Nutritional state-dependent changes in subcortical limbic structures in anorexia nervosa are linked to leptin, ghrelin, and neurofilament light

Anorexia nervosa (AN) involves limbic dysfunction, yet its neurobiology remains unclear. Examining morphological alterations in subcortical limbic regions across AN's nutritional states and associations with neuroendocrine markers may improve understanding. We hypothesized that subcortical limbic volumes would be reduced in AN, normalize partially following short-term weight-restoration, and fully after long-term recovery. We examined whether leptin, ghrelin, neurofilament light (NFL), and brain-derived neurotrophic factor (BDNF) predict subcortical limbic dynamics. We studied 547 female individuals (aged 12-30 years): 168 with acute AN, 113 reassessed after ≈3 months of weight-restoration (>14% BMI increase), 80 long-term weight-recovered individuals, and 299 healthy controls. Ten subcortical limbic structures were segmented with FreeSurfer. Blood concentrations of leptin, ghrelin, NFL, and BDNF were measured. Group comparisons and marker associations were analyzed with mixed-effects models. Mediation was tested via regression-based mediation models. Most subcortical limbic volumes were reduced in AN (mean = -5.3%; Cohen's d-range = 0.24-0.76) but normalized after short-term weight-restoration (longitudinal change: mean = +5.8%; d-range = 0.30-0.56), except residual hypothalamic reductions. Rising leptin mediated weight gain-related volumetric increases in the left inferior tubular hypothalamus (proportion mediated = 52.8%) and left (96.7%) and right (156.8%) nucleus accumbens. Declining ghrelin mediated volumetric increase of the right nucleus accumbens (77.8%). Decreasing NFL following weight-restoration predicted increases in two hypothalamic subunits, the fornix, and right nucleus accumbens (d-range = 0.56-0.98). BDNF was unrelated to limbic dynamics. Subcortical limbic alterations in AN exceed other mental disorders, highlighting neuroplasticity. Neuroendocrine recovery (leptin and ghrelin) may reverse, and reduced axonal damage (NFL) may indicate neurostructural alterations in homeostatic and reward-related regions, with prognostic and therapeutic relevance in AN.