Repeated fluvoxamine treatment recovers early postnatal stress-induced hypersociability-like behavior in adult rats.

Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress-induced emotional dysfunction.

Unusual social behavior in HPC-1/syntaxin1A knockout mice is caused by disruption of the oxytocinergic neural system.

HPC-1/syntaxin1A (STX1A), a neuronal soluble N-ethylmaleimide-sensitive fusion attachment protein receptor, contributes to neural function in the CNS by regulating transmitter release. Recent studies reported that STX1A is associated with human neuropsychological disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder. Previously, we showed that STX1A null mutant mice (STX1A KO) exhibit neuropsychological abnormalities, such as fear memory deficits, attenuation of latent inhibition, and unusual social behavior. These observations suggested that STX1A may be involved in the neuropsychological basis of these abnormalities. Here, to study the neural basis of social behavior, we analyzed the profile of unusual social behavior in STX1A KO with a social novelty preference test, which is a useful method for quantification of social behavior. Interestingly, the unusual social behavior in STX1A KO was partially rescued by intracerebroventricular administration of oxytocin (OXT). In vivo microdialysis studies revealed that the extracellular OXT concentration in the CNS of STX1A KO was significantly lower compared with wild-type mice. Furthermore, dopamine-induced OXT release was reduced in STX1A KO. These results suggested that STX1A plays an important role in social behavior through regulation of the OXTergic neural system. Dopamine (DA) release is reduced in CNS of syntaxin1A null mutant mice (STX1A KO). Unusual social behavior was observed in STX1A KO. We found that oxytocin (OXT) release, which was stimulated by DA, was reduced and was rescued the unusual social behavior in STX1A KO was rescued by OXT. These results indicated that STX1A plays an important role in promoting social behavior through regulation of DA-induced OXT release in amygdala.

Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale.

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others' social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning.

Effects of early-life abuse differ across development: infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala.

Abuse during early life, especially from the caregiver, increases vulnerability to develop later-life psychopathologies such as depression. Although signs of depression are typically not expressed until later life, signs of dysfunctional social behavior have been found earlier. How infant abuse alters the trajectory of brain development to produce pathways to pathology is not completely understood. Here we address this question using two different but complementary rat models of early-life abuse from postnatal day 8 (P8) to P12: a naturalistic paradigm, where the mother is provided with insufficient bedding for nest building; and a more controlled paradigm, where infants undergo olfactory classical conditioning. Amygdala neural assessment (c-Fos), as well as social behavior and forced swim tests were performed at preweaning (P20) and adolescence (P45). Our results show that both models of early-life abuse induce deficits in social behavior, even during the preweaning period; however, depressive-like behaviors were observed only during adolescence. Adolescent depressive-like behavior corresponds with an increase in amygdala neural activity in response to forced swim test. A causal relationship between the amygdala and depressive-like behavior was suggested through amygdala temporary deactivation (muscimol infusions), which rescued the depressive-like behavior in the forced swim test. Our results indicate that social behavior deficits in infancy could serve as an early marker for later psychopathology. Moreover, the implication of the amygdala in the ontogeny of depressive-like behaviors in infant abused animals is an important step toward understanding the underlying mechanisms of later-life mental disease associated with early-life abuse.

Neuroradiological advances detect abnormal neuroanatomy underlying neuropsychological impairments: the power of PET imaging.

Medical imaging has made a major contribution to cerebral dysfunction due to inherited diseases, as well as injuries sustained with modern living, such as car accidents, falling down, and work-related injuries. These injuries, up until the introduction of sensitive techniques such as positron emission tomography (PET), were overlooked because of heavy reliance on structural imaging techniques such as MRI and CT. These techniques are extremely insensitive for dysfunction caused by such underlying disorders. We believe that the use of these highly powerful functional neuroimaging technologies, such as PET, has substantially improved our ability to assess these patients properly in the clinical setting, to determine their natural course, and to assess the efficacy of various interventional detections. As such the contribution from the evolution of PET technology has substantially improved our knowledge and ability over the past 3 decades to help patients who are the victims of serious deficiencies due to these injuries. In particular, in recent years the use of PET/CT and soon PET/MRI will provide the best option for a structure-function relationship in these patients. We are of the belief that the clinical effectiveness of PET in managing these patients can be translated to the use of this important approach in bringing justice to the victims of many patients who are otherwise uncompensated for disorders that they have suffered without any justification. Therefore, legally opposing views about the relevance of PET in the court system by some research groups may not be justifiable. This has proven to be the case in many court cases, where such imaging techniques have been employed either for criminal or financial compensation purposes in the past 2 decades.

Grey matter abnormalities in social anxiety disorder: a pilot study.

While a number of studies have explored the functional neuroanatomy of social anxiety disorder (SAD), data on grey matter integrity are lacking. We conducted structural MRI scans to examine the cortical thickness of grey matter in individuals with SAD. 13 unmedicated adult patients with a primary diagnosis of generalized social anxiety disorder and 13 demographically (age, gender and education) matched healthy controls underwent 3T structural magnetic resonance imaging. Cortical thickness and subcortical volumes were estimated using an automated algorithm (Freesurfer Version 4.5). Compared to controls, social anxiety disorder patients showed significant bilateral cortical thinning in the fusiform and post central regions. Additionally, right hemisphere specific thinning was found in the frontal, temporal, parietal and insular cortices of individuals with social anxiety disorder. Although uncorrected cortical grey matter volumes were significantly lower in individuals with SAD, we did not detect volumetric differences in corrected amygdala, hippocampal or cortical grey matter volumes across study groups. Structural differences in grey matter thickness between SAD patients and controls highlight the diffuse neuroanatomical networks involved in both social anxiety and social behavior. Additional work is needed to investigate the causal mechanisms involved in such structural abnormalities in SAD.

Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2.

Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit's ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.

Economic games quantify diminished sense of guilt in patients with damage to the prefrontal cortex.

Damage to the ventromedial prefrontal cortex (VMPFC) impairs concern for other people, as reflected in the dysfunctional real-life social behavior of patients with such damage, as well as their abnormal performances on tasks ranging from moral judgment to economic games. Despite these convergent data, we lack a formal model of how, and to what degree, VMPFC lesions affect an individual's social decision-making. Here we provide a quantification of these effects using a formal economic model of choice that incorporates terms for the disutility of unequal payoffs, with parameters that index behaviors normally evoked by guilt and envy. Six patients with focal VMPFC lesions participated in a battery of economic games that measured concern about payoffs to themselves and to others: dictator, ultimatum, and trust games. We analyzed each task individually, but also derived estimates of the guilt and envy parameters from aggregate behavior across all of the tasks. Compared with control subjects, the patients donated significantly less and were less trustworthy, and overall our model found a significant insensitivity to guilt. Despite these abnormalities, the patients had normal expectations about what other people would do, and they also did not simply generate behavior that was more noisy. Instead, the findings argue for a specific insensitivity to guilt, an abnormality that we suggest characterizes a key contribution made by the VMPFC to social behavior.

GluD1 knockout mice with a pure C57BL/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior.

The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.

Can progressive and non-progressive behavioural variant frontotemporal dementia be distinguished at presentation?

BACKGROUND: Recent findings suggest that patients with behavioural variant frontotemporal dementia (bv-FTD) differ in their disease progression (progressive vs non-progressive patients). The current study investigates whether the two groups can be discriminated by their clinical features at first presentation. METHODS: Archival clinical data of the Early Onset Dementia Clinic, Cambridge, UK, were analysed for 71 patients with bv-FTD: 45 progressive and 26 non-progressive cases with more than 3 years of follow-up. RESULTS: The subgroups were largely indistinguishable on the basis of the presenting clinical features but could be distinguished on general cognitive (Addenbrooke's Cognitive Examination-revised) and selected supportive diagnostic features (distractibility, stereotypic speech, impaired activities of daily living (ADLs) and current depression). CONCLUSIONS: Progressive and non-progressive patients are difficult to differentiate on the basis of current clinical diagnostic criteria for FTD but a combination of general cognitive, executive dysfunction and impaired ADL measures appear to be the most promising discriminators.

A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.

Of brain and bone: the unusual case of Dr. A.

Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick's disease), who presented with a profound behavioral disturbance characterized by acquired sociopathy. We conducted a detailed genetic, pathological, neuroimaging and cognitive study, including a battery of tests designed to investigate Dr. A's abilities to understand emotional cues and to infer mental states and intentions to others (theory of mind). Dr. A's genetic profile suggests the possibility that a mutation causing hereditary multiple exostoses, Ext2, may play a role in the pattern of neurodegeneration in frontotemporal dementia since knockout mice deficient in the Ext gene family member, Ext1, show severe CNS defects including loss of olfactory bulbs and abnormally small cerebral cortex. Dr. A showed significant impairment in emotion comprehension, second order theory of mind, attribution of intentions, and empathy despite preserved general cognitive abilities. Voxel-based morphometry on structural MRI images showed significant atrophy in the medial and right orbital frontal and anterior temporal regions with sparing of dorsolateral frontal cortex. This case demonstrates that social and emotional dysfunction in FTD can be dissociated from preserved performance on classic executive functioning tasks. The specific pattern of anatomical damage shown by VBM emphasizes the importance of the network including the superior medial frontal gyrus as well as temporal polar areas, in regulation of social cognition and theory of mind. This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.

Neural circuitry of submissive behavior in social anxiety disorder: A preliminary study of response to direct eye gaze.

Fear of eye gaze is common in social anxiety disorder (SAD) and may represent an evolutionarily conserved submissive behavior. SAD subjects and healthy volunteers who underwent functional magnetic resonance imaging showed significant differences in neural activity in amygdala, fusiform, insula, anterior cingulate and prefrontal cortex in response to direct versus averted gaze. Neural response to direct gaze may identify brain regions important in the pathophysiology of SAD.

The zebrafish subcortical social brain as a model for studying social behavior disorders.

Social behaviors are essential for the survival and reproduction of social species. Many, if not most, neuropsychiatric disorders in humans are either associated with underlying social deficits or are accompanied by social dysfunctions. Traditionally, rodent models have been used to model these behavioral impairments. However, rodent assays are often difficult to scale up and adapt to high-throughput formats, which severely limits their use for systems-level science. In recent years, an increasing number of studies have used zebrafish (Danio rerio) as a model system to study social behavior. These studies have demonstrated clear potential in overcoming some of the limitations of rodent models. In this Review, we explore the evolutionary conservation of a subcortical social brain between teleosts and mammals as the biological basis for using zebrafish to model human social behavior disorders, while summarizing relevant experimental tools and assays. We then discuss the recent advances gleaned from zebrafish social behavior assays, the applications of these assays to studying related disorders, and the opportunities and challenges that lie ahead.

Atypical functional connectome hierarchy in autism.

One paradox of autism is the co-occurrence of deficits in sensory and higher-order socio-cognitive processing. Here, we examined whether these phenotypical patterns may relate to an overarching system-level imbalance-specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Combining connectome gradient and stepwise connectivity analysis based on task-free functional magnetic resonance imaging (fMRI), we demonstrated atypical connectivity transitions between sensory and higher-order default mode regions in a large cohort of individuals with autism relative to typically-developing controls. Further analyses indicated that reduced differentiation related to perturbed stepwise connectivity from sensory towards transmodal areas, as well as atypical long-range rich-club connectivity. Supervised pattern learning revealed that hierarchical features predicted deficits in social cognition and low-level behavioral symptoms, but not communication-related symptoms. Our findings provide new evidence for imbalances in network hierarchy in autism, which offers a parsimonious reference frame to consolidate its diverse features.

Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) strikes hardest at the frontal lobes, but the sites of earliest injury remain unclear. OBJECTIVE: To determine atrophy patterns in distinct clinical stages of bvFTD, testing the hypothesis that the mildest stage is restricted to frontal paralimbic cortex. DESIGN: A bvFTD cohort study. SETTING: University hospital dementia clinic. PARTICIPANTS: Patients with bvFTD with Clinical Dementia Rating (CDR) scale scores of 0.5 (n = 15), 1 (n = 15), or 2 to 3 (n = 15) age and sex matched to each other and to 45 healthy controls. MAIN OUTCOME MEASURES: Magnetic resonance voxel-based morphometry estimated gray matter and white matter atrophy at each disease stage compared with controls. RESULTS: Patients with a CDR score of 0.5 had gray matter loss in frontal paralimbic cortices, but atrophy also involved a network of anterior cortical and subcortical regions. A CDR score of 1 showed more extensive frontal gray matter atrophy and white matter losses in corpus callosum and brainstem. A CDR score of 2 to 3 showed additional posterior insula, hippocampus, and parietal involvement, with white matter atrophy in presumed frontal projection fibers. CONCLUSIONS: Very mild bvFTD targets a specific subset of frontal and insular regions. More advanced disease affects white matter and posterior gray matter structures densely interconnected with the sites of earliest injury.

Oxytocin receptor gene variations and socio-emotional effects of MDMA: A pooled analysis of controlled studies in healthy subjects.

Methylenedioxymethamphetamine (MDMA) increases oxytocin, empathy, and prosociality. Oxytocin plays a critical role in emotion processing and social behavior and has been shown to mediate the prosocial effects of MDMA in animals. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the oxytocin receptor (OXTR) may influence the emotional and social effects of MDMA in humans. The effects of common genetic variants of the OXTR (rs53576, rs1042778, and rs2254298 SNPs) on the emotional, empathogenic, and prosocial effects of MDMA were characterized in up to 132 healthy subjects in a pooled analysis of eight double-blind, placebo-controlled studies. In a subset of 53 subjects, MDMA produced significantly greater feelings of trust in rs1042778 TT genotypes compared with G allele carriers. The rs53576 and rs225498 SNPs did not moderate the subjective effects of MDMA in up to 132 subjects. None of the SNPs moderated MDMA-induced impairments in negative facial emotion recognition or enhancements in emotional empathy in the Multifaceted Empathy Test in 69 subjects. MDMA significantly increased plasma oxytocin concentrations. MDMA and oxytocin concentrations did not differ between OXTR gene variants. The present results provide preliminary evidence that OXTR gene variations may modulate aspects of the prosocial subjective effects of MDMA in humans. However, interpretation should be cautious due to the small sample size. Additionally, OXTR SNPs did not moderate the subjective overall effect of MDMA (any drug effect) or feelings of "closeness to others". TRIAL REGISTRATION: ClinicalTrials.gov: http://www.clinicaltrials.gov, No: NCT00886886, NCT00990067, NCT01136278, NCT01270672, NCT01386177, NCT01465685, NCT01771874, and NCT01951508.

Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders.

Neuroimaging technology has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. The knowledge gained from imaging research and from the postmortem studies that have been guided by imaging data is catalyzing a paradigm shift in which primary mood disorders are conceptualized as illnesses that involve abnormalities of brain structure, as well as of brain function. These data suggest specific hypotheses regarding the neural mechanisms underlying pathological emotional processing in mood disorders. They particularly support a role for dysfunction within the prefrontal cortical and striatal systems that normally modulate limbic and brainstem structures involved in mediating emotional behavior in the pathogenesis of depressive symptoms.

Neuroanatomical correlates of behavioural disorders in dementia.

Neurodegenerative diseases are associated with profound changes in social and emotional function. The emergence of increasingly sophisticated methods for measuring brain volume has facilitated correlation of local changes in tissue content with cognitive and behavioural changes in neurodegenerative disease. The current study examined neuroanatomical correlates of behavioural abnormalities, as measured by the Neuropsychiatric Inventory, in 148 patients with dementia using voxel-based morphometry. Of 12 behaviours examined, 4 correlated with tissue loss: apathy, disinhibition, eating disorders and aberrant motor behaviour. Increasing severity across these four behaviours was associated with tissue loss in the ventral portion of the right anterior cingulate cortex (vACC) and adjacent ventromedial superior frontal gyrus (vmSFG), the right ventromedial prefrontal cortex (VMPC) more posteriorly, the right lateral middle frontal gyrus, the right caudate head, the right orbitofrontal cortex and the right anterior insula. In addition, apathy was independently associated with tissue loss in the right vmSFG, disinhibition with tissue loss in the right subgenual cingulate gyrus in the VMPC, and aberrant motor behaviour with tissue loss in the right dorsal ACC and left premotor cortex. These data strongly support the involvement of the right hemisphere in mediating social and emotional behaviour and highlight the importance of distinct regions on the medial wall of the right frontal lobe in regulating different behaviours. Furthermore, the findings underscore the utility of studying patients with dementia for understanding the neuroanatomical basis of social and emotional functions.