Transcranial Magnetic Stimulation and Constraint Induced Language Therapy for Alzheimer Disease

A Phase II, Randomized, Blinded Study of Transcranial Magnetic Stimulation and Constraint Induced Language Therapy for the Treatment of Chronic Aphasia - Alzheimer Disease Sub-study

Impaired verbal communication is a cardinal symptom of Alzheimer Disease (AD) and the source of enormous distress and disability. Effective therapies for this deficit are lacking. In light of the emerging literature demonstrating that Transcranial Magnetic Stimulation (TMS) improves general cognition in subjects with Alzheimer Disease (AD), the investigators propose to study the effectiveness of TMS as a therapy for impaired verbal communication. The hypothesis to be tested is that TMS combined with Constraint Induced Language Therapy (CILT) improves verbal communication more than sham TMS and CILT. A second aim is to use state-of-the-art neuroimaging to understand the mechanisms underlying any beneficial effect of the treatment.

TMS is a technique by which a brief electrical current is induced in brain tissue causing a brief suppression of the excitability of the underlying tissue; the technique, which was introduced in the 1980s and has been extensively used around the world, has been shown to transiently improve or disrupt specific cognitive operations. To achieve this end, a coil is positioned against the subject's head. The delivery of a single pulse begins with the discharge of current from a capacitor into a circular or figure-of-eight coil; this electrical current generates a brief magnetic field of up to 2.2 Tesla. As the pulse of electricity has a rise time of 0.2 ms. and a duration of 1 ms., the magnetic field changes in intensity quite rapidly. Because the magnetic field passes freely through the scalp, skull, and meninges, the flux in the magnetic field induces a small electric field in the brain that transiently alters neural activity.

TMS may be delivered in a variety of ways. The investigators propose to use 10 Hz TMS; that is, TMS pulses will be delivered at a frequency of 10/second, for a total of 1200 pulses. Using the figure-of-eight coil to be employed here, TMS is thought to affect activity in approximately 1 cubic cm. of cortex. Many investigators have employed TMS for AD with a frequency of 10 Hz and most have delivered 1200 pulses per session.

The baseline phase will consist of 3 sessions, each lasting 1-2 hours depending on the stamina of the subject. The point of the baseline testing is to characterize the subject's language function. To that end, a number of standard language and neuropsychological tasks will be administered. These include the Western Aphasia Battery, Pyramids and Palm Trees test, Figural Fluency Test, word and non-word repetition tasks, spontaneous narrative production, CILT stimulus naming, and the Repeatable Battery for the Assessment of Neuropsychological Status. Additionally, during the baseline, subjects will undergo MRI of the brain or, if they have a contraindication to MRI, a CAT scan of the head. No contrast will be used.

In the treatment phase, there will be 10 TMS sessions over 2 consecutive weeks in which 30 two-second stimulation trains of 10 Hz TMS will be delivered every 30 seconds to the left inferior pars triangularis and to the left posterior superior left temporal gyrus at 100% motor threshold. There will be a total of 600 pulses to each site in each session for a total of 1200 pulses per session. Each TMS treatment session will be immediately followed by a 60-90 minute session of CILT.

There will be two 3-month post-treatment visits and two 6-month post-treatment visits in which the full battery of language and cognitive assessments will be repeated. Subjects who are able to undergo MRI scanning will have anatomic and fMRI scans at the first 6-month post-treatment visit.

The investigators will pair TMS with CILT which has been shown to have positive outcomes in post-stroke aphasia. CILT invokes use-dependent learning in communicative interactions by requiring spoken output and restricting use of alternative forms of communication, such as gestures. The investigators will use a dual card-matching task modeled after Maher et al. As in the original CILT design, the participant interacts verbally with a conversational partner (here, the speech language pathologist), in turn requesting a card of given description and complying with the partner's request. In this way, the treatment targets both production and comprehension. Moreover, as verbal targets increase in linguistic complexity across the protocol ("a ball", "throw a ball"; "Do you have a ball"?), a variety of lexical and phrasal structures are targeted. Studies of CILT have reported gains on multiple language behaviors, supporting its broad engagement of the language network.

Inclusion Criteria:

• A diagnosis of mild-moderate AD as defined by the National Institute of Aging - Alzheimer's Disease and Related Disorders Association criteria
• Mild-moderate cognitive impairment, indicated by Mini-Mental Status Exam (MMSE) scores between 23 and 15 inclusive
• Must be right handed as defined by the Edinburgh Handedness Inventory
• Must be a native English speaker
• Must be able to understand the nature of the study, and give informed consent

Exclusion Criteria:

• History of stroke
• History of seizure
• History of any other significant neurologic disease (e.g., ALS)
• Significant depression as defined by the Geriatric Depression Scale.
• Any significant medical disorder that, in the view of the investigators, could threaten the subject's ability to complete the study (e.g., cancer, significant cardiac disease)
• Any contraindications to TMS, including uncontrolled seizures, previous brain surgery, and history of tinnitus