No effects of cerebellar transcranial random noise stimulation on cerebellar brain inhibition, visuomotor learning, and pupil diameter.

Cerebellar brain inhibition (CBI) is an inhibitory output from the cerebellum to the primary motor cortex, which is decreased in early motor learning. Transcranial random noise stimulation (tRNS) is a noninvasive brain stimulation to induce brain plastic changes; however, the effects of cerebellar tRNS on CBI and motor learning have not been investigated yet to our knowledge. In this study, whether cerebellar tRNS decreases CBI and improves motor learning was examined, and pupil diameter was measured to examine physiological changes due to the effect of tRNS on motor learning. Thirty-four healthy subjects were assigned to either the cerebellar tRNS group or the Sham group. The subjects performed visuomotor tracking task with ten trials each in the early and late learning stages while receiving the stimulus intervention. CBI and motor evoked potentials were measured before the learning task, after the early learning stage, and after the late learning stage, and pupil diameter was measured during the task. There was no change in CBI in both groups. No group differences in motor learning rates were observed at any learning stages. Pupil diameter was smaller in the late learning stage than in the early learning stage in both groups. The cerebellar tRNS was suggested not to induce changes in CBI and improvement in motor learning, and it did not affect pupil diameter.

Region-specific Effects of Transcranial Direct Current Stimulation Over Posterior Parietal Cortex and Cerebellum on Standing Postural Displacement After Prism Adaptation.

Prism adaptation (PA) induces the after-effects of adapted tasks and transfers after-effects of non-adapted tasks, in which PA with pointing movements transfers to postural displacement during eyes-closed standing. However, the neural mechanisms underlying the transfer of PA after-effects on standing postural displacement remain unclear. The present study investigated the region-specific effects of transcranial direct current stimulation (tDCS) over the posterior parietal cortex (PPC) and cerebellum during prism exposure (PE) on standing postural displacement in healthy adults. Forty-two healthy young adults were grouped into pointing during PE with cathodal tDCS over the right PPC, anodal tDCS over the right cerebellum, and sham tDCS groups. They received 20 min of tDCS, during which they pointed to the visual targets while wearing prism lenses with a leftward visual shift (30 diopters) for 15 min. During the early PE, the pointing errors in the cerebellum group were significantly displaced more accurately toward the targets than those in the PPC group. However, after leftward PE, all groups had similar rightward displacements of the straight-ahead pointing with eyes closed. The PPC group only exhibited significant rightward center-of-pressure displacement during eyes-closed standing with feet-closed after leftward PE. The perception of longitudinal body axis rotation, as an indicator of the subjective body vertical axis, did not differ significantly between the pre- and post-evaluations in all groups. These results show that the PPC during PE could make an important neural contribution to inducing transfer of PA after-effect on standing postural displacement.

Electric field envelope focality in superficial brain areas with linear alignment montage in temporal interference stimulation.

Temporal interference stimulation (TIS) uses two pairs of conventional transcranial alternating current stimulation (tACS) electrodes, each with a different frequency, to generate a time-varying electric field (EF) envelope (EFE). The EFE focality in primary somatosensory and motor cortex areas of a standard human brain was computed using newly defined linear alignment montages. Sixty head volume conductor models constructed from magnetic resonance images were considered to evaluate interindividual variability. Six TIS and two tACS electrode montages were considered, including linear and rectangular alignments. EFEs were computed using the scalar-potential finite-difference method. The computed EFE was projected onto the standard brain space for each montage. Computational results showed that TIS and tACS generated different EFE and EF distributions in postcentral and precentral gyri regions. For TIS, the EFE amplitude in the target areas had lower variability than the EF strength of tACS. However, bipolar tACS montages showed higher focality in the superficial postcentral and precentral gyri regions than in TIS. TIS generated greater EFE penetration than bipolar tACS at depths <5-10 mm below the brain surface. From group-level analysis, tACS with a bipolar montage was preferred for targets <5-10 mm in depth (gyral crowns) and TIS for deeper targets. TIS with a linear alignment montage could be an effective method for deep structures and sulcal walls. These findings provide valuable insights into the choice of TIS and tACS for stimulating specific brain regions.

Effects of transcranial alternating current stimulation to the supplementary motor area on motor learning.

Transcranial alternating current stimulation (tACS) is a noninvasive method for brain stimulation that artificially modulates oscillatory brain activity in the cortical region directly beneath the electrodes by applying a weak alternating current. Beta (ß) oscillatory activity in the supplementary motor area (SMA) is involved in motor planning and maintenance, whereas gamma (γ) oscillatory activity is involved in the updating of motor plans. However, the effect of applying tACS to the SMA on motor learning has not yet been investigated. This study assessed the effects of applying tACS to the SMA on motor learning. Forty-two right-handed healthy adults (age 20.6 ± 0.5 years, 24 men and 18 women) were included. Motor learning was assessed using a visuomotor tracking task with pinch tension of the right thumb and right forefinger. Each trial lasted 60 s, and the error rates were measured. Conductive rubber electrodes were attached to the SMA and the left shoulder for tACS. Stimulation was applied at an intensity of 1.0 mA and frequencies of 70 and 20 Hz in the γ-tACS and ß-tACS treatment groups, respectively. The sham group was only administered a fade-in/out. The visuomotor tracking task was performed for 10 trials before tACS and 10 trials after tACS. Two trials were conducted on the following day to determine motor skill retention. The average deviation measured during 60 s was considered the error value. Pre-stimulation learning rate was calculated as the change in error rate. Post-stimulation learning rate and retention rate were calculated as the change in error rate after stimulation and on the day after stimulation, respectively. In both the stimulation groups, differences in pre-stimulation learning, post-stimulation learning, and retention rates were not significant. However, in the γ-tACS group, baseline performance and pre-stimulation learning rate were positively correlated with post-stimulation learning rate. Therefore, applying γ-tACS to the SMA can increase post-stimulation learning rate in participants exhibiting low baseline performance and high pre-stimulation learning rate. Our findings suggest that motor learning can be effectively enhanced by applying γ-tACS to the SMA based on an individual's motor and learning abilities.

Influence of postural control difficulty on changes in spatial orienting of attention after leftward prism adaptation.

Prism adaptation (PA) affects visuospatial attention such as spatial orienting in both the right and left hemifields; however, the systematic after-effects of PA on visuospatial attention remain unclear. Visuospatial attention can be affected by non-spatial attentional factors, and postural control difficulty, which delays the reaction time (RT) to external stimulation, may be one such factor. Therefore, we aimed to investigate the influence of postural control difficulty on changes in spatial orienting of attention after leftward PA. Seventeen healthy young adults underwent 15-min and 5-min PA procedures for a leftward visual shift (30 diopters). Participants underwent the Posner cueing test immediately before (pre-evaluation) and in between and after the PA procedures (post-evaluations) while standing barefoot on the floor (normal standing condition) and on a balance-disc (balance standing condition). In the pre-evaluation, RTs in the balance standing condition were significantly longer compared to those in the normal standing condition for targets appearing in both the right and left hemifields. Leftward PA improved the RT for targets appearing in the right, but no left, hemifield in the balance standing condition, such that RTs for targets in the right hemifield in the post-evaluation were not significantly different between the two standing conditions. However, leftward PA did not significantly change RTs for targets in both hemifields in the normal standing condition. Therefore, postural control difficulty may enhance sensitivity to the features of the visuospatial cognitive after-effects of leftward PA.

Changes in Resting-State Brain Activity After Cognitive Behavioral Therapy for Chronic Pain: A Magnetoencephalography Study.

Cognitive behavioral therapy (CBT) is believed to be an effective treatment for chronic pain due to its association with cognitive and emotional factors. Nevertheless, there is a paucity of magnetoencephalography (MEG) investigations elucidating its underlying mechanisms. This study investigated the neurophysiological effects of CBT employing MEG and analytical techniques. We administered resting-state MEG scans to 30 patients with chronic pain and 31 age-matched healthy controls. Patients engaged in a 12-session group CBT program. We conducted pretreatment (T1) and post-treatment (T2) MEG and clinical assessments. MEG data were examined within predefined regions of interest, guided by the authors' and others' prior magnetic resonance imaging studies. Initially, we selected regions displaying significant changes in power spectral density and multiscale entropy between patients at T1 and healthy controls. Then, we examined the changes within these regions after conducting CBT. Furthermore, we applied support vector machine analysis to MEG data to assess the potential for classifying treatment effects. We observed normalization of power in the gamma2 band (61-90 Hz) within the right inferior frontal gyrus (IFG) and multiscale entropy within the right dorsolateral prefrontal cortex (DLPFC) of patients with chronic pain after CBT. Notably, changes in pain intensity before and after CBT positively correlated with the alterations of multiscale entropy. Importantly, responders predicted by the support vector machine classifier had significantly higher treatment improvement rates than nonresponders. These findings underscore the pivotal role of the right IFG and DLPFC in ameliorating pain intensity through CBT. Further accumulation of evidence is essential for future applications. PERSPECTIVE: We conducted MEG scans on 30 patients with chronic pain before and after a CBT program, comparing results with 31 healthy individuals. There were CBT-related changes in the right IFG and DLPFC. These results highlight the importance of specific brain regions in pain reduction through CBT.

Individual and group-level optimization of electric field in deep brain region during multichannel transcranial electrical stimulation.

Electrode montage optimization for transcranial electric stimulation (tES) is a challenging topic for targeting a specific brain region. Targeting the deep brain region is difficult due to tissue inhomogeneity, resulting in complex current flow. In this study, a simplified protocol for montage optimization is proposed for multichannel tES (mc-tES). The purpose of this study was to reduce the computational cost for mc-tES optimization and to evaluate the mc-tES for deep brain regions. Optimization was performed using a simplified protocol for montages under safety constraints with 20 anatomical head models. The optimization procedure is simplified using the surface EF of the deep brain target region, considering its small volume and non-concentric distribution of the electrodes. Our proposal demonstrated that the computational cost was reduced by >90%. A total of six-ten electrodes were necessary for robust EF in the target region. The optimization with surface EF is comparable to or marginally better than using conventional volumetric EF for deep brain tissues. An electrode montage with a mean injection current amplitude derived from individual analysis was demonstrated to be useful for targeting the deep region at the group level. The optimized montage and injection current were derived at the group level. Our proposal at individual and group levels showed great potential for clinical application.

Effects of transcutaneous auricular vagus nerve stimulation at left cymba concha on experimental pain as assessed with the nociceptive withdrawal reflex, and correlation with parasympathetic activity.

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0 mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10 min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10 min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application.

Transcranial alternating current stimulation does not affect microscale learning.

A theory has been posited that microscale learning, which involves short intervals of a few seconds during explicit motor skill learning, considerably enhances performance. This phenomenon correlates with diminished beta-band activity in the frontal and parietal regions. However, there is a lack of neurophysiological studies regarding the relationship between microscale learning and implicit motor skill learning. In the present study, we aimed to determine the effects of transcranial alternating current stimulation (tACS) during short rest periods on microscale learning in an implicit motor task. We investigated the effects of 20-Hz ß-tACS delivered during short rest periods while participants performed an implicit motor task. In Experiments 1 and 2, ß-tACS targeted the right dorsolateral prefrontal cortex and the right frontoparietal network, respectively. The participants performed a finger-tapping task using their nondominant left hand, and microscale learning was separately analyzed for micro-online gains (MOnGs) and micro-offline gains (MOffGs). Contrary to our expectations, ß-tACS exhibited no statistically significant effects on MOnGs or MOffGs in either Experiment 1 or Experiment 2. In addition, microscale learning during the performance of the implicit motor task was improved by MOffGs in the early learning phase and by MOnGs in the late learning phase. These results revealed that the stimulation protocol employed in this study did not affect microscale learning, indicating a novel aspect of microscale learning in implicit motor tasks. This is the first study to examine microscale learning in implicit motor tasks and may provide baseline information that will be useful in future studies.

Prism adaptation during balance standing enhances the transfer after-effect on standing postural displacement.

Prism adaptation (PA) is a sensorimotor adaptation paradigm that induces after-effects of adapted tasks and transfer after-effects of non-adapted tasks. Previous studies showed inconsistent results of transfer after-effects of adaptation to a leftward prismatic shift on the center-of-pressure (COP) displacement during eyes-closed standing. Challenging balance during PA increases the generalization of the internal model to untrained movements, resulting in increased transfer after-effects. The present study aimed to investigate the transfer after-effects of PA with challenging balance on standing postural displacement. Thirty healthy young adults were grouped into floor standing and balance-disc standing groups during leftward PA and pointed to targets while adapting to a leftward visual shift (30 diopters) for 20 min. After leftward PA, both groups had a significant rightward displacement of straight-ahead pointing with eyes closed. However, the COP position during eyes-closed standing with feet-closed was significantly displaced rightward only in the balance-disc standing group after leftward PA. These results show that challenging balance might increase the somatosensory and proprioceptive information for standing postural control, resulting in increased transfer after-effects of leftward PA on rightward standing postural displacement.

The effects of transcranial electrical stimulation of the left dorsolateral prefrontal cortex on tactile spatial discrimination performance.

The dorsolateral prefrontal cortex (DLPFC) plays a key role in tactile perceptual discrimination performance. Both transcranial random noise stimulation (tRNS) and anodal transcranial pulsed current stimulation (tPCS) have been shown to modulate neural activity in cortical regions. In this study, we aimed to determine whether tRNS and anodal tPCS over the left DLPFC would improve tactile perceptual discrimination performance of the right index finger in healthy neurological individuals. Subjects underwent a grating orientation task before, immediately after, and 30 min after applying tRNS in Experiment 1 or anodal tPCS in Experiment 2. tRNS application on the left DLPFC tended to enhance tactile perceptual discrimination performance. In contrast, the application of anodal tPCS over the left DLPFC did not affect tactile perceptual discrimination performance. These findings indicate that transcranial electrical stimulation to the left DLPFC may improve tactile perceptual discrimination performance, with effects that depend on stimulus modality.

Beta resting-state functional connectivity predicts tactile spatial acuity.

Tactile perception is a complex phenomenon that is processed by multiple cortical regions via the primary somatosensory cortex (S1). Although somatosensory gating in the S1 using paired-pulse stimulation can predict tactile performance, the functional relevance of cortico-cortical connections to tactile perception remains unclear. We investigated the mechanisms by which corticocortical and local networks predict tactile spatial acuity in 42 adults using magnetoencephalography (MEG). Resting-state MEG was recorded with the eyes open, whereas evoked responses were assessed using single- and paired-pulse electrical stimulation. Source data were used to estimate the S1-seed resting-state functional connectivity (rs-FC) in the whole brain and the evoked response in the S1. Two-point discrimination threshold was assessed using a custom-made device. The beta rs-FC revealed a negative correlation between the discrimination threshold and S1-superior parietal lobule, S1-inferior parietal lobule, and S1-superior temporal gyrus connection (all P < 0.049); strong connectivity was associated with better performance. Somatosensory gating of N20m was also negatively correlated with the discrimination threshold (P = 0.015), with weak gating associated with better performance. This is the first study to demonstrate that specific beta corticocortical networks functionally support tactile spatial acuity as well as the local inhibitory network.

Effects of noisy galvanic vestibular stimulation on functional reach test.

Balance disorders are a risk factor for falls in older individuals, and an increased center of pressure (COP) sway path length during standing and decreased reach distance in the functional reach test (FRT) predispose them to falls. Reportedly, noisy galvanic vestibular stimulation (nGVS) reduces COP sway path length during standing in young and community-dwelling older individuals and suggested to be a promising approach to improve balance function. However, the effect of nGVS on FRT remains unclear. Therefore, this study aimed to clarify the effect of nGVS on the FRT reach distance. This study has a cross-over design and included 20 healthy young adults. Interventions under nGVS (stimulation intensity: 0.2 mA) and sham (stimulation intensity: 0 mA) conditions were randomly administered to each participant. The participants underwent COP sway during standing measurements and FRT pre-intervention and post-intervention under each condition, and COP sway path length and the FRT reach distance were calculated. Statistical analysis revealed a significant decrease in post-intervention COP sway path length compared with pre-intervention COP sway path length under the nGVS condition. Conversely, the FRT reach distance remained the same under both nGVS and sham conditions. Thus, nGVS may improve the standing balance function but cannot change the FRT reach distance in healthy young individuals.

Influences of different cognitive loads on central common neural drives to the ankle muscles during dual-task walking.

While dual-task walking with additional cognitive tasks may decrease walking performance, many studies have also shown increases in walking performance during dual tasks, especially as cognitive load increases. However, the neural mechanisms that cause changes in postural control during dual tasks according to the difference in cognitive load remain unclear. Therefore, this study aimed to investigate the influence of different cognitive loads on the neural control of muscle activity during dual-task walking using intra- and intermuscular coherence analyses. Eighteen healthy young adults were subjected to treadmill walking measurements in a single-task condition (normal walking without cognitive load) and two dual-task conditions (watching digits and digit 2-back task) with the measurements of reaction time to auditory stimulation. During walking with the digit 2-back task, stride-time variability was significantly reduced compared to that during normal walking, and reaction time was significantly delayed compared to those during normal walking and walking with watching digits. The peak value of the tibialis anterior intramuscular coherence in the beta band (15-35 Hz) significantly increased during walking with the digit 2-back task than that during walking with watching digits. The present results suggest that young adults can increase their central common neural drive and decrease their walking variability for concentration on cognitive tasks during dual-task walking.

Association between somatosensory sensitivity and regional gray matter volume in healthy young volunteers: a voxel-based morphometry study.

Two-point discrimination (2PD) test reflects somatosensory spatial discrimination ability, but evidence on the relationship between 2PD and cortical gray matter (GM) volume is limited. This study aimed to analyze the relationship between cortical GM volume and 2PD threshold in young healthy individuals and to clarify the characteristics of brain structure reflecting the individual differences in somatosensory function. 2PD was measured in 42 healthy (20 females) volunteers aged 20-32 years using a custom-made test system that can be controlled by a personal computer. The 2PD of the right index finger measured with this device has been confirmed to show good reproducibility. T1-weighted images were acquired using a 3-T magnetic resonance imaging scanner for voxel-based morphometry analysis. The mean 2PD threshold was 2.58 ± 0.54 mm. Whole-brain multiple regression analysis of the relationship between 2PD and GM volume showed that a lower 2PD threshold (i.e. better somatosensory function) significantly correlated with decreased GM volume from the middle temporal gyrus to the inferior parietal lobule (IPL) in the contralateral hemisphere. In conclusion, a lower GM volume in the middle temporal gyrus and IPL correlates with better somatosensory function. Thus, cortical GM volume may be a biomarker of somatosensory function.

Transcranial direct current stimulation over the right intraparietal sulcus improves response inhibition.

Various situations in our everyday life call for response inhibition, mechanisms deputed to outright stop an ongoing course of action. This function reportedly involves the activity of the right intraparietal sulcus (rIPS). This study aimed to determine whether transcranial direct current stimulation (tDCS) intervention to the rIPS alters response inhibition. We investigated 15 healthy adults performing a stop signal task before and after tDCS intervention. We applied tDCS with 1.5 mA to the rIPS directly above (P4) and the left supraorbital area for 20 min. The stimulation conditions involved Anodal, cathodal, and pseudo-stimulation. Each participant performed a stop signal task under all stimulation conditions. The changes in response inhibition function were evaluated by comparing the stop signal reaction times (SSRT) before and after the tDCS intervention. Under the Anodal condition, SSRT was significantly shorter after than before the intervention (p = 0.014). Under the Anodal and Cathodal conditions, we could observe a significantly positive correlation between the SSRT before the tDCS intervention and the difference in SSRT before and after tDCS intervention (Anodal condition: r = 0.823, p < 0.001; Cathodal condition: r = 0.831, p < 0.001). No such correlation could be found under the Sham condition. In summary, this study demonstrated that Anodal-tDCS intervention for rIPS improves response-inhibitory function and the stimulus effect depends on the response-inhibitory function of the participant prior to stimulation.

Changes in excitability and GABAergic neuronal activity of the primary somatosensory cortex after motor learning.

Introduction: It is widely known that motor learning changes the excitability of the primary motor cortex. More recently, it has been shown that the primary somatosensory cortex (S1) also plays an important role in motor learning, but the details have not been fully examined. Therefore, we investigated how motor skill training affects somatosensory evoked potential (SEP) in 30 neurologically healthy subjects. Methods: SEP N20/P25_component and N20/P25 SEP paired-pulse depression (SEP-PPD) were assessed before and immediately after complex or simple visuomotor tasks. Results: Motor learning was induced more efficiently by the complex visuomotor task than by the simple visuomotor task. Both the N20/P25 SEP amplitude and N20/P25 SEP-PPD increased significantly immediately after the complex visuomotor task, but not after the simple visuomotor task. Furthermore, the altered N20/P25 SEP amplitude was associated with an increase in motor learning efficiency. Conclusion: These results suggest that motor learning modulated primary somatosensory cortex excitability.

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation.

This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04-0.15 Hz) and high-frequency (HF) (0.15-0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex.

Interoceptive accuracy is related to the psychological mechanisms of the burning mouth syndrome: a cross-sectional study.

BACKGROUND: Different perspectives are needed to understand the pathophysiology of burning mouth syndrome (BMS), including physiological and psychological standpoints. The significance of interoception in chronic pain has been suggested. However, few studies have investigated this relationship in BMS. Therefore, we examined the role of interoception in BMS. METHODS: This is a cross-sectional study. BMS patients (N = 64) participated in the study. We used interoceptive accuracy (IAc) based on the heartbeat counting task. Then, participants were divided into high and low IAc groups, and their scores on clinical assessment including pain and psychological evaluation were compared. RESULTS: The Visual Analogue Scale scores indicating pain in low IAc patients, but not high IAc patients, were positively correlated with the Beck Depression Inventory-Second Edition (BDI-II) and the State-Trait Anxiety Inventory-State (STAI-S) Scores. CONCLUSIONS: Interoception might play a role in the pathophysiology of BMS.