Using Repetitive Transcranial Magnetic Stimulation to Study the Role of Frontostriatal Circuit in Major Depressive Disorder
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional

Summary: 
      Major depressive disorder (MDD) is a common, severe, and often life-threatening illness that
      involves the body, mood, and thoughts. The natural course of MDD tends to worsen without
      treatment, while people with MDD can lead healthy and productive lives when the illness is
      effectively treated. Up to 50% of the patients show no response to current available
      antidepressants.Two major non-invasive brain stimulation (NIBS) tools have been applied for
      the treatment of psychiatric diseases so far, transcranial magnetic and direct current
      stimulation (TMS, tDCS). TMS induces a strong magnetic field (magnetic pulses) through the
      skull into the brain, which generates electrical currents in brain tissue and induces
      neuronal firing, leading to after-effects, i.e. neuroplasticity, eventually. Neuronal effects
      of rTMS has been proven to last beyond the actual time of stimulation, enabling altered brain
      activity for an extended period of time. Adding on rTMS treatment could even give a chance to
      treat the physical comorbidities and enhance cognitive function in MDD. Nevertheless,
      underlying neurobiological mechanism of rTMS treatment remains unclear. Reports showed
      chronic psychosocial stressors are associated with altered frontal-striatal circuitry
      activation and connectivity. Indeed, aberrant fronto-striatal connectivity and reduced
      sustain fronto-striatal activation were noticed in MDD patients. However, the specific
      correlations between fronto-striatal connectivity changes and rTMS treatment outcomes in MDD
      remain unclear. In this study fMRI will be used to measure the possible correlations between
      the fronto-striatal circuit activation / connectivity with (1) mood symptoms presentations,
      (2) neurocognitive measurements, (3) HPA and ANS activities, and (4) immune and metabolic
      status (cytokines, adipokines and insulin levels) in patients with MDD. Then the possible
      changes in fronto-striatal FC over a four-week treatment course with 10 Hz rTMS stimulation
      to left dorsolateral prefrontal cortex will be measured. The FC changes will be tested to
      find out whether correlate with treatment outcomes, HPA and ANS activity; and
      immune/metabolic indices changes.

      We hypothesize that rTMS as an add-on therapy would change the fronto-striatal FC that
      correlated with mood symptom improvement, neurocognitive measurements, HPA and ANS activity,
      inflammatory and metabolic homeostasis in patients with MDD.
    

Detailed description: 
      BACKGROUNDＡND SIGNIFICANCE:

        1. The scale of the global impact of MDD is substantial, with mental illness constituting
           an estimated 7.4% of the world's measurable burden of disease. With a period of
           sustained disruption of mood, patients with MDD have the symptoms of distortions in
           perception and somatic functioning, and impairment in social functioning. Among the
           possible comorbidities, epidemiologic evidences have indicated increased risk of
           metabolic disturbances in MDD patients. The metabolic disturbances are correlated with
           higher morbidity and mortality in patients with MDD. Comorbid diabetes and MDD are a
           major clinical challenge as the outcomes of both conditions are worsened by the other.

        2. Although there are several types of antidepressant medications used to treat depressive
           disorders, up to 50% of the patients do not show response to antidepressants treatment.
           Importantly, increased inflammasome activation, cognitive impairment, and insulin
           resistance follow the non-remitting and recurrence in treating MDD, and might further
           dampen antidepressant treatment response. Moreover, the systemic effect of
           antidepressants treatment has linked to increased risk of metabolic disturbance.

           Recently, the development of non-invasive brain stimulation (NIBS) has provided
           alternative therapeutic options for psychiatric disorders. Two major NIBS tools have
           been applied for the treatment of psychiatric diseases so far, transcranial magnetic and
           direct current stimulation (TMS, tDCS). TMS includes induction of a strong magnetic
           field (magnetic pulses) through the skull into the brain. The magnetic pulses generate
           electrical currents in brain tissue and consequently induce neuronal firing. Repetitive
           TMS (rTMS) induces after-effects of the intervention, i.e. neuroplasticity. In general,
           low frequency (<1 Hz) rTMS reduces neuronal activity and cortical excitability, while
           higher frequency (>5 Hz) rTMS results in excitability enhancement. Neuronal effects of
           rTMS been proven to last beyond the actual time of stimulation, enabling altered brain
           activity for an extended period of time. The rTMS has emerged as a promising alternative
           strategy for treatment-resistant depression; however, the underlying neurobiological
           mechanisms are still not fully understood. In addition, adding on rTMS treatment could
           give a chance to treating the physical comorbidities and enhance cognitive function in
           MDD. The incorporation of biological assessments into future rTMS clinical studies will
           help in this regard.

        3. The frontal-striatal circuits mediate broadly dissociable cognitive and behavioural
           processes through limbic (ventromedial prefrontal regions, ventral striatum - VS,
           ventral tegmental area - VTA), motor (supplementary motor areas - SMAs, putamen,
           substantia nigra) and cognitive (lateral prefrontal and caudate) functional connectivity
           (FC). Reports had showed chronic psychosocial stressors are associated with altered
           frontal-striatal circuitry activation and connectivity. Structure and functional
           abnormalities of the striatum and frontal cortex have been reported consistently in
           studies in mood disorders. In MDD, patients are characterized by aberrant
           fronto-striatal connectivity and reduced sustain fronto-striatal activation. The MDD
           related executive dysfunction also showed clinical presentations and neuroimaging
           findings consistent with frontal-striatal circuitry abnormalities. Within the circuit,
           striatum is associated with reward and motor processing systems and receives
           emotion-related information and motivation from the frontal lobe, anterior cingulate
           cortex, and amygdala. The high incidence of depressive symptomatology following left
           frontal and basal ganglia lesions also implicate their roles in MDD.

           The dysfunctional fronto-striatal circuits also link to the metabolic comorbidities and
           cognitive deficits, that involved executive functioning, attention, processing speed,
           and working memory in patients with mood disorders. Regarding metabolic control, the
           fronto-striatal functional connectivity changes affect food craving. And the altered
           reciprocal loop from the medial prefrontal cortex could promote overeating and metabolic
           disturbance. Moreover, animal and clinical studies had suggested that striatal dopamine
           signaling plays a role in systemic glucose regulation. On the opposite, brain circuitry
           connectivity could be enhanced by either glucose loading or insulin challenge. Moreover,
           insulin resistance related aberrant functional circuitry has been demonstrated in
           patients with type 2 diabetes. Individuals with insulin resistance also showed aberrant
           fronto-striatal connectivity with failure to shift from reward toward cognitive control
           circuit.

        4. Changes in the ability to sustain fronto-striatal connectivity during the regulation of
           positive affect are associated with gains in positive affect through anti-depressants
           treatment. Duloxetine has been noted to modulate the FC between striatum and
           dorsolateral prefrontal cortex while showing symptomatic improvement. Moreover, the
           fronto-striatal connectivity attenuation among reward-processing regions could predict
           response to psychotherapy in MDD. Therefore, the degree of connectivity within the
           fronto-striatal circuit has been considered as a predictive biomarker of remission in
           treating MDD. Changes in FC might also relate to outcome of rTMS treatment of MDD. The
           FC variations represent the mechanism of action of rTMS and explain the individual
           difference in treatment outcome. However, the specific correlations between
           fronto-striatal connectivity changes and rTMS treatment outcomes in MDD remain unclear.

      By using fMRI, in this project we will first measure the possible correlations between the
      fronto-striatal circuit activation/connectivity with (1) mood symptoms presentations, (2)
      neurocognitive measurements, (3) HPA and ANS activities, and (4) immune and metabolic status
      (cytokines, adipokines and insulin levels) in patients with MDD. Then we will measure the
      possible changes in fronto-striatal FC over a four-week treatment course with 10 Hz rTMS
      stimulation to left dorsolateral prefrontal cortex. We will test if the FC changes correlate
      with treatment outcomes, HPA and ANS activity; and immune/metabolic indices changes.

      HYPOTHESIS:

      We hypothesize that rTMS as an add-on therapy would change the fronto-striatal FC that
      correlated with mood symptom improvement, neurocognitive measurements, HPA and ANS activity,
      inflammatory and metabolic homeostasis in patients with MDD.
    

Intervention name(s): Repetitive transcranial magnetic stimulation (rTMS)
Intervention type(s): Device
Intervention description(s): A total of 12 sessions of rTMS (5 sessions per week for 2 weeks, follow by 1 session per week for next 2 weeks) .
Other intervention name(s): Antidepressants
Intervention MeSH terms: Antidepressive Agents
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Repetitive Transcranial Magnetic Stimulation (rTMS); Major Depressive Disorder (MDD)