Neuropathological investigation of patients with prolonged anorexia nervosa

OBJECTIVES: Recent neuroimaging studies have indicated that the mesolimbic pathway, known to work as reward neuronal circuitry, regulates cognitive–behavioral flexibility in prolonged anorexia nervosa (AN). Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues. METHODS: The neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum. RESULTS: Histologically, neuronal deformation with cytoplasmic shrinkage was seen in reward‐related brain regions, such as the orbitofrontal cortex/anterior cingulate cortex. The NAcc showed massive GFAP‐positive astrocytes and dot‐like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP‐positive astrocytes in the NAcc (P = 0.0079) and VTA (P = 0.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18 to 25 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway. CONCLUSION: Our findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward‐related network might induce neuropsychiatric symptoms associated with AN.