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The Brain Resource International Database and Brain Resource, Sydney, NSW, Australia and San Francisco, CA, USA Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampalprefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P = 0.005) and symptoms (depression and anxiety, P < 0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P = 0.013), heart rate elevations (P = 0.0002) and a decline in working memory (P = 0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P < 0.001), and associated lateral prefrontal cortex (P < 0.001) and, in turn, higher depression (P = 0.005). Higher depression was associated with poorer working memory (P = 0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P < 0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P = 0.003) and associated medial prefrontal cortex (P < 0.001), which in turn predicted startle-elicited heart rate variability (P = 0.026) and higher anxiety (P = 0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

Although there have been tremendous advances in the understanding of human dysfunctions in the brain circuitry for self-reflection, emotion, and cognitive control, a brain-based taxonomy for mental disease is still lacking. As a result, these advances have not been translated into actionable clinical tools, and the language of brain circuits has not been incorporated into training programmes. To address this gap, I present this synthesis of published work, with a focus on functional imaging of circuit dysfunctions across the spectrum of mood and anxiety disorders. This synthesis provides the foundation for a taxonomy of putative types of dysfunction, which cuts across traditional diagnostic boundaries for depression and anxiety and includes instead distinct types of neural circuit dysfunction that together reflect the heterogeneity of depression and anxiety. This taxonomy is suited to specifying symptoms in terms of underlying neural dysfunction at the individual level and is intended as the foundation for building mechanistic research and ultimately guiding clinical practice.

A disturbance in the interactions between distributed cortical regions may underlie the cognitive and perceptual dysfunction associated with schizophrenia. In this article, nonlinear measures of cortical interactions and graph-theoretical metrics of network topography are combined to investigate this schizophrenia ''disconnection hypothesis.'' This is achieved by analyzing the spatiotemporal structure of resting state scalp EEG data previously acquired from 40 young subjects with a recent first episode of schizophrenia and 40 healthy matched controls. In each subject, a method of mapping the topography of nonlinear interactions between cortical regions was applied to a widely distributed array of these data. The resulting nonlinear correlation matrices were converted to weighted graphs. The path length (a measure of large-scale network integration), clustering coefficient (a measure of ''cliquishness''), and hub structure of these graphs were used as metrics of the underlying brain network activity. The graphs of both groups exhibited high levels of local clustering combined with comparatively short path lengths-features consistent with a ''small-world'' topology-as well as the presence of strong, central hubs. The graphs in the schizophrenia group displayed lower clustering and shorter path lengths in comparison to the healthy group. Whilst still ''small-world,'' these effects are consistent with a subtle randomization in the underlying network architecture-likely associated with a greater number of links connecting disparate clusters. This randomization may underlie the cognitive disturbances characteristic of schizophrenia. Hum Brain Mapp 30: [403][404][405][406][407][408][409][410][411][412][413][414][415][416] 2009. V V C 2007 Wiley-Liss, Inc.

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The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion, inhibition of glucagon release, and inhibition of gastric emptying and food intake (5,6). GLP-1 analogues are therefore currently under development as a new treatment for type 2 diabetes (7-9). Gut-derived PYY acts as a potent satiety signal and reduces food intake in mice and humans (10). Despite the physiological and pharmacological interest in L-cellderived peptides, however, little is known about the molecular mechanisms underlying the stimulus-secretion coupling in these cells.GLP-1 secretion after a meal can be divided into two phases: an early phase that begins within minutes and lasts for 30 -60 min and an overlapping second phase that causes prolonged secretion for 1-3 h (1,2). L-cells are highly polarized with an apical surface facing into the gut lumen, suggesting that they sense nutrients directly. However, the majority of L-cells are found in the distal gut, starting in humans at the level of the jejunum and increasing in number throughout the ileum and colon (11-13). It has therefore been argued that the early phase of GLP-1 release does not reflect direct nutrient sensing by L-cells, because they are ill-placed to receive nutrients delivered from the esophagus. An alternative or additional mechanism for the early phase includes the involvement of humoral and neuronal factors (14). The magnitude of the late phase is enhanced by ␣-glucosidase inhibitors, suggesting that this reflects the increased delivery to and sensing of glucose by distal L-cells (15).Using an L-cell model, GLUTag (16), we showed recently that low concentrations (0.5 mmol/l) of glucose stimulate GLP-1 secretion and the firing of action potentials, via a mechanism involving the closure of ATP-sensitive potassium (K ATP ) channels (17). Similar channels in pancreatic ␤-cells are believed to respond to changes in the metabolic rate, mediated through alterations in the concentrations of adenine nucleotides ATP and ADP. As K ATP channels are inhibited by ATP and activated by MgADP, the increasing ATP/MgADP ratio in ␤-cells that accompanies a rise in the plasma glucose results in K ATP channel closure, membrane depolarization, opening of voltage-gated calcium channels, calcium entry, and insulin release (18 -20). For both the GLUTag cell line and the related STC-1 cell line, an involvement of voltage-gated L-type Ca 2ϩ channels in the response to nutrients has been demonstrated (21).The characteristics of sugar-dependent GLP-1 secretion have been investigated previously in human studies and perfused ileum preparations. Whereas metabolizable sugars, such as glucose, fructose, and galactose, are potent stimuli for GLP-1 release, the nonmetabolizable sugars methyl-␣-glucopyranoside and 3-O-methylglucose also triggered secretion (2,(22)(23)(24)(25). These findings cannot all be explained by a mechanism involving K ATP channel closure in response to increased metabolism in the L-cell. Additional studies on perfused ileum showed that the effects of

Adolescence to early adulthood is a period of dramatic transformation in the healthy human brain. However, the relationship between the concurrent structural and functional changes remains unclear. We investigated the impact of age on both neuroanatomy and neurophysiology in the same healthy subjects (n = 138) aged 10 to 30 years using magnetic resonance imaging (MRI) and resting electroencephalography (EEG) recordings. MRI data were segmented into gray and white matter images and parcellated into large-scale regions of interest. Absolute EEG power was quantified for each lobe for the slow-wave, alpha and beta frequency bands. Gray matter volume was found to decrease across the age bracket in the frontal and parietal cortices, with the greatest change occurring in adolescence. EEG activity, particularly in the slow-wave band, showed a similar curvilinear decline to gray matter volume in corresponding cortical regions. An inverse pattern of curvilinearly increasing white matter volume was observed in the parietal lobe. We suggest that the reduction in gray matter primarily reflects a reduction of neuropil, and that the corresponding elimination of active synapses is responsible for the observed reduction in EEG power.

BackgroundPrecision medicine is a new and important topic in psychiatry. Psychiatry has not yet benefited from the advanced diagnostic and therapeutic technologies that form an integral part of other clinical specialties. Thus, the vision of precision medicine as applied to psychiatry – ‘precision psychiatry’ – promises to be even more transformative than in other fields of medicine, which have already lessened the translational gap.DiscussionHerein, we describe ‘precision psychiatry’ and how its several implications promise to transform the psychiatric landscape. We pay particular attention to biomarkers and to how the development of new technologies now makes their discovery possible and timely. The adoption of the term ‘precision psychiatry’ will help propel the field, since the current term ‘precision medicine’, as applied to psychiatry, is impractical and does not appropriately distinguish the field. Naming the field ‘precision psychiatry’ will help establish a stronger, unique identity to what promises to be the most important area in psychiatry in years to come.ConclusionIn summary, we provide a wide-angle lens overview of what this new field is, suggest how to propel the field forward, and provide a vision of the near future, with ‘precision psychiatry’ representing a paradigm shift that promises to change the landscape of how psychiatry is currently conceived.