Name: Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network (Video) | JoVE Journal
Uploaded: 2010-12-28T17:00:00.000+00:00
Duration: 11 min 2 s
Description: Learn to combine transcranial magnetic stimulation and fMRI for examining the default mode network. This method enables researchers to modulate cortical excitability and observe resulting changes in brain activation patterns.

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1. Preparation
<ol class="lalpha">
<li>To begin, obtain a baseline anatomical scan of your subject. This should be done several days before the actual experiment.</li>
<li>Next, load the scan into your frameless stereotactic software package.</li>
<li>Finally, locate and target your stimulation coordinates. In this case, we will be targeting the left inferior parietal lobule.</li>
</ol>
2. The Initial Scan
<ol class="lalpha">
<li>On the day of the experiment, your subject will, once again, start in the MRI machine.</li>
<li>Begin with an anatomical scan.</li>
<li>Next, conduct three functional experimentation runs. For this experiment, the task is quite simple: A fixation point is presented in the subject's central field of vision, and he/she is to simply stare at it passively.</li>
</ol>
3. TMS Preparation
<ol class="lalpha">
<li>Because the effects of rTMS are transitory, time is of the essence when combining TMS and fMRI. It is imperative you get the subject back into the scanner as soon as possible after stimulation cessation. Because of this, you'll want to use a portable TMS device stationed in a room adjacent to or as close as possible to the scanning-bay as possible. In this case, we're using a portable set-up in an observation suite next door to the scanner.</li>
<li>Load your subject's pre-targeted baseline MRI into the stereotactic software package.</li>
<li>Finally, link and calibrate your stimulating coil with the stereotaxy equipment - in this case, we'll align a set of infrared sensors to register coil centrality.</li>
</ol>
4. Determining TMS Parameters
<ol class="lalpha">
<li>When the subject arrives, sit him/her comfortably in a chair.</li>
<li>Next, calibrate your subject's head with the sterotaxy equipment. In this case, we'll use infrared sensors to register several positioning anchors: both ears, the nose, and the nasion.</li>
<li>Determine your subject's resting motor threshold.</li>
<li>If we want to excite the subject's cortex, we will set the TMS machine to 20 Hz with a stimulation power of 110% motor threshold. If we want to inhibit the subject's cortex, we will set the TMS machine to 1 Hz at 110% motor threshold. Although you'll want to explore both parameters throughout the course of a full study, we will only look at a 20 Hz excitatory rTMS chain in this article.</li>
<li>Finally, set up a stimulation pattern of 2 second trains with 28 second rest periods.</li>
</ol>
5. TMS Stimulation
<ol class="lalpha">
<li>Prior to stimulation, prepare the subject to go directly in the scanner following TMS. This includes removal of metal and ensuring the subject has used the restroom.</li>
<li>Holding the coil tangential to the scalp, use your stereotaxy equipment to locate and target the subject's stimulation site.</li>
<li>Turn on the machine's coil cooling system.</li>
<li>Begin stimulation! For this protocol, we will conduct 45 total stimulation trains. At 2 seconds a train with 28 second breaks, we will have a total stim time of 23 minutes.</li>
</ol>
6. Back to the Scanner
<ol class="lalpha">
<li>Once stimulation is complete, it is important to get the subject back into the scanner as soon as possible. To make this transition as seamless as possible, ensure your scanner is prepared and ready to go. Our advice is to raise the body platform, and reduce the number and duration of localizer scans to a bare minimum.</li>
</ol>
7. Final Scan
<ol class="lalpha">
<li>Because the effects of rTMS are transitory, the final scanning session should begin with the functional runs. Again, we'll conduct three, 6-minute runs of passive fixation.</li>
<li>After the experimental runs are complete, finish with an anatomical scan.</li>
</ol>
8. Representative Results
<img src="/files/ftp_upload/2271/2271fig1.jpg" alt="Brain activity diagram, TMS study, left and right hemispheres, pre and post-stimulation comparison." data-altupdatedat="1788235205000" data-alt="Figure 1"> Figure 1.The data suggests that 20 Hz rTMS stimulation to the left inferior parietal lobule, although facilitating local excitability, acts to decrease functional connectivity within the default network.

<ol><li>Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., Shulman, G. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+default+mode+of+brain+function%5BTitle%5D)+AND+%22Proc.+Nat.+Acad.+Sciences%22%5BJournal%5D)">A default mode of brain function.</a> Proc. Nat. Acad. Sciences. 98 (2), 676-682 (2001).</li>
<li>Buckner, R. L., Andrews-Hanna, J. R., Schacter, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+brain%27s+default+network%3A+anatomy%2C+function+and+relevance+to+disease%5BTitle%5D)+AND+%22Ann.+N.Y.+Acad.+Sci%22%5BJournal%5D)">The brain's default network: anatomy, function and relevance to disease.</a> Ann. N.Y. Acad. Sci. 1124, 1-38 (2008).</li>
<li>Raichle, M. E., Snyder, A. Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+default+mode+of+brain+function%3A+a+brief+history+of+an+evolving+idea%5BTitle%5D)+AND+%22Neuroimage%22%5BJournal%5D)">A default mode of brain function: a brief history of an evolving idea.</a> Neuroimage. 37 (4), 1083-1090 (2007).</li>
<li>Whitfield-Gabrieli, S., Thermenos, H. W., Milanovic, S., Tsuang, M. T., Faraone, S. V., McCarley, R. W., Shenton, M. E., Green, A. I., Nieto-Castanon, A., LaViolette, P., Wojcik, J., Gabrieli, J. D., Sidman, L. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hyperactivity+and+hyperconnectivity+of+the+default+network+in+schizophrenia+and+in+first-degreerelatives+of+persons+with+schizophrenia%5BTitle%5D)+AND+%22Proc.+Nat.+Acad.+Sciences%22%5BJournal%5D)">Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degreerelatives of persons with schizophrenia.</a> Proc. Nat. Acad. Sciences. 106 (4), 1279-1284 (2009).</li>
<li>Pomarol-Clotet, E., Salvardor, R., Sarro, S., Gomar, J., Vila, F., Martinez, A., Guerrrero, A., Ortiz-Gil, J., Sans-Sansa, B., Capdevila, A., Cebamanos, J. M., McKenna, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Failure+to+deactivate+the+prefrontal+cortex+in+schizophrenia%3A+dysfunction+of+the+default+mode+network%3F%5BTitle%5D)+AND+%22Psychol+Med%22%5BJournal%5D)">Failure to deactivate the prefrontal cortex in schizophrenia: dysfunction of the default mode network?</a> Psychol Med. 38 (8), 1185-1193 (2008).</li>
<li>Garrity, A. G., Pearlson, G. D., McKiernan, K., Lloyd, D., Kiehl, K. A., Calhoun, V. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Aberrant+%22default+mode%22+functional+connectivity+in+schizophrenia%5BTitle%5D)+AND+%22American+Journal+of+Psychiatry%22%5BJournal%5D)">Aberrant "default mode" functional connectivity in schizophrenia.</a> American Journal of Psychiatry. 164, 450-457 (2007).</li>
<li>Kennedy, D. P., Redcay, E., Courchesne, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Failing+to+deactivate%3A+Resting+functional+abnormalities+in+autism%5BTitle%5D)+AND+%22Proc.+Nat.+Acad.+Sciences%22%5BJournal%5D)">Failing to deactivate: Resting functional abnormalities in autism.</a> Proc. Nat. Acad. Sciences. 103 (21), 8275-8280 (2007).</li>
<li>c Buckner, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G., Sachs, R., Fotenos, A. F., Sheline, Y. I., Klunk, W. E., Mathis, C. A., Morris, J. C., Mintun, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Molecular%2C+structural%2C+and+functional+characterizations+of+Alzheimer%27s+disease%3A+evidence+for+a+relationship+between+default+activity%2C+amyloid%2C+and+memory%5BTitle%5D)+AND+%22Journal+of+Neuroscience%22%5BJournal%5D)">Molecular, structural, and functional characterizations of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.</a> Journal of Neuroscience. 34, 7709-7717 (2005).</li>
<li><a target="_blank" href="http://scholar.google.com/scholar?hl=en&safe=off&q=%22Handbook+of+Transcranial+Magnetic+Stimulation%22">Handbook of Transcranial Magnetic Stimulation</a>. Pascual-Leone, A., Davey, M., Wassermann, E. M., Rothwell, J., Puri, B. , Edward Arnold. London. (2002).</li>
</ol>

No conflicts of interest declared.

When conducting an offline TMS/MRI experiment, arguably the most important consideration involves the swift and effortless transition from the site of stimulation to the MRI bay. As such, it would be worth revisiting several of the aforementioned ideas suggested to aid in this transition. First: use a portable TMS machine set up in a location as close to the MRI bay as possible. Two: circumvent any automatic stand-by or equivalent mechanism programmed into the MRI equipment. Three: ensure the platform is raised an...

<table><tbody><tr><td>MRI Equipped for fMRI (pictured in video is a Philips)</td><td></td><td></td><td></td></tr><tr><td>TMS Device Capable of Repetitive Stimulation (pictured in video is a Magstim)</td><td></td><td></td><td></td></tr><tr><td>Frameless Stereotaxy Equipment (pictured in video is Brainsight)</td><td></td><td></td><td></td></tr><tr><td>Ear Plugs</td><td></td><td></td><td></td></tr><tr><td>Chair for Subject during Stimulation</td><td></td><td></td><td></td></tr><tr><td>Back Projection Screen or MRI Compatible Goggles</td><td></td><td></td><td></td></tr><tr><td>Blank Stimuli Screen</td><td></td><td></td><td></td></tr></tbody></table>

combining transcranial magnetic stimulation and fmri to examine the default mode network

Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest."1,2,3 It is thought the default mode network corresponds to self-referential or "internal mentation".2,3
It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia 4,5,6 and autism spectrum disorders 7 whilst hypo-activation of the network has been linked to Alzheimer's and other neurodegenerative diseases 8). As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses.9
In order to explore the default mode network's propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools.

In this article, we examine the methodology and considerations relevant to the combination of TMS and fMRI to examine the effects of brain stimulation on the default network.

The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful ...

The overall goal of this procedure is to alter cortical excitability using repetitive trans cranial magnetic stimulation, and then examine these effects on default network brain activation using functional MRI. This is accomplished by first obtaining a baseline anatomical scan of your subject that can be used for targeting a cortical stimulation site. The second step of the procedure is to acquire several runs of resting state FMRI prior to stimulation.The third step of the procedure is to apply TMS to the selected cortical target using stimulation parameters chosen for their modulatory effects. The final step of the procedure is to again, acquire several runs of functional imaging. Ultimately, results can be obtained that show TMS induced changes in default network activation through blood oxygenated level dependent imaging analysis.The main advantage of this technique over FMRI alone is that with TMS, we can modulate one area to observe network dynamics. This method can help to answer key questions in the field of cognitive neuroscience. Not only can it better elucidate interactions within a given resting network such as the default network, it can also help us to better understand the interactions between the default network and other resting state networks.Several days prior to the actual TMS and functional imaging experiments. Have your subject come to the scanner for a baseline anatomical scan that will be used for neuro navigation during the TMS procedure. Begin by having your subject complete.All necessary paperwork, including a research consent form and any other study documents. Include a standard MRI screening form and review this to assure that there are no counter indications for MRI, such as stents or aneurysm clips. Also, take this opportunity to pre-screen the subject for TMS and explain the details of the experiment.Next, bring your subject over to the scanner and set him or her up on the scanner bed. A T one weighted 3D SPGR MP rage or similar scan should be acquired with a field of view to include the entire head, including the ears, nose, and scalp. A slice thickness of about one millimeter is recommended.Load this scan into your frameless stereotactic software package that will be used for neuro navigation during the TMS procedure and use this software to locate and target your stimulation coordinates. For this experiment, we'll be targeting the left inferior parietal lole seen here on the day of the experiment. Keep in mind that the neuromodulatory effects of RTMS are transitory and that timers of the essence when conducting combined TMS and FMRI experiments.Therefore, the following steps should be taken to assure timely transition between experimental steps. First, position a portable TMS device in a room adjacent or as close to the scanning bay as possible. In this experiment, the system is set up in the observation suite next door to the scanner.Be sure however, that all non MRI compatible equipment remains outside the five line at all times. Second, assure that the subjects previously acquired and pre targeted anatomical MRI is loaded into the stereotactic software package and ready for use during the TMS procedure. Finally, attach the stereo taxi equipment to the stimulating coil and calibrate the coil with your chosen software package.Here a set of infrared sensors are aligned to register coil centrality. Once the experimental setup is complete, prepare the subject for MRI scanning rescreen for MRI safety and have your subject remove all metal and ensure that he or she has used the restroom. Bring your subject into the scanner room and comfortably position him or her on the scanner bed, providing back and neck support as needed to assure comfort.During the scans, plug in your head coil and use foam padding around the subject's head to reduce head motion artifact. Acquire your LOCALIZER scans and an initial and anatomical scan. Next, conduct three six minute functional experimental runs.We suggest the following parameters, echo planar imaging with 2.5 a second TR three millimeter voxel size, and a whole brain field of view view. During each run, a fixation point is presented in the subject central field of vision, and the subject is instructed to relax and stare at it passively. A simple fixation task such as this is appropriate for examining default network activation.Once the initial functional scanning session is complete, help your subject out of the scanner and have him or her sit comfortably. A chair adjacent to the TMS setup. Provide earplugs for hearing protection during the stimulation.Next, introduce your subject to the TMS machine and stimulation coil. Discharge a few pulses near the subject's head so that he or she is familiar with the loud clicking noise and discharge a pulse over the hand so that he or she can feel the tapping sensation it creates. Now you're ready to calibrate your subject's head with the stereo taxi equipment.First place an infrared tracker on the subject's head here. Infrared sensors are used to register several anatomical landmarks, including both ears, the nose, and the nasion. These landmarks are recorded by the stereotactic software package so that the previously acquired anatomical scan is coregistered to the subject's head.Next, determine your subject's resting motor threshold. For this protocol, use single pulses over primary motor cortex as seen here, move the coil around and adjust stimulation intensity until you find the area that elicits four out of eight muscle twitches in the contralateral hand. Finally, set the TMS machine intensity and parameters to those that will be used during stimulation.For this experiment, 20 hertz stimulation at 110%motor threshold is used with a stimulation pattern of two second trains and 28 second rest periods, which has been shown to increase cortical excitability. In future experiments, one hertz stimulation can be used to explore inhibitory effects. We are now ready to begin the TMS portion of the experiment, so again, assure that the subject is comfortable and prepared to go directly back into the scanner.Following the TMS session. Prior to stimulation, hold the coil tangential to the scalp and use the stereo ataxia equipment and software display to locate and target the subject's previously determined cortical stimulation site turn on the machine's cooling system. Now holding the coil in over the cortical target, begin stimulation.Conducting 45 stimulation trains with the previously defined parameters at two seconds per train. With 28 second breaks, there should be a total stimulation time of 23 minutes immediately after TMS assure that the subject is brought back to the scanner bed as quickly as possible, and begin with the final functional imaging session to assure transient offline TMS effects are reduce the number and length of localizer scans to a bare minimum so that the functional runs can be initialized. Quickly use the same imaging parameters as the initial scans being three six minute runs of passive fixation using the same fixation paradigm.Once all functional imaging is complete, obtain a final high resolution anatomical scan with the same imaging parameters as used in previously obtained sessions. And finally, help your subject out of the scanner. Be sure to transfer and archive all imaging data and to thank your subject for participating.Once data is acquired for at least 15 subjects, use the FMRI processing package of your choice for imaging post-processing and subsequent multi-subject analysis representative results for 20 hertz stimulation to the left inferior parietal lole are shown here. Although 20 hertz TMS stimulation facilitates local excitability data shows, it decreases functional connectivity within the default network. When attempting this procedure, it is important to remember to transfer the subject as quickly as possible following the stimulation into the scanner so that the transient effects of RTMS can be imaged.We can also alter the TMS stimulation parameters. For example, we can increase the intensity of the TMS machine to assess whether the effect on the default network is parametric. We can also try using theta birth stimulation.Finally, we can see the effects of TMS by doing different kinds of MRI designs after TMS, such as block designs or event related designs. During a cognitive task.

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Research

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Source: Lioumis, P. et al. Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex. J. Vis. Exp. (2018)This video demonstrates a protocol for combining transcranial magnetic stimulation and electroencephalography to assess cortical excitability and the balance between excitation and inhibition in the dorsolateral prefrontal cortex.

Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

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Learn to combine transcranial magnetic stimulation and fMRI for examining the default mode network. This method enables researchers to modulate cortical excitability and observe resulting changes in brain activation patterns.

Combining Transcranial Magnetic Stimulation and fMRI to Examine the Default Mode Network

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