Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users.

Cannabis is the most commonly used illicit drug in the world. However, because of a changing legal landscape and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly cannabis impairment. Importantly, a growing body of evidence suggests that regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo-controlled, cross-over study assessed the acute influence of cannabis on the brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional and 12 chronic cannabis users received acute doses of cannabis (300-µg/kg delta-9-tetrahydrocannabinol) and placebo and underwent ultrahigh field functional magnetic resonance imaging and magnetic resonance spectroscopy. In occasional users, cannabis induced significant neurometabolic alterations in reward circuitry, namely, decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in chronic users. The finding that cannabis altered circuitry and distorted behavior in occasional, but not chronic users, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users. Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment, of which is important to understand in the context of the long-term therapeutic use of cannabis-based medications, as well as in the context of public health and safety of cannabis use when performing day-to-day operations.

Age-related differences in task-induced brain activation is not task specific: Multivariate pattern generalization between metacognition, cognition and perception.

Adolescence is associated with widespread maturation of brain structures and functional connectivity profiles that shift from local to more distributed and better integrated networks, which are active during a variety of cognitive tasks. Nevertheless, the approach to examine task-induced developmental brain changes is function-specific, leaving the question open whether functional maturation is specific to the particular cognitive demands of the task used, or generalizes across different tasks. In the present study we examine the hypothesis that functional brain maturation is driven by global changes in how the brain handles cognitive demands. Multivariate pattern classification analysis (MVPA) was used to examine whether age discriminative task-induced activation patterns generalize across a wide range of information processing levels. 25 young (13-years old) and 22 old (17-years old) adolescents performed three conceptually different tasks of metacognition, cognition and visual processing. MVPA applied within each task indicated that task-induced brain activation is consistent and reliably different between ages 13 and 17. These age-discriminative activation patterns proved to be common across the different tasks used, despite the differences in cognitive demands and brain structures engaged by each of the three tasks. MVP classifiers trained to detect age-discriminative patterns in brain activation during one task were significantly able to decode age from brain activation maps during execution of other tasks with accuracies between 63 and 75%. The results emphasize that age-specific characteristics of task-induced brain activation have to be understood at the level of brain-wide networks that show maturational changes in their organization and processing efficacy during adolescence.

Intrinsic functional architecture of the macaque dorsal and ventral lateral frontal cortex.

Investigations of the cellular and connectional organization of the lateral frontal cortex (LFC) of the macaque monkey provide indispensable knowledge for generating hypotheses about the human LFC. However, despite numerous investigations, there are still debates on the organization of this brain region. In vivo neuroimaging techniques such as resting-state functional magnetic resonance imaging (fMRI) can be used to define the functional circuitry of brain areas, producing results largely consistent with gold-standard invasive tract-tracing techniques and offering the opportunity for cross-species comparisons within the same modality. Our results using resting-state fMRI from macaque monkeys to uncover the intrinsic functional architecture of the LFC corroborate previous findings and inform current debates. Specifically, within the dorsal LFC, we show that 1) the region along the midline and anterior to the superior arcuate sulcus is divided in two areas separated by the posterior supraprincipal dimple, 2) the cytoarchitectonically defined area 6DC/F2 contains two connectional divisions, and 3) a distinct area occupies the cortex around the spur of the arcuate sulcus, updating what was previously proposed to be the border between dorsal and ventral motor/premotor areas. Within the ventral LFC, the derived parcellation clearly suggests the presence of distinct areas: 1) an area with a somatomotor/orofacial connectional signature (putative area 44), 2) an area with an oculomotor connectional signature (putative frontal eye fields), and 3) premotor areas possibly hosting laryngeal and arm representations. Our results illustrate in detail the intrinsic functional architecture of the macaque LFC, thus providing valuable evidence for debates on its organization.NEW & NOTEWORTHY Resting-state functional MRI is used as a complementary method to invasive techniques to inform current debates on the organization of the macaque lateral frontal cortex. Given that the macaque cortex serves as a model for the human cortex, our results help generate more fine-tuned hypothesis for the organization of the human lateral frontal cortex.

Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication.

Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing.

Reverse inference of memory retrieval processes underlying metacognitive monitoring of learning using multivariate pattern analysis.

Monitoring of learning is only accurate at some time after learning. It is thought that immediate monitoring is based on working memory, whereas later monitoring requires re-activation of stored items, yielding accurate judgements. Such interpretations are difficult to test because they require reverse inference, which presupposes specificity of brain activity for the hidden cognitive processes. We investigated whether multivariate pattern classification can provide this specificity. We used a word recall task to create single trial examples of immediate and long term retrieval and trained a learning algorithm to discriminate them. Next, participants performed a similar task involving monitoring instead of recall. The recall-trained classifier recognized the retrieval patterns underlying immediate and long term monitoring and classified delayed monitoring examples as long-term retrieval. This result demonstrates the feasibility of decoding cognitive processes, instead of their content.

Comparative analysis of the macroscale structural connectivity in the macaque and human brain.

The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, seems to constitute a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level and offer a quantitative translational bridge between macaque and human research.

Mapping the hierarchical layout of the structural network of the macaque prefrontal cortex.

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC.

Difficulty sensitivity replaces reward sensitivity during adolescence: Task-related fMRI and functional connectivity during self-regulative learning choices.

AIM: We examined age-related differences in valuation and cognitive control circuits during value-based decision-making. METHODS: 13-year-olds (N = 25) and 17-year-olds (N = 22) made a metacognitive choice to be tested or not on an upcoming learning task, based on reward and difficulty associated with word-pairs. To investigate whether these determinants of subjective value are differently processed at different ages, we performed region-of-interest(ROI)-based analyses of task-related and functional connectivity data. RESULTS: We observed age-related differences in responsiveness of valuation structures (amygdala, ventral striatum, ventromedial prefrontal cortex) and caudate nucleus, with activity modulated by reward in 13-year-olds, while in 17-year-olds activity being responsive to difficulty. These accompanied age-related differences in functional connectivity between medial prefrontal and striatal/amygdala seeds. DISCUSSION: These results are in line with current views that sensitivity changes for reward and difficulty during adolescence are the result of a maturational switch in effort-related signalling in the cognitive control circuit, which increasingly regulates value-signalling structures.

Unravelling the intrinsic functional organization of the human lateral frontal cortex: a parcellation scheme based on resting state fMRI.

Human and nonhuman primates exhibit flexible behavior. Functional, anatomical, and lesion studies indicate that the lateral frontal cortex (LFC) plays a pivotal role in such behavior. LFC consists of distinct subregions exhibiting distinct connectivity patterns that possibly relate to functional specializations. Inference about the border of each subregion in the human brain is performed with the aid of macroscopic landmarks and/or cytoarchitectonic parcellations extrapolated in a stereotaxic system. However, the high interindividual variability, the limited availability of cytoarchitectonic probabilistic maps, and the absence of robust functional localizers render the in vivo delineation and examination of the LFC subregions challenging. In this study, we use resting state fMRI for the in vivo parcellation of the human LFC on a subjectwise and data-driven manner. This approach succeeds in uncovering neuroanatomically realistic subregions, with potential anatomical substrates including BA 46, 44, 45, 9 and related (sub)divisions. Ventral LFC subregions exhibit different functional connectivity (FC), which can account for different contributions in the language domain, while more dorsal adjacent subregions mark a transition to visuospatial/sensorimotor networks. Dorsal LFC subregions participate in known large-scale networks obeying an external/internal information processing dichotomy. Furthermore, we traced "families" of LFC subregions organized along the dorsal-ventral and anterior-posterior axis with distinct functional networks also encompassing specialized cingulate divisions. Similarities with the connectivity of macaque candidate homologs were observed, such as the premotor affiliation of presumed BA 46. The current findings partially support dominant LFC models.

Methylphenidate as a treatment option for substance use disorder: a transdiagnostic perspective.

A transition in viewing mental disorders from conditions defined as a set of unique characteristics to one of the quantitative variations on a collection of dimensions allows overlap between disorders. The overlap can be utilized to extend to treatment approaches. Here, we consider the overlap between attention-deficit/hyperactivity disorder and substance use disorder to probe the suitability to use methylphenidate as a treatment for substance use disorder. Both disorders are characterized by maladaptive goal-directed behavior, impaired cognitive control, hyperactive phasic dopaminergic neurotransmission in the striatum, prefrontal hypoactivation, and reduced frontal cortex gray matter volume/density. In addition, methylphenidate has been shown to improve cognitive control and normalize associated brain activation in substance use disorder patients and clinical trials have found methylphenidate to improve clinical outcomes. Despite the theoretical basis and promising, but preliminary, outcomes, many questions remain unanswered. Most prominent is whether all patients who are addicted to different substances may equally profit from methylphenidate treatment.

Maturation of task-induced brain activation and long range functional connectivity in adolescence revealed by multivariate pattern classification.

The present study uses multivariate pattern classification analysis to examine maturation in task-induced brain activation and in functional connectivity during adolescence. The multivariate approach allowed accurate discrimination of adolescent boys of respectively 13, 17 and 21years old based on brain activation during a gonogo task, whereas the univariate statistical analyses showed no or only very few, small age-related clusters. Developmental differences in task activation were spatially distributed throughout the brain, indicating differences in the responsiveness of a wide range of task-related and default mode regions. Moreover, these distributed age-distinctive patterns generalized from a simple gonogo task to a cognitively and motivationally very different gambling task, and vice versa. This suggests that functional brain maturation in adolescence is driven by common processes across cognitive tasks as opposed to task-specific processes. Although we confirmed previous reports of age-related differences in functional connectivity, particularly for long range connections (>60mm), these differences were not specific to brain regions that showed maturation of task-induced responsiveness. Together with the task-independency of brain activation maturation, this result suggests that brain connectivity changes in the course of adolescence affect brain functionality at a basic level. This basic change is manifest in a range of tasks, from the simplest gonogo task to a complex gambling task.

The "why" and "how" of JointICA: results from a visual detection task.

Since several years, neuroscience research started to focus on multimodal approaches. One such multimodal approach is the combination of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). However, no standard integration procedure has been established so far. One promising data-driven approach consists of a joint decomposition of event-related potentials (ERPs) and fMRI maps derived from the response to a particular stimulus. Such an algorithm (joint independent component analysis or JointICA) has recently been proposed by Calhoun et al. (2006). This method provides sources with both a fine spatial and temporal resolution, and has shown to provide meaningful results. However, the algorithm's performance has not been fully characterized yet, and no procedure has been proposed to assess the quality of the decomposition. In this paper, we therefore try to answer why and how JointICA works. We show the performance of the algorithm on data obtained in a visual detection task, and compare the performance for EEG recorded simultaneously with fMRI data and for EEG recorded in a separate session (outside the scanner room). We perform several analyses in order to set the necessary conditions that lead to a sound decomposition, and to give additional insights for exploration in future studies. In that respect, we show how the algorithm behaves when different EEG electrodes are used and we test the robustness with respect to the number of subjects in the study. The performance of the algorithm in all the experiments is validated based on results from previous studies.

Task-specific subnetworks extend from prefrontal cortex to striatum.

Functional magnetic resonance imaging (fMRI) studies on the dynamic representation of task content focus preferentially on the cerebral cortex. However, neurophysiological studies report coding of task-relevant features also by neurons in the striatum, suggesting basal ganglia involvement in cognitive decision-making. Here we use fMRI data to show that also in humans the striatum is an integrated part of the cognitive brain network. Twelve participants performed 3 cognitive tasks in the scanner, i.e., the Eriksen flanker task, a 2-back matching spatial working memory task, and a response scheme switching task. First, we use region of interest-based multivariate pattern classification to demonstrate that each task reliably induces a unique activity pattern in the striatum and in the lateral prefrontal cortex. We show that the three tasks can also be distinguished in putamen, caudate nucleus and ventral striatum alone. We additionally establish that the contribution of striatum to cognition is not sensitive to habituation or learning. Secondly, we use voxel-to-voxel functional connectivity to establish that voxels in the lateral prefrontal cortex and in the striatum that prefer the same task show significantly stronger functional coupling than voxel pairs in these remote structures that prefer different tasks. These results suggest that striatal neurons form subnetworks with cognition-related regions of the prefrontal cortex. These remote neuron populations are interconnected via functional couplings that exceed the time of execution of the specific tasks.

Object Recognition and Dorsal Stream Vulnerabilities in Children With Early Brain Damage.

Aim: Visual functions of the dorsal stream are considered vulnerable in children with early brain damage. Considering the recognition of objects in suboptimal representations a dorsal stream dysfunction, we examined whether children with early brain damage and impaired object recognition had either general or selective dorsal stream dysfunctions. Method: In a group of children with early brain damage (n = 48) we evaluated the dorsal stream functioning. To determine whether these patients had an increased risk of a dorsal stream dysfunction we compared the percentage of patients with impaired object recognition, assessed with the L94, with the estimated base rate. Then we evaluated the performance levels on motion perception, visual attention and visuomotor tasks in patients with (n = 18) and without (n = 11) object recognition abnormalities. A general dorsal stream dysfunction was considered present if a patient showed at least one abnormally low score in two out of three additional dorsal stream functions. Results: Six of the eighteen (33.3%) patients with object recognition problems scored abnormally low on at least two additional dorsal stream functions. This was significantly higher than the base rate (p = 0.01). The difference of 24.1% between the patients with and without object recognition problems was not significant. Of the patients with object recognition problems 72.2% had at least 1 dorsal weakness, whereas this was only the case in 27.3% of patients without object recognition problems. Compared to patients with normal object recognition, patients with object recognition problems scored significantly more abnormally low on motion perception and visual attention (ps = 0.03) but did not differ on visuomotor skills. Conclusion: Children with object recognition problems seem at risk for other dorsal stream dysfunctions, but dysfunctions might be rather specific than general. Multiple functions/aspects should be evaluated in neuropsychological assessment of children at risk.

Developmental changes between ages 13 and 21 years in the extent and magnitude of the BOLD response during decision making.

Developmental neuroimaging results have suggested a progression in focalization in functional activations from childhood to adulthood. The mechanisms underlying this process are thought to be an age-related decrease in activation extent as well as an increased magnitude in task-related areas. The present study aimed to evaluate these notions while controlling for confounders that may bias towards focalization. We used adolescent subjects in small age ranges. In addition, head motion corrections were incorporated in statistical analyses and regions of interest were identified for each participant separately to overcome inter-individual variability in anatomy and functional organization. Activation patterns of 13-, 17- and 21-year-old males were compared during the decision phase of a challenging and complex gambling paradigm. The BOLD amplitude enhanced with increasing age, modulated by task conditions. First, response amplitude during difficult, endogenous relative to exogenous decisions increased with age. This decision difficulty effect was most pronounced in 21-year-olds, both in areas associated with task execution and default mode areas. Second, deciding to pass as opposed to gamble exerted more effort in inferior frontal and parietal areas only by 13- and 17-year-olds. There was neither an age-related decrease in activation extent, nor any qualitative shifts in activated areas as suggested by the focalization hypothesis. These results suggest that although different age groups throughout adolescence engage similar brain areas during decision making, the response magnitude in these areas increases with age particularly during difficult task conditions, providing that confounding factors are controlled.

Clinical Assessment of Visual Motion Perception in Children With Brain Damage: A Comparison With Base Rates and Control Sample.

Aim: In this study, we examined (1) the presence of abnormally low scores (below 10th percentile) in various visual motion perception aspects in children with brain damage, while controlling for their cognitive developmental delay; (2) whether the risk is increased in comparison with the observation and expectation in a healthy control group and healthy population. Methods: Performance levels of 46 children with indications of brain damage (Mage = 7y4m, SD = 2y4m) on three visual motion perception aspects (global motion, motion speed, motion-defined form) were evaluated. We used developmental age as entry of a preliminary reference table to classify the patient's performance levels. Then we compared the percentages of abnormally low scores with percentages expected in the healthy population using estimated base rates and the observed percentages in the control sample (n = 119). Results: When using developmental age as reference level, the percentage of low scores on at least one of the three tasks was significantly higher than expected in the healthy population [19/46, 41% (95%CI: 28-56%), p = 0.03]. In 15/19 (79% [95%CI: 61-97%] patients only one aspect of motion perception was affected. Four patients performed abnormally low on two out of three tasks, which is also higher than expected (4/46, 8.7%, 95%CI: 2.4-20.8% vs. 2.1%; z = 2.61, p < 0.01). The observed percentages in the patient group were also higher than found in the control group. Interpretation: There is some evidence that children with early brain damage have an increased risk of isolated and combined motion perception problems, independent of their performance IQ.

Distributed task coding throughout the multiple demand network of the human frontal-insular cortex.

The large variety of tasks that humans can perform is governed by a small number of key frontal-insular regions that are commonly active during task performance. Little is known about how this network distinguishes different tasks. We report on fMRI data in twelve participants while they performed four cognitive tasks. Of 20 commonly active frontal-insular regions in each hemisphere, five showed a BOLD response increase with increased task demands, regardless of the task. Although active in all tasks, each task invoked a unique response pattern across the voxels in each area that proved reliable in split-half multi-voxel correlation analysis. Consequently, voxels differed in their preference for one or more of the tasks. Voxel-based functional connectivity analyses revealed that same preference voxels distributed across all areas of the network constituted functional sub-networks that characterized the task being executed.

Removal of BCG artifacts from EEG recordings inside the MR scanner: a comparison of methodological and validation-related aspects.

Multimodal approaches are of growing interest in the study of neural processes. To this end much attention has been paid to the integration of electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data because of their complementary properties. However, the simultaneous acquisition of both types of data causes serious artifacts in the EEG, with amplitudes that may be much larger than those of EEG signals themselves. The most challenging of these artifacts is the ballistocardiogram (BCG) artifact, caused by pulse-related electrode movements inside the magnetic field. Despite numerous efforts to find a suitable approach to remove this artifact, still a considerable discrepancy exists between current EEG-fMRI studies. This paper attempts to clarify several methodological issues regarding the different approaches with an extensive validation based on event-related potentials (ERPs). More specifically, Optimal Basis Set (OBS) and Independent Component Analysis (ICA) based methods were investigated. Their validation was not only performed with measures known from previous studies on the average ERPs, but most attention was focused on task-related measures, including their use on trial-to-trial information. These more detailed validation criteria enabled us to find a clearer distinction between the most widely used cleaning methods. Both OBS and ICA proved to be able to yield equally good results. However, ICA methods needed more parameter tuning, thereby making OBS more robust and easy to use. Moreover, applying OBS prior to ICA can optimize the data quality even more, but caution is recommended since the effect of the additional ICA step may be strongly subject-dependent.

Hippocampal malrotation in pediatric patients with epilepsy associated with complex prefrontal dysfunction.

PURPOSE: The cognitive consequences of hippocampal malrotation (HIMAL) were investigated in a matched control study of children with epilepsy. METHODS: Seven children with HIMAL were compared on a range of memory and attention tasks with 21 control children with epilepsy without temporal role pathology and 7 children with epilepsy and magnetic resonance imaging (MRI)-documented hippocampal sclerosis. In addition, in a statistical morphometric analysis, MRI studies from four children with HIMAL were compared to similar images of 20 age-matched typically developing control children. RESULTS: Although the task battery was sensitive to the memory deficit of the children with hippocampal sclerosis, it did not reveal memory impairment in the patients with HIMAL. In contrast, the patients with HIMAL were impaired on the attentionally more demanding dual tasks, compared to both the control and the hippocampal sclerosis group. The structural MRI analysis revealed morphometric abnormalities in the tail of the affected hippocampus, the adjacent neocortex, and the ipsilateral medial thalamus. The basal forebrain was bilaterally affected. Abnormalities in remote cortex were found in the ipsilateral temporal lobe, the contralateral anterior cingulate gyrus, and bilateral in the dorsolateral and lateral-orbitofrontal prefrontal cortex. DISCUSSION: Because the prefrontal cortical regions have been shown to be active during dual-task performance, the MRI results converge with the neuropsychological findings of impairment on these tasks. We conclude that HIMAL had no direct memory repercussions, but was secondary to subtle but widespread neurologic abnormalities that also affected morphology and functioning of the prefrontal cortex.

Antenatal maternal anxiety modulates the BOLD response in 20-year-old men during endogenous cognitive control.

Evidence is building for an association between the level of anxiety experienced by a mother during pregnancy and offspring cognition and structural and functional brain correlates. The current study uses fMRI to examine the association between prenatal exposure to maternal anxiety and brain activity associated with endogenous versus exogenous cognitive control in 20-year-old males. Endogenous cognitive control refers to the ability to generate control over decisions, strategies, conflicting information and so on, from within oneself without external signals, while exogenous control is triggered by external signals. In line with previous results of this long-term follow-up study we found that 20-year-olds of mothers reporting high levels of anxiety during weeks 12-22 of pregnancy exhibited a different pattern of decision making in a Gambling paradigm requiring endogenous cognitive control, compared to adults of mothers reporting low to average levels of anxiety. Moreover, the blood oxygenation level dependent (BOLD) response in a number of prefrontal cortical areas was modulated by the level of antenatal maternal anxiety. In particular, a number of right lateralized clusters including inferior frontal junction, that were modulated in the adults of mothers reporting low to average levels of anxiety during pregnancy by a task manipulation of cognitive control, were not modulated by this manipulation in the adults of mothers reporting high levels of anxiety during pregnancy. These differences in brain functional correlates provide a neurobiological underpinning for the hypothesis of an association between exposure to maternal anxiety in the prenatal life period and a deficit in endogenous cognitive control in early adulthood.