David Goldsmith

Neural Correlates of Social Cooperation and Non-Cooperation as a Function of Psychopathy

BACKGROUND Psychopathy is a disorder involving a failure to experience many emotions that are necessary for appropriate social behavior. In this study, we probed the behavioral, emotional, and neural correlates of psychopathic traits within the context of a dyadic social interaction. METHODS Thirty subjects were imaged with functional magnetic resonance imaging while playing an iterated Prisoners Dilemma game with human confederates who were outside the scanner. Subjects also completed two self-report psychopathy questionnaires. RESULTS Subjects scoring higher on psychopathy, particularly males, defected more often and were less likely to continue cooperating after establishing mutual cooperation with a partner. Further, they experienced more outcomes in which their cooperation was not reciprocated (cooperate-defect outcome). After such outcomes, subjects scoring high in psychopathy showed less amygdala activation, suggesting weaker aversive conditioning to those outcomes. Compared with low-psychopathy subjects, subjects higher in psychopathy also showed weaker activation within orbitofrontal cortex when choosing to cooperate and showed weaker activation within dorsolateral prefrontal and rostral anterior cingulate cortex when choosing to defect. CONCLUSIONS These findings suggest that whereas subjects scoring low on psychopathy have emotional biases toward cooperation that can only be overcome with effortful cognitive control, subjects scoring high on psychopathy have an opposing bias toward defection that likewise can only be overcome with cognitive effort.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

The neural correlates of the affective response to unreciprocated cooperation

Humans excel at reciprocal altruism in which two individuals exchange altruistic acts to their mutual advantage. The evolutionary stability of this system depends on recognition of and discrimination against non-reciprocators, and the human mind is apparently specialized for detecting non-reciprocators. Here we investigate the neural response to non-reciprocation of cooperation by imaging human subjects with fMRI as they play an iterated Prisoners dilemma game with two assumed human partners. Unreciprocated cooperation was associated with greater activity in bilateral anterior insula, left hippocampus and left lingual gyrus, compared with reciprocated cooperation. These areas were also more responsive to unreciprocated cooperation than to unsuccessful risk taking in a non-social context. Finally, functional connectivity between anterior insula and lateral orbitofrontal cortex (OFC) in response to unreciprocated cooperation predicted subsequent defection. The anterior insula is involved in awareness of visceral, autonomic feedback from the body and, in concert with the lateral orbitofrontal cortex, may be responsible for negative feeling states that bias subsequent social decision making against cooperation with a non-reciprocating partner.

Social cognitive neural networks during in-group and out-group interactions.

Several functionally connected networks of activity have now been identified in the resting human brain that may be amplified or attenuated by specific goal-directed tasks. However, it is not known whether there exists a particular network that becomes more active when a person is engaged in a social interaction. fMRI was used to measure brain activity in subjects as they completed a social interactive task and a non-social control task sharing many of the same features. Comparison across the two tasks revealed a network of functionally connected areas that was consistently more active in the social task. This network included default mode network areas, raising the possibility that activity previously observed in default mode regions at rest is related to social cognition. Within this network, information appears to flow from regions involved in salience detection (e.g. anterior insula) to regions involved in mentalizing (dorsomedial prefrontal cortex) to regions involved in executive control (dorsolateral prefrontal cortex). In a second experiment, subjects played the same social interactive task with alleged members of both an experimentally induced in-group and out-group. The default mode network was again active during the task, and several noteworthy differences distinguished interactions with in-group and out-group partners, providing a potential neural substrate for the human tendency to more readily identify with in-group members and more readily distrust, fear and discriminate against out-group members.

3-Alkylfurans as useful synthetic equivalents for substituted δ2-butenolides

Abstract Substituted δ 2 -butenolides may be prepared from furan equivalents by regiospecific metallation, sulfenylation and/or silylation, removal of the sulfur group and peracid oxidation.

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.

Towards an Immunophenotype of Schizophrenia: Progress, Potential Mechanisms, and Future Directions

The evidence to date, coupled with advances in immunology and genetics has afforded the field an unparalleled opportunity to investigate the hypothesis that a subset of patients with schizophrenia may manifest an immunophenotype, toward new potential diagnostics and therapeutics to reduce risk, alleviate symptoms, and improve quality of life in both at-risk populations and patients with established schizophrenia. In this paper, we will first summarize the findings on immune dysfunction in schizophrenia, including (1) genetic, prenatal, and premorbid immune risk factors and (2) immune markers across the clinical course of the disorder, including cytokines; C-reactive protein; immune cells; antibodies, autoantibodies and comorbid autoimmune disorders; complement; oxidative stress; imaging of neuroinflammation; infections; and clinical trials of anti-inflammatory agents and immunotherapy. We will then discuss a potential mechanistic framework toward increased understanding of a potential schizophrenia immunophenotype. We will then critically appraise the existing literature, and discuss suggestions for the future research agenda in this area that are needed to rigorously evaluate this hypothesis.

Ultrasonically accelerated cycloaddition - rearrangement of enol ethers

Abstract Cycloaddition-rearrangement reactions of methyl cyclohexenyl ethers with p-bromobenzenesulfonyl azide in neat homogeneous admixture are substanially accelerated by low-wattage ultrasound. Using ultrasound approximately the same yields of reaaranged products are obtained in less time at lower temperature than observed at ambient sonic frequencies and elevated temperature. A previously unreported product structural type has also been found.

The reaction of β,γ-unsaturated acids with phenylselenenyl chloride.: Decarboxylative elimination vs phenylselenolactonization.

Abstract β,γ-Unsaturated acids react with phenylselenenyl chloride to form simple adducts, selenolactones (cyclization), or allylphenyl selenides (decarboxylation) depending on the substitution pattern of the starting acid.

What does plasma CRP tell us about peripheral and central inflammation in depression

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma ( n  = 89) and CSF ( n  = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p  < 0.05), and a strong correlation was found between plasma and CSF CRP ( r  = 0.855, p  < 0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p  < 0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM ( r  = 0.236, p  = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia ( r  = 0.301, p  = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.