Strategies and safety simulations for ultrasonic cervical spinal cord neuromodulation.

Objective. Focused ultrasound spinal cord neuromodulation has been demonstrated in small animals. However, most of the tested neuromodulatory exposures are similar in intensity and exposure duration to the reported small animal threshold for possible spinal cord damage. All efforts must be made to minimize the risk and assure the safety of potential human studies, while maximizing potential treatment efficacy. This requires an understanding of ultrasound propagation and heat deposition within the human spine.Approach. Combined acoustic and thermal modelling was used to assess the pressure and heat distributions produced by a 500 kHz source focused to the C5/C6 level via two approaches (a) the posterior acoustic window between vertebral posterior arches, and (b) the lateral intervertebral foramen from which the C6 spinal nerve exits. Pulse trains of fifty 0.1 s pulses (pulse repetition frequency: 0.33 Hz, free-field spatial peak pulse-averaged intensity: 10 W cm-2) were simulated for four subjects and for ±10 mm translational and ±10∘rotational source positioning errors.Main results.Target pressures ranged between 20%-70% of free-field spatial peak pressures with the posterior approach, and 20%-100% with the lateral approach. When the posterior source was optimally positioned, peak spine heating values were below 1 ∘C, but source mispositioning resulted in bone heating up to 4 ∘C. Heating with the lateral approach did not exceed 2 ∘C within the mispositioning range. There were substantial inter-subject differences in target pressures and peak heating values. Target pressure varied three to four-fold between subjects, depending on approach, while peak heating varied approximately two-fold between subjects. This results in a nearly ten-fold range between subjects in the target pressure achieved per degree of maximum heating.Significance. This study highlights the utility of trans-spine ultrasound simulation software and need for precise source-anatomy positioning to assure the subject-specific safety and efficacy of focused ultrasound spinal cord therapies.

Concurrent spinal and brain imaging with optically pumped magnetometers.

BACKGROUND: The spinal cord and its interactions with the brain are fundamental for movement control and somatosensation. However, brain and spinal electrophysiology in humans have largely been treated as distinct enterprises, in part due to the relative inaccessibility of the spinal cord. Consequently, there is a dearth of knowledge on human spinal electrophysiology, including the multiple pathologies that affect the spinal cord as well as the brain. NEW METHOD: Here we exploit recent advances in the development of wearable optically pumped magnetometers (OPMs) which can be flexibly arranged to provide coverage of both the spinal cord and the brain in relatively unconstrained environments. This system for magnetospinoencephalography (MSEG) measures both spinal and cortical signals simultaneously by employing custom-made scanning casts. RESULTS: We evidence the utility of such a system by recording spinal and cortical evoked responses to median nerve stimulation at the wrist. MSEG revealed early (10 - 15 ms) and late (>20 ms) responses at the spinal cord, in addition to typical cortical evoked responses (i.e., N20). COMPARISON WITH EXISTING METHODS: Early spinal evoked responses detected were in line with conventional somatosensory evoked potential recordings. CONCLUSION: This MSEG system demonstrates the novel ability for concurrent non-invasive millisecond imaging of brain and spinal cord.

The complex landscape of TMS devices: A brief overview.

The increasing application of TMS in research and therapy has spawned an ever-growing number of commercial and non-commercial TMS devices and technology development. New CE-marked devices appear at a rate of approximately one every two years, with new FDA-approved application of TMS occurring at a similar rate. With the resulting complex landscape of TMS devices and their application, accessible information about the technological characteristics of the TMS devices, such as the type of their circuitry, their pulse characteristics, or permitted protocols would be beneficial. We here present an overview and open access database summarizing key features and applications of available commercial and non-commercial TMS devices (http://www.tmsbase.info). This may guide comparison and decision making about the use of these devices. A bibliometric analysis was performed by identifying commercial and non-commercial TMS devices from which a comprehensive database was created summarizing their publicly available characteristics, both from a technical and clinical point of view. In this document, we introduce both the commercial devices and prototypes found in the literature. The technical specifications that unify these devices are briefly analysed in two separate tables: power electronics, waveform, protocols, and coil types. In the prototype TMS systems, the proposed innovations are focused on improving the treatment regarding the patient: noise cancellation, controllable parameters, and multiple stimulation. This analysis shows that the landscape of TMS is becoming increasingly fragmented, with new devices appearing ever more frequently. The review provided here can support development of benchmarking frameworks and comparison between TMS systems, inform the choice of TMS platforms for specific research and therapeutic applications, and guide future technology development for neuromodulation devices. This standardisation strategy will allow a better end-user choice, with an impact on the TMS manufacturing industry and a homogenisation of patient samples in multi-centre clinical studies. As an open access repository, we envisage the database to grow along with the dynamic development of TMS devices and applications through community-lead curation.

The impact of brain lesions on tDCS-induced electric fields.

Transcranial direct current stimulation (tDCS) can enhance motor and language rehabilitation after stroke. Though brain lesions distort tDCS-induced electric field (E-field), systematic accounts remain limited. Using electric field modelling, we investigated the effect of 630 synthetic lesions on E-field magnitude in the region of interest (ROI). Models were conducted for two tDCS montages targeting either primary motor cortex (M1) or Broca's area (BA44). Absolute E-field magnitude in the ROI differed by up to 42% compared to the non-lesioned brain depending on lesion size, lesion-ROI distance, and lesion conductivity value. Lesion location determined the sign of this difference: lesions in-line with the predominant direction of current increased E-field magnitude in the ROI, whereas lesions located in the opposite direction decreased E-field magnitude. We further explored how individualised tDCS can control lesion-induced effects on E-field. Lesions affected the individualised electrode configuration needed to maximise E-field magnitude in the ROI, but this effect was negligible when prioritising the maximisation of radial inward current. Lesions distorting tDCS-induced E-field, is likely to exacerbate inter-individual variability in E-field magnitude. Individualising electrode configuration and stimulator output can minimise lesion-induced variability but requires improved estimates of lesion conductivity. Individualised tDCS is critical to overcome E-field variability in lesioned brains.

Effects of transcranial static magnetic field stimulation over the left dorsolateral prefrontal cortex on random number generation.

OBJECTIVE: Focal application of transcranial static magnetic field stimulation (tSMS) is a neuromodulation technique, with predominantly inhibitory effects when applied to the motor, somatosensory or visual cortex. Whether this approach can also transiently interact with dorsolateral prefrontal cortex (DLPFC) function remains unclear. The suppression of habitual or competitive responses is one of the core executive functions linked to DLPFC function. This study aimed to assess the impact of tSMS on the prefrontal contributions to inhibitory control and response selection by means of a RNG task. METHODS: We applied 20 min of tSMS over the left DLPFC of healthy subjects, using a real/sham cross-over design, during performance of a RNG task. We used an index of randomness calculated with the measures of entropy and correlation to assess the impact of stimulation on DLPFC function. RESULTS: The randomness index of the sequences generated during the tSMS intervention was significantly higher compared to those produced in the sham condition. CONCLUSIONS: Our results indicate that application of tSMS transiently modulates specific functional brain networks in DLPFC, which indicate a potential use of tSMS for treatment of neuropsychiatric disorders. SIGNIFICANCE: This study provides evidence for the capacity of tSMS for modulating DLPFC function.

Spatiotemporal organisation of human sensorimotor beta burst activity.

Beta oscillations in human sensorimotor cortex are hallmark signatures of healthy and pathological movement. In single trials, beta oscillations include bursts of intermittent, transient periods of high-power activity. These burst events have been linked to a range of sensory and motor processes, but their precise spatial, spectral, and temporal structure remains unclear. Specifically, a role for beta burst activity in information coding and communication suggests spatiotemporal patterns, or travelling wave activity, along specific anatomical gradients. We here show in human magnetoencephalography recordings that burst activity in sensorimotor cortex occurs in planar spatiotemporal wave-like patterns that dominate along two axes either parallel or perpendicular to the central sulcus. Moreover, we find that the two propagation directions are characterised by distinct anatomical and physiological features. Finally, our results suggest that sensorimotor beta bursts occurring before and after a movement can be distinguished by their anatomical, spectral, and spatiotemporal characteristics, indicating distinct functional roles.

High precision magnetoencephalography reveals increased right-inferior frontal gyrus beta power during response conflict.

Flexibility of behavior and the ability to rapidly switch actions is critical for adaptive living in humans. It is well established that the right-inferior frontal gyrus (R-IFG) is recruited during outright action-stopping, relating to increased beta (12-30 Hz) power. It has also been posited that inhibiting incorrect response tendencies and switching is central to motor flexibility. However, it is not known if the commonly reported R-IFG beta signature of response inhibition in action-stopping is also recruited during response conflict, which would suggest overlapping networks for stopping and switching. In the current study, we analyzed high precision magnetoencephalography (hpMEG) data recorded with multiple within subject recording sessions (trials n > 10,000) from 8 subjects during different levels of response conflict. We hypothesized that a R-IFG-triggered network for response inhibition is domain general and therefore also involved in mediating response conflict. We tested whether R-IFG showed increased beta power dependent on the level of response conflict. Using event-related spectral perturbations and linear mixed modeling, we found that R-IFG beta power increased for response conflict trials. The R-IFG beta increase was specific to trials with strong response conflict, and increased R-IFG beta power related to less error. This supports a more generalized role for R-IFG beta, beyond simple stopping behavior towards response switching.

Neural dynamics of illusory tactile pulling sensations.

Directional tactile pulling sensations are integral to everyday life, but their neural mechanisms remain unknown. Prior accounts hold that primary somatosensory (SI) activity is sufficient to generate pulling sensations, with alternative proposals suggesting that amodal frontal or parietal regions may be critical. We combined high-density EEG with asymmetric vibration, which creates an illusory pulling sensation, thereby unconfounding pulling sensations from unrelated sensorimotor processes. Oddballs that created opposite direction pulls to common stimuli were compared to the same oddballs after neutral common stimuli (symmetric vibration) and to neutral oddballs. We found evidence against the sensory-frontal N140 and in favor of the midline P200 tracking the emergence of pulling sensations, specifically contralateral parietal lobe activity 264-320ms, centered on the intraparietal sulcus. This suggests that SI is not sufficient to generate pulling sensations, which instead depend on the parietal association cortex, and may reflect the extraction of orientation information and related spatial processing.

Inter-individual variability in current direction for common tDCS montages.

The direction of applied electric current relative to the cortical surface is a key determinant of transcranial direct current stimulation (tDCS) effects. Inter-individual differences in anatomy affect the consistency of current direction at a cortical target. However, the degree of this variability remains undetermined. Using current flow modelling (CFM), we quantified the inter-individual variability in tDCS current direction at a cortical target (left primary motor cortex, M1). Three montages targeting M1 using circular electrodes were compared: PA-tDCS directed current perpendicular to the central sulcus in a posterior-anterior direction relative to M1, ML-tDCS directed current parallel to the central sulcus in a medio-lateral direction, and conventional-tDCS applied electrodes over M1 and the contralateral forehead. In 50 healthy brain scans from the Human Connectome Project, we extracted current direction and intensity from the grey matter surface in the sulcal bank (M1BANK) and gyral crown (M1CROWN), and neighbouring primary somatosensory cortex (S1BANK and S1CROWN). Results confirmed substantial inter-individual variability in current direction (50%-150%) across all montages. Radial inward current produced by PA-tDCS was predominantly located in M1BANK, whereas for conventional-tDCS it was clustered in M1CROWN. The difference in radial inward current in functionally distinct subregions of M1 raises the testable hypothesis that PA-tDCS and conventional-tDCS modulate cortical excitability through different mechanisms. We show that electrode locations can be used to closely approximate current direction in M1 and precentral gyrus, providing a landmark-based method for tDCS application to address the hypothesis without the need for MRI. By contrast, ML-tDCS current was more tangentially orientated, which is associated with weaker somatic polarisation. Substantial inter-individual variability in current direction likely contributes to variable neuromodulation effects reported for these protocols, emphasising the need for individualised electrode montages, including the control of current direction.

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.

Unstable Belief Formation and Slowed Decision-making: Evidence That the Jumping-to-Conclusions Bias in Schizophrenia Is Not Linked to Impulsive Decision-making.

BACKGROUND: Jumping-to-conclusions (JTC) is a prominent reasoning bias in schizophrenia (SCZ). While it has been linked to not only psychopathological abnormalities (delusions and impulsive decision-making) but also unstable belief formation, its origin remains unclear. We here directly test to which extend JTC is associated with delusional ideation, impulsive decision-making, and unstable belief formation. METHODS: In total, 45 SCZ patients were compared with matched samples of 45 patients with major depressive disorder (MDD) and 45 healthy controls (HC) as delusions and JTC also occur in other mental disorders and the general population. Participants performed a probabilistic beads task. To test the association of JTC with measures of delusions (Positive and Negative Syndrome Scale [PANSS]positive, PANSSpositive-factor, and Peter Delusions Inventory [PDI]), Bayesian linear regressions were computed. For the link between JTC and impulsive decision-making and unstable beliefs, we conducted between-group comparisons of "draws to decision" (DTD), "decision times" (DT), and "disconfirmatory evidence scores" (DES). RESULTS: Bayesian regression obtained no robust relationship between PDI and DTD (all |R2adj| ≤ .057, all P ≥ .022, all Bayes Factors [BF01] ≤ 0.046; α adj = .00833). Compared with MDD and HC, patients with SCZ needed more time to decide (significantly higher DT in ambiguous trials: all P ≤ .005, r2 ≥ .216; numerically higher DT in other trials). Further, SCZ had unstable beliefs about the correct source jar whenever unexpected changes in bead sequences (disconfirmatory evidence) occurred (compared with MDD: all P ≤ .004 and all r2 ≥ .232; compared with HC: numerically higher DES). No significant correlation was observed between DT and DTD (all P ≥ .050). CONCLUSIONS: Our findings point toward a relationship of JTC with unstable belief formation and do not support the assumption that JTC is associated with impulsive decision-making.

Differences in outcomes following an intensive upper-limb rehabilitation program for patients with common central nervous system-acting drug prescriptions.

Background: Difficulty using the upper-limb is a major barrier to independence for many patients post-stroke or brain injury. High dose rehabilitation can result in clinically significant improvements in function even years after the incident; however, there is still high variability in patient responsiveness to such interventions that cannot be explained by age, sex, or time since stroke. Methods: This retrospective study investigated whether patients prescribed certain classes of central nervous system-acting drugs-γ-aminobutyric acid (GABA) agonists, antiepileptics, and antidepressants-differed in their outcomes on the three-week intensive Queen Square Upper-Limb program. For 277 stroke or brain injury patients (167 male, median age 52 years (IQR: 21), median time since incident 20 months (IQR: 26)) upper-limb impairment and activity was assessed at admission to the program and at six months post-discharge, using the upper limb component of the Fugl-Meyer, Action Research Arm Test, and Chedoke Arm and Hand Activity Inventory. Drug prescriptions were obtained from primary care physicians at referral. Specification curve analysis was used to protect against selective reporting results and add robustness to the conclusions of this retrospective study. Results: Patients with GABA agonist prescriptions had significantly worse upper-limb scores at admission but no evidence for a significant difference in program-induced improvements was found. Additionally, no evidence of significant differences in patients with or without antiepileptic drug prescriptions on either admission to, or improvement on, the program was found in this study. Although no evidence was found for differences in admission scores, patients with antidepressant prescriptions experienced reduced improvement in upper-limb function, even when accounting for anxiety and depression scores. Conclusions: These results demonstrate that, when prescribed typically, there was no evidence that patients prescribed GABA agonists performed worse on this high-intensity rehabilitation program. Patients prescribed antidepressants, however, performed poorer than expected on the Queen Square Upper-Limb rehabilitation program. While the reasons for these differences are unclear, identifying these patients prior to admission may allow for better accommodation of differences in their rehabilitation needs.

Evidence that endpoint feedback facilitates intermanual transfer of visuomotor force learning by a cognitive strategy.

Humans continuously adapt their movement to a novel environment by recalibrating their sensorimotor system. Recent evidence, however, shows that explicit planning to compensate for external changes, i.e., a cognitive strategy, can also aid performance. If such a strategy is planned in external space, it should improve performance in an effector-independent manner. We tested this hypothesis by examining whether promoting a cognitive strategy during a visual-force adaptation task performed in one hand can facilitate learning for the opposite hand. Participants rapidly adjusted the height of visual bar on screen to a target level by isometrically exerting force on a handle using their right hand. Visuomotor gain increased during the task and participants learned the increased gain. Visual feedback was continuously provided for one group, whereas for another group only the endpoint of the force trajectory was presented. The latter has been reported to promote cognitive strategy use. We found that endpoint feedback produced stronger intermanual transfer of learning and slower response times than continuous feedback. In a separate experiment, we found evidence that aftereffects are reduced when only endpoint feedback is provided, a finding that has been consistently observed when cognitive strategies are used. The results suggest that intermanual transfer can be facilitated by a cognitive strategy. This indicates that the behavioral observation of intermanual transfer can be achieved either by forming an effector-independent motor representation or by sharing an effector-independent cognitive strategy between the hands.NEW & NOTEWORTHY The causes and consequences of cognitive strategy use are poorly understood. We tested whether a visuomotor task learned in a manner that may promote cognitive strategy use causes greater generalization across effectors. Visual feedback was manipulated to promote cognitive strategy use. Learning consistent with cognitive strategy use for one hand transferred to the unlearned hand. Our result suggests that intermanual transfer can result from a common cognitive strategy used to control both hands.

Increasing human motor skill acquisition by driving theta-gamma coupling.

Skill learning is a fundamental adaptive process, but the mechanisms remain poorly understood. Some learning paradigms, particularly in the memory domain, are closely associated with gamma activity that is amplitude modulated by the phase of underlying theta activity, but whether such nested activity patterns also underpin skill learning is unknown. Here, we addressed this question by using transcranial alternating current stimulation (tACS) over sensorimotor cortex to modulate theta-gamma activity during motor skill acquisition, as an exemplar of a non-hippocampal-dependent task. We demonstrated, and then replicated, a significant improvement in skill acquisition with theta-gamma tACS, which outlasted the stimulation by an hour. Our results suggest that theta-gamma activity may be a common mechanism for learning across the brain and provides a putative novel intervention for optimizing functional improvements in response to training or therapy.

Laminar dynamics of high amplitude beta bursts in human motor cortex.

Motor cortical activity in the beta frequency range is one of the strongest and most studied movement-related neural signals. At the single trial level, beta band activity is often characterized by transient, high amplitude, bursting events rather than slowly modulating oscillations. The timing of these bursting events is tightly linked to behavior, suggesting a more dynamic functional role for beta activity than previously believed. However, the neural mechanisms underlying beta bursts in sensorimotor circuits are poorly understood. To address this, we here leverage and extend recent developments in high precision MEG for temporally resolved laminar analysis of burst activity, combined with a neocortical circuit model that simulates the biophysical generators of the electrical currents which drive beta bursts. This approach pinpoints the generation of beta bursts in human motor cortex to distinct excitatory synaptic inputs to deep and superficial cortical layers, which drive current flow in opposite directions. These laminar dynamics of beta bursts in motor cortex align with prior invasive animal recordings within the somatosensory cortex, and suggest a conserved mechanism for somatosensory and motor cortical beta bursts. More generally, we demonstrate the ability for uncovering the laminar dynamics of event-related neural signals in human non-invasive recordings. This provides important constraints to theories about the functional role of burst activity for movement control in health and disease, and crucial links between macro-scale phenomena measured in humans and micro-circuit activity recorded from animal models.

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.