Anorexia nervosa (AN) is a severe eating disorder that typically begins during adolescence. It is the third most common chronic illness affecting adolescent females and has the highest mortality rate among all psychiatric disorders. Chronic starvation associated with AN results in medical complications that affect every organ system in the body. In adolescent-onset AN, a particularly concerning complication involves abnormalities in neuroanatomy or neurofunctional such as brain structure and cognitive function. Dynamic structural brain changes and cognitive maturation that occur during adolescence may be compromised by AN with long-term consequences. Cognitive deficits may also hinder treatment efforts and contribute to illness chronicity.
The relationship between menstrual function and cognitive functioning in female subjects with adolescent-onset AN has reported by Harold. The volumetric analysis of brain structure supports the reversibility of structural brain abnormalities after weight recovery and correction of hypercortisolemia. Moreover, cognitive function and brain structure were differentially associated with clinical variables, menstrual status and cortisol levels, respectively. Taken together, future research in adolescent-onset AN should focus on the interaction between sex hormones and neurotransmitter systems that may not manifest as detectable structural brain changes. Clinical investigation addressing the role of estrogen in mediating cognitive function in AN also requires additional study.
Although acutely ill patients with AN show smaller brain tissue volumes and deficits in broad neuropsychological functioning, the current literature is inconclusive about the temporal course, mechanisms, and reversibility of these abnormalities.
Inconsistent findings may be attributed to study design limitations, such as small sample size, short follow-up periods, and the lack of appropriate control groups. The lack of a consistent definition of recovery also makes cross-study comparisons difficult.
Magnetic resonance (MR) studies demonstrated the persistence of gray-matter deficits and cerebrospinal fluid (CSF) elevations but normal white-matter volumes among weight-restored participants with adolescent-onset AN. These findings suggest incomplete reversibility of structural brain abnormalities in this patient group. Moreover, gray-matter volumes were positively associated with BMI and negatively associated with 24-hour urinary free cortisol (UFC) when patients were acutely ill with AN. Examination of these clinical variables at follow-up could help clarify their roles in mediating neural abnormalities in adolescent-onset AN.
Although weight restoration is an important goal of treatment and indicator of recovery from AN, menstrual function may remain abnormal in some weight-recovered patients and normal in some low-weight patients.29 These observations highlight the possibility that weight and menstrual function may have independent effects on brain structure and cognitive function in AN. Research has shown that low circulating estrogen levels, coupled with amenorrhea, have been associated with cognitive impairment in animals and humans.
No studies have examined the specific relationship between menstrual function and brain structure or cognitive function in female subjects with adolescent-onset AN.
Despite a long time interval (>6 years) since the initial diagnosis of AN, clinical participants exhibited ventricular enlargements, which are commonly reported during the acute stages of AN.8–17 Additional examination revealed that only participants who remained low weight had these anomalies; weight-recovered participants had intermediate ventricular volumes that did not differ from either low-weight participants or control subjects. This observation is consistent with previous reports of ventricular volume reduction to normal levels with weight recovery.11–13,17
Harold reported that volumes of total gray matter, white matter, and CSF were comparable between clinical participants and control subjects. These results replicate some studies but contradict others. Mixed findings may be attributed to differences in patient variables, such as length of follow-up. In a previous study by our group that reported reductions in gray matter and white matter volumes in recovered patients,11 the follow-up period was 2.7 ± 0.3 years compared with 6.5 ± 1.7 years in the present study. Another explanation may relate to differences in the ability to detect volume changes in the ventricles compared with gross tissue compartments. Assuming that the ventricles expand to fill losses in brain tissue volume, the same absolute volume change represents different percentage changes depending on the size of the brain regions measured. Therefore, changes in small regions, such as the ventricles, may be a more sensitive indicator of structural brain abnormalities than changes in total tissue volume.
Although weight recovery may be associated with the reversal of structural brain abnormalities in adolescent-onset AN, the mechanism through which this effect is achieved remains unclear. In this regard, nutrition may not be the sole factor, because current BMI was not correlated with volumetric brain measures in clinical participants. Clinical participants and control subjects also had comparable blood pressures, serum albumin, and total protein levels, which suggests that dehydration and altered oncotic pressure are unlikely mechanisms for structural brain abnormalities observed in our participants with AN. Alternatively, high cortisol levels have been associated with structural brain abnormalities during the acute stages of AN. Indeed, in the current follow-up study, cortisol levels were negatively correlated with hippocampal volumes and positively correlated with temporal horn volumes in clinical participants. Sensitivity of the hippocampus to cortisol because of the dense population of corticosteroid receptors62 and proximity of the temporal horn to the hippocampus may explain why significant correlations were detected in these regions. The relationship between cortisol levels and structural brain abnormalities seems to persist into the recovery stages of AN.
Although clinical participants had higher cortisol levels than control subjects, their mean level was within the reference range. Consistent with previous research, this result suggests that cortisol levels normalize after weight recovery in AN.35 Correction of hypercortisolemia has also been associated with reversal of structural brain abnormalities in Cushing syndrome.
Notably, children and adolescents with Cushing syndrome may experience especially rapid and complete reversal of structural brain abnormalities compared with adult patients. These observations may explain why normal hippocampal volumes were found in participants with adolescent-onset AN in this study, whereas sustained hippocampal shrinkage was seen in patients with primarily adult-onset AN.59 In addition, amygdala volumes may not increase with corrected hypercortisolemia, even in children with Cushing syndrome.
Inclusion of the amygdala in the previous hippocampal analysis may also explain differences in findings. The parallels between adolescent-onset AN and Cushing syndrome in terms of structural brain abnormalities during periods of hypercortisolemia, reversal of anomalies after decline of cortisol levels, and perhaps better potential for younger patients to achieve such reversals64 underscore the possibility that cortisol levels may contribute to the development of structural brain changes in adolescent-onset AN.
Participants with a history of adolescent-onset AN showed deficits in cognitive functioning over a broad range of neuropsychological domains compared with healthy control subjects. In terms of clinical correlates, we replicated previous reports of the lack of association between cognitive performance and weight recovery, cortisol levels, and severity of comorbid psychiatric symptoms. In contrast, clinical participants who remained amenorrheic or had irregular menses had the lowest scores on all of the tested domains, followed by those who had resumed menses or who were on OCP, and was highest among healthy control subjects. Importantly, effect sizes between participants with absent or irregular menses and control subjects were large, whereas participants with regular menses had similar scores to those on OCP and did not differ from control subjects. Amenorrhea or menstrual irregularity may, thus, be associated with cognitive impairments in adolescent-onset AN.
The influence of estrogen and menstrual function on cognitive performance is an active area of research in several female conditions, including menopause, surgically induced menopause, premature ovarian failure, and Turner’s syndrome. Abnormal menstrual function and estrogen depletion are generally associated with the presence of cognitive deficiencies. Notably, these effects may be more pronounced in younger than older female subjects,68 making menstrual function especially relevant in the study of cognitive functioning in adolescent-onset AN.
The mechanisms through which menstrual function influences cognitive function in adolescent-onset AN are unclear. One possibility is by modification of brain structure. Reduced circulating estrogen after ovariectomy led to a loss of dendritic spines of the CA1 hippocampal pyramidal cells69 and impaired working memory in rodents. Although the microscopic examination of dendritic spines is not feasible in live humans, we could not detect greater volumetric abnormalities among participants with absent or irregular menses in this study. A logistic regression conducted retrospectively additionally demonstrated the lack of contribution of menstrual function to structural brain volumes, in contrast to cognitive function. Using menstrual status as the dependent variable (amenorrhea or irregular menses versus regular menses or OCP) and volumes of the temporal horn and hippocampus (both block 1) and oral language scores (block 2) as the independent variables, oral language scores Another possible mechanism involves the ability of estrogen to improve blood circulation. Increased cerebral blood flow has been documented in menopausal women receiving estrogen replacement therapy. In particular, gains were most significant in the temporal and parietal lobes. Similar increases in blood flow to brain regions such as the hippocampus may occur in female subjects with adolescent-onset AN after the resumption of regular menses, protecting the brain from metabolic compromise associated with hypoxia.
Estrogen may also modulate cognition by altering neurotransmission. In rats, ovariectomy has been shown to reduce serotonin 2A receptor density, which, in turn, increased after estradiol administration. Postmenopausal women receiving estrogen also had increased serotonin 2A receptor binding. In contrast, serotonin 1A receptor mRNA and binding decreased after estradiol treatment in ovariectomized rats. Functionally, estrogen enhanced serotonin 1A-mediated acetylcholine release that is important in learning and memory and may modulate serotonin 2A receptor-mediated working memory and executive function. It is, therefore, conceivable that fluctuating estrogen levels influence cognition in AN by altering the dynamics of the serotonin system.
Reduced and increased binding of the serotonin 2A and serotonin 1A receptors, respectively, have been found in low-weight and weight-recovered participants with AN. Although these differences may reflect preexisting anomalies, low circulating estrogen levels associated with amenorrhea may sustain or exacerbate underlying serotonin abnormalities. Although no association was found between estradiol levels and serotonin 1A or 2A binding in 1 study, a small sample size and restricted estradiol ranges could have precluded detection of significant findings. How serotonin transmission influences cognitive functioning in AN is not clear at present, but possible aggravation of existing serotonergic abnormalities by estrogen depletion underscores that the return of menstrual function and normal circulating estrogen levels may be key in reducing the magnitude of neural or cognitive abnormalities or both in adolescent-onset AN.
Women with anorexia nervosa (AN) have aberrant cognitions about food and altered activity in prefrontal cortical and somatosensory regions to food images. However, differential effects on the brain when thinking about eating food between healthy women and those with AN is unknown.
Preliminary data suggest that thinking about eating food shown in images increases visual and prefrontal cortical neural responses in females with AN, which may underlie cognitive biases towards food stimuli and ruminations about controlling food intake. Future studies are needed to explicitly test how thinking about eating activates restraint cognitions, specifically in those with restricting vs. binge-purging AN subtypes.
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