Antidepressant Mechanisms of Transcranial Magnetic Stimulation
Condition: Depression
MeSH terms: Depression
Study type: Interventional

Summary: 
      This study utilizes resting state fMRI, arterial spin labelling imaging, diffusion tensor
      imaging, structural MR-imaging, and MR-spectroscopy of GABA and Glutamate to probe the
      antidepressant mechanisms of repetitive transcranial magnetic stimulation (rTMS). The above
      imaging modalities will be acquired before and after an open-label 5 week course of rTMS for
      depression in currently depressed individuals with treatment resistant depression. Changes in
      functional, structural, and neurochemical markers will be investigated in rTMS responders and
      nonresponders to elucidate mechanisms of plasticity that correlate with treatment response.
      Additionally, functional, structural, and neurochemical signatures at baseline that correlate
      with subsequent treatment response will be investigated.
    

Detailed description: 
      Repetitive Transcranial Magnetic Stimulation (rTMS) applied over the left dorsolateral
      prefrontal cortex (DLPFC) alleviates mood in major depression. This treatment received FDA
      approval in 2009 and is now in routine clinical use for the treatment of major depression. A
      recently published sham-controlled study showed a response rate of 14% in real rTMS compared
      to 5% in sham rTMS. The response, defined by a greater than 50% reduction in the Hamilton
      Depression Rating Scale from pre-treatment to post-treatment, was also found to be 14% in one
      recent meta-analysis. The inclusion criteria in these studies admitted a broad spectrum of
      participants, ranging from subjects having a first major depressive episode, to those having
      failed multiple medication trials, suggesting that a subgroup with a more robust response may
      be masked by an unresponsive group. Abnormal function of the left frontal lobe accompanies
      major depression and this may be normalized by rTMS Cerebral blood flow measured with SPECT
      imaging was reduced in the left DLPFC of depressed subjects and was increased during and
      after a course of rTMS over the left DLPFC. Decreased blood flow was found in a broader
      region of frontal and paralimbic regions in depressed individuals and treatment success was
      associated with decreased blood flow in the inferior frontal lobes both pre- and post-
      treatment. Greater post-treatment vs. pre-treatment BOLD activation of left frontal regions
      was demonstrated using fMRI in a planning task that engages the frontal lobes. Left
      prefrontal myo-inositol is reduced in depressed subjects and this is normalized by rTMS. The
      above functional abnormalities view the frontal lobe in isolation. However, recent work has
      demonstrated a network-based structural marker of risk for familial depression consisting of
      decreased cortical and white mater volume. Resting state fMRI (rs-fMRI) tests cross-regional
      temporal coherence in low frequency oscillations in brain responses (~0.1 Hz) that are
      believed to represent spontaneous neural activity. Correlated spontaneous fluctuations are
      understood to reflect functional connections between brain regions that arise through a
      history of co-activation across one's lifetime. Previous work has shown that depressed
      patients exhibit altered functional connectivity patterns as gauged by rs-fMRI, and some
      studies suggest that these differences may be mitigated by treatment with antidepressant
      medications. However, whether and how TMS may affect functional connectivity is unknown. I
      propose to acquire the several described MRI types both before and after rTMS treatment in a
      search for predictive markers of rTMS treatment success as well as markers of
      treatment-induced change. Arterial spin labeling will be acquired to measure the blood flow
      distribution throughout the brain, both to confirm the SPECT results already reported and to
      test for additional regions of change. Resting state fMRI will be collected and DTI will be
      used to explore the structural basis of functional network changes. Structural MRI will be
      collected to measure cortical thickness and white matter volumes that may be predictive of
      rTMS response. Magnetic resonance spectroscopy will be collected to confirm the previously
      reported finding of rTMS-induced myo-inositol changes, as well as to consider the
      Glutamate/Glutamine and GABA spectra, given the importance of these neurotransmitters in
      theories of depression.
    

Intervention name(s): Repetitive transcranial magnetic stimulation
Intervention type(s): Device
Intervention description(s): Active repetitive transcranial magnetic stimulation for 25 days (Monday through Friday for 5 consecutive weeks). Active rTMS with the FDA approved Neuronetics TMS system. Each treatment will target the left dorsolateral prefrontal cortex. rTMS will be administered at 10Hz with a duty cycle of 4 seconds on and 26 seconds off for 37.5 min.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Magnetic stimulation of the brain; Antidepressant mechanisms