Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation

This technique provides insight into how brain circuits go awry, in psychiatric and neurological disorders. And how we can manipulate brain activity to repair these dysfunctional circuits to enhance behavior. By directly activating and inhibiting brain excitability and circuitry, this technique enables shifting of neuro-scientific focus from observation to causation, and provides a deeper understanding of the brain and behavior.

Non-invasive brain stimulation can be used to both assess and treat many neurological disorders and can help improve diagnoses and therapies, based on more sophisticated models of brain behavior connections. This method can not only counteract altered connectivity patterns in the motor system, but also in cognitive networks associated with physiological aging, psychiatric and neurological disorders. After screening participants for right handedness and any contraindications to TMS and MRI, inform each participant about the study objectives, procedures, and risks approved by the local institutional review board and obtain written consent.

For placement of the EMG electrodes, have the participant sit comfortably in the experimental chair, with both arms supported in a relaxed position and provide a chin rest to keep the head movement to a minimum during the stimulation. Use a mild abrasive to clean the skin over the muscle of interest. Using a belly tendon electrode arrangement, place one disposable silver silver chloride electrode on the belly muscle, and another on a nearby bony landmark as a reference site on both hands of the participant.

Then connect a ground electrode to the owners styloid process, then check between each electrode in the skin to confirm a complete contact. Placing tape over the surface of the electrode to improve the skin surface contact as necessary. Before the TMS session, upload the participants structural MRI scan to a neuro-navigation system.

Within the scan, place a trajectory marker at the hand knob the anatomical landmark that corresponds to M-one. In the left precentral gyrus 45 degrees from the mid sagittal line, and approximately perpendicular to the central sulcus. Record and name the anatomical landmark, with the neuro-navigation system, and place a second trajectory marker over the non-motor area of interest.

Then record and name the second location with the neuro-navigation system. First, calibrate each TMS coil with the calibration block, and place the head tracker securely on the head of the participant so that the tracker is in view throughout the duration of the experiment. Co-register the anatomical landmarks on the participants head, to the neuro-navigation system.

To localize and threshold with coil two, first position the center of the coil over the target M-one location, to induce a posterior-anterior current direction in the brain. To find the optimal location for activation of the target muscle, deliver pulses to M-one at 30%of the machines maximum stimulator output, and observe whether the delivered stimulation produces a muscle twitch. Determine the amplitude of the motor-evoked potential recorded with the EMG electrodes from the muscle activity displayed by the data acquisition system.

If a motor-evoked potential or a visible muscle twitch is not observed, continue to increase the stimulator output by 5%increments. When a response is observed, lower the intensity in a stepwise manner to the lowest intensity, that produces at least five out of 10 motor-evoked potential responses with an amplitude of at least 50 micro volts, while the participant is abreast to determine the resting motor threshold. To localize and threshold with coil M-one, use the M-one coil to determine the optimal stimulation location.

Determine the lowest stimulator intensity needed to generate motor-evoked potentials of at least one millivolt, in five out of 10 trials in the target hand muscle, when the muscle is completely relaxed. Then mark and record the position of the M-one coil, within the neuro-navigation system. For dual-site TMS when the participant is in the resting state, connect the figure eight-shaped coils to two individual TMS stimulators.

Deliver the test stimuli over M-one with the M-one coil, and deliver the conditioning stimuli to the other area of interest with coil two. Determine the percentage of the maximum stimulator output intensity for the conditioning stimulus for coil two as demonstrated. For the test stimulus, use the previously determined intensity that elicits motor-evoked potential amplitudes of approximately one millivolt in the targeted quiescent hand muscle, and set the precise interstimulus interval between the conditioning and test stimuli.

Position the M-one coil over the left M-one and position coil two over the other area of interest. Deliver the test stimuli alone trials with the M-one coil. For the paired pulse trials, deliver the conditioning stimuli with coil two followed by the testing stimuli to the M-one coil at the predetermined interstimulus interval, using a four second data acquisition sweep for each trial, followed by one second inter-trial interval.

To deliver the program to TMS pulses, use the trigger button on the TMS machine for the supplied control software, or use the custom-made coding script from the external controller. Using the previously described method, examine the functional interactions between different cortical areas interconnected to M-one, but during the preparatory phase of a task that engages the network. To deliver repeated pairs of monophasic pulses to two different cortical areas over short periods using a custom-made coding script, generate 100 pairs of stimuli at 0.2 hertz for 8.3 minutes per stimulus.

For the experimental cPAS to M-one condition, deliver the first pulse of each stimuli pair over the non-motor area with coil two, before delivering the second pulse over M-one with the M-one coil, with an interstimulus interval of five milliseconds. Pulse intensity for both coils, should be previously determined during thresholding and localization. After obtaining baseline corticospinal measurements with the M-one coil, obtain corticospinal measurements with the M-one coil at different times after cPAS, to examine the time course of the TMS induced effect on brain excitability.

Here the size of a representative motor-evoked potential response elicited in the first dorsal interosseous muscle by TMS for an unconditioned test, or conditioned stimulus from the posterior parietal cortex, while the participant was at rest, or planning a goal directed grasping action to an object as shown. At rest, the posterior parietal cortex exerts an inhibitory influence on ipsilateral M-one, as shown by the decrease in MEP amplitudes, potentiated by a sub-threshold conditioning stimulus delivered over PPC, five milliseconds prior to a super threshold testing stimulus over M-one. During the preparation of a grasp action, this net inhibitory drive at rest from the posterior parietal cortex, switch to facilitation.

Normalization of the motor-evoked potential amplitudes to testing stimuli alone trials for each condition, and plotting as a ratio for motor-evoked potential amplitude reveal that the posterior parietal cortex M-one interaction was facilitated from rest, when planning an object directed grasp. In these analysis, the changes in motor-evoked potential amplitudes during the administration of the cPAS protocol, can be observed. Motor-evoked potential amplitudes induced by paired stimulation of the posterior parietal cortex and M-one, gradually increased over time during the stimulation protocol, suggesting plastic effects at the level of the parietal-motor connection, M-one corticospinal neurons or both.

The size of the motor-evoked potential amplitudes increased 10 minutes after the cPAS protocol, suggesting that motor excitability after effects were induced after administration of the repeated pairs of cortical stimuli over the posterior parietal cortex and the M-one. This protocol can be applied to other brain regions or used in conjunction with brain imaging to study cortical connectivity and its effect on cognition, sensory perception and mood. Standardizing these dual sight protocols, will enable improvements in experimental design and the optimization of targeted therapies.

Reducing morbidity and impairments in neurological and psychiatric disorders.