rTMS as a Treatment for PPA
Condition: Logopenic Variant Primary Progressive Aphasia; Non-Fluent Primary Progressive Aphasia
MeSH terms: Aphasia; Aphasia, Primary Progressive; Pick Disease of the Brain; Frontotemporal Dementia; Primary Progressive Nonfluent Aphasia
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Primary progressive aphasia (PPA) includes three variants. Two such variants, the
      non-fluent/agrammatic variant (nfvPPA) and the logopenic variant (lvPPA), are characterized
      by progressive word-finding difficulties and effortful speech. Efforts to slow or halt this
      progression have been largely unsuccessful. As such, there is a desperate need for novel
      treatment strategies in PPA.

      Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive way of
      stimulating cortical targets in a focal and reproducible manner. Therapeutic benefits from
      rTMS have been demonstrated when it is applied in many sequential sessions. For example,
      repeated sessions of rTMS to left dorsolateral prefrontal cortex (dlPFC) is approved by the
      US Food and Drug administration as a treatment for major depressive disorder. With respect to
      language, high frequency rTMS increases the response rate for picture naming in healthy
      individuals. rTMS has also been shown to improve the number of correct naming responses in
      patients with Alzheimer's disease. Further, in a sham controlled study, Cotelli and
      colleagues demonstrated that in a group of 10 nfvPPA patients high frequency rTMS over the
      left and right dlPFC during object and action naming tasks improved the percent of correct
      responses for action, but not object naming. Finally, in a sham controlled single case study,
      Finocchiaro et al. applied high frequency rTMS to the left inferior mid-frontal gyrus for 3
      sessions consisting of five consecutive days (treatment or sham). They found a significant
      and lasting improvement in the patient's performance on verb production when comparing active
      rTMS to sham rTMS or baseline. These studies have contributed valuable insights into the
      potential use of rTMS in treating the language symptoms of PPA patients.
    

Detailed description: 
      15-20 patients with a confirmed diagnosis of either nfvPPA or lvPPA (made by a specialized
      clinician) will be recruited. Patients must have a mild to moderate language impairment and
      must be native English speakers. Exclusion criteria include contraindications to receiving
      Magnetic Resonance Imaging (MRI) scanning or rTMS (e.g. metallic or electromagnetically
      activated implants, cranial mass lesions, surgical aneurysm clips), the presence of
      significant medical, neurological or psychiatric co-morbid symptoms and patients without
      study partners.

      It will take approximately 2 weeks to complete this research study, but the exact timing will
      vary according to patient, investigator and equipment availability. Each patient will have a
      total of up to 11 study visits. Greater than 11 visits may take place in the event that
      patients' language improves significantly following rTMS in order to test the sustainability
      of the improvement. Visits will take place at the MGH Martinos Center for Biomedical Imaging.

      The first visit (lasting 3-4 hours) will include obtainment of informed consent, baseline
      assessments, and a baseline MRI scan (which will be used for subsequent rTMS targeting).
      After this, patients will return for two blocks of 20Hz rTMS to left dlpfc: one in which they
      receive active rTMS and one in which they receive sham rTMS. Both active and sham rTMS will
      be delivered as high frequency stimulation (20 hertz, 20Hz). To accomplish this, an rTMS coil
      capable of delivering active or sham stimulation will be employed. Order of active and sham
      blocks will be counterbalanced across participants. During each block rTMS (active or sham)
      will be administered daily for 5 days (Monday through Friday). Neuropsychological testing,
      including thorough language evaluations, will be done before and after each block of rTMS.
      Repeat MRI imaging will be performed at the end of each of the two blocks. rTMS visit
      durations will be as follows: Monday visits will last approximately 3-4 hours, Tuesday,
      Wednesday and Thursday visits will last approximately 1-2 hours and Friday visits will last
      approximately 5 hours.
    

Intervention name(s): Active rTMS; SHAM rTMS
Intervention type(s): Device; Device
Intervention description(s): All study participants will receive one block of active rTMS. Each block will consist of daily sessions of 20Hz active rTMS delivered to the left dorsolateral prefrontal cortex (dlPFC) over five days (Monday through Friday).; All study participants will receive one block of SHAM rTMS. Each block will consist of daily sessions of 20Hz SHAM rTMS delivered to the left dorsolateral prefrontal cortex (dlPFC) over five days (Monday through Friday).
Intervention model: Single Group Assignment
Intervention model description: Within-subject crossover design
Masking: None (Open Label)
Primary purpose: Other
Keywords: rTMS; PPA