Prefrontal Cortex Connectivity and BDNF Fluctuations May Play a Role in Ketamine Mechanism of Action

MRI brain scan
Blood draws and resting-state functional magnetic resonance imaging scans were obtained at the preinfusion baseline, at 100 and 120 minutes postinfusion, and at 24 hours after baseline.

A randomized double-blind placebo-controlled study published in the World Journal of Biological Psychiatry demonstrated that ketamine infusion may be associated with acute and 24-hour changes in brain-derived neurotrophic factor (BDNF) levels. These ketamine-induced BDNF changes were linked to dorsomedial prefrontal cortex (dmPFC) resting-state functional connectivity (RSFC) alterations.

Marie Woelfer, MD, from the Clinical Affective Neuroimaging Laboratory in Magdeburg, Germany, and colleagues assessed acute and 24-hour changes in plasma BDNF levels after ketamine infusion to determine potential drug mechanisms. Healthy volunteers were randomly assigned to receive either 0.5 mg/kg ketamine or 0.9% saline (placebo) via infusion pump.

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Blood draws and resting-state functional magnetic resonance imaging scans were obtained at the preinfusion baseline, at 100 and 120 minutes postinfusion, and at 24 hours after baseline. Plasma BDNF levels were quantitatively assayed using a sandwich enzyme-linked immunosorbent assay. Based on prior evidence suggesting acute and sustained dmPFC changes after ketamine infusion, the investigators performed seed definition in the dmPFC and calculated seed-based RSFC maps. They conducted whole-brain regression to identify any correlation between plasma BDNF and RSFC changes.

A total of 80 healthy volunteers (mean age 25.89±5.29 years; 33 women) were enrolled, with complete data available for 53 subjects (ketamine: n=26; placebo: n=27). Significantly greater increases in BDNF plasma levels were observed in the ketamine vs placebo group at both 2 hours (t, −2.51; uncorrected P =.015) and 24 hours (t, −2.77; uncorrected P <.007) postinfusion.

In the whole-brain regression model, the ketamine and placebo groups displayed significantly different associations between BDNF fluctuations and dmPFC connectivity to the posterior cingulate cortex (PCC) (P <.001), medial PFC (P <.001), right superior temporal gyrus (STemp; P =.014), left inferior temporal gyrus (ITemp; P =.033), and left cerebellum (P =.029) at 24 hours. For the ketamine group, BDNF increases after 24 hours were associated with a decrease in RSFC between dmPFC seed and PCC (P <.001), medial PFC (P <.001), STemp (P =.015), ITemp (P =.014), and cerebellum (P =.005) clusters. In the placebo group, however, only left ITemp RSFC changes were related to 24-hour BDNF alterations.

When examining subgroups in terms of 24-hour BDNF alterations, the investigators found that only the ketamine group with increased plasma BDNF levels displayed significant RSFC decreases for medial PFC, PCC, ITemp, and STemp (corrected P <.0025). In addition, stronger RSFC changes between seed and PCC, medial PFC, and lateral PFC clusters at 100 minutes associated with greater BDNF change at 24 hours were significantly different in the ketamine vs placebo groups (P <.05).

The regions implicated in the study’s findings overlap with the spatial distribution of the default mode network. As a study limitation, investigators noted that plasma BDNF was used as a proxy because BDNF levels in the human brain cannot be measured directly.

The exact mechanism by which ketamine causes RSFC changes is unclear and warrants further study. “Particularly when BDNF increase are observed following ketamine, a disconnection from dmPFC after 24 h is seen and may reflect synaptic plasticity effects,” the study authors wrote. They further claimed that data may also be useful in the study of ketamine infusion for treatment-resistant depression.

Disclosure: Multiple study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Woelfer M, Li M, Colic L, et al. Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex [published online November 4, 2019]. World J Biol Psychiatry. doi:10.1080/15622975.2019.1679391