Oszillatorische Gamma-Band-Aktivität bei der Verarbeitung auditorischer Reize im Kurzzeitgedächtnis im MEG

Recent studies have suggested an important role of cortical gamma oscillatory activity (30-100 Hz) as a correlate of encoding, maintaining and retrieving auditory, visual or tactile information in and from memory. It was shown that these cortical stimulus representations were modulated by attention processes. Gamma-band activity (GBA) occurred as an induced response peaking at approximately 200-300 ms after stimulus presentation. Induced cortical responses appear as non-phase-locked activity and are assumed to reflect active cortical processing rather than passive perception. Induced GBA peaking 200-300 ms after stimulus presentation has been assumed to reflect differences between experimental conditions containing various stimuli. By contrast, the relationship between specific oscillatory signals and the representation of individual stimuli has remained unclear. The present study aimed at the identification of such stimulus-specific gamma-band components. We used magnetoencephalography (MEG) to assess gamma activity during an auditory spatial delayed matching-to-sample task. 28 healthy adults were assigned to one of two groups R and L who were presented with only right- or left-lateralized sounds, respectively. Two sample stimuli S1 with lateralization angles of either 15° or 45° deviation from the midsagittal plane were used in each group. Participants had to memorize the lateralization angle of S1 and compare it to a second lateralized sound S2 presented after an 800-ms delay phase. S2 either had the same or a different lateralization angle as S1. After the presentation of S2, subjects had to indicate whether S1 and S2 matched or not. Statistical probability mapping was applied to the signals at sensor level to identify spectral amplitude differences between 15° and 45° stimuli. We found distinct gamma-band components reflecting each sample stimulus with center frequencies ranging between 59 and 72 Hz in different sensors over parieto-occipital cortex contralateral to the side of stimulation. These oscillations showed maximal spectral amplitudes during the middle 200-300 ms of the delay phase and decreased again towards its end. Additionally, we investigated correlations between the activation strength of the gamma-band components and memory task performance. The magnitude of differentiation between oscillatory components representing 'preferred' and 'nonpreferred' stimuli during the final 100 ms of the delay phase correlated positively with task performance. These findings suggest that the observed gamma-band components reflect the activity of neuronal networks tuned to specific auditory spatial stimulus features. The activation of these networks seems to contribute to the maintenance of task-relevant information in short-term memory.Ergebnisse aus aktuellen Studien legen nahe, dass kortikale oszillatorische Aktivität im Gamma-Bereich (30-100 Hz) eine wichtige Rolle für verschiedene kognitive Prozesse spielt. Dazu zählen das Kodieren, die Aufrechterhaltung und der Abruf auditorischer, visueller oder taktiler Informationen in das bzw. aus dem Gedächtnis. Es konnte gezeigt werden, dass diese kortikale Aktivität durch Aufmerksamkeitsprozesse beeinflusst wird. Gamma-Aktivität trat bei vorangegangenen Untersuchungen als induzierte Antwort ca. 200-300 ms nach Stimuluspräsentation auf. Es wird angenommen, dass diese nicht phasengebundenen kortikalen Reizantworten aktive kortikale Verarbeitungs-prozesse widerspiegeln. In früheren Studien wurde induzierte Gamma-Aktivität während der Aufrechterhaltung von Stimulusinformationen über Regionen gefunden, die an der Verarbeitung aufgabenrelevanter Reizmerkmale beteiligt sind. Diese Antworten im Gamma-Bereich spiegelten Unterschiede zwischen verschieden experimentellen Bedingungen wider, jedoch ist wenig über die Repräsentation spezifischer Stimuluseigenschaften durch Gamma-Aktivität bekannt. Mit der vorliegenden Studie haben wir versucht, solche stimulus spezifischen Gamma-Komponenten zu untersuchen. Dafür verwendeten wir Magnetenzephalographie (MEG) und eine auditorische räumliche “delayed matching-to-sample“ Aufgabe. 28 gesunde Erwachsene wurden dabei zwei verschiedenen Gruppen zugeordnet. Gruppe R bekam rechtslateralisierte Stimuli präsentiert, während diese in Gruppe L linkslateralisiert waren. Dabei unterschieden sich die Reize nur in ihrer räumlichen Charakteristik, die Klangmuster blieben unverändert. In beiden Gruppen wurden zwei Beispielstimuli S1 mit Lateralisierungswinkeln von 15° bzw. 45° verwendet. Die Probanden mussten sich den Lateralisierungswinkel von S1 merken und anschließend mit einem zweiten Stimulus S2, der nach einer Verzögerungsphase von 800 ms präsentiert wurde, vergleichen. S2 hatte dabei entweder den gleichen Lateralisierungswinkel wie S1, oder unterschied sich darin von dem ersten Stimulus. Nach der Präsentation von S2 mussten die Probanden signalisieren, ob die Lateralisierungswinkel der beiden Stimuli übereinstimmten oder nicht. Die Signale der einzelnen Sensoren wurden mit einem statistischen Wahrscheinlichkeitsmapping untersucht. Dabei wollten wir Unterschiede in der spektralen Amplitude für Stimuli mit 15° bzw. 45° Lateralisierungswinkel identifizieren. Wir konnten spezifische Gamma-Aktivität für alle Beispielstimuli nachweisen. Die Signale wurden im Bereich von 59-72 Hz gefunden und waren über dem parieto-okzipitalen Kortex jeweils kontralateral zur stimulierten Seite lokalisiert. Die maximalen Spektralamplituden dieser Oszillationen traten während der mittleren 200-300 ms der Verzögerungsphase auf und nahmen zu ihrem Ende hin ab. Zusätzlich haben wir Korrelationen zwischen der Aktivierungsstärke der Gamma-Komponenten und dem Abschneiden bei der Gedächtnisaufgabe untersucht. Dabei zeigte sich, dass der Unterschied der oszillatorischen Antworten auf bevorzugte und nicht-bevorzugte Stimuli während der letzten 100 ms der Verzögerungsphase positiv mit der Leistung in der Gedächtnisaufgabe korrelierte. Diese Ergebnisse sprechen dafür, dass die beobachteten Gamma Komponenten die Aktivität neuronaler Netzwerke, die auf die Verarbeitung räumlicher auditorischer Information spezialisiert sind, widerspiegeln. Die Aktivierung dieser Netzwerke scheint zur Aufrechterhaltung aufgabenbezogener Information im Kurzzeitgedächtnis beizutragen

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

Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia

A data-driven approach to responder subgroup identification after paired continuous theta burst stimulation

Background: Modulation of cortical excitability by transcranial magnetic stimulation (TMS) is used for investigating human brain functions. A common observation is the high variability of long-term depression (LTD)-like changes in human (motor) cortex excitability. This study aimed at analyzing the response subgroup distribution after paired continuous theta burst stimulation (cTBS) as a basis for subject selection. Methods: The effects of paired cTBS using 80% active motor threshold (AMT) in 31 healthy volunteers were assessed at the primary motor cortex (M1) corresponding to the representation of the first dorsal interosseous (FDI) muscle of the left hand, before and up to 50 min after plasticity induction. The changes in motor evoked potentials (MEPs) were analyzed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM) and computed ABC analysis. Results: The probability density distribution of the MEP changes from baseline was tri-modal , showing a clear separation at 80.9%. Subjects displaying at least this degree of LTD-like changes were n = 6 responders. By contrast, n = 7 subjects displayed a paradox response with increase in MEP. Reassessment using ABC analysis as alternative approach led to the same n = 6 subjects as a distinct category. Conclusion: Depressive effects of paired cTBS using 80% AMT endure at least 50 min, however, only in a small subgroup of healthy subjects. Hence, plasticity induction by paired cTBS might not reflect a general mechanism in human motor cortex excitability. A mathematically supported criterion is proposed to select responders for enrolment in assessments of human brain functional networks using virtual brain lesions

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

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