So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

https://bic.berkeley.edu/sites/default/files/Rossi_09_TMS%20safety%20review.pdf

Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

The insula is a brain structure implicated in disparate cognitive, affective, and regulatory functions, including interoceptive awareness, emotional responses, and empathic processes. While classically considered a limbic region, recent evidence from network analysis suggests a critical role for the insula, particularly the anterior division, in high-level cognitive control and attentional processes. The crucial insight and view we present here is of the anterior insula as an integral hub in mediating dynamic interactions between other large-scale brain networks involved in externally oriented attention and internally oriented or self-related cognition. The model we present postulates that the insula is sensitive to salient events, and that its core function is to mark such events for additional processing and initiate appropriate control signals. The anterior insula and the anterior cingulate cortex form a “salience network” that functions to segregate the most relevant among internal and extrapersonal stimuli in order to guide behavior. Within the framework of our network model, the disparate functions ascribed to the insula can be conceptualized by a few basic mechanisms: (1) bottom–up detection of salient events, (2) switching between other large-scale networks to facilitate access to attention and working memory resources when a salient event is detected, (3) interaction of the anterior and posterior insula to modulate autonomic reactivity to salient stimuli, and (4) strong functional coupling with the anterior cingulate cortex that facilitates rapid access to the motor system. In this manner, with the insula as its integral hub, the salience network assists target brain regions in the generation of appropriate behavioral responses to salient stimuli. We suggest that this framework provides a parsimonious account of insula function in neurotypical adults, and may provide novel insights into the neural basis of disorders of affective and social cognition.

/pdf/saliency-switching-attention-and-control-a-network-model-of-4nzu8lqybn.pdf

Saliency, switching, attention and control: a network model of insula function

Sir,

In their Letter to the Editor, Kitazawa and Kansaku responded to our meta-analysis on sex differences in language lateralization measured with functional imaging techniques (Sommer et al , 2004) Though Kitazawa and Kansaku gave an interesting interpretation of the data, we do not agree with the alternative calculation of the effect sizes of two studies they suggested

Kitazawa and Kansaku hypothesized that sex differences in language lateralization may be present only when subjects listen to stories, since two studies (Kansaku et al , 2000; Philips et al …

Size does count: a reply to Kitazawa and Kansaku

Aim There is an ongoing debate regarding the optimal timing of discontinuation of antipsychotic drugs for patients with first episode psychosis. Although most guidelines recommend maintenance therapy for at least 1 or 2 years after reaching remission, study results indicate that early discontinuation may be beneficial for at least a subsample of patients. To date, little is known about which medication strategies are applied in patients recovering from a first psychotic episode. In this study, we examined the beliefs and practices of clinicians on medication discontinuation. Methods We performed a survey among 50 experienced Dutch psychiatrists to assess how often specific treatment strategies have been applied in the past 12 months, as well as their knowledge and expectations with respect to medication discontinuation. Results Psychiatrists estimated that, after remission, they continued medication at the same dose for at least 12 months in 51.2% of cases, continued in a reduced dose in 33.8% of cases and discontinued medication in 9.1% of cases after 4.4 months of remission on average. Although the medication is discontinued in only a relatively small proportion of patients, almost half of all clinicians (45.9%) used this strategy at least once in the past 12 months. Conclusions There is substantial practice variation in antipsychotic medication strategies after remission from a first psychotic episode. Future research on long-term effects of early medication discontinuation can guide clinicians in making evidence-based decisions when treating first-episode patients.

Medication strategies in first episode psychosis patients: A survey among psychiatrists.

Recently, the case for an immune component in the etiology of schizophrenia has regained support,1, 2 leading to randomized controlled trials to explore treatment with immunosuppressive and anti-inflammatory drugs.3 Both postmortem4 and in-vivo studies5, 6 provided indications for an increased proinflammatory status in the brain of patients with recent-onset schizophrenia. A common characteristic of most, if not all, autoimmune diseases (AD) is their favorable response to immunoablation and rescue with BMT. It was established in radiation chimeras more than 50 years ago that the immunological and hematological systems have a common stem cell. In the wake of this discovery came a series of investigations into the role of the BM in autoimmune disorders (AD) demonstrating that both hereditary AD and the susceptibility for induced AD could be transferred by hematopoietic SCTs and that both forms of AD in experimental animals could be cured by an allogeneic BMT from healthy donors.7

We therefore searched among long-term survivors after allogeneic BMT (SCT) for patients with a coexisting AD at the time of the transplant. Up to 1998, case histories of a total of 22 such patients were retrieved, all but one of whom went into CR of their AD.8 These findings did not initiate treatment of AD patients with allogeneic BMT because of the high risks of this procedure. However, after it was demonstrated both in rats with induced systemic arthritis and in rats with an experimental allergic encephalomyelitis (a model for multiple sclerosis) that autologous BMTs were potentially equally effective as allogeneic transplants, this modality has been widely explored for treating refractory AD of all sorts.9 The European Group for Blood and Bone Marrow Transplantation (EBMT) estimates that worldwide around 3000 AD patients had been treated with autologous BMT; 1200 cases were entered in the EBMT database by June 2011.10 Overall, the 5-year survival rate of the first 900 cases analyzed was 85%, with 43% PFS.

At present, around 50 000 hematopoietic SCT are registered annually. Considering a conservative prevalence estimate for schizophrenia of 8 per 1000, the registries can be expected to contain data on many survivors with coincident schizophrenia at the time of transplant. Information on the clinical course of schizophrenia after SCT would greatly enhance our understanding of the role of immune processes in schizophrenia. We have therefore asked the EBMT and the Center for Blood and Marrow Transplantation Research (CIBMTR) at the Medical College of Wisconsin about the feasibility of searching their databases for such cases. Simultaneously we call upon hematologists and psychiatrists to inform us directly of their relevant case histories. We are submitting this appeal to the respective professional journals and websites. We think this approach may save time and money in identifying cases that are not into the databases of the international registries.

Please send the information about your cases, including identification numbers if registered, to one of us in Utrecht, E-mail: ln.thcertucmu@remmos.i

/pdf/call-for-case-histories-of-bmt-in-patients-with-coincident-akegc5bnhg.pdf

Call for case histories of BMT in patients with coincident schizophrenia

Koch et al. [1] discuss our results regarding volume increases in the dentate gyrus (DG) [2] in the interesting context of research into stress-related disorders and fear generalization in combination with neurogenesis. While our research included severely depressed patients, Koch et al. [1] raise the possibility that findings may be generalized to wider diagnostic groups, including trauma patients (i.e., PTSD) and patients with an anxiety disorder. In the following we would like to discuss this wider interpretation of our results and shed light on the further steps needed to be taken in years to come. We recognize that our work serves as a next step into understanding the molecular mechanisms behind severe depression (and perhaps other stress-related disorders) and the development of new therapies aiming to correct pathophysiological mechanisms. In short, using 7-tesla magnetic resonance imaging (MRI) we found that after ten sessions of electroconvulsive therapy (ECT) the volume of the DG was significantly increased in severely depressed patients, leaving the other subfields of the hippocampus unaffected. These findings point in the direction of increased neurogenesis after ECT, although other functional recovery processes (such as synaptogenesis, axonal sprouting, and angiogenesis) may also contribute to the increase in volume. In healthy controls (n= 8), this increase was not present. In addition, we found that baseline DG volume could predict clinical response (measured with the 17-item Hamilton Depression Rating scale; HAM-D, where higher scores indicate more severely depressed patients) in a regression model. Furthermore, we found that the change in volume was associated to a change in HAM-D score (i.e., larger treatment responses were associated to greater increases in volume). Importantly, our technical equipment has two major advantages:

https://pure.rug.nl/ws/files/119591078/Manuscript_DG_Koch.pdf

Iris E. C. Sommer

Papers

Size does count: a reply to Kitazawa and Kansaku

Medication strategies in first episode psychosis patients: A survey among psychiatrists.

Call for case histories of BMT in patients with coincident schizophrenia

The dentate gyrus in depression: directions for future research.

Immuno-Psychiatry: Facts and Prospects