Tonio Heidegger

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.

Interactions between short-interval intracortical inhibition and short-latency afferent inhibition in human motor cortex

Transcranial magnetic stimulation (TMS) allows the testing of various inhibitory processes in human motor cortex. Here we aimed at gaining more insight into the underlying physiology by studying the interactions between short‐interval intracortical inhibition (SICI) and short‐latency afferent inhibition (SAI). SICI and SAI were examined in a slightly contracting hand muscle of healthy subjects by measuring inhibition of a test motor‐evoked potential conditioned by a sub‐threshold motor cortical magnetic pulse (S1) or an electrical pulse (P) applied to the ulnar nerve at the wrist, respectively. SICI alone and SAI alone had similar magnitude when S1 intensity was set to 90% active motor threshold and P intensity to three times the perceptual sensory threshold. SICI was reduced or even disinhibited when P was co‐applied, and SAI was reduced or disinhibited when S1 was co‐applied. These interactions did not depend on the exact timing of arrival of P and S1 in motor cortex. A control experiment with a S1 intensity lowered to 70% active motor threshold excluded a contribution by short‐interval intracortical facilitation. Finally, SICI with co‐applied P correlated linearly with SICI alone with a slope of the regression line close to 1 whereas SAI did not correlate with SAI when S1 was co‐applied with a slope of the regression line close to zero. Data indicate that S1 largely eliminates the effects of P when applied together, suggesting dominance of S1 over P. Findings strongly support the idea that SICI and SAI are mediated through two distinct and reciprocally connected subtypes of GABAergic inhibitory interneurons with convergent projections onto the corticospinal neurons. Furthermore, dominance of S1 over P is compatible with the notion that the SICI interneurons target the corticospinal neurons closer to their axon initial segment than the SAI interneurons.

Distinct gamma-band components reflect the short-term memory maintenance of different sound lateralization angles.

Oscillatory activity in human electro- or magnetoencephalogram has been related to cortical stimulus representations and their modulation by cognitive processes. Whereas previous work has focused on gamma-band activity (GBA) during attention or maintenance of representations, there is little evidence for GBA reflecting individual stimulus representations. The present study aimed at identifying stimulus-specific GBA components during auditory spatial short-term memory. A total of 28 adults were assigned to 1 of 2 groups who were presented with only right- or left-lateralized sounds, respectively. In each group, 2 sample stimuli were used which differed in their lateralization angles (15° or 45°) with respect to the midsagittal plane. Statistical probability mapping served to identify spectral amplitude differences between 15° versus 45° stimuli. Distinct GBA components were found for each sample stimulus in different sensors over parieto-occipital cortex contralateral to the side of stimulation peaking during the middle 200–300 ms of the delay phase. The differentiation between “preferred” and “nonpreferred” stimuli during the final 100 ms of the delay phase correlated with task performance. These findings suggest that the observed GBA components reflect the activity of distinct networks tuned to spatial sound features which contribute to the maintenance of task-relevant information in short-term memory.

Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical–Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings

Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.

Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex

Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double‐blind randomized placebo‐controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long‐term potentiation (LTP)‐like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS‐induced LTP‐like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP‐like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP‐like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma‐amino butyric acid‐dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage‐gated sodium channels by lamotrigine, may also depress PAS‐induced LTP‐like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED‐related adverse effects on important LTP‐dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP‐like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP‐associated process.

Alpha synchronization during auditory spatial short-term memory

Recent studies have suggested an active role of cortical &agr; oscillations for cognitive functions including short-term memory. We used magnetoencephalography to assess &agr; activity during an auditory spatial delayed matching-to-sample task compared with a nonmemory control condition. In the memory task, participants had to memorize the lateralization angle of a noise stimulus S1 and compare it with another lateralized sound S2 presented after an 800-ms delay phase. Whereas &agr; desynchronization following S1 was observed over superior temporal areas under both conditions, only the memory task was accompanied by posterior parietal &agr; synchronization during the subsequent delay period. The findings are consistent with the notion of &agr; activity reflecting active inhibition of interfering processes during memory maintenance of spatial sounds.

Behavioral relevance of gamma-band activity for short-term memory-based auditory decision-making

Oscillatory activity in the gamma‐band range has been established as a correlate of cognitive processes, including perception, attention and memory. Only a few studies, however, have provided evidence for an association between gamma‐band activity (GBA) and measures of behavioral performance. Here we focused on the comparison between sample and test stimuli S1 and S2 during an auditory spatial short‐term memory task. Applying statistical probability mapping to magnetoencephalographic recordings from 28 human subjects, we identified GBA components distinguishing nonidentical from identical S1–S2 pairs. This activity was found at frequencies between 65 and 90 Hz and was localized over posterior cortical regions contralateral to the hemifield in which the stimuli were presented. The 10 best task performers showed higher amplitudes of this GBA component than the 10 worst performers. This group difference was most pronounced between about 150 and 300 ms after stimulus onset. Apparently the decision about whether test stimuli matched the stored representation of previously presented sample sounds relied partly on the oscillatory activation of networks representing differences between both stimuli. This result could be replicated by reanalyzing the combined data from two previous studies assessing short‐term memory for sound duration and sound lateralization, respectively. Similarly to our main study, GBA amplitudes to nonmatching vs. matching S1–S2 pairs were higher in good performers than poor performers. The present findings demonstrate the behavioral relevance of GBA.

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input–output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation.

Effects of lamotrigine on human motor cortex plasticity.

OBJECTIVE Besides its use in epilepsy, lamotrigine (LTG) is also effective as mood stabilizer. The pathophysiology of mood disorders may incorporate a dysfunction of neuronal plasticity and animal experiments suggest that mood stabilizers influence induction of long-term potentiation (LTP) and -depression (LTD), two major forms of synaptic plasticity. However, the exact modes of action of LTG and its impact on neuronal plasticity in humans remain unclear. METHODS Here, we tested the effects of a single oral dose of LTG (300 mg) on motor cortical plasticity induced by paired associative stimulation (PAS(25)), a protocol that typically induces LTP-like plasticity, in 26 young healthy adults in a placebo-controlled, randomized, double-blind crossover design. We stratified analysis of the LTG effects according to the individual PAS(25) response in the placebo session (14 LTP-responders vs. 12 LTD-responders). Plasticity was indexed by motor evoked potential (MEP) amplitudes recorded before and for 60 min after PAS(25). RESULTS LTG resulted in a significant reduction of the LTP-like MEP increase in the LTP-responders and a reduction of the LTD-like MEP decrease in the LTD-responders, with the majority of LTD-responders even showing an MEP increase. CONCLUSIONS In summary, LTG differentially modulated cortical plasticity induced by non-invasive brain stimulation in human subjects depending on their individual intrinsic propensity for expressing LTP-like or LTD-like plasticity. SIGNIFICANCE Findings contribute to our understanding of the anticonvulsant and antidepressant clinical effects of LTG, which have been suggested to occur, at least in part, through downregulation of LTP (epilepsy) and LTD (depressive disorders).

Acute effects of lithium on excitability of human motor cortex

OBJECTIVE Lithium has been widely used to treat bipolar affective disorder for over 60years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS). METHODS Ten healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450mg, 900mg, or 1350mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input-output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration. RESULTS Two hours post drug administration, 450mg of lithium carbonate increased the slope of the MEP IO-curve while 1350mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation. CONCLUSIONS The acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose-response relationship. SIGNIFICANCE Findings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.