Robust hierarchically organized whole-brain patterns of dysconnectivity in schizophrenia spectrum disorders observed after personalized intrinsic network topography.

BACKGROUND: Spatial patterns of brain functional connectivity can vary substantially at the individual level. Applying cortical surface-based approaches with individualized rather than group templates may accelerate the discovery of biological markers related to psychiatric disorders. We investigated cortico-subcortical networks from multi-cohort data in people with schizophrenia spectrum disorders (SSDs) and healthy controls (HC) using individualized connectivity profiles. METHODS: We utilized resting-state and anatomical MRI data from n = 406 participants (n = 203 SSD, n = 203 HC) from four cohorts. Functional timeseries were extracted from previously defined intrinsic network subregions of the striatum, thalamus, and cerebellum as well as 80 cortical regions of interest, representing six intrinsic networks using (1) volume-based approaches, (2) a surface-based group atlas approaches, and (3) Personalized Intrinsic Network Topography (PINT). RESULTS: The correlations between all cortical networks and the expected subregions of the striatum, cerebellum, and thalamus were increased using a surface-based approach (Cohen's D volume vs. surface 0.27-1.00, all p < 10-6 ) and further increased after PINT (Cohen's D surface vs. PINT 0.18-0.96, all p < 10-4 ). In SSD versus HC comparisons, we observed robust patterns of dysconnectivity that were strengthened using a surface-based approach and PINT (Number of differing pairwise-correlations: volume: 404, surface: 570, PINT: 628, FDR corrected). CONCLUSION: Surface-based and individualized approaches can more sensitively delineate cortical network dysconnectivity differences in people with SSDs. These robust patterns of dysconnectivity were visibly organized in accordance with the cortical hierarchy, as predicted by computational models.

Molecular neuroanatomy of anorexia nervosa.

Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.

Developmentally divergent sexual dimorphism in the cortico-striatal-thalamic-cortical psychosis risk pathway.

Structural and functional cortico-striatal-thalamic-cortical (CSTC) circuit abnormalities have been observed in schizophrenia and the clinical high-risk state. However, this circuit is sexually dimorphic and changes across neurodevelopment. We examined effects of sex and age on structural and functional properties of the CSTC circuit in a large sample of youth with and without psychosis spectrum symptoms (PSS) from the Philadelphia Neurodevelopmental Cohort. T1-weighted and resting-state functional MRI scans were collected on a 3T Siemens scanner, in addition to participants' cognitive and psychopathology data. After quality control, the total sample (aged 11-21) was n = 1095 (males = 485, females = 610). Structural subdivisions of the striatum and thalamus were identified using the MAGeT Brain segmentation tool. Functional seeds were segmented based on brain network connectivity. Interaction effects among PSS group, sex, and age on striatum, thalamus, and subdivision volumes were examined. A similar model was used to test effects on functional connectivity of the CSTC circuit. A sex by PSS group interaction was identified, whereby PSS males had higher volumes and PSS females had lower volumes in striatal and thalamic subdivisions. Reduced functional striato-cortical connectivity was found in PSS youth, primarily driven by males, whereby younger male PSS youth also exhibited thalamo-cortical hypo-connectivity (compared to non-PSS youth), vs. striato-cortical hyper-connectivity in older male PSS youth (compared to non-PSS youth). Youth with PSS demonstrate sex and age-dependent differences in striatal and thalamic subdivision structure and functional connectivity. Further efforts at biomarker discovery and early therapeutic intervention targeting the CSTC circuit in psychosis should consider effects of sex and age.

Changes in brain functional connectivity after chronic haloperidol in rats: a network analysis.

Although the effects of haloperidol (HAL) have been extensively examined in experimental animals at the cellular and brain regional levels, the effects of prolonged HAL treatment on functional connectivity in the brain have not yet been addressed. Here we used expression of the immediate early gene zif268 as a marker of neural activity to examine changes in brain regional interactivity after 12 wk of HAL treatment in rats. zif268 expression was measured by in situ hybridization in 83 brain regions of HAL- and vehicle (VEH)-treated controls and correlations among all brain regions were computed separately for the two treatment groups. The strongest correlations in each group were used for network construction. It was found that VEH and HAL networks were equally segregated and integrated, and that both networks display small world organization. Compared to the VEH network, the HAL network showed enhanced interactivity between the dorsolateral striatum and thalamus, and between different subdivisions of the thalamus. It will be of interest to determine the extent to which the observed changes in functional connectivity may be related to dyskinesias, to changes in motivated behaviours and/or to the therapeutic effects of chronic HAL. By identifying the connectivity features of a chronic HAL network in the absence of other manipulations, the current findings may provide a reference signature pattern to be targeted in future efforts to discriminate between the neural bases of different behavioural outcomes arising from chronic HAL treatment.

Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial.

BACKGROUND: Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels. METHODS: In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course. RESULTS: The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohen's d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects. CONCLUSIONS: These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia.

Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.

BACKGROUND: Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. METHOD/PRINCIPAL FINDINGS: 53 healthy individuals between 18-59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3' untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. CONCLUSIONS: Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD.

Combined topical and intracameral anesthesia in penetrating keratoplasty.

BACKGROUND: The standard of care for penetrating keratoplasty (PKP) is either retrobulbar or peribulbar anesthesia combined with seventh cranial nerve akinesia or general anesthesia. These methods are known to be associated with rare but potentially serious adverse ocular and systemic events. PURPOSE: To determine the safety and efficacy of combined topical and intracameral anesthesia in addition to intravenous sedation for repeat penetrating keratoplasty (PKP). SETTING: Tertiary-care university hospital. METHODS: In this prospective study, combined topical tetracaine 0.5% and 0.2 cc intracameral 1% lidocaine along with i.v. sedation with midazolam and fentanyl were used for patients undergoing repeat PKP in 15 eyes of 15 selected patients. The indication for surgery was failed corneal graft. Verbal pain scale (VPS, 0-3) was recorded preoperatively, intraoperatively at 3 time-points (after trephination, after placing 8 interrupted sutures, and after placing the running suture), and postoperatively (1 hour postoperatively, overnight pain, and 1 day postoperatively). Patient and surgeon satisfaction were assessed postoperatively using a scale (1-5). After surgery patients were asked for their preferences comparing the current use of topical anesthesia compared with retrobulbar anesthesia used for their initial PKP. RESULTS: The mean intraoperative VPS score was 0.51 +/- 0.32 (range 0-1.33), and the mean postoperative VPS score was 0.47 +/- 0.50 (range 0-1.67). There were no serious intraoperative or postoperative complications. All patients reported high mean satisfaction score of 4.67 +/- 0.49 (range 4-5). The mean satisfaction score reported by the surgeon was 4.47 +/- 0.63 (range 3-5). All patients but 1 (93.3%) preferred combined topical over retrobulbar anesthesia, which they had in their previous surgery. CONCLUSIONS: We found combined topical and intracameral anesthesia to be safe and effective in our selected group of patients undergoing repeat PKP, and it may provide a satisfactory alternative anesthetic modality for patients in whom general, retrobulbar, or peribulbar anesthesia may be contraindicated.