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Many studies over the recent decades have attempted the modulation of motor learning using brain stimulation. Alternating currents allow for researchers not only to electrically stimulate the brain, but to further investigate the effects of specific frequencies, in and beyond the context of their endogenous associations. Transcranial alternating current stimulation (tACS) has therefore been used during motor learning to modulate aspects of acquisition, consolidation and performance of a learned motor skill. Despite numerous reviews on the effects of tACS, and its role in motor learning, there are few studies which synthesize the numerous frequencies and their respective theoretical mechanisms as they relate to motor and perceptual processes. Here we provide a short overview of the main stimulation frequencies used in motor learning modulation (e.g., alpha, beta, and gamma), and discuss the effect and proposed mechanisms of these studies. We summarize with the current state of the field, the effectiveness and variability in motor learning modulation, and novel mechanistic proposals from other fields., (© 2024. The Author(s).)

Introduction: Prediction error (PE) is key to perception in the predictive coding framework. However, previous studies indicated the varied neural activities evoked by PE in tinnitus patients. Here, we aimed to reconcile the conflict by (1) a more nuanced view of PE, which could be driven by changing stimulus (stimulus-driven PE [sPE]) and violation of current context (context-driven PE [cPE]) and (2) investigating the aberrant connectivity networks that are engaged in the processing of the two types of PEs in tinnitus patients. Methods: Ten tinnitus patients with normal hearing and healthy controls were recruited, and a local-global auditory oddball paradigm was applied to measure the electroencephalographic difference between the two groups during sPE and cPE conditions. Results: Overall, the sPE condition engaged bottom-up and top-down connections, whereas the cPE condition engaged mostly top-down connections. The tinnitus group showed decreased sensitivity to the sPE and increased sensitivity to the cPE condition. Particularly, the auditory cortex and posterior cingulate cortex were the hubs for processing cPE in the control and tinnitus groups, respectively, showing the orientation to an internal state in tinnitus. Furthermore, tinnitus patients showed stronger connectivity to the parahippocampus and pregenual anterior cingulate cortex for the establishment of the prediction during the cPE condition. Conclusion: These results begin to dissect the role of changes in stimulus characteristics versus changes in the context of processing the same stimulus in mechanisms of tinnitus generation.

Research indicates that hearing loss significantly contributes to tinnitus, but it alone does not fully explain its occurrence, as many people with hearing loss do not experience tinnitus. To identify a secondary factor for tinnitus generation, we examined a unique dataset of individuals with intermittent chronic tinnitus, who experience fluctuating periods of tinnitus. EEGs of healthy controls were compared to EEGs of participants who reported perceiving tinnitus on certain days, but no tinnitus on other days.. The EEG data revealed that tinnitus onset is associated with increased theta activity in the pregenual anterior cingulate cortex and decreased theta functional connectivity between the pregenual anterior cingulate cortex and the auditory cortex. Additionally, there is increased alpha effective connectivity from the dorsal anterior cingulate cortex to the pregenual anterior cingulate cortex. When tinnitus is not perceived, differences from healthy controls include increased alpha activity in the pregenual anterior cingulate cortex and heightened alpha connectivity between the pregenual anterior cingulate cortex and auditory cortex. This suggests that tinnitus is triggered by a switch involving increased theta activity in the pregenual anterior cingulate cortex and decreased theta connectivity between the pregenual anterior cingulate cortex and auditory cortex, leading to increased theta-gamma cross-frequency coupling, which correlates with tinnitus loudness. Increased alpha activity in the dorsal anterior cingulate cortex correlates with distress. Conversely, increased alpha activity in the pregenual anterior cingulate cortex can transiently suppress the phantom sound by enhancing theta connectivity to the auditory cortex. This mechanism parallels chronic neuropathic pain and suggests potential treatments for tinnitus by promoting alpha activity in the pregenual anterior cingulate cortex and reducing alpha activity in the dorsal anterior cingulate cortex through pharmacological or neuromodulatory approaches., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose concerning the research paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ability to perceive pain presents an interesting evolutionary advantage to adapt to an ever-changing environment. However, in the case of chronic pain (CP), pain perception hinders the capacity of the system to adapt to changing sensory environments. Similar to other chronic perceptual disorders, CP is also proposed to be a maladaptive compensation to aberrant sensory predictive processing. The local-global oddball paradigm relies on learning hierarchical rules and processing environmental irregularities at a local and global level. Prediction errors (PE) between actual and predicted input typically trigger an update of the forward model to limit the probability of encountering future PEs. It has been hypothesised that CP hinders forward model updating, reflected in increased local deviance and decreased global deviance. In the present study, we used the local-global paradigm to examine how CP influences hierarchical learning relative to healthy controls. As hypothesised, we observed that deviance in the stimulus characteristics evoked heightened local deviance and decreased global deviance of the stimulus-driven PE. This is also accompanied by respective changes in theta phase locking that is correlated with the subjective pain perception. Changes in the global deviant in the stimulus-driven-PE could also be explained by dampened attention-related responses. Changing the context of the auditory stimulus did not however show a difference in the context-driven PE. These findings suggest that CP is accompanied by maladaptive forward model updating where the constant presence of pain perception disrupts local deviance in non-nociceptive domains. Furthermore, we hypothesise that the auditory-processing based biomarker identified here could be a marker of domain-general dysfunction that could be confirmed by future research., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose concerning the research paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.

Chronic neuropathic pain and chronic tinnitus have been likened to phantom percepts, in which a complete or partial sensory deafferentation results in a filling in of the missing information derived from memory. 150 participants, 50 with tinnitus, 50 with chronic pain and 50 healthy controls underwent a resting state EEG. Source localized current density is recorded from all the sensory cortices (olfactory, gustatory, somatosensory, auditory, vestibular, visual) as well as the parahippocampal area. Functional connectivity by means of lagged phase synchronization is also computed between these regions of interest. Pain and tinnitus are associated with gamma band activity, reflecting prediction errors, in all sensory cortices except the olfactory and gustatory cortex. Functional connectivity identifies theta frequency connectivity between each of the sensory cortices except the chemical senses to the parahippocampus, but not between the individual sensory cortices. When one sensory domain is deprived, the other senses may provide the parahippocampal 'contextual' area with the most likely sound or somatosensory sensation to fill in the gap, applying an abductive 'duck test' approach, i.e., based on stored multisensory congruence. This novel concept paves the way to develop novel treatments for pain and tinnitus, using multisensory (i.e. visual, vestibular, somatosensory, auditory) modulation with or without associated parahippocampal targeting., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tinnitus is the perception of a continuous sound in the absence of an external source. Although the role of the auditory system is well investigated, there is a gap in how multisensory signals are integrated to produce a single percept in tinnitus. Here, we train participants to learn a new sensory environment by associating a cue with a target signal that varies in perceptual threshold. In the test phase, we present only the cue to see whether the person perceives an illusion of the target signal. We perform two separate experiments to observe the behavioral and electrophysiological responses to the learning and test phases in 1 ) healthy young adults and 2 ) people with continuous subjective tinnitus and matched control subjects. We observed that in both parts of the study the percentage of false alarms was negatively correlated with the 75% detection threshold. Additionally, the perception of an illusion goes together with increased evoked response potential in frontal regions of the brain. Furthermore, in patients with tinnitus, we observe no significant difference in behavioral or evoked response in the auditory paradigm, whereas patients with tinnitus were more likely to report false alarms along with increased evoked activity during the learning and test phases in the visual paradigm. This emphasizes the importance of integrity of sensory pathways in multisensory integration and how this process may be disrupted in people with tinnitus. Furthermore, the present study also presents preliminary data supporting evidence that tinnitus patients may be building stronger perceptual models, which needs future studies with a larger population to provide concrete evidence on. NEW & NOTEWORTHY Tinnitus is the continuous phantom perception of a ringing in the ears. Recently, it has been suggested that tinnitus may be a maladaptive inference of the brain to auditory anomalies, whether they are detected or undetected by an audiogram. The present study presents empirical evidence for this hypothesis by inducing an illusion in a sensory domain that is damaged (auditory) and one that is intact (visual). It also presents novel information about how people with tinnitus process multisensory stimuli in the audio-visual domain.

The perception of a continuous phantom in a sensory domain in the absence of an external stimulus is explained as a maladaptive compensation of aberrant predictive coding, a proposed unified theory of brain functioning. If this were true, these changes would occur not only in the domain of the phantom percept but in other sensory domains as well. We confirm this hypothesis by using tinnitus (continuous phantom sound) as a model and probe the predictive coding mechanism using the established local-global oddball paradigm in both the auditory and visual domains. We observe that tinnitus patients are sensitive to changes in predictive coding not only in the auditory but also in the visual domain. We report changes in well-established components of event-related EEG such as the mismatch negativity. Furthermore, deviations in stimulus characteristics were correlated with the subjective tinnitus distress. These results provide an empirical confirmation that aberrant perceptions are a symptom of a higher-order systemic disorder transcending the domain of the percept., (© 2024. The Author(s).)

Objectives: Tinnitus subtypes are proposed to lie on a continuum of different symptom dimensions rather than be categorical. However, there is no comprehensive empirical data showing this complex relationship between different tinnitus symptoms. The objective of this study is to provide empirical evidence for the dimensional nature of tinnitus and how different auditory and non-auditory symptoms interact with each other through complex interactions. We do this using graph theory, a mathematical tool that empirically maps this complex interaction. This way, graph theory can be utilised to highlight a new and possibly important outlook on how we can understand the heterogeneous nature of tinnitus., Design: In the current study, we use the screening databases of the Treatment Evaluation of Neuromodulation for Tinnitus-Stage A1 (TENT-A1) and A2 (TENT-A2) randomised trials to delineate the dimensional relationship between different clinical measures of tinnitus as a secondary data analysis. We first calculate the empirical relationship by computing the partial correlation. Following this, we use different measures of centrality to describe the contribution of different clinical measures to the overall network. We also calculate the stability of the network and compare the similarity and differences between TENT-A1 and TENT-A2., Results: Components of the auditory subnetwork (loudness discomfort level, sound sensitivity, average hearing loss and high frequency hearing loss) are highly inter-connected in both networks with sound sensitivity and loudness discomfort level being highly influential with high measures of centrality. Furthermore, the relationship between the densely connected auditory subnetwork with tinnitus-related distress seems to vary at different levels of distress, hearing loss, duration and age of the participants., Conclusion: Our findings provide first-time evidence for tinnitus varying in a dimensional fashion illustrating the heterogeneity of this phantom percept and its ability to be perceptually integrated, yet behaviourally segregated on different symptomatic dimensions., (© 2024. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)

Recent experiments in rats and humans have indicated that the effects of non-invasive electrical stimulation are primarily due to transcutaneous stimulation of peripheral nerves, specifically the greater occipital nerve. This stimulation pathway activates communication gateways from the periphery to the brain, impacting memory consolidation. In this invited commentary, I delve into and offer additional insights concerning the enhancement of episodic memory through transcutaneous electrical stimulation of the greater occipital nerve, building upon the findings published by my laboratory in both Science Advances and Elife . Our research on non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) has shown to enhance episodic memory consolidation and promote communication between the locus coeruleus (LC) pathway and the hippocampus based on resting connectivity functional MRI. The LC, primarily responsible for releasing noradrenaline and dopamine, plays a crucial role in post-encoding memory stabilization. This suggests that NITESGON can improve memory but does not affect immediate learning. The concept of behavioural tagging, where weak memories can be stabilized through strong or novel events, and how NITESGON activates a memory consolidation through this mechanism are discussed. The role of NITESGON in enhancing memory stabilization is highlighted, providing a non-pharmaceutical solution with minimal side effects. The potential application of NITESGON in neurological conditions, including Alzheimer's disease, attention deficit hyperactivity disorder and post-traumatic stress disorder, is also discussed, emphasizing its promising therapeutic prospects., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

The predictive coding theory is currently widely accepted as the theoretical basis of perception and chronic perceptual disorders are explained as the maladaptive compensation of the brain to a prediction error. Although this gives us a general framework to work with, it is still not clear who may be more susceptible and/or vulnerable to aberrations in this system. In this paper, we study changes in predictive coding through the lens of tinnitus and pain. We take a step back to understand how the predictive coding system develops from infancy, what are the different neural and bio markers that characterise this system in the acute, transition and chronic phases and what may be the factors that pose a risk to the aberration of this system. Through this paper, we aim to identify people who may be at a higher risk of developing chronic perceptual disorders as a reflection of aberrant predictive coding, thereby giving future studies more facets to incorporate in their investigation of early markers of tinnitus, pain and other disorders of predictive coding. We therefore view this paper to encourage the thinking behind the development of preclinical biomarkers to maladaptive predictive coding.

Auditory perceptual learning is an experience-dependent form of auditory learning that can improve substantially throughout adulthood with practice. A key mechanism associated with perceptual learning is synaptic plasticity. In the last decades, an increasingly better understanding has formed about the neural mechanisms related to auditory perceptual learning. Research in animal models found an association between the functional organization of the primary auditory cortex and frequency discrimination ability. Several studies observed an increase in the area of representation to be associated with improved frequency discrimination. Non-invasive brain stimulation techniques have been related to the promotion of plasticity. Despite its popularity in other fields, non-invasive brain stimulation has not been used much in auditory perceptual learning. The present review has discussed the application of non-invasive brain stimulation methods in auditory perceptual learning by discussing the mechanisms, current evidence and challenges, and future directions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This review aims to highlight modern neurostimulation approaches that are effectively activating the hippocampus and enhancing episodic memory performance. The hippocampus is a brain region known to play an essential role in episodic memory processes. However, as it is nestled deep within the brain, it has been a challenging target for traditional neurostimulation approaches, with studies reporting inconsistent memory effects. Recent studies suggest more than half of the electrical current from non-invasive transcranial electrical stimulation (tES) methods may be attenuated by the human scalp, skull, and cerebral spinal fluid. Thus, this review aims to highlight novel neurostimulation approaches that are showing promise as alternative routes for activating hippocampal circuitry. Early evidence suggests temporal interference, closed-loop and individualized protocols, sensory stimulation and peripheral nerve-targeted tES protocols warrant further investigation. These approaches each provide promising routes for activating the hippocampus by a) increasing its functional connectiveness to key brain regions, b) strengthening synaptic plasticity mechanisms, or c) enhancing neural entrainment specifically within and between theta and gamma frequencies in these regions. Importantly, these three functional mechanisms and the hippocampus' structural integrity are negatively impacted throughout the progression of Alzheimer's Disease, with episodic memory deficits likewise evident in early stages. Consequently, depending on further validation of the approaches reviewed here, these techniques could offer significant applied therapeutic value for patients suffering from memory deficits or neurodegenerative diseases including amnestic Mild Cognitive Impairment or Alzheimer's disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Brain stimulation has been used in motor learning studies with success in improving aspects of task learning, retention, and consolidation. Using a variety of motor tasks and stimulus parameters, researchers have produced an array of literature supporting the efficacy of brain stimulation to modulate motor task learning. We discuss the use of transcranial direct current stimulation, transcranial alternating current stimulation, and peripheral nerve stimulation to modulate motor learning. In a novel approach, we review literature of motor learning modulation in terms of learning stage, categorizing learning into acquisition, consolidation, and retention. We endeavour to provide a current perspective on the stage-specific mechanism behind modulation of motor task learning, to give insight into how electrical stimulation improves or hinders motor learning, and how mechanisms differ depending on learning stage. Offering a look into the effectiveness of peripheral nerve stimulation for motor learning, we include potential mechanisms and overlapping features with transcranial stimulation. We conclude by exploring how peripheral stimulation may contribute to the results of studies that employed brain stimulation intracranially., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Chronic pain is processed by at least three well-known pathways, two pain provoking pathways including a medial 'suffering' and lateral 'painfulness' pathway. A third descending pain pathway modulates pain but is predominantly inhibitory. Chronic pain can be seen as an imbalance between the two pain-provoking and the pain inhibitory pathways. If this assumption is correct, then the imbalance between pain input and pain suppression should reverse and normalize in response to successful, i.e., pain reducing burstDR spinal cord stimulation, one of the current treatment options for neuropathic pain., Materials and Methods: Fifteen patients, who received spinal cord stimulation for failed back surgery were included in this study, using source localized electrical brain activity and connectivity recording via EEG to identify the purported imbalance., Results: BurstDR spinal cord stimulation induces a significant change in EEG activity in both the left and right somatosensory cortex (SSC) for both θ and γ oscillations. In the dorsal anterior cingulate cortex (dACC), we observed a significant drop in both α and β oscillations. This reduction is accompanied by a change in pain intensity and suffering. BurstDR spinal cord stimulation is also associated with a reduction in θ at the pregenual anterior cingulate cortex (pgACC). Analyzing effective connectivity indicates that for the θ band, more information is sent from the pgACC to the left and right SSC. For α, increased information is sent from the pgACC to the dACC and both the left and right SSC. This is associated with a reduced θ-γ coupling in the SSC and reduced α-β coupling in dACC., Conclusion: This study suggests that chronic pain is indeed an imbalance between the ascending and descending pathways in the brain and that burst spinal cord stimulation can normalize this imbalance in the brain., Competing Interests: Declaration of competing interest Dirk De Ridder has a patent for burst stimulation. Sven Vanneste has no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by 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.

Recent technological improvements have positioned us at the threshold of innovative discoveries that will assist in new perspectives and avenues of research. Increased attention has been directed towards peripheral nerve stimulation, particularly of the vagus, trigeminal, or greater occipital nerve, due to their unique pathway that engages neural circuits within networks involved in higher cognitive processes. Here, we question whether the effects of transcutaneous electrical stimulation are mediated by synergistic interactions of multiple neuromodulatory networks, considering this pathway is shared by more than one neuromodulatory system. By spotlighting this attractive transcutaneous pathway, this opinion piece aims to acknowledge the contributions of four vital neuromodulators and prompt researchers to consider them in future investigations or explanations., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pain can be regarded as an emergent property of multiple interacting, dynamically changing brain networks and thus needs a targeted treatment approach. A novel high-definition transcranial infraslow pink-noise stimulation (HD-tIPNS) technique was developed to modulate the key hubs of the three main nociceptive pathways simultaneously, ie, the pregenual anterior cingulate cortex (pgACC) (descending inhibitory pathway), the dorsal anterior cingulate cortex (dACC) (medial nociceptive pathway), and both somatosensory cortices (S1) (lateral nociceptive pathway). This study aimed to evaluate safety and verify whether a single session of HD-tIPNS may disrupt functional and effective connectivity between targeted cortical regions., Materials and Methods: A pilot double-blind randomized two-arm placebo-controlled parallel trial was conducted. Participants (N = 30) with chronic low back pain were equally randomized to receive a single session of either sham stimulation or HD-tIPNS (targeting the pgACC, dACC, and bilateral S1). Primary outcomes included safety and electroencephalographic measures, and secondary outcomes included pain measures, collected after treatment. A Mann-Whitney U test was used to compare between-group differences in percentage changes with baseline for each outcome measures. A Wilcoxon signed-rank test was used to identify difference in effective connectivity measure before and after HD-tIPNS., Results: No serious adverse events were reported. A significant decrease in instantaneous functional connectivity was noted between the pgACC and dACC (U = 47.0, Z = -2.72, p = 0.007) and the pgACC and left S1 (U = 41.0, Z = -2.97, p = 0.003) in the infraslow band after HD-tIPNS when compared with sham stimulation. A significant decrease in instantaneous effective connectivity was noted in the direction of the dACC to the pgACC (Z = -2.10, p = 0.035), in the infraslow band after HD-tIPNS when compared with baseline. No changes in clinical pain measures were detected., Conclusions: HD-tIPNS can safely modulate the functional and effective connectivity between targeted pain-related cortical hubs. Further studies are warranted to evaluate whether repeated exposures to HD-tIPNS can incur clinical benefits through inducing changes in functional and effective connectivity at targeted cortical regions., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is ACTRN12621001438842., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Most memories that are formed are forgotten, while others are retained longer and are subject to memory stabilization. We show that non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) using direct current during learning elicited a long-term memory effect. However, it did not trigger an immediate effect on learning. A neurobiological model of long-term memory proposes a mechanism by which memories that are initially unstable can be strengthened through subsequent novel experiences. In a series of studies, we demonstrate NITESGON's capability to boost the retention of memories when applied shortly before, during, or shortly after the time of learning by enhancing memory consolidation via activation and communication in and between the locus coeruleus pathway and hippocampus by plausibly modulating dopaminergic input. These findings may have a significant impact for neurocognitive disorders that inhibit memory consolidation such as Alzheimer's disease., Competing Interests: AL, LM, YH, AM, SV No competing interests declared, (© 2023, Luckey et al.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Evidence-based medicine (EBM) is generally accepted as the gold standard for high-quality medicine and, thus, for managing patients with tinnitus. EBM integrates the best available scientific information with clinical experience and patient values to guide decision-making about clinical management. To help health care providers and clinicians, the available evidence is commonly translated into medical or clinical guidelines based on a consensus. These involve a systematic review of the literature and meta-analytic aggregation of research findings followed by the formulation of clinical recommendations. However, this approach also has limitations, which include a lack of consideration of individual patient characteristics, the susceptibility of guideline recommendations to material and immaterial conflicts of interest of guideline authors and long latencies till new knowledge is implemented in guidelines. A further important aspect in interpreting the existing literature is that the absence of evidence is not evidence of absence. These circumstances could result in the decoupling of recommendations and their supporting evidence, which becomes evident when guidelines from different countries differ in their recommendations. This opinion paper will discuss how these weaknesses can be addressed in tinnitus.

Pain and tinnitus share common pathophysiological mechanisms, clinical features, and treatment approaches. A source-localized resting-state EEG study was conducted in 150 participants: 50 healthy controls, 50 pain, and 50 tinnitus patients. Resting-state activity as well as functional and effective connectivity was computed in source space. Pain and tinnitus were characterized by increased theta activity in the pregenual anterior cingulate cortex, extending to the lateral prefrontal cortex and medial anterior temporal lobe. Gamma-band activity was increased in both auditory and somatosensory cortex, irrespective of the pathology, and extended to the dorsal anterior cingulate cortex and parahippocampus. Functional and effective connectivity were largely similar in pain and tinnitus, except for a parahippocampal-sensory loop that distinguished pain from tinnitus. In tinnitus, the effective connectivity between parahippocampus and auditory cortex is bidirectional, whereas the effective connectivity between parahippocampus and somatosensory cortex is unidirectional. In pain, the parahippocampal-somatosensory cortex is bidirectional, but parahippocampal auditory cortex unidirectional. These modality-specific loops exhibited theta-gamma nesting. Applying a Bayesian brain model of brain functioning, these findings suggest that the phenomenological difference between auditory and somatosensory phantom percepts result from a vicious circle of belief updating in the context of missing sensory information. This finding may further our understanding of multisensory integration and speaks to a universal treatment for pain and tinnitus-by selectively disrupting parahippocampal-somatosensory and parahippocampal-auditory theta-gamma activity and connectivity., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There exist no objective markers for tinnitus or tinnitus disorders, which complicates diagnosis and treatments. The combination of EEG with sophisticated classification procedures may reveal biomarkers that can identify tinnitus and accurately differentiate different levels of distress experienced by patients. EEG recordings were obtained from 129 tinnitus patients and 142 healthy controls. Linear support vector machines were used to develop two classifiers: the first differentiated tinnitus patients from controls, while the second differentiated tinnitus patients with low and high distress levels. The classifier for healthy controls and tinnitus patients performed with an average accuracy of 96 and 94% for the training and test sets, respectively. For the distress classifier, these average accuracies were 89 and 84%. Minimal overlap was observed between the features of the two classifiers. EEG-derived features made it possible to accurately differentiate healthy controls and tinnitus patients as well as low and high distress tinnitus patients. The minimal overlap between the features of the two classifiers indicates that the source of distress in tinnitus, which could also be involved in distress related to other conditions, stems from different neuronal mechanisms compared to those causing the tinnitus pathology itself., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Chronic low back pain (CLBP) is a disabling condition worldwide. In CLBP, neuroimaging studies demonstrate abnormal activities in cortical areas responsible for pain modulation, emotional, and sensory components of pain experience [i.e., pregenual and dorsal anterior cingulate cortex (pgACC, dACC), and somatosensory cortex (SSC), respectively]. This pilot study, conducted in a university setting, evaluated the feasibility, safety, and acceptability of a novel electroencephalography-based infraslow-neurofeedback (EEG ISF-NF) technique for retraining activities in pgACC, dACC and SSC and explored its effects on pain and disability. Participants with CLBP (n = 60), recruited between July'20 to March'21, received 12 sessions of either: ISF-NF targeting pgACC, dACC + SSC, a ratio of pgACC*2/dACC + SSC, or Placebo-NF. Descriptive statistics demonstrated that ISF-NF training is feasible [recruitment rate (7 participants/month), dropouts (25%; 20-27%), and adherence (80%; 73-88%)], safe (no adverse events reported), and was moderate to highly acceptable [Mean ± SD: 7.8 ± 2.0 (pgACC), 7.5 ± 2.7 (dACC + SCC), 8.2 ± 1.9 (Ratio), and 7.7 ± 1.5 (Placebo)]. ISF-NF targeting pgACC demonstrated the most favourable clinical outcomes, with a higher proportion of participants exhibiting a clinically meaningful reduction in pain severity [53%; MD (95% CI): - 1.9 (- 2.7, - 1.0)], interference [80%; MD (95% CI): - 2.3 (- 3.5, - 1.2)], and disability [73%; MD (95% CI): - 4.5 (- 6.1, - 2.9)] at 1-month follow-up. ISF-NF training is a feasible, safe, and an acceptable treatment approach for CLBP., (© 2023. The Author(s).)

Tinnitus can be defined as the conscious perception of phantom sounds in the absence of corresponding external auditory signals. Tinnitus can develop in the setting of sudden sensorineural hearing loss (SSNHL), but the underlying mechanism is largely unknown. Using electroencephalography, we investigated differences in afferent node capacity between 15 SSNHL patients without tinnitus (NT) and 30 SSNHL patients with tinnitus (T). Where the T group showed increased afferent node capacity in regions constituting a "triple brain network" [default mode network (DMN), central executive network (CEN), and salience network (SN)], the NT group showed increased information flow in regions implicated in temporal auditory processing and noise-canceling pathways. Our results demonstrate that when all components of the triple network are activated due to sudden-onset auditory deprivation, tinnitus ensues. By contrast, auditory processing-associated and tinnitus-suppressing networks are highly activated in the NT group, to overcome the activation of the triple network and effectively suppress the generation of tinnitus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Park, Lee, Koo, Vanneste, De Ridder, Lim and Song.)

This study explored the effect of electroencephalographic infraslow neurofeedback (EEG ISF-NF) training on effective connectivity and tested whether such effective connectivity changes are correlated with changes in pain and disability in people with chronic low back pain. This involved secondary analysis of a pilot double-blinded randomised placebo-controlled study. Participants ( n = 60) were randomised to receive ISF-NF targeting either the pregenual anterior cingulate cortex (pgACC), dorsal anterior cingulate and somatosensory cortex (dACC + S1), ratio of pgACC*2/dACC + S1, or Sham-NF. Resting-state EEG and clinical outcomes were assessed at baseline, immediately after intervention, and at one-week and one-month follow-up. Kruskal-Wallis tests demonstrated significant between-group differences in effective connectivity from pgACC to S1L at one-month follow up and marginal significant changes from S1L to pgACC at one-week and one-month follow up. Mann-Whitney U tests demonstrated significant increases in effective connectivity in the ISF-NF up-training pgACC group when compared to the Sham-NF group (pgACC to S1L at one-month ( p = 0.013), and S1L to pgACC at one-week ( p = 0.008) and one-month follow up ( p = 0.016)). Correlational analyses demonstrated a significant negative correlation (ρ = -0.630, p = 0.038) between effective connectivity changes from pgACC to S1L and changes in pain severity at one-month follow-up. The ISF-NF training pgACC can reduce pain via influencing effective connectivity between pgACC and S1L.

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES., Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided., Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity., Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases., Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials., (Copyright © 2022 International Federation of Clinical Neurophysiology. All rights reserved.)

Objective: High Definition transcranial Direct Current Stimulation (HD-tDCS) has been shown to improve cognitive performance in individuals with chronic traumatic brain injury (TBI), although electrophysiological mechanisms remain unclear., Methods: Veterans with TBI underwent active anodal (N = 15) vs sham (N = 10) HD-tDCS targeting the pre-supplementary motor area (pre-SMA). A Go-NoGo task was conducted simultaneously with electroencephalography (EEG) at baseline and after intervention completion., Results: We found increased theta event-related spectral perturbation (ERSP) and inter-trial phase coherence (ITPC) during Go in the frontal midline electrodes overlying the pre-SMA after active HD-tDCS intervention, but not after sham. We also found increased theta phase coherence during Go between the frontal midline and left posterior regions after active HD-tDCS. A late increase in alpha-theta ERSP was found in the left central region after active HD-tDCS. Notably, lower baseline theta ERSP/ITPC in the frontal midline region predicted more post-intervention improvement in Go performance only in the active group., Conclusions: There are local and interregional oscillatory changes in response to HD-tDCS modulation in chronic TBI., Significance: These findings may guide future research in utilizing EEG time-frequency metrics not only to measure interventional effects, but also in selecting candidates who may optimally respond to treatment., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests or personal relationships relevant to the work., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Harnessing the lifelong potential of the human brain for neuroplasticity may serve to maintain the viability of neural structures and postpone the onset of cognitive decline. The absence of effective pharmacological interventions to counter memory decline has encouraged scientists to test the possibility that noninvasive electrical stimulation may serve as an additional tool to improve memory abilities.Previous research showed that electrical stimulation of the greater occipital nerve enhances memory recall performance in young and older healthy subjects. This study aims to extend these findings to determine the effect of transcutaneous electrical stimulation of the greater occipital nerve on the improvement of episodic memory in individuals with amnestic Mild Cognitive Impairment (aMCI)., Methods/design: This study is a prospective, double-blind, placebo-controlled, randomized parallel-group study. A total of 100 individuals with a diagnosis of aMCI according to NIA/AA will be recruited. Participants will be randomly assigned to one of four groups. One group will receive active non-invasive transcutaneous electrical stimulation of greater occipital nerve (NITESGON), while three groups will serve as controls (i.e., sham NITESGON, active NITESGON with local anesthesia, and active NITESGON on the C5/C6 nerve). The primary outcome, i.e., memory recall, will be determined by a word association task, and will be recorded at baseline, 7 days after NITESGON, and 28 days after NITESGON. The secondary outcome is neurophysiological changes determined by resting state EEG and will be assessed immediately before and after NITESGON., Discussion: The results will add new insights into improving episodic memory in individuals with aMCI., Trial Registration: #NCT05289804 (clinicaltrial.gov)., Protocol Approval Id: #SPREC102021-23 (Ethics Committee at Trinity College Dublin, School of Psychology)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Tinnitus is defined as the conscious awareness of a sound without an identifiable external sound source, and tinnitus disorder as tinnitus with associated suffering. Chronic tinnitus has been anatomically and phenomenologically separated into three pathways: a lateral "sound" pathway, a medial "suffering" pathway, and a descending noise-canceling pathway. Here, the triple network model is proposed as a unifying framework common to neuropsychiatric disorders. It proposes that abnormal interactions among three cardinal networks-the self-representational default mode network, the behavioral relevance-encoding salience network and the goal-oriented central executive network-underlie brain disorders. Tinnitus commonly leads to negative cognitive, emotional, and autonomic responses, phenomenologically expressed as tinnitus-related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, encoding the behavioral relevance of the sound stimulus. Chronic tinnitus can also become associated with the self-representing default mode network and becomes an intrinsic part of the self-percept. This is likely an energy-saving evolutionary adaptation, by detaching tinnitus from sympathetic energy-consuming activity. Eventually, this can lead to functional disability by interfering with the central executive network. In conclusion, these three pathways can be extended to a triple network model explaining all tinnitus-associated comorbidities. This model paves the way for the development of individualized treatment modalities.

More than 10% of the population suffers from tinnitus, which is a phantom auditory condition that is coded within the brain. A new neuromodulation approach to treat tinnitus has emerged that combines sound with electrical stimulation of somatosensory pathways, supported by multiple animal studies demonstrating that bimodal stimulation can elicit extensive neural plasticity within the auditory brain. More recently, in a large-scale clinical trial, bimodal neuromodulation combining sound and tongue stimulation drove significant reductions in tinnitus symptom severity during the first 6 weeks of treatment, followed by diminishing improvements during the second 6 weeks of treatment. The primary objective of the large-scale randomized and double-blinded study presented in this paper was to determine if background wideband noise as used in the previous clinical trial was necessary for bimodal treatment efficacy. An additional objective was to determine if adjusting the parameter settings after 6 weeks of treatment could overcome treatment habituation effects observed in the previous study. The primary endpoint at 6-weeks involved within-arm and between-arm comparisons for two treatment arms with different bimodal neuromodulation settings based on two widely used and validated outcome instruments, Tinnitus Handicap Inventory and Tinnitus Functional Index. Both treatment arms exhibited a statistically significant reduction in tinnitus symptoms during the first 6-weeks, which was further reduced significantly during the second 6-weeks by changing the parameter settings (Cohen's d effect size for full treatment period per arm and outcome measure ranged from - 0.7 to - 1.4). There were no significant differences between arms, in which tongue stimulation combined with only pure tones and without background wideband noise was sufficient to reduce tinnitus symptoms. These therapeutic effects were sustained up to 12 months after the treatment ended. The study included two additional exploratory arms, including one arm that presented only sound stimuli during the first 6 weeks of treatment and bimodal stimulation in the second 6 weeks of treatment. This arm revealed the criticality of combining tongue stimulation with sound for treatment efficacy. Overall, there were no treatment-related serious adverse events and a high compliance rate (83.8%) with 70.3% of participants indicating benefit. The discovery that adjusting stimulation parameters overcomes previously observed treatment habituation can be used to drive greater therapeutic effects and opens up new opportunities for optimizing stimuli and enhancing clinical outcomes for tinnitus patients with bimodal neuromodulation., (© 2022. The Author(s).)

Introduction: Chronic low back pain (CLBP) is a common disabling health condition. Current treatments demonstrate modest effects, warranting newer therapies. Brain imaging demonstrates altered electrical activities in cortical areas responsible for pain modulation, emotional and sensory components of pain experience. Treatments targeting to change electrical activities of these key brain regions may produce clinical benefits. This pilot study aims to (1) evaluate feasibility, safety and acceptability of a novel neuromodulation technique, high-definition transcranial infraslow pink noise stimulation (HD-tIPNS), in people with CLBP, (2) explore the trend of effect of HD-tIPNS on pain and function, and (3) derive treatment estimates to support sample size calculation for a fully powered trial should trends of effectiveness be present., Methods and Analysis: A pilot, triple-blinded randomised two-arm placebo-controlled parallel trial. Participants (n=40) with CLBP will be randomised to either sham stimulation or HD-tIPNS (targeting somatosensory cortex and dorsal and pregenual anterior cingulate cortex). Primary outcomes include feasibility and safety measures, and clinical outcomes of pain (Brief Pain Inventory) and disability (Roland-Morris disability questionnaire). Secondary measures include clinical, psychological, quantitative sensory testing and electroencephalography collected at baseline, immediately postintervention, and at 1-week, 1-month and 3 months postintervention. All data will be analysed descriptively. A nested qualitative study will assess participants perceptions about acceptability of intervention and analysed thematically., Ethics and Dissemination: Ethical approval has been obtained from Health and Disability Ethics Committee (Ref:20/NTB/67). Findings will be reported to regulatory and funding bodies, presented at conferences, and published in a scientific journal., Trial Registration Number: ACTRN12620000505909p., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this study was to identify and describe clusters of patients with similar characteristics presenting with sciatica caused by a lumbar disc herniation in secondary care., Methods: Forty-six percent (n = 163) of the eligible patients (n = 352) completed all questionnaires and were included in a hierarchical cluster analysis. The analysis was based on baseline characteristics for pain, pain awareness and catastrophizing, disability and quality of life (QOL). Clusters were compared for the use of pain medication, employment status and allocated treatment., Results: Three significant clusters were identified. Cluster 2 (n = 49), coined the painfulness cluster, reported the lowest baseline characteristics for pain (>5) and disability together with a higher health-related QOL. Patients in cluster 3, labeled the painfulness and suffering cluster, had relatively high pain scores for back and leg pain (>6), high pain awareness and catastrophizing, i.e. suffering, but relatively limited disability and maintained QOL. Cluster 1 (n = 71), the painfulness-suffering and disability cluster, was characterized by the most severe back and leg pain (>7), high pain awareness and catastrophizing with the lowest QOL and highest disability. Patients in cluster 1 underwent significantly more surgery and used the most extensive pain medication (WHO III)., Conclusion: This research gives insight in the complex population with sciatica and is of added value to the recent, sparsely existing literature on relevant patient subgroups in the low back and leg pain population. The data suggest that VAS scores < 6 do not lead to suffering and VAS scores < 7 not to disability., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In the past decade, a rising interest in transcranial electrical stimulation has emerged owing to its advantageous capacity to facilitate the extraction of casual links between neuromodulation and the obtained behavioral effects in cognitive performance. However, an insufficient number of direct comparative studies between transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) effects on associative memory have caused optimal parameters and procedural application to remain undefined., Objective: The current study aimed to comparatively investigate the effects of tDCS and tACS applied to the occipital nerve (ON), targeting the locus coeruleus, on associative memory performance., Methods: We employed a randomized, double-blind, two-visit, active-controlled study design. 85 cognitively normal adults were assigned to receive either active ON-tDCS, 40 Hz ON-tACS, sham ON-tDCS, or 1 Hz ON-tACS during encoding of a 50-word Swahili-English associative memory recall task. To evaluate the effects of electrical stimulation, we measured the cumulative rate of learning on Day 1 and to assess possible long-term effects, we measured the number of words recalled on Day 7., Results: Results presented two notable findings: (1) participants who received 40 Hz ON-tACS learned significantly more words on Day 1 (F 3,81  = 4.37, p = .007, η 2  = 0.14), and (2) participants who received 40 Hz ON-tACS or active ON-tDCS recalled significantly more words on Day 7 (F 3,81  = 11.08, p < .001, η 2  = 0.29)., Conclusions: The evidence from this study alludes to 40 Hz ON-tACS and active ON-tDCS inducing distinct behavioral effects, whereby 40 Hz ON-tACS generated an effect during memory encoding via enhanced attention, however, active ON-tDCS elicited an offline effect transpiring during consolidation. Further neuroimaging studies are needed to validate these findings and proposed mechanisms of action., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute pain is a physiological response that causes an unpleasant sensory and emotional experience in the presence of actual or potential tissue injury. Anatomically and symptomatically, chronic pathological pain can be divided into three distinct but interconnected pathways, a lateral "painfulness" pathway, a medial "suffering" pathway and a descending pain inhibitory circuit. Pain (fullness) can exist without suffering and suffering can exist without pain (fullness). The triple network model is offering a generic unifying framework that may be used to understand a variety of neuropsychiatric illnesses. It claims that brain disorders are caused by aberrant interactions within and between three cardinal brain networks: the self-representational default mode network, the behavioral relevance encoding salience network and the goal oriented central executive network. A painful stimulus usually leads to a negative cognitive, emotional, and autonomic response, phenomenologically expressed as pain related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, which encodes behavioral relevance of the painful stimuli and the central sympathetic control network. When pain lasts longer than the healing time and becomes chronic, the pain- associated somatosensory cortex activity may become functionally connected to the self-representational default mode network, i.e., it becomes an intrinsic part of the self-percept. This is most likely an evolutionary adaptation to save energy, by separating pain from sympathetic energy-consuming action. By interacting with the frontoparietal central executive network, this can eventually lead to functional impairment. In conclusion, the three well-known pain pathways can be combined into the triple network model explaining the whole range of pain related co-morbidities. This paves the path for the creation of new customized and personalized treatment methods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Ridder, Vanneste, Smith and Adhia.)

Tinnitus is hypothesised to be a predictive coding problem. Previous research indicates lower sensitivity to prediction errors (PEs) in tinnitus patients while processing auditory deviants corresponding to tinnitus-specific stimuli. However, based on research with patients with hallucinations and no psychosis we hypothesise tinnitus patients may be more sensitive to PEs produced by auditory stimuli that are not related to tinnitus characteristics. Specifically in patients with minimal to no hearing loss, we hypothesise a more top-down subtype of tinnitus that may be driven by maladaptive changes in an auditory predictive coding network. To test this, we use an auditory oddball paradigm with omission of global deviants, a measure that is previously shown to empirically characterise hierarchical prediction errors (PEs). We observe: (1) increased predictions characterised by increased pre-stimulus response and increased alpha connectivity between the parahippocampus, dorsal anterior cingulate cortex and parahippocampus, pregenual anterior cingulate cortex and posterior cingulate cortex; (2) increased PEs characterised by increased P300 amplitude and gamma activity and increased theta connectivity between auditory cortices, parahippocampus and dorsal anterior cingulate cortex in the tinnitus group; (3) increased overall feed-forward connectivity in theta from the auditory cortex and parahippocampus to the dorsal anterior cingulate cortex; (4) correlations of pre-stimulus theta activity to tinnitus loudness and alpha activity to tinnitus distress. These results provide empirical evidence of maladaptive changes in a hierarchical predictive coding network in a subgroup of tinnitus patients with minimal to no hearing loss. The changes in pre-stimulus activity and connectivity to non-tinnitus specific stimuli suggest that tinnitus patients not only produce strong predictions about upcoming stimuli but also may be predisposed to stimulus a-specific PEs in the auditory domain. Correlations with tinnitus-related characteristics may be a biomarker for maladaptive changes in auditory predictive coding., Competing Interests: Declaration of Competing Interest The authors declare no competing interests, (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tinnitus, the auditory phantom percept, is a well-known heterogenous disorder with multiple subtypes. Researchers and clinicians have tried to classify these subtypes according to clinical profiles, aetiologies, and response to treatment with little success. The occurrence of overlapping tinnitus subtypes suggests that the disorder exists along a continuum of severity, with no clear distinct boundaries. In this perspective, we propose a neuro-mechanical framework, viewing tinnitus as a dimensional disorder which is a complex interplay of its behavioural, biological and neurophysiological phenotypes. Moreover, we explore the potential of these dimensions as interacting networks without a common existing cause, giving rise to tinnitus. Considering tinnitus as partially overlapping, dynamically changing, interacting networks, each representing a different aspect of the unified tinnitus percept, suggests that the interaction of these networks determines the phenomenology of the tinnitus, ultimately leading to a dimensional spectrum, rather than a categorical subtyping. A combination of a robust theoretical framework and strong empirical evidence can advance our understanding of the functional mechanisms underlying tinnitus and ultimately, improve treatment strategies., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As the human brain works in a Bayesian manner to minimize uncertainty toward external stimuli, the deafferented brain may generate tinnitus in an attempt to fill in missing auditory information, e.g. due to hearing loss. However, not everybody with hearing loss develops tinnitus. Understanding the differences between people with hearing loss who develop tinnitus versus those who do not offers a unique opportunity to unravel critical brain areas involved in the generation of a phantom sound. In this study, we compared resting-state quantitative electroencephalography between hearing loss patients with (HL-T) and without tinnitus (HL-NT) to identify cortical oscillatory signatures that may reveal prerequisites for the selective development of tinnitus in subjects with hearing loss. We enrolled 65 subjects with HL-NT and 65 subjects with HL-T whose tinnitus handicap inventory scores were <16 (grade 1) to minimize the bias induced by distress-induced cortical activity changes. Subjects in the HL-T and HL-NT groups were matched in terms of the bilateral hearing threshold (0.25-8 kHz) using nearest neighbor method. Compared to the HL-NT group, the HL-T group showed significantly higher activity in the right parahippocampus for the beta 1 frequency band, in the left inferior parietal lobule (IPL) for the beta 2 frequency band, and in the right IPL for the beta 3- and gamma frequency bands. Functional connectivity analyses revealed that the HL-T group had significantly higher connectivity than the HL-NT group between both parahippocampal gyri and the right IPL for the delta frequency band, and between the left posterior cingulate cortex (PCC) and right IPL for the beta 2 frequency band. These results suggest that tinnitus may be perceived only if auditory memory stored in the parahippocampus is actively linked to the IPL-based "circuit breaker" system and the circuit breaker signal is connected to the PCC-based default mode network (DMN). Thus, when the circuit breaker system regards tinnitus secondary to peripheral deafferentation as a salient event and then the DMN regards tinnitus as a norm, subjects with hearing loss may consciously perceive tinnitus. The results of this study further refine the recently proposed Bayesian model and decipher the neurobiological mechanism of the selective development of tinnitus in subjects with hearing loss., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

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.)

Anodal high definition transcranial direct current stimulation (HD-tDCS) targeting the pre-supplementary motor area/dorsal anterior cingulate cortex (pre-SMA/dACC) has recently been shown to improve verbal retrieval deficits in veterans with chronic traumatic brain injury (TBI) (Motes et al., 2020), but predictors of treatment response are unclear. We hypothesized that baseline delayed verbal recall, a sensitive measure for post-TBI chronic cognitive decline, would predict therapeutic effects of HD-tDCS targeting the pre-SMA/dACC for verbal retrieval deficits. Standardized verbal retrieval measures were administered at baseline, immediately after and 8 weeks after treatment completion. We applied mixed generalized linear modeling as a post-hoc subgroup analysis to the verbal retrieval scores that showed significant improvement in Motes at el. (2020) to examine effects of active stimulation across the groups with baseline-intact delayed recall (N = 10) and baseline-impaired delayed recall (N = 8), compared to sham (N = 7). Individuals with impaired baseline delayed recall showed significant improvement (compared to baseline) in both category fluency and color-word inhibition/switch, while individuals with intact delayed recall showed significant improvement only in color-word inhibition/switch. Baseline delayed verbal recall may therefore be considered as a predictor for future electromodulation studies targeting frontal structures to treat TBI-related verbal deficits., (Published by Elsevier B.V.)

Objectives: Paranoia manifests similarly in subclinical and clinical populations and is related to distress and impairment. Previous work links paranoia to amygdala hyperactivity and reduced activation of the ventrolateral prefrontal cortex (VLPFC), a region thought to regulate amygdala activity., Methods: This study aimed to reduce subclinical paranoia in 40 undergraduates by increasing activity of the VLPFC via single-session transcranial Direct Current Stimulation (tDCS). A double-blind, crossover (active vs. sham stimulation) design was used., Results: Paranoia significantly decreased after active stimulation (d z  = 0.51) but not sham (d z  = 0.19), suggesting that tDCS of VLPFC was associated with mean-level reductions in paranoia., Conclusion: These findings demonstrate preliminary support for the role of single-session active stimulation to the VLPFC for reducing subclinical paranoia in healthy individuals., Practitioner Points: In both clinical and subclinical populations, paranoia is related to distress and poorer functional outcomes. Paranoia has been linked to overactivation of the amygdala, a brain region responsible for detecting salience and threat, and reduced activation of the ventrolateral prefrontal cortex (VLPFC), a region thought to modulate and regulate amygdala activity. In this study, transcranial direct current stimulation (tDCS) of the VLPFC reduced self-reported paranoia in healthy undergraduate students. tDCS may be a promising intervention for reducing paranoia in subclinical and clinical populations. Effects were relatively small and require replication with larger subclinical samples and with clinical samples., (© 2021 The British Psychological Society.)

Along with phantom pain, tinnitus, a phantom auditory perception occurring in the absence of an external acoustic stimulus, is one of the most representative phantom perceptions that develops in subjects with decreased peripheral sensory input. Although tinnitus is closely associated with peripheral hearing loss (HL), it remains unclear why only some individuals with HL develop tinnitus. In this study, we investigated the differences between 65 HL with tinnitus (HL-T) and 104 HL with no tinnitus (HL-NT) using a resting-state electroencephalography data-based volume entropy model of the brain network, by comparing the afferent node capacities, that quantify the contribution of each node to the spread of information, of all Brodmann areas. While the HL-T group showed increased information flow in areas involved in Bayesian inference (the left orbitofrontal cortex, the left subgenual anterior cingulate cortex, and the left ventrolateral prefrontal cortex) and auditory memory storage (the right hippocampus/parahippocampus), the HL-NT group showed increased afferent node capacity in hub areas of the default mode network (DMN; the right posterior cingulate cortex and the right medial temporal gyrus). These results suggest that the balance of activity between the Bayesian inferential network (updating missing auditory information by retrieving auditory memories from the hippocampus/parahippocampus) and DMN (maintaining the "silent status quo") determines whether phantom auditory perception occurs in a brain with decreased peripheral auditory input., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Research demonstrates a relationship between faulty visual attention and poorer social cognition in schizophrenia. One potential explanatory model suggests abnormal neuromodulation in specific neural networks may result in reduced attention to socially important cues, leading to poorer understanding of another's emotional state or intentions., Objective: The current study experimentally manipulated neural networks using tDCS to examine this potential causal mechanism. The primary aim was to determine whether stimulation to the right temporoparietal junction (rTPJ) improves visual attention, and secondary aims were to determine whether 1) stimulation improves social cognitive performance and 2) visual attention moderates this improved performance., Method: Using a double-blind crossover design, 69 individuals with schizophrenia underwent both active and sham stimulation to either the rTPJ of the ventral attention network (n = 36) or the dorsomedial prefrontal cortex of the social brain network (dmPFC; n = 33). Following stimulation, participants completed tasks assessing emotion recognition and mentalizing. Concurrent eye tracking assessed visual attention, measuring proportion of time spent attending to areas of interest., Results: For emotion recognition, stimulation failed to impact either visual attention or social cognitive task accuracy. Similarly, neurostimulation failed to affect visual attention on the mentalizing task. However, exploratory analyses demonstrated that mentalizing accuracy significantly improved after stimulation to the active comparator, dmPFC, with no improvement after stimulation to rTPJ., Conclusion: Results demonstrate limited effect of a single stimulation session on visual attention and emotion recognition accuracy but provide initial support for an alternate neural mechanism for mentalizing, highlighting the importance of executive functions over visual attention., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Previous studies show that activity in the posterior default mode network (pDMN), including the posterior cingulate cortex and the precuneus, is correlated with the success of long-term episodic memory retrieval. However, the role of the anterior DMN (aDMN) including the medial prefrontal cortex is still unclear. Some studies show that activating the medial prefrontal cortex improves memory retrieval while other studies show deactivation of the medial prefrontal cortex in successful retrieval of episodic memories, suggesting a possible functional dissociation between the aDMN and pDMN., Objective: In the current study, we aim to causally explore this probable dissociation using high-definition transcranial direct current stimulation (HD-tDCS)., Methods: We perform a randomised double-blinded two-visit placebo-controlled study with 84 healthy young adults. During Visit 1 they learn 75 Swahili-English word-associations. Seven days later, they randomly receive either anodal, cathodal or sham HD-tDCS targeting the pDMN or aDMN while they recall what they have previously learned., Results: We demonstrate that anodal stimulation of the pDMN and cathodal stimulation of the aDMN, equally improve the percentage of Swahili-English word-associations recalled 7 days after learning., Conclusions: Modulating the activity in the aDMN and pDMN causally affect memory retrieval performance. HD-tDCS of the aDMN and pDMN shows that anodal stimulation of the pDMN and cathodal stimulation of the aDMN increases memory retrieval performance one week after the learning phase. Given consistent evidence, it is highly likely that we are increasing the activity in the pDMN with anodal pDMN stimulation. However, it is not clear if cathodal HD-tDCS targetting aDMN works via decoupling from the pDMN or via indirectly disinhibit pDMN., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Episodic memory retention and retrieval decline are the most common impairments observed in amnestic mild cognitive impairment (aMCI) patients who progress to Alzheimer's disease (AD). Clinical electroencephalography research shows that patients with dementia due to AD exhibit a slowing of neural electrical activity in the parietal cortex. Memory research has further suggested that successful memory performance is associated with changes in a posterior cingulate-parahippocampal cortical network together with increased θ-γ oscillatory coupling, where θ oscillations act as carrier waves for γ oscillations, which contain the actual information. However, the neurophysiological link between the memory research and clinical studies investigating aMCI and AD is lacking. In this study, we look at brain activity in aMCI and how it relates to memory performance. We demonstrate decreased γ power in the posterior cingulate cortex and the left and right parahippocampus in aMCI patients in comparison to control participants. This goes together with reduced θ coherence between the posterior cingulate cortex and parahippocampus associated with altered memory performance aMCI patients in comparison to control participants. In addition, comparing patients with aMCI to control participants reveals an effect for θ-γ coupling for the posterior cingulate cortex, and the left and right parahippocampus. Taken together, our results show that parahippocampus and posterior cingulate cortex interact via θ-γ coupling, which is associated with memory recollection and is altered in aMCI patients, offering a potential candidate mechanism for memory decline in aMCI., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)