Neural response to aggressive and positive interactions in violent offenders and nonviolent individuals.

BACKGROUND: Due to its severe negative consequences, human violence has been targeted by a vast number of studies. Yet, neurobiological mechanisms underlying violence are still widely unclear and it seems necessary to aim for high ecological validity to learn about mechanisms contributing to violence in real life. METHODS: The present functional magnetic resonance imaging (fMRI) study investigated the neurofunction of individuals with a history of violent offenses compared with that of controls using a laboratory paradigm requesting individuals to empathically engage in videos depicting provocative aggressive and positive social interactions from a first-person perspective. RESULTS: The contrast of aggressive vs. positive scenarios revealed midbrain activation patterns associated with caudal periaqueductal gray (PAG) in violent offenders; In controls, the rostral PAG was involved. Additionally, only in controls, this contrast revealed an involvement of the amygdaloidal complex. Moreover, in violent offenders the contrast of positive vs. aggressive situations revealed an involvement of areas in the insula, post-central gyrus and anterior cingulate cortex. CONCLUSIONS: Our results support findings on the differential role of PAG subdivisions in response to threat and point to altered processing of positive social interactions in violent offenders. They further support the notion that changes in PAG recruitment might contribute to violent individuals "taking action" instead of freezing in case of threatening situations.

Origin and evolution of human cognition.

We investigate which of the higher cognitive abilities or types of intelligence characteristic of humans are found, even in preliminary form, in non-human animals, predominantly primates, or whether qualitatively different ("unique") human abilities exist. This concerns (1) tool use and fabrication, (2) problem solving, (3) gaze following, (4) mirror self-recognition, (5) imitation, (6) metacognition, (7) theory of mind, (8) consciousness, (9) prosociality, and (10) language. We found that none of these abilities can be regarded as unique to humans without precursors in non-human primates. The observed differences in cognitive functions, underlying brain mechanisms and resulting behaviors correlate best with differences in the information processing capacity as an equivalent of general intelligence based on the number of cortical neurons, packing density and axonal conduction velocity plus long-range cortical fascicles. The biggest quantitative change appears to concern the origin of syntactical language, but this was preceded by an increased mental ability to manipulate sequential events within working memory.

How is your mind-set? Proof of concept for the measurement of the level of emotional development.

BACKGROUND: In persons with intellectual and developmental disabilities, not only cognitive brain functions, but also socio-emotional processing networks may be impaired. This study aims to validate the Scale of Emotional Development-Short (SED-S) to provide an instrument for the assessment of socio-emotional brain functions. METHOD: The SED-S was applied in 160 children aged 0-12 years. Criterion validity was investigated at item and scale level in terms of the agreement between the scale classification and the child's chronological age. Additionally, interrater reliability and internal consistency were assessed. RESULTS: For the majority of items, the expected response pattern emerged, showing the highest response probabilities in the respective target age groups. Agreement between the classification of the different SED-S domains and chronological age was high (κw = 0.95; exact agreement = 80.6%). Interrater reliability at domain level ranged from κw = .98 to 1.00 and internal consistency was high (α = .99). CONCLUSION: The study normed the SED-S in a sample of typically developing children and provides evidence for criterion validity on item, domain and scale level.

Neuronal factors determining high intelligence.

Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity--factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner.

Convergent evolution of complex brains and high intelligence.

Within the animal kingdom, complex brains and high intelligence have evolved several to many times independently, e.g. among ecdysozoans in some groups of insects (e.g. blattoid, dipteran, hymenopteran taxa), among lophotrochozoans in octopodid molluscs, among vertebrates in teleosts (e.g. cichlids), corvid and psittacid birds, and cetaceans, elephants and primates. High levels of intelligence are invariantly bound to multimodal centres such as the mushroom bodies in insects, the vertical lobe in octopodids, the pallium in birds and the cerebral cortex in primates, all of which contain highly ordered associative neuronal networks. The driving forces for high intelligence may vary among the mentioned taxa, e.g. needs for spatial learning and foraging strategies in insects and cephalopods, for social learning in cichlids, instrumental learning and spatial orientation in birds and social as well as instrumental learning in primates.

The Influence of Genome and Cell Size on Brain Morphology in Amphibians.

In amphibians, nerve cell size is highly correlated with genome size, and increases in genome and cell size cause a retardation of the rate of development of nervous (as well as nonnervous) tissue leading to secondary simplification. This yields an inverse relationship between genome and cell size on the one hand and morphological complexity of the tectum mesencephali as the main visual center, the size of the torus semicircularis as the main auditory center, the size of the amphibian papilla as an important peripheral auditory structure, and the size of the cerebellum as a major sensorimotor center. Nervous structures developing later (e.g., torus and cerebellum) are more affected by secondary simplification than those that develop earlier (e.g., the tectum). This effect is more prominent in salamanders and caecilians than in frogs owing to larger genome and cells sizes in the former two taxa. We hypothesize that because of intragenomic evolutionary processes, important differences in brain morphology can arise independently of specific environmental selection.

Tracking functional brain changes in patients with depression under psychodynamic psychotherapy using individualized stimuli.

OBJECTIVE: Neurobiological models of depression posit limbic hyperactivity that should normalize after successful treatment. For psychotherapy, though, brain changes in patients with depression show substantial variability. Two critical issues in relevant studies concern the use of unspecific stimulation experiments and relatively short treatment protocols. Therefore changes in brain reactions to individualized stimuli were studied in patients with depression after eight months of psychodynamic psychotherapy. METHODS: 18 unmedicated patients with recurrent major depressive disorder were confronted with individualized and clinically derived content in a functional MRI experiment before (T1) and after eight months (T2) of psychodynamic therapy. A control group of 17 healthy subjects was also tested twice without intervention. The experimental stimuli were sentences describing each participant's dysfunctional interpersonal relationship patterns derived from clinical interviews based on Operationalized Psychodynamic Diagnostics (OPD). RESULTS: At T1 patients showed enhanced activation compared to controls in several limbic and subcortical regions, including amygdala and basal ganglia, when confronted with OPD sentences. At T2 the differences in brain activity between patients and controls were no longer apparent. Concurrently, patients had improved significantly in depression scores. CONCLUSIONS: Using ecologically valid stimuli, this study supports the model of limbic hyperactivity in depression that normalizes after treatment. Without a control group of untreated patients measured twice, though, changes in patients' brain activity could also be attributed to other factors than psychodynamic therapy.

Impact of early adversity on glucocorticoid regulation and later mental disorders.

Early adverse experiences such as abuse or neglect can influence brain development and consequently bring forth a predisposition toward mental and behavioral disorders. Many authors suggest that long-term changes in the functionality of the HPA axis might be involved in mediating this relationship. The direction of change and its consequences have not been clarified though: Do early adverse experiences yield a stable glucocorticoid hyperfunction or a long-term glucocorticoid hypofunction, and how is this change of functionality associated with mental or behavioral disorders? This review summarizes correlative findings and illustrates inconsistencies of current research literature. It focuses on the specific neurochemical milieu accompanying early adverse experiences and discusses possible interactions of the glucocorticoid system with oxytocin and components of the serotonergic system. On the basis of this physiological view, a novel two-pathway model is presented, according to which specific early experiences are associated with characteristic early changes in the functionality of these systems and result in a predisposition to distinct mental and behavioral disorders.

Changes in prefrontal-limbic function in major depression after 15 months of long-term psychotherapy.

Neuroimaging studies of depression have demonstrated treatment-specific changes involving the limbic system and regulatory regions in the prefrontal cortex. While these studies have examined the effect of short-term, interpersonal or cognitive-behavioural psychotherapy, the effect of long-term, psychodynamic intervention has never been assessed. Here, we investigated recurrently depressed (DSM-IV) unmedicated outpatients (N = 16) and control participants matched for sex, age, and education (N = 17) before and after 15 months of psychodynamic psychotherapy. Participants were scanned at two time points, during which presentations of attachment-related scenes with neutral descriptions alternated with descriptions containing personal core sentences previously extracted from an attachment interview. Outcome measure was the interaction of the signal difference between personal and neutral presentations with group and time, and its association with symptom improvement during therapy. Signal associated with processing personalized attachment material varied in patients from baseline to endpoint, but not in healthy controls. Patients showed a higher activation in the left anterior hippocampus/amygdala, subgenual cingulate, and medial prefrontal cortex before treatment and a reduction in these areas after 15 months. This reduction was associated with improvement in depressiveness specifically, and in the medial prefrontal cortex with symptom improvement more generally. This is the first study documenting neurobiological changes in circuits implicated in emotional reactivity and control after long-term psychodynamic psychotherapy.

Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk.

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.

Evolution of the brain and intelligence in primates.

Primates are, on average, more intelligent than other mammals, with great apes and finally humans on top. They generally have larger brains and cortices, and because of higher relative cortex volume and neuron packing density (NPD), they have much more cortical neurons than other mammalian taxa with the same brain size. Likewise, information processing capacity is generally higher in primates due to short interneuronal distance and high axonal conduction velocity. Across primate taxa, differences in intelligence correlate best with differences in number of cortical neurons and synapses plus information processing speed. The human brain stands out by having a large cortical volume with relatively high NPD, high conduction velocity, and high cortical parcellation. All aspects of human intelligence are present at least in rudimentary form in nonhuman primates or some mammals or vertebrates except syntactical language. The latter can be regarded as a very potent "intelligence amplifier."

Urinary bladder cancer risk in relation to a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor-binding protein-3 (IGFBP3) gene.

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5-10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case-control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case-control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.

Neurophysiological correlates of laboratory-induced aggression in young men with and without a history of violence.

In order to further understand the mechanisms involved in planning an aggressive act, we conducted an event-related potential (ERP) study of young men with and without a history of violence. Participants completed a competitive reaction time task (based on the Taylor aggression paradigm) against a virtual opponent. In "passive" blocks, participants were punished by the opponent when losing the trial but could not punish, when winning, whereas in "active" blocks, participants were able to punish the opponent when winning, but were not punished when losing. Participants selected punishment strength in a decision phase prior to each reaction time task and were informed whether they had won or lost in the outcome phase. Additionally, a flanker task was conducted to assess basic performance monitoring. Violent participants selected stronger punishments, especially in "active" blocks. During the decision phase, a frontal P200 was more pronounced for violent participants, whereas non-violent participants showed an enhanced frontal negativity around 300 ms. The P200 might reflect the decision to approach the opponent at a very early state, the latter negativity could reflect inhibition processes, leading to a more considerate reaction in non-violent participants. During the outcome phase, a Feedback-Related Negativity was seen in both groups. This effect was most pronounced when losing entailed a subsequent inability to retaliate. The groups did not differ in the flanker task, indicating intact basic performance monitoring. Our data suggest that the planning of an aggressive act is associated with distinct brain activity and that such activity is differentially represented in violent and non-violent individuals.

Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype.

Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.

Individualized and clinically derived stimuli activate limbic structures in depression: an fMRI study.

OBJECTIVES: In the search for neurobiological correlates of depression, a major finding is hyperactivity in limbic-paralimbic regions. However, results so far have been inconsistent, and the stimuli used are often unspecific to depression. This study explored hemodynamic responses of the brain in patients with depression while processing individualized and clinically derived stimuli. METHODS: Eighteen unmedicated patients with recurrent major depressive disorder and 17 never-depressed control subjects took part in standardized clinical interviews from which individualized formulations of core interpersonal dysfunction were derived. In the patient group such formulations reflected core themes relating to the onset and maintenance of depression. In controls, formulations reflected a major source of distress. This material was thereafter presented to subjects during functional magnetic resonance imaging (fMRI) assessment. RESULTS: Increased hemodynamic responses in the anterior cingulate cortex, medial frontal gyrus, fusiform gyrus and occipital lobe were observed in both patients and controls when viewing individualized stimuli. Relative to control subjects, patients with depression showed increased hemodynamic responses in limbic-paralimbic and subcortical regions (e.g. amygdala and basal ganglia) but no signal decrease in prefrontal regions. CONCLUSIONS: This study provides the first evidence that individualized stimuli derived from standardized clinical interviewing can lead to hemodynamic responses in regions associated with self-referential and emotional processing in both groups and limbic-paralimbic and subcortical structures in individuals with depression. Although the regions with increased responses in patients have been previously reported, this study enhances the ecological value of fMRI findings by applying stimuli that are of personal relevance to each individual's depression.

Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk.

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt-PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04-1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05-1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12-1.25; P < 0.0001). However, the odds ratio is relatively small.

[Neurobiological aspects of reactive and proactive violence in antisocial personality disorder and "psychopathy"]. / Neurobiologische Aspekte reaktiver und proaktiver Gewalt bei antisozialer Persönlichkeitsstörung und "Psychopathie".

Impulsive-reactive violent offenders show increased autonomic activity in response to negative emotional and threatening stimuli. A volume reduction and/or activity decrease of frontal brain structures associated with impulse control and the regulation of fear and anger are likewise found in combination with a fear-related hyperactivity of the amygdala. In addition, impulsive aggression is facilitated by variants of gene polymorphisms influencing the serotonergic system. Conversely, proactive-instrumental violent offender with psychopathy, who are characterized by a lack of empathy and remorse, demonstrate an autonomic hypo-responsivity as well as dysfunctions of the amygdala and of cortical regions related to empathic and social behavior. Developmentally, aggressive children exhibit temperamental differences from early childhood on that are characteristic of a developmental pathway towards either reactive or proactive violence later in life. Exposure to negative environmental factors like ineffective parenting or childhood maltreatment has been related to a heightened risk for developing reactive violence. A developmental trajectory of proactive violence, however, has been related to a mostly genetically determined callous unemotional temperament of the child that disrupts the parental socialization efforts during childhood.

Susceptibility to urinary bladder cancer: relevance of rs9642880[T], GSTM1 0/0 and occupational exposure.

Recently, a genome-wide single nucleotide polymorphism association study has identified a sequence variant 30 kb upstream of the c-Myc gene (allele T of rs9642880) that confers susceptibility to bladder cancer. However, the role of exposure to bladder carcinogens has not been considered. This prompted us to analyse the relevance of this polymorphism in 515 bladder cancer cases and 893 controls where the quality and quantity of occupational exposure to bladder carcinogens has been documented. When we analysed a hospital-based case-control series not selected for occupational exposure, rs9642880[T] was influential, in contrast to GSTM1 0/0. However, in a case-control series of patients that have been occupationally exposed to aromatic amines and polycyclic aromatic hydrocarbons, rs9642880[T] was not influential but GSTM1 0/0 was significantly associated with bladder cancer risk. Therefore, the degree to which rs9642880[T] and GSTM1 0/0 confer susceptibility to urinary bladder cancer seems to depend on the extent of exposure to urinary bladder carcinogens.

UDP-glucuronosyltransferase 2B7 C802T (His268Tyr) polymorphism in bladder cancer cases.

A study of Chinese benzidine workers indicated elevated levels of UDP-glucuronosyltransferase (UGT) 2B7 T/T activity in carriers for development of bladder cancer. The present study was designed to investigate the possible impact of the presence of UGT2B7 genotype on bladder cancer risk in Caucasians. UGT2B7 polymorphism at locus C(802)T (His(268)Tyr) was detected using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based procedure. The study group consisted of 211 bladder cancer cases and 210 controls suffering from different urological diseases, but without any history of cancer. Both groups were recruited from a Department of Urology located in a center of former chemical and rubber industries in Germany. Furthermore, 171 bladder cancer cases with a history of occupational exposure to aromatic amines surveyed for compensation due to an occupational disease were investigated. T/T genotype frequencies in bladder cancer cases, urological controls, and exposed patients appeared similar (27 vs. 35 vs. 25%). This study indicated that there were ethnic differences between Caucasian and Chinese general populations with respect to the UGT2B7 genotype. Furthermore, in contrast to an earlier investigation in benzidine-exposed Chinese bladder cancer patients, no relevant differences between bladder cancer patients and urological hospital controls were observed in Germany.