Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (‘biotypes’) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

/pdf/resting-state-connectivity-biomarkers-define-4er6wkn0hg.pdf

Resting-state connectivity biomarkers define neurophysiological subtypes of depression

Allostasis: A model of predictive regulation

Food restriction alters stress and feeding pathways in the brain, and promotes binge eating of high-fat foods upon subsequent exposure to stress.

/pdf/systems-neuroscience-the-stress-of-dieting-3qulvhjo0l.pdf

Systems neuroscience: the stress of dieting.

“Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior

Neurodevelopmental programming - the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development - requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.

/pdf/epigenetic-and-transgenerational-reprogramming-of-brain-2mr12e41v5.pdf

Epigenetic and transgenerational reprogramming of brain development.

https://www.cell.com/neuron/pdf/S0896-6273(14)00905-2.pdf

Improving and Accelerating Drug Development for Nervous System Disorders

Long-term weight management by dieting has a high failure rate. Pharmacological targets have focused on appetite reduction, although less is understood as to the potential contributions of the stress state during dieting in long-term behavioral modification. In a mouse model of moderate caloric restriction in which a 10-15% weight loss similar to human dieting is produced, we examined physiological and behavioral stress measures. After 3 weeks of restriction, mice showed significant increases in immobile time in a tail suspension test and stress-induced corticosterone levels. Increased stress was associated with brain region-specific alterations of corticotropin-releasing factor expression and promoter methylation, changes that were not normalized with refeeding. Similar outcomes were produced by high-fat diet withdrawal, an additional component of human dieting. In examination of long-term behavioral consequences, previously restricted mice showed a significant increase in binge eating of a palatable high-fat food during stress exposure. Orexigenic hormones, melanin-concentrating hormone (MCH) and orexin, were significantly elevated in response to the high-fat diet only in previously restricted mice. Furthermore, administration of the MCH receptor-1 antagonist GSK-856464 [4-(4-ethyl-5-methylsulfanyl-1,2,4-triazol-3-yl)pyridine] significantly reduced total caloric intake in these mice during high-fat access. These results reveal reprogramming of key central pathways involved in regulating stress responsivity and orexigenic drives by moderate caloric restriction experience. In humans, such changes would be expected to reduce treatment success by promoting behaviors resulting in weight regain, and suggest that management of stress during dieting may be beneficial in long-term maintenance.

https://www.jneurosci.org/content/jneuro/30/48/16399.full.pdf

Caloric Restriction Experience Reprograms Stress and Orexigenic Pathways and Promotes Binge Eating

Prenatal stress programming of offspring feeding behavior and energy balance begins early in pregnancy.

The task given to the committee (Committee on the Use of Chimpanzees in Biomedical and Behavioral Research) by the NIH (National Institutues of Health) asked two questions about the need for chimpanzees in research: (1) Is biomedical research with chimpanzees “necessary for research discoveries and to determine the safety and efficacy of new prevention or treatment strategies?” and (2) Is behavioral research using chimpanzees “necessary for progress in understanding social, neurological, and behavioral factors that influence the development, prevention, or treatment of disease?” In responding to these questions, the committee concluded that the potential reasons for undertaking biomedical and behavioral research as well as the protocols used in each area are different enough to require different sets of criteria. However, the committee developed both sets of criteria guided by the following three principles: The knowledge gained must be necessary to advance the public’s health; There must be no other research model by which the knowledge could be obtained, and the research cannot be ethically performed on human subjects; The animals used in the proposed research must be maintained either in ethologically appropriate physical and social environments or in natural habitats. These principles are the basis for the specific criteria that the committee established to assess current and future use of the chimpanzee in biomedical and behavioral research (see Recommendations 1 and 2).

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

Although there is a high burden associated with nervous system disorders, development of new therapeutics remains stagnant. Over the last decade, fewer new drugs for nervous system disorders have garnered approval in comparison to other therapeutic areas. Current data suggest that drug development, from the start of a discovery program to regulatory approval, can take an average of 12 to 15 years. This familiar statistic prompts an equally familiar question: Can the therapeutic development time line be improved and accelerated by addressing challenges and developing opportunities?*

Diana E Pankevich

Papers

Improving and Accelerating Drug Development for Nervous System Disorders

Caloric Restriction Experience Reprograms Stress and Orexigenic Pathways and Promotes Binge Eating

Prenatal stress programming of offspring feeding behavior and energy balance begins early in pregnancy.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary