The Development of Socially Directed Attention: An Functional Magnetic Resonance Imaging Study in Infant Monkeys.

Socially guided visual attention, such as gaze following and joint attention, represents the building block of higher-level social cognition in primates, although their neurodevelopmental processes are still poorly understood. Atypical development of these social skills has served as early marker of autism spectrum disorder and Williams syndrome. In this study, we trace the developmental trajectories of four neural networks underlying visual and attentional social engagement in the translational rhesus monkey model. Resting-state fMRI (rs-fMRI) data and gaze following skills were collected in infant rhesus macaques from birth through 6 months of age. Developmental trajectories from subjects with both resting-state fMRI and eye-tracking data were used to explore brain-behavior relationships. Our findings indicate robust increases in functional connectivity (FC) between primary visual areas (primary visual cortex [V1] - extrastriate area 3 [V3] and V3 - middle temporal area, ventral motion areas middle temporal area - AST, as well as between TE and amygdala (AMY) as infants mature. Significant FC decreases were found in more rostral areas of the pathways, such as areas temporal area occipital part - TE in the ventral object pathway, V3 - lateral intraparietal (LIP) of the dorsal visual attention pathway and V3 - temporo-parietal area of the ventral attention pathway. No changes in FC were found between cortical areas LIP-FEF and temporo-parietal area - Area 12 of the dorsal and ventral attention pathways or between AST-AMY and AMY-insula. Developmental trajectory of gaze following revealed a period of dynamic changes with gradual increases from 1 to 2 months, followed by slight decreases from 3 to 6 months. Exploratory association findings across the 6-month period showed that infants with higher gaze following had lower FC between primary visual areas V1-V3, but higher FC in the dorsal attention areas V3-LIP, both in the right hemisphere. Together, the first 6 months of life in rhesus macaques represent a critical period for the emergence of gaze following skills associated with maturational changes in FC of socially guided attention pathways.

Sensitivity to change of joint count composite indices in 72 patients with systemic sclerosis.

OBJECTIVES: We validated the responsiveness of joint count composite indices (JCCIs) in 72 patients with systemic sclerosis (SSc). METHODS: Changes in Disease Activity Score of 28 Joints using ESR and CRP (DAS28-ESR, DAS28-CRP), Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) were evaluated in a one-year follow-up study. Charts of patients including swollen/tender joint counts, laboratory signs of inflammation, and visual analogue scales referring to disease activity, severity and pain were also blindly categorized by two rheumatologists as improved, unchanged or deteriorated. These categories were used as references for the determination of effect size (ES) and standardised response mean (SRM). RESULTS: Articular inflammation improved in 15, deteriorated in 12, and remained unchanged in 45 (63%) patients with SSc based on the concordant opinion of two clinical investigators. All four JCCIs were sensitive to changes (ES>1; SRM>1). The correlation between changes in JCCIs and the physicians' evaluation was high (r >0.68; p<0.001). Arthritis was predominantly prone to change in patients with high JCCIs, impaired functional status, anti-RNA polymerase III antibodies and patients on DMARD therapy. Synovitis was more prevalent in patients with early diffuse SSc, and tended to improve during the follow-up. CONCLUSIONS: All four JCCIs were sensitive to changes, if tender/swollen joints were present at baseline. Articular inflammation was most prone to change in patients with high JCCIs, impaired functional status and already decreased health-related quality of life at baseline.

Obesogenic diet-associated C-reactive protein predicts reduced central dopamine and corticostriatal functional connectivity in female rhesus monkeys.

Alterations in dopamine (DA) signaling and reductions in functional connectivity (FC; a measure of temporal correlations of activity between different brain regions) within dopaminergic reward pathways are implicated in the etiology of psychopathology and have been associated with increased concentrations of inflammatory markers, including C-reactive protein. Peripheral and central inflammatory cytokines that have been shown to disrupt DA signaling and corticostriatal FC are associated with C-reactive protein, an acute phase reactant that is used translationally as a marker of systemic inflammation. One factor that can significantly increase systemic inflammation to produce neuroadaptations in reward pathways is a diet that results in fat mass accumulation (e.g. obesogenic diet). The current study in female rhesus monkeys maintained in a standard laboratory chow (n = 18) or on obesogenic diet (n = 16) for 12-months tested the hypothesis that an obesogenic diet would alter central DA and homovanillic acid (HVA) concentrations, and be associated with increased CRP concentrations and decreased FC between corticostriatal regions at 12-months following dietary intervention. We specifically assessed FC between the nucleus accumbens (NAcc) and two sub-regions of the prefrontal cortex (PFC) previously associated with CRP concentrations, the ventromedial PFC (vmPFC) and the orbitofrontal cortex (OFC), which are also involved in emotional and motivational salience assessment, and in goal-directed behavior, impulse control and the salience/value of food, respectively. Results showed that CSF DA concentrations were decreased (p = 0.002), HVA:DA ratios were increased (p = 0.016), and body mass index was increased (p = 0.047) over the 12-months of consuming an obesogenic diet. At 12-months, females maintained in the obesogenic diet exhibited higher CRP concentrations than females consuming chow-only (p = 0.008). Linear regression analyses revealed significant CRP by dietary condition interactions on DA concentrations (ß = -5.10; p = 0.017) and HVA:DA ratios (ß = 5.14; p = 0.029). Higher CRP concentrations were associated with lower CSF DA concentrations (r = -0.69; p = 0.004) and greater HVA:DA ratios only in females maintained in the obesogenic dietary condition (r = 0.58; p = 0.024). Resting-state magnetic resonance neuroimaging (rs-fMRI) in a subset of females from each diet condition (n = 8) at 12-months showed that higher CRP concentrations were associated decreased FC between the NAcc and subregions of the prefrontal cortex (PFC; p's < 0.05). Decreased FC between the NAcc and PFC subregions were also associated with lower concentrations of DA and greater HVA:DA ratios (p's < 0.05). Overall, these data suggest that increased inflammatory signaling driving heightened CRP levels may mediate the adverse consequences of obesogenic diets on DA neurochemistry and corticostriatal connectivity.

Developmental outcomes of early adverse care on amygdala functional connectivity in nonhuman primates.

Despite the strong link between childhood maltreatment and psychopathology, the underlying neurodevelopmental mechanisms are poorly understood and difficult to disentangle from heritable and prenatal factors. This study used a translational macaque model of infant maltreatment in which the adverse experience occurs in the first months of life, during intense maturation of amygdala circuits important for stress and emotional regulation. Thus, we examined the developmental impact of maltreatment on amygdala functional connectivity (FC) longitudinally, from infancy through the juvenile period. Using resting state functional magnetic resonance imaging (MRI) we performed amygdala-prefrontal cortex (PFC) region-of-interest and exploratory whole-brain amygdala FC analyses. The latter showed (a) developmental increases in amygdala FC with many regions, likely supporting increased processing of socioemotional-relevant stimuli with age; and (b) maltreatment effects on amygdala coupling with arousal and stress brain regions (locus coeruleus, laterodorsal tegmental area) that emerged with age. Maltreated juveniles showed weaker FC than controls, which was negatively associated with infant hair cortisol concentrations. Findings from the region-of-interest analysis also showed weaker amygdala FC with PFC regions in maltreated animals than controls since infancy, whereas bilateral amygdala FC was stronger in maltreated animals. These effects on amygdala FC development may underlie the poor behavioral outcomes associated with this adverse experience.

Efficacy of intensive hand physical therapy in patients with systemic sclerosis.

OBJECTIVES: To evaluate the efficacy of a three-week period of complex and intensive hand physical therapy on hand function in patients with systemic sclerosis (SSc). METHODS: Thirty-one patients with SSc were treated. Hand stretching exercises, ergotherapy supplemented with thermal and mud baths, whirlpool therapy and soft tissue massage were daily used during a three-week period. The control SSc group (n=22) received similar management for their large joints leaving out their hands. The primary outcomes of this study were the Health Assessment Questionnaire (HAQ) and the Disabilities of the Arm, Shoulder and Hand (DASH). Hand Anatomic Index (HAI), Cochin Hand Function (CHFT) and clinical characteristics were also assessed before starting the therapy and six months afterwards. RESULTS: Six months after the investigation period, only the group receiving hand physical therapy showed improvement in HAQ and DASH scores compared to the baseline values (p<0.05). The improvement in median HAQ value (25%-75% quartiles) reached the clinical meaningful rate (baseline 1.125/0.625-1.625/ versus 0.75/0.25-1.5/ at six months). Visual analogue scales of global pain (p<0.01) and Raynaud's phenomenon (p<0.05) also had better results than at baseline. HAI, gripping strength and CHFT also showed some improvement, but did not reach the significance level of change by the end of the six-month observation period. CONCLUSIONS: The complex physical therapy caused favourable changes in both the HAQ and the DASH indicating that this particular program had some long-term beneficial effect on hand function in patients with SSc.

Validation of disease activity indices using the 28 joint counts in systemic sclerosis.

OBJECTIVES: To validate the Disease Activity Score 28 using ESR (DAS28-ESR) and CRP (DAS28-CRP), the Simplified Disease Activity Index and the Clinical Disease Activity Index used in RA for SSc patients. METHODS: Seventy-seven SSc patients, 40 RA patients, 20 patients with primary RP (PRP) and 28 healthy volunteers were assessed. Besides the disease activity composite indices, the European Scleroderma Study Group Activity Index (EScSG-AI), the HAQ-DI, the Cochin Hand Function Scale and the Short Form Health Survey (SF36) were evaluated. The validation procedure included the assessment for truth, discrimination and feasibility. RESULTS: DAS28-ESR, DAS28-CRP, Simplified Disease Activity Index and Clinical Disease Activity Index showed significant correlation with EScSG-AI, HAQ-DI, Cochin Hand Function Scale and the physical component of SF36 (P < 0.001). All four indices discriminated patients with SSc from RA, PRS and healthy controls, respectively (P < 0.01). With the exception of DAS28-CRP, the other three indices also discriminated between subgroups of SSc based on value of EScSG-AI (⩽3 and >3) (P < 0.05). All four disease activity composite indices showed a good inter- and intraobserver reliability based on repeated measures of two independent investigators (P < 0.001). CONCLUSION: All four disease activity composite indices were found to be valid measures for assessing arthritis in SSc. DAS28-ESR showed the best performance regarding reliability and construct validity.

No effects of a single 3G UMTS mobile phone exposure on spontaneous EEG activity, ERP correlates, and automatic deviance detection.

Potential effects of a 30 min exposure to third generation (3G) Universal Mobile Telecommunications System (UMTS) mobile phone-like electromagnetic fields (EMFs) were investigated on human brain electrical activity in two experiments. In the first experiment, spontaneous electroencephalography (sEEG) was analyzed (n = 17); in the second experiment, auditory event-related potentials (ERPs) and automatic deviance detection processes reflected by mismatch negativity (MMN) were investigated in a passive oddball paradigm (n = 26). Both sEEG and ERP experiments followed a double-blind protocol where subjects were exposed to either genuine or sham irradiation in two separate sessions. In both experiments, electroencephalograms (EEG) were recorded at midline electrode sites before and after exposure while subjects were watching a silent documentary. Spectral power of sEEG data was analyzed in the delta, theta, alpha, and beta frequency bands. In the ERP experiment, subjects were presented with a random series of standard (90%) and frequency-deviant (10%) tones in a passive binaural oddball paradigm. The amplitude and latency of the P50, N100, P200, MMN, and P3a components were analyzed. We found no measurable effects of a 30 min 3G mobile phone irradiation on the EEG spectral power in any frequency band studied. Also, we found no significant effects of EMF irradiation on the amplitude and latency of any of the ERP components. In summary, the present results do not support the notion that a 30 min unilateral 3G EMF exposure interferes with human sEEG activity, auditory evoked potentials or automatic deviance detection indexed by MMN.

Treatment with sofosbuvir attenuates the adverse neurodevelopmental consequences of Zika virus infection in infant rhesus macaques.

Zika virus (ZIKV) infection during infancy in a rhesus macaque (RM) model negatively impacts brain development resulting in long-term behavioral alterations. The current study investigated whether postexposure prophylaxis could alleviate these negative neurodevelopmental consequences. Three RM infants received a 14-day course of sofosbuvir (SOF; 15 mg/kg p.o.) treatment starting at 3 days post-infection with a Puerto Rican strain of ZIKV (PRVABC59) and were then monitored longitudinally for one year. In contrast to ZIKV-infected infant RMs who did not receive SOF, postexposure SOF treatment mitigated the neurodevelopmental, behavioral and cognitive changes seen after postnatal ZIKV infection even while not accelerating viral clearance from the blood. These data suggest that antiviral treatment may help ameliorate some, but not all, of the neurodevelopmental abnormalities associated with early postnatal ZIKV infection.

Functional maturation in visual pathways predicts attention to the eyes in infant rhesus macaques: Effects of social status.

Differences in looking at the eyes of others are one of the earliest behavioral markers for social difficulties in neurodevelopmental disabilities, including autism. However, it is unknown how early visuo-social experiences relate to the maturation of infant brain networks that process visual social stimuli. We investigated functional connectivity (FC) within the ventral visual object pathway as a contributing neural system. Densely sampled, longitudinal eye-tracking and resting state fMRI (rs-fMRI) data were collected from infant rhesus macaques, an important model of human social development, from birth through 6 months of age. Mean trajectories were fit for both datasets and individual trajectories from subjects with both eye-tracking and rs-fMRI data were used to test for brain-behavior relationships. Exploratory findings showed infants with greater increases in FC between left V1 to V3 visual areas have an earlier increase in eye-looking before 2 months. This relationship was moderated by social status such that infants with low social status had a stronger association between left V1 to V3 connectivity and eye-looking than high status infants. Results indicated that maturation of the visual object pathway may provide an important neural substrate supporting adaptive transitions in social visual attention during infancy.

Heritability of social behavioral phenotypes and preliminary associations with autism spectrum disorder risk genes in rhesus macaques: A whole exome sequencing study.

Nonhuman primates and especially rhesus macaques (Macaca mulatta) have been indispensable animal models for studies of various aspects of neurobiology, developmental psychology, and other aspects of neuroscience. While remarkable progress has been made in our understanding of influences on atypical human social behavior, such as that observed in autism spectrum disorders (ASD), many significant questions remain. Improved understanding of the relationships among variation in specific genes and variation in expressed social behavior in a nonhuman primate would benefit efforts to investigate risk factors, developmental mechanisms, and potential therapies for behavioral disorders including ASD. To study genetic influences on key aspects of social behavior and interactions-individual competence and/or motivation for specific aspects of social behavior-we quantified individual variation in social interactions among juvenile rhesus macaques using both a standard macaque ethogram and a macaque-relevant modification of the human Social Responsiveness Scale. Our analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, with estimated quantitative genetic effects similar to that described for ASD in human children. We also performed exome sequencing and analyzed variants in 143 genes previously suggested to influence risk for human ASD. We find preliminary evidence for genetic association between specific variants and both individual behaviors and multi-behavioral factor scores. To our knowledge, this is the first demonstration that spontaneous social behaviors performed by free-ranging juvenile rhesus macaques display significant genetic heritability and then to use exome sequencing data to examine potential macaque genetic associations in genes associated with human ASD.

Exposure to an inhomogeneous static magnetic field increases thermal pain threshold in healthy human volunteers.

In the present experiment, the effect of a single 30 min inhomogeneous static magnetic field (SMF) exposure on thermal pain threshold (TPT) was examined in 15 young healthy human volunteers. The SMF had a maximum peak-to-peak amplitude of 330 mT with a maximum gradient of 13.2 T/m. In either of two experimental sessions (SMF or SHAM), four blocks of 12 TPT trials were carried out under SMF or SHAM exposure on all fingertips of the dominant hand, excluding the thumb. TPT and visual analog scale (VAS) data were recorded at 0, 15, and 30 min exposure time, and 30 min following exposure. SMF treatment resulted in a statistically significant increase in TPT during the entire exposure duration and diminished within-block thermal habituation, leaving pain perception unchanged. These results indicate that SMF-induced peripheral neuronal or circulatory mechanisms may be involved in the observed TPT increase by setting the pain fibre adaptation potential to higher levels.

Construct validity evaluation of the European Scleroderma Study Group activity index, and investigation of possible new disease activity markers in systemic sclerosis.

OBJECTIVES: To evaluate the construct validity of the European Scleroderma Study Group (EScSG) activity index and to propose modifications if necessary. METHODS: One hundred and thirty-one consecutive patients were investigated and re-evaluated 1 year later. Modified Rodnan skin score (MRSS), skin ulcers and joint contracture numbers, hand anatomic index (HAI), BMI, spirometry, carbon monoxide diffusing capacity (DL(CO)), left ventricular ejection fraction, pulmonary arterial hypertension, HAQ Disability Index (HAQ-DI), patient skin self-assessment questionnaire and several biomarkers were recorded, in addition to the data required for the EScSG activity index. Statistical analysis was performed by categorical principal component analysis (CATPCA). RESULTS: The EScSG activity index appeared in the same dimension as the HAQ-DI, ulcer score and joint contractures, MRSS, patient-reported skin score and HAI by CATPCA. Parameters of lung involvement appeared in another dimension. We constructed a 12-point activity index that was equally associated with both dimensions, by adding the forced vital capacity/DL(CO), change in DL(CO), change in the ulcer scores, HAQ-DI and patient-reported skin score. Biomarkers including vascular endothelial growth factor, soluble P-selectin glycoprotein ligand-1, CRP and albumin were related to both the EScSG and the 12-point index, though they did not improve the total variance of the model. CONCLUSION: The construct validity of the EScSG activity index is good, though the lung-related disease activity may not be sufficiently represented. Further validation steps may be required for both the EScSG and our 12-point activity index.

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques.

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.

Establishment and partial validation of a patient skin self-assessment questionnaire in systemic sclerosis.

OBJECTIVES: To construct a patient self-assessment questionnaire testing whether patients can provide valid information about their skin thickness, tethering and thinness. METHODS: The questionnaire contained questions about the 17 body areas identical to those investigated in the Modified Rodnan Skin Score (MRSS). The baseline and 1 yr follow-up values of thickening, tethering and thinning were scored on a scale of 0-3, by 131 consecutive patients. RESULTS: The questionnaire was feasible. The test-retest reliability was good, with an intraclass correlation coefficient of 0.5-0.6. The MRSS correlated with the 17-area thickness score (rho = 0.435, P < 0.001). Both the patient-reported thickness and tethering scores and the expert-measured MRSS and tethering scores correlated highly with each other (rho = 0.523, P < 0.001 and rho = 0.637, P < 0.001, respectively). The patient-reported thinness scores did not show any correlation with the examiner-measured skin thickening/tethering. All thickness-related scores were sorted into the same factor by principal component analysis. Conversely, skin thinness scores were sorted into a distinct factor. Skin thickness scores reported by diffuse SSc patients were different from those of the limited SSc cases (P < 0.05). CONCLUSIONS: We validated the skin thickness domain of the questionnaire, except the responsiveness. Because of the low mean MRSS of patients in this investigation, the patient self-assessment validation procedure should be repeated with cases exhibiting more extensive skin involvement. Patient-reported and examiner-measured tethering may not be used as independent instruments of skin involvement. The skin thinness domain may contain valuable independent information, therefore it also merits further investigation.

Chemogenetic Inhibition of the Amygdala Modulates Emotional Behavior Expression in Infant Rhesus Monkeys.

Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low-dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eye-tracking task, compared with vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent amygdala lesions in infant monkeys, such that neonatal lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results may help support the notion that the more extensive behavior changes seen after early lesions are manifested from brain reorganization that occur after permanent damage. The current study provides a proof of principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior.

Diet matters: Glucocorticoid-related neuroadaptations associated with calorie intake in female rhesus monkeys.

Exposure to psychosocial stressors increases consumption of palatable, calorically dense diets (CDD) and the risk for obesity, especially in females. While consumption of an obesogenic diet and chronic stress have both been shown to decrease dopamine 2 receptor (D2R) binding and alter functional connectivity (FC) within the prefrontal cortex (PFC) and the nucleus accumbens (NAcc), it remains uncertain how social experience and dietary environment interact to affect reward pathways critical for the regulation of motivated behavior. Using positron emission tomography (PET) and resting state functional connectivity magnetic resonance neuroimaging (rs-fMRI), in female rhesus monkeys maintained in a low calorie chow (n = 18) or a dietary choice condition (chow and a CDD; n = 16) for 12 months, the current study tested the overarching hypothesis that the adverse social experience resulting from subordinate social status would interact with consumption of an obesogenic diet to increase caloric intake that would be predicted by greater cortisol, lower prefrontal D2R binding potential (D2R-BP) and lower PFC-NAcc FC. Results showed that the consequences of adverse social experience imposed by chronic social subordination vary significantly depending on the dietary environment and are associated with alterations in prefrontal D2R-BP and FC in NAcc-PFC sub-regions that predict differences in caloric intake, body weight gain, and fat accumulation. Higher levels of cortisol in the chow-only condition were associated with mild inappetence, as well as increased orbitofrontal (OFC) D2R-BP and greater FC between the NAcc and the dorsolateral PFC (dlPFC) and ventromedial PFC (vmPFC). However, increased cortisol release in females in the dietary choice condition was associated with reduced prefrontal D2R-BP, and opposite FC between the NAcc and the vmPFC and dlPFC observed in the chow-only females. Importantly, the degree of these glucocorticoid-related neuroadaptations predicted significantly more total calorie intake as well as more consumption of the CDD for females having a dietary choice, but had no relation to calorie intake in the chow-only condition. Overall, the current findings suggest that dietary environment modifies the consequences of adverse social experience on reward pathways and appetite regulation and, in an obesogenic dietary environment, may reflect impaired cognitive control of food intake.

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques.

The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.

The telltale face: possible mechanisms behind defector and cooperator recognition revealed by emotional facial expression metrics.

In this study, we investigated the role of facial cues in cooperator and defector recognition. First, a face image database was constructed from pairs of full face portraits of target subjects taken at the moment of decision-making in a prisoner's dilemma game (PDG) and in a preceding neutral task. Image pairs with no deficiencies (n = 67) were standardized for orientation and luminance. Then, confidence in defector and cooperator recognition was tested with image rating in a different group of lay judges (n = 62). Results indicate that (1) defectors were better recognized (58% vs. 47%), (2) they looked different from cooperators (p < .01), (3) males but not females evaluated the images with a relative bias towards the cooperator category (p < .01), and (4) females were more confident in detecting defectors (p < .05). According to facial microexpression analysis, defection was strongly linked with depressed lower lips and less opened eyes. Significant correlation was found between the intensity of micromimics and the rating of images in the cooperator-defector dimension. In summary, facial expressions can be considered as reliable indicators of momentary social dispositions in the PDG. Females may exhibit an evolutionary-based overestimation bias to detecting social visual cues of the defector face.