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 3...

<ol>
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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 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 ...

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17.6K visualizações.  University of Pennsylvania. Nós exploramos o uso da estimulação magnética transcraniana repetitiva (EMTr) para melhorar as habilidades de linguagem em pacientes com acidente vascular cerebral crônica e não-fluente afasia. Após a identificação de um site no giro frontal direito para cada paciente que responde perfeitamente ao estímulo, temos por meta neste site durante 10 dias de tratamento com EMTr.