Neurocognition in individuals at high familial risk of mood disorders with or without subsequent onset of depression.

BACKGROUND: Neurocognitive performance deficits have been observed in mood disorder patients and their unaffected relatives and may therefore qualify as endophenotypes. However, the precise time course of neurocognitive deficits has not been studied so that it is unknown whether neurocognitive abnormalities reflect the early effects of familial vulnerability to mood disorders or if they emerge at illness onset. METHOD: A neuropsychological test battery was administered at baseline and after a 2-year follow-up interval in 111 initially unaffected young adults at high familial risk of mood disorders and 93 healthy controls (HC). During the follow-up period, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the remainder remaining well (HR-well). Linear mixed-effects models were used to investigate differences and longitudinal changes in the domains of attentional processing, working memory, verbal learning and memory, and cognitive flexibility. RESULTS: Reduced long delay verbal memory and extradimensional set-shifting performance across both time points were found in the HR-well group relative to controls. The HR-MDD group displayed decreased extradimensional set-shifting abilities across both time points as compared with the HC group only. There were no significant performance differences between the two high-risk groups. CONCLUSIONS: Reduced verbal memory and cognitive flexibility are familial trait markers for vulnerability to mood disorders in individuals with a close family history of bipolar disorder. Both neurocognitive performance deficits appear to be relatively stable over a 2-year time period and do not appear to be linked to the onset of MDD. These findings support their use as stable quantitative endophenotypes for mood disorders.

Determinants of adult functional outcome in adolescents receiving special educational assistance.

BACKGROUND: This study investigates the role of IQ, autistic traits and challenging behaviours in affecting adult outcomes among adolescents who receive special educational assistance. METHODS: A total of 58 participants were recruited from an ongoing longitudinal study. All received assessments of IQ, behavioural patterns (using the Childhood Behaviour Checklist - CBCL) and autistic traits (using the Social Communication Questionnaire - SCQ) during adolescence and were followed up 6 years later (at a mean age of 22 years) using the World Health Organization Disability Assessment Schedule II (WHO-DAS II) to assess functional outcome. RESULTS: A significant positive relationship was found between CBCL score and WHO-DAS II score (ß = 0.511, P = 0.001). IQ score showed a negative relationship with total WHO-DAS II score (ß = -0.247, P = 0.04). SCQ score was not found to significantly influence total WHO-DAS II score (ß = -0.028, P = 0.84). CONCLUSIONS: Although the role of global intellectual ability is important, these results stress the highly predictive value of adolescent behaviours on functional outcomes in adult life among young adults receiving special educational assistance.

Hippocampal function in schizophrenia and bipolar disorder.

BACKGROUND: The hippocampus plays a central role in memory formation. There is considerable evidence of abnormalities in hippocampal structure and function in schizophrenia, which may differentiate it from bipolar disorder. However, no previous studies have compared hippocampal activation in schizophrenia and bipolar disorder directly. METHOD: Fifteen patients with schizophrenia, 14 patients with bipolar disorder and 14 healthy comparison subjects took part in the study. Subjects performed a face-name pair memory task during functional magnetic resonance imaging (fMRI). Differences in blood oxygen level-dependent (BOLD) activity were determined during encoding and retrieval of the face-name pairs. RESULTS: The patient groups showed significant differences in hippocampal and prefrontal cortex (PFC) activation during face-name pair learning. During encoding, patients with schizophrenia showed decreased anterior hippocampal activation relative to subjects with bipolar disorder, whereas patients with bipolar disorder showed decreased dorsal PFC activation relative to patients with schizophrenia. During retrieval, patients with schizophrenia showed greater activation of the dorsal PFC than patients with bipolar disorder. Patients with schizophrenia also differed from healthy control subjects in the activation of several brain regions, showing impaired superior temporal cortex activation during encoding and greater dorsal PFC activation during retrieval. These effects were evident despite matched task performance. CONCLUSIONS: Patients with schizophrenia showed deficits in hippocampal activation during a memory task relative to patients with bipolar disorder. The disorders were further distinguished by differences in PFC activation. The results demonstrate that these disorders can distinguished at a group level using non-invasive neuroimaging.

A common neural system mediating two different forms of social judgement.

BACKGROUND: A wide range of neuropsychiatric conditions, including schizophrenia and autistic spectrum disorder (ASD), are associated with impairments in social function. Previous studies have shown that individuals with schizophrenia and ASD have deficits in making a wide range of social judgements from faces, including decisions related to threat (such as judgements of approachability) and decisions not related to physical threat (such as judgements of intelligence). We have investigated healthy control participants to see whether there is a common neural system activated during such social decisions, on the basis that deficits in this system may contribute to the impairments seen in these disorders. METHOD: We investigated the neural basis of social decision making during judgements of approachability and intelligence from faces in 24 healthy participants using functional magnetic resonance imaging (fMRI). We used conjunction analysis to identify common brain regions activated during both tasks. RESULTS: Activation of the amygdala, medial prefrontal cortex, inferior prefrontal cortex and cerebellum was seen during performance of both social tasks, compared to simple gender judgements from the same stimuli. Task-specific activations were present in the dorsolateral prefrontal cortex in the intelligence task and in the inferior and middle temporal cortex in the approachability task. CONCLUSIONS: The present study identified a common network of brain regions activated during the performance of two different forms of social judgement from faces. Dysfunction of this network is likely to contribute to the broad-ranging deficits in social function seen in psychiatric disorders such as schizophrenia and ASD.

Set shifting and reversal learning in patients with bipolar disorder or schizophrenia.

BACKGROUND: Bipolar disorder and schizophrenia have both been associated with deficits in extra-dimensional set shifting (EDS). Deficits in reversal learning (RL) have also been shown in schizophrenia but not in bipolar disorder. This study sought to assess the specificity of these findings in a direct comparison of clinically stable patients with each disorder. METHOD: The intra-dimensional/extra-dimensional (IDED) set-shifting task, part of the Cambridge Neuropsychological Test Automated Battery (CANTAB), was administered to 30 patients with schizophrenia, 47 with bipolar disorder and a group of 44 unaffected controls. EDS and RL errors were compared between the groups and related to measures of current and past psychiatric symptoms and medication. RESULTS: Both groups of patients with schizophrenia or bipolar disorder made more EDS and RL errors than controls. Neither measure separated the two disorders, even when the analysis was restricted to euthymic patients. No relationship was found with prescribed medication. CONCLUSIONS: Patients with bipolar disorder or schizophrenia show common deficits in EDS and RL. These deficits do not seem to be attributable to current symptoms and are consistent with disrupted networks involving the ventral prefrontal cortex.

Prefrontal gyral folding and its cognitive correlates in bipolar disorder and schizophrenia.

OBJECTIVE: We sought to address whether dorsal or ventral prefrontal gyrification is abnormal in bipolar disorder and to determine its diagnostic specificity and cognitive associations. METHOD: Forty-two out-patients with bipolar disorder, 28 with schizophrenia and 37 controls underwent magnetic resonance imaging. All subjects also underwent IQ and executive assessments using tasks whose performance has been localized to the ventral or dorsal prefrontal cortex. Cortical folding was quantified using the gyrification index (GI) and related to the cognitive measures. RESULTS: Patients with bipolar disorder showed reduced prefrontal gyrification compared with controls but did not differ from patients with schizophrenia. Neither ventral nor dorsal GI was preferentially affected in either disorder. Current IQ was positively and significantly correlated with GI. CONCLUSION: Patients with bipolar disorder and patients with schizophrenia have reduced prefrontal gyrification affecting both ventral and dorsal subregions. These reductions were significantly associated with cognitive impairments occurring in both disorders.

The effects of a neuregulin 1 variant on white matter density and integrity.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

Functional and metabolic effects of extracellular magnesium in normoxic and ischemic myocardium.

Metabolic and functional responses to extracellular Mg2+ concentration ([Mg2+]o) were studied in perfused rat heart. Elevations of [Mg2+]o from 1.2 to 2.4, 5.0, and 8.0 mM dose dependently reduced contractile function and myocardial oxygen consumption (MVO2) up to 80%. Intracellular Mg2+ concentration ([Mg2+]i) remained stable (0.45-0.50 mM) during perfusion with 1.2-5. 0 mM [Mg2+]o but increased to 0.81 +/- 0.14 mM with 8.0 mM [Mg2+]o. Myocardial ATP was unaffected by [Mg2+]o, phosphocreatine (PCr) increased up to 25%, and Pi declined by up to 50%. Free energy of ATP hydrolysis (DeltaGATP) increased from -60 to -64 kJ/mol. Adenosine efflux declined in parallel with changes in MVO2 and [AMP]. At comparable workload and MVO2, the effects of [Mg2+]o on cytosolic free energy were mimicked by reduced extracellular Ca2+ concentration ([Ca2+]o) or Ca2+ antagonism with verapamil. Moreover, functional and energetic effects of [Mg2+]o were reversed by elevated [Ca2+]o. Despite similar reductions in preischemic function and MVO2, metabolic and functional recovery from 30 min of global ischemia was enhanced in hearts treated with 8.0 mM [Mg2+]o vs. 2.0 microM verapamil. It is concluded that 1) 1.2-8.0 mM [Mg2+]o improves myocardial cytosolic free energy indirectly by reducing metabolic rate and Ca2+ entry; 2) [Mg2+]i does not respond rapidly to elevations in [Mg2+]o from 1.2 to 5.0 mM and is uninvolved in acute functional and metabolic responses to [Mg2+]o; 3) adenosine formation in rat heart is indirectly reduced during elevated [Mg2+]o; and 4) 8.0 mM [Mg2+]o provides superior protection during ischemia-reperfusion compared with functionally equipotent Ca2+ channel blockade.

Bioenergetics and control of oxygen consumption in the in situ rat heart.

Control of respiration by products of ATP hydrolysis was examined in the in situ rat heart using a purpose-built nuclear magnetic resonance (NMR) coil. The in situ ratio of phosphocreatine to ATP concentrations ([PCr]/[ATP]) was 2.30 +/- 0.05, free Mg2+ concentration ([Mg2+]) was 0.57 mM, and cytosolic pH was 7.35 +/- 0.03 (n = 7). Basal inorganic phosphate concentration ([Pi]) was below NMR detection but was estimated to be 0.83 mM. The [ATP]/[ADP] [Pi] ratio, free ADP concentration ([ADP]), and free energy of ATP hydrolyses (delta GATP) were calculated to be 700,000 +/- 78,000 M-1, 18 +/- 3 microM, and -63.93 +/- 0.33 kJ/mol in situ, respectively (n = 7). In contrast, in the Langendorff perfused rat heart [ATP]/[ADP] [Pi] was only 76,140 +/- 12,830 M-1, [ADP] was 65 +/- 9 microM, and delta GATP was -59.92 +/- 0.48 kJ/mol (n = 7), all indicative of a lower energy state in vitro. Epinephrine infusion in situ (0.9 microgram.min-1.kg-1) increased the rate-pressure product 2.05-fold. During stimulation [ATP] was stable at 97 +/- 3% signal intensity, [PCr] declined by 25%, and [Pi] increased to 1.83 mM. Cytosolic pH was 7.27 +/- 0.01 and [Mg2+] was 0.64 +/- 0.05 mM. [PCr]/[ATP] declined to 1.83 +/- 0.13, and [ATP]/[ADP] [Pi] fell to 108,000 +/- 15,000 M-1. delta GATP only fell marginally to -59.56 +/- 0.49 kJ/mol. Free [ADP] increased threefold to 55 +/- 10 microM. Infusion of 2.8 +/- 0.5 microgram.min-1.kg-1 epinephrine increased the rate-pressure product 2.7-fold, further reduced [ATP]/[ADP] [Pi] (5% of basal), and elevated [ADP] more than fourfold without changing [ATP]. We conclude that the in situ heart is highly energetic compared with isolated perfused hearts and operates at a different metabolic "set-point." Because free [ADP] and [Pi] in situ approximate apparent Michaelis constants for mitochondrial respiration in vitro and increase with increased cardiac work, we conclude that each fulfills the criteria for the kinetic control of O2 consumption in the in situ rat myocardium.

Circulatory and metabolic responses in awake dogs to infusion of iso-rANP/(rBNP).

We reported that a second rat atrial peptide, iso-atrial natriuretic peptide (iso-rANP(1-45)) and a potential putative homologue, iso-rANP(17-45) (identical with rat brain natriuretic peptide except for one amino acid) elicited circulatory and renal responses in anesthetized rats. In the present studies, low-dose intravenous infusions of iso-rANP(1-45) (6.3-25 pmol kg-1 min-1) and iso-rANP(17-45) (12.5-50 pmol kg-1 min-1) into conscious dogs produced subtle circulatory effects compared to control studies. Relative to oxygen consumption, cardiac output was lower and total peripheral resistance higher with both iso-rANP(1-45) and iso-rANP(17-45). Heart rate tended to be slightly lower relative to control studies during peptide infusions, and the highest infusion doses caused a decrease in mean arterial pressure. Plasma protein increased and plasma osmolality decreased with iso-rANP(1-45); infusion of iso-rANP(17-45) caused a decrease in the respiratory exchange ratio. The mechanism of action of iso-rANP may have been direct, via an active receptor. However, we previously reported for these same experiments that infusion of iso-rANP(1-45) and iso-rANP(17-45) increased plasma ANP and decreased plasma renin activity. Thus, circulatory changes during infusion of iso-rANP were consistent with an indirect mechanism related to increased endogenous ANP.

Infusion of iso-rANP(1-45) or (17-45) increases plasma immunoreactive ANP and lowers plasma renin activity and aldosterone.

We have reported that a second rat atrial natriuretic peptide, iso-rANP (1-45), as well as the putative ANP homologue, iso-rANP (17-45), elicited circulatory and renal responses in the rat similar to those found after administration of ANP. Iso-rANP also interacted with ANP to potentiate the observed biological activity in the rat. In the present studies in awake dogs, intravenous infusion of low doses (6.3-50 pmol.kg-1.min-1) of iso-rANP(1-45) and iso-rANP(17-45) increased plasma immunoreactive ANP and suppressed plasma renin activity (PRA) and aldosterone. Iso-rANP, like ring-deleted analogues of ANP, may have displaced ANP from ANP clearance receptors to increase plasma ANP concentration, since factors influencing myocardial ANP release were not changed. The effect of iso-rANP (1-45) and (17-45) in lowering PRA and plasma aldosterone may therefore have been indirect, via ANP stimulation of active guanylate cyclase-linked ANP receptors. However, an additional direct effect of iso-rANP on an active receptor cannot be excluded.