Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABAA receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl− transporter, KCC2, leading to a reduction in intracellular Cl− that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl− levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.

The human faculty for object-mediated action, including tool use and imitation, exceeds that of even our closest primate relatives and is a key foundation of human cognitive and cultural uniqueness. In humans and macaques, observing object-directed grasping actions activates a network of frontal, parietal, and occipitotemporal brain regions, but differences in human and macaque activation suggest that this system has been a focus of selection in the primate lineage. To study the evolution of this system, we performed functional neuroimaging in humans' closest living relatives, chimpanzees. We compare activations during performance of an object-directed manual grasping action, observation of the same action, and observation of a mimed version of the action that consisted of only movements without results. Performance and observation of the same action activated a distributed frontoparietal network similar to that reported in macaques and humans. Like humans and unlike macaques, these regions were also activated by observing movements without results. However, in a direct chimpanzee/human comparison, we also identified unique aspects of human neural responses to observed grasping. Chimpanzee activation showed a prefrontal bias, including significantly more activity in ventrolateral prefrontal cortex, whereas human activation was more evenly distributed across more posterior regions, including significantly more activation in ventral premotor cortex, inferior parietal cortex, and inferotemporal cortex. This indicates a more "bottom-up" representation of observed action in the human brain and suggests that the evolution of tool use, social learning, and cumulative culture may have involved modifications of frontoparietal interactions.

Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, a segmental overgrowth syndrome, is caused by post zygotic somatic mutations in PIK3CA, a gene involved in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. Prenatal ultrasound findings of lymphovascular malformations, segmental overgrowth and skeletal defects can raise suspicion for CLOVES syndrome, but molecular confirmation of PIK3CA mutations on prenatally obtained samples is challenging because of somatic mosaicism. We detected a mosaic disease-causing mutation in PIK3CA by sequencing of DNA extracted from cultured amniotic cells, but not from DNA directly prepared from an amniotic fluid sample in a fetus with prenatally suspected CLOVES syndrome. The infant was born prematurely and displayed severe lymphovascular malformations and segmental overgrowth consistent with a clinical diagnosis of CLOVES syndrome; he passed away at 29 days of life. We discuss the complexities and limitations of genetic testing for somatic mosaic mutations in the prenatal period and highlight the potential need for multiple approaches to arrive at a molecular diagnosis.

Research has shown that autistic adults have poor health outcomes. We conducted a systematic review to identify existing interventions to address health outcomes for autistic adults and to determine whether these interventions address the priorities of the autistic community. We searched PubMed for articles that included an intervention, a primary health outcome measured at the individual (not system) level, and a sample population of at least 50% autistic adults. Studies were excluded if they were not peer-reviewed, had a focus on caregivers, were expert opinions on specific interventions, untested protocols, or interventions without a primary health outcome. Out of the 778 articles reviewed, 19 were found to meet the stated criteria. Based on the evidence gathered, two were considered emerging evidence-based approaches: cognitive behavioral approaches and mindfulness. The remaining interventions included in the review did not have sufficient evidence to support current use with this population. The majority of the studies included samples of young autistic adults, primarily male, without an intellectual disability. Anxiety, quality of life, depression, and behavioral issues were among the health outcomes measured in the final included articles. More research on preferred interventions with prioritized health outcomes of the autistic adult population is needed. Lay abstract Autistic adults have more health problems then their same-aged peers. Yet little research has been conducted that focuses on addressing these health problems. In order to guide future research, it is important to know what intervention studies have been done to improve health outcomes among autistic adults. The project team and student assistants read studies that were published between 2007 and 2018 in the online research database, PubMed. We looked for studies published in English, which were peer-reviewed and included (1) an intervention, (2) an outcome that was related to health, and (3) a study group that included autistic adults. We did not include studies that had outcomes about employment (unless there was a health outcome), studies about caregivers or caregiving, or expert opinions about interventions. Of 778 reviewed articles, 19 studies met all of the criteria above. Within these studies, two approaches were found to have emerging evidence for their use in autistic adults: cognitive behavioral interventions and mindfulness-based approaches for improved mental health outcomes. The remaining intervention approaches did not have enough articles to support their use. Many of the outcomes were about reduced symptoms of co-occurring mental health diagnoses (e.g. reduced anxiety, depression). Most of the participants in these studies were male and did not have intellectual disability. Most study participants were adults younger than 40. There are not many intervention studies that address health outcomes among autistic adults. More research is needed on interventions which are desired by the adult autism community and address preferred health outcomes such as increased quality of life or well-being.

Maladaptive patterns of attention to emotional stimuli are a common feature of posttraumatic stress disorder (PTSD), with growing evidence supporting sustained attention to threatening stimuli across trauma samples. However, it remains unclear how different PTSD symptom clusters are associated with attentional bias patterns, particularly in urban civilian settings with high rates of trauma exposure and PTSD. The present study examined associations among these variables in 70 traumatized primarily African American women. PTSD was measured using the Clinician Administered PTSD Scale, and eye tracking was used to measure patterns of attention as participants engaged in an attention bias (dot probe) task to emotional faces; average initial fixation (1 s) and dwell duration (overall time spent looking at emotional face versus neutral face across the 5 s task) were used to assess attention bias patterns toward emotional faces. Women with PTSD showed significantly longer dwell duration toward angry faces than women without PTSD (F = 5.16, p < .05). Bivariate correlation analyses with the PTSD symptom clusters showed a significant association between average initial fixation toward angry faces and higher levels of avoidance symptoms (r = 0.29, p < .05) as well as sustained attention to angry faces and higher levels of re-experiencing symptoms (r = 0.24, p < .05). Using separate linear regression models based on initial significant correlations, we found that PTSD avoidance symptoms were significantly related to average initial fixation toward angry faces (R2∆ = 0.09, p < .05) and PTSD re-experiencing symptoms were significantly related to dwell duration toward angry faces (R2∆ = 0.06, p < .05). These findings contribute to evidence that PTSD is related to both initial vigilance and sustained attention to threat and that certain symptom clusters may either drive or be more impacted by attentional biases, highlighting the benefits of addressing attentional biases within treatment.

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Threat-related attention biases have been implicated in the development and maintenance of PTSD symptoms. Research examining mechanisms through which threat-related attention biases are associated with PTSD is scarce. Negative affect, a transdiagnostic risk factor for many types of psychopathology, is one potential mechanism that has yet to be examined. Thus, the present study (n = 92) tested the indirect effect of attention bias on PTSD via negative affect using rigorous eyetracking methodology in a sample of urban-dwelling, trauma-exposed African-American women. We found support for the hypothesis that attention bias toward threat was indirectly associated with PTSD symptoms through increased negative affect. These results suggest that negative affect may be an important etiological process through which attention bias patterns could impact PTSD symptom severity. This finding is particularly important since negative affect can be directly addressed in the context of treatment. Implications for psychological and pharmacological therapeutic interventions targeting threat-related attention biases and negative affect are discussed.

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. Significance Statement Many neurodevelopmental disorders exhibit abnormal structural or functional amygdala development and altered socioemotional behavior. To date, developmental neuroscience studies have relied on permanent lesion techniques to investigate how atypical amygdala development impacts socioemotional behaviors, which may not adequately recapitulate the role of amygdala dysfunction in the manifestation of aberrant behavior. The present study sought to demonstrate that chemogenetic techniques based on designer receptors exclusively activated by designer drugs (DREADDs) could be used to transiently inhibit amygdala activity in infant monkeys, resulting in alterations in socioemotional behavior. This proof-of-principle study supports the use of chemogenetics for developmental neuroscience research, providing an opportunity to broaden our understanding of how changes in neuronal activity across early postnatal development influences behavior and clinical symptoms.