Treatment-Induced Neuropathy in Diabetes (TIND)-Developing a Disease Model in Type 1 Diabetic Rats.

Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.

Baseline sensorimotor GABA levels shape neuroplastic processes induced by motor learning in older adults.

Previous research in young adults has demonstrated that both motor learning and transcranial direct current stimulation (tDCS) trigger decreases in the levels of gamma-aminobutyric acid (GABA) in the sensorimotor cortex, and these decreases are linked to greater learning. Less is known about the role of GABA in motor learning in healthy older adults, a knowledge gap that is surprising given the established aging-related reductions in sensorimotor GABA. Here, we examined the effects of motor learning and subsequent tDCS on sensorimotor GABA levels and resting-state functional connectivity in the brains of healthy older participants. Thirty-six older men and women completed a motor sequence learning task before receiving anodal or sham tDCS to the sensorimotor cortex. GABA-edited magnetic resonance spectroscopy of the sensorimotor cortex and resting-state (RS) functional magnetic resonance imaging data were acquired before and after learning/stimulation. At the group level, neither learning nor anodal tDCS significantly modulated GABA levels or RS connectivity among task-relevant regions. However, changes in GABA levels from the baseline to post-learning session were significantly related to motor learning magnitude, age, and baseline GABA. Moreover, the change in functional connectivity between task-relevant regions, including bilateral motor cortices, was correlated with baseline GABA levels. These data collectively indicate that motor learning-related decreases in sensorimotor GABA levels and increases in functional connectivity are limited to those older adults with higher baseline GABA levels and who learn the most. Post-learning tDCS exerted no influence on GABA levels, functional connectivity or the relationships among these variables in older adults.

Differential Regulation of Human Paired Associative Stimulation-Induced and Theta-Burst Stimulation-Induced Plasticity by L-type and T-type Ca2+ Channels.

Activity-dependent changes of postsynaptic Ca2+-concentration are influenced by a variety of different Ca2+-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca2+-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). Although, surprisingly, static corticospinal excitability was increased by the combination of DXM and NDP, PAS-induced facilitation was blocked. TBS-induced facilitation of corticospinal excitability, which has previously been shown to be turned into depression by L-type VGCC blocker NDP (Wankerl K, Weise D, Gentner R, Rumpf J, Classen J. 2010. L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci. 30(18):6197-6204.), was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS-induced plasticity may point to an important role of backpropagating action potentials in PAS-induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity.

Dissociating Parieto-Frontal Networks for Phonological and Semantic Word Decisions: A Condition-and-Perturb TMS Study.

Left posterior inferior frontal gyrus (pIFG) and supramarginal gyrus (SMG) are key regions for phonological decisions, whereas angular gyrus (ANG) and anterior IFG (aIFG) are associated with semantics. However, it is less clear whether the functional contribution of one area changes in the presence of a dysfunctional area within the network. Using repetitive transcranial magnetic stimulation (rTMS), we first tested whether perturbing one area would disrupt behavior. Second, we applied a condition-and-perturb approach, combining parietal offline rTMS with frontal online rTMS to investigate how the functional contribution of a frontal region changes in the presence of a dysfunctional parietal region. We found that rTMS over SMG or pIFG delayed phonological decisions, but this was not enhanced by combining supramarginal rTMS with pIFG rTMS. In contrast, semantic decisions were only impaired when angular rTMS was combined with aIFG rTMS. We infer that offline rTMS caused a dysfunction of ANG which increased the functional relevance of aIFG for semantic decisions and sensitized this network to the disruptive effects of aIFG rTMS. The results provide causal evidence that ANG and aIFG contribute to semantics and that the functional significance of one area within this network depends on the functional integrity of the other.

Placebo-induced changes in excitatory and inhibitory corticospinal circuits during motor performance.

Despite behavioral evidence showing placebo modulations of motor performance, the neurophysiological underpinnings of these effects are still unknown. By applying transcranial magnetic stimulation (TMS) over the primary motor cortex, we investigated whether a placebo modulation of force could change the excitability of the corticospinal system. Healthy human volunteers performed a motor task by pressing a piston as strongly as possible with the right index finger. Two experimental groups were instructed that treatment with peripheral low-frequency transcutaneous electrical nerve stimulation (TENS) applied on the first dorsal interosseus would induce force enhancement. One experimental group was conditioned about the effects of TENS with a surreptitious amplification of the visual feedback signaling the force level. The other group, instead, was only verbally influenced, without conditioning. At the end of the instructive placebo procedure, the two experimental groups reached higher levels of force, believed that TENS had been effective and expected to perform better compared with two control groups, who were not influenced about TENS. Moreover, the experimental groups presented enhanced excitability of the corticospinal system in the muscle specifically involved in the task (first dorsal interosseus), as shown by increased amplitude of the motor evoked potentials and decreased duration of the cortical silent period (the latter only in the conditioned group). Crucially, the TMS pulse was delivered when all the subjects exerted the same amount of force, ruling out bottom-up influences. These findings hint at a top-down, cognitive enhancement of corticospinal excitability as a neural signature of placebo modulation of motor performance.

After-training emotional interference may modulate sequence awareness in a serial reaction time task.

The purpose of the present experiment was to investigate the effects of emotional interference on consolidation of sequential learning. In different sessions, 6 groups of subjects were initially trained on a serial reaction time task (SRTT). To modulate consolidation of the newly learned skill, subjects were exposed, after the training, to 1 of 3 (positive, negative or neutral) different classes of emotional stimuli which consisted of a set of emotional pictures combined with congruent emotional musical pieces or neutral sound. Emotional intervention for each subject group was done in 2 different time intervals (either directly after the training session or 6 h later). After a 72 h post-training interval, each group was retested on the SRTT. Re-test performance was evaluated in terms of response times and accuracy during execution of a target sequence. Emotional intervention did not influence either response times or accuracy of re-testing SRTT target task performance, both variables sensitive to implicit knowledge acquired during SRTT training. However, explicit awareness of sequence knowledge after 72 h was enhanced when negative stimuli had been applied at 0 h after training. These findings suggest that consolidation of explicit aspects of procedural learning may be more responsive toward emotional interference than implicit aspects.

Paired associative stimulation of the auditory system: a proof-of-principle study.

BACKGROUND: Paired associative stimulation (PAS) consisting of repeated application of transcranial magnetic stimulation (TMS) pulses and contingent exteroceptive stimuli has been shown to induce neuroplastic effects in the motor and somatosensory system. The objective was to investigate whether the auditory system can be modulated by PAS. METHODS: Acoustic stimuli (4 kHz) were paired with TMS of the auditory cortex with intervals of either 45 ms (PAS(45 ms)) or 10 ms (PAS(10 ms)). Two-hundred paired stimuli were applied at 0.1 Hz and effects were compared with low frequency repetitive TMS (rTMS) at 0.1 Hz (200 stimuli) and 1 Hz (1000 stimuli) in eleven healthy students. Auditory cortex excitability was measured before and after the interventions by long latency auditory evoked potentials (AEPs) for the tone (4 kHz) used in the pairing, and a control tone (1 kHz) in a within subjects design. RESULTS: Amplitudes of the N1-P2 complex were reduced for the 4 kHz tone after both PAS(45 ms) and PAS(10 ms), but not after the 0.1 Hz and 1 Hz rTMS protocols with more pronounced effects for PAS(45 ms). Similar, but less pronounced effects were observed for the 1 kHz control tone. CONCLUSION: These findings indicate that paired associative stimulation may induce tonotopically specific and also tone unspecific human auditory cortex plasticity.

L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans.

The ability of synapses to undergo persistent activity-dependent potentiation or depression [long-term potentiation (LTP)/long-term depression (LTD)] may be profoundly altered by previous neuronal activity. Although natural neuronal activity can be experimentally manipulated in vivo, very little is known about the in vivo physiological mechanisms involved in regulating this metaplasticity in models of LTP/LTD. To examine whether Ca(2+) signaling may influence metaplasticity in vivo in humans, we used continuous theta burst stimulation (cTBS) (Huang et al., 2005), a noninvasive novel repetitive magnetic stimulation protocol known to induce persistent alterations of corticospinal excitability whose polarity is changed by previous voluntary motor activity. When directed to the naive motor cortex, cTBS induced long-lasting potentiation of corticospinal excitability, but depression under the influence of nimodipine (NDP), an L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist. Both aftereffects were blocked by dextromethorphan, an NMDA receptor antagonist, supporting the notion that these bidirectional cTBS-induced alterations of corticospinal excitability map onto LTP and LTD as observed in animal studies. A short period of voluntary contraction and a small dose of NDP were each ineffective in blocking the cTBS-induced potentiation. However, when both interventions were combined, a depression was induced, and the magnitude of this depression increased with the dose of NDP. These findings suggest that Ca(2+) dynamics determine the polarity of LTP/LTD-like changes in vivo. L-VGCCs may act as molecular switches mediating metaplasticity induced by endogenous neuronal activation.

Consensus: New methodologies for brain stimulation.

We briefly summarized several new stimulation techniques. There are many new methods of human brain stimulation, including modification of already known methods and brand-new methods. In this article, we focused on theta burst stimulation (TBS), repetitive monophasic pulse stimulation, paired- and quadri-pulse stimulation, transcranial alternating current stimulation (tACS), paired associative stimulation, controllable pulse shape TMS (cTMS), and deep-brain TMS. For every method, we summarized the state of the art and discussed issues that remain to be addressed.

Consensus: Can transcranial direct current stimulation and transcranial magnetic stimulation enhance motor learning and memory formation?

Noninvasive brain stimulation has developed as a promising tool for cognitive neuroscientists. Transcranial magnetic (TMS) and direct current (tDCS) stimulation allow researchers to purposefully enhance or decrease excitability in focal areas of the brain. The purpose of this article is to review information on the use of TMS and tDCS as research tools to facilitate motor memory formation, motor performance, and motor learning in healthy volunteers. Studies implemented so far have mostly focused on the ability of TMS and tDCS to elicit relatively short-lasting motor improvements and the mechanisms underlying these changes have been only partially investigated. Despite limitations, including the scarcity of data, work that has been already accomplished raises the exciting hypothesis that currently available noninvasive transcranial stimulation techniques could modulate motor learning and memory formation in healthy humans and potentially in patients with neurologic and psychiatric disorders.

A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex.

Synaptic plasticity is conspicuously dependent on the temporal order of the pre- and postsynaptic activity. Human motor cortical excitability can be increased by a paired associative stimulation (PAS) protocol. Here we show that it can also be decreased by minimally changing the interval between the two associative stimuli. Corticomotor excitability of the abductor pollicis brevis (APB) representation was tested before and after repetitively pairing of single right median nerve simulation with single pulse transcranial magnetic stimulation (TMS) delivered over the optimal site for activation of the contralateral APB. Following PAS, depression of TMS-evoked motor-evoked potentials (MEPs) was induced only when the median nerve stimulation preceded the TMS pulse by 10 ms, while enhancement of cortical excitability was induced using an interstimulus interval of 25 ms, suggesting an important role of the sequence of cortical events triggered by the two stimulation modalities. Experiments using F-wave studies and electrical brain stem stimulation indicated that the site of the plastic changes underlying the decrease of MEP amplitudes following PAS (10 ms) was within the motor cortex. MEP amplitudes remained depressed for approximately 90 min. The decrease of MEP amplitudes was blocked when PAS(10 ms) was performed under the influence of dextromethorphan, an N-methyl-d-aspartate-receptor antagonist, or nimodipine, an L-type voltage-gated calcium-channel antagonist. The physiological profile of the depression of human motor cortical excitability following PAS(10 ms) suggests long-term depression of synaptic efficacy to be involved. Together with earlier findings, this study suggests that strict temporal Hebbian rules govern the induction of long-term potentiation/long-term depression-like phenomena in vivo in the human primary motor cortex.