Effects of antiepileptic drugs on cortical excitability in humans: A TMS-EMG and TMS-EEG study.

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco-physiological characterization of TEPs will facilitate utilization of TMS-EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.

Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study.

Alpha-5 gamma-aminobutyric acid type A receptors (α5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebo-controlled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS-EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific α5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke. SIGNIFICANCE STATEMENT: The extrasynaptic α-5 gamma-aminobutyric acid type A receptor (α5-GABAAR) regulates neuronal excitability through tonic inhibition in the mammalian brain. Tonic inhibition is important for many fundamental processes such as plasticity and learning. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. This study demonstrates that S44819, a selective α5-GABAAR antagonist, increases cortical excitability in healthy human subjects, as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography. Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods. The actions of S44819 may be suitable to improve plasticity and learning.

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.

TMS-EEG signatures of GABAergic neurotransmission in the human cortex.

Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.

Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS-EEG.

GABAB-receptor (GABABR) mediated inhibition is important in regulating neuronal excitability. The paired-pulse transcranial magnetic stimulation (TMS) protocol of long-interval intracortical inhibition (LICI) likely reflects this GABABergic inhibition. However, this view is based on indirect evidence from electromyographic (EMG) studies. Here we combined paired-pulse TMS with simultaneous electroencephalography (paired-pulse TMS-EEG) and pharmacology to directly investigate mechanisms of LICI at the cortical level. We tested the effects of a conditioning stimulus (CS100) applied 100ms prior to a test stimulus (TS) over primary motor cortex on TS-evoked EEG-potentials (TEPs). Healthy subjects were given a single oral dose of baclofen, a GABABR agonist, or diazepam, a positive modulator at GABAARs, in a placebo-controlled, pseudo-randomized double-blinded crossover study. LICI was quantified as the difference between paired-pulse TEPs (corrected for long-lasting EEG responses by the conditioning pulse) minus single-pulse TEPs. LICI at baseline (i.e. pre-drug intake) was characterized by decreased P25, N45, N100 and P180 and increased P70 TEP components. Baclofen resulted in a trend towards the enhancement of LICI of the N45 and N100, and significantly enhanced LICI of the P180. In contrast, diazepam consistently suppressed LICI of late potentials (i.e. N100, P180), without having an effect on LICI of earlier (i.e. P25, N45 and P70) potentials. These findings demonstrate for the first time directly at the system level of the human cortex that GABABR-mediated cortical inhibition contributes to LICI, while GABAAR-mediated inhibition occludes LICI. Paired-pulse TMS-EEG allows investigating cortical GABABR-mediated inhibition more directly and specifically than hitherto possible, and may thus inform on network abnormalities caused by disordered inhibition, e.g. in patients with schizophrenia or epilepsy.

Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that can alter cortical excitability in human subjects for hours beyond the stimulation period. It thus has potential as a therapeutic tool in neuropsychiatric disorders associated with alterations in cortical excitability. However, rTMS-induced neural plasticity remains insufficiently understood at the cellular level. To learn more about the effects of repetitive magnetic stimulation (rMS), we established an in vitro model of rMS using mouse organotypic entorhino-hippocampal slice cultures. We assessed the outcome of a high-frequency (10 Hz) rMS protocol on functional and structural properties of excitatory synapses in mature hippocampal CA1 pyramidal neurons. Whole-cell patch-clamp recordings, immunohistochemistry, and time-lapse imaging techniques revealed that rMS induces a long-lasting increase in glutamatergic synaptic strength, which is accompanied by structural remodeling of dendritic spines. The effects of rMS on spine size were predominantly seen in small spines, suggesting differential effects of rMS on subpopulations of spines. Furthermore, our data indicate that rMS-induced postsynaptic changes depend on the NMDA receptor-mediated accumulation of GluA1-containing AMPA receptors. These results provide first experimental evidence that rMS induces coordinated functional and structural plasticity of excitatory postsynapses, which is consistent with a long-term potentiation of synaptic transmission.

Network perturbation-based biomarkers of depression and treatment response.

Using concurrent TMS-EEG, Han et al.1 identified temporal and spectral signatures of depression in a prefrontal-orbitofrontal-hippocampal network, which renormalized after rTMS. This highlights the relevance of causal network perturbation for the assessment of disease-related network states and their therapeutic modulation.

State-dependent and timing-dependent bidirectional associative plasticity in the human SMA-M1 network.

The supplementary motor area (SMA-proper) plays a key role in the preparation and execution of voluntary movements. Anatomically, SMA-proper is densely reciprocally connected to primary motor cortex (M1), but neuronal coordination within the SMA-M1 network and its modification by external perturbation are not well understood. Here we modulated the SMA-M1 network using MR-navigated multicoil associative transcranial magnetic stimulation in healthy subjects. Changes in corticospinal excitability were assessed by recording motor evoked potential (MEP) amplitude bilaterally in a hand muscle. We found timing-dependent bidirectional Hebbian-like MEP changes during and for at least 30 min after paired associative SMA-M1 stimulation. MEP amplitude increased if SMA stimulation preceded M1 stimulation by 6 ms, but decreased if SMA stimulation lagged M1 stimulation by 15 ms. This associative plasticity in the SMA-M1 network was highly topographically specific because paired associative stimulation of pre-SMA and M1 did not result in any significant MEP change. Furthermore, associative plasticity in the SMA-M1 network was strongly state-dependent because it required priming by near-simultaneous M1 stimulation to occur. We conclude that timing-dependent bidirectional associative plasticity is demonstrated for the first time at the systems level of a human corticocortical neuronal network. The properties of this form of plasticity are fully compatible with spike-timing-dependent plasticity as defined at the cellular level. The necessity of priming may reflect the strong interhemispheric connectivity of the SMA-M1 network. Findings are relevant for better understanding reorganization and potentially therapeutic modification of neuronal coordination in the SMA-M1 network after cerebral lesions such as stroke.

The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs.

The term neuroplasticity encompasses structural and functional modifications of neuronal connectivity. Abnormal neuroplasticity is involved in various neuropsychiatric diseases, such as dystonia, epilepsy, migraine, Alzheimer's disease, fronto-temporal degeneration, schizophrenia, and post cerebral stroke. Drugs affecting neuroplasticity are increasingly used as therapeutics in these conditions. Neuroplasticity was first discovered and explored in animal experimentation. However, non-invasive brain stimulation (NIBS) has enabled researchers recently to induce and study similar processes in the intact human brain. Plasticity induced by NIBS can be modulated by pharmacological interventions, targeting ion channels, or neurotransmitters. Importantly, abnormalities of plasticity as studied by NIBS are directly related to clinical symptoms in neuropsychiatric diseases. Therefore, a core theme of this review is the hypothesis that NIBS-induced plasticity can explore and potentially predict the therapeutic efficacy of CNS-acting drugs in neuropsychiatric diseases. We will (a) review the basics of neuroplasticity, as explored in animal experimentation, and relate these to our knowledge about neuroplasticity induced in humans by NIBS techniques. We will then (b) discuss pharmacological modulation of plasticity in animals and humans. Finally, we will (c) review abnormalities of plasticity in neuropsychiatric diseases, and discuss how the combination of NIBS with pharmacological intervention may improve our understanding of the pathophysiology of abnormal plasticity in these diseases and their purposeful pharmacological treatment.

Homeostatic metaplasticity of corticospinal excitatory and intracortical inhibitory neural circuits in human motor cortex.

Homeostatic metaplasticity, a fundamental principle for maintaining overall synaptic weight in the physiological range in neuronal networks, was demonstrated at the cellular and systems level predominantly for excitatory synaptic neurotransmission. Although inhibitory networks are crucial for regulating excitability, it is largely unknown to what extent homeostatic metaplasticity of inhibition also exists. Here, we employed intermittent and continuous transcranial magnetic theta burst stimulation (iTBS, cTBS) of the primary motor cortex in healthy subjects for induction of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity. We studied metaplasticity by testing the interactions of priming TBS with LTP/LTD-like plasticity induced by subsequent test TBS. Changes in excitatory neurotransmission were measured by the input-output curve of motor-evoked potentials (IO-MEP), and changes in GABA(A)ergic inhibitory neurotransmission by the IO of short-interval intracortical inhibition (IO-SICI, four conditioning stimulus intensities of 70-100% active motor threshold, interstimulus interval 2.0 ms). Non-primed iTBS increased IO-MEP, while non-primed cTBS decreased IO-MEP. Pairing of identical protocols (iTBSiTBS, cTBScTBS) resulted in suppression of the non-primed TBS effects on IO-MEP, and pairing of different protocols (cTBSiTBS, iTBScTBS) enhanced the test TBS effects on IO-MEP. While non-primed TBS did not result in significant changes of IO-SICI, iTBSiTBS resulted in IO-SICI decrease, and cTBScTBS in IO-SICI increase compared with the non-primed conditions. The changes in SICI induced by priming TBS correlated with the changes in MEP induced by subsequent test TBS. Findings demonstrate that plasticity in both excitatory and inhibitory circuits in the human motor cortex are regulated by homeostatic metaplasticity, and that priming effects on inhibition contribute to the homeostatic regulation of metaplasticity in excitatory circuits.

TMS-EEG signatures of glutamatergic neurotransmission in human cortex.

Neuronal activity in the brain reflects an excitation-inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation-inhibition balance.

Brain oscillation-synchronized stimulation of the left dorsolateral prefrontal cortex in depression using real-time EEG-triggered TMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. OBJECTIVE: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD. METHODS: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. RESULTS: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. CONCLUSIONS: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.

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.

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

Objectives: 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).Methods: 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.Results: 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 (F1= 10.18; P = 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.Conclusions: 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.ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Musical Sonification of Arm Movements in Stroke Rehabilitation Yields Limited Benefits.

Neurologic music therapy in rehabilitation of stroke patients has been shown to be a promising supplement to the often strenuous conventional rehabilitation strategies. The aim of this study was threefold: (i) replicate results from a previous study with a sample from one clinic (henceforth called Site 1; N = 12) using an already established recording system, and (ii) conceptually replicate previous findings with a less costly hand-tracking system in Site 2 (N = 30), and (iii) compare both sub-studies' outcomes to estimate the efficiency of neurologic music therapy. Stroke patients in both sites were randomly assigned to treatment or control groups and received daily training of guided sequential upper limb movements additional to their standard stroke rehabilitation protocol. Treatment groups received sonification (i.e., changes in musical pitch) of their movements when they moved their affected hand up and down to reproduce a sequence of the first six notes of a C major scale. Controls received the same movement protocol, however, without auditory feedback. Sensors at the upper arm and the forearm (Xsens) or an optic sensor device (Leapmotion) allowed to measure kinematics of movements and movement smoothness. Behavioral measures pre and post intervention included the Fugl-Meyer assessment (FMA) and the Stroke Impact Scale (SIS) and movement data. Bayesian regression did not show evidence supporting an additional effect of sonification on clinical mobility assessments. However, combined movement data from both sites showed slight improvements in movement smoothness for the treatment group, and an advantage for one of the two motion capturing systems. Exploratory analyses of EEG-EMG phase coherence during movement of the paretic arm in a subset of patients suggested increases in cortico-muscular phase coherence specifically in the ipsilesional hemisphere after sonification therapy, but not after standard rehabilitation therapy. Our findings show that musical sonification is a viable treatment supplement to current neurorehabilitation methods, with limited clinical benefits. However, given patients' enthusiasm during training and the low hardware price of one of the systems it may be considered as an add-on home-based neurorehabilitation therapy.

The effects of a single dose of fluoxetine on practice-dependent plasticity.

OBJECTIVE: To determine whether a single dose of fluoxetine increases corticomotoneuronal excitability, motor performance and practice-dependent plasticity. METHODS: Twelve healthy adults completed this placebo-controlled, pseudo-randomized, double-blind crossover study. Transcranial magnetic stimulation (TMS) was used to assess corticomotoneuronal excitability, and two uni-axial accelerometers measured kinetics of fastest possible ballistic voluntary thumb movements and TMS-evoked thumb movements. Six hours after administration of either 20 mg of the serotonin reuptake inhibitor fluoxetine or placebo, participants practiced ballistic thumb movements in the direction opposite to the TMS-evoked thumb movements. The primary outcome of this study was the proportion of thumb movements that fell within the target-training zone (TTZ) during and for 30 min after the practice. RESULTS: All participants demonstrated practice-dependent plasticity evidenced by an increase of TMS-evoked thumb movements falling into the TTZ (P = 0.045), with no difference between drugs. There was a significant increase in peak acceleration of the practiced voluntary thumb movements (P = 0.002), but no DRUG by TIME interaction. Motor-evoked potential amplitudes were not changed by drug intake or practice. CONCLUSIONS: A single dose of 20 mg of fluoxetine did not enhance corticomotoneuronal excitability, performance of a ballistic thumb movement task, or practice-dependent plasticity in healthy adults. SIGNIFICANCE: Longer administration fluoxetine may be necessary to enhance motor performance and plasticity.

Cortical Excitability and Interhemispheric Connectivity in Early Relapsing-Remitting Multiple Sclerosis Studied With TMS-EEG.

Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing-remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0-2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.

Reduced Performance During a Sentence Repetition Task by Continuous Theta-Burst Magnetic Stimulation of the Pre-supplementary Motor Area.

The pre-supplementary motor area (pre-SMA) is engaged in speech comprehension under difficult circumstances such as poor acoustic signal quality or time-critical conditions. Previous studies found that left pre-SMA is activated when subjects listen to accelerated speech. Here, the functional role of pre-SMA was tested for accelerated speech comprehension by inducing a transient "virtual lesion" using continuous theta-burst stimulation (cTBS). Participants were tested (1) prior to (pre-baseline), (2) 10 min after (test condition for the cTBS effect), and (3) 60 min after stimulation (post-baseline) using a sentence repetition task (formant-synthesized at rates of 8, 10, 12, 14, and 16 syllables/s). Speech comprehension was quantified by the percentage of correctly reproduced speech material. For high speech rates, subjects showed decreased performance after cTBS of pre-SMA. Regarding the error pattern, the number of incorrect words without any semantic or phonological similarity to the target context increased, while related words decreased. Thus, the transient impairment of pre-SMA seems to affect its inhibitory function that normally eliminates erroneous speech material prior to speaking or, in case of perception, prior to encoding into a semantically/pragmatically meaningful message.

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials.

BACKGROUND: Inhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2-3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively. OBJECTIVE/HYPOTHESIS: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI. METHODS: PpTMS-EEG was applied to the left motor cortex in 16 healthy subjects in a randomized, double-blind placebo-controlled crossover design, testing the effects of a single oral dose 20 mg of diazepam, a positive modulator at the GABAA receptor, vs. 50 mg of the GABAB receptor agonist baclofen on SICI of TEPs. RESULTS: We found significant SICI of the N100 and P180 TEPs prior to drug intake. Diazepam reduced SICI of the N100 TEP, while baclofen enhanced it. Compared to our previous ppTMS-EEG results on LICI, the SICI effects on TEPs, including their drug modulation, were largely analogous. CONCLUSIONS: Findings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle.

Early improvement of executive test performance during antidepressant treatment predicts treatment outcome in patients with Major Depressive Disorder.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 -patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96.