of tinnitus intensity after CI in patients with SSD. Also, relatively increased activity of the right dorsolateral prefrontal cortex and decreased connectivity between distress-related areas such as the orbitofrontal cortex/parahippocampus and sensory-perception areas such as the AC/precuneus were found in patients with relatively slight improvement in tinnitus-related distress as compared with those with marked improvement. The current study suggests that preoperative cortical oscillations can be applied to predict post-CI tinnitus reduction in patients with SSD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Tinnitus is defined as an intrinsic sound perception that cannot be attributed to an external sound source. Distress in tinnitus patients is related to increased beta activity in the dorsal part of the anterior cingulate and the amount of distress correlates with network activity consisting of the amygdala-anterior cingulate cortex-insula-parahippocampus. Previous research also revealed that distress is associated to a higher sympathetic (OS) tone in tinnitus patients and tinnitus suppression to increased parasympathetic (PS) tone., Methodology: The aim of the present study is to investigate the relationship between tinnitus distress and the autonomic nervous system and find out which cortical areas are involved in the autonomic nervous system influences in tinnitus distress by the use of source localized resting state electroencephalogram (EEG) recordings and electrocardiogram (ECG). Twenty-one tinnitus patients were included in this study., Conclusions: The results indicate that the dorsal and subgenual anterior cingulate, as well as the left and right insula are important in the central control of heart rate variability in tinnitus patients. Whereas the sympathovagal balance is controlled by the subgenual and pregenual anterior cingulate cortex, the right insula controls sympathetic activity and the left insula the parasympathetic activity. The perceived distress in tinnitus patients seems to be sympathetically mediated.

Unlabelled: In tinnitus, PET and other functional imaging modalities have shown functional changes not only in the auditory cortex but also in nonauditory regions such as the limbic, frontal, and parietal areas. Nonetheless, disparities in task dimension among studies, low statistical power due to small sample size, and the intrinsic uncertainty of a modality that measures activity indirectly limit the comprehensive understanding of the results from PET studies. These difficulties prompted us to undertake a metaanalysis of PET studies on tinnitus using a coordinate-based technique (activation-likelihood estimation) to retrieve the most consistent activation areas across different task dimensions and to compare the results with those from other imaging modalities., Methods: We performed 2 activation-likelihood estimation metaanalyses on data from 10 studies with 56 foci in which we examined the contrast between tinnitus individuals and controls and the difference in activation between sound stimuli and resting state in tinnitus individuals., Results: The studies show that the most consistently activated regions in tinnitus subjects, compared with controls, were the left primary and bilateral secondary auditory cortices, left middle and bilateral inferior temporal gyri, left parahippocampal area, left geniculum body, left precuneus, right anterior cingulate cortex, right claustrum, right middle and inferior frontal gyri, and right angular gyrus. The relatively activated area under sound stimuli, compared with resting state, in tinnitus subjects was the secondary auditory cortex. Our study reconfirms the findings of previous quantitative electroencephalography or magnetoencephalography studies because most of the 14 brain areas with significant activation found in our metaanalysis replicate these earlier data. Our results suggest that the areas described in the tinnitus network are solidly replicable regardless of the applied functional imaging technique., Conclusion: This study proves that PET is a useful modality for tinnitus research and solidifies human tinnitus research itself by confirming previously described brain areas involved in the generation and maintenance of tinnitus.

Tinnitus is the continuous perception of an internal auditory stimulus. This permanent sound often affects a person's emotional state inducing distress and depressive feelings changes in 6-25% of the affected population. Distress and depression are two distinct emotional states. Whereas distress describes a transient aversive state, interfering with a person's ability to adequately adapt to stressors, depressive feelings should rather be considered as a more constant emotional state. Based on previous observations in chronic pain, posttraumatic stress disorder and depression, we assume that both states are related to separate neural circuits. We used the Dutch version of the Tinnitus Questionnaire to assess the global index of distress together with the Beck Depression Inventory to evaluate the depressive symptoms accompanying tinnitus. Furthermore sLORETA analysis was performed to correlate current density distribution with distress and depression scores, revealing a lateralization effect of depression versus distress. Distress is mainly correlated with alpha 2, beta 1 and beta 2 activity of the right frontopolar cortex and orbitofrontal cortex in combination with beta 2 activation of the anterior cingulate cortex. In contrast, the more permanent depressive alterations induced by tinnitus are associated with activity of alpha 2 activity in the left frontopolar and orbitofrontal cortex. These specific neural circuits are embedded in a greater neural network, with the parahippocampal region functioning as a crucial linkage between both tinnitus related pathways.

Tinnitus is an auditory phantom percept with a tone, hissing, or buzzing sound in the absence of any objective physical sound source. Persons with tinnitus engage in a number of health behaviors to manage tinnitus. This can go from prescription medication, masking devices, behavioral training techniques to cortical implants. Potentially less adaptive methods of coping with tinnitus, such as the use of alcohol, are poorly studied. The purpose of this study was to further explore the neurobiological mechanism of tinnitus improvement by the use of alcohol. We observed differences in the alpha, beta and gamma frequency band when comparing resting-state EEG before and after alcohol intake. More precisely increased synchronized alpha1 activity was found in the posterior cingulate cortex and decreased synchronized alpha2 activity was demonstrated in orbitofrontal cortex, ventrolateral prefrontal cortex and subcallosal anterior cingulate cortex after alcohol intake. Increased synchronized activity was found in a region between the pregenual and dorsal anterior cingulate cortex and the left insula for beta and decreased activity in the precuneus after alcohol intake. For the gamma frequency band decreased synchronized activity in the precuneus and the posterior cingulate cortex was demonstrated after alcohol intake. Region of interest analyses in auditory cortices and parahippocampal area revealed however no differences in the different frequency bands before and after alcohol consumption.

Bifrontal transcranial direct current stimulation (tDCS), with the anodal electrode overlying the right and the cathodal electrode overlying the left dorsolateral prefrontal cortex, has been shown to suppress tinnitus significantly in 30% of patients. The source localized resting-state electrical activity is recorded before and after bifrontal tDCS in patients who respond to tDCS to unravel the mechanism by which tDCS suppresses tinnitus. The present electroencephalography study (N = 12) provides support for the ability of bifrontal tDCS to suppress tinnitus intensity and tinnitus-related distress by modulation of the pregenual anterior cingulate cortex, parahippocampal area and right primary auditory cortex in resting-state spontaneous brain activity. These findings provide direct support for tDCS having an impact not only directly on the underlying dorsolateral prefrontal cortex but also indirectly on functionally connected brain areas relevant for tinnitus distress and tinnitus intensity, respectively., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Background: Tinnitus, the perception of a sound without an external sound source, can lead to variable amounts of distress., Methodology: In a group of tinnitus patients with variable amounts of tinnitus related distress, as measured by the Tinnitus Questionnaire (TQ), an electroencephalography (EEG) is performed, evaluating the patients' resting state electrical brain activity. This resting state electrical activity is compared with a control group and between patients with low (N = 30) and high distress (N = 25). The groups are homogeneous for tinnitus type, tinnitus duration or tinnitus laterality. A group blind source separation (BSS) analysis is performed using a large normative sample (N = 84), generating seven normative components to which high and low tinnitus patients are compared. A correlation analysis of the obtained normative components' relative power and distress is performed. Furthermore, the functional connectivity as reflected by lagged phase synchronization is analyzed between the brain areas defined by the components. Finally, a group BSS analysis on the Tinnitus group as a whole is performed., Conclusions: Tinnitus can be characterized by at least four BSS components, two of which are posterior cingulate based, one based on the subgenual anterior cingulate and one based on the parahippocampus. Only the subgenual component correlates with distress. When performed on a normative sample, group BSS reveals that distress is characterized by two anterior cingulate based components. Spectral analysis of these components demonstrates that distress in tinnitus is related to alpha and beta changes in a network consisting of the subgenual anterior cingulate cortex extending to the pregenual and dorsal anterior cingulate cortex as well as the ventromedial prefrontal cortex/orbitofrontal cortex, insula, and parahippocampus. This network overlaps partially with brain areas implicated in distress in patients suffering from pain, functional somatic syndromes and posttraumatic stress disorder, and might therefore represent a specific distress network.

Background: Tinnitus is an auditory sensation characterized by the perception of sound or noise in the absence of any external sound source. Based on neurobiological research, it is generally accepted that most forms of tinnitus are attributable to maladaptive plasticity due to damage to auditory system. Changes have been observed in auditory structures such as the inferior colliculus, the thalamus and the auditory cortex as well as in non-auditory brain areas. However, the observed changes show great variability, hence lacking a conclusive picture. One of the reasons might be the selection of inhomogeneous groups in data analysis., Methodology: The aim of the present study was to delineate the differences between the neural networks involved in narrow band noise and pure tone tinnitus conducting LORETA based source analysis of resting state EEG., Conclusions: Results demonstrated that narrow band noise tinnitus patients differ from pure tone tinnitus patients in the lateral frontopolar (BA 10), PCC and the parahippocampal area for delta, beta and gamma frequency bands, respectively. The parahippocampal-PCC current density differences might be load dependent, as noise-like tinnitus constitutes multiple frequencies in contrast to pure tone tinnitus. The lateral frontopolar differences might be related to pitch specific memory retrieval.

Tinnitus is an auditory phantom percept with a tone, hissing, or buzzing sound in the absence of any objective physical sound source. About 6% to 25% of the affected people report interference with their lives as tinnitus causes a considerable amount of distress. However, the underlying neurophysiological mechanism for the development of tinnitus-related distress remains not well understood. Hence we focus on the cortical and subcortical source differences in resting-state EEG between tinnitus patients with different grades of distress using continuous scalp EEG recordings and Low Resolution Electromagnetic Tomography (LORETA). Results show more synchronized alpha activity in the tinnitus patients with a serious amount of distress with peaks localized to various emotion-related areas. These areas include subcallosal anterior cingulate cortex, the insula, parahippocampal area and amygdala. In addition, less alpha synchronized activity was found in the posterior cingulate cortex, precuneus and DLPFC. A comparison between the tinnitus group with distress and the Nova Tech EEG (NTE) normative database demonstrated increased synchronized alpha and beta activity and less synchronized delta and theta activity in the dorsal anterior cingulate cortex in tinnitus patients with distress. It is interesting that the areas found show some overlap with the emotional component of the pain matrix and the distress related areas in asthmatic dyspnea. Unpleasantness of pain activates the anterior cingulate and prefrontal cortices, amygdala, and insula. As such, it might be that distress is related to alpha and beta activity in the dorsal anterior cingulate cortex, the amount of distress perceived to an alpha network consisting of the amygdala-anterior cingulate cortex-insula-parahippocampal area., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Phonological working memory is key to vocabulary acquisition, spoken word recognition, real-time language processing, and reading. Transcranial direct current stimulation, when coupled with behavioral training, has been shown to facilitate speech motor output processes, a key component of nonword repetition, the primary task used to assess phonological working memory. In this study, we examined the efficacy of combining overt nonword repetition training with anodal high-definition transcranial direct current stimulation (HD tDCS) to the presupplementary motor area (preSMA) to enhance nonword repetition. Objective: This study investigated whether 20 min of active or sham anodal HD tDCS targeting preSMA concurrently with a nonword repetition task differentially impacted nonword repetition ability. Method: Twenty-eight neurotypical college-age adults (18-25 years; 19 females, eight males, one nonbinary) completed a 20-min nonword repetition training task where they received either active or sham 1-mA anodal HD tDCS to the preSMA while overtly repeating a list of four-, five-, six-, and seven-syllable English-like nonwords presented in a random order. Whole nonword accuracy and error patterns (phoneme and syllable) were measured prior to and following training. Results: Following training, both groups showed a decrease in nonword repetition accuracy. The drop in performance was significantly greater for the active stimulation group compared to the sham stimulation group at the four-syllable nonword length. Discussion: The findings suggest that targeting the speech motor component of nonword repetition through overt training and HD tDCS to the preSMA does not enhance phonological working memory ability.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

This article aims to reevaluate our approach to female vulnerability to Alzheimer's disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOEɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that hyperacusis, an abnormal hypersensitivity to ordinary environmental sounds, may be characterized by certain resting-state cortical oscillatory patterns, even with no sound stimulus. However, previous studies are limited in that most studied subjects with other comorbidities that may have affected cortical activity. In this regard, to assess ongoing cortical oscillatory activity in idiopathic hyperacusis patients with no comorbidities, we compared differences in resting-state cortical oscillatory patterns between five idiopathic hyperacusis subjects and five normal controls. The hyperacusis group demonstrated significantly higher electrical activity in the right auditory-related cortex for the gamma frequency band and left superior parietal lobule (SPL) for the delta frequency band versus the control group. The hyperacusis group also showed significantly decreased functional connectivity between the left auditory cortex (AC) and left orbitofrontal cortex (OFC), between the left AC and left subgenual anterior cingulate cortex (sgACC) for the gamma band, and between the right insula and bilateral dorsal anterior cingulate cortex (dACC) and between the left AC and left sgACC for the theta band versus the control group. The higher electrical activity in the SPL may indicate a readiness of “circuit-breaker” activity to shift attention to forthcoming sound stimuli. Also, because of the disrupted salience network, consisting of the dACC and insula, abnormally increased salience to all sound stimuli may emerge, as a consequence of decreased top-down control of the AC by the dACC and dysfunctional emotional weight attached to auditory stimuli by the OFC. Taken together, abnormally enhanced attention and salience to forthcoming sound stimuli may render hyperacusis subjects hyperresponsive to non-noxious auditory stimuli. [ABSTRACT FROM AUTHOR]

Occipital nerve field (OCF) stimulation with subcutaneously implanted electrodes is used to treat headaches, more generalized pain, and even failed back surgery syndrome via unknown mechanisms. Transcranial direct current stimulation (tDCS) can predict the efficacy of implanted electrodes. The purpose of this study is to unravel the neural mechanisms involved in global pain suppression, mediated by occipital nerve field stimulation, within the realm of fibromyalgia. Nineteen patients with fibromyalgia underwent a placebo-controlled OCF tDCS. Electroencephalograms were recorded at baseline after active and sham stimulation. In comparison with healthy controls, patients with fibromyalgia demonstrate increased dorsal anterior cingulate cortex, increased premotor/dorsolateral prefrontal cortex activity, and an imbalance between pain-detecting dorsal anterior cingulate cortex and pain-suppressing pregenual anterior cingulate cortex activity, which is normalized after active tDCS but not sham stimulation associated with increased pregenual anterior cingulate cortex activation. The imbalance improvement between the pregenual anterior cingulate cortex and the dorsal anterior cingulate cortex is related to clinical changes. An imbalance assumes these areas communicate and, indeed, abnormal functional connectivity between the dorsal anterior cingulate cortex and pregenual anterior cingulate cortex is noted to be caused by a dysfunctional effective connectivity from the pregenual anterior cingulate cortex to the dorsal anterior cingulate cortex, which improves and normalizes after real tDCS but not sham tDCS. In conclusion, OCF tDCS exerts its effect via activation of the descending pain inhibitory pathway and de-activation of the salience network, both of which are abnormal in fibromyalgia. [ABSTRACT FROM AUTHOR]

Recently burst stimulation and 10 kHz stimulation have been developed as novel stimulation designs. Both appear to be superior to classical tonic stimulation in the amount of responders and the amount of pain suppression and have as an extra advantage that they are paresthesia-free. This evolution is very important as it shifts the focus of research from better targeting by developing new lead configurations to better communication with the nervous system. It can be envisioned that this is only the start of a new trend in spinal cord, brain, and peripheral nerve stimulation and that more new stimulation designs will be developed in the near future such as pseudorandom burst stimulation, pleasure stimulation, noise stimulation and reconditioning stimulation. This evolution mandates a new approach in the development of internal pulse generators, and the most obvious approach is to develop an upgradable stimulator, on which new stimulation designs can be downloaded, analogous to the apps people download on their smartphones. This will create a shift from hardware driven products to software driven stimulators. [ABSTRACT FROM PUBLISHER]

Tinnitus is the perception of a sound in the absence of an external sound source. It is characterized by sensory components such as the perceived loudness, the lateralization, the tinnitus type (pure tone, noise-like) and associated emotional components, such as distress and mood changes. Source localization of quantitative electroencephalography (qEEG) data demonstrate the involvement of auditory brain areas as well as several non-auditory brain areas such as the anterior cingulate cortex (dorsal and subgenual), auditory cortex (primary and secondary), dorsal lateral prefrontal cortex, insula, supplementary motor area, orbitofrontal cortex (including the inferior frontal gyrus), parahippocampus, posterior cingulate cortex and the precuneus, in different aspects of tinnitus. Explaining these non-auditory brain areas as constituents of separable subnetworks, each reflecting a specific aspect of the tinnitus percept increases the explanatory power of the non-auditory brain areas involvement in tinnitus. Thus, the unified percept of tinnitus can be considered an emergent property of multiple parallel dynamically changing and partially overlapping subnetworks, each with a specific spontaneous oscillatory pattern and functional connectivity signature. [ABSTRACT FROM AUTHOR]

Background: Tinnitus refers to auditory phantom sensation. It is estimated that for 2% of the population this auditory phantom percept severely affects the quality of life, due to tinnitus related distress. Although the overall distress levels do not differ between sexes in tinnitus, females are more influenced by distress than males. Typically, pain, sleep, and depression are perceived as significantly more severe by female tinnitus patients. Studies on gender differences in emotional regulation indicate that females with high depressive symptoms show greater attention to emotion, and use less anti-rumination emotional repair strategies than males. Methodology: The objective of this study was to verify whether the activity and connectivity of the resting brain is different for male and female tinnitus patients using resting-state EEG. Conclusions: Females had a higher mean score than male tinnitus patients on the BDI-II. Female tinnitus patients differ from male tinnitus patients in the orbitofrontal cortex (OFC) extending to the frontopolar cortex in beta1 and beta2. The OFC is important for emotional processing of sounds. Increased functional alpha connectivity is found between the OFC, insula, subgenual anterior cingulate (sgACC), parahippocampal (PHC) areas and the auditory cortex in females. Our data suggest increased functional connectivity that binds tinnitus-related auditory cortex activity to auditory emotion-related areas via the PHC-sgACC connections resulting in a more depressive state even though the tinnitus intensity and tinnitusrelated distress are not different from men. Comparing male tinnitus patients to a control group of males significant differences could be found for beta3 in the posterior cingulate cortex (PCC). The PCC might be related to cognitive and memory-related aspects of the tinnitus percept. Our results propose that sex influences in tinnitus research cannot be ignored and should be taken into account in functional imaging studies related to tinnitus. [ABSTRACT FROM AUTHOR]