The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Measuring the brain's response to transcranial magnetic stimulation (TMS) with electroencephalography (EEG) offers unique insights into the cortical circuits activated following stimulation, particularly in non-motor regions where less is known about TMS physiology. However, the mechanisms underlying TMS-evoked EEG potentials (TEPs) remain largely unknown. We assessed TEP sensitivity to changes in excitatory neurotransmission mediated by n-methyl-d-aspartate (NMDA) receptors following stimulation of non-motor regions. In fourteen male volunteers, resting EEG and TEPs from prefrontal (PFC) and parietal (PAR) cortex were measured before and after administration of either dextromethorphan (NMDA receptor antagonist) or placebo across two sessions in a double-blinded pseudo-randomised crossover design. At baseline, there were amplitude differences between PFC and PAR TEPs across a wide time range (15-250 ms), however the signals were correlated after ~80 ms, suggesting early peaks reflect site-specific activity, whereas late peaks reflect activity patterns less dependent on the stimulated sites. Early TEP peaks were not reliably altered following dextromethorphan compared to placebo, although findings were less clear for later peaks, and low frequency resting oscillations were reduced in power. Our findings suggest that early TEP peaks (<80 ms) from PFC and PAR reflect stimulation site specific activity that is largely insensitive to changes in NMDA receptor-mediated neurotransmission.Nigel C. Rogasch, Carl Zipser, Ghazaleh Darmani, Tuomas P. Mutanen, Mana Biabani, Christoph Zrenner, Debora Desideri, Paolo Belardinelli, Florian Müller-Dahlhaus, Ulf Zieman

Bayesian Wavelet Shrinkage of the Haar-Fisz Transformed Wavelet Periodogram.

It is increasingly being realised that many real world time series are not stationary and exhibit evolving second-order autocovariance or spectral structure. This article introduces a Bayesian approach for modelling the evolving wavelet spectrum of a locally stationary wavelet time series. Our new method works by combining the advantages of a Haar-Fisz transformed spectrum with a simple, but powerful, Bayesian wavelet shrinkage method. Our new method produces excellent and stable spectral estimates and this is demonstrated via simulated data and on differenced infant electrocardiogram data. A major additional benefit of the Bayesian paradigm is that we obtain rigorous and useful credible intervals of the evolving spectral structure. We show how the Bayesian credible intervals provide extra insight into the infant electrocardiogram data

Resistant Against De-depression: LTD-Like Plasticity in the Human Motor Cortex Induced by Spaced cTBS

The long-term depression (LTD)-like changes in human primary motor cortex (M1) excitability induced by continuous theta burst stimulation (cTBS) are subject to reversal (i.e., de-depression) following behavioral engagement of M1, limiting its therapeutic potential under behaviorally relevant conditions. Experiments in animals suggest that the repeated, spaced application of stimulation trains may consolidate synaptic plasticity, making it resistant to reversal by physiological activity. Although there is evidence that repeated cTBS prolongs LTD-like M1 neuroplasticity in humans, whether these effects are resistant to de-depression has not been tested. We investigated whether the neuroplastic effects of paired cTBS trains were resistant to de-depression by a sustained, submaximal voluntary contraction of the hand muscles. In the absence of cTBS, voluntary contraction had no effect on motor evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. While the LTD-like MEP depression induced by a single cTBS was abolished by subsequent voluntary contraction, paired cTBS induced MEP depression that was resistant to reversal. This MEP depression was also resistant to reversal when an experimental de-depression protocol was used instead of a voluntary contraction. Our findings suggest that repeated cTBS applications consolidate LTD-like M1 neuroplasticity, which may have important implications for the clinical application of cTBS.Mitchell R. Goldsworthy, Florian Müller-Dahlhaus, Michael C. Ridding, and Ulf Zieman

Inter-subject variability of LTD-like plasticity in human motor cortex: a matter of preceding motor activation

Abstract not availableMitchell R. Goldsworthy, Florian Müller-Dahlhaus, Michael C. Ridding, Ulf Zieman

Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons

Repetitive transcranial magnetic stimulation (rTMS) of the human brain can lead to long-lasting changes in cortical excitability. However, the cellular and molecular mechanisms which underlie rTMS-induced plasticity remain incompletely understood. Here, we used repetitive magnetic stimulation (rMS) of mouse entorhino-hippocampal slice cultures to study rMS-induced plasticity of excitatory postsynapses. By employing whole-cell patch-clamp recordings of CA1 pyramidal neurons, local electrical stimulations, immunostainings for the glutamate receptor subunit GluA1 and compartmental modeling, we found evidence for a preferential potentiation of excitatory synapses on proximal dendrites of CA1 neurons (2-4 h after stimulation). This rMS-induced synaptic potentiation required the activation of voltage-gated sodium channels, L-type voltage-gated calcium channels and N-methyl-D-aspartate-receptors. In view of these findings we propose a cellular model for the preferential strengthening of excitatory synapses on proximal dendrites following rMS in vitro, which is based on a cooperative effect of synaptic glutamatergic transmission and postsynaptic depolarization

Plasma brain-derived neurotrophic factor (pBDNF) and executive dysfunctions in patients with major depressive disorder

<p><b>Objectives:</b> Executive dysfunctions are frequently seen in patients with major depressive disorder (MDD) and normalise in many cases during effective antidepressant therapy. This study investigated whether a normalisation of executive dysfunctions during antidepressant treatment correlates with or can be predicted by clinical parameters or levels of brain-derived neurotrophic factor (BDNF).</p> <p><b>Methods:</b> In 110 MDD patients with executive dysfunctions (percentile <16), executive functions and plasma BDNF levels were analysed at baseline, and days 14 and 56 of an antidepressant treatment. BDNF exon IV and P11 methylation status was studied at baseline.</p> <p><b>Results:</b> Eighty patients (73%) experienced a normalisation of executive dysfunctions, while 30 (27%) suffered from persistent dysfunctions until day 56. Patients with persistent dysfunctions had significantly higher HAMD scores at days 14 and 56, and lower plasma BDNF levels at each time point than patients with a normalisation of dysfunctions (<i>F</i>₁= 10.18; <i>P</i> = 0.002). This was seen for verbal fluency, but not processing speed. BDNF exon IV and p11 promoter methylation was not associated with test performance.</p> <p><b>Conclusions:</b> Our results corroborate a concomitant amelioration of executive dysfunctions with successful antidepressant therapy and support a role of BDNF in the neural mechanisms underlying the normalisation of executive dysfunctions in MDD.</p> <p><b>ClinicalTrials.gov number:</b> NCT00974155; EudraCT: 2008-008280-96</p