Aberrant functional connectivity between reward and inhibitory control networks in pre-adolescent binge eating disorder.

BACKGROUND: Behavioral features of binge eating disorder (BED) suggest abnormalities in reward and inhibitory control. Studies of adult populations suggest functional abnormalities in reward and inhibitory control networks. Despite behavioral markers often developing in children, the neurobiology of pediatric BED remains unstudied. METHODS: 58 pre-adolescent children (aged 9-10-years) with BED (mBMI = 25.05; s.d. = 5.40) and 66 age, BMI and developmentally matched control children (mBMI = 25.78; s.d. = 0.33) were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in resting-state functional MRI functional connectivity (FC) within and between reward and inhibitory control networks. A seed-based approach was employed to assess nodes in the reward [orbitofrontal cortex (OFC), nucleus accumbens, amygdala] and inhibitory control [dorsolateral prefrontal cortex, anterior cingulate cortex (ACC)] networks via hypothesis-driven seed-to-seed analyses, and secondary seed-to-voxel analyses. RESULTS: Findings revealed reduced FC between the dlPFC and amygdala, and between the ACC and OFC in pre-adolescent children with BED, relative to controls. These findings indicating aberrant connectivity between nodes of inhibitory control and reward networks were corroborated by the whole-brain FC analyses. CONCLUSIONS: Early-onset BED may be characterized by diffuse abnormalities in the functional synergy between reward and cognitive control networks, without perturbations within reward and inhibitory control networks, respectively. The decreased capacity to regulate a reward-driven pursuit of hedonic foods, which is characteristic of BED, may in part, rest on this dysconnectivity between reward and inhibitory control networks.

Sex differences in regional gray matter density in pre-adolescent binge eating disorder: a voxel-based morphometry study.

BACKGROUND: Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with broad medical and psychiatric morbidity, and obesity. While BED may be characterized by altered cortical morphometry, no evidence to date examined possible sex-differences in regional gray matter characteristics among those with BED. This is especially important to consider in children, where BED symptoms often emerge coincident with rapid gray matter maturation. METHODS: Pre-adolescent, 9-10-year old boys (N = 38) and girls (N = 33) with BED were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development Study. We investigated sex differences in gray matter density (GMD) via voxel-based morphometry. Control sex differences were also assessed in age and body mass index and developmentally matched control children (boys N = 36; girls N = 38). Among children with BED, we additionally assessed the association between dorsolateral prefrontal (dlPFC) GMD and parent-reported behavioral approach and inhibition tendencies. RESULTS: Girls with BED uniquely demonstrate diffuse clusters of greater GMD (p < 0.05, Threshold Free Cluster Enhancement corrected) in the (i) left dlPFC (p = 0.003), (ii) bilateral dmPFC (p = 0.004), (iii) bilateral primary motor and somatosensory cortex (p = 0.0003) and (iv) bilateral precuneus (p = 0.007). Brain-behavioral associations suggest a unique negative correlation between GMD in the left dlPFC and behavioral approach tendencies among girls with BED. CONCLUSIONS: Early-onset BED may be characterized by regional sex differences in terms of its underlying gray matter morphometry.

Frequency-specific medial septal nucleus deep brain stimulation improves spatial memory in MK-801-treated male rats.

BACKGROUND: Few treatments exist for the cognitive symptoms of schizophrenia. Pharmacological agents resulting in glutamate N-methyl-d-aspartate (NMDA) receptor hypofunction, such as MK-801, mimic many of these symptoms and disrupt neural activity. Recent evidence suggests that deep brain stimulation (DBS) of the medial septal nucleus (MSN) can modulate medial prefrontal cortex (mPFC) and hippocampal activity and improve spatial memory. OBJECTIVE: Here, we examine the effects of acute MK-801 administration on oscillatory activity within the septohippocampal circuit and behavior. We also evaluate the potential for MSN stimulation to improve cognitive behavioral measures following MK-801 administration. METHODS: 59 Sprague Dawley male rats received either acute intraperitoneal (IP) saline vehicle injections or MK-801 (0.1 mg/kg). Theta (5-12 Hz), low gamma (30-50 Hz) and high frequency oscillatory (HFO) power were analyzed in the mPFC, MSN, thalamus and hippocampus. Rats underwent MSN theta (7.7 Hz), gamma (100 Hz) or no stimulation during behavioral tasks (Novel object recognition (NOR), elevated plus maze, Barnes maze (BM)). RESULTS: Injection of MK-801 resulted in frequency-specific changes in oscillatory activity, decreasing theta while increasing HFO power. Theta, but not gamma, stimulation enhanced the anxiolytic effects of MK-801 on the elevated plus maze. While MK-801 treated rats exhibited spatial memory deficits on the Barnes maze, those that also received MSN theta, but not gamma, stimulation found the escape hole sooner. CONCLUSIONS: These findings demonstrate that acute MK-801 administration leads to altered neural activity in the septohippocampal circuit and impaired spatial memory. Further, these findings suggest that MSN theta-frequency stimulation improves specific spatial memory deficits and may be a possible treatment for cognitive impairments caused by NMDA hypofunction.

mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia.

Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.

Mechanisms of Bacterial Colonization of the Respiratory Tract.

Respiratory tract infections are an important cause of morbidity and mortality worldwide. Chief among these are infections involving the lower airways. The opportunistic bacterial pathogens responsible for most cases of pneumonia can cause a range of local and invasive infections. However, bacterial colonization (or carriage) in the upper airway is the prerequisite of all these infections. Successful colonizers must attach to the epithelial lining, grow on the nutrient-limited mucosal surface, evade the host immune response, and transmit to a susceptible host. Here, we review the molecular mechanisms underlying these conserved stages of carriage. We also examine how the demands of colonization influence progression to disease. A range of bacteria can colonize the upper airway; nevertheless, we focus on strategies shared by many respiratory tract opportunistic pathogens. Understanding colonization opens a window to the evolutionary pressures these pathogens face within their animal hosts and that have selected for attributes that contribute to virulence and pathogenesis.

High-beta/low-gamma frequency activity reflects top-down predictive coding during a spatial working memory test.

Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.

Four-year follow-up on 68 patients with a new post-operatively adjustable long-term implant for post-prostatectomy stress incontinence: ProACT™.

AIMS: This paper presents 4-year follow-up results for patients enrolled in a pivotal study conducted to support an FDA premarket approval application (PMAA). The study evaluated the safety and efficacy of the ProACT Adjustable Continence Therapy for the treatment of post-prostatectomy stress urinary incontinence (SUI). METHODS: The clinical study involved 11 clinical sites and enrolled 160 subjects, all male. A total of 124 subjects met study criteria and 123 were implanted with ProACT. Baseline and outcomes for 68 patients who completed 4-year follow-up visits are reported. Endpoints included 24-h pad weight, Incontinence Quality of Life Questionnaire (I-QOL), UCLA Prostate Cancer Index-Urinary Function (PCI-UF), residual volume, and incidence and severity of device or procedure-related adverse events. RESULTS: Statistically significant improvements during follow-up were observed in 24-h pad weight, for which the mean pre-implant urine loss was 293 g, which was reduced at 4 years to 73 g (P < 0.001). Reductions in pad weight were observed across all levels of pre-implant SUI severity. Significant improvements were also seen in quality of life as measured by the I-QOL (P < 0.001) as well as measures of urinary function and pad use. One procedure-related SAE (retention) was reported among the 68 subjects; the SAE was resolved without clinical meaningful sequalae. CONCLUSIONS: These results confirm the long-term safety and efficacy of this newly FDA-approved therapy, showing significant improvements in both objective and subjective measures of SUI in mild, moderate, and severely incontinent male patients. The implant procedure is minimally invasive, and complications are generally mild and easily resolvable.

Sacral neuromodulation treating chronic pelvic pain: a meta-analysis and systematic review of the literature.

INTRODUCTION AND HYPOTHESIS: Sacral neuromodulation (SNM) is gaining popularity as a treatment option for chronic pelvic pain (CPP). Our hypothesis is that SNM is effective in improving CPP. METHODS: A systematic search was conducted through September 2018. Peer-reviewed studies using pre- and postpain intensity scores were selected. The primary outcome was pain improvement on a 10-point visual analog scale (VAS) (adjusted or de novo) in patients with CPP. Secondary outcomes included comparing SNM approaches and etiologies and evaluating lower urinary tract symptoms (LUTS). RESULTS: Fourteen of 2175 studies, evaluating 210 patients, were eligible for further analysis. The overall VAS pain score improvement was significant [weighted mean difference (WMD) -4.34, 95% confidence interval (CI) = -5.22, to-3.64, p < 0.0001)]. Regarding SNM approach, both standard and caudal approaches had significant reduction in pain scores: WMD -4.32, CI 95% = -5.32, to -3.31 (p < 0.001) for the standard approach, compared with WMD -4.63, 95% CI = -6.57 to -2.69 (P < 0.001), for the caudal approach (p = 0.75). While significant improvement in pain was observed both in patients with and without interstitial cystitis/bladder pain syndrome (IC/BPS), the observed improvement was lower in patients with (WMD -4.13, CI 95% -5.36 to -2.90 versus without (WMD -5.72, CI 95% = -6.18, to-5.27) IC/BPS (p = 0.02). SNM was effective in treating voiding symptoms (frequency, urgency, nocturia) associated with IC/BPS (all p < 0.01). CONCLUSIONS: SNM is an effective therapy for CPP in both IC/BSP and non-IC/BSP patients, with better results in non-IC/BSP patients. Outcomes of the antegrade caudal approach were comparable with the standard retrograde approach.

Five-Year Followup Results of a Prospective, Multicenter Study of Patients with Overactive Bladder Treated with Sacral Neuromodulation.

PURPOSE: We evaluated the therapeutic success rate, changes in quality of life and safety of sacral neuromodulation 5 years after InterStim™ implantation. Included in study were subjects with bothersome symptoms of overactive bladder, including urinary urge incontinence and/or urgency-frequency, in whom at least 1 anticholinergic medication failed and 1 medication had not been tried. MATERIALS AND METHODS: Therapeutic success was defined as a urinary urge incontinence or urgency-frequency response of 50% or greater improvement in average leaks or voids per day, or return to normal voiding, defined as fewer than 8 voids per day. Quality of life was evaluated by ICIQ-OABqol (International Consultation on Incontinence Modular Questionnaire). Safety was evaluated through adverse events. RESULTS: Of the 340 subjects who completed the test stimulation 272 had an implant, of whom 91% were female. Mean age was 57 years. At baseline 202 subjects with urinary urge incontinence had a mean ± SD of 3.1 ± 2.7 leaks per day and 189 with urgency-frequency had a mean of 12.6 ± 4.5 voids per day. The 5-year therapeutic success rate was 67% (95% CI 60-74) using modified completers analysis and 82% (95% CI 76-88) using completers analysis. Subjects with urinary urge incontinence had a mean reduction from baseline of 2.0 ± 2.2 leaks per day and subjects with urgency-frequency had a mean reduction of 5.4 ± 4.3 voids per day (each completers analysis p <0.0001). Subjects showed improvement in all ICIQ-OABqol measures (p <0.0001). The most common device related adverse events were an undesirable change in stimulation in 60 of the 272 subjects (22%), implant site pain in 40 (15%) and therapeutic product ineffectiveness in 36 (13%). CONCLUSIONS: This multicenter study shows that sacral neuromodulation had sustained efficacy and quality of life improvements, and an acceptable safety profile through 5 years in subjects with overactive bladder.

Pyramidal cell-selective GluN1 knockout causes impairments in salience attribution and related EEG activity.

Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.

Baseline symptom severity and therapeutic success in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients.

INTRODUCTION: The InSite trial is a prospective, multicenter post-approval study of subjects receiving sacral neuromodulation (SNM) therapy with the InterStim® System. Enrolled subjects had bothersome symptoms of overactive bladder (OAB). The purpose of this analysis was to determine if severity of baseline symptoms had an impact on clinical outcomes. METHODS: For device implant, therapeutic success was defined as a ≥50% improvement in average leaks/day, or in voids/day or a return to normal voiding frequency. Groups were dichotomized into less versus more severe based on median number of leaks and voids. Subjects were grouped as less severe <2 leaks/day for UI; <11 voids/day for UF and more severe ≥2 leaks/day for UI; ≥11 voids/day for UF. Therapeutic success at 12 and 24 months were compared between groups. RESULTS: Three hundred and forty subjects completed test stimulation and 272 (80%) subjects received a full system implant. On average UI subjects had 1.3 leaks/day in the less severe group and 4.5 leaks/day in the more severe group. UI success rates were not statistically different between severity groups at 12 months or 24 months). At baseline, on average UF subjects had 9.4 voids/day for the less severe group and 15.1 voids/day for the more severe group. UF success rates were not statistically different between severity groups at 12 months or 24 months. CONCLUSION: Data evaluating efficacy based on symptom severity demonstrates that SNM is effective in treating both less severe and more severely affected groups for both UI and UF at 12 and 24 months.

Treatment with an adjustable long-term implant for post-prostatectomy stress incontinence: The ProACT™ pivotal trial.

AIMS: This paper presents 18-month follow-up results for patients enrolled in a pivotal study conducted to support an FDA premarket approval application (PMAA). The trial evaluated the safety and efficacy of the ProACT Adjustable Continence Therapy for the treatment of post-prostatectomy stress urinary incontinence (SUI). METHODS: The clinical study involved 11 clinical sites and enrolled 160 subjects. A total of 124 subjects met study criteria and 123 underwent ProACT implantation from July 2005 through June 2007, of whom 98 completed 18-month follow-up. Endpoints included 24-h pad weight, Incontinence Quality of Life Questionnaire (I-QOL), UCLA Prostate Cancer Index-Urinary Function (PCI-UF), residual volume, and device or procedure-related adverse events (AEs). RESULTS: The mean surgical time was 32 min. Statistically significant improvements during follow-up were observed in 24-h pad weight, for which the cohort mean pre-implant urine loss was 399 g, which was reduced at 18 months to 160 g (P < 0.001). Reductions in pad weight were observed across all levels of pre-implant SUI severity. Significant improvements were also seen in quality of life as measured by the I-QOL (P < 0.001) as well as measures of urinary function and pad count. One procedure-related serious adverse event (SAE), retention, was reported among the 124 subjects; the SAE was resolved without clinical meaningful sequalae. CONCLUSIONS: These results demonstrate the safety and efficacy of this newly FDA-approved therapy, showing significant improvements in objective and subjective measures of SUI in mild, moderate, and severely incontinent male patients. The duration of the implant procedure is short, and complications are mild and easily resolvable.

International Continence Society best practice statement for use of sacral neuromodulation.

AIMS: Sacral neuromodulation (SNM) is an accepted therapy for a variety of conditions. However, despite over 20 years of experience, it remains a specialized procedure with a number of subtleties. Here we present the recommendations issued from the International Continence Society (ICS) SNM Consensus Panel. METHODS: Under the auspices of the ICS, eight urologists, three colorectal surgeons and two urogynecologists, covering a wide breadth of geographic and specialty interest representation, met in January 2017 to discuss best practices for neuromodulation. Suggestions for statements were submitted in advance and specific topics were assigned to committee members, who prepared and presented supporting data to the group, at which time each topic was discussed in depth. Best practice statements were formulated based on available data. This document was then circulated to multiple external reviewers after which final edits were made and approved by the group. RESULTS: The present recommendations, based on the most relevant data available in the literature, as well as expert opinion, address a variety of specific and at times problematic issues associated with SNM. These include the use of SNM for a variety of underlying conditions, need for pre-procedural testing, use of staged versus single-stage procedures, screening for success during the trial phase, ideal anesthesia, device implantation, post-procedural management, trouble-shooting loss of device function, and future directions for research. CONCLUSIONS: These guidelines undoubtedly constitute a reference document, which will help urologists, gynecologists, and colorectal surgeons optimize their use of SNM for refractory urinary urgency and frequency, UUI, NOR, and FI.

Protocadherin 10 alters γ oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits.

Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10+/-) has been investigated as a proxy for ASD. Male Pcdh10+/- mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10+/- mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10+/- mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10+/- mice, male Pcdh10+/- mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10+/- mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABAB agonist remediated these electrophysiological alterations among male Pcdh10+/-mice. Pcdh10+/- mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10+/- mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD.

Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage Trafficking.

Infections are a common cause of infant mortality worldwide, especially due to Streptococcus pneumoniae. Colonization is the prerequisite to invasive pneumococcal disease, and is particularly frequent and prolonged in children, though the mechanisms underlying this susceptibility are unknown. We find that infant mice exhibit prolonged pneumococcal carriage, and are delayed in recruiting macrophages, the effector cells of clearance, into the nasopharyngeal lumen. This lack of macrophage recruitment is paralleled by a failure to upregulate chemokine (C-C) motif ligand 2 (Ccl2 or Mcp-1), a macrophage chemoattractant that is required in adult mice to promote clearance. Baseline expression of Ccl2 and the related chemokine Ccl7 is higher in the infant compared to the adult upper respiratory tract, and this effect requires the infant microbiota. These results demonstrate that signals governing macrophage recruitment are altered at baseline in infant mice, which prevents the development of appropriate innate cell infiltration in response to pneumococcal colonization, delaying clearance of pneumococcal carriage.

From provocation to aggression: the neural network.

BACKGROUND: In-vivo observations of neural processes during human aggressive behavior are difficult to obtain, limiting the number of studies in this area. To address this gap, the present study implemented a social reactive aggression paradigm in 29 healthy men, employing non-violent provocation in a two-player game to elicit aggressive behavior in fMRI settings. RESULTS: Participants responded more aggressively after high provocation reflected in taking more money from their opponents. Comparing aggression trials after high provocation to those after low provocation revealed activations in neural circuits involved in aggression: the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), and the insula. In general, our findings indicate that aggressive behavior activates a complex, widespread brain network, reflecting a cortico-limbic interaction and overlapping with circuits underlying negative emotions and conflicting decision-making. Brain activation during provocation in the OFC was associated with the degree of aggressive behavior in this task. CONCLUSION: Therefore, data suggest there is greater susceptibility for provocation, rather than less inhibition of aggressive tendencies, in individuals with higher aggressive responses. This further supports the hypothesis that reactive aggression can be seen as a consequence of provocation of aggressive emotional responses and parallel evaluative regulatory processes mediated mainly by the insula and prefrontal areas (OFC, mPFC, dlPFC, and ACC) respectively.

The nature and consequences of cognitive deficits among tobacco smokers with HIV: a comparison to tobacco smokers without HIV.

HIV-infected smokers lose more years of life to tobacco-related disease than HIV. Since neurocognitive deficits are common among those with HIV and are associated with smoking persistence, these deficits may be a unique barrier to smoking cessation among HIV-infected smokers. Documenting unique differences in and correlates of cognition among HIV-infected smokers is a critical step towards developing a population-specific tobacco cessation treatment. We compared neurocognitive function between HIV-infected (n = 103) and HIV-uninfected smokers (n = 70), accounting for demographic and smoking-related variables. We also evaluated whether HIV-related health outcomes (e.g., CD4 count, viral load, depression ratings, quality of life [QoL]) and HAART adherence were associated with cognition. Participants completed neurocognitive tasks (N-back and Continuous Performance Task [CPT]) measuring working memory, attention, and processing speed, and intra-individual variability. Stepwise regression models were conducted and validated with resampling techniques. HIV-infected smokers performed worse than HIV-uninfected smokers on working memory, processing speed, and intra-individual variability (all p < 0.01). ROC analysis for the model including cognitive measures demonstrated 85% area under the curve, which indicates "good prediction" for distinguishing between HIV-infected and HIV-uninfected smokers. This was a significant improvement over the model including demographic and smoking-related variables only (p = 0.0003). Among HIV-infected smokers, neurocognitive performance was negatively associated with QoL and depression ratings. Smoking cessation interventions for HIV-infected smokers should consider cognitive neurorehabilitation as a potential strategy to decrease the likelihood of nicotine relapse and decrease tobacco-related morbidity in this population.

The effect of sacral neuromodulation on pregnancy: a systematic review.

INTRODUCTION AND HYPOTHESIS: To evaluate the effects of sacral neuromodulation (SNM) on pregnancy and the impact of delivery on SNM function. METHODS: A systematic search was conducted through January 2016. We selected studies including women who had SNM and a subsequent pregnancy. RESULTS: Out of 2,316, eight studies were included, comprising 22 patients (26 pregnancies). SNM indications were Fowler's syndrome in 11, urinary retention in 6, fecal incontinence in 1, fecal and urinary urgency in 1, overactive bladder in 1, intractable interstitial cystitis in 1, and myelodysplasia in 1. SNM stayed on in 8 pregnancies. In the remaining 18 pregnancies in which the device was deactivated, 7 had recurrent urinary tract infections, including 1 with pyelonephritis and 2 who requested reactivation owing to recurrent symptoms. Outcomes were reported in 25 pregnancies, 16 had Cesarean section (CS) and 9 had vaginal delivery, including 2 operative deliveries. Out of 25, two infants had pilonidal sinus and motor tic disorder (exhibited at the age of 2 years), both from the same mother. After delivery, SNM was functioning in 15 (60%), 4 required reprogramming, and 3 required replacement (1 had recurrence of fecal incontinence after her operative delivery with evidence of displaced leads and 1 patient reported decreased SNM effects after her two CS), and 3 decided to remove the device (2 out of 3 patients were free of symptoms after SNM deactivation and requested removal). CONCLUSION: Within the current limited evidence, the decision regarding SNM activation or deactivation should be individualized. A registry for those patients is recommended.

Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia. SIGNIFICANCE STATEMENT: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.