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Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression.

ABSTRACT: Although in theory sham repetitive transcranial magnetic stimulation (rTMS) has no inherent therapeutic value, nonetheless, such placebo stimulations may have relevant therapeutic effects in clinically depressed patients. On the other hand, antidepressant responses to sham rTMS are quite heterogeneous across individuals and its neural underpinnings have not been explored yet. The current brain imaging study aims to detect baseline neural fingerprints resulting in clinically beneficial placebo rTMS treatment responses. We collected resting-state functional magnetic resonance imaging data prior to a registered randomized clinical trial of accelerated placebo stimulation protocol in patients documented with treatment-resistant depression (http://clinicaltrials.gov/show/NCT01832805). In addition to global brain connectivity and rostral anterior cingulate cortex (rACC) seed-based functional connectivity (FC), elastic-net regression and cross-validation procedures were used to identify baseline intrinsic brain connectivity biomarkers for sham-rTMS responses. Placebo responses to accelerated sham rTMS were correlated with baseline global brain connectivity in the rACC/ventral medial prefrontal cortex (vmPFC). Concerning the rACC seed-based FC analysis, the placebo response was associated positively with the precuneus/posterior cingulate (PCun/PCC) cortex and negatively with the middle frontal gyrus. Our findings provide first brain imaging evidence for placebo responses to sham stimulation being predictable from rACC rsFC profiles, especially in brain areas implicated in (re)appraisal and self-focus processes.

SUBMITTER: Wu GR

PROVIDER: S-EPMC7267925 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression.

Wu Guo-Rong GR Wang Xiaowan X Baeken Chris C

Human brain mapping 20191021 3

Although in theory sham repetitive transcranial magnetic stimulation (rTMS) has no inherent therapeutic value, nonetheless, such placebo stimulations may have relevant therapeutic effects in clinically depressed patients. On the other hand, antidepressant responses to sham rTMS are quite heterogeneous across individuals and its neural underpinnings have not been explored yet. The current brain imaging study aims to detect baseline neural fingerprints resulting in clinically beneficial placebo rT ...[more]

PMID: 31633261

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Project description:Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

Project description:High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r?=?0.48; P?=?.02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r?=?0.6; P?<?.001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.clinicaltrials.gov Identifier:NCT02178696.

Dataset Information

Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression.

Publications

Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression.

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