Pregnancy renders anatomical changes in hypothalamic substructures of the human brain that relate to aspects of maternal behavior.

Animal studies have shown that pregnancy is associated with neural adaptations that promote maternal care. The hypothalamus represents a central structure of the mammalian maternal brain and hormonal priming of specific hypothalamic nuclei plays a key role in the induction and expression of maternal behavior. In humans, we have previously demonstrated that becoming a mother involves changes in grey matter anatomy, primarily in association areas of the cerebral cortex. In the current study, we investigated whether pregnancy renders anatomical changes in the hypothalamus. Using an advanced delineation technique, five hypothalamic substructures were defined in longitudinal MRI scans of 107 women extracted from two prospective pre-conception cohort studies, including 50 women who were scanned before and after pregnancy and 57 nulliparous control women scanned at a similar time interval. We showed that becoming a mother is associated with volume reductions in the anterior-superior, superior tuberal and posterior hypothalamus. In addition, these structural changes related to hormonal levels during pregnancy and specific aspects of self-reported maternal behavior in late pregnancy, including maternal-fetal attachment and nesting behavior. These findings show that pregnancy leads to changes in hypothalamic anatomy and suggest that these contribute to the development of maternal behavior in humans, supporting the conservation of key aspects of maternal brain circuitry and their role in maternal behavior across species.

Theory of mind during pregnancy and postpartum: A systematic review.

Pregnancy is associated with prominent structural changes in brain areas involved in Theory of Mind (ToM), pointing to the possibility of modifications in ToM-related behavior and brain responses in parents. We performed a systematic review screening for studies that examined ToM in pregnant and/or early postpartum parents. The evaluation of the included 12 studies allowed us to construct an overview of ToM changes during pregnancy and postpartum as well as other associated factors, such as oxytocin, mental health, and parental behavior. Four studies examined ToM changes by comparing pregnant/early postpartum parents with nulliparous parents or prepregnancy measures. They reported no differences between groups measured with a self-report questionnaire but found group differences using an experimental approach. The results from the summarized studies further suggest a mediatory role of oxytocin between ToM and certain parental behavior. In addition, while no link between postpartum depression and ToM was observed, findings do point to an association between depressive and remote maternal behavior and anxious attachment style and ToM abilities in pregnant participants. Research findings regarding the interaction of ToM with both parity and maternal attachment to the fetus are ambivalent. Overall, research on this topic is scarce, limiting our ability to draw firm conclusions and stressing the need for further research on this topic. This review presents an overview of research findings on ToM and associated factors in pregnancy and the postpartum period and discusses directions for future research.

Mapping the effects of pregnancy on resting state brain activity, white matter microstructure, neural metabolite concentrations and grey matter architecture.

While animal studies have demonstrated a unique reproduction-related neuroplasticity, little is known on the effects of pregnancy on the human brain. Here we investigated whether pregnancy is associated with changes to resting state brain activity, white matter microstructure, neural metabolite concentrations and grey matter architecture using a comprehensive pre-conception cohort study. We show that pregnancy leads to selective and robust changes in neural architecture and neural network organization, which are most pronounced in the Default Mode Network. These neural changes correlated with pregnancy hormones, primarily third-trimester estradiol, while no associations were found with other factors such as osmotic effects, stress and sleep. Furthermore, the changes related to measures of maternal-fetal bonding, nesting behavior and the physiological responsiveness to infant cues, and predicted measures of mother-infant bonding and bonding impairments. These findings suggest there are selective pregnancy-related modifications in brain structure and function that may facilitate peripartum maternal processes of key relevance to the mother-infant dyad.

Less can be more: Fine tuning the maternal brain.

PAWLUSKI, J.L., Hoekzema, E., Leuner, B., and Lonstein, J.S. Less can be more: Fine tuning the maternal brain. NEUROSCI BIOBEHAV REV (129) XXX-XXX, 2022. Plasticity in the female brain across the lifespan has recently become a growing field of scientific inquiry. This has led to the understanding that the transition to motherhood is marked by some of the most significant changes in brain plasticity in the adult female brain. Perhaps unexpectedly, plasticity occurring in the maternal brain often involves a decrease in brain volume, neurogenesis and glial cell density that presumably optimizes caregiving and other postpartum behaviors. This review summarizes what we know of the 'fine-tuning' of the female brain that accompanies motherhood and highlights the implications of these changes for maternal neurobehavioral health. The first part of the review summarizes structural and functional brain changes in humans during pregnancy and postpartum period with the remainder of the review focusing on neural and glial plasticity during the peripartum period in animal models. The aim of this review is to provide a clear understanding of when 'less is more' in maternal brain plasticity and where future research can focus to improve our understanding of the unique brain plasticity occurring during matrescence.

Do Pregnancy-Induced Brain Changes Reverse? The Brain of a Mother Six Years after Parturition.

Neuroimaging researchers commonly assume that the brain of a mother is comparable to that of a nulliparous woman. However, pregnancy leads to pronounced gray matter volume reductions in the mother's brain, which have been associated with maternal attachment towards the baby. Beyond two years postpartum, no study has explored whether these brain changes are maintained or instead return to pre-pregnancy levels. The present study tested whether gray matter volume reductions detected in primiparous women are still present six years after parturition. Using data from a unique, prospective neuroimaging study, we compared the gray matter volume of 25 primiparous and 22 nulliparous women across three sessions: before conception (n = 25/22), during the first months of postpartum (n = 25/21), and at six years after parturition (n = 7/5). We found that most of the pregnancy-induced gray matter volume reductions persist six years after parturition (classifying women as having been pregnant or not with 91.67% of total accuracy). We also found that brain changes at six years postpartum are associated with measures of mother-to-infant attachment. These findings open the possibility that pregnancy-induced brain changes are permanent and encourage neuroimaging studies to routinely include pregnancy-related information as a relevant demographic variable.

Becoming a mother entails anatomical changes in the ventral striatum of the human brain that facilitate its responsiveness to offspring cues.

In mothers, offspring cues are associated with a powerful reinforcing value that motivates maternal care. Animal studies show that this is mediated by dopamine release into the nucleus accumbens, a core component of the brain's reward system located in the ventral striatum (VStr). The VStr is also known to respond to infant signals in human mothers. However, it is unknown whether pregnancy modifies the anatomy or functionality of this structure, and whether such modifications underlie its strong reactivity to offspring cues. Therefore, we analyzed structural and functional neuroimaging data from a unique pre-conception prospective cohort study involving first-time mothers investigated before and after their pregnancy as well as nulliparous control women scanned at similar time intervals. First, we delineated the anatomy of the VStr in each subject's neuroanatomical space and examined whether there are volumetric changes in this structure across sessions. Then, we tested if these changes could predict the mothers' brain responses to visual stimuli of their infants. We found decreases in the right VStr and a trend for left VStr reductions in the women who were pregnant between sessions compared to the women who were not. Furthermore, VStr volume reductions across pregnancy were associated with infant-related VStr responses in the postpartum period, with stronger volume decreases predicting stronger functional activation to offspring cues. These findings provide the first indications that the transition to motherhood renders anatomical adaptations in the VStr that promote the strong responsiveness of a mother's reward circuit to cues of her infant.

The Paternal Transition Entails Neuroanatomic Adaptations that are Associated with the Father's Brain Response to his Infant Cues.

The transition into fatherhood is a life-changing event that requires substantial psychological adaptations. In families that include a father figure, sensitive paternal behavior has been shown to positively impact the infant's development. Yet, studies exploring the neuroanatomic adaptations of men in their transition into fatherhood are scarce. The present study used surface-based methods to reanalyze a previously published prospective magnetic resonance imaging dataset comprised of 20 first-time fathers (preconception-to-postpartum) and 17 childless men. We tested if the transition into fatherhood entailed changes in cortical volume, thickness, and area and whether these changes were related to 2 indicators of paternal experience. Specifically, we tested if such changes were associated with (1) the baby's age and/or (2) the fathers' brain activity in response to pictures of their babies compared with an unknown baby. Results indicated that first-time fathers exhibited a significant reduction in cortical volume and thickness of the precuneus. Moreover, higher volume reduction and cortical thinning were associated with stronger brain responses to pictures of their own baby in parental brain regions. This is the first study showing preconception-to-postpartum neuroanatomical adaptations in first-time fathers associated with the father's brain response to cues of his infant.

Pregnancy and adolescence entail similar neuroanatomical adaptations: A comparative analysis of cerebral morphometric changes.

Mapping the impact of pregnancy on the human brain is essential for understanding the neurobiology of maternal caregiving. Recently, we found that pregnancy leads to a long-lasting reduction in cerebral gray matter volume. However, the morphometric features behind the volumetric reductions remain unexplored. Furthermore, the similarity between these reductions and those occurring during adolescence, another hormonally similar transitional period of life, still needs to be investigated. Here, we used surface-based methods to analyze the longitudinal magnetic resonance imaging data of a group of 25 first-time mothers (before and after pregnancy) and compare them to those of a group of 25 female adolescents (during 2 years of pubertal development). For both first-time mothers and adolescent girls, a monthly rate of volumetric reductions of 0.09 mm3 was observed. In both cases, these reductions were accompanied by decreases in cortical thickness, surface area, local gyrification index, sulcal depth, and sulcal length, as well as increases in sulcal width. In fact, the changes associated with pregnancy did not differ from those that characterize the transition during adolescence in any of these measures. Our findings are consistent with the notion that the brain morphometric changes associated with pregnancy and adolescence reflect similar hormonally primed biological processes.

Brain plasticity in pregnancy and the postpartum period: links to maternal caregiving and mental health.

Pregnancy and the postpartum period involve numerous physiological adaptations that enable the development and survival of the offspring. A distinct neural plasticity characterizes the female brain during this period, and dynamic structural and functional changes take place that accompany fundamental behavioral adaptations, stimulating the female to progress from an individual with self-directed needs to being responsible for the care of another life. While many animal studies detail these modifications, an emerging body of research reveals the existence of reproduction-related brain plasticity in human mothers too. Additionally, associations with aspects of maternal caregiving point to adaptive changes that benefit a woman's transition to motherhood. However, the dynamic changes that affect a woman's brain are not merely adaptive, and they likely confer a vulnerability for the development of mental disorders. Here, we review the changes in brain structure and function that a woman undergoes during the peripartum period, outlining associations between these neural alterations and different aspects of maternal care. We additionally discuss peripartum mood disorders and postpartum psychosis, and review the neuroimaging studies that investigate the neural bases of these conditions.

Pregnancy leads to long-lasting changes in human brain structure.

Pregnancy involves radical hormone surges and biological adaptations. However, the effects of pregnancy on the human brain are virtually unknown. Here we show, using a prospective ('pre'-'post' pregnancy) study involving first-time mothers and fathers and nulliparous control groups, that pregnancy renders substantial changes in brain structure, primarily reductions in gray matter (GM) volume in regions subserving social cognition. The changes were selective for the mothers and highly consistent, correctly classifying all women as having undergone pregnancy or not in-between sessions. Interestingly, the volume reductions showed a substantial overlap with brain regions responding to the women's babies postpartum. Furthermore, the GM volume changes of pregnancy predicted measures of postpartum maternal attachment, suggestive of an adaptive process serving the transition into motherhood. Another follow-up session showed that the GM reductions endured for at least 2 years post-pregnancy. Our data provide the first evidence that pregnancy confers long-lasting changes in a woman's brain.

Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes.

Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure.

Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder.

We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD.

The neuroanatomical basis of panic disorder and social phobia in schizophrenia: a voxel based morphometric study.

OBJECTIVE: It is known that there is a high prevalence of certain anxiety disorders among schizophrenic patients, especially panic disorder and social phobia. However, the neural underpinnings of the comorbidity of such anxiety disorders and schizophrenia remain unclear. Our study aims to determine the neuroanatomical basis of the co-occurrence of schizophrenia with panic disorder and social phobia. METHODS: Voxel-based morphometry was used in order to examine brain structure and to measure between-group differences, comparing magnetic resonance images of 20 anxious patients, 20 schizophrenic patients, 20 schizophrenic patients with comorbid anxiety, and 20 healthy control subjects. RESULTS: Compared to the schizophrenic patients, we observed smaller grey-matter volume (GMV) decreases in the dorsolateral prefrontal cortex and precentral gyrus in the schizophrenic-anxiety group. Additionally, the schizophrenic group showed significantly reduced GMV in the dorsolateral prefrontal cortex, precentral gyrus, orbitofrontal cortex, temporal gyrus and angular/inferior parietal gyrus when compared to the control group. CONCLUSIONS: Our findings suggest that the comorbidity of schizophrenia with panic disorder and social phobia might be characterized by specific neuroanatomical and clinical alterations that may be related to maladaptive emotion regulation related to anxiety. Even thought our findings need to be replicated, our study suggests that the identification of neural abnormalities involved in anxiety, schizophrenia and schizophrenia-anxiety may lead to an improved diagnosis and management of these conditions.

Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain.

The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.

Stimulant drugs trigger transient volumetric changes in the human ventral striatum.

The ventral striatum (VStr) integrates mesolimbic dopaminergic and corticolimbic glutamatergic afferents and forms an essential component of the neural circuitry regulating impulsive behaviour. This structure represents a primary target of psychostimulant medication, the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), and is biochemically modified by these drugs in animals. However, the effects of stimulants on the human VStr remain to be determined. We acquired anatomical brain MRI scans from 23 never-medicated adult patients with ADHD, 31 adult patients with a history of stimulant treatment and 32 control subjects, and VStr volumes were determined using individual rater-blinded region of interest delineation on high-resolution neuroanatomical scans. Furthermore, we also extracted VStr volumes before and after methylphenidate treatment in a subsample of the medication-naïve adult patients as well as in 20 never-medicated children with ADHD. We observed smaller VStr volumes in adult patients with a history of stimulant treatment in comparison to never-medicated patients. Moreover, our longitudinal analyses uncovered a reduction of grey matter volume in the bilateral VStr in adult patients after exposure to methylphenidate, which was followed by volumetric recovery to control level. In children, the same pattern of VStr volume changes was observed after treatment with methylphenidate. These findings suggest that the altered VStr volumes previously observed in patients with ADHD may represent a transitory effect of stimulant exposure rather than an intrinsic feature of the disorder. More generally, these data show that stimulant drugs can render plastic volume changes in human VStr neuroanatomy.

An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD.

Spontaneous fluctuations can be measured in the brain that reflect dissociable functional networks oscillating at synchronized frequencies, such as the default mode network (DMN). In contrast to its diametrically opposed task-positive counterpart, the DMN predominantly signals during a state of rest, and inappropriate regulation of this network has been associated with inattention, a core characteristic of attention-deficit/hyperactivity disorder (ADHD). To examine whether abnormalities can be identified in the DMN component of patients with ADHD, we applied an independent components analysis to resting state functional magnetic resonance imaging data acquired from 22 male medication-naïve adults with ADHD and 23 neurotypical individuals. We observed a stronger coherence of the left dorsolateral prefrontal cortex (dlPFC) with the DMN component in patients with ADHD which correlated with measures of selective attention. The increased left dlPFC-DMN coherence also surfaced in a whole-brain replication analysis involving an independent sample of 9 medication-naïve adult patients and 9 controls. In addition, a post hoc seed-to-voxel functional connectivity analysis using the dlPFC as a seed region to further examine this region's suggested connectivity differences uncovered a higher temporal coherence with various other neural networks and confirmed a reduced anticorrelation with the DMN. These results point to a more diffuse connectivity between functional networks in patients with ADHD. Moreover, our findings suggest that state-inappropriate neural activity in ADHD is not confined to DMN intrusion during attention-demanding contexts, but also surfaces as an insufficient suppression of dlPFC signaling in relation to DMN activity during rest. Together with previous findings, these results point to a general dysfunction in the orthogonality of functional networks.

Laminar thickness alterations in the fronto-parietal cortical mantle of patients with attention-deficit/hyperactivity disorder.

Although Attention-Deficit/Hyperactivity Disorder (ADHD) was initially regarded as a disorder exclusive to childhood, nowadays its prevalence in adulthood is well established. The development of novel techniques for quantifying the thickness of the cerebral mantle allows the further exploration of the neuroanatomical profiles underlying the child and adult form of the disorder. To examine the cortical mantle in children and adults with ADHD, we applied a vertex-wise analysis of cortical thickness to anatomical brain MRI scans acquired from children with (n = 43) and without ADHD (n = 41), as well as a group of adult neurotypical individuals (n = 31), adult patients with a history of stimulant treatment (n = 31) and medication-naïve adults with ADHD (n = 24). We observed several clusters of reduced laminar cortical thickness in ADHD patients in comparison to neurotypical individuals. These differences were primarily located in the dorsal attention network, including the bilateral inferior and superior parietal cortex and a section of the frontal cortex (centered on the superior frontal and precentral gyrus bilaterally). Further laminar thickness deficits were observed in the bilateral orbitofrontal cortex and medial occipital cortex. The deficits in the cortical surface were especially pronounced in the child sample, while adult patients showed a more typical laminar thickness across the cerebral mantle. These findings show that the neuroanatomical profile of ADHD, especially the childhood form of the disorder, involves robust alterations in the cortical mantle, which are most prominent in brain regions subserving attentional processing.

In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain.

The GABA-ergic system, known to regulate neural tissue genesis during cortical development, has been postulated to play a role in cerebral aging processes. Using in vivo molecular imaging and voxel-wise quantification, we aimed to assess the effects of aging on the benzodiazepine (BDZ) recognition site of the GABA(A) receptor. To visualize BDZ site availability, [(11)C]-flumazenil microPET acquisitions were conducted in young and old rats. The data were analyzed and region of interest analyses were applied to validate the voxel-wise approach. We observed decreased [(11)C]-flumazenil binding in the aged rat brains in comparison with the young control group. More specifically, clusters of reduced radioligand uptake were detected in the bilateral hippocampus, cerebellum, midbrain, and bilateral frontal and parieto-occipital cortex. Our results support the pertinence of voxel-wise quantification in the analysis of microPET data. Moreover, these findings indicate that the aging process involves declines in neural BDZ recognition site availability, proposed to reflect alterations in GABA(A) receptor subunit polypeptide expression.

Response inhibition and reward anticipation in medication-naïve adults with attention-deficit/hyperactivity disorder: a within-subject case-control neuroimaging study.

BACKGROUND: Previous research suggests that ADHD patients are characterized by both reduced activity in the inferior frontal gyrus (IFG) during response inhibition tasks (such as the Go-NoGo task), and reduced activity in the ventral striatum during reward anticipation tasks (such as the Monetary-Incentive-Delay [MID] task). However, no prior research has applied either of these paradigms in medication-naïve adults with ADHD, nor have these been implemented in an intrasubject manner. METHODS: The sample consisted of 19 medication-naïve adults with ADHD and 19 control subjects. Main group analyses were based on individually defined regions of interest: the IFG and the VStr for the Go-NoGo and the MID task respectively. In addition, we analyzed the correlation between the two measures, as well as between these measures and the clinical symptoms of ADHD. RESULTS: We observed reduced bilateral VStr activity in adults with ADHD during reward anticipation. No differences were detected in IFG activation on the Go-NoGo paradigm. Correlation analyses suggest that the two tasks are independent at a neural level, but are related behaviorally in terms of the variability of the performance reaction time. Activity in the bilateral VStr but not in the IFG was associated negatively with symptoms of hyperactivity/impulsivity. CONCLUSIONS: Results underline the implication of the reward system in ADHD adult pathophysiology and suggest that frontal abnormalities during response inhibition performance may not be such a pivotal aspect of the phenotype in adulthood. In addition, our findings point toward response variability as a core feature of the disorder.