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).

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.

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 Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's 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 Crow's 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.

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.

Women with autistic-spectrum disorder: magnetic resonance imaging study of brain anatomy.

BACKGROUND: Our understanding of anatomical differences in people with autistic-spectrum disorder, is based on mixed-gender or male samples. AIMS: To study regional grey-matter and white-matter differences in the brains of women with autistic-spectrum disorder. METHOD: We compared the brain anatomy of 14 adult women with autistic-spectrum disorder with 19 controls using volumetric magnetic resonance imaging and voxel-based morphometry. RESULTS: Women with autistic-spectrum disorder had a smaller density bilaterally of grey matter in the fronto-temporal cortices and limbic system, and of white matter in the temporallobes (anterior) and pons. In contrast, they had a larger white-matter density bilaterally in regions of the association and projection fibres of the frontal, parietal, posterior temporal and occipital lobes, in the commissural fibres of the corpus callosum (splenium) and cerebellum (anterior lobe). Further, we found a negative relationship between reduced grey-matter density in right limbic regions and social communication ability. CONCLUSIONS: Women with autistic-spectrum disorder have significant differences in brain anatomy from controls, in brain regions previously reported as abnormal in adult men with the disorder. Some anatomical differences may be related to clinical symptoms.

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.

Oestrogen: brain ageing, cognition and neuropsychiatric disorder.

The effects of oestrogen on brain ageing, cognition and neuropsychiatric disorder are an important public health issue, which, despite intensive research, has yet to be resolved. Evidence from basic science demonstrates that oestrogen has multiple protective effects on neurons and neurotransmitter systems. However, the evidence for oestrogen having a clinical role in the treatment and prevention of neuropsychiatric disorders is not well established. Here we review research into the effects of oestrogen on brain maturation and function and discuss the role for oestrogen replacement therapy (ERT) as a therapeutic tool.

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 Alzheimer's 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.

In vivo effects of estrogen on human brain.

Age-related brain disorders such as Alzheimer's 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 estrogen's 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.