S.M.A.R.T. F.U.S: Surrogate Model of Attenuation and Refraction in Transcranial Focused Ultrasound.

Low-intensity focused ultrasound (LIFU) is an increasingly applied method for achieving non-invasive brain stimulation. However, transmission of ultrasound through the human skull can substantially affect focal point characteristics of LIFU, including dramatic attenuation in intensity and refraction of focal point location. These effects depend on a high-dimensional parameter space, making these effects difficult to estimate from previous work. Instead, focal point properties of LIFU experiments are often estimated using numerical simulation of LIFU sonication through skull. However, this procedure presents many entry barriers to even computationally savvy investigators and often requires expensive computational hardware, impeding LIFU research. We present a novel MATLAB toolbox (data: doi:10.5068/D1QD60; Matlab Scripts: https://doi.org/10.5281/zenodo.5811122) for rapidly estimating beam properties of LIFU transmitted through bone. Users provide specific values for frequency of LIFU, bone thickness, angle at which LIFU is applied, depth of the LIFU focal point, and diameter of the transducer used and receive an estimation of the degree of refraction/attenuation expected for the given parameters.

Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science.

AIM: In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. METHODS: To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. RESULTS: We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. CONCLUSION: In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a "virtuous cycle," leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.

Real time and delayed effects of subcortical low intensity focused ultrasound.

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.

A systematic comparison of structural-, structural connectivity-, and functional connectivity-based thalamus parcellation techniques.

The thalamus consists of several histologically and functionally distinct nuclei increasingly implicated in brain pathology and important for treatment, motivating the need for development of fast and accurate thalamic parcellation. The contrast between thalamic nuclei as well as between the thalamus and surrounding tissues is poor in T1- and T2-weighted magnetic resonance imaging (MRI), inhibiting efforts to date to segment the thalamus using standard clinical MRI. Automatic parcellation techniques have been developed to leverage thalamic features better captured by advanced MRI methods, including magnetization prepared rapid acquisition gradient echo (MP-RAGE), diffusion tensor imaging (DTI), and resting-state functional MRI (fMRI). Despite operating on fundamentally different image contrasts, these methods claim a high degree of agreement with the Morel stereotactic atlas of the thalamus. However, no comparison has been undertaken to compare the results of these disparate parcellation methods. We have implemented state-of-the-art structural-, diffusion-, and functional imaging-based thalamus parcellation techniques and used them on a single set of subjects. We present the first systematic qualitative and quantitative comparison of these methods. The results show that DTI parcellation agrees more with structural parcellation in the larger thalamic nuclei, while rsfMRI parcellation agrees more with structural parcellation in the smaller nuclei. Structural parcellation is the most accurate in the delineation of small structures such as the habenular, antero-ventral, and medial geniculate nuclei.

Working Memory Systems in the Rat.

A fundamental feature of memory in humans is the ability to simultaneously work with multiple types of information using independent memory systems. Working memory is conceptualized as two independent memory systems under executive control [1, 2]. Although there is a long history of using the term "working memory" to describe short-term memory in animals, it is not known whether multiple, independent memory systems exist in nonhumans. Here, we used two established short-term memory approaches to test the hypothesis that spatial and olfactory memory operate as independent working memory resources in the rat. In the olfactory memory task, rats chose a novel odor from a gradually incrementing set of old odors [3]. In the spatial memory task, rats searched for a depleting food source at multiple locations [4]. We presented rats with information to hold in memory in one domain (e.g., olfactory) while adding a memory load in the other domain (e.g., spatial). Control conditions equated the retention interval delay without adding a second memory load. In a further experiment, we used proactive interference [5-7] in the spatial domain to compromise spatial memory and evaluated the impact of adding an olfactory memory load. Olfactory and spatial memory are resistant to interference from the addition of a memory load in the other domain. Our data suggest that olfactory and spatial memory draw on independent working memory systems in the rat.

Pathogenesis of vascular complications in Cushing's syndrome.

Chronic exposure to high glucocorticoid levels in Cushing's syndrome (CS) is often associated with alterations in the hemostatic system and the expression of prothrombotic phenotypes. Increased frequency of both atherothrombotic and venous thromboembolic events (VTE) has been reported in patients with CS. In general, cardiovascular complications in these patients cause a five-fold increase in mortality compared to the normal population. Although numerous abnormalities in the hemostatic system have been detected in patients with CS, the underlying mechanisms of the prothrombotic state are not fully elucidated. High levels of factor VIII and von Willebrand factor, with evidence of enhanced thrombin generation and decreased fibrinolytic activity, have been documented in several studies. However, it is not clear to what extent these changes contribute to the shift of hemostatic balance towards the hypercoagulable state and expression of thrombophilic phenotypes. Thrombosis is usually a multicausal disease, and all three components of the so-called Virchow triad, namely 1) vascular abnormalities and endothelial dysfunction, 2) hypercoagulability and 3) stasis, may play a variable role in the pathogenesis of the prothrombotic state in CS patients. Larger studies are needed to establish strategies for prevention of cardiovascular complications in patients with Cushing's syndrome.

Role of the aryl hydrocarbon receptor-interacting protein in familial isolated pituitary adenoma.

Pituitary adenomas are typically sporadic benign tumors. However, approximately 5% of cases have been found to be familial in origin. Of these, approximately 40% occur in the absence of multiple endocrine neoplasia type 1 or Carney complex and have been termed 'familial isolated pituitary adenoma' (FIPA). Recently, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been described in 15-20% of these families, identifying an autosomal dominant condition with incomplete penetrance termed 'pituitary adenoma predisposition'. Pituitary adenoma predisposition cohorts show a marked disposition to develop large, aggressive somatotroph, somatolactotroph or lactotroph adenomas, typically presenting at a young age. AIP mutation families have a distinct clinical phenotype compared with AIP mutation-negative FIPA families. Current evidence suggests that AIP is a tumor-suppressor gene. AIP has been demonstrated to interact with a number of cellular proteins, including several nuclear receptors, heat-shock protein 90 and survivin, although the mechanism of the tumor-suppressor effect is unknown. This article summarizes available data regarding the role of AIP in pituitary tumorigenesis and the clinical features of FIPA.