Department of Veterans Affairs Merit Review Grant

Project Title: Neural Networks and Language Recovery in Aphasia from Stroke: fMRI studies

PURPOSE: The purpose of this 4-year fMRI research is to study brain reorganization for language in patients with left hemisphere (LH) stroke who have chronic nonfluent aphasia. This fMRI research is fundamental and critical to the PI's NIH RO1 grant, Transcranial Magnetic Stimulation (TMS) to Improve Speech in nonfluent aphasia, which was recently renewed for 5 years, 2006-11. There is no overlap in the studies. The NIH grant provides the TMS (real and sham) and only one type of fMRI (overt picture naming, pre- and post-, real or sham TMS). This VA grant provides 3 different fMRI tasks - Overt Propositional Speech fMRI; and Nonverbal Semantic Decision tasks for Nouns, and for Actions.

We have observed that application of TMS to a portion of right (R) Broca's homologue (posterior, R pars triangularis, PTr), results in significantly improved picture naming ability at 2 and 8 Mo. after the last (10th) TMS treatment, in aphasia patients who began TMS at 5-11 years poststroke. Also, half of these nonfluent aphasia patients improved their Phrase Length in propositional speech, post-TMS.

RATIONALE: We and others have observed that patients with chronic, nonfluent aphasia (poor, hesitant speech) have overactivation of R hemisphere (RH) cortical language homologues. We hypothesize this represents a maladaptive plasticity and probably poor active inhibition during speech. Slow, 1 Hz TMS can be used to suppress cortical excitability. Our goal is to use 1 Hz TMS to inhibit/suppress the overactivation in RH language homologues. Our early TMS research has shown that suppression of R PTr in these patients is associated with improved speech. The fMRI studies proposed in this VA grant will help to investigate the neurophysiological changes underlying improvement post-TMS in propositional speech and in nonverbal semantic decision tasks. The new MRI technique, diffusion tensor imaging (DTI) will be used to study WM pathways subjacent to cortex treated with TMS.

DESIGN: Randomized, sham-control, incomplete crossover design with 32 patients (16 mild-moderate; 16 severe nonfluent), half receive real TMS series only; half, sham TMS 1st, and real 2nd. Language, Neuropsych. testing, and fMRIs are performed at Entry, and at 2 Mo. post-10 real or sham TMS treatments; and at 6 Mo. post real. There are 4 Projects: 1) fMRI during overt propositional speech (Overt Picture Descriptions/Story Telling; 2) fMRI during a Nonverbal Semantic Decision Task with Superordinate Noun Icons; 3) fMRI during a Nonverbal Semantic Decision Task with Action and Object Icons; 4) DTI. DTI is performed only at Entry (all subjects). Normal controls (n=8) do not receive TMS; they are studied with fMRI at Entry, at 2 and 6 Mo. later.

HYPOTHESES: Following the real TMS to suppress R PTr, there will be less overactivation on fMRI (better modulation) in RH language homologues, and new LH activation (including L perilesional areas and L SMA). This will be associated with improved propositional speech (BDAE) and nonverbal semantic decision ability at 2 and 6 Mo. post-real TMS. No language or fMRI changes are expected post-sham TMS. The fMRIs performed 3x with the normal controls are not expected to show change, but will document the neural networks for the fMRI tasks.

Project Start: This research is a continuation of Dr. Naeser's VA Merit Review research grant on neuroimaging in aphasia, which has been ongoing since the 1970's. The current VA grant is expected to begin funding in January, 2007.

NIH, National Institute on Deafness and Other Communication Disorders Grant.

Grant Number: R01DC005672

Project Title: Transcranial Magnetic Stimulation to Improve Speech

This project is a continuation of our previous research that investigates whether repetitive transcranial magnetic stimulation (rTMS) can be used to improve speech in chronic nonfluent aphasia. Functional MRI studies in these patients have shown "over-activation" in right (R) perisylvian language homologues; possibly representing a maladaptive plasticity. Our hypothesis is that suppression of this over-activation with TMS may improve speech. Significant improvement in picture naming was observed immediately following rTMS for 10 minutes to suppress R posterior pars triangularis (R BA 45), with decreased reaction time (RT). Application of 1-Hz rTMS to suppress 3 other R ROIs produced no improvement.

In a later phase of the study, we applied 1-Hz rTMS to R BA 45 for 20 minutes daily, 10 days. Significant improvement in picture naming was observed at 2 months post-TMS; and at 8 months post-TMS, despite no individualized speech therapy. Pilot studies with sham rTMS have shown no effect.

This research uses a blinded, sham-controlled, incomplete crossover design (20 mild-moderate nonfluent patients; 20 severe nonfluent patients) with fMRI to study mechanisms of action of TMS. To insure recruitment of an adequate number of patients, there is a second site - the University of Pennsylvania, Department of Neurology, H. Branch Coslett, M.D. co-investigator. Half of the patients will be studied in Philadelphia.

We have developed an overt naming fMRI BOLD paradigm for use with nonfluent patients. Pilot data indicate that pre-rTMS, there is over-activation in R frontal areas (including R inferior frontal gyrus, R BA 45; and motor cortex-mouth), with little activation in temporal lobe, and there is poor naming performance. Post-rTMS where 1-Hz rTMS was applied to R BA 45 for 20 min. daily, 10 days, improved naming was associated with less over-activation in R BA 45 and M1-mouth, with new temporal lobe activation. See Figure 1 below.

Overt naming fMRI is obtained pre-real/sham rTMS, and at 2 months post-real/sham rTMS. Those receiving sham rTMS are then crossed-over to real-rTMS. We hypothesize that patients who receive real rTMS will have significant improvement in picture naming at 2 months post-real rTMS, versus those who receive sham rTMS. We further hypothesize that only the real rTMS group will show suppression of R BA 45 on fMRI following rTMS treatment.

Relevance to public health: The U.S. population is increasing in age; thus, an increase in stroke and need for sophisticated treatment. The number of people with aphasia in the U.S. today is estimated to be 1 million; 80,000 new cases each year. This research has direct clinical relevance for aphasia patients.

Project Start: April 1, 2006. This current funding is a continuation of previous NIH funding for this research that began July 5, 2002.

Project End: March 31, 2011

overt naming fMRI

Figure 1. Three overt naming fMRIs in a chronic nonfluent aphasia patient treated with 1 Hz rTMS to suppress R posterior Pars Triangularis: pre-rTMS (9 Yr. poststroke), and at 3 and 16 Mo. post-rTMS (11 Yr. poststroke). Note increased L perilesional and L SMA activation (white arrow) on fMRI at 16 Mo. post-rTMS (best naming score, 58%). Source: P. Martin, M. Naeser, K. Doron, F. Fregni, J. Kurland, M. Nicholas. E. Baker, A. Pascual-Leone. New Shift to L SMA Activation with Improved Overt Naming fMRI at 11 Years Poststroke in Nonfluent Aphasia after rTMS to Suppress R BA 45. Poster presented at Organization for Human Brain Mapping Meeting, Toronto, Canada, June, 2005.