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Efforts on selective neural stimulation have concentrated on segregating axons based on their size and geometry. Nonetheless, axons of the white matter or peripheral nerves may also differ in their electrophysiological properties. The primary objective of this study was to investigate the possibility of selective activation of axons by leveraging an assumed level of diversity in passive (Cm & Gleak) and active membrane properties (Ktemp & Gnamax). First, the stimulus waveforms with hyperpolarizing (HPP) and depolarizing pre-pulsing (DPP) were tested on selectivity in a local membrane model. The default value of membrane capacitance (Cm) was found to play a critical role in sensitivity of the chronaxie time (Chr) and rheobase (Rhe) to variations of all the four membrane parameters. Decreasing the default value of Cm, and thus the passive time constant of the membrane, amplified the sensitivity to the active parameters, Ktemp and GNamax, on Chr. The HPP waveform could selectively activate neurons even if they were diversified by membrane leakage (Gleak) only, and produced higher selectivity than DPP when parameters are varied in pairs. Selectivity measures were larger when the passive parameters (Cm & Gleak) were varied together, compared to the active parameters. Second, this novel mechanism of selectivity was investigated with non-rectangular waveforms for the stimulating phase (and HPP) in the same local membrane model. Simulation results suggest that Kt2 is the most selective waveform followed by Linear and Gaussian waveforms. Traditional rectangular pulse was among the least selective of all. Finally, a compartmental axon model confirmed the main findings of the local model that Kt2 is the most selective, but rank ordered the other waveforms differently. These results suggest a potentially novel mechanism of stimulation selectivity, leveraging electrophysiological variations in membrane properties, that can lead to various neural prosthetic applications.

This work proposes and computationally investigate the use of magnetic neural stimulation as an alternative to electrical stimulation to achieve selective activation of rat sciatic nerve. In particular, they assess the effectiveness of an array of small coils to obtain selective neural stimulation, as compared to a single coil. Specifically, an array of four mm-sized coils is used to stimulate rat sciatic nerve, targeting the regions of fascicles that are associated with different muscles of the leg. To evaluate the selectivity of activation, a three-dimensional heterogeneous multi-resolution nerve model is implemented using the impedance method for the computation of the magnetic and electric fields in the nerve. The performance metric ‘selectivity index’ is defined that measures the recruitment of the targeted region compared to other non-targeted regions of the nerve. The selectivity index takes values between −1 (least selective) and 1 (most selective). For each targeted region, a selectivity index of 0.75 or better is predicted for the proposed array configuration. The results suggest that an array of coils can provide superior spatial control of the electric field induced in the neural tissue compared to traditional extraneural electrode arrays, thus opening the possibility to applications where selective neurostimulation is of interest.

One of the most challenging problems in peripheral nerve stimulation is the ability to activate selectively small axons without large ones. Electrical stimulation of peripheral nerve activates large diameter fibers before small ones. Currently available techniques for selective activation of small axons without large ones require long-duration stimulation pulses (>500 micros) and large stimulation amplitude, which shorten battery life of the implanted stimulator and could lead to electrode corrosion. In the current study, the hypothesis that small axons can be recruited before large ones with narrow pulse width (50 micros) using an electrode array was tested in both simulations simulation and experiments in the cat lateral gastrocnemius (LG) model. The LG nerve innervates both LG and soleus muscle groups with axons within 10-13 and 8-12 microm diameter ranges, respectively. A finite element model of LG nerve was constructed and simulations showed that, when activating 40% of LG, a conventional tripolar electrode activated only 9% of soleus whereas the electrode arrays of 5, 7, and 11 contacts activated 39, 46, and 60% of soleus respectively, suggesting that the arrays could activate small axons before fully recruiting large axons. In animal experiments, peak twitch force of LG and soleus were plotted as a function of stimulation amplitude to indicate the recruitment curve. At 40% activation of LG, a conventional tripolar electrode activated only 7% of soleus whereas the electrode arrays of 5, 7, and 11 contacts activated 43, 48, and 72% of soleus respectively. The electrode arrays also decreased significantly the recruitment curve slopes to only 10-20% of the value obtained for the tripolar electrode in both computer simulations and experiments. In conclusion, the 5-, 7-, and 11-contact arrays can be used to reverse the recruitment order of peripheral nerve stimulation with a narrow pulse.

Abstract Background The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. Methods Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. Results Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60–120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. Conclusions Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.

Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo-controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory- and excitability-diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation-elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke.

•Selective and Distributed Attention to speech engage a similar array of brain regions.•Even when both are task-relevant, the neural representation of concurrent speech is biased.•Results are in line with proposed bottlenecks for concurrent speech processing.•Individual differences suggest that these bottlenecks do not necessarily eliminate representation of task-irrelevant speech. Speech comprehension is severely compromised when several people talk at once, due to limited perceptual and cognitive resources. In such circumstances, top-down attention mechanisms can actively prioritize processing of task-relevant speech. However, behavioral and neural evidence suggest that this selection is not exclusive, and the system may have sufficient capacity to process additional speech input as well. Here we used a data-driven approach to contrast two opposing hypotheses regarding the system's capacity to co-represent competing speech: Can the brain represent two speakers equally or is the system fundamentally limited, resulting in tradeoffs between them? Neural activity was measured using magnetoencephalography (MEG) as human participants heard concurrent speech narratives and engaged in two tasks: Selective Attention, where only one speaker was task-relevant and Distributed Attention, where both speakers were equally relevant. Analysis of neural speech-tracking revealed that both tasks engaged a similar network of brain regions involved in auditory processing, attentional control and speech processing. Interestingly, during both Selective and Distributed Attention the neural representation of competing speech showed a bias towards one speaker. This is in line with proposed ‘bottlenecks’ for co-representation of concurrent speech and suggests that good performance on distributed attention tasks may be achieved by toggling attention between speakers over time.

•Measured fMRI BOLD contrast during ventrolateral thalamus DBS in pig model.•In vivo evaluation of a novel 16-channel directional DBS lead.•Directional stimulation around the lead differentially affected sensorimotor cortices.•Increased sensorimotor cortex effect with the electric field aligned along the lead. Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy. [Display omitted]

Bilingualism profoundly affects the brain, yielding functional and structural changes in cortical regions dedicated to language processing and executive function [Crinion J, et al. (2006) Science 312:1537–1540; Kim KHS, et al. (1997) Nature 388:171–174]. Comparatively, musical training, another type of sensory enrichment, translates to expertise in cognitive processing and refined biological processing of sound in both cortical and subcortical structures. Therefore, we asked whether bilingualism can also promote experience-dependent plasticity in subcortical auditory processing. We found that adolescent bilinguals, listening to the speech syllable [da], encoded the stimulus more robustly than age-matched monolinguals. Specifically, bilinguals showed enhanced encoding of the fundamental frequency, a feature known to underlie pitch perception and grouping of auditory objects. This enhancement was associated with executive function advantages. Thus, through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound. This study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions.

Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

Brain mechanisms of visual selective attention involve both local and network-level activity changes at specific oscillatory rhythms, but their interplay remains poorly explored. Here, we investigate anticipatory and reactive effects of feature-based attention using separate fMRI and EEG recordings, while participants attended to one of two spatially overlapping visual features (motion and orientation). We focused on EEG source analysis of local neuronal rhythms and nested oscillations and on graph analysis of connectivity changes in a network of fMRI-defined regions of interest, and characterized a cascade of attentional effects at multiple spatial scales. We discuss how the results may reconcile several theories of selective attention, by showing how β rhythms support anticipatory information routing through increased network efficiency, while reactive α-band desynchronization patterns and increased α-γ coupling in task-specific sensory areas mediate stimulus-evoked processing of task-relevant signals.