*6.3. Neuropsychology*

Patients with AN often have difficulties in several aspects of cognition that may be linked to reduced neuroplasticity and hippocampal function, such as memory, learning and cognitive flexibility. Apparent deficits in memory in AN include overgeneralising autobiographical memories [147,148], poor immediate and delayed recall of story details [149], recall of locations [150] and pattern recognition memory [151]. Patients with AN have a negative bias when constructing future-directed thoughts compared to healthy controls [152], which may be related to a negative bias in memory retrieval [153]; it has been hypothesised that generating future-directed thoughts is reliant on the flexible recombination of events from the past [154]. Relatedly, adults with AN show selective impairments in aspects of cognitive flexibility such as task switching, which are also apparent in adults recovered from AN [155]. Whilst such depletions in cognition may not be at a threshold to be deemed an "impairment" [155], they may be precipitating or maintaining factors and are likely to contribute to the significant difficulty in engaging with psychological therapies.

Amongst and related to ketamine's neurobiological actions, there are several qualities of ketamine that are likely to address the difficulties in several aspects of neuropsychology in AN. Ketamine has multifaceted effects on the memory [156], which is contingent on the dosage and length of use. For example, chronic ketamine abuse is associated with decrements in the episodic memory, working memory and semantic memory, the former two of which abate following drug cessation [156]. At subanaesthetic doses, ketamine has similar, albeit transient, effects. These effects have been harnessed in research examining whether ketamine as an adjunct to exposure therapy can be used to block the reconsolidation of trauma-related memories [157]. Reconsolidation refers to the process whereby the strength and course of existing memory traces are modified. Additionally, ketamine can facilitate extinction learning, which describes the process of a new memory being formed rather than an existing memory being modified; inhibitory learning is thought to antagonise the old memory [157]. Our team found preliminary evidence for generalised impairments in extinction learning in AN [158]. It is possible that ketamine may facilitate extinction learning against feared foods and food-related situations in patients with AN.

As aforementioned, individuals with AN often experience social anxiety [48]. Previous research has demonstrated that individuals with eating disorders have a higher vigilance for social signs of rejection and avoid social rewards [159]. Importantly, this sensitivity to interpersonal conflict and anxiety around social situations can interfere with the therapeutic bond and, thus, the outcomes of therapy. Ketamine has been reported to increase the social functioning of patients with depression, reducing rejection sensitivity, social avoidance, pessimistic thinking and a bias towards negative information, which facilitates a therapeutic bond [160].

Ketamine can induce alterations in bodily perceptions, including feelings of lightness and floating [161,162]. Patients with AN tend to report high levels of cognitive control and cognitive rigidity [163,164]. Patients also report that their eating disorders often feel intertwined with their identities [165] and report anguish at physically "taking up space" [166,167]. Additionally, disconnection from the self, others and the world is core to AN [168–170]. It is possible that ketamine may have an additional therapeutic impact for patients with AN by promoting flexibility, ego dissolution, detachment from one's internal dialogue and openness to experiences [162]. Moreover, the mystical and spiritual experiences that often manifest during ketamine treatment [162] may enable patients to connect with their spirituality and alter their perceptions of both themselves in the context of the wider world and of the universe itself.
