Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic “fingerprints” that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease.

Human cortex is patterned by a complex and interdigitated web of large-scale functional networks. Recent methodological breakthroughs reveal variation in the size, shape, and spatial topography of cortical networks across individuals. While spatial network organization emerges across development, is stable over time, and is predictive of behavior, it is not yet clear to what extent genetic factors underlie interindividual differences in network topography. Here, leveraging a nonlinear multidimensional estimation of heritability, we provide evidence that individual variability in the size and topographic organization of cortical networks are under genetic control. Using twin and family data from the Human Connectome Project (n = 1,023), we find increased variability and reduced heritability in the size of heteromodal association networks (h2: M = 0.34, SD = 0.070), relative to unimodal sensory/motor cortex (h2: M = 0.40, SD = 0.097). We then demonstrate that the spatial layout of cortical networks is influenced by genetics, using our multidimensional estimation of heritability (h2-multi; M = 0.14, SD = 0.015). However, topographic heritability did not differ between heteromodal and unimodal networks. Genetic factors had a regionally variable influence on brain organization, such that the heritability of network topography was greatest in prefrontal, precuneus, and posterior parietal cortex. Taken together, these data are consistent with relaxed genetic control of association cortices relative to primary sensory/motor regions and have implications for understanding population-level variability in brain functioning, guiding both individualized prediction and the interpretation of analyses that integrate genetics and neuroimaging.

Clear evidence supports a dimensional view of psychiatric illness. Within this framework the expression of disorder-relevant phenotypes is often interpreted as a breakdown or departure from normal brain function. Conversely, health is reified, conceptualized as possessing a single ideal state. We challenge this concept here, arguing that there is no universally optimal profile of brain functioning. The evolutionary forces that shape our species select for a staggering diversity of human behaviors. To support our position we highlight pervasive population-level variability within large-scale functional networks and discrete circuits. We propose that, instead of examining behaviors in isolation, psychiatric illnesses can be best understood through the study of domains of functioning and associated multivariate patterns of variation across distributed brain systems.

Humans are often remarkably fast at learning novel tasks from instructions. Such rapid instructed task learning (RITL) likely depends upon the formation of new associations between long-term memory representations, which must then be actively maintained to enable successful task implementation. Consequently, we hypothesized that RITL relies more heavily on a proactive mode of cognitive control, in which goal-relevant information is actively maintained in preparation for anticipated high control demands. We tested this hypothesis using a recently developed cognitive paradigm consisting of 60 novel tasks involving RITL and 4 practiced tasks, with identical task rules and stimuli used across both task types. A robust behavioral cost was found in novel relative to practiced task performance, which was present even when the two were randomly inter-mixed, such that task-switching effects were equated. Novelty costs were most prominent under time-limited preparation conditions. In self-paced conditions, increased preparation time was found for novel trials, and was selectively associated with enhanced performance, suggesting greater proactive control for novel tasks. These results suggest a key role for proactive cognitive control in the ability to rapidly learn novel tasks from instructions.

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Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

Human cortex is patterned by a complex and interdigitated web of large-scale functional networks. Recent methodological breakthroughs reveal variation in the size, shape, and spatial topography of cortical networks across individuals. While spatial network organization emerges across development, is stable over time, and predictive of behavior, it is not yet clear to what extent genetic factors underlie inter-individual differences in network topography. Here, leveraging a novel non-linear multi-dimensional estimation of heritability, we provide evidence that individual variability in the size and topographic organization of cortical networks are under genetic control. Using twin and family data from the Human Connectome Project (n=1,023), we find increased variability and reduced heritability in the size of heteromodal association networks (h2: M=0.33, SD=0.071), relative to unimodal sensory/motor cortex (h2: M=0.44, SD=0.051). We then demonstrate that the spatial layout of cortical networks is influenced by genetics, using our multi-dimensional estimation of heritability (h2-multi; M=0.14, SD=0.015). However, topographic heritability did not differ between heteromodal and unimodal networks. Genetic factors had a regionally variable influence on brain organization, such that the heritability of network topography was greatest in prefrontal, precuneus, and posterior parietal cortex. Taken together, these data are consistent with relaxed genetic control of association cortices relative to primary sensory/motor regions, and have implications for understanding population-level variability in brain functioning, guiding both individualized prediction and the interpretation of analyses that integrate genetics and neuroimaging.

Purpose of Review Endovascular therapy for acute ischemic stroke secondary to large vessel occlusion (LVO) is time-dependent. Prehospital patients with suspected LVO stroke should be triaged directly to specialized stroke centers for endovascular therapy. This review describes advances in LVO detection among prehospital suspected stroke patients. Recent Findings Clinical prehospital stroke severity tools have been validated in the prehospital setting. Devices including EEG, SSEPs, TCD, cranial accelerometry, and volumetric impedance phase-shift-spectroscopy have recently published data regarding LVO detection in hospital settings. Mobile stroke units bring thrombolysis and vessel imaging to patients. Summary The use of a prehospital stroke severity tool for LVO triage is now widely supported. Ease of use should be prioritized as there are no meaningful differences in diagnostic performance amongst tools. LVO diagnostic devices are promising, but none have been validated in the prehospital setting. Mobile stroke units improve patient outcomes and cost-effectiveness analyses are underway.