Introduction
reduction of anterior insula, dissociative amnesia, anxiety, dissociative, psychiatric disorders, amnesia, paranoid thoughts, dissociative depersonalization, hostility
CORTEX, ADVERSE EFFECT
Racemic ketamine (1:1 esketamine: arketamine) is a non-competitive antagonist of the N-methyl-D-aspartate glutamate receptor and an FDA-approved dissociative anesthetic. It was introduced into clinical practice in the US in the 1960’s as a novel agent that could produce effective sedation and analgesia while maintaining cardiorespiratory stabilityThe doses of ketamine used for these psychiatric disorders commonly induce acute dissociation and other altered states of consciousness (ASCs). While some of these non-ordinary states are associated with acute changes in effect as well as longer-term therapeutic affective changes, they can also cause unpleasant psychotomimetic experiences compared to placeboMechanistic studies have demonstrated that ketamine acutely induces multiple changes in affective neural circuit activityKetamine-induced dissociation can encompass a broad range of altered states that span the spectrum of aversive experiences, from relieving negative states to boosting positive feelings. Depersonalization and derealization involve disconnection from one’s body and surroundingsBeyond relief from negative affective experiences, ketamine has also been observed to open the capacity for positive experiences, such as feelings of pleasure, love, and peace. On the other hand, ketamine has been reported to produce states experienced as aversive, such as hostility, fear, or horror related to paranoid thoughts, impairment in cognition, losing control, or gaps in memory (amnesia). Furthermore, dissociation is generally viewed as an adverse effect in the medical model of ketamine administrationTo unpack how ketamine-induced dissociative and altered states influence affective states, it is essential to understand the neural mechanisms that underlie these effects. In this study, we used blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) to assess neural activity engaged by positive and negative affective social stimuli following acute ketamine infusions that induced dissociative and altered states of consciousness. We focused on the anterior insula, amygdala, and anterior cingulate cortex (ACC), key regions in the brain’s affective circuit established in randomized controlled designsThe activity of amygdala, anterior insula, sgACC, and dACC in response to affective stimuli is the pertinent target for investigating the neural basis of ketamine-induced dissociative experiences such as depersonalization. There is emerging evidence that, relative to a non-placebo baseline condition, ketamine modulates anterior insula, amygdala, and ACC activity in response to facial emotion stimuli during BOLD fMRIThe present study design incorporated several key features. First, we assessed multiple aspects of ketamine-induced ASCs, integrated with BOLD fMRI, to probe positive and negative affective brain states using a tightly controlled experimental design that included double-blinding, randomization to limit carry-over effects, and a placebo control condition. Second, we infused ketamine or placebo over a period of 40 min, exactly matching the standard therapeutic designs. In contrast, prior mechanistic studies have tended to utilize a ketamine infusion protocol that involved infusing a bolus, then initializing a maintenance infusion to maintain blood concentrations at a stable level. We chose to use the standard therapeutic approach (0.5 mg/kg infused over 40 min) to facilitate the future clinical translation of the mechanistic findings. Third, due to our multi-modal approach, we were positioned to test whether specific aspects of ketamine-induced dissociation and other ASCs modulated acute changes in neural activity.We had the following objectives: (1) to test whether specific aspects of dissociation and other ASCs differed across dose conditions; (2) to test the dose-dependent effects of ketamine on brain activity in response to emotional expressions; and (3) to test whether specific aspects of ketamine-induced dissociation and other ASCs mediated the effect of dose on acute changes in neural activity during emotional processing. We hypothesized that ketamine would induce multiple types of dissociative and altered experiences in a dose-dependent manner that mediate distinct effects on anterior insula and amygdala neural targets in response to affective stimuli. Specifically, we investigated whether experiences such as dissociative depersonalization, derealization, and altered states of bliss would mediate a reduction of anterior insula and amygdala activity, reflecting relief from negative affective states and the promotion of positive ones, whereas other states, including dissociative amnesia, anxiety, and impaired control and cognition, might instead increase anterior insula and amygdala activity, reflecting an exacerbation of negative affective brain states.