Network Modulation in Alzheimer's Disease
Condition: Alzheimer Disease; Primary Progressive Aphasia; Mild Cognitive Impairment
MeSH terms: Alzheimer Disease; Aphasia; Aphasia, Primary Progressive; Pick Disease of the Brain; Frontotemporal Dementia; Cognitive Dysfunction
Study type: Interventional

Summary: 
      The purpose of this study is to assess the effects of non-invasive brain stimulation on
      memory and language ability in patients with two phenotypic variations of underlying
      Alzheimer disease pathology: amnestic mild cognitive impairment (aMCI) and logopenic variant
      of primary progressive aphasia (lvPPA). This study will use repetitive Transcranial Magnetic
      Stimulation (rTMS) to stimulate nodes of networks that are thought to be affected in these
      two conditions. Specifically, a node of the Default Mode Network (DMN)-the angular gyrus
      (AG)-will be stimulated in aMCI patients; and a node of the language network-the posterior
      inferior frontal gyrus (pIFG) will be stimulated in patients with lvPPA.

      We will use functional connectivity MRI (fcMRI) to assess changes in functional network
      architecture following the stimulation. We will also assess putative cognitive improvements
      resulting from the stimulation by in-depth language testing in lvPPA patients and in-depth
      memory testing in aMCI patients.
    

Detailed description: 
      Specific Aims

      Aim 1: To investigate the feasibility of selective rTMS modulation of the Default Mode
      Network (DMN) vs. language network in patients with aMCI and lvPPA. We will assess the
      reliability of the rTMS/fcMRI approach to network modulation by studying the same subjects
      over repeated sessions, with the same methodology, including appropriate sham stimulation
      conditions.

      Hypothesis 1a: Changes in network functional connectivity following excitatory rTMS to AG (a
      node of the DMN) and pIFG (a node of the language network) across identical stimulation
      sessions separated in time, will show minimal within subject variability in aMCI and lvPPA
      patients, respectively, thus confirming the reliability of the approach and the
      reproducibility of prior findings demonstrating connectivity changes within the DMN and
      language networks.

      Hypothesis 1b: High frequency rTMS to pIFG will reliably increase pIFG-SMG-pMTG functional
      connectivity within the language network; high frequency rTMS to AG will reliably increase
      functional connectivity between pIPL and HF in the DMN.

      Hypothesis 1c: The changes in network functional connectivity will be selective, in that
      stimulation to AG (in the DMN) will not modulate connectivity within the language network,
      while stimulation to pIFG (in the language network) will not modulate DMN connectivity.

      Aim 2: To assess the effects of rTMS modulation on memory and language function in patients
      with aMCI and lvPPA.

      Hypothesis 2a: Excitatory rTMS to the language network will be associated with improved
      language performance in patients with lvPPA.

      Hypothesis 2b: Excitatory rTMS to the DMN will be associated with improved memory performance
      in patients with aMCI.

      Hypothesis 2c: Cognitive improvements will persist for at least two weeks following cessation
      of rTMS.

      Aim 3: To identify the functional network mechanisms underlying cognitive improvement in
      patients with aMCI and lvPPA after rTMS.

      Hypothesis 3a: Alterations in intrinsic functional connectivity (as assessed with fcMRI)
      within each network following rTMS will correlate with improved cognitive performance.

      Hypothesis 3b: Patients with a greater degree of atrophy and tau pathology within each
      network (assessed in a prior study) at baseline will predict a lesser response to rTMS.

      We will recruit up to 20 patients with aMCI and up to 20 patients with lvPPA (with amyloid
      and tau imaging or CSF biomarkers supportive of underlying AD pathology). We will first
      perform a baseline functional connectivity MRI (fcMRI), the purpose of which will be to
      obtain individualized network maps which can be used to target the networks of interest
      during future sessions.

      This will be followed by up to two weeks of five consecutive days of stimulation (Monday
      through Friday). aMCI patients will receive stimulation to the angular gyrus (AG) node of the
      DMN, and lvPPA patients will receive stimulation to the posterior inferior frontal gyrus
      (pIFG) node of the language network. During one of the two weeks stimulation will be active,
      and during the other week stimulation will be SHAM. Order of active and SHAM stimulation
      blocks will be counterbalanced.

      We will concomitantly assess the effects of rTMS modulation on memory and language function
      in patients with aMCI and lvPPA, and in so doing identify the functional network mechanisms
      underlying cognitive improvement after rTMS. Language and memory assessments will be
      performed on days 1 (Monday) , 3 (Wednesday) and 5 (Friday) of the week. Finally, to assess
      the distributed effects of the stimulation upon functional connectivity, fcMRI will be
      performed on days 1 (Monday) and 5 (Friday).

      We anticipate these results will lead to an impactful manuscript showing proof-of-concept
      data: 1) that it is possible to improve memory in aMCI and language in lvPPA using rTMS
      targeted selectively to the relevant brain network, and: 2) regarding mechanisms underlying
      the effects of rTMS on network function.
    

Intervention name(s): repetitive transcranial magnetic stimulation (rTMS)
Intervention type(s): Device
Intervention description(s): rTMS is a method to focally and reversibly stimulate a pre-specified cortical target. rTMS works through the principle of electromagnetic induction.
Intervention model: Crossover Assignment
Intervention model description: Patients with each condition will each undergo, in a crossover, within-subject design, two clocks of rTMS: active and SHAM.The order of active and SHAM blocks will be counterbalanced across subjects.
Masking: Single (Participant)
Primary purpose: Treatment