The impact of social disparity on prefrontal function in childhood

The prefrontal cortex (PFC) develops from birth through late adolescence. This extended developmental trajectory provides many opportunities for experience to shape the structure and function of the PFC. To date, a few studies have reported links between parental socioeconomic status (SES) and prefrontal function in childhood, raising the possibility that aspects of environment associated with SES impact prefrontal function. Considering that behavioral measures of prefrontal function are associated with learning across multiple domains, this is an important area of investigation. In this study, we used fMRI to replicate previous findings, demonstrating an association between parental SES and PFC function during childhood. In addition, we present two hypothetical mechanisms by which SES could come to affect PFC function of this association: language environment and stress reactivity. We measured language use in the home environment and change in salivary cortisol before and after fMRI scanning. Complexity of family language, but not the child's own language use, was associated with both parental SES and PFC activation. Change in salivary cortisol was also associated with both SES and PFC activation. These observed associations emphasize the importance of both enrichment and adversity-reduction interventions in creating good developmental environments for all children.     

Effects of age and MAOA genotype on the neural processing of social rejection

Adolescents are often sensitive to peer rejection, a factor that might contribute to the risk of affective disorder in this age group. Previous studies suggest a significant overlap among socioaffective brain regions involved in the response to social rejection, regions continuing to develop functionally during adolescence and regions influenced by monoamine oxidase A (MAOA) polymorphism. The current study investigated whether the neural response to social rejection is functionally immature in adolescents compared with adults, and whether these responses are modulated by MAOA genotype. Blood‐oxygen‐level‐dependent response was measured with functional magnetic resonance imaging during a rejection‐themed emotional Stroop task in 19 adolescents (aged 14–16) and 16 adults (aged 23–28) genotyped for MAOA polymorphism. Similar numbers of MAOA‐L and MAOA‐H carriers were recruited to maximize power to detect genotype effects. Main effects of rejection stimuli (relative to neutral and acceptance control stimuli) were seen in predicted socioaffective brain regions. Adolescents did not show the adult pattern of modulation by rejection stimuli in the right ventrolateral prefrontal cortex, suggesting continued functional maturation of this regulatory region during adolescence. Age and genotype interacted in the left amygdala, in which the predicted effect of genotype on responses to rejection stimuli was seen in the adults, but not in the adolescents. The data suggest continued functional development of the circuitry underlying the processing of social rejection between adolescence and adulthood, and show that the effects of MAOA genotype on neural responses may vary with age.     

Developmental Changes in Task‐Induced Brain Deactivation in Humans Revealed by a Motor Task

Performing tasks activates relevant brain regions in adults while deactivating task‐irrelevant regions. Here, using a well‐controlled motor task, we explored how deactivation is shaped during typical human development and whether deactivation is related to task performance. Healthy right‐handed children (8–11 years), adolescents (12–15 years), and young adults (20–24 years; 20 per group) underwent functional magnetic resonance imaging with their eyes closed while performing a repetitive button‐press task with their right index finger in synchronization with a 1‐Hz sound. Deactivation in the ipsilateral sensorimotor cortex (SM1), bilateral visual and auditory (cross‐modal) areas, and bilateral default mode network (DMN) progressed with development. Specifically, ipsilateral SM1 and lateral occipital deactivation progressed prominently between childhood and adolescence, while medial occipital (including primary visual) and DMN deactivation progressed from adolescence to adulthood. In adults, greater cross‐modal deactivation in the bilateral primary visual cortices was associated with higher button‐press timing accuracy relative to the sound. The region‐specific deactivation progression in a developmental period may underlie the gradual promotion of sensorimotor function segregation required in the task. Task‐induced deactivation might have physiological significance regarding suppressed activity in task‐irrelevant regions. Furthermore, cross‐modal deactivation develops to benefit some aspects of task performance in adults.     

Social instability in adolescence differentially alters dendritic morphology in the medial prefrontal cortex and its response to stress in adult male and female rats

Adolescence is an important period for HPA axis development and synapse maturation and reorganization in the prefrontal cortex (PFC). Thus, stress during adolescence could alter stress‐sensitive brain regions such as the PFC and may alter the impact of future stressors on these brain regions. Given that women are more susceptible to many stress‐linked psychological disorders in which dysfunction of PFC is implicated, and that this increased vulnerability emerges in adolescence, stress during this time could have sex‐dependent effects. Therefore, we investigated the effects of adolescent social instability stress (SIS) on dendritic morphology of Golgi‐stained pyramidal cells in the medial PFC of adult male and female rats. We then examined dendritic reorganization following chronic restraint stress (CRS) with and without a rest period in adult rats that had been stressed in adolescence. Adolescent SIS conferred long‐term alterations in prelimbic of males and females, whereby females show reduced apical length and basilar thin spine density and males show reduced basilar length. CRS in adulthood failed to produce immediate dendritic remodeling in SIS rats. However, CRS followed by a rest period reduced apical dendritic length and increases mushroom spine density in adolescently stressed adult males. Conversely, CRS followed by rest produced apical outgrowth and decreased mushroom spine density in adolescently stressed adult females. These results suggest that stress during adolescence alters development of the PFC and modulates stress‐induced dendritic changes in adulthood.     

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background

Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.

Methodology/Principal Findings

Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.

Conclusion/Significance

Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.     

Voluntary regulation of the functional state and its influence on the effectiveness of cognitive activity during adolescence

We have analyzed the impact of voluntary relaxation on the functional organization and the effectiveness of the voluntary prestimulus attention in performing cognitive tasks in adolescents at the ages of 12–13 and 13–14 years. The effectiveness of cognitive task performance (audio-verbal short-term memory) was estimated on the basis of the number of correctly remembered words. We have found that both age groups are characterized by reduced capacity for voluntary relaxation and its impact on the effectiveness of cognitive task performance. The analysis of the coherence function of EEG rhythmic components in a situation of voluntary attention focused on the performance of cognitive tasks showed no significant change in the interaction of the prefrontal cortex with other cortical areas during the switch from quiet wakefulness or post-relaxation state to the preparation to perform the task, which is typical of adults and young children. Our findings can be a result of sub-optimal functioning of voluntary regulation mechanisms and organization of activities during adolescence.     

Emotional and cognitive changes during adolescence

Adolescence is a critical period for maturation of neurobiological processes that underlie higher cognitive functions and social and emotional behavior. Recent studies have applied new advances in magnetic resonance imaging to increase understanding of the neurobiological changes that occur during the transition from childhood to early adulthood. Structural imaging data indicate progressive and regressive changes in the relative volumes of specific brain regions, although total brain volume is not significantly altered. The prefrontal cortex matures later than other regions and its development is paralleled by increased abilities in abstract reasoning, attentional shifting, response inhibition and processing speed. Changes in emotional capacity, including improvements in affective modulation and discrimination of emotional cues, are also seen during adolescence. Functional imaging studies using cognitive and affective challenges have shown that frontal cortical networks undergo developmental changes in processing. In summary, brain regions that underlie attention, reward evaluation, affective discrimination, response inhibition and goal-directed behavior undergo structural and functional re-organization throughout late childhood and early adulthood. Evidence from recent imaging studies supports a model by which the frontal cortex adopts an increasingly regulatory role. These neurobiological changes are believed to contribute, in part, to the range in cognitive and affective behavior seen during adolescence.     

Age Differences in Neural Activity during Slot Machine Gambling: An fMRI Study

This study aimed to assess the potential association between age-related prefrontal brain changes and slot machine gambling, an activity that has become increasingly popular among older adults. Functional magnetic resonance imaging was used to assess healthy older and younger adults whilst playing a slot machine. Results revealed that the older group over-recruited several bilateral and contralateral brain structures relative to the younger group. Specifically, older adults exhibited increased neural activation in the superior prefrontal cortex and left orbitofrontal cortex, indicating greater reliance on these structures. These results suggest a compensatory mechanism, by which older adults recruit a greater number of neural networks from both hemispheres to complete the same gambling task as their younger peers. The broader implications of these findings are discussed in relation to theories of neurocognitive and degenerative change that occurs in late adulthood.     

Differential Contributions of Dorso-Ventral and Rostro-Caudal Prefrontal White Matter Tracts to Cognitive Control in Healthy Older Adults

Prefrontal cortex mediates cognitive control by means of circuitry organized along dorso-ventral and rostro-caudal axes. Along the dorso-ventral axis, ventrolateral PFC controls semantic information, whereas dorsolateral PFC encodes task rules. Along the rostro-caudal axis, anterior prefrontal cortex encodes complex rules and relationships between stimuli, whereas posterior prefrontal cortex encodes simple relationships between stimuli and behavior. Evidence of these gradients of prefrontal cortex organization has been well documented in fMRI studies, but their functional correlates have not been examined with regard to integrity of underlying white matter tracts. We hypothesized that (a) the integrity of specific white matter tracts is related to cognitive functioning in a manner consistent with the dorso-ventral and rostro-caudal organization of the prefrontal cortex, and (b) this would be particularly evident in healthy older adults. We assessed three cognitive processes that recruit the prefrontal cortex and can distinguish white matter tracts along the dorso-ventral and rostro-caudal dimensions –episodic memory, working memory, and reasoning. Correlations between cognition and fractional anisotropy as well as fiber tractography revealed: (a) Episodic memory was related to ventral prefrontal cortex-thalamo-hippocampal fiber integrity; (b) Working memory was related to integrity of corpus callosum body fibers subserving dorsolateral prefrontal cortex; and (c) Reasoning was related to integrity of corpus callosum body fibers subserving rostral and caudal dorsolateral prefrontal cortex. These findings confirm the ventrolateral prefrontal cortex''s role in semantic control and the dorsolateral prefrontal cortex''s role in rule-based processing, in accordance with the dorso-ventral prefrontal cortex gradient. Reasoning-related rostral and caudal superior frontal white matter may facilitate different levels of task rule complexity. This study is the first to demonstrate dorso-ventral and rostro-caudal prefrontal cortex processing gradients in white matter integrity.     

Reduced Prefrontal Cortex Hemodynamic Response in Adults with Methamphetamine Induced Psychosis: Relevance for Impulsivity

Patients with methamphetamine abuse/dependence often exhibit high levels of impulsivity, which may be associated with the structural abnormalities and functional hypoactivities observed in the frontal cortex of these subjects. Although near-infrared spectroscopy (NIRS) is a simple and non-invasive method for characterizing the clinical features of various psychiatric illnesses, few studies have used NIRS to directly investigate the association between prefrontal cortical activity and inhibitory control in patients with methamphetamine-induced psychosis (MAP). Using a 24-channel NIRS system, we compared hemodynamic responses during the Stroop color-word task in 14 patients with MAP and 21 healthy controls matched for age, sex and premorbid IQ. In addition, we used the Barrett Impulsivity Scale-11 (BIS-11) to assess impulsivity between subject groups. The MAP group exhibited significantly less activation in the anterior and frontopolar prefrontal cortex accompanied by lower Stroop color-word task performance, compared with controls. Moreover, BIS-11 scores were significantly higher in the MAP group, and were negatively correlated with the hemodynamic responses in prefrontal cortex. Our data suggest that reduced hemodynamic responses in the prefrontal cortex might reflect higher levels of impulsivity in patients with MAP, providing new insights into disrupted inhibitory control observed in MAP.     

Changes in cerebral functional organization during cognitive development

It has been just under a decade since contemporary neuroimaging tools, such as functional magnetic resonance imaging, were first applied to developmental questions. These tools provide invaluable information on how brain anatomy, function and connectivity change during development. Studies using these methods with children and adolescents show that brain regions that support motor and sensory function mature earliest, whereas higher-order association areas, such as the prefrontal cortex, which integrate these functions, mature later.     

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise

Adolescence is a highly dynamic period of development, which includes the final organizational phases of neural maturation within the prefrontal cortex (PFC). The organizational events of neural pruning and myelination occur in a sex‐specific manner, potentially giving rise to the disparities in mood disorders in adulthood. Because of the extended developmental time period of the PFC, environmental insults, including psychosocial stressors, may play a major role in steering the maturation of this region. In this review, the literature surrounding the sex specific alterations that occur in the PFC in rodent models following adolescent stress will be discussed. This will be complimented by a brief review on the state of human research in PFC sex differences in the development of white matter and cytoarchitecture across the lifespan. Taken together, the impact of developmental psychosocial stress on the circuitry of the PFC and resulting adult phenotypes will be summarized with a focus on the importance of considering sex differences in order to build a better understanding of developmental influences on adult disorders.     

Gender differences of brain activity in the conflicts based on implicit self-esteem

There are gender differences in global and domain-specific self-esteem and the incidence of some psychiatric disorders related to self-esteem, suggesting that there are gender differences in the neural basis underlying one's own self-esteem. We investigated gender differences in the brain activity while subjects (14 males and 12 females) performed an implicit self-esteem task, using fMRI. While ventromedial prefrontal cortex (vmPFC) was significantly activated in females, medial and dorsomedial PFC (dmPFC) were activated in males in the incongruent condition (self = negative) compared with the congruent condition (self = positive). Additionally, scores on the explicit self-esteem test were negatively correlated with vmPFC activity in females and positively correlated with dmPFC activity in males. Furthermore, the functional relationships among the regions found by direct gender comparisons were discussed based on the somatic-marker model. These showed that, compared to males, females more firmly store even the incongruent associations as part of their schematic self-knowledge, and such associations automatically activate the neural networks for emotional response and control, in which vmPFC plays a central role. This may explain female cognitive/behavioral traits; females have more tendency to ruminate more often than males, which sometimes results in a prolonged negative affect.     

Pubertal maturation modifies the regulation of insulin-like growth factor-I receptor signaling by estradiol in the rat prefrontal cortex

The transition from adolescence to adulthood is accompanied by substantial plastic modifications in the cerebral cortex, including changes in the growth and retraction of neuronal processes and in the rate of synaptic formation and neuronal loss. Some of these plastic changes are prevented in female rats by prepubertal ovariectomy. The ovarian hormone estradiol modulates neuronal differentiation and survival and these effects are in part mediated by the interaction with insulin-like growth factor-I (IGF-I). In this study, we have explored whether the activation by estradiol of some components of IGF-I receptor signaling is altered in the prefrontal cortex during puberty. Estradiol administration to rats ovariectomized after puberty resulted, 24 h after the hormonal administration, in a sustained phosphorylation of Akt and glycogen synthase kinase 3 beta in the prefrontal cortex. However, this hormonal effect was not observed in animals ovariectomized before puberty. These findings suggest that during pubertal maturation there is a programming by ovarian hormones of the future regulatory actions of estradiol on IGF-I receptor signaling in the prefrontal cortex. The modification in the regulation of IGF-I receptor signaling by estradiol during pubertal maturation may have implications for the developmental changes occurring in the prefrontal cortex in the transition from adolescence to adulthood.     

Childhood Emotional Maltreatment Severity Is Associated with Dorsal Medial Prefrontal Cortex Responsivity to Social Exclusion in Young Adults

Children who have experienced chronic parental rejection and exclusion during childhood, as is the case in childhood emotional maltreatment, may become especially sensitive to social exclusion. This study investigated the neural and emotional responses to social exclusion (with the Cyberball task) in young adults reporting childhood emotional maltreatment. Using functional magnetic resonance imaging, we investigated brain responses and self-reported distress to social exclusion in 46 young adult patients and healthy controls (mean age = 19.2±2.16) reporting low to extreme childhood emotional maltreatment. Consistent with prior studies, social exclusion was associated with activity in the ventral medial prefrontal cortex and posterior cingulate cortex. In addition, severity of childhood emotional maltreatment was positively associated with increased dorsal medial prefrontal cortex responsivity to social exclusion. The dorsal medial prefrontal cortex plays a crucial role in self-and other-referential processing, suggesting that the more individuals have been rejected and maltreated in childhood, the more self- and other- processing is elicited by social exclusion in adulthood. Negative self-referential thinking, in itself, enhances cognitive vulnerability for the development of psychiatric disorders. Therefore, our findings may underlie the emotional and behavioural difficulties that have been reported in adults reporting childhood emotional maltreatment.     

Effects of Acute or Chronic Ethanol Exposure during Adolescence on Behavioral Inhibition and Efficiency in a Modified Water Maze Task

Ethanol is well known to adversely affect frontal executive functioning, which continues to develop throughout adolescence and into young adulthood. This is also a developmental window in which ethanol is misused by a significant number of adolescents. We examined the effects of acute and chronic ethanol exposure during adolescence on behavioral inhibition and efficiency using a modified water maze task. During acquisition, rats were trained to find a stable visible platform onto which they could escape. During the test phase, the stable platform was converted to a visible floating platform (providing no escape) and a new hidden platform was added in the opposite quadrant. The hidden platform was the only means of escape during the test phase. In experiment 1, adolescent animals received ethanol (1.0g/kg) 30min before each session during the test phase. In experiment 2, adolescent animals received chronic intermittent ethanol (5.0g/kg) for 16 days (PND30 To PND46) prior to any training in the maze. At PND72, training was initiated in the same modified water maze task. Results from experiment 1 indicated that acute ethanol promoted behavioral disinhibition and inefficiency. Experiment 2 showed that chronic intermittent ethanol during adolescence appeared to have no lasting effect on behavioral disinhibition or new spatial learning during adulthood. However, chronic ethanol did promote behavioral inefficiency. In summary, results indicate that ethanol-induced promotion of perseverative behavior may contribute to the many adverse behavioral sequelae of alcohol intoxication in adolescents and young adults. Moreover, the long-term effect of adolescent chronic ethanol exposure on behavioral efficiency is similar to that observed after chronic exposure in humans.     

Executive control during episodic retrieval: multiple prefrontal processes subserve source memory

During recognition, one may sense items as familiar (item memory) and additionally recollect specific contextual details of the earlier encounters (source memory). Cognitive theory suggests that, unlike item memory, source memory requires controlled cue specification and monitoring processes. Functional imaging suggests that such processes may depend on left prefrontal cortex (PFC). However, the nature and possible anatomical segregation of these processes remains unknown. Using functional magnetic resonance imaging, we isolated distinct response patterns in left PFC during source memory consistent with semantic analysis/cue specification (anterior ventrolateral), recollective monitoring (posterior dorsolateral and frontopolar), and phonological maintenance/rehearsal (posterior ventrolateral). Importantly, cue specification and recollective monitoring responses were not seen during item memory and were unaffected by retrieval success, demonstrating that the mere attempt to recollect episodic detail engages multiple control processes with different left PFC substrates.     

Prefrontal cortex NG2 glia undergo a developmental switch in their responsiveness to exercise

Aerobic exercise is known to influence brain function, e.g., enhancing executive function in both children and adults, with many of these influences being attributed to alterations in neurogenesis and neuronal function. Yet oligodendroglia in adult brains have also been reported to be highly responsive to exercise, including in the prefrontal cortex (PFC), a late myelinating region implicated in working memory. However, whether exercise affects oligodendroglia or myelination in juveniles, either in the PFC or in other brain regions, remains unknown. To address this, both juvenile and young adult mice were provided free access to running wheels for four weeks followed by an analysis of oligodendrocyte development and myelination in the PFC and the corpus callosum, a major white matter tract. Working memory and PFC NG2+ cell development were both affected by exercise in juvenile mice, yet surprisingly these exercise‐mediated effects were distinct in juveniles and young adults. In the PFC, NG2+ cell proliferation was increased in exercising juveniles, but not young adults, whereas newly‐born oligodendrocyte production was increased in exercising young adults, but not juveniles. Although no overall changes in myelin genes were found, elevated levels of Monocarboxylate Transporter 1, a glial lactate transporter important during active myelination, were found in the PFC of exercising young adults. Overall our findings reveal that long‐term exercise modulates PFC glial development and does so differentially in juvenile and young adult mice, providing insight into the cellular responses that may underlie cognitive benefits to teenagers and young adults in response to exercise. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 687–700, 2018