Human impulsive aggression: a sleep research perspective

Impulsive aggression is commonly associated with personality disorders, in particular antisocial and borderline personality disorders as well as with conduct disorder and intermittent explosive disorder. The relationship between impulsive aggression and testosterone is well established in many studies. One of the aims of this study was to characterize the relationship between earlier-mentioned different categorical psychiatric diagnosis describing human impulsive aggression and sleep using polysomnography and spectral power analysis. Another aim was to study the relationship between serum testosterone and sleep in persons with severe aggressive behaviour. Subjects for the study were 16 males charged with highly violent offences and ordered for a pretrial forensic psychiatric examination. The antisocials with borderline personality disorder comorbidity had significantly more awakenings and lower sleep efficiency compared with the subjects with only antisocial personality disorder. The subjects with severe conduct disorder in childhood anamnesis had higher amount of S4 sleep and higher relative theta and delta power in this sleep stage compared with males with only mild or moderate conduct disorder. The same kind of sleep architecture was associated with intermittent explosive disorder. In subgroups with higher serum testosterone levels also the amount of S4 sleep and the relative theta and delta power in this sleep stage were increased. The study gives further support to the growing evidence of brain dysfunction predisposing to severe aggressive behaviour and strengthens the view that there are different subpopulations of individuals with antisocial personality varying in impulsiveness. The differences in impulsiveness are reflected in sleep architecture as well.     

Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website “www.clinicaltrials.gov” using the terms “schizophrenia AND cognition,” “schizophrenia AND neurocognition,” “schizophrenia AND neurocognitive tests,” “schizophrenia AND MATRICS,” “schizophrenia AND MCCB,” “schizophrenia AND BACS,” “schizophrenia AND COGSTATE,” and “schizophrenia AND CANTAB” and “first-episode schizophrenia AND cognition.” The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.     

Facilitation of secondary site kindling in the dorsal hippocampus following forebrain bisection

Bisection of the corpus callosum and hippocampal commissure, after the kindling of one dorsal hippocampus (primary site), had no effect on the rate of generalized kindled seizure development in the contralateral dorsal hippocampus (secondary site). The rate of kindling in the secondary site was very rapid in both intact and commissure-bisected rats, resulting in a positive transfer between the two sites of approximately 90%. In addition, the afterdischarge threshold response of the secondary site, after commissurotomy but before secondary site kindling, revealed mature local epileptogenesis. These observations support the suggestion that the positive transfer observed between the dorsal hippocampi is based on bilateral epileptogenesis during primary site kindling. Bisection of the anterior corpus callosum lateralized the forelimb convulsion while the hippocampal commissure independently mediated the laterality of the hippocampal afterdischarge. Commissurotomy had no significant influence on the latency to onset or offset of these motor and electrographic responses. These results are compared with those from the amygdala, and their implication for the laterality of epileptogenesis is discussed.     

Behavioral assessment of functional deficit in rats with contusive spinal cord injury

We have previously reported a method for assessing functional deficits in rats after contusive spinal cord injury in which a Combined Behavioral Score (CBS) is calculated that is indicative of the overall percent deficit (Exp. Neurol., 88: 123-134, 1985). The test battery used includes several neurologic tests as well as the Motor Score in which use of the hindlimbs in locomotion is graded. In this report we present correction criteria in order to reduce potential interlaboratory variability in assessing functional deficit by the CBS. Groups of rats were subjected to contusive injury using a weight drop technique. The calculated CBS at 4 weeks was compared to that obtained if the Motor Score was over- or underestimated by 1 grade. The results indicated a considerable effect on the calculated CBS, especially when the Motor Score was underestimated in mildly injured animals. Behavioral test data were examined in terms of the distribution of the responses to the various other behavioral tests in relation to the Motor Score. The results were used to develop a set of correction criteria that minimized the effects on the CBS of subjective errors in the Motor Score.     

Cortical Atrophy Predicts Visual Performance in Long-Term Central Retinal Disease; GCL,pRNFL and Cortical Thickness Are Key Biomarkers

PurposeThe aim of this study was to assess both retinal and cortical structure in a cohort of patients with long-term acquired central retinal disease in order to identify potential disease biomarkers and to explore the relationship between the anterior and posterior visual pathways.MethodsFourteen participants diagnosed with long-term central retinal disease underwent structural assessments of the retina using spectral-domain optical coherence tomography, including macular ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (pRNFL) thickness. Structural magnetic resonance imaging was used to measure visual cortex, including cortical volume of the entire occipital lobe and cortical thickness of the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively.ResultsMean thickness was significantly reduced in both the macular GCL and the inferior temporal pRNFL across patients. Cortical thickness was significantly reduced in both the occipital pole and calcarine sulcus, representing the central and peripheral retina, respectively. Disease duration significantly correlated with GCL thickness with a large effect size, whereas a medium effect size suggests the possibility that cortical thickness in the occipital pole may correlate with visual acuity.ConclusionsLong-term central retinal disease is associated with significant structural changes to both the retina and the brain. Exploratory analysis suggests that monitoring GCL thickness may be a sensitive biomarker of disease progression and reductions in visual cortical thickness may be associated with reduced visual acuity. Although this study is limited by its heterogeneous population, larger cohort studies would be needed to better establish some of the relationships detected between disease dependent structural properties of the anterior and posterior visual pathway given the effect sizes reported in our exploratory analysis.     

Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Objective:Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, the roles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remain obscure.Methods:The expression and prognostic values of P1- and P2-HNF4A were evaluated in The Cancer Genome Atlas (TCGA) databases and GC tissues. Then, functional assays of P1- and P2-HNF4A were conducted both in vivo and in vitro. High-throughput RNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays.Results:HNF4A amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage. Moreover, P1-HNF4A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues (P < 0.05), but no significant differences were found in P2-HNF4A expression (P > 0.05). High P1-HNF4A expression indicated poor prognoses in GC patients (P < 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration in vitro (P < 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumor growth (P < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A in GC tissues.Conclusions:P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.