A novel theta-controlled vibrotactile brain-computer interface to treat chronic pain: a pilot study.

Limitations in chronic pain therapies necessitate novel interventions that are effective, accessible, and safe. Brain-computer interfaces (BCIs) provide a promising modality for targeting neuropathology underlying chronic pain by converting recorded neural activity into perceivable outputs. Recent evidence suggests that increased frontal theta power (4-7 Hz) reflects pain relief from chronic and acute pain. Further studies have suggested that vibrotactile stimulation decreases pain intensity in experimental and clinical models. This longitudinal, non-randomized, open-label pilot study's objective was to reinforce frontal theta activity in six patients with chronic upper extremity pain using a novel vibrotactile neurofeedback BCI system. Patients increased their BCI performance, reflecting thought-driven control of neurofeedback, and showed a significant decrease in pain severity (1.29 ± 0.25 MAD, p = 0.03, q = 0.05) and pain interference (1.79 ± 1.10 MAD p = 0.03, q = 0.05) scores without any adverse events. Pain relief significantly correlated with frontal theta modulation. These findings highlight the potential of BCI-mediated cortico-sensory coupling of frontal theta with vibrotactile stimulation for alleviating chronic pain.

IpsiHand Brain-Computer Interface Therapy Induces Broad Upper Extremity Motor Recovery in Chronic Stroke.

Background and Purpose: Chronic hemiparetic stroke patients have very limited benefits from current therapies. Brain-computer interface (BCI) engaging the unaffected hemisphere has emerged as a promising novel therapeutic approach for chronic stroke rehabilitation. This study investigated the effectiveness of the IpsiHand System, a contralesionally-controlled BCI therapy in chronic stroke patients with impaired upper extremity motor function. We further explored neurophysiological features of motor recovery affected by BCI. We hypothesized that BCI therapy would induce a broad motor recovery in the upper extremity (proximal and distal), and there would be corresponding changes in baseline theta and gamma oscillations, which have been shown to be associated with motor recovery. Methods: Thirty chronic hemiparetic stroke patients performed a therapeutic BCI task for 12 weeks. Motor function assessment data and resting state electroencephalogram (EEG) signals were acquired before initiating BCI therapy and across BCI therapy sessions. The Upper Extremity Fugl-Meyer assessment (UEFM) served as a primary motor outcome assessment tool. Theta-gamma cross-frequency coupling (CFC) was computed and correlated with motor recovery. Results: Chronic stroke patients achieved significant motor improvement with BCI therapy. We found significant improvement in both proximal and distal upper extremity motor function. Importantly, motor function improvement was independent of Botox application. Theta-gamma CFC enhanced bilaterally over the C3 and C4 motor electrodes following BCI therapy. We observed significant positive correlations between motor recovery and theta gamma CFC increase across BCI therapy sessions. Conclusions: BCI therapy resulted in significant motor function improvement across the proximal and distal upper extremities of patients. This therapy was significantly correlated with changes in baseline cortical dynamics, specifically theta-gamma CFC increases in both the right and left motor regions. This may represent rhythm-specific cortical oscillatory mechanism for BCI-driven motor rehabilitation in chronic stroke patients.

Preoperative functional connectivity by magnetic resonance imaging for refractory neocortical epilepsy.

Objective: Patients with refractory epilepsy experience extensive and invasive clinical testing for seizure onset zones treatable by surgical resection. However, surgical resection can fail to provide therapeutic benefit, and patients with neocortical epilepsy have the poorest therapeutic outcomes. This case series studied patients with neocortical epilepsy who were referred for surgical treatment. Prior to surgery, patients volunteered for resting-state functional magnetic resonance imaging (rs-fMRI) in addition to imaging for the clinical standard of care. This work examined the variability of functional connectivity in patients, estimated from rs-fMRI, for associations with surgical outcomes. Methods: This work examined pre-operative structural imaging, pre-operative rs-fMRI, and post-operative structural imaging from seven epilepsy patients. Review of the clinical record provided Engel classifications for surgical outcomes. A novel method assessed pre-operative rs-fMRI from patients using comparative rs-fMRI from a large cohort of healthy control subjects and estimated Gibbs distributions for functional connectivity in patients compared to healthy controls. Results: Three patients had Engel classification Ia, one patient had Engel classification IIa, and three patients had Engel classification IV. Metrics for variability of functional connectivity, including absolute differences of the functional connectivity of each patient from healthy control averages and probabilistic scores for absolute differences, were higher for patients classified as Engel IV, for whom epilepsy surgery provided no meaningful improvement. Significance: This work continues on-going efforts to use rs-fMRI to characterize abnormal functional connectivity in the brain. Preliminary evidence indicates that the topography of variant functional connectivity in epilepsy patients may be clinically relevant for identifying patients unlikely to have favorable outcomes after epilepsy surgery. Widespread topographic variations of functional connectivity also support the hypothesis that epilepsy is a disease of brain resting-state networks.

Relief of chronic pain associated with increase in midline frontal theta power.

Introduction: There is a need to identify objective cortical electrophysiological correlates for pain relief that could potentially contribute to a better pain management. However, the field of developing brain biomarkers for pain relief is still largely underexplored. Objectives: The objective of this study was to investigate cortical electrophysiological correlates associated with relief from chronic pain. Those features of pain relief could serve as potential targets for novel therapeutic interventions to treat pain. Methods: In 12 patients with chronic pain in the upper or lower extremity undergoing a clinically indicated nerve block procedure, brain activity was recorded by means of electroencephalogram before and 30 minutes after the nerve block procedure. To determine the specific cortical electrophysiological correlates of relief from chronic pain, 12 healthy participants undergoing cold-pressor test to induce experimental acute pain were used as a control group. The data were analyzed to characterize power spectral density patterns of pain relief and identify their source generators at cortical level. Results: Chronic pain relief was associated with significant delta, theta, and alpha power increase at the frontal area. However, only midfrontal theta power increase showed significant positive correlation with magnitude of reduction in pain intensity. The sources of theta power rebound were located in the left dorsolateral prefrontal cortex (DLPFC) and midline frontal cortex. Furthermore, theta power increase in the midline frontal cortex was significantly higher with chronic vs acute pain relief. Conclusion: These findings may provide basis for targeting chronic pain relief via modulation of the midline frontal theta oscillations.

Theta-gamma coupling as a cortical biomarker of brain-computer interface-mediated motor recovery in chronic stroke.

Chronic stroke patients with upper-limb motor disabilities are now beginning to see treatment options that were not previously available. To date, the two options recently approved by the United States Food and Drug Administration include vagus nerve stimulation and brain-computer interface therapy. While the mechanisms for vagus nerve stimulation have been well defined, the mechanisms underlying brain-computer interface-driven motor rehabilitation are largely unknown. Given that cross-frequency coupling has been associated with a wide variety of higher-order functions involved in learning and memory, we hypothesized this rhythm-specific mechanism would correlate with the functional improvements effected by a brain-computer interface. This study investigated whether the motor improvements in chronic stroke patients induced with a brain-computer interface therapy are associated with alterations in phase-amplitude coupling, a type of cross-frequency coupling. Seventeen chronic hemiparetic stroke patients used a robotic hand orthosis controlled with contralesional motor cortical signals measured with EEG. Patients regularly performed a therapeutic brain-computer interface task for 12 weeks. Resting-state EEG recordings and motor function data were acquired before initiating brain-computer interface therapy and once every 4 weeks after the therapy. Changes in phase-amplitude coupling values were assessed and correlated with motor function improvements. To establish whether coupling between two different frequency bands was more functionally important than either of those rhythms alone, we calculated power spectra as well. We found that theta-gamma coupling was enhanced bilaterally at the motor areas and showed significant correlations across brain-computer interface therapy sessions. Importantly, an increase in theta-gamma coupling positively correlated with motor recovery over the course of rehabilitation. The sources of theta-gamma coupling increase following brain-computer interface therapy were mostly located in the hand regions of the primary motor cortex on the left and right cerebral hemispheres. Beta-gamma coupling decreased bilaterally at the frontal areas following the therapy, but these effects did not correlate with motor recovery. Alpha-gamma coupling was not altered by brain-computer interface therapy. Power spectra did not change significantly over the course of the brain-computer interface therapy. The significant functional improvement in chronic stroke patients induced by brain-computer interface therapy was strongly correlated with increased theta-gamma coupling in bihemispheric motor regions. These findings support the notion that specific cross-frequency coupling dynamics in the brain likely play a mechanistic role in mediating motor recovery in the chronic phase of stroke recovery.

Spatial and Frequency-specific Electrophysiological Signatures of Tonic Pain Recovery in Humans.

The objective of this study was to comprehensively investigate patterns of brain activities associated with pain recovery following experimental tonic pain in humans. Specific electrophysiological features of pain recovery may either be monitored or be modulated through neurofeedback (NF) as a novel chronic pain treatment. The cold pressor test was applied with simultaneous electroencephalogram (EEG) recording. EEG data were acquired, and analyzed to define: (1) EEG power topography patterns of pain recovery; (2) source generators of pain recovery at cortical level; (3) changes in functional connectivity associated with pain recovery; (4) features of phase-amplitude coupling (PAC) as it relates to pain recovery. The novel finding of this study is that recovery from pain was characterized by significant theta power rebound at the left fronto-central area. The sources of theta power over-recovery were located in the left dorsolateral prefrontal cortex (DLPFC), cingulate cortex, left insula and contralateral sensorimotor cortex. These effects were paralleled by theta band connectivity increase within hemispheres in a prefrontal-somatosensory network and interhemispherically between prefrontal and parietal areas. In addition, this study revealed significant reduction in PAC between theta/alpha and gamma oscillations during recovery period following tonic pain. These findings have largely been replicated across two identical sessions. Our study emphasizes the association between pain recovery and left lateral prefrontal theta power rebound, and significant over-recovery of functional connectivity in prefrontal-sensorimotor neural network synchronized at theta frequencies. These findings may provide basis for chronic pain treatment by modulating neural oscillations at theta frequencies in left prefrontal cortex.

Electrophysiological investigation of the contribution of attention to altered pain inhibition processes in patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with chronic abdominal pain and altered pain processing. The aim of this study was to examine whether attentional processes contribute to altered pain inhibition processes in patients with IBS. Nine female patients with IBS and nine age-/sex-matched controls were included in a pain inhibition paradigm using counter-stimulation and distraction with electroencephalography. Patients with IBS showed no inhibition of pain-related brain activity by heterotopic noxious counter-stimulation (HNCS) or selective attention. In the control group, HNCS and selective attention decreased the N100, P260 and high-gamma oscillation power. In addition, pain-related high-gamma power in sensorimotor, anterior cingulate and left dorsolateral prefrontal cortex was decreased by HNCS and selective attention in the control group, but not in patients with IBS. These results indicate that the central pain inhibition deficit in IBS reflects interactions between several brain processes related to pain and attention.

Integration of bilateral nociceptive inputs tunes spinal and cerebral responses.

Together with the nociceptive system, pain protects the body from tissue damage. For instance, when the RIII-reflex is evoked by sural nerve stimulation, nociceptive inputs activate flexor muscles and inhibit extensor muscles of the affected lower limb while producing the opposite effects on the contralateral muscles. But how do the spinal cord and brain integrate concurrent sensorimotor information originating from both limbs? This is critical for evoking coordinated responses to nociceptive stimuli, but has been overlooked. Here we show that the spinal cord integrates spinal inhibitory and descending facilitatory inputs during concurrent bilateral foot stimulation, resulting in facilitation of the RIII-reflex and bilateral flexion. In these conditions, high-gamma oscillation power was also increased in the dorsolateral prefrontal, anterior cingulate and sensorimotor cortex, in accordance with the involvement of these regions in cognitive, motor and pain regulation. We propose that the brain and spinal cord can fine-tune nociceptive and pain responses when nociceptive inputs arise from both lower limbs concurrently, in order to allow adaptable behavioural responses.

Improving working memory and pain inhibition in older persons using transcranial direct current stimulation.

The aim of the present study was to examine whether transcranial Direct Current Stimulation (tDCS) could enhance working memory and pain inhibition in older persons. Fifteen volunteers (7 women, 8 men; mean ± SD: 64 ± 4.4 y.o.) participated in two tDCS sessions during which an n-back task was performed with two levels of working memory load, while painful stimulation was delivered at the ankle. The experiment included five within-subject counterbalanced conditions (pain alone and 0-back or 2-back with or without pain) performed twice during each session. Compared with the pre-tDCS baseline, anodal tDCS decreased response times and improved pain inhibition by working memory in the 2-back condition (p < 0.01), but not in the 0-back or pain alone conditions, while sham tDCS produced no effect (all p > 0.3). These results indicate that working memory and pain inhibition can be improved by tDCS in older persons.

Cortical integration of bilateral nociceptive signals: when more is less.

Integration of nociceptive information is essential to produce adapted responses, to promote body integrity and survival. However, how the brain integrates nociceptive inputs from different body areas remains unknown. The aim of this study was to examine the cortical integration of bilateral nociceptive inputs evoked by laser heat stimuli. Sixteen healthy volunteers (8 F, 8 M; age: 25.5 ± 4.3) were recruited to participate in one session during which painful laser stimuli were applied to their hands with 2 Nd:YAP laser systems. Electroencephalographic activity was recorded to measure laser-evoked potentials and event-related spectral perturbations. Twenty nociceptive stimuli were applied in each of the 4 counterbalanced conditions: (1) right hand, (2) left hand, and both hands with (3) attention to the right or (4) attention to the left. Compared with unilateral conditions, N2 and P2 peak amplitude as well as gamma oscillation power were decreased in bilateral conditions (P < 0.05), but these effects were not affected by the direction of attention (P > 0.1). By contrast, pain was not significantly different in any condition (P > 0.05). These findings show that although more nociceptive inputs reach the brain with multiple nociceptive stimuli, their sensory representation is decreased while pain perception remains unchanged. These interactions between cerebral processing of nociceptive information from different body regions could support coordinated behavioral responses when pain origins from multiple sources.

Enhancement of pain inhibition by working memory with anodal transcranial direct current stimulation of the left dorsolateral prefrontal cortex.

The aim of this study was to examine whether transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) enhances pain inhibition by improving working memory (WM). Forty healthy volunteers participated in two tDCS sessions. Pain was evoked by electrical stimulation at the ankle. Participants performed an n-back task (0-back and 2-back). The experimental protocol comprised five counterbalanced conditions (0-back, 2-back, pain, 0-back with pain and 2-back with pain) that were performed twice (pre-tDCS baseline and during tDCS). Compared with the pre-tDCS baseline values, anodal tDCS decreased response times for the 2-back condition (p < 0.01) but not for the 0-back condition (p > 0.5). Anodal tDCS also decreased pain ratings marginally in the 2-back with pain condition, but not the 0-back with pain condition (p = 0.052 and p > 0.2, respectively). No effect was produced by sham tDCS for any condition (p > 0.2). These results indicate that tDCS of the left DLPFC may enhance pain inhibition by improving WM.

Inhibition of Pain and Pain-Related Brain Activity by Heterotopic Noxious Counter-Stimulation and Selective Attention in Chronic Non-Specific Low Back Pain.

The aim of the present study was to assess inhibition of pain and somatosensory-evoked potentials (SEPs) by heterotopic noxious counter-stimulation (HNCS) and by selective attention in patients with chronic non-specific LBP. Seventeen patients and age/sex-matched controls were recruited (10 men, 7 women; mean age ±â€¯SD: 43.3 ±â€¯10.4 and 42.7 ±â€¯11.1, respectively). On average, patients with LBP reported pain duration of 7.6 ±â€¯6.5 years, light to moderate disability (19.3 ±â€¯5.7/100) and low clinical pain intensity (21.8 ±â€¯1.5/100), while pain catastrophizing, state and trait anxiety and depressive symptoms were not significantly different between groups (all p's >0.05). HNCS and selective attention had differential inhibitory effects on pain and SEP, but no difference was observed between groups. Across both groups, HNCS decreased pain (p = 0.06) as well as the N100 and the N150 components of SEP (p's <0.001), while selective attention only decreased pain (p < 0.01) and the N100 (p<0.001). In contrast, the P260 was decreased by HNCS only when attention was directed toward the HNCS stimulus (p<0.01). This indicates that patients with the characteristics described above do not show altered pain inhibitory mechanisms involved in HNCS and selective attention. Importantly, this experiment was carefully designed to control for non-specific effects associated with the repetition of the test stimulus and the effect of an innocuous counter-stimulation. It remains to be determined if these results hold for patients with severe LBP and psychological symptoms or whether symptom severity may be associated with pain inhibition deficits.

The mechanism of back pain relief by spinal manipulation relies on decreased temporal summation of pain.

The aim of the present study was to determine whether thoracic spinal manipulation (SM) decreases temporal summation of back pain. The study comprised two controlled experiments including 16 and 15 healthy participants, respectively. Each study included six sessions during which painful or non-painful electrical stimulations were delivered in three conditions: (1) control (2) light mechanical stimulus (MS) or (3) SM. Electrical stimulation was applied on the thoracic spine (T4), in the area where SM and MS were performed. In Experiment 1, electrical stimulation consisted in a single 1-ms pulse while a single or repeated train of ten 1-ms pulses was used in Experiment 2. SM involved articular cavitation while MS was a calibrated force of 25N applied manually for 2s. For the single pulse, changes in pain or tactile sensation in the SM or MS sessions compared with the CTL session were not significantly different (all p's>0.05). In contrast, temporal summation of pain was decreased in the SM session compared with the CTL session for both the single and repeated train (p's<0.05). Changes were not significant for the MS sessions (all p's>0.05) and no effect was observed for the tactile sensation (all p's>0.1). These results indicate that SM produces specific inhibitory effects on temporal summation of back pain, consistent with the involvement of a spinal anti-nociceptive mechanism in clinical pain relief by SM. This provides the first mechanistic evidence of back pain relief by spinal manipulation.

Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aß-fibre activation.

Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aß-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aß-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.

Attention shifting in Parkinson's disease: an analysis of behavioral and cortical responses.

OBJECTIVE: The study was designed to examine persistent (input selection) versus transient (input shifting) mechanisms of attention control in Parkinson's disease (PD). METHOD: The study identifies behavioral and neural markers of selective control and shifting control using a novel combination of a flanker task with an attentional set-shifting task, and it compares patients with PD with matched controls. Event-related brain potentials (ERPs) were recorded, and analyses focused on frontally distributed N2 waves, parietally distributed P3 waves, and error-related negativities (Ne/ERN). RESULTS: Controls showed robust shifting costs (prolonged response times), but patients with PD did not show evidence for comparable shifting costs. Patients with PD made more errors than controls when required to shift between attentional sets, but also when they had to initially maintain an attentional set. At the neural level it was found that contrary to controls, patients with PD did not display any N2 and P3 augmentations on shift trials. Patients with PD further did not display any error-related activity or posterror N2 augmentation. CONCLUSIONS: Our results reveal that intact selective control and disrupted shifting control are dissociable in patients with PD, but additional work is required to dissect the proportionate effects of disease and treatment on shifting control in PD. Our ERP-based approach opens a new window onto an understanding of motor and cognitive flexibility that seems to be associated with the dopaminergic innervation of cortico-striatal loops.

Absence of congruency sequence effects reveals neurocognitive inflexibility in Parkinson's disease.

The effects of Parkinson's disease (PD) on action selection in conflictual situations were examined in an experiment using the flanker task in combination with event-related brain potentials (ERPs). More specifically, we investigated the effects of PD on behavioral and neuronal indicators of both instantaneous (within-trial flanker congruency effects) and sequence-dependent (between-trial congruency sequence effects) distractor interference. Consistent with the existing literature, congruency-sensitive ERP components (i.e., fronto-central N2 and positive 'dips' of the lateralized readiness potential, LRP) were observed over medial-frontal and lateral-central regions, respectively. For situations requiring instantaneous action control, patients with PD and healthy controls showed similar congruency effects on reaction time, as well as on N2 and LRP 'dip' amplitudes. As expected, controls showed reliable congruency sequence effects on reaction time, as well as on N2 and LRP 'dip' amplitudes. However, patients with PD were completely unaffected by the congruence sequence across consecutive trials, as revealed by reaction time, as well as by N2 and LRP 'dip' amplitudes. The data imply that the effects of PD on action selection are largely restricted to a lack of adaptive modulation in time which we refer to as neurocognitive inflexibility, in the context of relatively spared abilities to instantaneously exert control over action selection. The findings are discussed in terms of basal ganglia dysfunction induced by PD which results primarily either in executive function deficits or in aberrant habit formation.