Neural basis of impaired cognitive flexibility in patients with anorexia nervosa.

BACKGROUND: Impaired cognitive flexibility in anorexia nervosa (AN) causes clinical problems and makes the disease hard to treat, but its neural basis has yet to be fully elucidated. The purpose of this study was to evaluate the brain activity of individuals with AN while performing a task requiring cognitive flexibility on the Wisconsin Card Sorting Test (WCST), which is one of the most frequently used neurocognitive measures of cognitive flexibility and problem-solving ability. METHODS: Participants were 15 female AN patients and 15 age- and intelligence quotient-matched healthy control women. Participants completed the WCST while their brain activity was measured by functional magnetic resonance imaging during the task. Brain activation in response to set shifting error feedback and the correlation between such brain activity and set shifting performance were analyzed. RESULTS: The correct rate on the WCST was significantly poorer for AN patients than for controls. Patients showed poorer activity in the right ventrolateral prefrontal cortex and bilateral parahippocampal cortex on set shifting than controls. Controls showed a positive correlation between correct rate and ventrolateral prefrontal activity in response to set shifting whereas patients did not. CONCLUSION: These findings suggest dysfunction of the ventrolateral prefrontal cortex and parahippocampal cortex as a cause of impaired cognitive flexibility in AN patients.

Increased brain histamine H1 receptor binding in patients with anorexia nervosa.

BACKGROUND: The central histaminergic neuron system modulates various brain functions, including eating behavior. We hypothesized that women have higher density of histamine H1 receptor (H1R) in the limbic system than men and that the density of central H1R is increased in patients with anorexia nervosa (AN). METHODS: Subjects were 12 female AN patients, 12 healthy female subjects, and 11 healthy male subjects. Positron emission tomography with H1R radioligand [(11)C]doxepin was performed on all subjects and regions of interest based analysis was conducted to evaluate brain H1R binding potential (BP). Abnormal eating behavior, depression, and anxiety of subjects were evaluated using the Eating Attitude Test-26 (EAT-26), Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI), respectively. RESULTS: Binding potential of [(11)C]doxepin in female subjects was significantly higher than that in male subjects at the following brain sites: amygdala, hippocampus, medial prefrontal cortex, orbitofrontal cortex, and temporal cortex. Anorexia nervosa patients showed significantly higher BP of [(11)C]doxepin in the amygdala and lentiform nucleus than the control female subjects. In AN patients, BP of [(11)C]doxepin in the amygdala and thalamus negatively correlated with EAT-26 scores. There was a significant negative correlation between BP of [(11)C]doxepin and SDS or STAI scores in the amygdala, anterior cingulate cortex, and orbitofrontal cortex of AN patients. CONCLUSIONS: These findings support the hypothesis that women have higher H1R density in the limbic system than men and suggest that AN patients may have higher expression of H1R in the limbic brain, particularly in the amygdala.

Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety.

OBJECTIVE: The objective of this study was to verify the hypothesis that variation of the serotonin transporter gene promoter region (5-HTTLPR) is associated with sensitivity to stress. METHODS: Genotyping of 5-HTTLPR and evaluation of emotional states were performed on 194 participants. Participants' emotional states were evaluated using the Perceived-Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Self-rating Depression Scale (SDS). RESULTS: There was significant GenderxGenotype interaction in STAI (state, P<.05; trait, P<.05). Females with the l/s genotype showed higher anxiety than those with the s/s genotype in both state and trait anxiety. Oppositely, males with the s/s genotype showed higher anxiety than those with the l/s genotype. CONCLUSION: On all emotional scales, females with the l/s genotype showed high scores, contrary to males with the same genotype. Therefore, our results suggest that 5-HTTLPR l allele may be one pathway that activates negative emotion in females but acts contrary in males.

The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH release in normal subjects.

OBJECTIVE: The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH secretion was studied in man using a GHRH antagonist (GHRH-Ant). DESIGN: Ten healthy adult males were studied for serum GH responses to arginine or insulin singly, or sequentially 120 min after GHRH injection with or without combined administration of GHRH-Ant. Further, GHRH, clonidine or l-dopa were sequentially administered to these subjects 120 min after the GHRH injection. RESULTS: The combined administration of GHRH-Ant distinctly inhibited the arginine- and insulin-induced GH release. When these four agents were sequentially administered 120 min after GHRH injection, the GH responses to clonidine and l-dopa disappeared completely while clear responses were observed to arginine and insulin administration. These responses to arginine and insulin were also completely inhibited by the combined administration of GHRH-Ant. CONCLUSIONS: These results indicate that clonidine and l-dopa stimulate GH secretion mainly through the release of hypothalamic GHRH, and that arginine- and insulin-induced hypoglycaemia stimulate GH secretion mainly through the inhibition of hypothalamic somatostatin release. However, the presence of endogenous hypothalamic GHRH seems to be essential for the maximal stimulation of GH release induced by arginine and insulin.

Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome.

BACKGROUND: Visceral hypersensitivity is one of the mechanisms of irritable bowel syndrome (IBS), but it does not explain the entire symptomatology, i.e., altered bowel habit with abdominal pain relieved by defecation. We tested our hypothesis that an abnormal link between luminal stimulation and mural response may have some role in the pathophysiology of IBS. METHODS: Patients with IBS (n = 10, median 21 years old, 5 male patients, 5 female patients) and healthy control subjects (n = 10, median 21 years old, 5 men, 5 women) were studied. A manometric catheter with three transducers was inserted to the descending colon and a balloon was placed in the distal sigmoid colon. Another catheter with three transducers was inserted to the duodenum. After baseline for 30min, the sigmoid colon was stimulated by balloon distention for 30min followed by recovery for 30min. Balloon distention was repeated 100 times, and each stimulation consisted of a 5-s inflation and a 10-s deflation, with a volume of 50ml maximum. The sensory threshold of balloon inflation was then examined, and plasma adrenocorticotropic hormone (ACTH) was measured with radioimmunoassay. RESULTS: Repetitive colonic distention induced a significant increase in motility indices (mmHg s/s%) of the descending colon in the IBS patients (from 118 +/- 25 to 333 +/- 108, P < 0.05) but not of those in controls (from 90 +/- 16 to 89 +/- 19). A significant group difference (P < 0.05), period effect (P < 0.02), and group x period interactions (P < 0.01) were detected with two-way ANOVA. Duodenal motility indices in controls were significantly reduced by colonic distention (from 169 +/- 25 to 104 +/- 14, P < 0.01), but those in the IBS patients were not (from 156 +/- 17 to 124 +/- 20). The sensory threshold of balloon inflation in the IBS patients (74 +/- 10ml) was significantly lower than that in controls (125 +/- 6ml, P < 0.001). There was no significant difference in plasma ACTH levels between the IBS patients and controls. CONCLUSIONS: Repetitive distention of the distal sigmoid colon below the sensory threshold induced orad exaggerated motility of the colon in IBS patients. The distention inhibited motility of the small intestine in healthy subjects, but this inhibition was blunted in IBS patients. These results suggest that IBS patients may have not only visceral hypersensitivity, but also an abnormal intestinal reflex.