http://brainmind.umin.jp/public/kojima2003c.pdf

The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

http://enigma.ini.usc.edu/wp-content/uploads/2010/04/Effect-of-COMT-Val108-158-Met-genotype-on-frontal-lobe-function-and-risk-for-schizophrenia.pdf

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

The complex organization of connectivity in the human brain is incompletely understood. Recently, topological measures based on graph theory have provided a new approach to quantify large-scale cortical networks. These methods have been applied to anatomical connectivity data on nonhuman species, and cortical networks have been shown to have small-world topology, associated with high local and global efficiency of information transfer. Anatomical networks derived from cortical thickness measurements have shown the same organizational properties of the healthy human brain, consistent with similar results reported in functional networks derived from resting state functional magnetic resonance imaging (MRI) and magnetoencephalographic data. Here we show, using anatomical networks derived from analysis of inter-regional covariation of gray matter volume in MRI data on 259 healthy volunteers, that classical divisions of cortex (multimodal, unimodal, and transmodal) have some distinct topological attributes. Although all cortical divisions shared nonrandom properties of small-worldness and efficient wiring (short mean Euclidean distance between connected regions), the multimodal network had a hierarchical organization, dominated by frontal hubs with low clustering, whereas the transmodal network was assortative. Moreover, in a sample of 203 people with schizophrenia, multimodal network organization was abnormal, as indicated by reduced hierarchy, the loss of frontal and the emergence of nonfrontal hubs, and increased connection distance. We propose that the topological differences between divisions of normal cortex may represent the outcome of different growth processes for multimodal and transmodal networks and that neurodevelopmental abnormalities in schizophrenia specifically impact multimodal cortical organization.

https://www.jneurosci.org/content/jneuro/28/37/9239.full.pdf

Hierarchical Organization of Human Cortical Networks in Health and Schizophrenia

Background Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Methods Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls(N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol- O -methyltransferase ( COMT ) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. Results A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. Conclusions A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/207823/yoa20701.pdf

Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia.

The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance.

/pdf/a-common-allele-in-the-oxytocin-receptor-gene-oxtr-impacts-197uz4kcs0.pdf

A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function

OBJECTIVE: Impaired attention has frequently been observed in studies of unaffected siblings of patients with schizophrenia. To assess the suitability of impaired attention for use as an intermediate phenotype in genetic studies, the authors estimated the relative risk of impaired attention in a large group of siblings. METHOD: The authors used the Continuous Performance Test, 1-9 version, with and without a distraction condition, to study 147 patients with schizophrenia, 193 of their siblings, and 47 normal comparison subjects. Relative risk (l) was estimated by using cutoff scores that were one, two, and three standard deviations below the mean sensitivity index value (d¢) of the normal comparison group in both Continuous Performance Test conditions. RESULTS: Patients but not their siblings performed worse than the normal comparison subjects in both conditions. Fifty percent of the patients, 24% of their siblings, and 18% of the normal comparison subjects scored one standard deviation below the mean sco...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.157.8.1309

Relative Risk of Attention Deficits in Siblings of Patients With Schizophrenia

Inhibition of compensatory ovarian hypertrophy in the mouse and vole: a comparison of Altschule's pineal extract, pineal indoles, vasopressin, and oxytocin

1. 1. If 21 day-old male rats are parathyroidectomized (PTX) and a week later are pinealectomized (PX) about 80 per cent of the animals exhibit repeated seizures during the first 8 hr following PX. Within 48 hr roughly 35 per cent of these animals die. 2. 2. The administration of FLA-63, a dopamine-β-hydroxylase inhibitor, 60 min after PX caused a rapid onset of the seizures in all the animals. Additionally, 100 per cent of the rats given FLA-63 were dead within 3 hr of PX. 3. 3. The injection of p-CPA, a tryptophan hydroxylase inhibitor, at 48 and 24 hr preceding PX, only slightly increased the frequency of the seizures. 4. 4. The administration of a melatonin-free pineal extract had no influence on the convulsive episodes in PTX + PX rats. 5. 5. In support of previously obtained biochemical data, the results suggested that depressed brain norepinephrine may somehow be related to the seizures in PTX + PX rats.

Effect of drugs which inhibit tryptophan hydroxylase or dopamine-β-hydroxylase on pinealectomy-induced seizures in parathyroidectomized rats

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Relative Risk of Attention Deficits in Siblings of Patients With Schizophrenia

Inhibition of compensatory ovarian hypertrophy in the mouse and vole: a comparison of Altschule's pineal extract, pineal indoles, vasopressin, and oxytocin

Effect of drugs which inhibit tryptophan hydroxylase or dopamine-β-hydroxylase on pinealectomy-induced seizures in parathyroidectomized rats