*6.2. Neuroplasticity and Neuromorphology*

Neuroplasticity is regulated by the noradrenergic, serotoninergic, anticholinergic and glutamate systems [117,118]. Neuropsychological studies of AN indicate reductions in neuroplasticity, with decreased cognitive flexibility, memory and learning, which will be discussed in the following section. Malnutrition, chronic stress and the presence of psychiatric comorbidities can lead to reductions in BDNF and hippocampal volume, together with increases in proinflammatory cytokines. The presence of neuroinflammation has been noted in AN, with studies finding increases in proinflammatory cytokines (e.g., TNF-α, IL-6 and IL-1β [119,120]), some of which normalise after weight restoration (e.g., IL-6 [120,121]). Additionally, chronic psychosocial stress can alter the proinflammatory cytokine pathways [122,123]. Stressors include, but are not limited to, childhood adversities and life events, caregiver stress and loneliness, all factors that can be linked to the development of AN [124].

Stress-induced depression-like behaviours in rodents are associated with increases in proinflammatory cytokines but also with decreases in BDNF and neurogenesis [125–127]. Inflammation and aberrant concentrations of BDNF have been noted in several other psychiatric disorders that are often comorbid with AN, such as PTSD and depression [128–132]. Thus, comorbidities may contribute to neuroinflammation in AN. Similar to in depression, patients with AN show low levels of BDNF, which generally resolves following weight restoration [133].

In the acute stages of AN, global decreases in grey matter volume of 4% to 5% are observed [134,135], which are more apparent in certain structures such as the hippocampus [136]. This region is particularly vulnerable to long-term malnutrition due to its high levels of neurogenesis [137–140]. Additionally, a loss of white matter is observed [141], which is more pronounced in adolescents with AN, perhaps resultant from the high vulnerability of the brain during development [135]. Generally, the grey and white matter volumes increase following weight restoration, although they are not always fully normalised [141]. Notably, one study found that white matter volume loss at admission in adolescents was predictive of recovery at 1 year; the interruption of white matter tract development as a result of malnutrition may contribute to chronicity [142].

We have speculated in previous publications that the effects of chronic malnutrition and traumatic events and/or chronic social stress associated with living with AN may contribute to neuroinflammation and both impaired neuroplasticity and neurogenesis [136]. However, these speculations are yet to be confirmed with robust empirical research, and many questions remain. Whilst there is little research investigating neurogenesis in human patients with AN, a study using an activity-based anorexia (ABA) rodent model found decreases in cell proliferation in the dentate gyrus following three days of ABA [143].

In people with AN, many of these parameters often normalise following weight restoration and recovery. However, a proportion of patients fail to weight restore (i.e., are "treatment-resistant") and thus experience persistent impairments in neuroplasticity, which is a likely barrier to successful treatment. Targeting neuroplasticity in treatment is likely to increase its success in both acute and chronic cases of AN.

As aforementioned, the antidepressant effects of ketamine appear to be mediated by an increased glutamate release [144], which has been linked to downward increases in BDNF, neurogenesis and synaptic plasticity. Relatedly, a structural MRI study demonstrated increases in the hippocampal volume following a single dose of ketamine, which was associated with the treatment response [145]. Additionally, ketamine may mitigate the effects of chronic stress on the brain [146], as well as associated increases in inflammatory markers [33]. Ketamine treatment has been shown to have positive effects on the neuropsychological parameters of memory and learning, which will be discussed in the following section.
