This work is supported by the following sources of funding: MAN: NIH 2R01 DC05672-04A2 RHH : NIH/NINDS 1K01NS060995-01A1 RHH: Robert Wood Johnson Foundation/ Harold Amos Medical Faculty Development Program

1. Pre-Treatment Evaluation
<ol>
	<li>Recruit patients who meet the eligibility requirements for the study. These criteria include a single, unilateral, left hemisphere ischemic stroke that spares the supplementary motor area (SMA), mild to moderate non-fluent speech (defined as the ability to produce meaningful words and at least a 2-4 word length string), between the ages of 18 and 75 and at least six months post-stroke.</li>
	<li>Additionally, all potential patients must be able to name at least three of the first 30 items on the Boston Naming Test15, an average of at least three pictures out of 20 when presented with ten sets of picture-naming stimuli taken from the Snodgrass and Vanderwart corpus16, and score at or above the 25th percentile on the subtests for word comprehension and commands on the Boston Diagnostic Aphasic Examination17.</li>
	<li>Conduct a medical screening examination to ensure patients are healthy enough to participate in the study, and that there are no contraindications to undergoing a Magnetic Resonance Imaging (MRI) scan or TMS.</li>
</ol>
2. Baseline Testing
<ol>
	<li>Administer a battery of standardized tests on three separate days to assess the extent of each patient's language impairment and deficits in other cognitive domains. The tests include the Cookie Theft picture description subtest of the BDAE18, BDAE (2nd Ed.) Subtests for Word Comprehension (Basic Word Discrimination) and Commands, Boston Naming Test15, sets of 40 line drawing stimuli taken from the Snodgrass and Vanderwart picture database16, and the Cognitive Linguistic Quick Test19 (CLQT).</li>
	<li>Initiate a baseline BOLD-fMRI study in which the patient performs a picture-naming task with oral response. Collect high resolution whole-brain T1-weighted images with a MPRAGE sequence (RT = 1,620 msec, TE = 3.87 msec, FA = 15, FOV = 192 x 256, slices = 160, voxel sizes = 1 mm3). Acquire functional volumes using a whole-brain T2*-weighted BOLD echoplanar sequence (TR = 3,000 sec, TE = 35 msec, FA = 90, FOV = 128 x 128, slices = 31, voxel sizes = 1.875 mm2, slice thickness = 4 mm).</li>
	<li>Randomize patients into either a group receiving real repetitive TMS (rTMS) or a group receiving initial sham stimulation (sTMS), followed by rTMS (Figure 1).</li>
</ol>
3. Identification of Optimal Sites of Stimulation
<ol>
	<li>In order to target rTMS to cortical sites in a precise and accurate manner, use a neuronavigational system (e.g. Brainsight, Rogue Research, Montreal) to co-register high-resolution whole-brain T1-weighted images (see 2.2 above) with the location of the patient and coil. For the rTMS group, determine resting motor threshold (RMT) via stimulation to right motor cortex and subsequent visual inspection20.</li>
	<li>During real rTMS, orient the coil with the handle in a posterior and inferior direction approximately 45&deg; clockwise from the downward position. For the sham group, administer sTMS with the coil perpendicular to the head so that only the outer rim of the lateral wing of the coil contacts the head. In this orientation, the peak magnetic field runs parallel to the skull and thus does not produce cortical stimulation.</li>
	<li>In six separate sessions conducted over five days (two sessions conducted on final day, with a 45-minute break in between sessions), administer ten minutes of either rTMS (600 pulses of 1 Hz at an intensity of 90% RMT) or sTMS to different sites in the right inferior frontal lobe: the primary motor cortex (M1) corresponding to the mouth, pars opercularis (BA 44), anterior pars triangularis (BA 45), dorsal posterior pars triangularis (BA 45), ventral posterior pars triangularis (BA 45), and pars orbitalis (BA 47; Figure 2). Randomize stimulation site order between patients.</li>
	<li>Have patients perform a 40-item picture-naming task immediately before and after each TMS session. Picture stimuli are taken from the Snodgrass and Vanderwart16 item set, the Peabody Picture Vocabulary Test21, and the International Picture Naming Project (IPNP) database22. The 40-item lists must be matched with respect to word length, frequency, and semantic category; in our item lists 20 items were novel while 20 were repeated throughout the testing sessions to assess for practice effects. Utterances should be counted as correct if they differ from the target by no more than one phoneme8. Word list order should be randomized across subjects and each subject should receive different word lists at every visit.</li>
	<li>Determine the optimal site of stimulation by performing one-sample t-tests comparing the change in picture-naming performance at each site to the mean change in naming performance for all other sites. Next, compare the change in performance at the optimal site to the variance of performance across all six pre-rTMS sessions; if the change in performance after rTMS is greater than two times the standard deviation of mean pre-TMS performance, it is unlikely that the benefit in naming performance is attributable to test-retest variability9.</li>
	<li>For sham site-finding, administer sTMS over the pars triangularis. This location acts as the "optimal site" for the sham arm of the treatment phase, as described in Protocol section 4.</li>
</ol>
4. Treatment Phase
<ol>
	<li>Administer rTMS or sTMS to the optimal stimulation site for ten days in a twelve-day period (stimulation on every weekday with weekends off).</li>
	<li>On the first day of stimulation, the order of events is as follows: have the patient undergo an fMRI (with concurrent picture-naming, as in baseline), administer the 40-item naming task, stimulate the optimal site using 20 min of either 1 Hz rTMS at 90% RMT or sTMS, administer the naming task again, and finally have the patient undergo a second fMRI with concurrent picture-naming.</li>
	<li>On days two through nine, the protocol consists of a 20-minute rTMS session (1,200 pulses), using 1 Hz rTMS at 90% RMT or sTMS.</li>
	<li>On day ten, stimulate the optimal site for 20 min with 1 Hz rTMS, preceded and followed by the picture-naming task. Of note, picture item lists shown on days one and ten should be different, but matched for frequency, word length, and semantic category as noted above.</li>
</ol>
5. Two- and Six-month Follow-up Visits
<ol>
	<li>Two months following day ten of either rTMS or sTMS, repeat baseline testing (step 2.1), as well as fMRI with concurrent picture-naming.</li>
	<li>Patients in the sham condition should then cross over to real TMS condition, beginning with the optimal site-finding phase (Figure 1).</li>
	<li>Six months following day ten of real rTMS stimulation, repeat baseline testing (as in step 2.1), and also have patients undergo another fMRI with a concurrent picture-naming task.</li>
</ol>

<ol>
	<li>Hamilton, R. H., Chrysikou, E. G., Coslett, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+of+aphasia+recovery+after+stroke+and+the+role+of+noninvasive+brain+stimulation.">Mechanisms of aphasia recovery after stroke and the role of noninvasive brain stimulation.</a> Brain Lang. 118, 40-50 (2011).</li><li>Wade, D. T., Hewer, R. L., David, R. M., Enderby, P. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Aphasia+after+stroke:+natural+history+and+associated+deficits.">Aphasia after stroke: natural history and associated deficits.</a> J. Neurol. Neurosurg. Psychiatry. 49, 11-16 (1986).</li><li>Maeda, F., Pascual-Leone, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+magnetic+stimulation:+studying+motor+neurophysiology+of+psychiatric+disorders.">Transcranial magnetic stimulation: studying motor neurophysiology of psychiatric disorders.</a> Psychopharmacology (Berl). 168, 359-376 (2003).</li><li>Elkin-Frankston, S., Fried, P. J., Pascual-Leone, A., Rushmore, R. J., Valero-Cabr, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+approach+for+documenting+phosphenes+induced+by+transcranial+magnetic+stimulation.">A novel approach for documenting phosphenes induced by transcranial magnetic stimulation.</a> J. Vis. Exp. (38), e1762 (2010).</li><li>Najib, U., Horvath, J. C., Silvanto, J., Pascual-Leone, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=State-dependency+effects+on+TMS:+a+look+at+motive+phosphene+behavior.">State-dependency effects on TMS: a look at motive phosphene behavior.</a> J. Vis. Exp. (46), e2273 (2010).</li><li>Horvath, J. C., Mathews, J., Demitrack, M. A., Pascual-Leone, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+NeuroStar+TMS+device:+conducting+the+FDA+approved+protocol+for+treatment+of+depression.">The NeuroStar TMS device: conducting the FDA approved protocol for treatment of depression.</a> J. Vis. Exp. (45), e2345 (2010).</li><li>Martin, P. I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transcranial+magnetic+stimulation+as+a+complementary+treatment+for+aphasia.">Transcranial magnetic stimulation as a complementary treatment for aphasia.</a> Semin. Speech Lang. 25, 181-191 (2004).</li><li>Naeser, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+picture+naming+in+chronic+aphasia+after+TMS+to+part+of+right+Broca's+area:+an+open-protocol+study.">Improved picture naming in chronic aphasia after TMS to part of right Broca's area: an open-protocol study.</a> Brain and Language. 93, 95-105 (2005).</li><li>Hamilton, R. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stimulating+conversation:+enhancement+of+elicited+propositional+speech+in+a+patient+with+chronic+non-fluent+aphasia+following+transcranial+magnetic+stimulation.">Stimulating conversation: enhancement of elicited propositional speech in a patient with chronic non-fluent aphasia following transcranial magnetic stimulation.</a> Brain Lang. 113, 45-50 (2010).</li><li>Turkeltaub, P. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Minimizing+within-experiment+and+within-group+effects+in+activation+likelihood+estimation+meta-analyses.">Minimizing within-experiment and within-group effects in activation likelihood estimation meta-analyses.</a> Hum. Brain Mapp. , (2011).</li><li>Medina, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Finding+the+Right+Words:+Transcranial+Magnetic+Stimulation+Improves+Discourse+Productivity+in+Non-fluent+Aphasia+After+Stroke.">Finding the Right Words: Transcranial Magnetic Stimulation Improves Discourse Productivity in Non-fluent Aphasia After Stroke.</a> Aphasiology. , (2012).</li><li>Barwood, C. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+language+performance+subsequent+to+low-frequency+rTMS+in+patients+with+chronic+non-fluent+aphasia+post-stroke.">Improved language performance subsequent to low-frequency rTMS in patients with chronic non-fluent aphasia post-stroke.</a> Eur. J. Neurol. , (2010).</li><li>Weiduschat, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+Repetitive+Transcranial+Magnetic+Stimulation+in+Aphasic+Stroke:+A+Randomized+Controlled+Pilot+Study.">Effects of Repetitive Transcranial Magnetic Stimulation in Aphasic Stroke: A Randomized Controlled Pilot Study.</a> Stroke. , (2011).</li><li>Naeser, M. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=TMS+suppression+of+right+pars+triangularis,+but+not+pars+opercularis,+improves+naming+in+aphasia.">TMS suppression of right pars triangularis, but not pars opercularis, improves naming in aphasia.</a> Brain Lang. 119, 206-213 (2011).</li><li>Kaplan, E., Goodglass, H., Weintraub, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Boston Naming Test (BNT). , (2001).</li><li>Snodgrass, J. G., Vanderwart, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+standardized+set+of+260+pictures:+norms+for+name+agreement,+image+agreement,+familiarity,+and+visual+complexity.">A standardized set of 260 pictures: norms for name agreement, image agreement, familiarity, and visual complexity.</a> J. Exp. Psychol. Hum. Learn. 6, 174-215 (1980).</li><li>Goodglass, H., Kaplan, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The assessment of aphasia and related disorders. , (1972).</li><li>Goodglass, H., Kaplan, E., Barresi, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Boston Diagnostic Aphasia Examination (BDAE). , (1983).</li><li>Helm-Estabrooks, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Cognitive linguistic quick test (CLQT): Examiner's manual. , (2001).</li><li>Rossini, P. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Non-invasive+electrical+and+magnetic+stimulation+of+the+brain,+spinal+cord+and+roots:+basic+principles+and+procedures+for+routine+clinical+application.+Report+of+an+IFCN+committee.">Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee.</a> Electroencephalogr. Clin. Neurophysiol. 91, 79-92 (1994).</li><li>Dunn, L. M., Peabody Hottel, J. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=picture+vocabulary+test+performance+of+trainable+mentally+retarded+children.">picture vocabulary test performance of trainable mentally retarded children.</a> Am. J. Ment. Defic. 65, 448-452 (1961).</li><li>Szekely, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+on-line+resource+for+psycholinguistic+studies.">A new on-line resource for psycholinguistic studies.</a> J. Mem. Lang. 51, 247-250 (2004).</li><li>Martin, P. I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Research+with+transcranial+magnetic+stimulation+in+the+treatment+of+aphasia.">Research with transcranial magnetic stimulation in the treatment of aphasia.</a> Curr. Neurol. Neurosci. Rep. 9, 451-458 (2009).</li><li>Duffau, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+insights+into+the+anatomo-functional+connectivity+of+the+semantic+system:+a+study+using+cortico-subcortical+electrostimulations.">New insights into the anatomo-functional connectivity of the semantic system: a study using cortico-subcortical electrostimulations.</a> Brain. 128, 797-810 (2005).</li><li>Picht, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessing+the+functional+status+of+the+motor+system+in+brain+tumor+patients+using+transcranial+magnetic+stimulation.">Assessing the functional status of the motor system in brain tumor patients using transcranial magnetic stimulation.</a> Acta Neurochir. (Wien). , (2012).</li><li>Fertonani, A., Rosini, S., Cotelli, M., Rossini, P. M., Miniussi, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Naming+facilitation+induced+by+transcranial+direct+current+stimulation.">Naming facilitation induced by transcranial direct current stimulation.</a> Behav. Brain Res. 208, 311-318 (2010).</li><li>Schlaug, G., Marchina, S., Wan, C. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+use+of+non-invasive+brain+stimulation+techniques+to+facilitate+recovery+from+post-stroke+aphasia.">The use of non-invasive brain stimulation techniques to facilitate recovery from post-stroke aphasia.</a> Neuropsychol. Rev. 21, 288-301 (2011).</li></ol>

The authors declare that they have no competing financial interests.

The goal of this article is to detail the steps for identifying a responsive target site in the right hemisphere in patients with chronic non-fluent aphasia. By doing so, we are able to stimulate that target region therapeutically, assess the effects of stimulation on language ability, and use low-frequency rTMS to elicit long-term improvements in naming and fluency in patients with chronic non-fluent aphasia. Our approach replicates and extends methods used by prior investigators, most notably Naeser and colleagues...

Aphasia-an acquired deficit of language ability-is a common and often debilitating consequence of stroke2. Although some degree of recovery from aphasia after acute stroke is typical, many patients experience at least some degree of persistent deficits, and existing language therapies are generally considered to be only modestly effective in facilitating recovery3-5. Recent years have seen the emergence of noninvasive stimulation techniques such as transcranial magnetic stimulation (TMS) as promising potential treatment approaches for a variety of deficits after stroke, including aphasia. TMS employs the principle of electromagnetic induction and involves the generation of a rapidly fluxing magnetic field in a coil of wire. When the coil is placed adjacent to the head of a subject, the magnetic field penetrates the scalp and skull, inducing a current in underlying cortical neurons that is sufficient to depolarize neuronal membranes and generate action potentials3. TMS parameters such as frequency, intensity, and number of pulses can be varied in order elicit different neurophysiologic, behavioral, and perceptual effects4,5. Repetitive TMS (rTMS) entails the administration of a series of pulses at a predetermined frequency and produces effects that can outlast the application of the stimulation. Germane to the current experiment, evidence shows that rTMS delivered at a low frequency (0.5-2 Hz) tends to focally decrease cortical excitability, while high-frequency stimulation has been associated with cortical excitation3. rTMS has been explored as a treatment for various neurologic and psychiatric disorders, most notably depression6.
A growing body of evidence suggests that low frequency rTMS may be used to enhance language recovery in persons with chronic stroke-induced aphasia. Naeser and colleagues7,8 were the first to apply 1 Hz inhibitory rTMS to the right inferior frontal gyrus for 20 min five days a week for two weeks in four right-handed patients with chronic non-fluent aphasia. Significant improvements in naming were observed, which persisted for at least eight months following completion of stimulation8. We subsequently replicated and extended these results, and have demonstrated that 1 Hz stimulation resulted in persistent improvements in both naming and spontaneous elicited speech in chronic non-fluent aphasic patients9-11. Encouragingly, the results of small studies such as these have been replicated in further investigations in patients with chronic stroke12, as well as in patients with subacute stroke and aphasia13.
One important and nearly ubiquitous feature of prior TMS studies in patients with non-fluent aphasia is that the salutary effects of stimulation appear to be site-specific. Adopting the approach initially employed by Naeser and colleagues, most investigations in which rTMS has been used to facilitate language recovery have targeted the right pars triangularis1 (Brodmann area 45). In fact, recent evidence has suggested that stimulation of other regions of the right inferior frontal gyrus may be ineffective, or may even have deleterious effects on language performance14, underscoring the need for careful individual identification of optimal stimulation sites.
Building upon the approach established by Naeser and colleagues8, our ongoing investigation explores the effects of inhibitory rTMS in the inferior frontal gyrus on language ability, and also examines the topographic specificity of rTMS effects in the right frontal lobe. In this article, we provide a detailed description of how an optimal site for stimulation can be identified in patients with chronic non-fluent aphasia. We then describe the administration of therapeutic rTMS and explain our techniques for assessing the efficacy of stimulation in enhancing language recovery in this population.

<table border="1">
 <tbody>
 <tr>
 <td>Name of Reagent/Material</td>
 <td>Company</td>
 <td>Catalog Number</td>
 <td>Comments</td>
 </tr>
 <tr>
 <td>Rapid transcranial magnetic stimulator</td>
 <td>Magstim</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>3.0 Trio Scanner</td>
 <td>Siemens</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>8 channel head coil</td>
 <td>Siemens</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>Brainsight neuronavigational system</td>
 <td>Rogue Research</td>
 <td></td>
 <td></td>
 </tr>
 </tbody>
</table>

utilizing repetitive transcranial magnetic stimulation to improve language function in stroke patients with chronic non-fluent aphasia

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six-month post-stimulation language testing.

In the site-finding phase of this investigation, most but not all patients respond optimally on the picture-naming task to stimulation of the right pars triangularis14. In our experience, patients' performance on picture naming is most consistently facilitated by stimulation of the ventral posterior aspect of the pars triangularis (Figure 3).
Long-term improvement in performance on standardized language assessments is illustrated in Figure 4. This ...

Watch this Scientific Journal Video about Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia at JoVE.com

Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia

We explore the use of repetitive transcranial magnetic stimulation (rTMS) to improve language abilities in patients with chronic stroke and non-fluent aphasia. After identifying a site in the right frontal gyrus for each patient that responds optimally to stimulation, we target this site during ten days of rTMS treatment.

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this ...

utilizing-repetitive-transcranial-magnetic-stimulation-to-improve

Research

JoVE Journal

Medicine

17.6K Views.  University of Pennsylvania. We explore the use of repetitive transcranial magnetic stimulation (rTMS) to improve language abilities in patients with chronic stroke and non-fluent aphasia. After identifying a site in the right frontal gyrus for each patient that responds optimally to stimulation, we target this site during ten days of rTMS treatment.

Video: Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia

Utilizing Transcranial Magnetic Stimulation to Study the Human Neuromuscular System

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade. While the use of TMS has expanded to the study of many systems and processes during this time, the original application and perhaps one of the most common uses of TMS involves studying the physiology, plasticity and function of the human neuromuscular system. Single pulse TMS applied to the motor cortex excites pyramidal neurons transsynaptically 2 (Figure 1) and results in a measurable electromyographic response that can be used to study and evaluate the integrity and excitability of the corticospinal tract in humans 3. Additionally, recent advances in magnetic stimulation now allows for partitioning of cortical versus spinal excitability 4,5. For example, paired-pulse TMS can be used to assess intracortical facilitatory and inhibitory properties by combining a conditioning stimulus and a test stimulus at different interstimulus intervals 3,4,6-8. In this video article we will demonstrate the methodological and technical aspects of these techniques. Specifically, we will demonstrate single-pulse and paired-pulse TMS techniques as applied to the flexor carpi radialis (FCR) muscle as well as the erector spinae (ES) musculature. Our laboratory studies the FCR muscle as it is of interest to our research on the effects of wrist-hand cast immobilization on reduced muscle performance6,9, and we study the ES muscles due to these muscles clinical relevance as it relates to low back pain8. With this stated, we should note that TMS has been used to study many muscles of the hand, arm and legs, and should iterate that our demonstrations in the FCR and ES muscle groups are only selected examples of TMS being used to study the human neuromuscular system.

Transcranial magnetic stimulation (TMS) is a non-invasive tool to gain insight on the physiology and function of the human nervous system. Here, we present our TMS techniques to study cortical excitability of the upper limb and lumbar musculature.

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade.  While ...

Assessment of Vascular Function in Patients With Chronic Kidney Disease

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.

The degree of vascular dysfunction and contributing physiological mechanisms can be assessed in patients with chronic kidney disease by measuring brachial artery flow-mediated dilation, aortic pulse-wave velocity, and vascular endothelial cell protein expression.

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Home-Based Transcranial Direct Current Stimulation Device Development: An Updated Protocol Used at Home in Healthy Subjects and Fibromyalgia Patients

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the cerebral cortex by a low-intensity direct current. tDCS is a low-cost technique with minimal adverse effects and easy application. This neurostimulation method has a promising future to improve pain therapy, treatment of neuropsychiatric disorders, and physical rehabilitation.
Current studies demonstrate the benefits of using tDCS over consecutive multiple sessions. However, the daily displacement to the specialized centers, travel costs, and disruptions to daily activities are some of the difficulties faced by patients. Thus, to be more comfortable, easy-to-use, and not disrupt daily commitments, a home-based tDCS was designed. Therefore, the objective of this study was to evaluate the feasibility of a portable tDCS device for home use in healthy subjects and fibromyalgia patients.
Despite increased tDCS use and a reasonably large body of research on the effects across a range of clinical conditions, there is a limited amount of research on developing secure devices that guarantee the dose and contain a block system to avoid excessive use. Therefore, we used a tDCS device with a security system to permit daily use for 20 minutes with a minimal interval of 12 hours between sessions. A programmer preconfigures the equipment, which has a neoprene cap that allows the electrode positions in any assembly, according to individualized protocols for treatments or research. After, researchers can assess the effectiveness of treatment, and its adherence using information kept in the device software.
Results suggest that the device is feasible for home use, with proper monitoring of adherence and contact impedance. There were reports of a few adverse effects, which do not differ from those reported in the literature in studies with the treatment under direct supervision.

This study provides an updated home-based tDCS protocol that enables subjects to receive the beneficial effects of tDCS at home with an easy to use device with settings to control the use and dosage, enhancing the feasibility for long-term use at home.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation (NIBS) method, which modulates the membrane potential of neurons in the ...

Updated Technique for Reliable, Easy, and Tolerated Transcranial Electrical Stimulation Including Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of brain stimulation presents several potential advantages compared to other techniques, as it is noninvasive, cost-effective, broadly deployable, and well-tolerated provided proper equipment and protocols are administered. Even though tDCS is apparently simple to perform, correct administration of the tDCS session, especially the electrode positioning and preparation, is vital for ensuring reproducibility and tolerability. The electrode positioning and preparation steps are traditionally also the most time consuming and error-prone. To address these challenges, modern tDCS techniques, using fixed-position headgear and pre-assembled sponge electrodes, reduce complexity and setup time while also ensuring that the electrodes are consistently placed as intended. These modern tDCS methods present advantages for research, clinic, and remote-supervised (at home) settings. This article provides a comprehensive step-by-step guide for administering a tDCS session using fixed-position headgear and pre-assembled sponge electrodes. This guide demonstrates tDCS using commonly applied montages intended for motor cortex and dorsolateral prefrontal cortex (DLPFC) stimulation. As described, selection of the head size and montage-specific headgear automates electrode positioning. Fully assembled pre-saturated snap-electrodes are simply affixed to the set position snap-connectors on the headgear. The modern tDCS method is shown to reduce setup time and reduce errors for both novice and expert operators. The methods outlined in this article can be adapted to different applications of tDCS as well as other forms of transcranial electrical stimulation (tES) such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). However, since tES is application specific, as appropriate, any methods recipe is customized to accommodate subject, indication, environment, and outcome specific features.

When administering transcranial direct current stimulation (tDCS), reproducible electrode preparation and placement are vital for a tolerated and effective session. The purpose of this article is to demonstrate updated modern setup procedures for the administration of tDCS and related transcranial electrical stimulation techniques, such as transcranial alternating current stimulation (tACS).

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of ...

Estimating Bilateral Atrial Function by Cardiovascular Magnetic Resonance Feature Tracking in Patients with Paroxysmal Atrial Fibrillation

Atrial fibrillation (AF) is the most common form of arrhythmia. Atrial remodeling is considered the most critical mechanism for the presence and development of atrial fibrillation. Also, atrial remodeling can lead to the enlargement and dysfunction of the left atrium (LA), resulting in thrombosis and heart failure. Functional changes in left atrial strain and strain rate occur before structural alterations and are closely associated with structural remodeling and left atrial fibrosis. These parameters are sensitive biomarkers for atrial function. Cardiac magnetic resonance feature tracking (CMR-FT) is a novel, non-invasive, post-processing technique that can evaluate left atrial strain and strain rate. The CMR-FT was utilized in this investigation to assess the bilateral atrium strain rate in individuals with paroxysmal AF. Modifications in each segmental strain were evaluated using segmental analysis. The CMR-FT is recommended for non-invasive evaluations in the clinical assessment of atrial strain among existing strain imaging techniques. Further, it is a flexible parameter measurement with good reproducibility, high soft-tissue resolution, and post-processing based on standard cine balanced steady-state free precision (bSSFP) long-axis images without requiring a new sequence acquisition.

The atrial function is associated with the strain and strain rate. The cardiac magnetic resonance feature tracking (CMR-FT) technique was used in this study to quantify left and right atrial global and segmental longitudinal strain and strain rate in individuals with paroxysmal atrial fibrillation.

Atrial fibrillation (AF) is the most common form of arrhythmia. Atrial remodeling is considered the most critical mechanism for the presence and ...

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

Navigated repetitive transcranial magnetic stimulation is a highly efficient non-invasive tool for mapping speech-related cortical areas. It helps in designing brain surgery and speeds up the direct cortical stimulation conducted during the surgery. This report describes how to perform speech cortical mapping reliably for preoperative evaluation and research.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional ...

Acupuncture Stimulation of Ears to Alleviate Sleeping Disorders in COPD Patients

Auricular Acupuncture as a Traditional Chinese Medicine Therapy for Chronic Obstructive Pulmonary Disease Combined with Sleep Disorders

Chronic obstructive pulmonary disease (COPD) is a clinical syndrome characterized by persistent and irreversible airflow limitation and chronic respiratory symptoms. It has a wide spectrum of complications, and sleep disorders, as part of it, are common in severe cases, especially in elderly patients. Long-term lack of sleep may lead to the aggravation of the original disease, reducing patients' quality of life. Benzodiazepines are mainly used for symptomatic treatment of COPD combined with sleep disorders. However, such drugs have the side effect of respiratory central inhibition and could probably aggravate hypoxia symptoms. Auricular acupuncture is a special method of treating physical and psychosomatic dysfunctions by stimulating specific points in the ear. This article explains the specific methods of clinical operation of auricular acupuncture in detail, including assessment of patient eligibility, medical devices used, acupuncture points, course of treatment, post-treatment care, responses to emergencies, etc. The Pittsburgh sleep quality index (PSQI) and chronic obstructive pulmonary disease assessment scale (CAT) were used as the observational index of this method. So far, clinical reports have proved that auricular acupuncture has a definite curative effect in the treatment of COPD combined with sleep disorders, and its advantages of simple operation, few adverse reactions are worthy of further study and promotion, which provide a reference for the clinical treatment of such diseases.

Author Spotlight: Utilizing Traditional Chinese Acupuncture of the Ear to Improve Sleep Disorders 

This protocol introduces an effective method to improve the sleep condition of patients with chronic obstructive pulmonary disease and alleviate cough symptoms by using auricular acupuncture techniques to percutaneously stimulate specific acupoints in the patients' ears.

Chronic obstructive pulmonary disease (COPD) is a clinical syndrome characterized by persistent and irreversible airflow limitation and chronic ...

Enhancing Stroke Rehabilitation with Virtual Reality-Based Occupational Training

Cognitive Function and Upper Limb Rehabilitation Training Post-Stroke Using a Digital Occupational Training System

Stroke rehabilitation often requires frequent and intensive therapy to improve functional recovery. Virtual reality (VR) technology has shown the potential to meet these demands by providing engaging and motivating therapy options. The digital occupational training system is a VR application that utilizes cutting-edge technologies, including multi-touch screens, virtual reality, and human-computer interaction, to offer diverse training techniques for advanced cognitive capacity and hand-eye coordination abilities. The objective of this study was to assess the effectiveness of this program in enhancing cognitive function and upper extremity rehabilitation in stroke patients. The training and assessment consist of five cognitive modules covering perception, attention, memory, logical reasoning, and calculation, along with hand-eye coordination training. This research indicates that after eight weeks of training, the digital occupational training system can significantly improve cognitive function, daily living skills, attention, and self-care abilities in stroke patients. This software can be employed as a time-saving and clinically effective rehabilitation aid to complement traditional one-on-one occupational therapy sessions. In summary, the digital occupational training system shows promise and offers potential financial benefits as a tool to support the functional recovery of stroke patients.

Author Spotlight: Rehabilitation of Stroke Patients With a Digital Occupational Training System

The current protocol outlines how the VR-based digital occupational training system enhances the rehabilitation of patients with cognitive impairment and upper limb dysfunction following a stroke.