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International audience; 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.

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&rsquo, 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.

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. Ministerio de Ciencia, Innovación y Universidades project (RTI2018-093952-B-100); Instituto de Salud Carlos III projects (CP16/00096 and PI17/00064); cofunded by European Regional Development Fund, “A way of making Europe” and by “La Caixa” Foundation under the project code LCF/PR/HR19/52160001, and by the European Research Council under the project code 883069. The project ASPIDE has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement number 801091. M.M.G. and S.S.C. were funded by Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (PFIS contract FI18/00255 and Miguel Servet Type I research contract CP16/00096, respectively), and cofunded by European Social Fund “Investing in your future.” The Centro Nacional de Investigaciones Cardiovasculares is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

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 noneiparous 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. This project was supported by an Innovational Research Incentives Scheme grant (Veni, 451-14-036 ) by the Netherlands Organisation for Scientific Research (NWO), the Netherlands , and a NARSAD Grant from the Brain & Behavior Research Foundation, U.S.A. (grant number 25312 ) awarded to Elseline Hoekzema, as well as a Ministerio de Ciencia, Innovación y Universidades (Spain) Instituto de Salud Carlos III project ( PI17/00064 ) and a Miguel Servet Type I research contract CP16/00096 awarded to Susanna Carmona. In addition, Magdalena Martínez-García was funded by a Ministerio de Ciencia, Innovación y Universidades (Spain), Instituto de Salud Carlos III ( PFIS contract FI18/00255 ) grant.

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.

[Image: see text] COVER ILLUSTRATION This image aims to reflect the parallelism that exists between the morphometric brain changes that occur during pregnancy and those that take place during adolescence. The image has no copyright and the neurons were inspired in one of the Ramon y Cajal drawings.

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.

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.

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-naive 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-naive 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.

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.

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.

Whereas molecular imaging studies in the aging human brain have predominantly demonstrated reductions in serotonin transporter (5-HTT) availability, the majority of the rodent studies, using autoradiographic methods, report increases in neural 5-HTT levels with age. To our knowledge, however, no previous rodent studies have assessed this topic in vivo, and therefore it remains unclear whether this discrepancy arises from methodological or inter-species differences. We performed an [(11)C]-DASB microPET study to evaluate the effects of aging on 5-HTT availability in the rat brain. To generate binding potential estimates, quantitative tracer kinetic modeling was applied using the simplified reference tissue model. A global increase in whole-brain [(11)C]-DASB binding potential was observed in the aged rats in comparison to the control group. More specifically, regional analyses revealed a highly significant increase in 5-HTT binding in the medial frontal cortex, and more modest increments in the midbrain/thalamus. Our results suggest that the frontal cortex represents a site of robust age-related alterations in the rat serotonergic system, and stress the need for further research assessing this topic in the human frontal cortex. Moreover, these findings suggest that the reported discrepancies between rodent and human data may reflect a divergence in the aging processes affecting human and rat serotonergic terminals.

Experience-based neuroplasticity has typically been associated with functional changes, but growing evidence indicates that training can also render dynamic structural alterations in the brain. Although research on training-induced morphological plasticity has consistently demonstrated rapid increases of gray matter volume in task-related regions, no studies have examined if local volumetric reductions in gray matter associated with certain psychiatric disorders may be reversible by adequate training. We aimed to assess whether a training program applied to ADHD patients can contravene some of the associated neuroanatomical alterations. High-resolution anatomical scans were acquired before and after the training period, and a whole-brain tensor-based morphometric approach was applied to extract a voxel-wise estimation of longitudinal changes in regional gray matter volume. Our results show focal volumetric gray matter increases in bilateral middle frontal cortex and right inferior-posterior cerebellum after cognitive training compared with the ADHD control group. The extent of gray matter volume increase in the inferior-posterior cerebellum was associated with attentional performance. These findings illustrate the capacity of the nervous system for rapid morphological adjustments in response to environmental triggers. Moreover, the dorsolateral prefrontal cortex and cerebellum are commonly considered sites of volumetric reduction in ADHD, and the inferior-posterior lobule of the cerebellum is associated with progressive symptom-related volume loss. Hence, the clusters of volumetric change observed in our study were confined to structures typically characterized by volume reduction in ADHD patients, providing preliminary indications that cognitive training may contravene some of the neuroanatomical deficits associated with the disorder.

The brain is a plastic entity that can undergo dynamic changes throughout the lifespan as a result of training. Attention‐deficit/hyperactivity disorder (ADHD) is commonly treated with psychostimulant medication, and the prevalence of ADHD medication prescription is a topic of heated scientific debate. In addition, cognitive training is frequently provided to patients with ADHD. Although psychostimulant effects have been thoroughly investigated, no previous studies have assessed the neural effects of cognitive training in ADHD. We applied fMRI‐paradigms of response inhibition and selective attention to chart the effects of a 10‐day cognitive training program in 19 unmedicated ADHD children receiving either cognitive or control training. The two resulting longitudinal datasets were analyzed using whole‐brain random‐effects general linear models. Although we observed no increases of activity in the control group, both fMRI‐datasets revealed enhanced activity after cognitive training in neural structures closely related to ADHD pathophysiology. On the inhibition paradigm, our results indicated increases in orbitofrontal, superior frontal, middle temporal, and inferior frontal cortex. The attentional task was characterized by increased activity in the cerebellum, which correlated with improvement on in‐scanner measures of attention. Our findings provide preliminary evidence that cognitive training enhances activity in neural structures typically affected by the disorder. Similar results have been obtained following methylphenidate administration, suggesting that training of cognitive functions may mimic the effects of psychostimulant medication on the brain. These findings postulate a neural account for the potency of cognitive training in ADHD, and hold clinical implications, supporting the inclusion of training programs in standard ADHD‐treatment. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Background Models of attention-deficit/hyperactivity disorder (ADHD) classically emphasize the relevance of executive processes and, recently, reward circuits. The neural bases of reward processes have barely been explored in relation to this disorder, in contrast to extensive neuroimaging studies that examine executive functions in patients with ADHD. To our knowledge, no previous studies have analyzed the volume of the ventral striatum, a key region for reward processes in ADHD children. Methods We used a manual region-of-interest approach to examine whether there were volumetric differences in the ventral striatum of ADHD children. Forty-two children/adolescents with ADHD (ages 6–18), and 42 healthy control subjects matched on age, gender, and handedness were selected for the study. Results The ADHD children presented significant reductions in both right and left ventro-striatal volumes ( t = 3.290, p = .001; and t = 3.486, p = .001, respectively). In addition, we found that the volume of the right ventral striatum negatively correlated with maternal ratings of hyperactivity/impulsivity ( r = −.503, p = .003). Conclusions Our study provides neuroanatomical evidence of alterations in the ventral striatum of ADHD children. These findings coincide with previous explicative models as well as with recent reports in behavioral and functional neuroimaging studies. Furthermore, the negative correlations we observed strongly uphold the relation between the ventral striatum and symptoms of hyperactivity/impulsivity.

A common approach to study neuronal aspects of emotional reactivity of borderline personality disorder (BPD) is to study the brain response to emotional faces with functional magnetic resonance imaging (fMRI). 10 BPD patients and 10 matched controls were submitted to an emotional discrimination task in which subjects had to identify an emotional face from a neutral face while fMRI data was acquired. BPD patients made more mistakes than controls in the discrimination task when negative faces were involved. The emotional discrimination task activated brain areas that are known to participate in processing of emotional faces (fusiform gyrus, insula and amygdala) regardless of the psychiatric condition. Additionally, BPD showed higher activation than controls in the middle and inferior temporal cortical areas, brain areas that participate in the processing of face features that carry emotional value. Furthermore, activity at this site correlated with impulsivity score in the Zuckerman-Kuhlman Personality Questionnaire. Our findings may be related to cognitive impairment that may be characteristic of the disorder.

Social cognitive neuroscience is beginning to unravel a neuroanatomy of social cognition, networks of brain regions especially involved in social cognition and social functioning. It is widely acknowledged that social functioning and social cognition are impaired in attention-deficit hyperactivity disorder (ADHD). Although an impressive amount of neuroscientific research has been conducted in ADHD, little effort has been made to link those deficits in social cognition and functioning to the well-known brain abnormalities detected in structural and functional neuroimaging studies. We review seven functional and magnetic resonance studies conducted at our laboratory in ADHD samples during the last 5 years in order to scrutinize whether the putative neuroanatomic regions underpinning social cognition are affected in ADHD. The orbitofrontal cortex (OFC), the caudate nucleus, the ventral striatum, and the cerebellum are among those regions that displayed functional or morphometric abnormalities in our ADHD samples. The OFC is clearly involved in social cognition, and several features of OFC dysfunction may be related to the social cognition and function impairment in ADHD. In contrast to the OFC, the role of the caudate nucleus, the ventral striatum, and the cerebellum is elusive. However, on one hand, there is converging evidence from human and animal neuropsychology, neuroscience, and psychiatry that support the role of such areas in social cognition, mainly through its involvement in emotional processing. On the other hand, the morphometric and functional ADHD abnormalities in these regions could account for the impoverished social functioning and the deficient social cognition skills of ADHD children.

Background:Joint hypermobility syndrome (JHS) has repeatedly been associated with anxiety and anxiety disorders, fibromyalgia, irritable bowel syndrome and temporomandibular joint disorder. However, the neural underpinnings of these associations still remain unclear. This study explored brain responses to facial visual stimuli with emotional cues using fMRI techniques in general population with different ranges of hypermobility.Methods:Fifty-one non-clinical volunteers (33 women) completed state and trait anxiety questionnaire measures, were assessed with a clinical examination for hypermobility (Beighton system) and performed an emotional face processing paradigm during functional neuroimaging.Results:Trait anxiety scores did significantly correlate with both state anxiety and hypermobility scores. BOLD signals of the hippocampus did positively correlate with hypermobility scores for the crying faces versus neutral faces contrast in ROI analyses. No results were found for any of the other studied ROIs. Additionally, hypermobility scores were also associated with other key affective processing areas (i.e. the middle and anterior cingulate gyrus, fusiform gyrus, parahippocampal region, orbitofrontal cortex and cerebellum) in the whole brain analysis.Conclusions:Hypermobility scores are associated with trait anxiety and higher brain responses to emotional faces in emotion processing brain areas (including hippocampus) described to be linked to anxiety and somatic symptoms. These findings increase our understanding of emotion processing in people bearing this heritable variant of collagen and the mechanisms through which vulnerability to anxiety and somatic symptoms arises in this population.

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. Funding was provided by the Fondo deInvestigación Sanitaria (Pi052381). MP is supportedby a FI grant of the Agencia de Gestió d’AjutsUniversitaris i de Recerca

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.

Methylphenidate (MPH) is the first choice of medical treatment for attention-deficit/hyperactivity disorder (ADHD). Its mechanism of action is to inhibit the reuptake of dopamine and noradrenaline mainly in the region of the striatum. It has been estimated that 10–30 % of patients with ADHD do not respond adequately to MPH. The aim of this study was to evaluate whether striatal differences exist between good and poor responders to MPH. The sample included 27 treatment-naive children with ADHD between the ages of 6 and 14. MPH administration started 1 day after the MRI acquisition. After a month, psychiatrists established the good or poor response to treatment according to clinical criteria. MRI images were analyzed using a technique based on regions of interest applied specifically to the caudate and accumbens nuclei. Sixteen patients showed good response to MPH and 11 a poor one. Regions of interest analysis showed that good responders had a higher concentration of gray matter in the head of both caudate nuclei and the right nucleus accumbens. Furthermore, a significant correlation was found between caudate and accumbens nuclei volume and the Conners’ Parent Rating Scale and Continuous Performance Test improvement. These results support the hypothesis of the involvement of the caudate and accumbens nuclei in MPH response and in ADHD pathophysiology.

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. Hum Brain Mapp 35:1261–1272, 2014. © 2013 Wiley Periodicals, Inc.

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-naive 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.

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, [C-11]-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 [C-11]-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. (C) 2012 Elsevier Inc. All rights reserved.

Aquest article té una correcció a 10.1371/annotation/7f26a4d8-ec45-4d43-a388-f2d0d4f1a76a 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.

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-naive adults with ADHD, nor have these been implemented in an intrasubject manner. Methods: The sample consisted of 19 medication-naive 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. Hum Brain Mapp 33:2350–2361, 2012. © 2011 Wiley Periodicals, Inc.

Experience‐based neuroplasticity has typically been associated with functional changes, but growing evidence indicates that training can also render dynamic structural alterations in the brain. Although research on training‐induced morphological plasticity has consistently demonstrated rapid increases of gray matter volume in task‐related regions, no studies have examined if local volumetric reductions in gray matter associated with certain psychiatric disorders may be reversible by adequate training. We aimed to assess whether a training program applied to ADHD patients can contravene some of the associated neuroanatomical alterations. High‐resolution anatomical scans were acquired before and after the training period, and a whole‐brain tensor‐based morphometric approach was applied to extract a voxel‐wise estimation of longitudinal changes in regional gray matter volume. Our results show focal volumetric gray matter increases in bilateral middle frontal cortex and right inferior–posterior cerebellum after cognitive training compared with the ADHD control group. The extent of gray matter volume increase in the inferior–posterior cerebellum was associated with attentional performance. These findings illustrate the capacity of the nervous system for rapid morphological adjustments in response to environmental triggers. Moreover, the dorsolateral prefrontal cortex and cerebellum are commonly considered sites of volumetric reduction in ADHD, and the inferior–posterior lobule of the cerebellum is associated with progressive symptom‐related volume loss. Hence, the clusters of volumetric change observed in our study were confined to structures typically characterized by volume reduction in ADHD patients, providing preliminary indications that cognitive training may contravene some of the neuroanatomical deficits associated with the disorder. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Rodent models are frequently used in aging re search to investigate biochemical age effects and aid in the development of therapies for pathological and non pathological age related degenerative processes In order to validate the use of animal models in aging research and pave the way for longitudinal intervention based animal studies, the consistency of cerebral aging processes across species needs to be evaluated The dopaminergic system seems particularly susceptible to the aging process, and one of the most consistent findings in human brain aging research is a decline in striatal D2-like receptor (D2R) availability, quantifiable by positron emission tomography (PET) imaging In this study we aimed to assess whether similar age effects can be discerned in rat brains, using in vivo molecular imaging with the radioactive compound [C-11] raclopride We observed a robust decline in striatal [C-11] raclopride uptake in the aged rats in comparison to the young control group, comprising a 41% decrement in striatal binding potential In accordance with human studies, these results indicate that substantial reductions in D2R availability can be measured in the aged striatal complex Our findings suggest that rat and human brains exhibit similar biochemical alterations with age in the striatal dopaminergic system, providing support for the pertinence of rodent models in aging research (C) 2010 IBRO Published by Elsevier Ltd All rights reserved