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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.

The SUNBURST Study, a USA‐based controlled cross‐over trial demonstrated that burst spinal cord stimulation was superior compared to tonic stimulation in suppressing chronic intractable pain. However, when on burst stimulation, participants preferred lower to higher amplitudes. This led to the hypothesis that lower burst amplitudes will correlate with lower pain scores while higher amplitudes will be associated with higher pain scores. To investigate correlations between burst amplitude and self‐reported pain and different psychosocial measures. One hundred participants in the SUNBURST study were randomized to receive burst or tonic stimulation, each for 12 weeks in a cross‐over manner. Complete data of 99 participants were used in this secondary analysis. Pearson correlations were conducted at 6‐, 12‐, 18‐, and 24‐weeks postactivation to determine the strength of linear relationships between burst amplitude and (1) the average seven‐day daily pain Visual Analogue Scale (VAS), (2) the different domains of the Pain Catastrophizing Scale (PCS), (3) the different domains of the SF‐36v2 (Quality Metric Incorporated, Lincoln, RI) Health Survey. In addition, correlations between tonic stimulation amplitude and the above‐mentioned outcome measures were examined. Significant positive correlations were identified between burst amplitude and total, “worst,” and “trunk” pain for VAS; all domains for PCS; and “Role‐Physical,” “Bodily Pain,” and “General Health” for SF‐36v2™ after 12‐weeks of burst stimulation. In burst spinal cord stimulation, in contrast to tonic stimulation, lower amplitudes are more effective in suppressing pain than high amplitudes.

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

Spinal cord stimulation (SCS) is routinely used for intractable pain syndromes. For SCS to be efficacious the painful area needs to be covered by SCS induced paresthesia symptoms. Recently, novel stimulation designs have been developed for spinal cord stimulation (SCS) that are superior to classical spinal cord stimulation and exert their effects without the mandatory paresthesia. Two such stimulation designs are burst stimulation and 10 kHz stimulation. Whereas the mechanism of action of burst SCS has been partly elucidated, in that it modulates the medial pain pathway in contrast to tonic stimulation, the mechanism of action of 10 kHz SCS is still enigmatic. The goal of this paper is to provide a perspective or informed opinion on the differences and similarities between burst SCS and 10 kHz stimulation by using a literature search on the two stimulation designs. Human clinical data, simulation studies, quantitative sensory testing, cellular investigations, and comparative animal and human studies all point in the same direction, namely that 10 kHz and burst SCS might both modulate the medial pain pathway, and could be fundamentally similar neurostimulation designs.

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

Electrical stimulation via implanted electrodes that overlie the cortex of the brain is an upcoming neurosurgical technique that was hindered for a long time by insufficient knowledge of how the brain functions in a dynamic, physiological, and pathological way, as well as by technological limitations of the implantable stimulation devices. This paper provides an overview of cortex stimulation via implantable devices and introduces future possibilities to improve cortex stimulation. Cortex stimulation was initially used preoperatively as a technique to localize functions in the brain and only later evolved into a treatment technique. It was first used for pain, but more recently a multitude of pathologies are being targeted by cortex stimulation. These disorders are being treated by stimulating different cortical areas of the brain. Risks and complications are essentially similar to those related to deep brain stimulation and predominantly include haemorrhage, seizures, infection, and hardware failures. For cortex stimulation to fully mature, further technological development is required to predict its outcomes and improve stimulation designs. This includes the development of network science‐based functional connectivity approaches, genetic analyses, development of navigated high definition transcranial alternating current stimulation, and development of pseudorandom stimulation designs for preventing habituation. In conclusion, cortex stimulation is a nascent but very promising approach to treating a variety of diseases, but requires further technological development for predicting outcomes, such as network science based functional connectivity approaches, genetic analyses, development of navigated transcranial electrical stimulation, and development of pseudorandom stimulation designs for preventing habituation.

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.

A definition of free will is the ability to select for or against a course of action to fulfill a desire, without extrinsic or intrinsic constraints that compel the choice. Free will has been linked to the evolutionary development of flexible decision making. In order to develop flexibility in thoughts and behavioral responses, learning mechanisms have evolved as a modification of reflexive behavioral strategies. The ultimate goal of the brain is to reduce uncertainty inherently present in a changing environment. A way to reduce the uncertainty, which is encoded by the rostral anterior cingulate, is to make multiple predictions about the environment which are updated in parallel by sensory inputs. The prediction/behavioral strategy that fits the sensory input best is then selected, becomes the next percept/behavioral strategy, and is stored as a basis for future predictions. Acceptance of predictions (positive feedback) is mediated via the accumbens, and switching to other predictions by the dorsal anterior cingulate cortex (ACC) (negative feedback). Maintenance of a prediction is encoded by the pregenual ACC. Different cingulate territories are involved in rejection, acceptance and maintenance of predictions. Free will is known to be decreased in multiple psychopathologies, including obsessive compulsive disorder and addictions. Methodology: In modern psychosurgery three target structures exist for obsessive compulsive disorder and addiction: the dorsal ACC, the nucleus accumbens, and/or the anterior limb of the internal capsula. Research in all three areas reports favorable results with acceptable side effects. Psychosurgical interventions seem to exert their effect by a common final common pathway mediated via the pregenual ACC. Successful neuromodulation increases the capacity to choose from different options for the affected individual, as well as inhibiting unwanted options, therefore increasing free will and free won't.

AbstractTinnitus is a condition characterized by the perception of auditory phantom sounds. It is known as the result of complex interactions between auditory and nonauditory regions. However, previous structural imaging studies on tinnitus patients showed evidence of significant white matter changes caused by hearing loss that are positively correlated with aging. Current study focused on which aspects of tinnitus pathologies affect the white matter integrity the most. We used the diffusion tensor imaging technique to acquire images that have higher contrast in brain white matter to analyze how white matter is influenced by tinnitus-related factors using voxel-based methods, region of interest analysis, and deterministic tractography. As a result, white matter integrity in chronic tinnitus patients was both directly affected by age and also mediated by the hearing loss. The most important changes in white matter regions were found bilaterally in the anterior corona radiata, anterior corpus callosum, and bilateral sagittal strata. In the tractography analysis, the white matter integrity values in tracts of right parahippocampus were correlated with the subjective tinnitus loudness.

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

Fibromyalgia is a disorder distinguished by pervasive musculoskeletal pain that has pervasive effects on affected individuals magnifying the importance of finding a safe and viable treatment option. The goal of this study is to investigate if transcranial direct current stimulation (tDCS) treatment can predict the outcome of occipital nerve field stimulation (ONFS) via a subcutaneous electrode. Nine patients with fibromyalgia were selected fulfilling the American College of Rheumatology‐90 criteria. The patients were implanted with a subcutaneous trial‐lead in the C2 dermatome innervated by the occipital nerve. After the treatment phase of ONFSusing a C2 implant, each patient participated in three sessions of tDCS. Stimulation outcomes for pain suppression were examined between the two methods to determine possible correlations. Positive correlation of stimulation effect was noted between the numeric rating scale changes for pain obtained by tDCStreatments and short‐term measures of ONFS, but no correlation was noted between tDCSand long‐term ONFSoutcomes. A correlation also was noted between short‐term ONS C2 implant pain suppression and long‐term ONS C2 implant treatment success. This pilot study suggests that tDCSis a predictive measure for success of OFNSin short‐term but cannot be used as a predictive measure for success of long‐term OFNS. Our data confirm previous findings that ONFSvia an implanted electrode can improve fibromyalgia pain in a placebo‐controlled way and exert a long‐term pain suppression effect for ONFSvia an implanted electrode.

Tinnitus, a phantom sensation experienced by people around the world, currently is endured without a known cure. Some find the condition tolerable, while others are tortured on a daily basis from the incessant phantom noises. For those who seek treatment, oftentimes, they have a comorbid condition (e.g., depression, anxiety, insomnia), which is treated pharmaceutically. These products aim to reduce the comorbities associated with tinnitus thereby minimizing the overall burden present. Because of the phantom nature of tinnitus, it is often compared to neurologic pain. Since pain can be managed with pharmaceutical options, it is reasonable to assume that similar agents might work to alleviate tinnitus. The effects of antidepressants, benzodiazepines, anticonvulsants, and glutamate antagonists are reviewed in this paper. Table 1 summarizes the pharmaceutical products discussed. Due to the variety of comorbid factors and potential causes of tinnitus, there may not be one pharmaceutical treatment that will combat every type of tinnitus. Nevertheless, a product that finally addresses the true cause of tinnitus, and not just its comorbidities, will benefit millions of people worldwide.

AbstractThe question arises whether functional connectivity (FC) changes between the distress and tinnitus loudness network during resting state depends on the amount of distress tinnitus patients' experience. Fifty-five patients with constant chronic tinnitus were included in this study. Electroencephalography (EEG) recordings were performed and seed-based (at the auditory cortex) source localized FC (lagged phase synchronization) was computed for the different EEG frequency bands. Results initially demonstrate that the correlation between loudness and distress is nonlinear. Loudness correlates with beta3 and gamma band activity in the auditory cortices, and distress with alpha1 and beta3 changes in the subgenual, dorsal anterior, and posterior cingulate cortex. In comparison to nontinnitus controls, seed-based FC differed between the left auditory cortices for the alpha1 and beta3 bands in a network encompassing the posterior cingulate cortex extending into the parahippocampal area, the anterior cingulate, and insula. Furthermore, distress changes the FC between the auditory cortex, encoding loudness, and different parts of the cingulate, encoding distress: the subgenual anterior, the dorsal anterior, and the posterior cingulate. These changes are specific for the alpha1 and beta3 frequency bands. These results fit with a recently proposed model that states that tinnitus is generated by multiple dynamically active separable but overlapping networks, each characterizing a specific aspect of the unified tinnitus percept, but adds to this concept that the interaction between these networks is a complex interplay of correlations and anti-correlations between areas involved in distress and loudness depending on the distress state of the tinnitus patient.

Fibromyalgia causes widespread musculo‐skeletal pain in the four quadrants of the body. Greater occipital nerve stimulation has recently shown beneficial effects in fibromyalgia patients on pain, fatigue, and mood disorders. Laser‐evoked potentials (LEPs) are used for research to understand the pathophysiological mechanisms of pain and to evaluate the effects of pain treatment. In fibromyalgia patients, LEPs tend to have a higher N2 amplitude, a tendency to shorter latencies, and patients have a lower pain threshold. Greater occipital nerve stimulation might exert a modulation of the medial pain pathways processing the affective motivational components of pain (unpleasantness) as well as the descending pain inhibitory pathways (reducing pain), both of which are contributing to the N2P2 peak. To test this hypothesis, the authors performed LEPs in a group of fibromyalgia patients with and without greater occipital nerve stimulation. Occipital nerve stimulation does not alter the amplitudes of the LEPrecordings, although a significant difference in latencies can be seen. More specifically, latencies of the N2P2 increased in the condition after stimulation, and especially at the Pz electrode. Our results suggest Occipital Nerve Stimulation (ONS) induces a modification of the balance between antinociceptive pain inhibitory pathways and pain‐provoking pathways.

Classical neuromodulation consists of applying electrical or magnetic stimuli to the nervous system to modulate ongoing activity and connectivity. However, recently, an exciting novel neuromodulation technique was developed in which stimulation of the vagal nerve was paired with simultaneous presentation of tones, demonstrating that it reverses a tinnitus percept in noise-exposed rats.

Conversion deafness is characterized by sudden hearing loss without any identifiable cause. In the current study, we investigated presumed conversion deafness in a cochlear implant user using H215O–positron emission tomography (PET) scan with speech and noise stimuli in conjunction with audiologic tests such as impedance test and auditory response telemetry. Also, by performing a follow-up PET scan after recovery and comparing prerecovery and postrecovery scans, we attempted to find possible neural substrates of conversion deafness.

Objective: Nonpulsatile tinnitus is an auditory phantom percept characterized as a tone, or a noise‐like sound such as a hissing or buzzing sound or polyphonic, in the absence of any objective physical sound source. Although advances have been made in symptomatic pharmacologic and nonpharmacologic treatments, these treatments are unable to eliminate the tinnitus sensation in most patients. A novel approach using noninvasive and invasive neuromodulation has emerged as an interesting and promising modality for tinnitus relief.

Objective: To evaluate the clinical efficacy of pain suppression in back area and lower extremities by recently developed plate electrodes for spinal cord stimulation through percutaneous access.

Noninvasive bimodal neuromodulation reduces tinnitus symptom severity within 12 weeks of treatment for up to 12 months after completing treatment.

Objective. To investigate possible neurobehavioral changes secondary to a mindfulness based intervention (MBI) training for individuals living with Parkinson’s disease (PD). Background. In the context of complementary medicine, MBIs are increasingly being used for stress reduction and in patient populations coping with chronic illness. The use of alternative and complementary medicine may be higher in patients with chronic conditions such as PD. However, behavioral effects of mindfulness training in PD have not yet been reported in the literature and this points to an unmet need and warrants further examination. Methods. A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Questionnaires and the UPDRS I–IV were obtained at baseline and 8-week follow-up. Results. Significant changes after the MBI were found including a 5.5 point decrease on the UPDRS motor score, an increase of 0.79 points on Parkinson’s disease questionnaire (PDQ-39) pain item, and a 3.15 point increase in the Five Facet Mindfulness Questionnaire observe facet. Conclusions. To the best of our knowledge, this is the first quantitative analysis of neurobehavioral effects of MBI in PD.