P-28 Oscillation phase-specific modulation of cortical excitability using closed-loop transcranial magnetic stimulation

Impairments in attentional, working memory and sensorimotor processing have been consistently reported in schizophrenia. However, the interaction between cognitive and sensorimotor impairments and the underlying neural mechanisms remains largely uncharted. We hypothesized that altered attentional processing in patients with schizophrenia, probed through saccadic inhibition, would partly explain impaired sensorimotor control and would be reflected as altered task-dependent modulation of cortical excitability and inhibition. Twenty-five stabilized patients with schizophrenia, 17 unaffected siblings and 25 healthy control subjects were recruited. Subjects performed visuomotor grip force-tracking alone (single-task condition) and with increased cognitive load (dual-task condition). In the dual-task condition, two types of trials were randomly presented: trials with visual distractors (requiring inhibition of saccades) or trials with addition of numbers (requiring saccades and addition). Both dual-task trial types required divided visual attention to the force-tracking target and to the distractor or number. Gaze was measured during force-tracking tasks, and task-dependent modulation of cortical excitability and inhibition were assessed using transcranial magnetic stimulation. In the single-task, patients with schizophrenia showed increased force-tracking error. In dual-task distraction trials, force-tracking error increased further in patients, but not in the other two groups. Patients inhibited fewer saccades to distractors, and the capacity to inhibit saccades explained group differences in force-tracking performance. Cortical excitability at rest was not different between groups and increased for all groups during single-task force-tracking, although, to a greater extent in patients (80%) compared to controls (40%). Compared to single-task force-tracking, the dual-task increased cortical excitability in control subjects, whereas patients showed decreased excitability. Again, the group differences in cortical excitability were no longer significant when failure to inhibit saccades was included as a covariate. Cortical inhibition was reduced in patients in all conditions, and only healthy controls increased inhibition in the dual-task. Siblings had similar force-tracking and gaze performance as controls but showed altered task-related modulation of cortical excitability and inhibition in dual-task conditions. In patients, neuropsychological scores of attention correlated with visuomotor performance and with task-dependant modulation of cortical excitability. Disorganization symptoms were greatest in patients with weakest task-dependent modulation of cortical excitability. This study provides insights into neurobiological mechanisms of impaired sensorimotor control in schizophrenia showing that deficient divided visual attention contributes to impaired visuomotor performance and is reflected in impaired modulation of cortical excitability and inhibition. In siblings, altered modulation of cortical excitability and inhibition is consistent with a genetic risk for cortical abnormality.

Modulation of cortical excitability and interhemispheric inhibition prior to rhythmic unimanual contractions

Transcranial magnetic stimulation (TMS) can be applied in different paradigms to obtain a measure of various aspects of cortical excitability. These different TMS paradigms provide information about different neurotransmitter systems, enhance our understanding about the pathophysiology of neuropsychiatric conditions, and in the future may be helpful as a guide for pharmacological interventions. In addition, repetitive TMS (rTMS) modulates cortical excitability beyond the duration of the rTMS trains themselves. Depending on rTMS parameters, a lasting inhibition or facilitation of cortical excitability can be induced. These effects can be demonstrated neurophysiologically or by combining rTMS with neuroimaging techniques. The effects do not remain limited to the cortical area directly targeted by rTMS, but affect a wider neural network transynaptically. Modulation of cortical excitability by rTMS may in the future be useful not only as a research tool but also as a therapeutic intervention in neurology, psychiatry, and neurorehabilitation.

Modulations in corticomotor excitability during passive upper-limb movement: Is there a cortical influence?

Background:Little is known about the modulation of cortical excitability in the prefrontal cortex during fear processing in humans. Here, we aimed to transiently modulate and test the cortical excitability during fear processing using transcranial magnetic stimulation (TMS) and brain oscillations in theta and alpha frequency bands with electroencephalography (EEG).Methods:We conducted two separate experiments (no-TMS and TMS). In the no-TMS experiment, EEG recordings were performed during the instructed fear paradigm in which a visual cue (CS+) was paired with an aversive unconditioned stimulus (electric shock), while the other visual cue was unpaired (CS-). In the TMS experiment, in addition the TMS was applied on the right dorsomedial prefrontal cortex (dmPFC). The participants also underwent structural MRI (magnetic resonance imaging) scanning and were assigned pseudo-randomly to both experiments, such that age and gender were matched. The cortical excitability was evaluated by time-frequency analysis and functional connectivity with weighted phase lag index (WPLI). We further linked the excitability patterns with markers of stress coping capability.Results:After visual cue onset, we found increased theta power in the frontal lobe and decreased alpha power in the occipital lobe during CS+ relative to CS- trials. TMS of dmPFC increased theta power in the frontal lobe and reduced alpha power in the occipital lobe during CS+. The TMS pulse increased the information flow from the sensorimotor region to the prefrontal and occipital regions in the theta and alpha bands, respectively during CS+ compared to CS-. Pre-stimulation frontal theta power (0.75–1 s) predicted the magnitude of frontal theta power changes after stimulation (1–1.25 s). Finally, the increased frontal theta power during CS+ compared to CS- was positively correlated with stress coping behavior.Conclusion:Our results show that TMS over dmPFC transiently modulated the regional cortical excitability and the fronto-occipital information flows during fear processing, while the pre-stimulation frontal theta power determined the strength of achieved effects. The frontal theta power may serve as a biomarker for fear processing and stress-coping responses in individuals and could be clinically tested in mental disorders.

Brain oscillations and frequency-dependent modulation of cortical excitability

Transcranial magnetic stimulation (TMS) is a safe, noninvasive, and painless way to stimulate the human motor cortex in behaving human subjects. When it is applied as a single-pulse, measurements such as central conduction time, motor threshold, silent-period duration, recruitment curve, and mapping of muscle representation can be determined. Paired-pulse TMS is a useful way to examine cortical excitability. Single and paired-pulse TMS have been applied to study plasticity following amputation and cortical excitability in patients with dystonia. Another form of TMS is repetitive TMS (rTMS), with stimuli delivered repeatedly to a single scalp site. High-frequency rTMS can be used to transiently inactivate different cortical areas to study their functions. rTMS can also modulate cortical excitability. At stimulus frequencies higher than 5 Hz, rTMS increases cortical excitability, and stimulation around 1 Hz reduces cortical excitability. Modulation of cortical excitability by rTMS has therapeutic potential in psychiatric and neurological disorders.

Reduced plastic brain responses to repetitive transcranial magnetic stimulation in severe obstructive sleep apnea syndrome

Background and purpose. Within the concept of interhemispheric competition, technical modulation of the excitability of motor areas in the contralesional and ipsilesional hemisphere has been applied in an attempt to enhance recovery of hand function following stroke. This review critically summarizes the data supporting the use of novel electrophysiological concepts in the rehabilitation of hand function after stroke. Summary of review. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are powerful tools to inhibit or facilitate cortical excitability. Modulation of cortical excitability may instantaneously induce plastic changes within the cortical network of sensorimotor areas, thereby improving motor function of the affected hand after stroke. No significant adverse effects have been noted when applying brain stimulation in stroke patients. To date, however, the clinical effects are small to moderate and short lived. Future work should elucidate whether repetitive administration of rTMS or tDCS over several days and the combination of these techniques with behavioral training (ie, physiotherapy) could result in an enhanced effectiveness. Conclusion. Brain stimulation is a safe and promising tool to induce plastic changes in the cortical sensorimotor network to improve motor behavior after stroke. However, several methodological issues remain to be answered to further improve the effectiveness of these new approaches.

O13 Exploring the modulators of cortical excitability

Transcranial static magnetic stimulation —From bench to bedside and beyond—

Neurophysiologische Techniken zur Hirnstimulation, wie die repetitive transkranielle Magnetstimulation und die transkranielle Gleichstromstimulation, können die Erregbarkeit der Hirnrinde abhängig von den gewählten Stimulationsparametern für einen die Stimulationszeit überdauernden Zeitraum hemmen (Inhibition) oder erhöhen (Fazilitation). Die Modulation der Erregbarkeit der Hirnrinde kann plastische Änderungen im funktionellen Zusammenspiel der sensomotorischen Hirnrindenareale in beiden Hemisphären induzieren. Dadurch können auch maladaptive Anpassungsprozesse infolge einer Hirnschädigung positiv beeinflusst werden. Innerhalb des Konzepts der interhemisphärischen Kompetition werden hirnstimulierende Verfahren zunehmend in der Rehabilitation von motorischen Störungen der oberen Extremität nach Schlaganfall angewendet. Die Arbeit gibt einen Überblick über die aktuelle Literatur zur Anwendung der repetitiven transkraniellen Magnetstimulation und der transkraniellen Gleichstromstimulation in der Therapie von Handfunktionsstörungen nach Schlaganfall.

Recent research in brain stimulation techniques (in the context of a variety of neurological conditions, including movement disorders, psychiatric disorders, and epilepsy) has turned toward understanding the induced effects of stimulation at a systems level. These efforts often involve stimulating one region of the brain and examining the response characteristics of another. In this vein, Stypulkowski et al1 recently published a study of hippocampal excitability and its changes in the context of both local hippocampal and remote electric stimulation of the anterior thalamus. The authors demonstrate that broadband local field potential (LFP) suppression can be produced in the hippocampus via either direct hippocampal or thalamic stimulation and that these effects are dependent on the stimulation parameters used. Additionally, the authors developed and demonstrated 2 closed-loop stimulation schemes in which stimulation therapy was selectively delivered and modulated on the basis of real-time feedback in the form of hippocampal theta band activity. The authors performed these studies in a sheep model (n = 3) with Medtronic model 3387 deep brain stimulation leads stereotactically placed in the hippocampus and model 3389 deep brain stimulation leads placed in the anterior thalamus unilaterally. Long-term implant durations ranged from 24 to 31 months, and stimulation experiments were performed in awake behaving animals. The novel implantable pulse generator (placed in a retroscapular location) was capable of both stimulating and performing LFP recordings concurrently. This system additionally was capable of triggering stimulation on the basis of band power changes selected by the investigator. Evoked potentials recorded with this system were obtained during anterior thalamic stimulation, with delays on the order of 50 to 100 milliseconds. Additionally, broadband suppression in hippocampal LFP activity was observed specifically with increases in the frequency of thalamic stimulation starting in the range of 40 Hz (1.0 V, 120-microsecond pulse width). With the use of a cycled thalamic stimulation pulsing regimen, the suppressed hippocampal theta band activity was shown to return between periods of stimulation. Like thalamic stimulation, direct hippocampal stimulation was capable of broadband hippocampal LFP suppression at frequencies in the 20-Hz range and above. However, in contrast to thalamic stimulation, when direct hippocampal stimulation was performed, the most sensitive parameter for inducing decreases in theta band power was the voltage amplitude of the stimulation. Direct hippocampal stimulation at amplitudes ranging from 0.4 to 0.8 V produced increasing suppression of hippocampal LFP activity. At a stimulation amplitude of 1.0 V, an excitatory burst of activity called an afterdischarge was produced, followed by a prolonged period of depressed hippocampal LFP activity. Afterdischarges were less likely to be induced by direct hippocampal stimulation during periods when the hippocampal LFP had already been suppressed with preceding preparatory stimulation. Evoked potentials produced in the hippocampus by thalamic stimulation were also suppressed when preparatory direct hippocampal stimulation was provided. The authors were also able to demonstrate 2 novel closed-loop control stimulation paradigms whereby the ambient theta band power recorded in the hippocampus was used to trigger deep brain stimulation, leading to suppression of power in this band pass. In the first paradigm, hippocampal theta band power at a specified threshold was used to control the delivery of short 10-second bursts of direct hippocampal stimulation (0.9 V, 300 microseconds, 50 Hz) that successfully produced LFP suppression and maintained this suppression over extended periods of time (Figure). The second closed-loop system demonstrated instead used continuous thalamic stimulation at a frequency of 40 Hz. Changes in recorded hippocampal theta band activity were used to modulate the amplitude of the continuous thalamic stimulation, and by this means, hippocampal activity was suppressed, which was also sustained over a period of time. In summary, Stypulkowski et al have now demonstrated (in awake behaving animals) that both local and remote deep brain stimulation can produce specific effects on hippocampal excitability. Two novel closed-loop control paradigms were demonstrated in which each successfully depressed hippocampal activity within a desired range. This kind of closed-loop deep brain stimulation paradigm is currently actively undergoing investigation with the hope that it can be applied to many different disease states, and because neuromodulation is delivered only when necessary, it is thought that this can be used to minimize possible side effects of stimulation and to increase battery lifetime while also maximizing therapeutic benefit.Figure: Closed-loop control of hippocampal activity. The top tracing demonstrates the hippocampal local field potential (LFP) activity recorded by the implantable pulse generator. The arrow indicates the time at which the closed-loop control paradigm is initiated. The second tracing demonstrates the hippocampal theta band power signal (4-9 Hz), with the dotted line representing the threshold level set for the delivery of direct stimulation. The third trace shows the hippocampal stimulation voltage, and the bottom figure is the LFP spectrogram. Reprinted from Brain Stimulation, Vol 7/3, Stypulkowski PH, Stanslaski SR, Jensen RM, Denison TJ, Giftakis JE, Brain Stimulation for Epilepsy - Local and Remote Modulation of Network Excitability, Pages No. 350-358, Copyright (2014), with permission from Elsevier.

Die Modulation kortikaler Exzitabilität durch transkranielle Stimulationsverfahren ist in den letzten Jahren ein Schwerpunkt in der neurophysiologischer Forschung geworden. Die transkranielle Magnetstimulation (TMS) ist dabei eine Methode zur Untersuchung und Beeinflussung neuronaler Prozesse im intakten menschlichen Gehirn. Veränderungen der kortikalen Exzitabilität sowie Imbalance exzitatorischer und inhibitorischer neuronaler Einflüsse spielen eine Rolle in der Pathophysiologie verschiedener neuropsychiatrischer Krankheiten wie z. B. beim chronischen Tinnitus. Die vorliegende Arbeit bietet eine Übersicht der Studien, welche mittels Applikation repetitiver transkranieller Magnetstimulation (rTMS) versuchten, Tinnituswahrnehmung zu beeinflussen.

Phasic modulation of corticomotor excitability during passive movement of the upper limb: effects of movement frequency and muscle specificity