NeuroDots: From Single-Target to Brain-Network Modulation: Why and What Is Needed?

OBJECTIVES: Current techniques in brain stimulation are still largely based on a phrenologic approach that a single brain target can treat a brain disorder. Nevertheless, meta-analyses of brain implants indicate an overall success rate of 50% improvement in 50% of patients, irrespective of the brain-related disorder. Thus, there is still a large margin for improvement. The goal of this manuscript is to 1) develop a general theoretical framework of brain functioning that is amenable to surgical neuromodulation, and 2) describe the engineering requirements of the next generation of implantable brain stimulators that follow from this theoretic model. MATERIALS AND METHODS: A neuroscience and engineering literature review was performed to develop a universal theoretical model of brain functioning and dysfunctioning amenable to surgical neuromodulation. RESULTS: Even though a single target can modulate an entire network, research in network science reveals that many brain disorders are the consequence of maladaptive interactions among multiple networks rather than a single network. Consequently, targeting the main connector hubs of those multiple interacting networks involved in a brain disorder is theoretically more beneficial. We, thus, envision next-generation network implants that will rely on distributed, multisite neuromodulation targeting correlated and anticorrelated interacting brain networks, juxtaposing alternative implant configurations, and finally providing solid recommendations for the realization of such implants. In doing so, this study pinpoints the potential shortcomings of other similar efforts in the field, which somehow fall short of the requirements. CONCLUSION: The concept of network stimulation holds great promise as a universal approach for treating neurologic and psychiatric disorders.

Intra/inter-observer reliability of cystoscopic sphincter evaluation in men undergoing sling surgery.

OBJECTIVES: To assess the intra/inter-observer reliability of cystoscopic sphincter evaluation (CSE) in men undergoing sling surgery for urinary incontinence and if possible to evaluate its correlation with the final clinical decision. PATIENTS AND METHODS: Two expert urologists prospectively filmed and recorded, incontinent patient's cystoscopies according to a standard scenario. Anonymised recordings where randomly offered to the same observer twice. The observers (medical students, urology residents and full urologist with 0-5, 5-10, >10 years of practice, respectively) were asked to assess and score the recordings without knowing any of the patients' characteristics. RESULTS: In total, 37 recordings were scored twice by the 26 observers. The intraclass correlation coefficient (ICC) for intra-observer reliability of the CSE was 0.54 (moderate), 0.58 (moderate) and 0.60 (substantial) for medical students, residents, and urologists, respectively. However, when stratifying observers according to their experience, the lowest agreement values were found between experts with >10 years of experience. The inter-observer reliability for the CSE ICCs ranged between 0.31and 0.53, with the lowest ICC value observed between urologists (0.31). CONCLUSIONS: The study demonstrates poor intra- and inter-observer reliability of the CSE. According to these results, a CSE does not add valuable information to the clinical evaluation. In this scenario, it should not be considered in isolation from the patient's characteristics.

A multi-phase, multi-centre development and validation of two maturity tools assessing the implementation of the FlaQuM co-creation roadmap.

BACKGROUND: As part of the new Flanders Quality Model (FlaQuM) towards sustainable quality management systems, a co-creation roadmap with six primary drivers and 19 building blocks that guides healthcare organisations has been developed. Currently, no assessment tool is available to monitor hospitals' quality management systems implementation according to this co-creation roadmap. Therefore, we aimed to measure the maturity of the implementation of the FlaQuM co-creation roadmap in hospitals. METHODS: A three-phase approach in co-design with 19 hospitals started with defining the scope, followed by establishing content validity through a literature review, involvement of content experts (n=47), 20 focus groups with content experts (n=79) and a Delphi round with healthcare quality managers (n=19) to test the content validity index (CVI). Construct validity was assessed by confirmatory factor analyses and convergent validity by Spearman's ρ correlation coefficients. RESULTS: Based on 17 included existing maturity instruments and sub-components of content experts, two maturity tools were developed according to the implementation of the FlaQuM co-creation roadmap: 1) a maturity matrix with 52 sub-components and 2) a co-creation scan with 19 statements. The overall scale-CVI varied between 93.3% and 90.0% in terms of relevance and clarity, respectively. In a sample of 119 healthcare professionals, factor analyses revealed a 6-factor structure and 16 (84.2%) of the 19 hypothesis for testing convergent validity between both maturity tools were statistically significant. CONCLUSION: Measuring the implementation of the FlaQuM co-creation roadmap and monitoring its maturity over time should be feasible by using these comprehensive maturity tools in hospitals. Results of both tools should be able to describe the current state of hospitals' implementation of the co-creation roadmap as basis for strategic improvement plans and next steps.

Tinnitus: Clinical Insights in Its Pathophysiology-A Perspective.

Tinnitus, the perception of sound without a corresponding external sound source, and tinnitus disorder, which is tinnitus with associated suffering, present a multifaceted clinical challenge due to its heterogeneity and its incompletely understood pathophysiology and especially due to the limited therapeutic options. In this narrative review, we give an overview on various clinical aspects of tinnitus including its heterogeneity, contributing factors, comorbidities and therapeutic pathways with a specific emphasis on the implications for its pathophysiology and future research directions. Tinnitus exhibits high perceptual variability between affected individuals (heterogeneity) and within affected individuals (temporal variability). Hearing loss emerges as predominant risk factor and the perceived pitch corresponds to areas of hearing loss, supporting the compensatory response theory. Whereas most people who have tinnitus can live a normal life, in 10-20% tinnitus interferes severely with quality of life. These patients suffer frequently from comorbidities such as anxiety, depression or insomnia, acting as both risk factors and consequences. Accordingly, neuroimaging studies demonstrate shared brain networks between tinnitus and stress-related disorders shedding light on the intricate interplay of mental health and tinnitus. The challenge lies in deciphering causative relationships and shared pathophysiological mechanisms. Stress, external sounds, time of day, head movements, distraction, and sleep quality can impact tinnitus perception. Understanding these factors provides insights into the interplay with autonomic, sensory, motor, and cognitive processes. Counselling and cognitive-behavioural therapy demonstrate efficacy in reducing suffering, supporting the involvement of stress and anxiety-related networks. Hearing improvement, especially through cochlear implants, reduces tinnitus and thus indirectly validates the compensatory nature of tinnitus. Brain stimulation techniques can modulate the suffering of tinnitus, presumably by alteration of stress-related brain networks. Continued research is crucial for unravelling the complexities of tinnitus. Progress in management hinges on decoding diverse manifestations, identifying treatment-responsive subtypes, and advancing targeted therapeutic approaches.

Brain-computer interface relieves chronic chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) includes negative sensations that remain a major chronic problem for cancer survivors. Previous research demonstrated that neurofeedback (a closed-loop brain-computer interface [BCI]) was effective at treating CIPN versus a waitlist control (WLC). The authors' a priori hypothesis was that BCI would be superior to placebo feedback (placebo control [PLC]) and to WLC in alleviating CIPN and that changes in brain activity would predict symptom report. METHODS: Randomization to one of three conditions occurred between November 2014 and November 2018. Breast cancer survivors no longer in treatment were assessed at baseline, at the end of 20 treatment sessions, and 1 month later. Auditory and visual rewards were given over 20 sessions based on each patient's ability to modify their own electroencephalographic signals. The Pain Quality Assessment Scale (PQAS) at the end of treatment was the primary outcome, and changes in electroencephalographic signals and 1-month data also were examined. RESULTS: The BCI and PLC groups reported significant symptom reduction. The BCI group demonstrated larger effect size differences from the WLC group than the PLC group (mean change score: BCI vs. WLC, -2.60 vs. 0.38; 95% confidence interval, -3.67, -1.46 [p = .000; effect size, 1.07]; PLC, -2.26; 95% confidence interval, -3.33, -1.19 [p = .001 vs. WLC; effect size, 0.9]). At 1 month, symptoms continued to improve only for the BCI group. Targeted brain changes at the end of treatment predicted symptoms at 1 month for the BCI group only. CONCLUSIONS: BCI is a promising treatment for CIPN and may have a longer lasting effect than placebo (nonspecific BCI), which is an important consideration for long-term symptom relief. Although scientifically interesting, the ability to separate real from placebo treatment may not be as important as understanding the placebo effects differently from effects of the intervention. PLAIN LANGUAGE SUMMARY: Chemotherapy-induced nerve pain (neuropathy) can be disabling for cancer survivors; however, the way symptoms are felt depends on how the brain interprets the signals from nerves in the body. We determined that the perception of neuropathy can be changed by working directly with the brain. Survivors in our trial played 20 sessions of a type of video game that was designed to change the way the brain processed sensation and movement. In this, our second trial, we again observed significant improvement in symptoms that lasted after the treatment was complete.

Measuring in-hospital quality multidimensionally by integrating patients', kin's and healthcare professionals' perspectives: development and validation of the FlaQuM-Quickscan.

BACKGROUND: Measuring quality is essential to drive improvement initiatives in hospitals. An instrument that measures healthcare quality multidimensionally and integrates patients', kin's and professionals' perspectives is lacking. We aimed to develop and validate an instrument to measure healthcare quality multidimensionally from a multistakeholder perspective. METHODS: A multi-method approach started by establishing content and face validity, followed by a multi-centre study in 17 Flemish (Belgian) hospitals to assess construct validity through confirmatory factor analysis, criterion validity through determining Pearson's correlations and reliability through Cronbach's alpha measurement. The instrument FlaQuM-Quickscan measures 'Healthcare quality for patients and kin' (part 1) and 'Healthcare quality for professionals' (part 2). This bipartite instrument mirrors 15 quality items and 3 general items (the overall quality score, recommendation score and intention-to-stay score). A process evaluation was organised to identify effective strategies in instrument distribution by conducting semi-structured interviews with quality managers. RESULTS: By involving experts in the development of quality items and through pilot testing by a multi-stakeholder group, the content and face validity of instrument items was ensured. In total, 13,615 respondents (5,891 Patients/kin and 7,724 Professionals) completed the FlaQuM-Quickscan. Confirmatory factor analyses showed good to very good fit and correlations supported the associations between the quality items and general items for both instrument parts. Cronbach's alphas supported the internal consistency. The process evaluation revealed that supportive technical structures and approaching respondents individually were effective strategies to distribute the instrument. CONCLUSIONS: The FlaQuM-Quickscan is a valid instrument to measure healthcare quality experiences multidimensionally from an integrated multistakeholder perspective. This new instrument offers unique and detailed data to design sustainable quality management systems in hospitals. Based on these data, hospital management and policymakers can set quality priorities for patients', kin's and professionals' care. Future research should investigate the transferability to other healthcare systems and examine between-stakeholders and between-hospitals variation.

Sustainable quality management in hospitals: The experiences of healthcare quality managers.

BACKGROUND: Quality management systems are essential in hospitals, but evidence shows a real literature gap on the sustainable implementation of quality. PURPOSE: This study aimed to explore and identify enablers towards sustainable quality management in hospitals. Research design and Study Sample: Interviews were conducted with 23 healthcare quality managers from 20 hospitals. Data collection and/or Analysis: Data collection and analysis were conducted simultaneously by using the Qualitative Analysis Guide of Leuven and following the COREQ Guidelines. Thematic analysis from interview transcripts was performed in NVivo 12. RESULTS: The results reveal two categories: (1) quality in the organisation's DNA and (2) quality in the professional's DNA. The first category consists of: bottom-up and top-down management, the organisation-wide integration of quality and an organisational culture shift. The second one consists of: quality awareness, understanding the added value, the encouragement and engagement, the accountability and ownership for quality. Moving towards sustainable quality management systems in hospitals requires a good interaction between a bottom-up approach and leadership to ensure continuous support from healthcare stakeholders. CONCLUSIONS: This study contributes to existing conceptual and theoretical foundations with practical insights into sustainable quality management. The findings can guide quality departments and hospital management to regain professionals' commitment to quality and to establish a sustainable quality management system.

Minimal Clinically Important Difference of Tinnitus Outcome Measurement Instruments-A Scoping Review.

OBJECTIVE: Tinnitus assessment and outcome measurement are complex, as tinnitus is a purely subjective phenomenon. Instruments used for the outcome measurement of tinnitus in the context of clinical trials include self-report questionnaires, visual analogue or numeric rating scales and psychoacoustic measurements of tinnitus loudness. For the evaluation of therapeutic interventions, it is critical to know which changes in outcome measurement instruments can be considered as clinically relevant. For this purpose, the concept of the minimal clinically important difference (MCID) has been introduced. STUDY DESIGN: Here we performed a literature research in PubMed in order to identify for which tinnitus outcome measurements MCID criteria have been estimated and which of these estimates fulfil the current methodological standards and can thus be considered as established. RESULTS: For most, but not all tinnitus outcome instruments, MCID calculations have been performed. The MCIDs for the Tinnitus Handicap Inventory (THI), the Tinnitus Questionnaire (TQ), the Tinnitus Functional Index (TFI) and visual analogue scales (VAS) vary considerably across studies. Psychoacoustic assessments of tinnitus such as loudness matching have not shown sufficient reliability and validity for the use as an outcome measurement. CONCLUSION: Future research should aim at the confirmation of the available estimates in large samples involving various therapeutic interventions and under the consideration of time intervals and baseline values. As a rule of thumb, an improvement of about 15% can be considered clinically meaningful, analogous to what has been seen in other entirely subjective pathologies like chronic pain.

EEG-Based Cortical Alterations in Individuals With Chronic Knee Pain Secondary to Osteoarthritis: A Cross-sectional Investigation.

Chronic painful knee osteoarthritis (OA) is a disabling physical health condition. Alterations in brain responses to arthritic changes in the knee may explain persistent pain. This study investigated source localized, resting-state electroencephalography activity and functional connectivity in people with knee OA, compared to healthy controls. Adults aged 44 to 85 years with knee OA (n = 37) and healthy control (n = 39) were recruited. Resting-state electroencephalography was collected for 10 minutes and decomposed into infraslow frequency (ISF) to gamma frequency bands. Standard low-resolution electromagnetic brain tomography statistical nonparametric maps were conducted, current densities of regions of interest were compared between groups and correlation analyses were performed between electroencephalography (EEG) measures and clinical pain and functional outcomes in the knee OA group. Standard low-resolution electromagnetic brain tomography nonparametric maps revealed higher (P = .006) gamma band activity over the right insula (RIns) in the knee OA group. A significant (P < .0001) reduction in ISF band activity at the pregenual anterior cingulate cortex, whereas higher theta, alpha, beta, and gamma band activity at the dorsal anterior cingulate cortex, pregenual anterior cingulate cortex, the somatosensory cortex, and RIns in the knee OA group were identified. ISF activity of the dorsal anterior cingulate cortex was positively correlated with pain measures and psychological distress scores. Theta and alpha activity of RIns were negatively correlated with pain interference. In conclusion, aberrations in infraslow and faster frequency EEG oscillations at sensory discriminative, motivational-affective, and descending inhibitory cortical regions were demonstrated in people with chronic painful knee OA. Moreover, EEG oscillations were correlated with pain and functional outcome measures. PERSPECTIVE: This study confirms alterations in the rsEEG oscillations and its relationship with pain experience in people with knee OA. The study provides potential cortical targets and the EEG frequency bands for neuromodulatory interventions for managing chronic pain experience in knee OA.

BurstDR spinal cord stimulation rebalances pain input and pain suppression in the brain in chronic neuropathic pain.

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 ß 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-ß 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.

Correlation Between Abdominal Wall Stimulation and Spinal Cord Stimulator Tip Location: A Nonrandomized Clinical Trial.

OBJECTIVES: This study aimed to investigate the correlation between the vertebral level of paddle placement and abdominal wall stimulation (AWS) after differential target multiplexed spinal cord stimulation (SCS) to improve the safety and effectiveness of SCS for patients with chronic pain, particularly those with low back pain (LBP). MATERIALS AND METHODS: The Correlation Between Abdominal Wall Stimulation and Spinal Cord Stimulator Tip Location study was a nonrandomized clinical trial that included 24 patients with SCS for persistent spinal pain syndrome (PSPS) type 2 (trial ID: NCT05565469). The intervention involved increasing stimulation amplitude to a maximum tolerable value and obtaining numerical rating scores for AWS. The primary outcome measure was the association between AWS, the neurostimulator tip, and conus medullaris location, whereas the secondary outcome was the pre-postinterventional difference in proportion of patients experiencing AWS. Patient demographics and postoperative imaging were assessed. Statistical analyses involved descriptive statistics, a descriptive logistic regression, and a McNemar test. RESULTS: The results of the study showed that seven (29%) of the 24 patients experienced AWS either previously or during interventional stimulation. However, there was no significant correlation found between AWS and the location of the neurostimulator tip or conus medullaris, and there was no difference in the pre-postinterventional proportion of patients experiencing AWS. CONCLUSIONS: The study concludes that a relatively high proportion of patients who received SCS for PSPS type 2 experienced or previously experienced AWS. There was no significant correlation found between the location of the neurostimulator tip and the occurrence of AWS. This suggests that AWS may not be solely dependent on the stimulation itself and emphasizes the need to consider other factors. Nonetheless, this study provides important insights into the occurrence of AWS in patients receiving SCS for PSPS type 2 and highlights the need for further research in this area. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT05565469.

Impact of the Standardization of Penile Cancer Care on the Quality of Care, Outcomes, and Academic-driven Centralization in a Single eUROGEN Referral Center.

BACKGROUND: Penile cancer (PeCa) represents a diagnostic and therapeutic challenge given the low patient volume, which may result in inadequate physician expertise and poor guideline adherence. Since 2015, we have developed a specific care pathway for PeCa in our tertiary referral center. OBJECTIVE: To evaluate the impact of a dedicated PeCa care pathway on patient management, the adequacy of pathological reporting, and oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively queried our institutional registry (S-66482) to identify patients who were surgically treated for PeCa between January 1989 and April 2022. The patient numbers were evaluated within a broader national context. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared patient, surgery, tumor, and pathological data before and after 2015. Kaplan-Meier analysis was used to compare local and regional recurrence rates and cancer-specific survival (CSS). RESULTS AND LIMITATIONS: Overall, 313 patients were included, of whom 204 (65.1%) were surgically treated after 2015. The median number of patients treated yearly was significantly higher after 2015 (26 vs 5; p < 0.01). Patients treated after 2015 more frequently had no palpable lymph nodes at diagnosis, despite similar primary tumor stage. After adoption of the PeCa care pathway, organ-sparing surgery (OSS) was more commonly performed (79.9% vs 57.8%; p < 0.01) despite local staging being similar and without observing a significant increase in positive margins. Surgical staging in patients with European Association of Urology intermediate- or high-risk tumors was conducted more frequently after 2015 (90% vs 41%; p < 0.01). Pathology reporting was standardized, and there was more frequent reporting of p16 staining status (81.4% vs 8.3%; p < 0.01), lymphovascular invasion (93.8% vs 44.3%; p < 0.01), and perineural invasion (92.4% vs 44.3%; p < 0.01) following implementation. CONCLUSIONS: Implementation of a standardized care pathway for PeCa resulted in higher rates of OSS and pathological nodal staging and more complete pathology reports. Considering that these changes were associated with an increase in the number of patients treated, academic-driven centralization may play a role in optimizing the management of these patients. PATIENT SUMMARY: We evaluated the impact of a care pathway for patients with penile cancer on patient management, the completeness of pathology reporting, and cancer control. We found that implementation of this pathway was associated with an increase in the number of patients treated, higher rates of organ-sparing surgery and lymph node staging, and more complete pathology reports. Centralization of care may play a role in optimizing the management of penile cancer.

Convergent Validity of 2 Widely Used Methodologies for Calculating the Hospital Standardized Mortality Ratio in Flanders, Belgium.

OBJECTIVES: To assess their construct validity, we compared results from 2 models used for estimating hospital standardized mortality ratios (HSMRs) in Belgium. The method of the Flemish Hospital Network (FHN) is based on a logistic regression for each of the 64 All Patient Refined Diagnosis-Related Groups that explain 80% of mortality and uses the Elixhauser score to correct for comorbidities. (H)SMRs published on the 3M-Benchmark-Portal are calculated by a simpler indirect standardization for All Patient Refined Diagnosis-Related Groups and risk of mortality (ROM) at discharge. METHODS: We used administrative data from all eligible hospital admissions in 22 Flemish hospitals between 2016 and 2019 (FHN, n = 682,935; 3M, n = 2,122,305). We evaluated model discrimination and accuracy and assessed agreement in estimated HSMRs between methods. RESULTS: The Spearman correlation between HSMRs generated by the FHN model and the standard 3M model was 0.79. Although 2 of 22 hospitals showed opposite classification results, that is, an HSMR significantly <1 according to the FHN method but significantly >1 according to the 3M model, classification agreement between methods was significant (agreement for 59.1% of hospitals, κ = 0.45). The 3M model ( c statistic = 0.96, adjusted Brier score = 26%) outperformed the FHN model (0.87, 17%). However, using ROM at admission instead of at discharge in the 3M model significantly reduced model performance ( c statistic = 0.94, adjusted Brier score = 21%), but yielded similar HSMR estimates and eliminated part of the discrepancy with FHN results. CONCLUSIONS: Results of both models agreed relatively well, supporting convergent validity. Whereas the FHN method only adjusts for disease severity at admission, the ROM indicator of the 3M model includes diagnoses not present on admission. Although diagnosis codes generated by complications during hospitalization have the tendency to increase the predictive performance of a model, these should not be included in risk adjustment procedures.

Tinnitus Guidelines and Their Evidence Base.

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.

A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study.

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.

Tinnitus and distress: an electroencephalography classification study.

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.

Exploring electroencephalographic infraslow neurofeedback treatment for chronic low back pain: a double-blinded safety and feasibility randomized placebo-controlled trial.

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.

Fatty Acid Amide Hydrolase: An Integrative Clinical Perspective.

Introduction: Fatty acid amide hydrolase (FAAH) is one of the main terminating enzymes of the endocannabinoid system (ECS). Since being discovered in 1996, the modulation of FAAH has been viewed as a compelling alternative strategy to obtain the beneficial effect of the ECS. With a considerable amount of FAAH-related publication over time, the next step would be to comprehend the proximity of this evidence for clinical application. Objective: This review intends to highlight the rationale of FAAH modulation and provide the latest evidence from clinical studies. Methods: Publication searches were conducted to gather information focused on FAAH-related clinical evidence with an extension to the experimental research to understand the biological plausibility. The subtopics were selected to be multidisciplinary to offer more perspective on the current state of the arts. Discussion: Experimental and clinical studies have demonstrated that FAAH was highly expressed not only in the central nervous system but also in the peripheral tissues. As the key regulator of endocannabinoid signaling, it would appear that FAAH plays a role in the modulation of mood and emotional response, reward system, pain perception, energy metabolism and appetite regulation, inflammation, and other biological processes. Genetic variants may be associated with some conditions such as substance/alcohol use disorders, obesity, and eating disorder. The advancement of functional neuroimaging has enabled the evaluation of the neurochemistry of FAAH in brain tissues and this can be incorporated into clinical trials. Intriguingly, the application of FAAH inhibitors in clinical trials seems to provide less striking results in comparison with the animal models, although some potential still can be seen. Conclusion: Modulation of FAAH has an immense potential to be a new therapeutic candidate for several disorders. Further exploration, however, is still needed to ensure who is the best candidate for the treatment strategy.