Theory of mind mediates the prospective relationship between abnormal social brain network morphology and chronic behavior problems after pediatric traumatic brain injury

Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the ‘social brain network’ (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2–8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems.     

Sex,violence, & rock n' roll: Longitudinal effects of music on aggression,sex, and prosocial behavior during adolescence

The current study examined longitudinal associations between listening to aggression, sex, and prosocial behavior in music on a number of behavioral outcomes across a one-year period during adolescence. Adolescents (N = 548, M age = 15.32, 52% female) completed a number of questionnaires on musical preferences, general media use, aggression, sexual outcomes, and prosocial behavior at two different time points separated by about one year. Using structural equation modeling to analyze the data, results revealed that listening to aggression in music was associated with increased aggression and decreased prosocial behavior over time, even when controlling for initial levels of these behaviors. Listening to sexual content in music was associated with earlier initiation of sexual intercourse and a trend for a higher number of sexual partners (reported at Time 2). Prosocial behavior in music was not associated with any behavioral outcome longitudinally. Collectively, these results suggest that listening to certain types of content in music can have a longitudinal effect on behavior during adolescence.     

Mechanisms for quick and variable responses.

Dominant and subordinate males produce neuroendocrine stress responses during aggressive social interaction. In addition, stress responsiveness has both acute and chronic temporal components. A neurochemical marker that distinguishes social status and aggression by temporal and regional differentiation is the activity of serotonergic nuclei and terminals. A unique model for distinguishing the relationships among the neuroendocrine machinery of stress, social status and behavior is the lizard Anolis carolinensis. Dominant males exhibit more aggression and have temporally advanced serotonergic responses. Chronic serotonergic activity is associated with subordinate social status and reduced aggression. Acute and chronic serotonergic responses occur in both dominant and subordinate males, and are distinguished temporally. This provides a fundamental question that may elucidate basic differences in behavior: What causes temporally advanced serotonergic activity in response to stress in dominant males? Secondarily, what is the neural basis for the acute and chronic responses? The neural mechanisms for transduction of the relevant behavioral signals are very plastic. Behavioral experience and visual stimuli can produce very rapid responses. Faster and greater responsiveness may be stimulated by restraint stress, social stress and the absence of social sign stimuli (e.g. eyespots of the lizard Anolis carolinensis). Stress response machinery provides regulatory factors necessary to modify social behavior, and to adapt it for specific contexts. Serotonergic activity is rapidly modified by glucocorticoids and GABA, and also by CRF under conditions of previous stress or in combination with AVP. Advancing acute elevation of serotonergic activity may be a distinguishing characteristic of dominant males. Social events add contextual conditioning to brain transmitter activity, with social information processed in a distributed fashion. Medial amygdala manifests delayed serotonergic response compared to hippocampus and nucleus accumbens, and is therefore a good candidate to mediate chronic stress responsiveness. Limiting or delaying acute effects, in addition to chronic serotonergic activity, may be the distinguishing characteristics of subordinate males. Monoamines, glucocorticoids, testosterone, CRF, AVP, AVT, play neuromodulatory roles producing context appropriate behavior.     

Vasopressin V1b receptor knockout reduces aggressive behavior in male mice

Increased aggression is commonly associated with many neurological and psychiatric disorders. Current treatments are largely empirical and are often accompanied by severe side effects, underscoring the need for a better understanding of the neural bases of aggression. Vasopressin, acting through its 1a receptor subtype, is known to affect aggressive behaviors. The vasopressin 1b receptor (V1bR) is also expressed in the brain, but has received much less attention due to a lack of specific drugs. Here we report that mice without the V1bR exhibit markedly reduced aggression and modestly impaired social recognition. By contrast, they perform normally in all the other behaviors that we have examined, such as sexual behavior, suggesting that reduced aggression and social memory are not simply the result of a global deficit in sensorimotor function or motivation. Fos-mapping within chemosensory responsive regions suggests that the behavioral deficits in V1bR knockout mice are not due to defects in detection and transmission of chemosensory signals to the brain. We suggest that V1bR antagonists could prove useful for treating aggressive behavior seen, for example, in dementias and traumatic brain injuries.     

Structural and functional biomarkers of the insula subregions predict sex differences in aggression subscales

Aggression is a common and complex social behavior that is associated with violence and mental diseases. Although sex differences were observed in aggression, the neural mechanism for the effect of sex on aggression behaviors remains unclear, especially in specific subscales of aggression. In this study, we investigated the effects of sex on aggression subscales, gray matter volume (GMV), and functional connectivity (FC) of each insula subregion as well as the correlation of aggression subscales with GMV and FC. This study found that sex significantly influenced (a) physical aggression, anger, and hostility; (b) the GMV of all insula subregions; and (c) the FC of the dorsal agranular insula (dIa), dorsal dysgranular insula (dId), and ventral dysgranular and granular insula (vId_vIg). Additionally, mediation analysis revealed that the GMV of bilateral dIa mediates the association between sex and physical aggression, and left dId–left medial orbital superior frontal gyrus FC mediates the relationship between sex and anger. These findings revealed the neural mechanism underlying the sex differences in aggression subscales and the important role of the insula in aggression differences between males and females. This finding could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior.     

Behavioral correlates of differences in neural metabolic capacity

Cytochrome oxidase is a rate-limiting enzyme in oxidative phosphorylation, the major energy-synthesizing pathway used by the central nervous system, and cytochrome oxidase histochemistry has been extensively utilized to map changes in neural metabolism following experimental manipulations. However, the value of cytochrome oxidase activity in predicting behavior has not been analyzed. We argue that this endeavor is important because genetic composition and embryonic environment can engender differences in baseline neural metabolism in pertinent neural circuits, and these differences could represent differences in the degree to which specific behaviors are ‘primed.’ Here we review our studies in which differences in cytochrome oxidase activity and in behavior were studied in parallel. Using mammalian and reptilian models, we find that embryonic experiences that shape the propensity to display social behaviors also affect cytochrome oxidase activity in limbic brain areas, and elevated cytochrome oxidase activity in preoptic, hypothalamic, and amygdaloid nuclei correlates with heightened aggressive and sexual tendencies. Selective breeding regimes were used to create rodent genetic lines that differ in their susceptibility to display learned helplessness and in behavioral excitability. Differences in cytochrome oxidase activity in areas like the paraventricular hypothalamus, frontal cortex, habenula, septum, and hippocampus correlate with differences in susceptibility to display learned helplessness, and differences in activity in the dentate gyrus and perirhinal and posterior parietal cortex correlate with differences in hyperactivity. Thus, genetic and embryonic manipulations that engender specific behavioral differences produce specific neurometabolic profiles. We propose that knowledge of neurometabolic differences can yield valuable predictions about behavioral phenotype in other systems.     

Rapid effects of estrogens on behavior: Environmental modulation and molecular mechanisms

Estradiol can modulate neural activity and behavior via both genomic and nongenomic mechanisms. Environmental cues have a major impact on the relative importance of these signaling pathways with significant consequences for behavior. First we consider how photoperiod modulates nongenomic estrogen signaling on behavior. Intriguingly, short days permit rapid effects of estrogens on aggression in both rodents and song sparrows. This highlights the importance of considering photoperiod as a variable in laboratory research. Next we review evidence for rapid effects of estradiol on ecologically-relevant behaviors including aggression, copulation, communication, and learning. We also address the impact of endocrine disruptors on estrogen signaling, such as those found in corncob bedding used in rodent research. Finally, we examine the biochemical mechanisms that may mediate rapid estrogen action on behavior in males and females. A common theme across these topics is that the effects of estrogens on social behaviors vary across different environmental conditions.     

Social behavior functions and related anatomical characteristics of vasotocin/vasopressin systems in vertebrates

The neuropeptide arginine vasotocin (AVT; non-mammals) and its mammalian homologue, arginine vasopressin (AVP) influence a variety of sex-typical and species-specific behaviors, and provide an integrational neural substrate for the dynamic modulation of those behaviors by endocrine and sensory stimuli. Although AVT/AVP behavioral functions and related anatomical features are increasingly well-known for individual species, ubiquitous species-specificity presents ever increasing challenges for identifying consistent structure–function patterns that are broadly meaningful. Towards this end, we provide a comprehensive review of the available literature on social behavior functions of AVT/AVP and related anatomical characteristics, inclusive of seasonal plasticity, sexual dimorphism, and steroid sensitivity. Based on this foundation, we then advance three major questions which are fundamental to a broad conceptualization of AVT/AVP social behavior functions: (1) Are there sufficient data to suggest that certain peptide functions or anatomical characteristics (neuron, fiber, and receptor distributions) are conserved across the vertebrate classes? (2) Are independently-evolved but similar behavior patterns (e.g. similar social structures) supported by convergent modifications of neuropeptide mechanisms, and if so, what mechanisms? (3) How does AVT/AVP influence behavior — by modulation of sensorimotor processes, motivational processes, or both? Hypotheses based upon these questions, rather than those based on individual organisms, should generate comparative data that will foster cross-class comparisons which are at present underrepresented in the available literature.     

Novel mechanisms for neuroendocrine regulation of aggression

In 1849, Berthold demonstrated that testicular secretions are necessary for aggressive behavior in roosters. Since then, research on the neuroendocrinology of aggression has been dominated by the paradigm that the brain receives gonadal hormones, primarily testosterone, which modulate relevant neural circuits. While this paradigm has been extremely useful, recent studies reveal important alternatives. For example, most vertebrate species are seasonal breeders, and many species show aggression outside of the breeding season, when gonads are regressed and circulating testosterone levels are typically low. Studies in birds and mammals suggest that an adrenal androgen precursor—dehydroepiandrosterone (DHEA)—may be important for the expression of aggression when gonadal testosterone synthesis is low. Circulating DHEA can be metabolized into active sex steroids within the brain. Another possibility is that the brain can autonomously synthesize sex steroids de novo from cholesterol, thereby uncoupling brain steroid levels from circulating steroid levels. These alternative neuroendocrine mechanisms to provide sex steroids to specific neural circuits may have evolved to avoid the “costs” of high circulating testosterone during particular seasons. Physiological indicators of season (e.g., melatonin) may allow animals to switch from one neuroendocrine mechanism to another across the year. Such mechanisms may be important for the control of aggression in many vertebrate species, including humans.     

The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis

All animals evaluate the salience of external stimuli and integrate them with internal physiological information into adaptive behavior. Natural and sexual selection impinge on these processes, yet our understanding of behavioral decision-making mechanisms and their evolution is still very limited. Insights from mammals indicate that two neural circuits are of crucial importance in this context: the social behavior network and the mesolimbic reward system. Here we review evidence from neurochemical, tract-tracing, developmental, and functional lesion/stimulation studies that delineates homology relationships for most of the nodes of these two circuits across the five major vertebrate lineages: mammals, birds, reptiles, amphibians, and teleost fish. We provide for the first time a comprehensive comparative analysis of the two neural circuits and conclude that they were already present in early vertebrates. We also propose that these circuits form a larger social decision-making (SDM) network that regulates adaptive behavior. Our synthesis thus provides an important foundation for understanding the evolution of the neural mechanisms underlying reward processing and behavioral regulation.     

Pharmacotherapy for severe aggression in a child with autism: "open label" evaluation of multiple medications on response frequency and intensity of behavioral intervention

Many persons who have developmental disabilities and challenging behaviors are treated with multiple medications combined with nonpharmacological approaches. However, the comparative effects from pharmacotherapy frequently are not assessed empirically, do not include corollary behavioral measures, and are not evaluated in the long term. The present single-case study incorporated behavioral assessment methodology in an “open label” evaluation of anticonvulsant (clonazepam), beta-blocking (propanolol), and antidepressant (sertraline and clomipramine) medications on severe aggression in a child with autism. Clinically significant reductions in aggressive behavior were attained with the administration of clomipramine and the reductive effects from the medication persisted for 1.7 years. In addition, clomipramine was associated with the elimination of crisis intervention procedures that had been required to manage the child's aggression. These findings add to the clinical literature describing effective treatment of serious behavior disorders in persons with developmental disabilities using antidepressant medication.     

Effortless retaliation: the neural dynamics of interpersonal intentions in the Chicken Game using brain–computer interface

The desire for retaliation is a common response across a majority of human societies. However, the neural mechanisms underlying aggression and retaliation remain unclear. Previous studies on social intentions are confounded by a low-level response-related brain activity. Using an Electroencephalogram (EEG)-based brain–computer interface combined with the Chicken Game, our study examined the neural dynamics of aggression and retaliation after controlling for nonessential response-related neural signals. Our results show that aggression is associated with reduced alpha event-related desynchronization (alpha-ERD), indicating reduced mental effort. Moreover, retaliation and tit-for-tat strategy use are also linked with smaller alpha-ERD. Our study provides a novel method to minimize motor confounds and demonstrates that choosing aggression and retaliation is less effortful in social conflicts.     

Individual differences in nucleus accumbens activity to food and sexual images predict weight gain and sexual behavior

Failures of self-regulation are common, leading to many of the most vexing problems facing contemporary society, from overeating and obesity to impulsive sexual behavior and STDs. One reason that people may be prone to engaging in unwanted behaviors is heightened sensitivity to cues related to those behaviors; people may overeat because of hyperresponsiveness to food cues, addicts may relapse following exposure to their drug of choice, and some people might engage in impulsive sexual activity because they are easily aroused by erotic stimuli. An open question is the extent to which individual differences in neural cue reactivity relate to actual behavioral outcomes. Here we show that individual differences in human reward-related brain activity in the nucleus accumbens to food and sexual images predict subsequent weight gain and sexual activity 6 months later. These findings suggest that heightened reward responsivity in the brain to food and sexual cues is associated with indulgence in overeating and sexual activity, respectively, and provide evidence for a common neural mechanism associated with appetitive behaviors.     

Reducing aggressive responses to social exclusion using transcranial direct current stimulation

A vast body of research showed that social exclusion can trigger aggression. However, the neural mechanisms involved in regulating aggressive responses to social exclusion are still largely unknown. Transcranial direct current stimulation (tDCS) modulates the excitability of a target region. Building on studies suggesting that activity in the right ventrolateral pre-frontal cortex (rVLPFC) might aid the regulation or inhibition of social exclusion-related distress, we hypothesized that non-invasive brain polarization through tDCS over the rVLPFC would reduce behavioral aggression following social exclusion. Participants were socially excluded or included while they received tDCS or sham stimulation to the rVLPFC. Next, they received an opportunity to aggress. Excluded participants demonstrated cognitive awareness of their inclusionary status, yet tDCS (but not sham stimulation) reduced their behavioral aggression. Excluded participants who received tDCS stimulation were no more aggressive than included participants. tDCS stimulation did not influence socially included participants’ aggression. Our findings provide the first causal test for the role of rVLPFC in modulating aggressive responses to social exclusion. Our findings suggest that modulating activity in a brain area (i.e. the rVLPFC) implicated in self-control and emotion regulation can break the link between social exclusion and aggression.     

The interactive effect of social pain and executive functioning on aggression: an fMRI experiment

Social rejection often increases aggression, but the neural mechanisms underlying this effect remain unclear. This experiment tested whether neural activity in the dorsal anterior cingulate cortex (dACC) and anterior insula in response to social rejection predicted greater subsequent aggression. Additionally, it tested whether executive functioning moderated this relationship. Participants completed a behavioral measure of executive functioning, experienced social rejection while undergoing functional magnetic resonance imaging and then completed a task in which they could aggress against a person who rejected them using noise blasts . We found that dACC activation and executive functioning interacted to predict aggression. Specifically, participants with low executive functioning showed a positive association between dACC activation and aggression, whereas individuals with high executive functioning showed a negative association. Similar results were found for the left anterior insula. These findings suggest that social pain can increase or decrease aggression, depending on an individual’s regulatory capability.     

Changes in social exploration of a lipopolysaccharides-treated conspecific in mice: role of environmental cues

Despite the many advantages offered by sociality in animals, one of its main drawbacks is the increased propensity to be exposed to parasites and pathogens. In infection (bacteria and viruses), one of the common symptoms used to describe an animal experiencing an acute inflammation is a “social disinterest”. According to the literature, this reduction in social behaviors would be an adaptive feature preventing further contamination. However, if the case of parasitic infection has been extensively studied, concerning inflammatory processes, no direct evidence of a proper isolation of sick animals by healthy conspecifics has been provided. The present study aimed to investigate the effects of endotoxin-induced inflammation (LPS, lipopolysaccharides) on the behavior of healthy conspecifics to verify a possible active social isolation of the immune-challenged animal. In addition, we applied variations to the functional significance of the situation by pre-exposing healthy subjects to unsanitary olfactory cues (i.e., 1,5-diaminopentane, odor of decaying flesh). Observations revealed several results: (1) no agonistic behavior was observed during dyadic encounter, whatever the immune status of the conspecifics or the olfactory stimulation; (2) endotoxin-induced inflammation triggered several behavioral changes in healthy conspecifics: increased inter-individual distance, decreased physical contacts, and changes in the modalities of social exploration (increased proportion of muzzle sniffing and decreased proportion of ano-genital sniffing); (3) these effects were more salient after olfactory priming with 1-,5-diaminopentane. Our data reveal that mice are able to discriminate the “state of sickness” in conspecifics use this information to support pertinent behavioral changes. Moreover, these results support the idea that mice would switch from a “controlled exposure” strategy under standard condition to a “pathogen avoidance” strategy under a specific unsanitary context.     

Heritability of aggression following social evaluation in middle childhood: An fMRI study

Middle childhood marks an important phase for developing and maintaining social relations. At the same time, this phase is marked by a gap in our knowledge of the genetic and environmental influences on brain responses to social feedback and their relation to behavioral aggression. In a large developmental twin sample (509 7‐ to 9‐year‐olds), the heritability and neural underpinnings of behavioral aggression following social evaluation were investigated, using the Social Network Aggression Task (SNAT). Participants viewed pictures of peers that gave positive, neutral, or negative feedback to the participant's profile. Next, participants could blast a loud noise toward the peer as an index of aggression. Genetic modeling revealed that aggression following negative feedback was influenced by both genetics and environmental (shared as well as unique environment). On a neural level (n = 385), the anterior insula and anterior cingulate cortex gyrus (ACCg) responded to both positive and negative feedback, suggesting they signal for social salience cues. The medial prefrontal cortex (mPFC) and inferior frontal gyrus (IFG) were specifically activated during negative feedback, whereas positive feedback resulted in increased activation in caudate, supplementary motor cortex (SMA), and dorsolateral prefrontal cortex (DLPFC). Decreased SMA and DLPFC activation during negative feedback was associated with more aggressive behavior after negative feedback. Moreover, genetic modeling showed that 13%–14% of the variance in dorsolateral PFC activity was explained by genetics. Our results suggest that the processing of social feedback is partly explained by genetic factors, whereas shared environmental influences play a role in behavioral aggression following feedback.     

Within-family conflict behaviors as predictors of conflict in adolescent romantic relations

Continuity in conflict behaviors from (a) adolescents’ behavior with parents and their behavior with romantic partners and (b) from parents’ marriage to adolescents’ romantic relationships were examined in a sample of 58 mother–father–adolescent families and the adolescents’ romantic partners. The social relations model was used to analyze within-family reports of own and partner conflict behavior. Mother–father consensus about adolescents’ use of physical aggression was associated with romantic partners’ reports of adolescents’ physical aggression. Less functional behaviors observed during observed marital conflict were associated with a range of less functional conflict behaviors in adolescents’ observed interactions with romantic partners, including withdrawal, verbal aggression, negativity, ineffective problem solving, and low cohesion. Within-family conflict and methodological issues in the use of partner and self-reports of conflict behaviors are discussed.     

Evolutionary background for stress-coping styles: relationships between physiological, behavioral, and cognitive traits in non-mammalian vertebrates

Reactions to stress vary between individuals, and physiological and behavioral responses tend to be associated in distinct suites of correlated traits, often termed stress-coping styles. In mammals, individuals exhibiting divergent stress-coping styles also appear to exhibit intrinsic differences in cognitive processing. A connection between physiology, behavior, and cognition was also recently demonstrated in strains of rainbow trout (Oncorhynchus mykiss) selected for consistently high or low cortisol responses to stress. The low-responsive (LR) strain display longer retention of a conditioned response, and tend to show proactive behaviors such as enhanced aggression, social dominance, and rapid resumption of feed intake after stress. Differences in brain monoamine neurochemistry have also been reported in these lines. In comparative studies, experiments with the lizard Anolis carolinensis reveal connections between monoaminergic activity in limbic structures, proactive behavior in novel environments, and the establishment of social status via agonistic behavior. Together these observations suggest that within-species diversity of physiological, behavioral and cognitive correlates of stress responsiveness is maintained by natural selection throughout the vertebrate sub-phylum.