Jiska S. Peper

Genetic influences on human brain structure: A review of brain Imaging studies in twins

Twin studies suggest that variation in human brain volume is genetically influenced. The genes involved in human brain volume variation are still largely unknown, but several candidate genes have been suggested. An overview of structural Magnetic Resonance (brain) Imaging studies in twins is presented, which focuses on the influence of genetic factors on variation in healthy human brain volume. Twin studies have shown that genetic effects varied regionally within the brain, with high heritabilities of frontal lobe volumes (90–95%), moderate estimates in the hippocampus (40–69%), and environmental factors influencing several medial brain areas. High heritability estimates of brain structures were revealed for regional amounts of gray matter (density) in medial frontal cortex, Heschls gyrus, and postcentral gyrus. In addition, moderate to high heritabilities for densities of Brocas area, anterior cingulate, hippocampus, amygdala, gray matter of the parahippocampal gyrus, and white matter of the superior occipitofrontal fasciculus were reported. The high heritability for (global) brain volumes, including the intracranium, total brain, cerebral gray, and white matter, seems to be present throughout life. Estimates of genetic and environmental influences on age‐related changes in brain structure in children and adults await further longitudinal twin‐studies. For prefrontal cortex volume, white matter, and hippocampus volumes, a number of candidate genes have been identified, whereas for other brain areas, only a few or even a single candidate gene has been found so far. New techniques such as genome‐wide scans may become helpful in the search for genes that are involved in the regulation of human brain volume throughout life. Hum Brain Mapp, 2007.

Testosterone Reduces Unconscious Fear but Not Consciously Experienced Anxiety: Implications for the Disorders of Fear and Anxiety

BACKGROUND The fear-reducing properties of testosterone have been firmly established in animals but not in humans. However, human data on the relation between testosterone, fear, and anxiety have predominantly involved questionnaires that index cortically executed conscious appraisal of anxious mood. Animal studies, on the other hand, indicate that the effects of testosterone on motivation and emotion are of subcortical origin and of unconscious nature. Presently, it was hypothesized that a single testosterone administration to humans would reduce unconscious fear but not consciously experienced anxiety. METHODS In a placebo-controlled, double-blind crossover design, a single dose of testosterone (.5 mg) or placebo was administered to 16 healthy female volunteers. Afterward, a masked emotional Stroop task measured unconscious emotional responses to fearful faces, while multiple self-reports of mood indexed consciously experienced anxiety. RESULTS As hypothesized, the habitual vigilant emotional response to the masked fearful face observed in the placebo condition was significantly reduced after testosterone was administered, while the self-reported measures of anxiety remained unaffected. CONCLUSIONS These data provide the first direct evidence for fear-reducing properties of testosterone in humans. Furthermore, by dissociating specific aspects of fear and anxiety in humans, this outcome highlights that testosterones effects on motivation and emotion concern the subcortical affective pathways of the brain.

Heritability of Regional and Global Brain Structure at the Onset of Puberty: A Magnetic Resonance Imaging Study in 9-Year-Old Twin Pairs

Puberty represents the phase of sexual maturity, signaling the change from childhood into adulthood. During childhood and adolescence, prominent changes take place in the brain. Recently, variation in frontal, temporal, and parietal areas was found to be under varying genetic control between 5 and 19 years of age. However, at the onset of puberty, the extent to which variation in brain structures is influenced by genetic factors (heritability) is not known. Moreover, whether a direct link between human pubertal development and brain structure exists has not been studied. Here, we studied the heritability of brain structures at 9 years of age in 107 monozygotic and dizygotic twin pairs (N = 210 individuals) using volumetric MRI and voxel‐based morphometry. Children showing the first signs of secondary sexual characteristics (N = 47 individuals) were compared with children without these signs, based on Tanner‐stages. High heritabilities of intracranial, total brain, cerebellum, and gray and white matter volumes (up to 91%) were found. Regionally, the posterior fronto‐occipital, corpus callosum, and superior longitudinal fascicles (up to 93%), and the amygdala, superior frontal and middle temporal cortices (up to 83%) were significantly heritable. The onset of secondary sexual characteristics of puberty was associated with decreased frontal and parietal gray matter densities. Thus, in 9‐year‐old children, global brain volumes, white matter density in fronto‐occipital and superior longitudinal fascicles, and gray matter density of (pre‐)frontal and temporal areas are highly heritable. Pubertal development may be directly involved in the decreases in gray matter areas that accompany the transition of our brains from childhood into adulthood. Hum Brain Mapp, 2009.

Sex steroids and brain structure in pubertal boys and girls: a mini-review of neuroimaging studies.

Puberty is an important period during development hallmarked by increases in sex steroid levels. Human neuroimaging studies have consistently reported that in typically developing pubertal children, cortical and subcortical gray matter is decreasing, whereas white matter increases well into adulthood. From animal studies it has become clear that sex steroids are capable of influencing brain organization, both during the prenatal period as well as during other periods characterized by massive sex steroid changes such as puberty. Here we review structural neuroimaging studies and show that the changes in sex steroids availability during puberty and adolescence might trigger a period of structural reorganization of grey and white matter in the developing human brain. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

The Teenage Brain Surging Hormones—Brain-Behavior Interactions During Puberty

In this paper, we discuss the surging hormones of puberty and their influences on adolescent behavior. We describe why these issues represent an interesting and important area of investigation, emphasizing their contributions to a specific set of developmental processes at the heart of the transition from childhood to adolescence. We briefly review the neuroendocrine underpinnings of human puberty. Our review focuses on evidence for behavioral (and neurobehavioral) effects of gonadal hormones and emphasizes the social and affective dimensions of these hormonal effects. More broadly, we consider how these hormonal events contribute to brain-behavior interactions that can bias early adolescent trajectories in both positive and negative directions, and in ways that may begin as small influences but can spiral into large-scale effects over time. These influences also appear to play an important role in functional and structural brain development during adolescence. Finally, we offer some thoughts on directions for future research in these areas.

The Teenage Brain

In this paper, we discuss the surging hormones of puberty and their influences on adolescent behavior. We describe why these issues represent an interesting and important area of investigation, emphasizing their contributions to a specific set of developmental processes at the heart of the transition from childhood to adolescence. We briefly review the neuroendocrine underpinnings of human puberty. Our review focuses on evidence for behavioral (and neurobehavioral) effects of gonadal hormones and emphasizes the social and affective dimensions of these hormonal effects. More broadly, we consider how these hormonal events contribute to brain-behavior interactions that can bias early adolescent trajectories in both positive and negative directions, and in ways that may begin as small influences but can spiral into large-scale effects over time. These influences also appear to play an important role in functional and structural brain development during adolescence. Finally, we offer some thoughts on directions for future research in these areas.

Delay Discounting and Frontostriatal Fiber Tracts: A Combined DTI and MTR Study on Impulsive Choices in Healthy Young Adults

Delay discounting, a measure of impulsive choice, has been associated with decreased control of the prefrontal cortex over striatum responses. The anatomical connectivity between both brain regions in delaying gratification remains unknown. Here, we investigate whether the quality of frontostriatal (FS) white matter tracts can predict individual differences in delay-discounting behavior. We use tract-based diffusion tensor imaging and magnetization transfer imaging to measure the microstructural properties of FS fiber tracts in 40 healthy young adults (from 18 to 25 years). We additionally explored whether internal sex hormone levels affect the integrity of FS tracts, based on the hypothesis that sex hormones modulate axonal density within prefrontal dopaminergic circuits. We calculated fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity, radial diffusivity (RD), and magnetization transfer ratio (MTR), a putative measure of myelination, for the FS tract. Results showed that lower integrity within the FS tract (higher MD and RD and lower FA), predicts faster discounting in both sexes. MTR was unrelated to delay-discounting performance. In addition, testosterone levels in males were associated with a lower integrity (higher RD) within the FS tract. Our study provides support for the hypothesis that enhanced structural integrity of white matter fiber bundles between prefrontal and striatal brain areas is associated with better impulse control.

Cerebral white matter in early puberty is associated with luteinizing hormone concentrations

Puberty is a period in which cerebral white matter grows considerably, whereas gray matter decreases. The first endocrinological marker of puberty in both boys and girls is an increased secretion of luteinizing hormone (LH). Here we investigated the phenotypic association between LH, global and focal gray and white matter in 104 healthy nine-year-old monozygotic and dizygotic twins. Volumetric MRI and voxel-based morphometry were applied to measure global gray and white matter and to estimate relative concentrations of regional cerebral gray and white matter, respectively. A possible common genetic origin of this association (genetic correlation) was examined. Results showed that higher LH levels are associated with a larger global white matter proportion and with higher regional white matter density. Areas of increased white matter density included the cingulum, middle temporal gyrus and splenium of the corpus callosum. No association between LH and global gray matter proportion or regional gray matter density was found. Our data indicate that a common genetic factor underlies the association between LH level and regional white matter density. We suggest that the increase of white matter growth during puberty reported earlier might be directly or indirectly mediated by LH production. In addition, genes involved in LH production may be promising candidate genes in neuropsychiatric illnesses with an onset in early adolescence.

Genetic influences on thinning of the cerebral cortex during development

During development from childhood to adulthood the human brain undergoes considerable thinning of the cerebral cortex. Whether developmental cortical thinning is influenced by genes and if independent genetic factors influence different parts of the cortex is not known. Magnetic resonance brain imaging was done in twins at age 9 (N = 190) and again at age 12 (N = 125; 113 repeated measures) to assess genetic influences on changes in cortical thinning. We find considerable thinning of the cortex between over this three year interval (on average 0.05 mm; 1.5%), particularly in the frontal poles, and orbitofrontal, paracentral, and occipital cortices. Cortical thinning was highly heritable at age 9 and age 12, and the degree of genetic influence differed for the various areas of the brain. One genetic factor affected left inferior frontal (Brocas area), and left parietal (Wernickes area) thinning; a second factor influenced left anterior paracentral (sensory-motor) thinning. Two factors influenced cortical thinning in the frontal poles: one of decreasing influence over time, and another independent genetic factor emerging at age 12 in left and right frontal poles. Thus, thinning of the cerebral cortex is heritable in children between the ages 9 and 12. Furthermore, different genetic factors are responsible for variation in cortical thickness at ages 9 and 12, with independent genetic factors acting on cortical thickness across time and between various brain areas during childhood brain development.

High frequency repetitive transcranial magnetic over the medial cerebellum induces a shift in the prefrontal electroencephalography gamma spectrum: a pilot study in humans

In the present study the anatomical projections from the medial cerebellum to the prefrontal cortex (PFC) were investigated in healthy human subjects, using high frequency repetitive transcranial magnetic (rTMS) stimulation and electroencephalography (EEG). Medial cerebellar rTMS, compared to placebo induced a significant shift in anterior asymmetry, from left to right dominance in the fast (30-50 Hz) EEG spectrum, whereas occipital and lateral cerebellum stimulation did not show such an effect. Moreover elevations in mood and alertness were reported again after medial cerebellar stimulation only. Taken together, these data confirm and further specify the assumed cerebellar modulation of PFC activity and affect.