Magnetoencephalographic neurofeedback training decreasesß-low-γphase-amplitude coupling of the motor cortex of healthy adults: a double-blinded randomized crossover feasibility study.

Objective.The coupling between the beta (13-30 Hz) phase and low gamma (50-100 Hz) amplitude in the motor cortex is thought to regulate motor performance. Abnormal phase-amplitude coupling (PAC) of beta-low gamma (ß-low-γPAC) is associated with motor symptoms of Parkinson's disease. However, the causal relationship betweenß-low-γPAC and motor performance in healthy subjects is unknown. We hypothesized that healthy subjects could change the strength of theß-low-γPAC in the resting state by neurofeedback training (NFT) to control theß-low-γPAC, such that the motor performance changes in accordance with the changes inß-low-γPAC in the resting state.Approach.We developed an NFT to control the strength of theß-low-γPAC in the motor cortex, which was evaluated by magnetoencephalography (MEG) using a current source estimation technique. Twenty subjects were enrolled in a double-blind randomized crossover trial to test the feasibility of the MEG NFT. In the NFT for 2 d, the subjects were instructed to reduce the size of a black circle whose radius was proportional (down-training) or inversely proportional (up-training) to the strength of theß-low-γPAC. The reaction times (RTs) to press a button according to some cues were evaluated before and after training. This study was registered at ClinicalTrials.gov (NCT03837548) and UMIN-CTR (UMIN000032937).Main results.Theß-low-γPAC during the resting state was significantly decreased after down-training, although not significantly after up-training. RTs tended to decrease after both trainings, however the differences were not statistically significant. There was no significant correlation between the changes inß-low-γPAC during rest and RTs.Significance.The proposed MEG NFT was demonstrated to change theß-low-γPAC of the motor cortex in healthy subjects. However, a relationship between PAC and RT has not yet been demonstrated.

Neurofeedback Training without Explicit Phantom Hand Movements and Hand-Like Visual Feedback to Modulate Pain: A Randomized Crossover Feasibility Trial.

Phantom limb pain is attributed to abnormal sensorimotor cortical representations, although the causal relationship between phantom limb pain and sensorimotor cortical representations suffers from the potentially confounding effects of phantom hand movements. We developed neurofeedback training to change sensorimotor cortical representations without explicit phantom hand movements or hand-like visual feedback. We tested the feasibility of neurofeedback training in fourteen patients with phantom limb pain. Neurofeedback training was performed in a single-blind, randomized, crossover trial using two decoders constructed using motor cortical currents measured during phantom hand movements; the motor cortical currents contralateral or ipsilateral to the phantom hand (contralateral and ipsilateral training) were estimated from magnetoencephalograms. Patients were instructed to control the size of a disk, which was proportional to the decoding results, but to not move their phantom hands or other body parts. The pain assessed by the visual analogue scale was significantly greater after contralateral training than after ipsilateral training. Classification accuracy of phantom hand movements significantly increased only after contralateral training. These results suggested that the proposed neurofeedback training changed phantom hand representation and modulated pain without explicit phantom hand movements or hand-like visual feedback, thus showing the relation between the phantom hand representations and pain. PERSPECTIVE: Our work demonstrates the feasibility of using neurofeedback training to change phantom hand representation and modulate pain perception without explicit phantom hand movements and hand-like visual feedback. The results enhance the mechanistic understanding of certain treatments, such as mirror therapy, that change the sensorimotor cortical representation.

Altered Thalamic Connectivity Due to Focused Ultrasound Thalamotomy in Patients with Essential Tremor.

BACKGROUND: Although stereotactic ablation surgery is known to ameliorate involuntary movement dramatically, little is known regarding alterations in whole-brain networks due to disruption of the deep brain nucleus. To explore changes in the whole-brain network after thalamotomy, we analyzed structural and functional connectivity alterations using resting-state functional magnetic resonance imaging and diffusion tensor imaging in patients with essential tremor who had undergone focused ultrasound (FUS) thalamotomy. METHODS: Seven patients with intractable essential tremors and 7 age-matched healthy controls were enrolled in the study. The tremor score in essential tremor patients was assessed, and resting-state functional magnetic resonance imaging and diffusion tensor imaging were performed before and 3 months after left ventral intermediate nucleus thalamotomy using FUS. RESULTS: There was a significant improvement in the tremor of the right hand after FUS thalamotomy. Seed-based functional connectivity analysis revealed a significant increase in functional connectivity between the left thalamus and the caudal part of the dorsal premotor cortex after FUS thalamotomy. Structural connectivity analysis did not detect statistically significant changes between before and after FUS. There was no correlation between the changes in functional connectivity and tremor score. CONCLUSIONS: Although the number of cases is small, our results show that functional connectivity between the thalamus and the premotor cortex increases after the amelioration of tremors by FUS thalamotomy. The lack of correlation between increased functional connectivity and clinical tremor scores suggests that the observed increase in functional connectivity may be a compensatory change in the secondary sensorimotor changes that occur after thalamotomy.

Voluntary control of semantic neural representations by imagery with conflicting visual stimulation.

Neural representations of visual perception are affected by mental imagery and attention. Although attention is known to modulate neural representations, it is unknown how imagery changes neural representations when imagined and perceived images semantically conflict. We hypothesized that imagining an image would activate a neural representation during its perception even while watching a conflicting image. To test this hypothesis, we developed a closed-loop system to show images inferred from electrocorticograms using a visual semantic space. The successful control of the feedback images demonstrated that the semantic vector inferred from electrocorticograms became closer to the vector of the imagined category, even while watching images from different categories. Moreover, modulation of the inferred vectors by mental imagery depended asymmetrically on the perceived and imagined categories. Shared neural representation between mental imagery and perception was still activated by the imagery under semantically conflicting perceptions depending on the semantic category.

Pain Control by Co-adaptive Learning in a Brain-Machine Interface.

Innovation in the field of brain-machine interfacing offers a new approach to managing human pain. In principle, it should be possible to use brain activity to directly control a therapeutic intervention in an interactive, closed-loop manner. But this raises the question as to whether the brain activity changes as a function of this interaction. Here, we used real-time decoded functional MRI responses from the insula cortex as input into a closed-loop control system aimed at reducing pain and looked for co-adaptive neural and behavioral changes. As subjects engaged in active cognitive strategies orientated toward the control system, such as trying to enhance their brain activity, pain encoding in the insula was paradoxically degraded. From a mechanistic perspective, we found that cognitive engagement was accompanied by activation of the endogenous pain modulation system, manifested by the attentional modulation of pain ratings and enhanced pain responses in pregenual anterior cingulate cortex and periaqueductal gray. Further behavioral evidence of endogenous modulation was confirmed in a second experiment using an EEG-based closed-loop system. Overall, the results show that implementing brain-machine control systems for pain induces a parallel set of co-adaptive changes in the brain, and this can interfere with the brain signals and behavior under control. More generally, this illustrates a fundamental challenge of brain decoding applications-that the brain inherently adapts to being decoded, especially as a result of cognitive processes related to learning and cooperation. Understanding the nature of these co-adaptive processes informs strategies to mitigate or exploit them.

Real-Time Neurofeedback to Modulate ß-Band Power in the Subthalamic Nucleus in Parkinson's Disease Patients.

The ß-band oscillation in the subthalamic nucleus (STN) is a therapeutic target for Parkinson's disease. Previous studies demonstrated that l-DOPA decreases the ß-band (13-30 Hz) oscillations with improvement of motor symptoms. However, it has not been elucidated whether patients with Parkinson's disease are able to control the ß-band oscillation voluntarily. Here, we hypothesized that neurofeedback training to control the ß-band power in the STN induces plastic changes in the STN of individuals with Parkinson's disease. We recorded the signals from STN deep-brain stimulation electrodes during operations to replace implantable pulse generators in eight human patients (3 male) with bilateral electrodes. Four patients were induced to decrease the ß-band power during the feedback training (down-training condition), whereas the other patients were induced to increase (up-training condition). All patients were blinded to their assigned condition. Adjacent contacts that showed the highest ß-band power were selected for the feedback. During the 10 min training, patients were shown a circle whose diameter was controlled by the ß-band power of the selected contacts. Powers in the ß-band during 5 min resting sessions recorded before and after the feedback were compared. In the down-training condition, the ß-band power of the selected contacts decreased significantly after feedback in all four patients (p < 0.05). In contrast, the ß-band power significantly increased after feedback in two of four patients in the up-training condition. Overall, the patients could voluntarily control the ß-band power in STN in the instructed direction (p < 0.05) through neurofeedback.

Induced sensorimotor brain plasticity controls pain in phantom limb patients.

The cause of pain in a phantom limb after partial or complete deafferentation is an important problem. A popular but increasingly controversial theory is that it results from maladaptive reorganization of the sensorimotor cortex, suggesting that experimental induction of further reorganization should affect the pain, especially if it results in functional restoration. Here we use a brain-machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. BMI training induces significant plasticity in the sensorimotor cortex, manifested as improved discriminability of movement information and enhanced prosthetic control. Contrary to our expectation that functional restoration would reduce pain, the BMI training with the phantom hand intensifies the pain. In contrast, BMI training designed to dissociate the prosthetic and phantom hands actually reduces pain. These results reveal a functional relevance between sensorimotor cortical plasticity and pain, and may provide a novel treatment with BMI neurofeedback.

[Communication with ALS patients: neurosurgical approach].

By progression of the disease, motor neurons degenerate in patients with amyotrophic lateral sclerosis (ALS) eventually lose nearly all voluntary muscles in the body. They are awake and aware but cannot move or communicate (locked-in state). Since the function of the brain is preserved, one possible measure to support their communication is to interpret their motor intention by decoding (deciphering) brain signals and present it with external devices. This technology called "brain-machine interface (BMI)" is now close to clinical use in Japan and USA.In our system, we record electrocorticogram (ECoG) obtained with subudural electrodes during their motor imagery, decode it and determine the movement they intended. So far, one patient of ALS with severe paralysis, implanted with this electrodes, successfully operated the PC communication tool only by thinking.

Modulation of neuronal activity after spinal cord stimulation for neuropathic pain; H(2)15O PET study.

Spinal cord stimulation (SCS) is an effective therapy for chronic neuropathic pain. However, the detailed mechanisms underlying its effects are not well understood. Positron emission tomography (PET) with H(2)(15)O was applied to clarify these mechanisms. Nine patients with intractable neuropathic pain in the lower limbs were included in the study. All patients underwent SCS therapy for intractable pain, which was due to failed back surgery syndrome in three patients, complex regional pain syndrome in two, cerebral hemorrhage in two, spinal infarction in one, and spinal cord injury in one. Regional cerebral blood flow (rCBF) was measured by H(2)(15)O PET before and after SCS. The images were analyzed with statistical parametric mapping software (SPM2). SCS reduced pain; visual analog scale values for pain decreased from 76.1+/-25.2 before SCS to 40.6+/-4.5 after SCS (mean+/-SE). Significant rCBF increases were identified after SCS in the thalamus contralateral to the painful limb and in the bilateral parietal association area. The anterior cingulate cortex (ACC) and prefrontal areas were also activated after SCS. These results suggest that SCS modulates supraspinal neuronal activities. The contralateral thalamus and parietal association area would regulate the pain threshold. The ACC and prefrontal areas would control the emotional aspects of intractable pain, resulting in the reduction of neuropathic pain after SCS.