M1 Stimulation Research Articles

Lateralized effects of post-learning transcranial direct current stimulation on motor memory consolidation in older adults: An fMRI investigation

Previous research has consistently demonstrated that older adults have difficulties transforming recently learned movements into robust, long-lasting memories (i.e., motor memory consolidation). One potential avenue to enhance consolidation in older individuals is the administration of transcranial direct current stimulation (tDCS) to task-relevant brain regions after initial learning. Although this approach has shown promise, the underlying cerebral correlates have yet to be revealed. Moreover, it is unknown whether the effects of tDCS are lateralized, an open question with implications for rehabilitative approaches following predominantly unilateral neurological injuries. In this research, healthy older adults completed a sequential motor task before and 6 h after receiving anodal or sham stimulation to right or left primary motor cortex (M1) while functional magnetic resonance images were acquired. Unexpectedly, anodal stimulation to right M1 following left-hand sequence learning significantly hindered consolidation as compared to a sham control, whereas no differences were observed with left M1 stimulation following right-hand learning. Impaired performance following right M1 stimulation was paralleled by sustained engagement of regions known to be critical for early learning stages, including the caudate nucleus and the premotor and parietal cortices. Thus, post-learning tDCS in older adults not only exerts heterogenous effects across the two hemispheres but can also disrupt ongoing memory processing.

Navigated transcranial magnetic stimulation of the primary somatosensory cortex evokes motor potentials in healthy humans’ flexor carpi radialis muscle - A pilot study

Background: Although previous studies targeted S1 by TMS to investigate its effect on the corticospinal pathway, there is no evidence if such stimuli produced by TMS would distinctly be restricted to it and not reach M1 interneurons adjacent to S1.Aim: We hypothesized that S1 vs. M1 stimulation-induced MEPs would be similar but smaller and less variable due to the focality of the magnetic pulse, considering that even if TMS is neuronavigated, the magnetic field is not selective enough and reaches M1 interneurons.Method: Healthy volunteers (n = 8, 2 females, age: 29.9 ± 5.49y) received single-pulse TMS over each hemisphere at each intensity of 90, 100, 110, and 120% of rMT in a randomized order. MEPs from the contralateral FCR were recorded.Results: We found no interhemispheric differences, but larger peak-to-peak amplitudes and variability of MEPs after M1 as compared to S1 stimulation. However, latency and waveforms of MEPs did not differ between S1 vs. M1 stimulation supporting the idea that TMS over S1 is not selective enough and can excite M1 interneurons thus producing MEPs on the contralateral FCR.Interpretation: Future studies should carefully consider these results when targeting S1 with TMS even if using a neuronavigation system.

Electrifying discourse: Anodal tDCS of the primary motor cortex selectively reduces action appraisal in naturalistic narratives

Non-invasive stimulation of the primary motor cortex (M1) modulates processing of decontextualized action words and sentences (i.e., verbal units denoting bodily motion). This suggests that language comprehension hinges on brain circuits mediating the bodily experiences evoked by verbal material. Yet, despite its relevance to constrain mechanistic language models, such a finding fails to reveal whether and how relevant circuits operate in the face of full-blown, everyday texts. Using a novel naturalistic discourse paradigm, we examined whether direct modulation of M1 excitability influences the grasping of narrated actions. Following random group assignment, participants received anodal transcranial direct current stimulation over the left M1, or sham stimulation of the same area, or anodal stimulation of the left ventrolateral prefrontal cortex. Immediately afterwards, they listened to action-laden and neutral stories and answered questions on information realized by verbs (denoting action and non-action processes) and circumstances (conveying locative or temporal details). Anodal stimulation of the left M1 selectively decreased outcomes on action-relative to non-action information –a pattern that discriminated between stimulated and sham participants with 74% accuracy. This result was particular to M1 and held irrespective of the subjects’ working memory and vocabulary skills, further attesting to its specificity. Our findings suggest that offline modulation of motor-network excitability might lead to transient unavailability of putative resources needed to evoke actions in naturalistic texts, opening promising avenues for the language embodiment framework.

Acute offline transcranial direct current stimulation does not change pain or anxiety produced by the cold pressor test

Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has an antalgic effect on acute experimental pain in healthy volunteers. Many published studies have used online stimulation (i.e., tDCS performed during painful stimulation). On the other hand, daily tDCS sessions have been proposed as a therapy for chronic pain (offline tDCS). In such cases, the therapeutic potential depends on the possible aftereffects of each tDCS session. We set out to investigate whether a single tDCS session before application of a classical experimental pain paradigm (the Cold Pressor Test, CPT) would be capable of modulating physiological measures of anxiety as well as pain perception. tDCS was applied to 30 healthy volunteers, 18–28 years old (mean 18.5), with the anode positioned over either the left M1 or the left dorsolateral prefrontal cortex (l-DLPFC), which has been linked to the affective aspects of experienced pain, including anxiety. All volunteers underwent the CPT procedure before and after a tDCS session. Real 2 mA tDCS sessions for 20 min were compared to sham stimulations. No significant difference was found for any variable after real tDCS sessions when compared to the sham stimulations. This result suggests that effective offline tDCS for chronic pain might have different mechanisms of action. Cumulative effects, functional targeting and the unintended simultaneous stimulation of both M1 and the l-DLPFC are likely responsible for the therapeutic effects of tDCS sessions in the clinical setting.

Distributed Motor Control of Limb Movements in Rat Motor and Somatosensory Cortex: The Sensorimotor Amalgam Revisited.

Which areas of the neocortex are involved in the control of movement, and how is motor cortex organized across species? Recent studies using long-train intracortical microstimulation demonstrate that in addition to M1, movements can be elicited from somatosensory regions in multiple species. In the rat, M1 hindlimb and forelimb movement representations have long been thought to overlap with somatosensory representations of the hindlimb and forelimb in S1, forming a partial sensorimotor amalgam. Here we use long-train intracortical microstimulation to characterize the movements elicited across frontal and parietal cortex. We found that movements of the hindlimb, forelimb, and face can be elicited from both M1 and histologically defined S1 and that representations of limb movement types are different in these two areas. Stimulation of S1 generates retraction of the contralateral forelimb, while stimulation of M1 evokes forelimb elevation movements that are often bilateral, including a rostral region of digit grasping. Hindlimb movement representations include distinct regions of hip flexion and hindlimb retraction evoked from S1 and hip extension evoked from M1. Our data indicate that both S1 and M1 are involved in the generation of movement types exhibited during natural behavior. We draw on these results to reconsider how sensorimotor cortex evolved.

Fibrinogen and magnesium combination biomaterials modulate macrophage phenotype, NF-kB signaling and crosstalk with mesenchymal stem/stromal cells

Macrophage behavior upon biomaterial implantation conditions the inflammatory response and subsequent tissue repair. The hypothesis behind this work was that fibrinogen (Fg) and magnesium (Mg) biomaterials, used in combination (FgMg) could act synergistically to modulate macrophage activation, promoting a pro-regenerative phenotype. Materials were characterized by scanning electron microscopy, Fg and Mg degradation products were quantified by atomic absorption spectroscopy and ELISA. Whole blood immune cells and primary human monocyte-derived macrophages were exposed to the biomaterials extracts in unstimulated (M0) or pro-inflammatory LPS or LPS-IFNγ (M1) conditions. Macrophage phenotype was evaluated by flow cytometry, cytokines secreted by whole blood cells and macrophages were measured by ELISA, and signaling pathways were probed by Western blotting. The secretomes of macrophages preconditioned with biomaterials extracts were incubated with human mesenchymal stem/stromal cells (MSC) and their effect on osteogenic differentiation was evaluated via Alkaline Phosphatase (ALP) activity and alizarin red staining. Scaffolds of Fg, alone or in the FgMg combination, presented similar 3D porous architectures. Extracts from FgMg materials reduced LPS-induced TNF-α secretion by innate immune cells, and macrophage M1 polarization upon LPS-IFNγ stimulation, resulting in lower cell surface CD86 expression, lower NFκB p65 phosphorylation and reduced TNF-α secretion. Moreover, while biomaterial extracts per se did not enhance MSC osteogenic differentiation, macrophage secretome, particularly from cells exposed to FgMg extracts, increased MSC ALP activity and alizarin red staining, compared with extracts alone. These findings suggest that the combination of Fg and Mg synergistically influences macrophage pro-inflammatory activation and crosstalk with MSC. Statement of significanceModulating macrophage phenotype by degradable and bioactive biomaterials is an increasingly explored strategy to promote tissue repair/regeneration. Fibrinogen (Fg) and magnesium (Mg)-based materials have been explored in this context. Previous work from our group showed that monocytes interact with fibrinogen adsorbed onto chitosan surfaces through TLR4 and that fibrinogen scaffolds promote in vivo bone regeneration. Also, magnesium ions have been reported to modulate macrophage pro-inflammatory M1 stimulation and to promote bone repair. Here we report, for the first time, the combination of Fg and Mg materials, hypothesizing that it could act synergistically on macrophages, directing them towards a pro-regenerative phenotype. As a first step towards proving/disproving our hypothesis we used extracts obtained from Fg, Mg and FgMg multilayer constructs. We observed that FgMg extracts led to a reduction in the polarization of macrophages towards a pro-inflammatory phenotype. Also, the secretome of macrophages exposed to extracts of the combination material promoted the expression of osteogenic markers by MSCs.

Cortical, Corticospinal, and Reticulospinal Contributions to Strength Training.

Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in 2 female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor-evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST), and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6 kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a 2 week washout period without weights. After a further 3 months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared with the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.SIGNIFICANCE STATEMENT We provide the first report of a strength training intervention in nonhuman primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whereas corticospinal and motoneuronal adaptations are not dominant factors.

Effects of transcranial direct current stimulation on cortex modulation by stimulation of the primary motor cortex and parietal cortex in humans

Aim of the study Transcranial magnetic stimulation (TMS) is used to measure corticospinal excitability (CSE) from the primary motor cortex (M1) in humans through motor-evoked potentials (MEPs). The variability of CSE responses to transcranial direct current stimulation (tDCS) protocols is high and needs to be reproduced in the healthy population. The M1 and posterior parietal cortex (PPC) are anatomically and functionally connected and could play a role in understanding the variability in CSE responses. We tested the individual MEPs following a common cathodal (ctDCS) protocol over the M1 and PPC. Materials and methods Twenty-eight healthy subjects were randomized for a ctDCS stimulation over the left M1 and PPC for 20 min on a separate days. The first dorsal interosseous muscle (FDI) contralateral stimulation of the left M1 was used as the resting motor threshold (RMT), while 15 single pulses 4–8 s apart at an intensity of 120% RMT were used to determine the baseline MEP amplitude and at T0, 5, 10, 20, 30, 40, 50, and 60 min after ctDCS stimulation in both sessions. Results A 20 min duration of ctDCS stimulation significantly deceased the CSE only at T0 (p = 0.046 at M1, p = 0.010 at PPC). Conclusion Our results suggested that PPC stimulation can modulate M1 excitability and PPC–M1 connectivity, but a significant effect is only observed immediately post ctDCS. The tDCS showed variability in response to the tDCS protocol is consistent with other non-invasive brain stimulation studies.

Quantitative Assessment of Pain Threshold Induced by a Single-Pulse Transcranial Magnetic Stimulation.

Transcranial magnetic stimulation (TMS) is commonly used in basic research to evaluate human brain function. Although scalp pain is a side effect, no studies have quantitatively assessed the TMS intensity threshold for inducing pain and whether sensitivity to TMS-induced pain differs between sexes. In the present study, we measured pain thresholds when single-pulse TMS was applied over either Broca’s area (BA) or left primary motor cortex (M1), and compared these thresholds with the motor threshold (MT) for inducing motor evoked potentials (MEPs) through M1 stimulation. Additionally, we compared the pain thresholds for BA and M1 between males and females. We found that pain thresholds for both sites were significantly lower than the MT. Furthermore, the pain threshold for BA was much lower than that for M1. No significant difference was observed between sexes. The results suggest that TMS at an intensity equivalent to MTs, which is often used in experimental or clinical studies, causes slight scalp pain. Experimental designs using TMS to evaluate functional relationships between brain and behavior should consider scalp pain and reduce its likelihood as much as possible.

Effects of high-frequency repetitive transcranial magnetic stimulation on reach-to-grasp performance in individuals with Parkinson's disease: a preliminary study.

Individuals with Parkinson's disease (PD) have deficits in reach-to-grasp (RTG) execution and visuospatial processing which may be a result of dopamine deficiency in two brain regions: primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC). We hypothesized that improvement following M1 stimulation would be the result of a direct impact on motor execution; whereas, DLPFC stimulation would improve the role of DLPFC in visuospatial processing. The aim of pilot study was to investigate the effects of HF-rTMS on RTG performance by stimulating either M1 or DLPFC. Thirty individuals with PD participated (H&Y stages I-III). All of them were more affected on the right side. Participants were allocated into three groups. The DLPFC group received HF-rTMS over left DLPFC; while, the M1 group received HF-rTMS over left M1 of extensor digitorum communis representational area. The control group received HF-rTMS over the vertex. Before and immediately post HF-rTMS, right-hand RTG performance was measured under no barrier and barrier conditions. Additionally, TMS measures including motor-evoked-potential (MEP) amplitude and cortical silent period (CSP) were determined to verify the effects of HF-rTMS. For the results, there were no significant differences among the three groups. However, only the M1 group showed a significant decrease in movement time immediately after HF-rTMS for a barrier condition. Moreover, the M1 group showed a near-significant increase in hand opening and transport velocity. As for the DLPFC group, there was a near-significant increase in temporal transport-grasp coordination and a significant increase in velocity. Increased MEP amplitudes and a significantly longer CSP in the M1 and DLPFC groups confirmed the effects of HF-rTMS. Regarding non-significant results among the three groups, it is still inconclusive whether there were different effects of the rTMS on the two stimulation areas. This is a preliminary study demonstrating that HF-rTMS to M1 may improve RTG execution; whereas, HF-rTMS to DLPFC may improve visuospatial processing demands of RTG.

Bmal1 integrates mitochondrial metabolism and macrophage activation.

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

Direct Impact of Motor Cortical Stimulation on the Blood Oxygen-level Dependent Response in Rats.

Purpose:Neuropathic pain is a complex and distressing chronic illness in modern medicine. Since 1990s, motor cortex stimulation (MCS) has emerged as a potential treatment for chronic neuropathic pain; however, the precise mechanisms underlying analgesia induced by MCS are not completely understood. The purpose of the present study was to investigate the blood oxygen-level dependent (BOLD) response in the brain during MCS.Methods:We inserted a bipolar tungsten electrode into the primary motor cortex (M1) of adult male Wistar rats. Functional magnetic resonance imaging (fMRI) scans were implemented simultaneously with the electrical stimulation of M1 and the BOLD signals taken from the fMRI were used as an index to reflect the response against MCS.Results:Our results demonstrated that the bilateral M1, ipsilateral caudate-putamen, and ipsilateral primary somatosensory cortex to the stimulation spot were activated after the onset of MCS. The BOLD signal time courses were analysed in these regions and similar temporal characteristics were found.Conclusion:By conducting direct cortical stimulation of the rodent brain to investigate its instant effect using fMRI, we identified encephalic regions directly involved in the instant motor cortical stimulation effects in healthy rat models. This result may be essential in establishing a foundation for further research on the underlying neuropathways associated with the MCS effects.

Transcranial direct current stimulation effects on hand sensibility as measured by an objective quantitative analysis device: a randomized single-blind sham-control crossover clinical trial.

Studies show that transcranial direct current stimulation (tDCS) can modulate somatosensory processing, but optimum parameters for tDCS effects on hand sensibility remain in question. We aimed to test the effects of anodal tDCS (atDCS) and cathodal tDCS (ctDCS) compared with sham tDCS (stDCS) of primary motor (M1) and sensory (S1) cortices on healthy subjects' hand sensibility. In this single-blind clinical trial, 30 randomized healthy volunteers received six tDCS sessions over 6 weeks: one session each of atDCS, ctDCS and stDCS over M1, and one session each of atDCS, ctDCS and stDCS over S1. Current perception threshold (CPT) was assessed using an objective quantitative analysis device (PainVision) at baseline, immediately (T0) and 30 min (T30) after each intervention. Our results showed that both atDCS and ctDCS of S1 and M1 significantly increased CPT. M1 ctDCS at T30 had the greatest effect of all M1 and S1 stimulation conditions (mean difference: 32.94%, Z: 3.12, effect size: 1.82, P < 0.001 The largest effect at S1 was for atDCS at T30 (mean difference: 29.87%, Z: 2.53, effect size: 1.72, P < 0.001. Our results are consistent with tDCS' modulatory effects on hand sensation, especially M1 ctDCS and S1 atDCS.

Muscarinic receptors promote castration-resistant growth of prostate cancer through a FAK-YAP signaling axis.

Prostate cancer innervation contributes to the progression of prostate cancer (PCa). However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa clinical specimens compared to all other cancer types, and that amplification or gain of their corresponding encoding genes (CHRM1 and CHRM3, respectively) represent a worse prognostic factor for PCa progression free survival. Moreover, m1 and m3 gene gain or amplification are frequent in castration-resistant PCa (CRPC) compared with hormone-sensitive PCa (HSPC) specimens. This was reflected in HSPC-derived cells, which show aberrantly high expression of m1 and m3 under androgen deprivation mimicking castration and androgen receptor inhibition. We also show that pharmacological activation of m1 and m3 signaling is sufficient to induce the castration-resistant growth of PCa cells. Mechanistically, we found that m1 and m3 stimulation induces YAP activation through FAK, whose encoding gene, PTK2 is frequently amplified in CRPC cases. Pharmacological inhibition of FAK and knockdown of YAP abolished m1 and m3-induced castration-resistant growth of PCa cells. Our findings provide novel therapeutic opportunities for muscarinic-signal-driven CRPC progression by targeting the FAK-YAP signaling axis.

Happy faces selectively increase the excitability of cortical neurons innervating frowning muscles of the mouth.

Although facial muscles are heavily involved in emotional expressions, there is still a lack of evidence about the role of face primary motor cortex (face M1) in the processing of facial recognition and expression. This work investigated the effects of the passive viewing of different facial expressions on face M1 and compared data with those obtained from the hand M1. Thirty healthy subjects were randomly assigned to two groups undergoing transcranial magnetic stimulation (TMS) of face or hand M1. In both groups, short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were probed in the depressor anguli oris (DAO) and first dorsal interosseous (FDI) muscles 300ms after presentation of a picture of a face that expressed happy, sad or neutral emotions. Statistical analysis of SICI showed a non-significant effect of muscle (F1,28 = 1.903, p = 0.179), but a significant effect of emotion (F2,56 = 6.860, p = 0.004) and a significant interaction between muscle and emotion (F2,56 = 5.072, p = 0.015). Post hoc analysis showed that there was a significant reduction of SICI in the DAO muscle after presentation of a face with a happy expression compared with a neutral face (p < 0.001). In the FDI, a significant difference was observed between neutral and sad expressions (p = 0.010) No clear differences in ICF were detected. The different responses of face and hand muscles to emotional stimuli may be due to their functional roles in emotional expression versus protection of the body.

P280 Combined proton and sodium MRI to study short-term effects of transcranial direct current stimulation of M1

P280 Combined proton and sodium MRI to study short-term effects of transcranial direct current stimulation of M1

Targeted tDCS selectively improves motor adaptation with the proximal and distal upper limb

BackgroundThe cerebellum and primary motor cortex (M1) are crucial to coordinated and accurate movements of the upper limbs. There is also appreciable evidence that these two structures exert somewhat divergent influences upon proximal versus distal upper limb control. Here, we aimed to differentially regulate the contribution of the cerebellum and M1 to proximal and distal effectors during motor adaptation, with transcranial direct current stimulation (tDCS). For this, we employed tasks that promote similar motor demands, but isolate whole arm from hand/finger movements, in order to functionally segregate the hierarchy of upper limb control. MethodsBoth young and older adults took part in a visuomotor rotation task; where they adapted to a 60° visuomotor rotation using either a hand-held joystick (requiring finger/hand movements) or a 2D robotic manipulandum (requiring whole-arm reaching movements), while M1, cerebellar or sham tDCS was applied. ResultsWe found that cerebellar stimulation improved adaptation performance when arm movements were required to complete the task, while in contrast stimulation of M1 enhanced adaptation during hand and finger movements only. This double-dissociation was replicated in an independent group of older adults, demonstrating that the behaviour remains intact in ageing. ConclusionsThese results suggest that stimulation of distinct motor areas can selectively improve motor adaptation in the proximal and distal upper limb. This also highlights new ways in which tDCS might be best applied to achieve reliable rehabilitation of upper limb motor deficits.

Modulating Brain Networks With Transcranial Magnetic Stimulation Over the Primary Motor Cortex: A Concurrent TMS/fMRI Study.

Stimulating the primary motor cortex (M1) using transcranial magnetic stimulation (TMS) causes unique multisensory experience such as the targeted muscle activity, afferent/reafferent sensory feedback, tactile sensation over the scalp and “click” sound. Although the human M1 has been intensively investigated using TMS, the experience of the M1 stimulation has not been elucidated at the whole brain. Here, using concurrent TMS/fMRI, we investigated the acute effect of the M1 stimulation of functional brain networks during task and at rest. A short train of 1 Hz TMS pulses applied to individuals’ hand area in the M1 during motor execution or at rest. Employing the independent component analysis (ICA), we showed the M1 stimulation decreased the motor networks activity when the networks were engaged in the task and increased the deactivation of networks when the networks were not involved in the ongoing task. The M1 stimulation induced the activation in the key networks involved in bodily self-consciousness (BSC) including the insular and rolandic operculum systems regardless of states. The degree of activation in these networks was prominent at rest compared to task conditions, showing the state-dependent TMS effect. Furthermore, we demonstrated that the M1 stimulation modulated other domain-general networks such as the default mode network (DMN) and attention network and the inter-network connectivity between these networks. Our results showed that the M1 stimulation induced the widespread changes in the brain at the targeted system as well as non-motor, remote brain networks, specifically related to the BSC. Our findings shed light on understanding the neural mechanism of the complex and multisensory experience of the M1 stimulation.

The differential roles of contralesional frontoparietal areas in cortical reorganization after stroke

BackgroundStudies examining the contribution of contralesional brain regions to motor recovery after stroke have revealed conflicting results comprising both supporting and disturbing influences. Especially the relevance of contralesional brain regions beyond primary motor cortex (M1) has rarely been studied, particularly concerning the temporal dynamics post-stroke. MethodsWe, therefore, used online transcranial magnetic stimulation (TMS) interference to longitudinally assess the role of contralesional (right) frontoparietal areas for recovery of hand motor function after left hemispheric stroke: contralesional M1, contralesional dorsal premotor cortex (dPMC), and contralesional anterior intraparietal sulcus (IPS). Fourteen stroke patients and sixteen age-matched healthy subjects performed motor tasks of varying complexity with their (paretic) right hand. Motor performance was quantified using three-dimensional kinematic data. All patients were assessed twice, (i) in the first week, and (ii) after more than three months post-stroke. ResultsWhile we did not observe a significant effect of TMS interference on movement kinematics following the stimulation of contralesional M1 and dPMC in the first week post-stroke, we found improvements of motor performance upon interference with contralesional IPS across motor tasks early after stroke, an effect that persisted into the later phase. By contrast, for dPMC, TMS-induced deterioration of motor performance was only evident three months post-stroke, suggesting that a supportive role of contralesional premotor cortex might evolve with reorganization. ConclusionWe here highlight time-sensitive and region-specific effects of contralesional frontoparietal areas after left hemisphere stroke, which may influence on neuromodulation regimes aiming at supporting recovery of motor function post-stroke.

A mechanistic integrative computational model of macrophage polarization: Implications in human pathophysiology.

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extremes are denoted as classical (M1) and alternative (M2) activation. To quantitatively decode the underlying principles governing macrophage phenotypic polarization and thereby harness its therapeutic potential in human diseases, a systems-level approach is needed given the multitude of signaling pathways and intracellular regulation involved. Here we develop the first mechanism-based, multi-pathway computational model that describes the integrated signal transduction and macrophage programming under M1 (IFN-γ), M2 (IL-4) and cell stress (hypoxia) stimulation. Our model was calibrated extensively against experimental data, and we mechanistically elucidated several signature feedbacks behind the M1-M2 antagonism and investigated the dynamical shaping of macrophage phenotypes within the M1-M2 spectrum. Model sensitivity analysis also revealed key molecular nodes and interactions as targets with potential therapeutic values for the pathophysiology of peripheral arterial disease and cancer. Through simulations that dynamically capture the signal integration and phenotypic marker expression in the differential macrophage polarization responses, our model provides an important computational basis toward a more quantitative and network-centric understanding of the complex physiology and versatile functions of macrophages in human diseases.