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Due to the high interindividual response variability following transcranial direct current stimulation (tDCS), it is apparent that further research of the long‐lasting effects of the stimulation technique is required. We aimed to investigate interindividual variability following anodal tDCS and cathodal tDCS in a large‐scale prospective cross‐over study. Motor cortex physiology measurements were obtained using transcranial magnetic stimulation (TMS) in 59 healthy participants comparing motor‐evoked potential (MEP) magnitudes following two tDCS paradigms: 1 mA anodal tDCS for 13 min and 1 mA cathodal tDCS for 9 min. Analysis compared MEP changes over time for both polarities. Additionally, we applied hierarchical cluster analysis to assess the dynamics of poststimulation changes. Overall, anodal tDCS resulted in a significant increase in corticospinal excitability lasting for 40 min poststimulation, whereas cathodal tDCS did not alter corticospinal excitability. Cluster analysis revealed for cathodal tDCS both a cluster showing significant stable MEP reduction and a second cluster displaying MEP increase over time. Two diametrical clusters were also found for anodal tDCS. Regardless of polarity, individuals with MEP increase following stimulation showed steeper cortical recruitment curves compared to the clusters with decreased MEP magnitudes. The observed findings confirm a bidirectional modulation of corticospinal excitability following 1 mA tDCS in separate subgroups and the relationship to cortical recruitment. 1mA anodal and cathodal transcranial direct current stimulation display a significant inter‐subject variability. Response clusters showing increases or decreases in corticospinal excitability following both anodal and cathodal tDCS can be extracted allowing for a separation of different response patterns. Regardless of polarity, clusters of increased corticospinal excitability following anodal or cathodal tDCS are characterized by steeper cortical recruitment. Our results help to better understand the individual response heterogeneity to standard motor‐cortical transcranial direct current stimulation.

Post-mortem and in vivo studies provide evidence for a link between reduced plasticity and dysconnectivity in schizophrenia patients. It has been suggested that the association between plasticity and connectivity contributes to the pathophysiology and symptomatology of schizophrenia. However, little is known about the impact of glutamate-dependent long-term depression (LTD)-like cortical plasticity on inter-hemispheric connectivity in schizophrenia patients. The aim of the present study was to investigate LTD-like cortical plasticity following excitability-diminishing cathodal transcranial direct current stimulation (tDCS) of the left primary motor cortex (M1) and its effects on the non-stimulated right M1. Eighteen schizophrenia patients and 18 matched (age, gender, handedness, and smoking status) control subjects were investigated in this study. Corticospinal excitability changes following tDCS and intra-cortical inhibitory circuits were monitored with transcranial magnetic stimulation. On the stimulated hemisphere, cathodal tDCS increased resting motor thresholds (RMT) in both groups and decreased motor-evoked potential (MEP) sizes in healthy controls to a greater extent compared to schizophrenia patients. On the non-stimulated hemisphere, RMTs were increased and MEPs were decreased only in the healthy control group. Our results confirm previous findings of reduced LTD-like plasticity in schizophrenia patients and offer hypothetical and indirect in vivo evidence for an association between LTD-like cortical plasticity and inter-hemispheric connectivity in schizophrenia patients. Moreover, our findings highlight the impact of plasticity on connectivity. Dysfunctional N -methyl d -aspartate receptors or modulation of dopaminergic transmission can explain these findings. Nevertheless, the effects of antipsychotic medication still need to be considered.

The mirror box illusion has proven a helpful therapy in pathologies such as phantom limb pain, and although the effect has been suggested to be a result of the interaction between pain, vision, touch, and proprioception, the mechanisms are still unknown. Multichannel (124) brain responses were investigated in healthy men ( N  = 11) and women ( N  = 14) during the mirror box illusion. Tactile somatosensory evoked potentials were recorded from the right thumb during two control conditions and two illusions: (control 1) no mirror: looking at the physical right thumb during stimulation, (control 2) no mirror: looking at the physical left thumb during stimulation, (illusion 1) mirror: the illusion that both thumbs were stimulated, and (illusion 2) mirror: the illusion that none of the thumbs were stimulated. In men, a significant medial shift in the y coordinate of the N70 dipole in illusion 2 ( P  = 0.021) was found when compared with illusion 1. No dipole shift was found for women. Additionally, men showed higher prevalence of P180 cingulate cortex activation during illusion 2 when compared with control 1 and 2 ( P  = 0.002). During illusion 2, the degree of conformity with the statement “The hand in the mirror feels like my other hand” was negatively correlated with the N70 x coordinate for men and positively correlated with the N70 z coordinate for women. In conclusion, short-term cortical plasticity can be induced by a mismatch between visual input and location of tactile stimulation in men. The present study suggests that gender differences exist in the perception of the mirror box illusion.

Hebbian plasticity is widely considered to be the mechanism by which information can be coded and retained in neurons in the brain. Homeostatic plasticity moves the neuron back towards its original state following a perturbation, including perturbations produced by Hebbian plasticity. How then does homeostatic plasticity avoid erasing the Hebbian coded information? To understand how plasticity works in the brain, and therefore to understand learning, memory, sensory adaptation, development and recovery from injury, requires development of a theory of plasticity that integrates both forms of plasticity into a whole. In April 2016, a group of computational and experimental neuroscientists met in London at a discussion meeting hosted by the Royal Society to identify the critical questions in the field and to frame the research agenda for the next steps. Here, we provide a brief introduction to the papers arising from the meeting and highlight some of the themes to have emerged from the discussions. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

Synapses undergo rapid activity-dependent plasticity to store information, which when left uncompensated can lead to destabilization of neural function. It has been well documented that homeostatic changes, which operate at a slower time scale, are required to maintain stability of neural networks. While there are many mechanisms that can endow homeostatic control, sliding threshold and synaptic scaling are unique in that they operate by providing homeostatic control of synaptic strength. The former mechanism operates by adjusting the threshold for synaptic plasticity, while the latter mechanism directly alters the gain of synapses. Both modes of homeostatic synaptic plasticity have been studied across various preparations from reduced systems, such as neuronal cultures, to intact circuitry. While most of the cellular and molecular mechanisms of homeostatic synaptic plasticity have been worked out using reduced preparations, there are unique challenges present in intact circuitry , which deserve further consideration. For example, in an intact circuit, neurons receive distinct set of inputs across their dendritic tree which carry unique information. Homeostatic synaptic plasticity needs to operate without compromising processing of these distinct set of inputs to preserve information processing while maintaining network stability. In this mini review, we will summarize unique features of homeostatic synaptic plasticity, and discuss how sliding threshold and synaptic scaling may act across different activity regimes to provide homeostasis.

The structure of human cortical bone evolves over multiple length scales from its basic constituents of collagen and hydroxyapatite at the nanoscale to osteonal structures at near-millimeter dimensions, which all provide the basis for its mechanical properties. To resist fracture, bone’s toughness is derived intrinsically through plasticity (e.g., fibrillar sliding) at structural scales typically below a micrometer and extrinsically (i.e., during crack growth) through mechanisms (e.g., crack deflection/bridging) generated at larger structural scales. Biological factors such as aging lead to a markedly increased fracture risk, which is often associated with an age-related loss in bone mass (bone quantity). However, we find that age-related structural changes can significantly degrade the fracture resistance (bone quality) over multiple length scales. Using in situ small-angle X-ray scattering and wide-angle X-ray diffraction to characterize submicrometer structural changes and synchrotron X-ray computed tomography and in situ fracture-toughness measurements in the scanning electron microscope to characterize effects at micrometer scales, we show how these age-related structural changes at differing size scales degrade both the intrinsic and extrinsic toughness of bone. Specifically, we attribute the loss in toughness to increased nonenzymatic collagen cross-linking, which suppresses plasticity at nanoscale dimensions, and to an increased osteonal density, which limits the potency of crack-bridging mechanisms at micrometer scales. The link between these processes is that the increased stiffness of the cross-linked collagen requires energy to be absorbed by \"plastic\" deformation at higher structural levels, which occurs by the process of microcracking.

The developing brain can respond quickly to altered sensory experience by circuit reorganization. During a critical period in early life, neurons in the primary visual cortex rapidly lose responsiveness to an occluded eye and come to respond better to the open eye. While physiological and some of the molecular mechanisms of this process have been characterized, its structural basis, except for the well-known changes in the thalamocortical projection, remains obscure. To elucidate the relationship between synaptic remodeling and functional changes during this experience-dependent process, we used 2-photon microscopy to image synaptic structures of sparsely labeled layer 2/3 neurons in the binocular zone of mouse primary visual cortex. Anatomical changes at presynaptic and postsynaptic sites in mice undergoing monocular visual deprivation (MD) were compared to those in control mice with normal visual experience. We found that postsynaptic spines remodeled quickly in response to MD, with neurons more strongly dominated by the deprived eye losing more spines. These postsynaptic changes parallel changes in visual responses during MD and their recovery after restoration of binocular vision. In control animals with normal visual experience, the formation of presynaptic boutons increased during the critical period and then declined. MD affected bouton formation, but with a delay, blocking it after 3 d. These findings reveal intracortical anatomical changes in cellular layers of the cortex that can account for rapid activity-dependent plasticity.

Activity-dependent plasticity is a fundamental requirement for human motor learning, which takes place at several stages of the motor system and involves various mechanisms in neuronal circuitry. Here, we investigate parameters of cortical and spinal excitability before and immediately after a single session of locomotion-like arm training (LMT) or sequential visuo-motor learning (VMT). Both training paradigms focused especially on mainly activating the flexor carpi radialis muscle (FCR). The activity-dependent change in the excitability of FCR-associated neurons was investigated using standard transcranial magnetic stimulation, including analysis of motor-evoked potentials (MEP) amplitude, short-interval intracortical inhibition and intracortical facilitation (ICF). Furthermore, spinal plasticity was also assessed by means of homosynaptic FCR H-reflex depression (HD). LMT decreased HD and ICF. In contrast, VMT had no significant effect on cortical and spinal parameters. There was a nonsignificant tendency of an increase in MEP amplitudes after both interventions. This implies that human locomotor-related learning involves spinal mechanisms. Despite the decreasing importance of quadrupedal coordination in the course of evolution, these changes in transsynaptic plasticity may reflect a persisting locomotor memory-encoding function in the spinal circuitry of the human upper extremities. Evaluating FCR HD might be helpful for the evaluation and development of locomotor rehabilitation strategies.

Abstract BACKGROUND In diffuse glioma, a multistage approach with iterative tailored surgical resections can be considered. OBJECTIVE To compare results of iterative intrasurgical brain mappings to investigate the potential and limitation of neuroplasticity at the individual stage, and to highlight to what extent it can influence the therapeutic strategy. METHODS Glioma patients who underwent 2 consecutive awake surgeries with cortical and subcortical stimulation were classified into group 1 (n = 23) if cortical mappings exhibited high level of plasticity (displacement of ≥2 sites) or into group 2 (n = 19) with low level of plasticity. RESULTS Clinical characteristics did not differ significantly between both groups. The borders of the tumors were mostly sharp in group 1 (82.6%) and rather indistinct in group 2 (84.2%), (P = .00001). Tumor remnants were more often cortical (± subcortical) in group 1 (39.1%) and more often purely subcortical in group 2 (68.4%; P = .009). In group 1, the time needed to recover independence was significantly shorter at reoperation (37.6 h vs 78.3 h after the first surgery, P = .00003) while this difference was not significant in group 2. The iterative extents of resection (EOR) remain comparable in group 1 (94% vs 92%, P = .40) but were significantly smaller in group 2 at reoperation (94% vs 88%, P = .05). CONCLUSION More efficient plasticity mechanisms are facilitated by cortical tumors with sharp borders, are associated with an increase of EOR at reoperation and with earlier functional recovery. Tumoral invasion of the white matter tracts represents the main limitation of neuroplasticity: this connectomal constraint limits EOR during second surgery.

The responsiveness to non-invasive neuromodulation protocols shows high inter-individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) – an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability – depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent. To this end, we used a sham-stimulation controlled, single-blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15min. We found that non-responders (subjects not showing an MEP increase of ≥10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups. Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre-interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level. •Non-responders to iTBS feature stronger baseline premotor-M1 connectivity.•Responders show a lasting increase in MEPs and rsFC after multiple iTBS blocks.•Increasing the iTBS dose does not induce responsiveness.