Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain ...unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory ...neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Objective:
Recent studies demonstrate the poor psychosocial outcomes associated with bipolar disorder. Occupational functioning, a key indicator of psychosocial disability, is often severely affected ...by the disorder. The authors describe the effect of acute treatment with interpersonal and social rhythm therapy on occupational functioning over a period of approximately 2.5 years.
Method:
Patients with bipolar I disorder were randomly assigned to receive either acute and maintenance interpersonal and social rhythm therapy, acute and maintenance intensive clinical management, acute interpersonal and social rhythm therapy and maintenance intensive clinical management, or acute intensive clinical management and maintenance interpersonal and social rhythm therapy, all with appropriate pharmacotherapy. Occupational functioning was measured with the UCLA Social Attainment Scale at baseline, at the end of acute treatment, and after 1 and 2 years of maintenance treatment.
Results:
The main effect of treatment did not reach conventional levels of statistical significance; however, the authors observed a significant time by initial treatment interaction. Participants initially assigned to interpersonal and social rhythm therapy showed more rapid improvement in occupational functioning than those initially assigned to intensive clinical management, primarily accounted for by greater improvement in occupational functioning during the acute treatment phase. At the end of 2 years of maintenance treatment, there were no differences between the treatment groups. A gender effect was also observed, with women who initially received interpersonal and social rhythm therapy showing more marked and rapid improvement. There was no effect of maintenance treatment assignment on occupational functioning outcomes.
Conclusions:
In this study, interpersonal and social rhythm therapy, with its emphasis on amelioration of interpersonal and role functioning, improved occupational functioning significantly more rapidly than did a psychoeducational and supportive approach with no such emphasis on functional capacities.
Context.Metal-poor globular clusters (GCs) can provide a probe of the earliest epoch of star formation in the Universe, being the oldest observable stellar systems. In addition, young and ...intermediate-age low-metallicity GCs are present in external galaxies. Nevertheless, inferring their evolutionary status by using integrated properties may suffer from large intrinsic uncertainty caused by the discrete nature of stars in stellar systems, especially in the case of faint objects. Aims.In this paper, we evaluate the intrinsic uncertainty (due to statistical effects) affecting the integrated colours and mass-to-light ratios as a function of the cluster's integrated visual magnitude ($M_V^{\rm tot}$), which represents a directly measured quantity. We investigate the case of metal-poor, single-burst stellar populations with age from a few million years to a likely upper value for the Galactic globular cluster ages (~15 Gyr). Methods.Our approach is based on Monte Carlo techniques for randomly generating stars distributed according to the cluster's mass function. Results.Integrated colours and mass-to-light ratios in different photometric bands are checked for good agreement with the observational values of low-metallicity Galactic clusters; the effect of different assumptions on the horizontal branch (HB) morphology is shown to be irrelevant, at least for the photometric bands explored here. We present integrated colours and mass-to-light ratios as a function of age for different assumptions on the cluster total V magnitude. We find that the intrinsic uncertainty cannot be neglected. In particular, in models with $M_V^{\rm tot}=-4$ the broad-band colours show an intrinsic uncertainty high enough to prevent the precise age of the cluster from being evaluated. The effects of different assumptions on the initial mass function and on the minimum mass for which carbon burning is ignited for both integrated colours and mass-to-light ratios are also analysed. Finally, the present predictions are compared with recent results available in the literature, showing non-negligible differences in some cases.
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CONTEXT Numerous studies have pointed to the failure of prophylaxis with pharmacotherapy alone in the treat ment of bipolar I disorder. Recent investigations have demonstrated benefits from the ...addition of psychoeducation or psychotherapy to pharmacotherapy in this population. OBJECTIVE To compare 2 psychosocial interventions: interpersonal and social rhythm therapy (IPSRT) and an intensive clinical management (ICM) approach in the treatment of bipolar I disorder. DESIGN Randomized controlled trial involving 4 treatment strategies: acute and maintenance IPSRT (IPSRT/IPSRT), acute and maintenance ICM (ICM/ICM), acute IPSRT followed by maintenance ICM (IPSRT/ICM), or acute ICM followed by maintenance IPSRT (ICM/IPSRT). The preventive maintenance phase lasted 2 years. SETTING Research clinic in a university medical center. PARTICIPANTS One hundred seventy-five acutely ill individuals with bipolar I disorder recruited from inpatient and outpatient settings, clinical referral, public presentations about bipolar disorder, and other public information activities. INTERVENTIONS Interpersonal and social rhythm therapy, an adaptation of Klerman and Weissman’s interpersonal psychotherapy to which a social rhythm regulation component has been added, and ICM. MAIN OUTCOME MEASURES Time to stabilization in the acute phase and time to recurrence in the maintenance phase. RESULTS We observed no difference between the treatment strategies in time to stabilization. After controlling for covariates of survival time, we found that participants assigned to IPSRT in the acute treatment phase survived longer without a new affective episode (P = .01), irrespective of maintenance treatment assignment. Participants in the IPSRT group had higher regularity of social rhythms at the end of acute treatment (P<.001). Ability to increase regularity of social rhythms during acute treatment was associated with reduced likelihood of recurrence during the maintenance phase (P = .05). CONCLUSION Interpersonal and social rhythm therapy appears to add to the clinical armamentarium for the management of bipolar I disorder, particularly with respect to prophylaxis of new episodes.Arch Gen Psychiatry. 2005;62:996-1004-->
Neuronal circuits across several systems display remarkable plasticity
to sensory input during postnatal development.
Experience-dependent refinements are often restricted to well-defined critical
...periods in early life, but how these are established remains mostly unknown.
A representative example is the loss of responsiveness in neocortex to an
eye deprived of vision. Here we show that the potential
for plasticity is retained throughout life until an inhibitory threshold is
attained. In mice of all ages lacking an isoform of GABA (γ-aminobutyric
acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before
the onset of their natural critical period, benzodiazepines selectively reduced
a prolonged discharge phenotype to unmask plasticity. Enhancing GABA-mediated
transmission early in life rendered mutant animals insensitive to monocular
deprivation as adults, similar to normal wild-type mice. Short-term presynaptic
dynamics reflected a synaptic reorganization in GAD65 knockout mice after
chronic diazepam treatment. A threshold level of inhibition within the visual
cortex may thus trigger, once in life, an experience-dependent critical period
for circuit consolidation, which may otherwise lie dormant.
Specific GABA A Circuits for Visual Cortical Plasticity Fagiolini, Michela; Fritschy, Jean-Marc; Löw, Karin ...
Science (American Association for the Advancement of Science),
03/2004, Volume:
303, Issue:
5664
Journal Article
Peer reviewed
Weak inhibition within visual cortex early in life prevents experience-dependent plasticity. Loss of responsiveness to an eye deprived of vision can be initiated prematurely by enhancing ...γ-aminobutyric acid (GABA)–mediated transmission with benzodiazepines. Here, we use a mouse “knockin” mutation to α subunits that renders individual GABA type A (GABA
A
) receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only α1-containing circuits were found to drive cortical plasticity, whereas α2-enriched connections separately regulated neuronal firing. This dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.
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The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in ...short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.
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