Effects of ketamine on brain function during metacognition of episodic memory

Abstract

Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N-methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d′) and led to larger metacognitive bias, with retrieval performance (d′) and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d′/d′). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness.

Unity and diversity of metacognition.

“…The RW-T (Figure 1E) represented a recognition task in relation to the EW-T conducted 90 min after completion of the EW-T, similar to our (Lehmann et al, 2021) and many other previous studies investigating metamemory (e.g., Baird et al, 2015). Participants were presented with a total of 150 word stimuli (five blocks of 30 trials) from the BAWL-R (Võ et al, 2009), comprised of 100 words that had been presented in the EW-T (“Old”), as well as 50 stimuli not shown before (“New”), in white on the center of a black screen.…”

Unique Effects of Sedatives, Dissociatives, Psychedelics, Stimulants, and Cannabinoids on Episodic Memory: A Review and Reanalysis of Acute Drug Effects on Recollection, Familiarity, and Metamemory

“…It is possible that these enhancements from dissociatives were not always apparent or significant because memory was tested on the same day as drug administration when some acute drug effects may have persisted. A recent study found a trend for ketamine at retrieval to impair metamemory (measured with metacognitive efficiency; Lehmann et al ., 2021), so any enhancement of metamemory from dissociatives at encoding might have been rendered null by lingering drug effects on retrieval. THC at encoding with retrieval 48 hours later (i.e., when drug effects have dissipated) was also found to enhance metamemory despite impairments of both recollection and familiarity.…”

“…Another study used the DPSD model and found some evidence for dextromethorphan at encoding to impair familiarity (Barrett et al, 2018), but the modeling approach may have produced unreliable estimates because of low trial counts. It is also unclear whether these dissociatives at encoding impact metamemory, as some studies found no impact (Lofwall et al, 2006;Carter, Kleykamp, et al, 2013;Lehmann et al, 2021), whereas others found impairments Unique acute drug effects on episodic memory of metamemory with higher doses of dextromethorphan (Carter, Reissig, et al, 2013). All of these studies measured metamemory with gamma except (Lehmann et al, 2021), which did measure metamemory with metacognitive efficiency (i.e., from the meta-d' model) and did not find any impact of ketamine at encoding on metamemory.…”

“…It is also unclear whether these dissociatives at encoding impact metamemory, as some studies found no impact (Lofwall et al, 2006;Carter, Kleykamp, et al, 2013;Lehmann et al, 2021), whereas others found impairments Unique acute drug effects on episodic memory of metamemory with higher doses of dextromethorphan (Carter, Reissig, et al, 2013). All of these studies measured metamemory with gamma except (Lehmann et al, 2021), which did measure metamemory with metacognitive efficiency (i.e., from the meta-d' model) and did not find any impact of ketamine at encoding on metamemory. Thus, as was the case for sedatives, an impairment in metamemory may be an artefact of the covariation between memory accuracy and metamemory measured with gamma.…”

“…Moreover, studies on the effects of dissociatives at retrieval have administered drugs shortly after encoding and tested memory shortly after, thereby conflating consolidation and retrieval effects. These studies find dissociatives to have little impact on memory accuracy (Honey et al ., 2005) with some evidence of diminished metamemory (Lehmann et al ., 2021).…”