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Recently, multifocal transcranial current stimulation (tCS) devices using several relatively small electrodes have been used to achieve more focal stimulation of specific cortical targets. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric disease are not solely the result of abnormality in one isolated brain region but represent alterations in brain networks. In this paper we describe a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. We show how, based on fMRI, PET, EEG or other data specifying a target map on the cortical surface for excitatory, inhibitory or neutral stimulation and a constraint on the maximal number of electrodes, a solution can be produced with the optimal currents and locations of the electrodes. The method described here relies on a fast calculation of multifocal tCS electric fields (including components normal and tangential to the cortical boundaries) using a five layer finite element model of a realistic head. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. Solutions are found using constrained least squares to optimize current intensities, while electrode number and their locations are selected using a genetic algorithm. For direct current tCS (tDCS) applications, we provide some examples of this technique using an available tCS system providing 8 small Ag/AgCl stimulation electrodes. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression. Finally, we extend these ideas to more general stimulation protocols, such as alternating current tCS (tACS). •We provide a method for optimizing the configuration of multifocal tDCS.•Optimization cortical target maps are based on fMRI, PET or other data.•Algorithm optimizes electrode currents and locations subject to safety constraints.•We highlight clinical applications in stroke and depression.•We discuss the generalization of these methods to tACS.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4×1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4×1 montage (4× cathode, surrounding a single central anode; montage radius ~3cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4×1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4×1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4×1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4×1-Ring montage for cortically targeted neuromodulation. ► Experimental transcranial electrical stimulation validates MRI-derived model of brain current delivery. ► High-Definition tDCS focally delivers current to motor cortex. ► Both TES and tDCS produce inward (normal) currents beneath the anode. ► The High-Definition electrode montage could be used for focal therapeutic tDCS.

The targeted stimulation of micropores based on the transformation of coal’s molecular structure is proposed due to the chemical properties and difficult-to-transform properties of micropores. Carbon disulfide (CS2) extraction is used as a targeted stimulation to reveal the internal evolution mechanism of micropore transformation. The variations of microcrystalline structures and micropores of bituminous coal and anthracite extracted by CS2 were analyzed with X-ray diffraction (XRD), low-temperature carbon dioxide (CO2) adsorption, and molecular simulation. The results show that CS2 extraction, with the broken chain effect, swelling effect, and aromatic ring rearrangement effect, can promote micropore generation of bituminous coal by transforming the microcrystalline structure. Furthermore, CS2 extraction on bituminous coal can decrease the average micropore size and increase the micropore volume and area. The aromatic layer fragmentation effect of CS2 extraction on anthracite, compared to the micropore generation effect of the broken chain effect and swelling effect, can enlarge micropores more remarkably, as it induces an enhancement in the average micropore size and a decline in the micropore volume and area. The research is expected to provide a theoretical basis for establishing reservoir stimulation technology based on CS2 extraction.

•Auditory stimuli were presented at specific phases of slow waves during sleep.•Inter-stimulus interval (ISI) determines global vs. local modulation of slow waves.•Short ISIs in stimulus trains enable local, phase-specific modulation of slow waves.•Long ISIs evoke a global K-complex response irrespective of the targeted phase.•Different EEG responses suggest the engagement of distinct neural circuits. Conflicting evidence exists regarding the role of the targeted slow-wave phase in determining the direction and spatial specificity of slow-wave activity (SWA) modulation via phase-targeted auditory stimulation (PTAS) during sleep. To reconcile these discrepancies, we re-analyzed high-density electroencephalography (hd-EEG) data from previous studies, focusing on SWA responses to auditory stimuli presented with varying inter-stimulus intervals (ISIs). Our analysis reveals that ISI is a primary determinant of PTAS-induced SWA modulation, exceeding the influence of targeted phase alone. Specifically, auditory stimulation with longer ISIs evoked a global increase in SWA, consistent with a stereotypical auditory-evoked K-complex (KC), independent of targeted phase. Conversely, longer stimulus trains with rapid successive stimulus presentation resulted in spatially localized, phase-dependent SWA modulation, with up-PTAS enhancing and down-PTAS reducing SWA locally around the targeted area. This distinction resolves inconsistencies in prior PTAS studies by demonstrating that phase alone is insufficient in predicting slow-wave responses. Rather, it was the ISI which determined whether PTAS resulted in a global, KC-mediated response or a local, phase-specific modulation of SWA. Consequently, our findings refine the mechanistic understanding of PTAS, suggesting that ISI regulates the engagement of distinct neural circuits and thereby potentially enables the targeted manipulation of specific slow-wave subtypes and their associated functions.

•Functionally localized V5 during pursuit show considerable inter-subject variation•Multimodal personalization based on individual MRI and combined EEG/MEG data•Personalized tDCS targeting V5 specifically modulates smooth pursuit initiation•No pursuit modulation by personalized targeting FEF, or normative tDCS of V5•Multimodal personalization accounts for inter-subject variation of anatomy/function Transcranial direct current stimulation (tDCS) for the modulation of smooth pursuit eye movements provides an ideal model for investigating sensorimotor integration. Within neural networks subserving smooth pursuit, visual area V5 is a core hub where visual motion information is integrated with oculomotor control. Here, we applied personalized tDCS explicitly targeting individual V5 in healthy human participants using algorithmic optimization informed by functional magnetic resonance imaging and combined electro- and magnetoencephalography. We hypothesized subtle modulation of sensorimotor integration during pursuit and assessed the effects of personalized anodal and cathodal tDCS targeting V5 compared to (a) sham stimulation, (b) personalized tDCS targeting the frontal eye field (FEF), and (c) conventional normative tDCS over V5. We found pursuit initiation specifically delayed during personalized cathodal tDCS targeting right V5 suggesting the involvement of distinct functional subregions of V5 in initial sensorimotor integration of visual motion information during pursuit eye movements. Results were extensively controlled by anodal and sham tDCS, different pursuit tasks, and finite-element simulations of individual electric fields. Importantly, in contrast to the two control experiments (personalized tDCS targeting FEF and normative tDCS over V5) personalized tDCS targeting V5 effectively modulated pursuit by adapting electric fields to individual anatomical and functional V5 properties. Our results provide evidence for the ability of personalized tDCS targeting V5 to introduce targeted subtle modulation of sensorimotor integration, specifically during smooth pursuit initiation. Further, our results indicate the potential of personalized tDCS to alter behavior as the main aspect of interest in human neuromodulation.

Background: We showed that seniors can improve their stereoscopic ability (stereoacuity) and corresponding reaction time with repetitive training and, furthermore, that these improvements through training are still present even after a longer period of time without training. Methods: Eleven seniors (average age: 85.90 years) trained twice a week for six weeks with dynamic stereoscopic perception training using a vision training apparatus (c-Digital Vision Trainer®). Stereoscopic training was performed in 12 training session (n = 3072) of visual tasks. The task was to identify and select one of four figures (stereoscopic stimuli) that was of a different disparity using a controller. The tests included a dynamic training (showing rotating balls) and a static test (showing plates without movement). Before and after training, the stereoacuity and the corresponding reaction times were identified with the static stereotest in order to determine the individual training success. The changes in respect to reaction time of stereoscopic stimuli with decreasing disparity were calculated. Results: After 6 weeks of training, reaction time improved in the median from 936 arcsec to 511 arcsec. Stereoscopic vision improved from 138 arcsec to 69 arcsec, which is an improvement of two levels of difficulty. After 6 months without training, the improvement, achieved by training, remained stable. Conclusions: In older people, visual training leads to a significant, long-lasting improvement in stereoscopic vision and the corresponding reaction time in seniors. This indicates cortical plasticity even in old age.

Abstract The function of rapid eye movement (REM) sleep in consolidating emotional memories and reducing emotional charge has been studied, but evidence remains conflicting. Our study employed the targeted memory reactivation (TMR) technique, which posits that specific sleep memories can be reactivated through sensory stimuli during sleep. Additionally, the late positive potential (LPP), a component of event-related brain potentials, was measured while participants (N = 16, 22.5 ± 1.2 years) viewed negative, neutral, or positive images (old images) paired with an odor stimulus. During subsequent REM sleep, the same odor was presented in the TMR condition, while an odorless stimulus was presented in the control condition. Upon awakening, participants performed the same task as before sleep, with new images added to test memory. The results demonstrated that TMR increased the LPP amplitude between 500 and 800 ms after image onset following sleep for negative old images; however, no changes were observed in the LPP in the same range for negative new images and neutral or positive images. TMR during REM sleep did not influence performance on the memory task, nor did it affect levels of arousal or emotional valence immediately after viewing the emotional images. These preliminary findings from our pilot study suggest that either the presentation of phenylethyl alcohol itself or the reprocessing induced by TMR during REM sleep selectively enhances the LPP in emotional processing of previously encountered negative stimuli. Due to the small sample size of this study, further investigation is warranted to evaluate the robustness of the results.

Sleep constitutes a privileged state for new memories to reactivate and consolidate. Previous work has demonstrated that consolidation can be bolstered experimentally either via delivery of reminder cues (targeted memory reactivation [TMR]) or via noninvasive brain stimulation geared toward enhancing endogenous sleep rhythms. Here, we combined both approaches, controlling the timing of TMR cues with respect to ongoing slow-oscillation (SO) phases. Prior to sleep, participants learned associations between unique words and a set of repeating images (e.g., car) while hearing a prototypical image sound (e.g., engine starting). Memory performance on an immediate test vs. a test the next morning quantified overnight memory consolidation. Importantly, two image sounds were designated as TMR cues, with one cue delivered at SO UP states and the other delivered at SO DOWN states. A novel sound was used as a TMR control condition. Behavioral results revealed a significant reduction of overnight forgetting for words associated with UP-state TMR compared with words associated with DOWN-state TMR. Electrophysiological results showed that UP-state cueing led to enhancement of the ongoing UP state and was followed by greater spindle power than DOWN-state cueing. Moreover, UP-state (and not DOWN-state) cueing led to reinstatement of target image representations. Together, these results unveil the behavioral and mechanistic effects of delivering reminder cues at specific phases of endogenous sleep rhythms and mark an important step for the endeavor to experimentally modulate memories during sleep.

Abstract Background The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. Methods Available literature was identified through a search of the US National Library of Medicine’s Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. Results The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. Conclusions The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.

•The effects of network-targeted tDCS on brain dynamics are specific to the stimulation network.•CEN-targeted tDCS induced the co-activation patterns dominated by CEN switch to patterns dominated by DMN.•The individual EF strength of salience network makes a large contribution on altered brain dynamics induced by tDCS.•The temporal indexes of brain dynamics during tDCS can be predicted by the networks’ EFs and temporal indexes at baseline.•The current study demonstrated the effectiveness and feasibility of network-targeted tDCS on modulating brain dynamics, which provide a new insight into the therapy for the brain disorders with abnormal brain dynamics. Brain networks should be ideal targets for non-invasive brain stimulation, as network dysfunction is a common feature of various neuropsychiatric disorders. Understanding the mechanisms of network-targeted stimulation is essential for advancing its clinical applications. The current study utilized simultaneous network-targeted transcranial direct current stimulation(tDCS) and functional magnetic resonance imaging (fMRI) to investigate the effects of tDCS targeting antagonistic networks on brain dynamics. A total of 143 healthy participants were recruited and assigned to receive central executive network (CEN)-targeted tDCS (C-targeted group), default mode network (DMN)-targeted tDCS (D-targeted group), or sham tDCS (sham group). fMRI data with three sections (pre-stimulation, during-stimulation, post-stimulation) were collected across all subjects. Individual electric field (EF) strength was simulated using individual head model. Six recurring brain patterns (co-activation patterns, CAPs) were identified. The temporal indices of these CAPs (occurrence, fraction time, persistence time) and their transition probabilities were calculated. This study first examined the effects of C-targeted / D-targeted / sham tDCS on temporal indices and further explored the contribution of brain networks’ EF strength on the altered temporal indices. C-targeted tDCS significantly increased the temporal indices of CAPs dominated by DMN and the transition probabilities from other CAPs to DMN-dominated CAPs during stimulation. Meanwhile, the decreased temporal indices of CAP dominated by CEN, and its transition probabilities to these CAPs were also found during C-targeted tDCS. In contrast, the d-targeted tDCS had only a slight effect on brain dynamics, while sham tDCS showed no significant impact. Further fusion analyses revealed that the EF strength in the salience network made a large contribution to the temporal indices of CAPs during stimulation, highlighting tight interactions within the triple networks. Moreover, integrating the EF strength of networks with large contributions and the pre-stimulation temporal indices effectively predicted the temporal indices of CAPs during stimulation. These findings suggest that C-targeted tDCS can modulate brain dynamics and emphasize the critical role of networks’ EF during stimulation. This study demonstrates the effectiveness and feasibility of network-targeted tDCS in modulating brain dynamics, providing a new choice for treating neuropsychiatric disorders characterized by aberrant brain dynamics. [Display omitted]