Oscillatory beta activity mediates neuroplastic effects of motor cortex stimulation in humans

Continuous theta burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation protocol that can inhibithumanmotor cortex (M1) excitability and impair movement for ≤1 h. While offering valuable insights into brain function and potential therapeutic benefits, these neuroplastic effects are highly variable between individuals. The source of this variability, and the electrophysiological mechanisms underlying the inhibitory after-effects, are largely unknown. In this regard, oscillatory activity at beta frequency (15-35 Hz) is of particular interest as it is elevated in motor disorders such as Parkinson's disease and modulated during the generation of movements. Here, we used a source-level magnetoencephalography approach to investigate the hypothesis that the presence of neuroplastic effects following cTBS is associated with concurrent changes in oscillatory M1 beta activity. M1 cortices were localized with a synthetic aperture magnetometry beamforming analysis of visually cued index finger movements. Virtual electrode analysis was used to reconstruct the spontaneous and movement-related oscillatory activity in bilateral M1 cortices, before and from 10 to 45 min after cTBS. We demonstrate that 40 s of cTBS applied over left M1 reduced corticospinal excitability in the right index finger of 8/16 participants. In these responder participants only, cTBS increased the power of the spontaneous beta oscillations in stimulated M1 and delayed reaction times in the contralateral index finger. No further changes were observed in the latency or power of movement-related beta oscillations. These data provide insights into the electrophysiological mechanisms underlying cTBS-mediated impairment of motor function and demonstrate the association between spontaneous oscillatory beta activity in M1 and the inhibition of motor function. © 2013 the authors.

Inter-individual variability in optimal current direction for transcranial magnetic stimulation of the motor cortex

We evaluated inter-individual variability in optimal current direction for biphasic transcranial magnetic stimulation (TMS) of the motor cortex. Motor threshold for first dorsal interosseus was detected visually at eight coil orientations in 45° increments. Each participant (n = 13) completed two experimental sessions. One participant with low test–retest correlation (Pearson's r < 0.5) was excluded. In four subjects, visual detection of motor threshold was compared to EMG detection; motor thresholds were very similar and highly correlated (0.94–0.99). Similar with previous studies, stimulation in the majority of participants was most effective when the first current pulse flowed towards postero-lateral in the brain. However, in four participants, the optimal coil orientation deviated from this pattern. A principal component analysis using all eight orientations suggests that in our sample the optimal orientation of current direction was normally distributed around the postero-lateral orientation with a range of 63° (S.D. = 13.70°). Whenever the intensity of stimulation at the target site is calculated as a percentage from the motor threshold, in order to minimize intensity and side-effects it may be worthwhile to check whether rotating the coil 45° from the traditional posterior–lateral orientation decreases motor threshold.

Resting state morphology predicts the effect of theta burst stimulation in false belief reasoning:ventrolateral prefrontal cortex in false belief reasoning

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Stimulation of GABAergic neurons of the lateral septum and its effect on movement speed

The lateral septum is associated with the regulation of innate behavior, motivation, and locomotion. Its complex interconnections with cognitive and affective regions such as the hippocampus, hypothalamus, and medial septum have made it an attractive region for studying how motivation regulates behavior in context-specific settings. This GABAergic brain region’s main output is the lateral hypothalamus, which provides downstream signaling of motor commands. Even though stimulation of lateral septum projections to the hypothalamus have shown to decrease running speed in free behaving mice, characterizing movement kinematics due to LS activation has not been studied. GABAergic medium spiny neurons of the lateral septum were selectively activated through the use of optogenetic techniques in transgenic mice. Photostimulation of the lateral septum at theta frequencies caused a non-significant decrease in head and back speed. 3D motion analysis of body movement under photostimulation was quantified, revealing a slow, linear decrease of body speed as photostimulation progressed. These results support the role of lateral septum activation in movement regulation and shed light on the specific manner in which stimulation of the LS gradually decreases movement speed.

High-speed label-free functional photoacoustic microscopy of mouse brain in action.

We present fast functional photoacoustic microscopy (PAM) for three-dimensional high-resolution, high-speed imaging of the mouse brain, complementary to other imaging modalities. We implemented a single-wavelength pulse-width-based method with a one-dimensional imaging rate of 100 kHz to image blood oxygenation with capillary-level resolution. We applied PAM to image the vascular morphology, blood oxygenation, blood flow and oxygen metabolism in both resting and stimulated states in the mouse brain.

Decoding Spontaneous Emotional States in the Human Brain.

Pattern classification of human brain activity provides unique insight into the neural underpinnings of diverse mental states. These multivariate tools have recently been used within the field of affective neuroscience to classify distributed patterns of brain activation evoked during emotion induction procedures. Here we assess whether neural models developed to discriminate among distinct emotion categories exhibit predictive validity in the absence of exteroceptive emotional stimulation. In two experiments, we show that spontaneous fluctuations in human resting-state brain activity can be decoded into categories of experience delineating unique emotional states that exhibit spatiotemporal coherence, covary with individual differences in mood and personality traits, and predict on-line, self-reported feelings. These findings validate objective, brain-based models of emotion and show how emotional states dynamically emerge from the activity of separable neural systems.

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised.

Neurorehabilitation of hand functions using brain computer interface

Introduction: Brain computer interface (BCI) is a promising new technology with possible application in neurorehabilitation after spinal cord injury. Movement imagination or attempted movement-based BCI coupled with functional electrical stimulation (FES) enables the simultaneous activation of the motor cortices and the muscles they control. When using the BCI- coupled with FES (known as BCI-FES), the subject activates the motor cortex using attempted movement or movement imagination of a limb. The BCI system detects the motor cortex activation and activates the FES attached to the muscles of the limb the subject is attempting or imaging to move. In this way the afferent and the efferent pathways of the nervous system are simultaneously activated. This simultaneous activation encourages Hebbian type learning which could be beneficial in functional rehabilitation after spinal cord injury (SCI). The FES is already in use in several SCI rehabilitation units but there is currently not enough clinical evidence to support the use of BCI-FES for rehabilitation. Aims: The main aim of this thesis is to assess outcomes in sub-acute tetraplegic patients using BCI-FES for functional hand rehabilitation. In addition, the thesis explores different methods for assessing neurological rehabilitation especially after BCI-FES therapy. The thesis also investigated mental rotation as a possible rehabilitation method in SCI. Methods: Following investigation into applicable methods that can be used to implement rehabilitative BCI, a BCI based on attempted movement was built. Further, the BCI was used to build a BCI-FES system. The BCI-FES system was used to deliver therapy to seven sub-acute tetraplegic patients who were scheduled to receive the therapy over a total period of 20 working days. These seven patients are in a 'BCI-FES' group. Five more patients were also recruited and offered equivalent FES quantity without the BCI. These further five patients are in a 'FES-only' group. Neurological and functional measures were investigated and used to assess both patient groups before and after therapy. Results: The results of the two groups of patients were compared. The patients in the BCI-FES group had better improvements. These improvements were found with outcome measures assessing neurological changes. The neurological changes following the use of the BCI-FES showed that during movement attempt, the activation of the motor cortex areas of the SCI patients became closer to the activation found in healthy individuals. The intensity of the activation and its spatial localisation both improved suggesting desirable cortical reorganisation. Furthermore, the responses of the somatosensory cortex during sensory stimulation were of clear evidence of better improvement in patients who used the BCI-FES. Missing somatosensory evoked potential peaks returned more for the BCI-FES group while there was no overall change in the FES-only group. Although the BCI-FES group had better neurological improvement, they did not show better functional improvement than the FES-only group. This was attributed mainly to the short duration of the study where therapies were only delivered for 20 working days. Conclusions: The results obtained from this study have shown that BCI-FES may induce cortical changes in the desired direction at least faster than FES alone. The observation of better improvement in the patients who used the BCI-FES is a good result in neurorehabilitation and it shows the potential of thought-controlled FES as a neurorehabilitation tool. These results back other studies that have shown the potential of BCI-FES in rehabilitation following neurological injuries that lead to movement impairment. Although the results are promising, further studies are necessary given the small number of subjects in the current study.

Comprendre l’interaction entre la douleur et le système moteur : une étude novatrice combinant la stimulation magnétique transcrânienne et l’électroencéphalographie

Résumé : L’interaction entre la douleur et le système moteur est bien connue en clinique et en réadaptation. Il est sans surprise que la douleur est un phénomène considérablement invalidant, affectant la qualité de vie de ceux et celles qui en souffrent. Toutefois, les bases neurophysiologiques qui sous-tendent cette interaction demeurent, encore aujourd’hui, mal comprises. Le but de la présente étude était de mieux comprendre les mécanismes corticaux impliqués dans l’interaction entre la douleur et le système moteur. Pour ce faire, une douleur expérimentale a été induite à l’aide d’une crème à base de capsaïcine au niveau de l’avant-bras gauche des participants. L'effet de la douleur sur la force des projections corticospinales ainsi que sur l’activité cérébrale a été mesuré à l’aide de la stimulation magnétique transcrânienne (TMS) et de l’électroencéphalographie (EEG), respectivement. L’analyse des données EEG a permis de révéler qu'en présence de douleur aiguë, il y a une augmentation de l’activité cérébrale au niveau du cuneus central (fréquence têta), du cortex dorsolatéral préfrontal gauche (fréquence alpha) ainsi que du cuneus gauche et de l'insula droite (toutes deux fréquence bêta), lorsque comparée à la condition initiale (sans douleur). Également, les analyses démontrent une augmentation de l'activité du cortex moteur primaire droit en présence de douleur, mais seulement chez les participants qui présentaient simultanément une diminution de leur force de projections corticales (mesurée avec la TMS t=4,45, p<0,05). Ces participants ont également montré une plus grande connectivité entre M1 et le cuneus que les participants dont la douleur n’a pas affecté la force des projections corticospinales (t=3,58, p<0,05). Ces résultats suggèrent qu’une douleur expérimentale induit, chez certains individus, une altération au niveau des forces de projections corticomotrices. Les connexions entre M1 et le cuneus seraient possiblement impliquées dans la survenue de ces changements corticomoteurs.

NFL-lipid nanocapsules for brain neural stem cell targeting in vitro and in vivo

International audience

Brain and cognitive development

'The Millennial Adolescent' offers contemporary, stimulating insights for those currently teaching as well as those preparing to teach. This book investigates the characteristics of Generation Y, using students own voices, generational theory and case studies. The text is structured around the principle that effective teachers need to know who they are teaching as well as what to teach, how to teach it, and how to assess the outcome. Using generational theory, 'The Millennial Adolescent' investigates the characteristics of Generation Y, or the Millennial Generation, and points out what all teachers need to know about working with this current generation of students who are described in a number of ways digital natives, team oriented, confident, multi-taskers, high achievers, and a generation unlike any other. The book contains well-known frameworks for developing understandings about adolescents, blended and contrasted with a contemporary socio-cultural construction of adolescence, set in our particular time, era and society. This book reflects the uniqueness of Australian contexts, while connecting with international trends and global patterns. Engaging and full of insights, this book is essential reading for all professionals dealing with adolescents.

The stimulation of healing within a rat calvarial defect by mPCL–TCP/collagen scaffolds loaded with rhBMP-2

Bone morphogenetic proteins (BMPs) have been widely investigated for their clinical use in bone repair and it is known that a suitable carrier matrix to deliver them is essential for optimal bone regeneration within a specific defect site. Fused deposited modeling (FDM) allows for the fabrication of medical grade poly 3-caprolactone/tricalcium phosphate (mPCL–TCP) scaffolds with high reproducibility and tailor designed dimensions. Here we loaded FDM fabricated mPCL–TCP/collagen scaffolds with 5 mg recombinant human (rh)BMP-2 and evaluated bone healing within a rat calvarial critical-sized defect. Using a comprehensive approach, this study assessed the newly regenerated bone employing microcomputed tomography (mCT), histology/histomorphometry, and mechanical assessments. By 15 weeks, mPCL–TCP/collagen/rhBMP-2 defects exhibited complete healing of the calvarium whereas the non- BMP-2-loaded scaffolds showed significant less bone ingrowth, as confirmed by mCT. Histomorphometry revealed significantly increased bone healing amongst the rhBMP-2 groups compared to non-treated scaffolds at 4 and 15 weeks, although the % BV/TV did not indicate complete mineralisation of the entire defect site. Hence, our study confirms that it is important to combine microCt and histomorphometry to be able to study bone regeneration comprehensively in 3D. A significant up-regulation of the osteogenic proteins, type I collagen and osteocalcin, was evident at both time points in rhBMP-2 groups. Although mineral apposition rates at 15 weeks were statistically equivalent amongst treatment groups, microcompression and push-out strengths indicated superior bone quality at 15 weeks for defects treated with mPCL–TCP/collagen/rhBMP-2. Consistently over all modalities, the progression of healing was from empty defect < mPCL–TCP/collagen < mPCL–TCP/collagen/rhBMP-2, providing substantiating data to support the hypothesis that the release of rhBMP-2 from FDM-created mPCL–TCP/collagen scaffolds is a clinically relevant approach to repair and regenerate critically-sized craniofacial bone defects. Crown Copyright 2008 Published by Elsevier Ltd. All rights reserved.

Corneal confocal microscopy : a novel noninvasive means to diagnose neuropathy in patients with Fabry disease

ABSTRACT: Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal esthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS)and heat-induced pain (HIP) were only significantly increased in males onERT (P<0.01). However, corneal sensation assessed withNCCAwas significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QSTand CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.