Brain State-dependent Brain Stimulation with Real-time Electroencephalography-Triggered Transcranial Magnetic Stimulation

The method combines EEG and TMS for realtime brain state dependent brain stimulation. This enables the TMS parcels to be synchronized with a specific phase of ongoing endogenous brain oscillations. Brain stimulation is a technique for modulating the brain by synchronizing individual TMS pulses with a specific EEG defined brain state.

The effect of the stimulation can be optimized. Standard TMS is already used to treat neurological and psychiatric diseases such as stroke and depression. EEG-synchronized TMS has the potential to improve treatment outcomes using personalized stimulation protocols.

We also use EEG-synchronized TMS to investigate the basic neurophysiology of brain oscillations in the human by comparing the effects that stimuli have which are identical but are applied during different brain states. The effects can be subtle and are easily washed out by other sources of experimental variability. We found that low stimulus intensity works best to observe the effect of sensory motor rhythm on cortical spinal excitability.

To conduct a closed loop experiment brain activity is recorded through EEG potentials from the scalp surface that are digitized by an EEG amplifier. The signal then passes to the EEG main unit and from there to the realtime device which controls the stimulator, thereby closing the signal loop between measuring and modulating brain activity. The realtime device analyzes the EEG oscillations and sends a trigger signal to the TMS stimulator when a predetermined trigger condition is met to pass a brief current pulse through the TMS coil that is placed on the head.

During the experiment the position of the coil on the head will be monitored with a neuro-navigation device. Connect the realtime output of the EEG system to the realtime device input and connect the output of the realtime device to the trigger input of the TMS stimulator. Register the study participant in the system, making sure that the protocol matches the layout of the EEG cap and that the relevant channels are sent to the realtime output.

On the computer controlling the realtime device load the software to control the realtime device and ensure that the realtime input channels match the configuration of the EEG system. Then turn on the TMS stimulator and set the configuration to external triggering. To monitor the coil position and to achieve an accurate and consistent TMS targeting within and across sessions load the individual structural MRI data into the navigation system software prior to starting the experiment for each participant.

Then attach a coil tracker to the stimulation coil and calibrate the coil. When the system is ready, place an appropriately sized EEG cap on the head of the study participant and use measuring tape to position the cap correctly. Push the hair aside so that the scalp is visible and prepare the scalp with an abrasive gel application.

Next apply conductive gel to the electrodes and check that the EEG electrode impedances are below five kiloohms. Cover the EEG cap with plastic wrap and fit a mesh cap above the plastic wrap to keep the cables in a fixed position to reduce the EEG artifact variability. Then apply adhesive tape to increase the stability of the multiple layers and tape a reflective head tracker to the subject's head to ensure stability throughout the experiment.

Attach the surface EMG electrodes to the cleaned and abraded target muscles and visually inspect the ongoing EEG and EMG signals for bad electrodes. Keep the bipolar EMG cables close together and close to the body of the study participant to reduce line noise pickup. Then use the pointer tool to co-register the head model with the relevant anatomical landmarks and pinpoint the EEG sensor locations to enable the subsequent estimation of the individual sources of the EEG activity.

To perform a realtime EEG-synchronized TMS experiment first determine the exact location where the TMS of the motor cortex evokes the strongest motor response from the hand muscles. Then mark this hotspot and coil position in the neuro-navigation software. Next fix the head of the subject with a vacuum pillow and fix the coil in the hotspot location with a mechanical arm.

To determine the threshold stimulation intensity gradually adjust the stimulation intensity until 50%of the TMS pulses result in a motor response. Here the intensity has been set to 110%of the threshold intensity. To configure the realtime system to combine multiple EEG channels to extract a specific oscillation, use a five channel laplacian spacial filter centered on electrode C3 to extract sensory motor rhythm.

To trigger TMS at either the positive or negative peak of this oscillation set the phase trigger condition to phase zero or phase pi randomly for each trial before arming the realtime device and setting the sequence to be repeated on a loop every two seconds. Then run the experiment for about 10 minutes to acquire a sufficient number of trials to differentiate phase specific stimulation effects. During the experiment the coil position will be monitored on the neuro-navigation system and the EEG and EMG signals will be monitored on the EEG system.

The raw data as well as pre-stimulus EEG and the post-stimulus muscle response for each condition are also displayed on the EEG system. The realtime device will perform spatial filtering to target the brain region of interest and band pass filtering to isolate the oscillation of interest, estimating the instantaneous amplitude and phase using autoregressive forward prediction and the Hilbert transform. This signal is then compared to the trigger condition.

If the power threshold and phase conditions are met the stimulator is triggered. Using the displayed online running averages, the accuracy of the phase targeting and the effect of phase on muscle response can be estimated during the experiment. In these figures an average pre-stimulus EEG signal in the 400 milliseconds before the TMS pulse for three predefined conditions and average elicited motor evoked potentials recorded from the right hand muscles are shown.

Taken together these results demonstrate that the negative EEG deflection of the micro-rhythm corresponds to a higher cortical excitability state leading to larger motor evoked potential amplitudes compared to the positive EEG deflection with a low inter-trial variability of the noted corticospinal excitability effects. We need a stable and clean EEG signal. The key is a well-prepared study participant who is relaxed, comfortable, and able to sit still.

This is an easy to use plug and play method to investigate whether large-scale cortical connectivity states have causal effects in perturbation based experiments. Looking at one localized oscillation, that's just the first step. We have been able to use findings from this technique to show that repetitive TMS have a negative peak of the ongoing sensory motor oscillations results and longterm potentiation like plasticity.

TMS is a safe and painless procedure. A very rare side effect is an epileptic seizure in vulnerable persons and occasionally mild temporary headache can occur.