Oscillatory neurofeedback networks and poststroke rehabilitative potential in severely impaired stroke patients.

Motor restoration after severe stroke is often limited. However, some of the severely impaired stroke patients may still have a rehabilitative potential. Biomarkers that identify these patients are sparse. Eighteen severely impaired chronic stroke patients with a lack of volitional finger extension participated in an EEG study. During sixty-six trials of kinesthetic motor imagery, a brain-machine interface turned event-related beta-band desynchronization of the ipsilesional sensorimotor cortex into opening of the paralyzed hand by a robotic orthosis. A subgroup of eight patients participated in a subsequent four-week rehabilitation training. Changes of the movement extent were captured with sensors which objectively quantified even discrete improvements of wrist movement. Albeit with the same motor impairment level, patients could be differentiated into two groups, i.e., with and without task-related increase of bilateral cortico-cortical phase synchronization between frontal/premotor and parietal areas. This fronto-parietal integration (FPI) was associated with a significantly higher volitional beta modulation range in the ipsilesional sensorimotor cortex. Following the four-week training, patients with FPI showed significantly higher improvement in wrist movement than those without FPI. Moreover, only the former group improved significantly in the upper extremity Fugl-Meyer-Assessment score. Neurofeedback-related long-range oscillatory coherence may differentiate severely impaired stroke patients with regard to their rehabilitative potential, a finding that needs to be confirmed in larger patient cohorts.

Direct modulation index: A measure of phase amplitude coupling for neurophysiology data.

Neural communication across different spatial and temporal scales is a topic of great interest in clinical and basic science. Phase-amplitude coupling (PAC) has attracted particular interest due to its functional role in a wide range of cognitive and motor functions. Here, we introduce a novel measure termed the direct modulation index (dMI). Based on the classical modulation index, dMI provides an estimate of PAC that is (1) bound to an absolute interval between 0 and +1, (2) resistant against noise, and (3) reliable even for small amounts of data. To highlight the properties of this newly-proposed measure, we evaluated dMI by comparing it to the classical modulation index, mean vector length, and phase-locking value using simulated data. We ascertained that dMI provides a more accurate estimate of PAC than the existing methods and that is resilient to varying noise levels and signal lengths. As such, dMI permits a reliable investigation of PAC, which may reveal insights crucial to our understanding of functional brain architecture in key contexts such as behaviour and cognition. A Python toolbox that implements dMI and other measures of PAC is freely available at https://github.com/neurophysiological-analysis/FiNN.

Evaluation of signal analysis algorithms for ipsilateral motor-evoked potentials induced by transcranial magnetic stimulation.

Objective. Evaluating ipsilateral motor-evoked potentials (iMEP) induced by transcranial magnetic stimulation is challenging. In healthy adults, isometric contraction is necessary to facilitate iMEP induction; therefore, the signal may be masked by the concurrent muscle activity. Signal analysis algorithms for iMEP evaluation need to be benchmarked and evaluated.Approach. An open analysis toolbox for iMEP evaluation was implemented on the basis of 11 previously reported algorithms, which were all threshold based, and a new template-based method based on data-driven signal decomposition. The reliability and validity of these algorithms were evaluated with a dataset of 4244 iMEP from 55 healthy adults.Main results.iMEP estimation varies drastically between algorithms. Several algorithms exhibit high reliability, but some appear to be influenced by background activity of muscle preactivation. Especially in healthy subjects, template-based approaches might be more valid than threshold-based ones. Measurement of iMEP persistence requires algorithms that reject some trials as MEP negative. The stricter the algorithms reject trials, the less reliable they generally are. Our evaluation identifies an optimally strict and reliable algorithm.Significance.We show different benchmarks and propose application for different use cases.

FiNN: A toolbox for neurophysiological network analysis.

Recently, neuroscience has seen a shift from localist approaches to network-wide investigations of brain function. Neurophysiological signals across different spatial and temporal scales provide insight into neural communication. However, additional methodological considerations arise when investigating network-wide brain dynamics rather than local effects. Specifically, larger amounts of data, investigated across a higher dimensional space, are necessary. Here, we present FiNN (Find Neurophysiological Networks), a novel toolbox for the analysis of neurophysiological data with a focus on functional and effective connectivity. FiNN provides a wide range of data processing methods and statistical and visualization tools to facilitate inspection of connectivity estimates and the resulting metrics of brain dynamics. The Python toolbox and its documentation are freely available as Supporting Information. We evaluated FiNN against a number of established frameworks on both a conceptual and an implementation level. We found FiNN to require much less processing time and memory than other toolboxes. In addition, FiNN adheres to a design philosophy of easy access and modifiability, while providing efficient data processing implementations. Since the investigation of network-level neural dynamics is experiencing increasing interest, we place FiNN at the disposal of the neuroscientific community as open-source software.

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets.

OBJECTIVES: Transcutaneous auricular vagus nerve stimulation (taVNS) modulates central and peripheral neurophysiology. Specifically, taVNS increases heart rate variability (HRV) indicating a shift in autonomic function towards parasympathetic predominance. However, knowledge on the influence of stimulation parameters and targets is scarce. We hypothesized that the location and charge per phase of taVNS influences HRV. MATERIALS AND METHODS: In thirteen healthy subjects, six different stimulation targets were investigated, i.e., cymba conchae, cavum conchae, outer tragus, inner tragus, crus helicis, and fossa triangularis. At each target, 24 parameter combinations were studied: Eight different electrical charges per phase were evaluated by investigating three pulse durations and eight charge-balanced current intensities, i.e., 100 µs (0.250-2 mA in steps of 0.250 mA), 260 µs (0.096-0.769 mA in steps of 0.096 mA), and 500 µs (0.050-0.400 mA in steps of 0.050 mA). In a parallel group design, left and right taVNS were compared to each other. 30 bursts at each parameter combination were applied with a periodicity of 1 Hz. Each burst consisted of five pulses applied at 25 Hz. RESULTS: HRV increased in a charge-dependent way with significant differences between the right and left ear. The targets with the strongest effects were the cymba conchae and fossa triangularis, and to a lesser extent the inner tragus. CONCLUSIONS: HRV is suitable to define taVNS parameters and targets for research and therapeutic purposes. Bursts of taVNS with a pulse duration of 100 µs and a current intensity of 2 mA are comfortable for the participants and effective in increasing HRV when applied at specific auricular locations. These findings need to be replicated in larger cohorts, and with longer stimulation and off-periods between conditions. Since results may differ in conditions with an impaired autonomic tone, future studies should also consider aged and patient populations.

Brain-Heart Interaction During Transcutaneous Auricular Vagus Nerve Stimulation.

OBJECTIVES: Transcutaneous auricular vagus nerve stimulation (taVNS) modulates brain activity and heart function. The induced parasympathetic predominance leads to an increase of heart rate variability (HRV). Knowledge on the corresponding cortical activation pattern is, however, scarce. We hypothesized taVNS-induced HRV increases to be related to modulation of cortical activity that regulates the autonomic outflow to the heart. MATERIALS AND METHODS: In thirteen healthy subjects, we simultaneously recorded 64-channel electroencephalography and electrocardiography during taVNS. Two taVNS stimulation targets were investigated, i.e., the cymba conchae and inner tragus, and compared to active control stimulation in the anatomical vicinity, i.e., at the crus helicis and outer tragus. We used intermitted stimulation bursts of 25 Hz applied at a periodicity of 1 Hz. HRV was estimated with different time-domain methodologies: standard deviation of RR (SDNN), the root mean squares of successive differences (RMSSD), the percentage of RR-intervals with at least 50 ms deviation from the preceding RR-interval (pNN50), and the difference of consecutive RR intervals weighted by their mean (rrHRV). RESULTS: The stimulation-induced HRV increases corresponded to frequency-specific oscillatory modulation of different cortical areas. All stimulation targets induced power modulations that were proportional to the HRV elevation. The most prominent changes that corresponded to HRV increases across all parameters and stimulation locations were frontal elevations in the theta-band. In the delta-band, there were frontal increases (RMSSD, pNN50, rrHRV, SDNN) and decreases (SDNN) across stimulation sites. In higher frequencies, there was a more divers activity pattern: Outer tragus/crus helicis stimulation increased oscillatory activity with the most prominent changes for the SDNN in frontal (alpha-band, beta-band) and fronto-parietal (gamma-band) areas. During inner tragus/cymba conchae stimulation the predominant pattern was a distributed power decrease, particularly in the fronto-parietal gamma-band. CONCLUSION: Neuro-cardiac interactions can be modulated by electrical stimulation at different auricular locations. Increased HRV during stimulation is correlated with frequency-specific increases and decreases of oscillatory activity in different brain areas. When applying specific HRV measures, cortical patterns related to parasympathetic (RMSSD, pNN50, rrHRV) and sympathetic (SDNN) modulation can be identified. Thus, cortical oscillations may be used to define stimulation locations and parameters for research and therapeutic purposes.

Peripheral Electrical Stimulation Modulates Cortical Beta-Band Activity.

Low-frequency peripheral electrical stimulation using a matrix electrode (PEMS) modulates spinal nociceptive pathways. However, the effects of this intervention on cortical oscillatory activity have not been assessed yet. The aim of this study was to investigate the effects of low-frequency PEMS (4 Hz) on cortical oscillatory activity in different brain states in healthy pain-free participants. In experiment 1, PEMS was compared to sham stimulation. In experiment 2, motor imagery (MI) was used to modulate the sensorimotor brain state. PEMS was applied either during MI-induced oscillatory desynchronization (concurrent PEMS) or after MI (delayed PEMS) in a cross-over design. For both experiments, PEMS was applied on the left forearm and resting-state electroencephalography (EEG) was recording before and after each stimulation condition. Experiment 1 showed a significant decrease of global resting-state beta power after PEMS compared to sham (p = 0.016), with a median change from baseline of -16% for PEMS and -0.54% for sham. A cluster-based permutation test showed a significant difference in resting-state beta power comparing pre- and post-PEMS (p = 0.018) that was most pronounced over bilateral central and left frontal sensors. Experiment 2 did not identify a significant difference in the change from baseline of global EEG power for concurrent PEMS compared to delayed PEMS. Two cluster-based permutation tests suggested that frontal beta power may be increased following both concurrent and delayed PEMS. This study provides novel evidence for supraspinal effects of low-frequency PEMS and an initial indication that the presence of a cognitive task such as MI may influence the effects of PEMS on beta activity. Chronic pain has been associated with changes in beta activity, in particular an increase of beta power in frontal regions. Thus, brain state-dependent PEMS may offer a novel approach to the treatment of chronic pain. However, further studies are warranted to investigate optimal stimulation conditions to achieve a reduction of pain.

Neuro-cardiac coupling predicts transcutaneous auricular vagus nerve stimulation effects.

BACKGROUND: Transcutaneous auricular Vagus Nerve Stimulation (taVNS) is a non-invasive neuromodulation technique that may constitute an effective treatment for a wide range of neurological, psychiatric, and medical conditions. One key challenge in taVNS research is the high interindividual response variability. To gain an understanding of this variability, reliable biomarkers for taVNS responsiveness would be highly desirable. In this study, we investigated physiological candidate biomarkers while systematically varying stimulation conditions and observing physiological state characteristics. METHODS: Forty-four healthy young adults received taVNS and sham-stimulation. Subjects were pseudo-randomly assigned to stimulation of the left or right ear. Each subject underwent six blocks of stimulation. Across blocks, respiration-locking (inhalation-locked taVNS vs. exhalation-locked taVNS vs. sham) and the electrode location (tragus vs. cymba conchae) were varied. We analyzed heart rate (HR), various heart rate variability (HRV) scores, and neuro-cardiac coupling (NCC), indexed by the relationship between electroencephalographic delta power and heartbeat length. RESULTS: We observed an effect of taVNS on HR and HRV scores during, but not after stimulation. The direction of the effects was consistent with parasympathetic activation. We did not observe any systematic influence of the stimulation conditions that we varied. However, we found baseline NCC scores to be significant predictors for the individual effect of taVNS on HRV scores. CONCLUSION: Cardiac effects of taVNS indicate parasympathetic activation. These effects were short lived, which might explain that some previous studies were unable to detect them. We propose NCC as a novel candidate biomarker for responsiveness to taVNS.

State-Dependent Gain Modulation of Spinal Motor Output.

Afferent somatosensory information plays a crucial role in modulating efferent motor output. A better understanding of this sensorimotor interplay may inform the design of neurorehabilitation interfaces. Current neurotechnological approaches that address motor restoration after trauma or stroke combine motor imagery (MI) and contingent somatosensory feedback, e.g., via peripheral stimulation, to induce corticospinal reorganization. These interventions may, however, change the motor output already at the spinal level dependent on alterations of the afferent input. Neuromuscular electrical stimulation (NMES) was combined with measurements of wrist deflection using a kinematic glove during either MI or rest. We investigated 360 NMES bursts to the right forearm of 12 healthy subjects at two frequencies (30 and 100 Hz) in random order. For each frequency, stimulation was assessed at nine intensities. Measuring the induced wrist deflection across different intensities allowed us to estimate the input-output curve (IOC) of the spinal motor output. MI decreased the slope of the IOC independent of the stimulation frequency. NMES with 100 Hz vs. 30 Hz decreased the threshold of the IOC. Human-machine interfaces for neurorehabilitation that combine MI and NMES need to consider bidirectional communication and may utilize the gain modulation of spinal circuitries by applying low-intensity, high-frequency stimulation.

Brain-Machine Neurofeedback: Robotics or Electrical Stimulation?

Neurotechnology such as brain-machine interfaces (BMI) are currently being investigated as training devices for neurorehabilitation, when active movements are no longer possible. When the hand is paralyzed following a stroke for example, a robotic orthosis, functional electrical stimulation (FES) or their combination may provide movement assistance; i.e., the corresponding sensory and proprioceptive neurofeedback is given contingent to the movement intention or imagination, thereby closing the sensorimotor loop. Controlling these devices may be challenging or even frustrating. Direct comparisons between these two feedback modalities (robotics vs. FES) with regard to the workload they pose for the user are, however, missing. Twenty healthy subjects controlled a BMI by kinesthetic motor imagery of finger extension. Motor imagery-related sensorimotor desynchronization in the EEG beta frequency-band (17-21 Hz) was turned into passive opening of the contralateral hand by a robotic orthosis or FES in a randomized, cross-over block design. Mental demand, physical demand, temporal demand, performance, effort, and frustration level were captured with the NASA Task Load Index (NASA-TLX) questionnaire by comparing these workload components to each other (weights), evaluating them individually (ratings), and estimating the respective combinations (adjusted workload ratings). The findings were compared to the task-related aspects of active hand movement with EMG feedback. Furthermore, both feedback modalities were compared with regard to their BMI performance. Robotic and FES feedback had similar workloads when weighting and rating the different components. For both robotics and FES, mental demand was the most relevant component, and higher than during active movement with EMG feedback. The FES task led to significantly more physical (p = 0.0368) and less temporal demand (p = 0.0403) than the robotic task in the adjusted workload ratings. Notably, the FES task showed a physical demand 2.67 times closer to the EMG task, but a mental demand 6.79 times closer to the robotic task. On average, significantly more onsets were reached during the robotic as compared to the FES task (17.22 onsets, SD = 3.02 vs. 16.46, SD = 2.94 out of 20 opportunities; p = 0.016), even though there were no significant differences between the BMI classification accuracies of the conditions (p = 0.806; CI = -0.027 to -0.034). These findings may inform the design of neurorehabilitation interfaces toward human-centered hardware for a more natural bidirectional interaction and acceptance by the user.

Online Mapping With the Deep Brain Stimulation Lead: A Novel Targeting Tool in Parkinson's Disease.

BACKGROUND: Beta-frequency oscillations (13-30 Hz) are a subthalamic hallmark in patients with Parkinson's disease, and there is increased interest in their utility as an intraoperative marker. OBJECTIVES: The objectives of this study were to assess whether beta activity measured directly from macrocontacts of deep brain stimulation leads could be used (a) as an intraoperative electrophysiological approach for guiding lead placements and (b) for physiologically informed stimulation delivery. METHODS: Every millimeter along the surgical trajectory, local field-potential data were collected from each macrocontact, and power spectral densities were calculated and visualized (n = 39 patients). This was done for online intraoperative functional mapping and post hoc statistical analyses using 2 methods: generating distributions of spectral activity along surgical trajectories and direct delineation (presence versus lack) of beta peaks. In a subset of patients, this approach was corroborated by microelectrode recordings. Furthermore, the match rate between beta peaks at the final target position and the clinically determined best stimulation site were assessed. RESULTS: Subthalamic recording sites were delineated by both methods of reconstructing functional topographies of spectral activity along surgical trajectories at the group level (P < 0.0001). Beta peaks were detected when any portion of the 1.5 mm macrocontact was within the microelectrode-defined subthalamic border. The highest beta peak at the final implantation site corresponded to the site of active stimulation in 73.3% of hemispheres (P < 0.0001). In 93.3% of hemispheres, active stimulation corresponded to the first-highest or second-highest beta peak. CONCLUSIONS: Online measures of beta activity with the deep brain stimulation macroelectrode can be used to inform surgical lead placement and contribute to optimization of stimulation programming procedures. © 2020 International Parkinson and Movement Disorder Society.

Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy.

BACKGROUND: Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement. METHODS: We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 â€‹Hz, 90 â€‹µs, 3-5 â€‹V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones. RESULTS: ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders. CONCLUSION: This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.

Different oscillatory entrainment of cortical networks during motor imagery and neurofeedback in right and left handers.

Volitional modulation and neurofeedback of sensorimotor oscillatory activity is currently being evaluated as a strategy to facilitate motor restoration following stroke. Knowledge on the interplay between this regional brain self-regulation, distributed network entrainment and handedness is, however, limited. In a randomized cross-over design, twenty-one healthy subjects (twelve right-handers [RH], nine left-handers [LH]) performed kinesthetic motor imagery of left (48 trials) and right finger extension (48 trials). A brain-machine interface turned event-related desynchronization in the beta frequency-band (16-22 Hz) during motor imagery into passive hand opening by a robotic orthosis. Thereby, every participant subsequently activated either the dominant (DH) or non-dominant hemisphere (NDH) to control contralateral hand opening. The task-related cortical networks were studied with electroencephalography. The magnitude of the induced oscillatory modulation range in the sensorimotor cortex was independent of both handedness (RH, LH) and hemispheric specialization (DH, NDH). However, the regional beta-band modulation was associated with different alpha-band networks in RH and LH: RH presented a stronger inter-hemispheric connectivity, while LH revealed a stronger intra-hemispheric interaction. Notably, these distinct network entrainments were independent of hemispheric specialization. In healthy subjects, sensorimotor beta-band activity can be robustly modulated by motor imagery and proprioceptive feedback in both hemispheres independent of handedness. However, right and left handers show different oscillatory entrainment of cortical alpha-band networks during neurofeedback. This finding may inform neurofeedback interventions in future to align them more precisely with the underlying physiology.

Extended enhancement of corticospinal connectivity with concurrent cortical and peripheral stimulation controlled by sensorimotor desynchronization.

BACKGROUND: Pairing cortical and peripheral input during motor imagery (MI)-related sensorimotor desynchronization (ERD) modulates corticospinal excitability at the cortical representation (hotspot) of the imagined movement. OBJECTIVE: To determine the effects of this associative stimulation protocol on the cortical motor map beyond the hotspot. METHODS: In healthy subjects, peripheral stimulation through passive hand opening by a robotic orthosis and single-pulse transcranial magnetic stimulation to the respective cortical motor representation were applied in a brain-machine interface environment. State-dependency was investigated by concurrent, delayed or non-specific stimulation with respect to ERD in the beta-band (16-22 Hz) during MI of finger extension. RESULTS: Concurrent stimulation led to increased excitability of an extended motor map. Delayed and non-specific stimulation led to heterogeneous changes, i.e., opposite patterns of increased excitability in either the center or the periphery of the motor map. CONCLUSION: These results could be instrumental in closed-loop, state-dependent stimulation in the context of neurorehabilitation.

Recruitment of Additional Corticospinal Pathways in the Human Brain with State-Dependent Paired Associative Stimulation.

Standard brain stimulation protocols modify human motor cortex excitability by modulating the gain of the activated corticospinal pathways. However, the restoration of motor function following lesions of the corticospinal tract requires also the recruitment of additional neurons to increase the net corticospinal output. For this purpose, we investigated a novel protocol based on brain state-dependent paired associative stimulation.Motor imagery (MI)-related electroencephalography was recorded in healthy males and females for brain state-dependent control of both cortical and peripheral stimulation in a brain-machine interface environment. State-dependency was investigated with concurrent, delayed, and independent stimulation relative to the MI task. Specifically, sensorimotor event-related desynchronization (ERD) in the ß-band (16-22 Hz) triggered peripheral stimulation through passive hand opening by a robotic orthosis and transcranial magnetic stimulation to the respective cortical motor representation, either synchronously or subsequently. These MI-related paradigms were compared with paired cortical and peripheral input applied independent of the brain state. Cortical stimulation resulted in a significant increase in corticospinal excitability only when applied brain state-dependently and synchronously to peripheral input. These gains were resistant to a depotentiation task, revealed a nonlinear evolution of plasticity, and were mediated via the recruitment of additional corticospinal neurons rather than via synchronization of neuronal firing. Recruitment of additional corticospinal pathways may be achieved when cortical and peripheral inputs are applied concurrently, and during ß-ERD. These findings resemble a gating mechanism and are potentially important for developing closed-loop brain stimulation for the treatment of hand paralysis following lesions of the corticospinal tract.SIGNIFICANCE STATEMENT The activity state of the motor system influences the excitability of corticospinal pathways to external input. State-dependent interventions harness this property to increase the connectivity between motor cortex and muscles. These stimulation protocols modulate the gain of the activated pathways, but not the overall corticospinal recruitment. In this study, a brain-machine interface paired peripheral stimulation through passive hand opening with transcranial magnetic stimulation to the respective cortical motor representation during volitional ß-band desynchronization. Cortical stimulation resulted in the recruitment of additional corticospinal pathways, but only when applied brain state-dependently and synchronously to peripheral input. These effects resemble a gating mechanism and may be important for the restoration of motor function following lesions of the corticospinal tract.