Effects of Ketamine on Brain Function During Metacognition

Post by Lani Cupo

What's the science?

Metacognition, or thinking about the process of thought itself, is considered to be essential to the experience of consciousness.  While some studies have used neuroimaging techniques in an attempt to localize brain regions integral to metacognition, little is known about the role of specific neurotransmitter receptors underlying consciousness. Previous metacognition research has indicated the importance of the N-methyl-D-aspartate (NMDA) glutamate receptor, bound by antagonists—such as ketamine—which, at sub-anesthetic doses, can induce a psychotropic state accompanied by euphoria and out-of-body experiences. This week in Neuroscience of Consciousness, Lehmann and colleagues conducted a double-blind, placebo-controlled pharmacological functional magnetic resonance imaging (fMRI) study, in order to investigate the role of the glutamate system in metacognition and its underlying neural activity following exposure to ketamine.

How did they do it?

In the laboratory, metacognition can be measured by asking participants to reflect “trial-by-trial” on their performance on behavioral tasks, such as recall in a memory task. These tests allow researchers to assess, not only performance on the task (referred to as type 1 responses) but also participants’ insight into that performance (referred to as type 2 responses). Fifty-three adult participants (29 females) were included in the study, and 24 of them received sub-anesthetic doses (2 mg/ml) of ketamine (29 received saline) during a task-based fMRI scan. After being placed in the scanner and initiating infusion with ketamine or saline control, two phases of the study were completed. 

In phase 1, participants took part in a memory task, encoding 120 words, 60 of which they also rated on “pleasantness” leading to a deeper encoding. In the retrieval phase of the task, for type 1 responses, participants were presented with 180 words, 60 of which they had never seen before, and were asked to press a button when they recognized the word from before. For type 2 responses, they were asked to rate how confident they were in their type 1 response, either by reporting on a 6-point scale (report condition) or merely placing the cursor on a color-coded digit on the scale (follow condition). This distinction allowed the authors to study the difference between true metacognition and the “follow” control condition. 

In phase 2, participants saw 100 words, half of which they rated on pleasantness for deep encoding and half of which they merely reported the number of syllables. An hour after the scan and ketamine infusion were finished, participants performed the same retrieval task from phase 1, without the influence of current ketamine exposure. Finally, participants filled out a questionnaire designed to assess altered states of consciousness.

What did they find?

Results from the questionnaire suggested ketamine significantly altered participants’ states of consciousness, but, as expected, did not affect performance on the memory task. In phase 1, participants displayed more metacognitive sensitivity on deeply-encoded words, implying they were better at assessing their performance on the task for these words. However, ketamine reduced participants’ metacognitive sensitivity. This suggests that ketamine significantly alters metacognition, even though it did not impair memory encoding itself. When the authors analyzed the fMRI data, they found that ketamine infusion was associated with a higher blood-oxygen level dependent signal (an indirect measure of brain activity) in five clusters in the parietal and occipital lobes during type 2 ratings. The authors note that these changes were present regardless of how ratings were reported (with both the report and follow conditions) suggesting they are not specific to true metacognitive processes. Behavioral results from phase 2 memory trials were in accordance with phase 1, however, metacognitive sensitivity was not impacted by ketamine in this phase. This finding confirms that ketamine did not impair memory-encoding, and implies that an hour after termination of ketamine exposure, metacognitive self-assessment of performance on the task was no longer impaired.

What's the impact?

This study is the first to investigate the effects of disrupting the glutamatergic system with ketamine on metacognition, showing that the pharmacological intervention may impair introspection. The authors acknowledge these results are too preliminary to attribute solely to the role of NMDA receptors, however, the evidence does suggest ketamine impacts metacognition. The present study provides a foundation for future investigations into the role of the glutamatergic system underlying metacognition and, ultimately, conscious experience.

Lehmann et al. Effects of ketamine on brain function during metacognition of episodic memory. Neuroscience of Consciousness (2021). Access the original scientific publication here.