This work was supported by the University of Michigan: MCubed Scholars Program and School of Kinesiology.

The following three TMS methods are described below. First, two methods are described to measure cortico-cortical connectivity using dual-site transcranial magnetic stimulation (dsTMS) while participants are either 1) at rest (resting state) or 2) performing an object-directed reach-to-grasp movement (task-dependent). Second, a cortical paired associative stimulation (cPAS) method is described to modulate the interplay between two brain areas in a controlled manner by pairing cortical stimuli (e.g., posterior parietal an...

The dual-site TMS method described here can be employed to investigate functional interactions between different cortical areas interconnected with the primary motor cortex while a participant is at rest or planning a goal-directed action. While brain imaging is correlative, basic knowledge from dual-site TMS methods can reveal causal brain-behavior relations associated with changes in cortico-cortical circuits. In addition, cortical paired associative stimulation with two TMS coils applied in areas interconnected with M...

Noninvasive brain stimulation is a promising assessment tool and treatment for many neurological disorders, such as Parkinson&#39;s disease, Alzheimer&#39;s disease, and stroke1,2,3,4. There is accumulating evidence establishing the relationship between the behavioral manifestations of neurological diseases and abnormalities of cortical excitability, neuroplasticity, cortico-cortical and cortico-subcortical connectivity5,6. Therefore, basic knowledge about brain network dynamics and plasticity in neurological conditions can provide invaluable insight into disease diagnosis, progression, and response to therapy. Functional magnetic resonance imaging (fMRI) is a useful tool to understand the complex relations between brain and behavior in both healthy and diseased brain networks and has the potential to improve treatment based on a network perspective7,8,9. However, fMRI is correlational in nature and cannot provide a causal link between brain function and behavior, nor manipulate functional connectivity to restore abnormal neural circuits associated with behavioral impairments in patients10,11,12. Transcranial magnetic stimulation (TMS) can both causally measure and modulate human brain function and behavior in health and disease3,13,14,15.
TMS is a safe, noninvasive method to stimulate the human brain16,17 and can be used to induce and measure plasticity18. This method can advance our understanding of causal relationships between individual brain areas and behavior10,11,12,19 and their specific functional interactions with other nodes of a brain network20,21,22,23. To date, most studies have focused on the human motor system, given that TMS to the hand area of the motor cortex (M1) can produce motor evoked potentials (MEPs) as physiological readouts for changes associated with motor behavior24, allowing examination of different inhibitory and excitatory circuits at the system level in the human brain25. Recent advances using a conditioning test TMS approach with two coils show that it is possible to measure functional interactions between different cortical areas. In the motor system, dual-site TMS experiments show that inputs from cortical areas interconnected with M1 can change with task demands, age, or disease14,26. Seminal work by Ferbert and colleagues has found that applying a conditioning stimulus to M1 prior to a test stimulus of the other M1 can result in inhibition of the MEP amplitude, a phenomenon known as short interval interhemispheric inhibition (SIHI)28. A number of TMS studies using this approach have also shown that M1 is strongly interconnected with the contralateral M1, ventral premotor cortex (PMv), dorsal premotor cortex (PMd), supplementary motor area (SMA), pre-SMA, primary sensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC) at rest27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42. Interestingly, the effect of stimulation from these cortical areas on motor cortical excitability are anatomically, temporally, and functionally specific to the ongoing brain activity during the preparation of a movement (state- and context-dependent43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,69). However, very few studies using dual-site TMS have characterized patterns of functional cortico-cortical connectivity with motor and cognitive impairments in patients with brain disorders70,71,72. This affords opportunities to develop new methods for assessing and treating motor and cognitive disorders.
Using this technique, it also has been found that repeated pairs of cortical TMS applied to cortical areas interconnected with M1 such as contralateral M168,69,70, PMv76,77,78, SMA71, and PPC80,81,82 can induce changes in synaptic efficiency in specific neural pathways based on the Hebbian principle of associative plasticity83,84,85,86 and enhance behavioral performance72,73,74. Still, few studies have used this approach to study circuit and plasticity dysfunction in neurological disorders2,75,76,77,78,79,80,81,82,83,84,90,91,92,93,94,95,96. It remains to be shown whether strengthening functionally specific neural pathways with TMS can restore activity in dysfunctional circuits, or whether the prospective strengthening of intact circuity can augment resilience97 in brain networks supporting motor and cognitive function across the lifespan and in disease. The lack of fundamental understanding of the neural mechanisms underlying neurological disorders and effects of stimulation on interconnected dysfunctional brain networks limits current treatment.
Despite its capability, TMS has yet to become a standard part of the armamentarium of neuroscience and clinical tools for understanding brain-behavior relations, pathophysiology of brain disorders, and the effectiveness of treatment. Therefore, to realize its potential and support its large-scale application, standardizing TMS methods is important because it is more likely to increase the rigor of future TMS experiments and reproducibility across independent laboratories. This article outlines how TMS can be used to both measure and manipulate functional interactions. Here, we describe this technique in the motor system (e.g., parieto-motor pathway44) by measuring TMS-based output measures (e.g., MEPs), where the method is best understood. However, it is important to note that this protocol also can be adapted to target functional coupling of other subcortical85, cerebellar86,87, and cortical areas.73,74,88 In addition, neuroimaging techniques such as EEG89,90,91 and fMRI92,93 can be used to assess the TMS-induced changes in activity and connectivity26,94. We conclude by proposing that the study of the functional involvement of circuit-level cortical connectivity with these TMS methods in both health and disease makes it possible to develop targeted diagnoses and innovative therapies based on more sophisticated network models of brain-behavior relations.

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			<td>Alpha B.I. D50 coil (coated)</td>
			<td>Magstim</td>
			<td></td>
			<td>50mm coil</td>
		</tr>
		<tr>
			<td>BrainSight 2.0 Software</td>
			<td>Rogue Research</td>
			<td></td>
			<td>Neuronavigation software</td>
		</tr>
		<tr>
			<td>BrainSight frameless Stereotactic System</td>
			<td>Rogue Research</td>
			<td></td>
			<td>Neuronavigation equiptment</td>
		</tr>
		<tr>
			<td>D702 Coil</td>
			<td>Magstim</td>
			<td></td>
			<td>70mm coil</td>
		</tr>
		<tr>
			<td>Discovery MR750</td>
			<td>General Electric</td>
			<td></td>
			<td>3.0T MRI machine</td>
		</tr>
		<tr>
			<td>Disposable Earplugs</td>
			<td>3M</td>
			<td></td>
			<td>Foam earplugs</td>
		</tr>
		<tr>
			<td>ECG Electrodes 30mm x 24mm</td>
			<td>Coviden-Kendall</td>
			<td>H124SG</td>
			<td>Disposable electrodes</td>
		</tr>
		<tr>
			<td>Four Channel Isolated Amplifier</td>
			<td>Intronix Technologies Corporation</td>
			<td>2024F</td>
			<td>EMG amplifier</td>
		</tr>
		<tr>
			<td>gGAMMAcap</td>
			<td>g.tec Medical Engineering</td>
			<td></td>
			<td>EEG head cap</td>
		</tr>
		<tr>
			<td>Micro1401-3</td>
			<td>Cambridge Electronic Design</td>
			<td></td>
			<td>Scientific data recorder and processing machine</td>
		</tr>
		<tr>
			<td>Nuprep Skin Prep Gel</td>
			<td>Weaver and Company</td>
			<td></td>
			<td>Skin prep abrasive gel</td>
		</tr>
		<tr>
			<td>Signal v.7</td>
			<td>Cambridge Electronic Design</td>
			<td></td>
			<td>Data acquisition and analysis software</td>
		</tr>
		<tr>
			<td>The Magstim BiStim2</td>
			<td>Magstim</td>
			<td></td>
			<td>Transcranial magnetic stimulator (two 2002 units)</td>
		</tr>
	</tbody>
</table>

measuring and manipulating functionally specific neural pathways in the human motor system with transcranial magnetic stimulation

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has provided important insights into fundamental processes of the brain like cognition, learning, and motor control. However, this approach cannot provide causal evidence for the involvement of brain areas of interest. Transcranial magnetic stimulation (TMS) is a powerful, noninvasive tool for studying the human brain that can overcome this limitation by transiently modifying brain activity. Here, we highlight recent advances using a paired-pulse, dual-site TMS method with two coils that causally probes cortico-cortical interactions in the human motor system during different task contexts. Additionally, we describe a dual-site TMS protocol based on cortical paired associative stimulation (cPAS) that transiently enhances synaptic efficiency in two interconnected brain areas by applying repeated pairs of cortical stimuli with two coils. These methods can provide a better understanding of the mechanisms underlying cognitive-motor function as well as a new perspective on manipulating specific neural pathways in a targeted fashion to modulate brain circuits and improve behavior. This approach may prove to be an effective tool to develop more sophisticated models of brain-behavior relations and improve diagnosis and treatment of many neurological and psychiatric disorders.

Figure 5 shows the size of an exemplar MEP response elicited in the FDI muscle by TMS for an unconditioned test stimuli (TS alone to M1, blue trace) or conditioned stimuli from PPC (CS-TS, red trace) while the participant was at rest (top panel) or planning a goal-directed grasping action to an object (bottom panel). At rest, the PPC exerts an inhibitory influence on ipsilateral M1, as shown by the decrease in MEP amplitudes potentiated by a subthreshold CS delivered over PPC 5 ms before a s...

Watch this Scientific Journal Video about Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation at JoVE.com

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

This article describes new approaches to measure and strengthen functionally specific neural pathways with transcranial magnetic stimulation. These advanced noninvasive brain stimulation methodologies can provide new opportunities for the understanding of brain-behavior relations and development of new therapies to treat brain disorders.

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has ...

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.

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8.9K 조회수.  University of Michigan. 이 기술은 뇌 회로가 정신 및 신경 장애에서 어떻게 엉망이되는지에 대한 통찰력을 제공합니다. 그리고 어떻게 우리가 행동을 강화하기 위해 이러한 기능 장애 회로를 복구하기 위해 뇌 활동을 조작 할 수 있습니다. 뇌 흥분성과 회로를 직접 활성화하고 억제함으로써 이 기술은 관찰에서 인과 관계로 신경 과학적 초점을 전환할 수 있게 해주며 뇌와 행동에 대한 심층적인 이?...