Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex

Recent experimental work in animals has emphasized the importance of homeostatic plasticity as a means of stabilizing the properties of neuronal circuits. Here, we report a phenomenon that indicates a homeostatic pattern of cortical plasticity in healthy human subjects. The experiments combined two techniques that can produce long-term effects on the excitability of corticospinal output neurons: transcranial direct current stimulation (TDCS) and repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex. "Facilitatory preconditioning" with anodal TDCS caused a subsequent period of 1 Hz rTMS to reduce corticospinal excitability to below baseline levels for >20 min. Conversely, "inhibitory preconditioning" with cathodal TDCS resulted in 1 Hz rTMS increasing corticospinal excitability for at least 20 min. No changes in excitability occurred when 1 Hz rTMS was preceded by sham TDCS. Thus, changing the initial state of the motor cortex by a period of DC polarization reversed the conditioning effects of 1 Hz rTMS. These preconditioning effects of TDCS suggest the existence of a homeostatic mechanism in the human motor cortex that stabilizes corticospinal excitability within a physiologically useful range

Phase Dependency of the Human Primary Motor Cortex and Cholinergic Inhibition Cancelation during Beta tACS

The human motor cortex has a tendency to resonant activity at about 20 Hz so stimulation should more readily entrain neuronal populations at this frequency. We investigated whether and how different interneuronal circuits contribute to such resonance by using transcranial magnetic stimulation (TMS) during transcranial alternating current stimulation (tACS) at motor (20 Hz) and a nonmotor resonance frequency (7 Hz). We tested different TMS interneuronal protocols and triggered TMS pulses at different tACS phases. The effect of cholinergic short-latency afferent inhibition (SAI) was abolished by 20 Hz tACS, linking cortical beta activity to sensorimotor integration. However, this effect occurred regardless of the tACS phase. In contrast, 20 Hz tACS selectively modulated MEP size according to the phase of tACS during single pulse, GABAAergic short-interval intracortical inhibition (SICI) and glutamatergic intracortical facilitation (ICF). For SICI this phase effect was more marked during 20 Hz stimulation. Phase modulation of SICI also depended on whether or not spontaneous beta activity occurred at ~20 Hz, supporting an interaction effect between tACS and underlying circuit resonances. The present study provides in vivo evidence linking cortical beta activity to sensorimotor integration, and for beta oscillations in motor cortex being promoted by resonance in GABAAergic interneuronal circuits

Testing rTMS-Induced Neuroplasticity: A Single Case Study of Focal Hand Dystonia

Focal hand dystonia in musicians is a neurological motor disorder in which aberrant plasticity is caused by excessive repetitive use. This work's purposes were to induce plasticity changes in a dystonic musician through five daily thirty-minute sessions of 1\u2009Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left M1 by using neuronavigated stimulation and to reliably measure the effect of these changes. To this aim, the relationship between neuroplasticity changes and motor recovery was investigated using fine-grained kinematic analysis. Our results suggest a statistically significant improvement in motor coordination both in a task resembling the dystonic-inducing symptoms and in a reach-to-grasp task. This single case study supports the safe and effective use of noninvasive brain stimulation in neurologic patients and highlights the importance of evaluating outcomes in measurable ways. This issue is a key aspect to focus on to classify the clinical expression of dystonia. These preliminary results promote the adoption of kinematic analysis as a valuable diagnostic tool

Glutamate-mediated blood-brain barrier opening. implications for neuroprotection and drug delivery

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders

Reach-To-Grasp Movements: A Multimodal Techniques Study

The aim of the present study was to investigate the correlation between corticospinal activity, kinematics, and electromyography (EMG) associated with the execution of precision and whole-hand grasps (WHGs). To this end, motor-evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS), EMG, and 3-D motion capture data have been simultaneously recorded during the planning and the execution of prehensile actions toward either a small or a large object. Differences in the considered measures were expected to distinguish between the two types of grasping actions both in terms of action preparation and execution. The results indicate that the index finger (FDI) and the little finger (ADM) muscles showed different activation patterns during grasping execution, but only the FDI appeared to distinguish between the two types of actions during motor preparation. Kinematics analysis showed that precision grips differed from WHGs in terms of displayed fingers distance when shaping before object\u2019s contact, and in terms of timing and velocity patterns. Moreover, significant correlations suggest a relationship between the muscular activation and the temporal aspects concerned with the index finger\u2019s extension during whole-hand actions. Overall, the present data seem to suggest a crucial role played by index finger as an early \u201cmarker\u201d of differential motor preparation for different types of grasps and as a \u201cnavigator\u201d in guiding whole-hand prehensile actions. Aside from the novelty of the methodological approach characterizing the present study, the data provide new insights regarding the level of crosstalk among different levels concerned with the neuro-behavioral organization of reach-to-grasp movements

Role of lateral and feedback connections in primary visual cortex in the processing of spatiotemporal regularity: a TMS study

Our human visual system exploits spatiotemporal regularity to interpret incoming visual signals. With a dynamic stimulus sequence of four collinear bars (predictors) appearing consecutively toward the fovea, followed by a target bar with varying contrasts, we have previously found that this predictable spatiotemporal stimulus structure enhances target detection performance and its underlying neural process starts in the primary visual cortex (area V1). However, the relative contribution of V1 lateral and feedback connections in the processing of spatiotemporal regularity remains unclear. In this study we measured human contrast detection of a briefly presented foveal target that was embedded in a dynamic collinear predictor-target sequence. Transcranial magnetic stimulation (TMS) was used to selectively disrupt V1 horizontal and feedback connections in the processing of predictors. The coil was positioned over a cortical location corresponding to the location of the last predictor prior to target onset. Single-pulse TMS at an intensity of 10% below phosphene threshold was delivered at 20 or 90ms after the predictor onset. Our analysis revealed that the delivery of TMS at both time windows equally reduced, but did not abolish, the facilitation effect of the predictors on target detection. Furthermore, if the predictors’ ordination was randomized to suppress V1 lateral connections, the TMS disruption was significantly more evident at 20ms than at 90ms time window. We suggest that both lateral and feedback connections contribute to the encoding of spatiotemporal regularity in V1. These findings develop understanding of how our visual system exploits spatiotemporal regularity to facilitate the efficiency of visual perception

HF-rTMS treatment decreases psychomotor retardation in medication-resistant melancholic depression

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Task-dependent Modulation of Cortical Excitability and Balance Control in Individuals with Post-concussion Syndrome

In most cases, symptoms resolve between 7-10 days post-concussion. However, in 10-15% of the concussed population, symptoms can remain unresolved for months to years following the head injury. The purpose of this thesis was two-fold, and was broken up into two studies, where the same individuals participated in both studies. The purpose of the first study was to quantify the differences in balance control between individuals with PCS (i.e., had been experiencing symptoms for \u3c30 days) and non-concussed individuals during a lower-limb reaching task. Participants completed a static balance assessment before and after a lower-limb reaching task, which incorporated a Go/No-Go paradigm. Results from this study revealed no differences in the static stability assessments, however, individuals with PCS demonstrated increased medial-lateral COP displacement as well as greater trunk pitch during the reaching task. Overall, the findings reveal persistent balance impairments in individuals with PCS, which may put this population at an increased risk of further injury. The purpose of the second study was to assess task-dependent modulation of cortical excitability prior to planned index finger abduction contractions comparing a non-concussed population to a population with PCS. The protocol in this study consisted of both single and paired-pulse transcranial magnetic stimulation (TMS) which was applied prior to the beginning of 3 different tasks (i.e., a rest condition with no plan to contract, a precision contraction, and a powerful contraction). In addition to the three tasks, participants also had to respond to a Go/No-Go cue. The results of this study revealed an increase in excitability prior to a precision contraction in both non-concussed and PCS groups. No differences in task-dependent modulation were found between the two groups with respect to intracortical facilitation and inhibition, however a negative correlation between number of symptoms reported (SCAT3 symptom evaluation) and intracortical facilitation was revealed. The increase in corticospinal excitability prior to a precision contraction was not explained by the two cortical mechanisms we assessed and may therefore be due to spinal modulation or a different cortical mechanism. Overall, based on the results from this thesis, it appears that individuals with PCS have balance impairments, which may be a result of an inability to maximally activate their postural muscles. Furthermore, it appears that those individuals who reported a higher number of symptoms had greater reductions in intracortical facilitation, likely reflecting the heterogeneity of this clinical group

Network based statistical analysis detects changes induced by continuous theta-burst stimulation on brain activity at rest

We combined continuous theta-burst stimulation (cTBS) and resting state (RS)-fMRI approaches to investigate changes in functional connectivity (FC) induced by right dorsolateral prefrontal cortex (DLPFC)-cTBS at rest in a group of healthy subjects. Seed-based fMRI analysis revealed a specific pattern of correlation between the right prefrontal cortex and several brain regions: based on these results, we defined a 29-node network to assess changes in each network connection before and after, respectively, DLPFC-cTBS and sham sessions. A decrease of correlation between the right prefrontal cortex and right parietal cortex (Brodmann areas 46 and 40, respectively) was detected after cTBS, while no significant result was found when analyzing sham-session data. To our knowledge, this is the first study that demonstrates within-subject changes in FC induced by cTBS applied on prefrontal area. The possibility to induce selective changes in a specific region without interfering with functionally correlated area could have several implications for the study of functional properties of the brain, and for the emerging therapeutic strategies based on transcranial stimulation