William J. Cutter

Influence of X chromosome and hormones on human brain development: a magnetic resonance imaging and proton magnetic resonance spectroscopy study of Turner syndrome.

BACKGROUND Women with Turner syndrome (TS; 45,X) lack a normal second X chromosome, and many are prescribed exogenous sex and growth hormones (GH). Hence, they allow us an opportunity to investigate genetic and endocrine influences on brain development. METHODS We examined brain anatomy and metabolism in 27 adult monosomic TS women and 21 control subjects with volumetric magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS In TS women, regional gray matter volume was significantly smaller in parieto-occipital cortex and caudate nucleus and larger in cerebellar hemispheres. White matter was reduced in the cerebellar hemispheres, parieto-occipital regions, and splenium of the corpus callosum but was increased in the temporal and orbitofrontal lobes and genui of corpus callosum. Women with TS had a significantly lower parietal lobe concentration of N-acetyl aspartate, and higher hippocampal choline. Also, among women with TS, there were significant differences in regional gray matter volumes and/or neuronal integrity, depending upon parental origin of X chromosome and oxandrolone and GH use. CONCLUSIONS X chromosome monosomy, imprinting and neuroendocrine milieu modulate human brain development-perhaps in a regionally specific manner.

Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study

BACKGROUND Autistic spectrum disorder (ASD) is characterized by stereotyped/obsessional behaviours and social and communicative deficits. However, there is significant variability in the clinical phenotype; for example, people with autism exhibit language delay whereas those with Asperger syndrome do not. It remains unclear whether localized differences in brain anatomy are associated with variation in the clinical phenotype. METHOD We used voxel-based morphometry (VBM) to investigate brain anatomy in adults with ASD. We included 65 adults diagnosed with ASD (39 with Asperger syndrome and 26 with autism) and 33 controls who did not differ significantly in age or gender. RESULTS VBM revealed that subjects with ASD had a significant reduction in grey-matter volume of medial temporal, fusiform and cerebellar regions, and in white matter of the brainstem and cerebellar regions. Furthermore, within the subjects with ASD, brain anatomy varied with clinical phenotype. Those with autism demonstrated an increase in grey matter in frontal and temporal lobe regions that was not present in those with Asperger syndrome. CONCLUSIONS Adults with ASD have significant differences from controls in the anatomy of brain regions implicated in behaviours characterizing the disorder, and this differs according to clinical subtype.

The neuroprotective effects of estrogen on the aging brain

The population of the western world is ageing. This increase in the elderly population will inevitably mean a rise in the prevalence of age-related cognitive decline and late-onset neuropsychiatric disorder, such as Alzheimers disease (AD). There are sex differences in the incidence and age of onset of these disorders. Sex steroids and sex chromosomes are therefore implicated in their pathophysiology. We have identified relevant past and current literature using a Medline search and from the references of relevant papers. These were then reviewed and relevant articles have been summarized and included in the review. Evidence is presented for the wide-ranging actions of estrogen in the brain at the cellular, metabolic and neurotransmitter levels as well as from the cognitive, AD, depression and cerebrovascular perspectives. The authors conclude that it is unlikely that estrogen will become a stand-alone treatment for any of these disorders, although there may still be a role as an adjunctive treatment and as a prophylactic measure.

Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

The influence of sex chromosome aneuploidy on brain asymmetry.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X–Y homologous gene [Crow (1993); Lancet 342:594–598]. In particular, females with Turners syndrome (TS) who have only one X‐chromosome exhibit deficits of spatial ability whereas males with Klinefelters syndrome (KS) who possess a supernumerary X‐chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crows prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal–occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero‐posterior axis.

Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women--a preliminary study.

Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinsons disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic system by sex hormones, as there is preliminary evidence that estrogen modulates treatment response in these disorders. Furthermore, sex differences in dopamine-mediated cognitive decline suggest estrogen may also play a role in healthy aging. However, the effects of estrogen on the dopaminergic system are poorly understood, and nobody has examined the effect of long-term estrogen therapy (ET) on this system. We compared dopaminergic responsivity (growth hormone (GH) response to apomorphine) in post-menopausal women on ET to women who were ET-naïve. GH response to subcutaneous apomorphine (0.005 mg/kg) was measured in two groups of healthy post-menopausal women aged between 55 and 70 years: those taking ET (n = 13) and those who had never taken ET (n = 13). Neither group was taking any other medication. GH was measured at 15 min intervals from -30 min before administration of apomorphine to 90 min post-administration. GH response was measured in two ways: area under the curve (AUC) and maximum response over baseline (GH). There were no between-group differences in demographic or baseline variables. The ET treated women had a significantly greater (p = 0.03) AUC than ET naïve women (mean +/- S.D.; 5.3 +/- 4.7 vs. 2.6 +/- 2.3). However, (GH) did not differ significantly between groups (6.1 mU/l +/- 6.2 vs. 2.7 mU/l +/- S.D. = 4.1). Also, analysis of GH response over time revealed a significant main effect of time (p < 0.0005), and a group by time interaction (p = 0.004) , but no significant main effect of group. Our results suggest that ET may enhance dopaminergic responsivity in post-menopausal women. Estrogen deficiency following menopause may partly explain age and gender differences in late-onset neuropsychiatric disorders.

Oestrogen, brain function, and neuropsychiatric disorders

Oestrogen has multiple effects on brain function There is an increasing amount of research on the neurobiological effects of oestrogen. Also, health professionals are being asked for guidance on whether women should be prescribed oestrogen and progestogen hormone replacement therapy (HRT) not only to treat vasomotor instability and reduce bone loss, but also in various neuropsychiatric disorders. However, it is controversial whether oestrogen is indicated in the treatment of disorders such as depression, Alzheimer’s disease, and schizophrenia. A recent large scale study examining the effects of HRT, funded by the National Institutes of Health (NIH) in the USA, was prematurely terminated owing to increased rates of breast cancer, heart disease, and stroke.1 Shortly afterwards, the WISDOM trial funded by the MRC in the United Kingdom was also terminated. This has reinforced the need to have solid indications for the use of oestrogen-only replacement therapy. Oestrogens affect the development and aging of brain regions that are crucial to higher cognitive functions (like memory) and are implicated in neuropsychiatric disorders such as Alzheimer’s disease. For example, oestrogens increase synaptic and dendritic spine density in the hippocampus. In rats, oophrectomy results in a decrease in dendritic spine density in CA1 pyramidal cells, but this is prevented by the administration of oestrogens. Moreover, synaptic spine density is related to circulating oestradiol levels.2 Until recently it was unclear how these oestrogen induced dendritic changes affected neuronal function. However, it has now been shown that oestrogen induces an increase in N-methyl-D-aspartate (NMDA) receptors in rat hippocampal neurones in the same region where an increase in dendritic spines is found, suggesting that the “new” oestrogen-induced spines are excitatory.3,4 Among the most biologically plausible explanations why HRT might ameliorate age associated deficits in memory are modulatory effects on the cholinergic system in brain regions …

5-HT, prefrontal function and aging: fMRI of inhibition and acute tryptophan depletion

Age-related declines in prefrontal functions and age-related declines in prefrontal serotonin (5-HT) are documented. The effect of 5-HT on prefrontal cortex (PFC) is also documented; however, no one has examined the effect of experimental 5-HT modulation on PFC in healthy older adults. We investigated the effect of 5-HT on brain functioning in 10 women over 55 (mean=63.0+/-5.3 years) during cognitive interference inhibition (Simon task) using fMRI and acute tryptophan depletion (ATD). ATD did not affect task performance; it did affect brain function. During sham/no depletion, participants activated brain regions associated with the Simon (e.g., left inferior PFC). During ATD, there was no prefrontal but alternative posterior brain activation. ATD relative to sham reduced activity in left inferior PFC, anterior cingulate and basal ganglia but increased activity within neocerebellum and parietal lobe. In older adults, ATD modulates task-relevant brain activation for cognitive interference inhibition and is associated with an anterior-to-posterior activation shift. Maintaining successful Simon performance during ATD is achieved by increasing cerebellar and parietal contributions to compensate for decreased fronto-cingulo-striatal involvement.

In Vivo Effects of Estrogen on Human Brain

Abstract: Age‐related brain disorders such as Alzheimers disease (AD) are becoming increasingly prevalent. Estrogen replacement therapy (ERT) has shown potential both as a preventive measure and treatment for such disorders. Good evidence from basic science demonstrates that estrogen has multiple protective effects on neurons and neurotransmitter systems, and the effects of ERT can be demonstrated on the human brain using techniques such as functional neuroimaging. However, the evidence for estrogens having a clinical role in the treatment and prevention of neuropsychiatric disorders is not well established. In this article we review research into the effects of estrogen on the human brain and we consider the role for ERT as a therapeutic tool.

Acute tryptophan depletion promotes an anterior-to-posterior fMRI activation shift during task switching in older adults

Studies have long reported that aging is associated with declines in several functions modulated by the prefrontal cortex, including executive functions like working memory, set shifting, and inhibitory control. The neurochemical basis to this is poorly understood, but may include the serotonergic system. We investigated the modulatory effect of serotonin using acute tryptophan depletion (ATD) during a cognitive switching task involving visual‐spatial set shifting modified for a functional MRI environment. Ten healthy women over 55 years were tested on two separate occasions in this within‐group double‐blind sham‐controlled crossover study to compare behavioral and physiological brain functioning following ATD and following a (“placebo”) sham depletion condition. ATD did not significantly affect task performance. It did modulate brain functional recruitment. During sham depletion women significantly activated the expected task‐relevant brain regions associated with the Switch task including prefrontal and anterior cingulate cortices. In contrast, following ATD participants activated posterior regions of brain more during switch than repeat trials. In addition to the main effects of depletion condition, a comparison of the ATD relative to the sham condition confirmed this anterior‐to‐posterior shift in activation. The posterior (increased) activation clusters significantly and negatively correlated with the reduced prefrontal activation clusters suggesting a compensation mechanism for reduced prefrontal activation during ATD. Thus, serotonin modulates an anterior‐to‐posterior shift of activation during cognitive switching in older adults. Neural adaptation to serotonin challenge during cognitive control may prove useful in determining cognitive vulnerability in older adults with a predisposition for serontonergic down‐regulation (e.g., in vascular or late life depression). Hum Brain Mapp 35:712–722, 2014.