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Transcranial Focused Ultrasound Stimulation (tFUS) is a new, rapidly growing field related to the study and treatment of brain circuits. Establishing safety cutoffs for focused ultrasound is crucial for non-ablative neurological ultrasound experiments. In addition to potential focal heating, there is concern about temperature elevation at the skin surface. Much work has been performed at or near the FDA guideline of ISPTA.3 = 720 mW/cm2, which technically only applies to diagnostic, not therapeutic, ultrasound. Furthermore, evidence of brain tissue damage on histology in the focal region has been shown not to occur until ISPTA.3 > 14 W/cm2. Therefore, this study was conducted across a range of intensities between these two values, evaluating both subjective and objective side effects. Subjective side effects encompassed any discomfort experienced during and after focused ultrasound stimulation, while objective side effects included clinical findings of skin irritation, such as erythema, edema, or burns. This study also examined how the skin temperature at the skin-transducer interface would change in order to assess whether there would be significant heating. The subjects did not experience any unpleasant sensation at the point of stimulation, including heat or pain, and no objective findings of skin irritation were observed following stimulation and the removal of the transducer. In addition, there was no intensity-dependent effect on temperature, and the maximal rise in temperature was 1.45 °C, suggesting that these parameters do not result in the heating of the skin at the interface in such a way that poses a risk to subjects when operating at or below the intensities tested in this experiment.

Unhealthy alcohol use, which encompasses heavy episodic drinking to alcohol use disorder, has been identified as a modifiable barrier to optimal HIV care continuum outcomes. Despite the demonstrated efficacy of couples-based interventions for addressing unhealthy alcohol use, there are no existing couples-based alcohol interventions designed specifically for people living with HIV. This study presents the development and refinement of a three-session couples-based motivational intervention (ReACH2Gether) to address unhealthy alcohol use among a sample of 17 sexual minority men living with HIV and their partners living in the United States. To increase potential population reach, the intervention was delivered entirely remotely. Throughout an original and a modified version, results indicated that the ReACH2Gether intervention was acceptable and there were no reports of intimate partner violence or adverse events. Session engagement and retention were high. In pre-post-test analyses, the ReACH2Gether intervention showed trends in reducing Alcohol Use Disorder Identification Test scores and increasing relationship-promoting dynamics, such as positive support behaviors and goal congruence around alcohol use. Results support the need for continued work to evaluate the ReACH2Gether intervention.

BackgroundOver the past 30 years, there have been significant advances in the understanding of the mechanisms associated with loss and recovery of consciousness following severe brain injury. This work has provided a strong grounding for the development of novel restorative therapeutic interventions. Although all interventions are aimed at modulating and thereby restoring brain function, the landscape of existing interventions encompasses a very wide scope of techniques and protocols. Despite vigorous research efforts, few approaches have been assessed with rigorous, high-quality randomized controlled trials. As a growing number of exploratory interventions emerge, it is paramount to develop standardized approaches to reporting results. The successful evaluation of novel interventions depends on implementation of shared nomenclature and infrastructure. To address this gap, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups and charged them with developing common data elements (CDEs). Here, we report the work of the Therapeutic Interventions Working Group.MethodsThe working group reviewed existing CDEs relevant to therapeutic interventions within the National Institutes of Health National Institute of Neurological Disorders and Stroke database and reviewed the literature for assessing key areas of research in the intervention space. CDEs were then proposed, iteratively discussed and reviewed, classified, and organized in a case report form (CRF).ResultsWe developed a unified CRF, including CDEs and key design elements (i.e., methodological or protocol parameters), divided into five sections: (1) patient information, (2) general study information, (3) behavioral interventions, (4) pharmacological interventions, and (5) device interventions.ConclusionsThe newly created CRF enhances systematization of future work by proposing a portfolio of measures that should be collected in the development and implementation of studies assessing novel interventions intended to increase the level of consciousness or rate of recovery of consciousness in patients with disorders of consciousness.

Static structure factors are computed for large-scale, mechanically stable, jammed packings of frictionless spheres (three dimensions) and disks (two dimensions) with broad, power-law size dispersity characterized by the exponent -β. The static structure factor exhibits diverging power-law behavior for small wave numbers, allowing us to identify a structural fractal dimension d_{f}. In three dimensions, d_{f}≈2.0 for 2.5≤β≤3.8, such that each of the structure factors can be collapsed onto a universal curve. In two dimensions, we instead find 1.0≲d_{f}≲1.34 for 2.1≤β≤2.9. Furthermore, we show that the fractal behavior persists when rattler particles are removed, indicating that the long-wavelength structural properties of the packings are controlled by the large particle backbone conferring mechanical rigidity to the system. A numerical scheme for computing structure factors for triclinic unit cells is presented and employed to analyze the jammed packings.

BackgroundLow intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively.Objective/hypothesisWe sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region.MethodsIn this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC).ResultstFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity.ConclusionWe demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

What is the relationship between language and complex thought? In the context of deductive reasoning there are two main views. Under the first, which we label here the language-centric view, language is central to the syntax-like combinatorial operations of complex reasoning. Under the second, which we label here the language-independent view, these operations are dissociable from the mechanisms of natural language. We applied continuous theta burst stimulation (cTBS), a form of noninvasive neuromodulation, to healthy adult participants to transiently inhibit a subregion of Broca's area (left BA44) associated in prior work with parsing the syntactic relations of natural language. We similarly inhibited a subregion of dorsomedial frontal cortex (left medial BA8) which has been associated with core features of logical reasoning. There was a significant interaction between task and stimulation site. Post hoc tests revealed that performance on a linguistic reasoning task, but not deductive reasoning task, was significantly impaired after inhibition of left BA44, and performance on a deductive reasoning task, but not linguistic reasoning task, was decreased after inhibition of left medial BA8 (however not significantly). Subsequent linear contrasts supported this pattern. These novel results suggest that deductive reasoning may be dissociable from linguistic processes in the adult human brain, consistent with the language-independent view.

Due to significant computational expense, discrete element method simulations of jammed packings of size-dispersed spheres with size ratios greater than 1:10 have remained elusive, limiting the correspondence between simulations and real-world granular materials with large size dispersity. Invoking a recently developed neighbor binning algorithm, we generate mechanically stable jammed packings of frictionless spheres with power-law size distributions containing up to nearly 4 000 000 particles with size ratios up to 1:100. By systematically varying the width and exponent of the underlying power laws, we analyze the role of particle size distributions on the structure of jammed packings. The densest packings are obtained for size distributions that balance the relative abundance of large-large and small-small particle contacts. Although the proportion of rattler particles and mean coordination number strongly depend on the size distribution, the mean coordination of nonrattler particles attains the frictionless isostatic value of six in all cases. The size distribution of nonrattler particles that participate in the load-bearing network exhibits no dependence on the width of the total particle size distribution beyond a critical particle size for low-magnitude exponent power laws. This signifies that only particles with sizes greater than the critical particle size contribute to the mechanical stability. However, for high-magnitude exponent power laws, all particle sizes participate in the mechanical stability of the packing.

Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, we empirically identify a mathematically specific critical point near which waking cortical oscillatory dynamics operate, which is known as the edge-of-chaos critical point, or the boundary between stability and chaos. We do so by applying the recently developed modified 0-1 chaos test to electrocorticography (ECoG) and magnetoencephalography (MEG) recordings from the cortices of humans and macaques across normal waking, generalized seizure, anesthesia, and psychedelic states. Our evidence suggests that cortical information processing is disrupted during unconscious states because of a transition of low-frequency cortical electric oscillations away from this critical point; conversely, we show that psychedelics may increase the information richness of cortical activity by tuning low-frequency cortical oscillations closer to this critical point. Finally, we analyze clinical electroencephalography (EEG) recordings from patients with disorders of consciousness (DOC) and show that assessing the proximity of slow cortical oscillatory electrodynamics to the edge-of-chaos critical point may be useful as an index of consciousness in the clinical setting.

What is the common denominator of consciousness across divergent regimes of cortical dynamics? Does consciousness show itself in decibels or in bits? To address these questions, we introduce a testbed for evaluating electroencephalogram (EEG) biomarkers of consciousness using dissociations between neural oscillations and consciousness caused by rare genetic disorders. Children with Angelman syndrome (AS) exhibit sleep-like neural dynamics during wakefulness. Conversely, children with duplication 15q11.2-13.1 syndrome (Dup15q) exhibit wake-like neural dynamics during non-rapid eye movement (NREM) sleep. To identify highly generalizable biomarkers of consciousness, we trained regularized logistic regression classifiers on EEG data from wakefulness and NREM sleep in children with AS using both entropy measures of neural complexity and spectral (i.e., neural oscillatory) EEG features. For each set of features, we then validated these classifiers using EEG from neurotypical (NT) children and abnormal EEGs from children with Dup15q. Our results show that the classification performance of entropy-based EEG biomarkers of conscious state is not upper-bounded by that of spectral EEG features, which are outperformed by entropy features. Entropy-based biomarkers of consciousness may thus be highly adaptable and should be investigated further in situations where spectral EEG features have shown limited success, such as detecting covert consciousness or anesthesia awareness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

ObjectiveTranscranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing.MethodsNeuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others.ResultsWith respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS.SignificanceThis study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

AimIn 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.MethodsTo 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.ResultsWe 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.ConclusionIn 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.

The global burden of mortality and morbidity caused by traumatic brain injury (TBI) is significant, and the heterogeneity of TBI patients and the relatively small sample sizes of most current neuroimaging studies is a major challenge for scientific advances and clinical translation. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Adult moderate/severe TBI (AMS-TBI) working group aims to be a driving force for new discoveries in AMS-TBI by providing researchers world-wide with an effective framework and platform for large-scale cross-border collaboration and data sharing. Based on the principles of transparency, rigor, reproducibility and collaboration, we will facilitate the development and dissemination of multiscale and big data analysis pipelines for harmonized analyses in AMS-TBI using structural and functional neuroimaging in combination with non-imaging biomarkers, genetics, as well as clinical and behavioral measures. Ultimately, we will offer investigators an unprecedented opportunity to test important hypotheses about recovery and morbidity in AMS-TBI by taking advantage of our robust methods for large-scale neuroimaging data analysis. In this consensus statement we outline the working group's short-term, intermediate, and long-term goals.

Relational integration is required when multiple explicit representations of relations between entities must be jointly considered to make inferences. We provide an overview of the neural substrate of relational integration in humans and the processes that support it, focusing on work on analogical and deductive reasoning. In addition to neural evidence, we consider behavioral and computational work that has informed neural investigations of the representations of individual relations and of relational integration. In very general terms, evidence from neuroimaging, neuropsychological, and neuromodulatory studies points to a small set of regions (generally left lateralized) that appear to constitute key substrates for component processes of relational integration. These include posterior parietal cortex, implicated in the representation of first-order relations (e.g., A:B); rostrolateral pFC, apparently central in integrating first-order relations so as to generate and/or evaluate higher-order relations (e.g., A:B::C:D); dorsolateral pFC, involved in maintaining relations in working memory; and ventrolateral pFC, implicated in interference control (e.g., inhibiting salient information that competes with relevant relations). Recent work has begun to link computational models of relational representation and reasoning with patterns of neural activity within these brain areas.

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.

BackgroundTraumatic brain injury (TBI) causes early seizures and is the leading cause of post-traumatic epilepsy. We prospectively assessed structural imaging biomarkers differentiating patients who develop seizures secondary to TBI from patients who do not.DesignMulticentre prospective cohort study starting in 2018. Imaging data are acquired around day 14 post-injury, detection of seizure events occurred early (within 1 week) and late (up to 90 days post-TBI).ResultsFrom a sample of 96 patients surviving moderate-to-severe TBI, we performed shape analysis of local volume deficits in subcortical areas (analysable sample: 57 patients; 35 no seizure, 14 early, 8 late) and cortical ribbon thinning (analysable sample: 46 patients; 29 no seizure, 10 early, 7 late). Right hippocampal volume deficit and inferior temporal cortex thinning demonstrated a significant effect across groups. Additionally, the degree of left frontal and temporal pole thinning, and clinical score at the time of the MRI, could differentiate patients experiencing early seizures from patients not experiencing them with 89% accuracy.Conclusions and relevanceAlthough this is an initial report, these data show that specific areas of localised volume deficit, as visible on routine imaging data, are associated with the emergence of seizures after TBI.

ObjectiveTo understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at 6 months after injury.MethodsFor this longitudinal analysis, clinical and MRI data were collected in a tertiary neurointensive care setting in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient, we collected T1- and T2-weighted MRI data acutely and at the 6-month follow-up, as well as acute measures of injury severity (Glasgow Coma Scale), follow-up measures of functional impairment (Glasgow Outcome Scale-extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory.ResultsIn the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first 6 months after injury across the brain. However, only atrophy within subcortical regions, particularly in the left thalamus, was associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good from bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could achieve only 20% accuracy.ConclusionDespite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute event and the longer-term disease of traumatic brain injury.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.

[This corrects the article DOI: 10.1093/nc/niaa005.][This corrects the article DOI: 10.1093/nc/niaa005.].

[This corrects the article DOI: 10.1093/nc/niaa005.][This corrects the article DOI: 10.1093/nc/niaa005.].

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long-term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large-scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.

Cerebral acidosis is a consequence of secondary injury mechanisms following traumatic brain injury (TBI), including excitotoxicity and ischemia, with potentially significant clinical implications. However, there remains an unmet clinical need for technology for non-invasive, high resolution pH imaging of human TBI for studying metabolic changes following injury. The current study examined 17 patients with TBI and 20 healthy controls using amine chemical exchange saturation transfer echoplanar imaging (CEST EPI), a novel pH-weighted molecular MR imaging technique, on a clinical 3T MR scanner. Results showed significantly elevated pH-weighted image contrast (MTRasym at 3 ppm) in areas of T2 hyperintensity or edema (P

In recent years, neuroimaging methods have been used to investigate how the human mind carries out deductive reasoning. According to some, the neural substrate of language is integral to deductive reasoning. According to others, deductive reasoning is supported by a language-independent distributed network including left frontopolar and frontomedial cortices. However, it has been suggested that activity in these frontal regions might instead reflect non-deductive factors such as working memory load and general cognitive difficulty. To address this issue, 20 healthy volunteers participated in an fMRI experiment in which they evaluated matched simple and complex deductive and non-deductive arguments in a 2 × 2 design. The contrast of complex versus simple deductive trials resulted in a pattern of activation closely matching previous work, including frontopolar and frontomedial "core" areas of deduction as well as other "cognitive support" areas in frontoparietal cortices. Conversely, the contrast of complex and simple non-deductive trials resulted in a pattern of activation that does not include any of the aforementioned "core" areas. Direct comparison of the load effect across deductive and non-deductive trials further supports the view that activity in the regions previously interpreted as "core" to deductive reasoning cannot merely reflect non-deductive load, but instead might reflect processes specific to the deductive calculus. Finally, consistent with previous reports, the classical language areas in left inferior frontal gyrus and posterior temporal cortex do not appear to participate in deductive inference beyond their role in encoding stimuli presented in linguistic format.

Sleep suffers during adolescence and is related to academic, emotional and social behaviors. How this normative change relates to ongoing brain development remains unresolved. The default mode network (DMN), a large-scale brain network important for complex cognition and socioemotional processing, undergoes intra-network integration and inter-network segregation during adolescence. Using resting state functional connectivity and actigraphy over 14 days, we examined correlates of naturalistic individual differences in sleep duration and quality in the DMN at rest in 45 human adolescents (ages 14-18). Variation in sleep quality, but not duration, was related to weaker intrinsic DMN connectivity, such that those with worse quality sleep evinced weaker intra-network connectivity at rest. These novel findings suggest sleep quality, a relatively unexplored sleep index, is related to adolescent brain function in a network that contributes to behavioral maturation and undergoes development during adolescence.

In recent years, the study of the neural basis of consciousness, particularly in the context of patients recovering from severe brain injury, has greatly benefited from the application of sophisticated network analysis techniques to functional brain data. Yet, current graph theoretic approaches, as employed in the neuroimaging literature, suffer from four important shortcomings. First, they require arbitrary fixing of the number of connections (i.e., density) across networks which are likely to have different "natural" (i.e., stable) density (e.g., patients vs. controls, vegetative state vs. minimally conscious state patients). Second, when describing networks, they do not control for the fact that many characteristics are interrelated, particularly some of the most popular metrics employed (e.g., nodal degree, clustering coefficient)-which can lead to spurious results. Third, in the clinical domain of disorders of consciousness, there currently are no methods for incorporating structural connectivity in the characterization of functional networks which clouds the interpretation of functional differences across groups with different underlying pathology as well as in longitudinal approaches where structural reorganization processes might be operating. Finally, current methods do not allow assessing the dynamics of network change over time. We present a different framework for network analysis, based on Exponential Random Graph Models, which overcomes the above limitations and is thus particularly well suited for clinical populations with disorders of consciousness. We demonstrate this approach in the context of the longitudinal study of recovery from coma. First, our data show that throughout recovery from coma, brain graphs vary in their natural level of connectivity (from 10.4 to 14.5%), which conflicts with the standard approach of imposing arbitrary and equal density thresholds across networks (e.g., time-points, subjects, groups). Second, we show that failure to consider the interrelation between network measures does lead to spurious characterization of both inter- and intra-regional brain connectivity. Finally, we show that Separable Temporal ERGM can be employed to describe network dynamics over time revealing the specific pattern of formation and dissolution of connectivity that accompany recovery from coma.

Motivational interviewing (MI) is often incorporated into screening, brief intervention, and referral to treatment (SBIRT) interventions in critical care settings to address alcohol and other drug use. However, cognitive status has been linked to differential response to MI sessions in emergency department (ED) settings. The current study examined one possible explanation for this differential response: whether higher versus lower mental status impacts patient response to clinician statements during MI sessions conducted in an ED. Participants were 126 patients receiving an MI-based single-session alcohol brief intervention, and 13 therapists who provided treatment. Participants completed a mental status exam (MSE) as part of the screening process. Intervention sessions were audio-taped, and transcribed and coded using the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003). The MISC 2.0 coded therapist behaviors that are related to the use of motivational interviewing, and patient language reflecting movement toward (change talk) or away from (sustain talk) changing personal alcohol use. Overall, patients responded in a similar manner to therapist MI behaviors regardless of high versus low level of mental functioning at the time of the intervention. Group differences emerged on patient response to only three specific therapist skills: giving information, open questions, and complex reflection. Thus, the differential effects of SBIRT in critical care settings do not appear to be a result of differences in the therapist and patient communication process.

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo-cortical system. However, thalamo-cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS-, i.e., low-level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high-level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo-cortical circuits could differentiate between VS, MCS-, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole-brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo-cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar-occipital connections when compared with MCS-. Moreover, MCS- exhibited significantly less thalamo-premotor and thalamo-temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo-cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431-443, 2017. © 2016 Wiley Periodicals, Inc.

Humans have developed multiple symbolic representations for numbers, including natural numbers (positive integers) as well as rational numbers (both fractions and decimals). Despite a considerable body of behavioral and neuroimaging research, it is currently unknown whether different notations map onto a single, fully abstract, magnitude code, or whether separate representations exist for specific number types (e.g., natural versus rational) or number representations (e.g., base-10 versus fractions). We address this question by comparing brain metabolic response during a magnitude comparison task involving (on different trials) integers, decimals, and fractions. Univariate and multivariate analyses revealed that the strength and pattern of activation for fractions differed systematically, within the intraparietal sulcus, from that of both decimals and integers, while the latter two number representations appeared virtually indistinguishable. These results demonstrate that the two major notations formats for rational numbers, fractions and decimals, evoke distinct neural representations of magnitude, with decimals representations being more closely linked to those of integers than to those of magnitude-equivalent fractions. Our findings thus suggest that number representation (base-10 versus fractions) is an important organizational principle for the neural substrate underlying mathematical cognition.

ObjectiveStudents referred to school administration for alcohol policies violations currently receive a wide variety of interventions. This study examined predictors of response to 2 interventions delivered to mandated college students (N = 598) using a stepped care approach incorporating a peer-delivered 15-min brief advice (BA) session (Step 1) and a 60- to 90-min brief motivational intervention (BMI) delivered by trained interventionists (Step 2).MethodAnalyses were completed in 2 stages. First, 3 types of variables (screening variables, alcohol-related cognitions, mandated student profile) were examined in a logistic regression model as putative predictors of lower risk drinking (defined as 3 or fewer heavy episodic drinking [HED] episodes and/or 4 or fewer alcohol-related consequences in the past month) 6 weeks following the BA session. Second, we used generalized estimating equations to examine putative moderators of BMI effects on HED and peak blood alcohol content compared with assessment only (AO) control over the 3-, 6-, and 9-month follow-ups.ResultsParticipants reporting lower scores on the Alcohol Use Disorders Identification Test, more benefits to changing alcohol use, and those who fit the "Bad Incident" profile at baseline were more likely to report lower risk drinking 6 weeks after the BA session. Moderation analyses revealed that Bad Incident students who received the BMI reported more HED at 9-month follow-up than those who received AO.ConclusionCurrent alcohol use as well as personal reaction to the referral event may have clinical utility in identifying which mandated students benefit from treatments of varying content and intensity.

BackgroundFew prospective studies have evaluated theory-driven approaches to the implementation of evidence-based opioid treatment. This study compared the effectiveness of an implementation model (Science to Service Laboratory; SSL) to training as usual (TAU) in promoting the adoption of contingency management across a multisite opioid addiction treatment program. We also examined whether the SSL affected putative mediators of contingency management adoption (perceived innovation characteristics and organizational readiness to change).MethodsSixty treatment providers (39 SSL, 21 TAU) from 15 geographically diverse satellite clinics (7 SSL, 8 TAU) participated in the 12-month study. Both conditions received didactic contingency management training and those in the predetermined experimental region received 9 months of SSL-enhanced training. Contingency management adoption was monitored biweekly, whereas putative mediators were measured at baseline, 3 months, and 12 months.ResultsRelative to providers in the TAU region, treatment providers in the SSL region had comparable likelihood of contingency management adoption in the first 20 weeks of the study, and then significantly higher likelihood of adoption (odds ratios = 2.4-13.5) for the remainder of the study. SSL providers also reported higher levels of one perceived innovation characteristic (Observability) and one aspect of organizational readiness to change (Adequacy of Training Resources), although there was no evidence that the SSL affected these putative mediators over time.ConclusionsResults of this study indicate that a fully powered randomized trial of the SSL is warranted. Considerations for a future evaluation are discussed.

Stepped care approaches for mandated college students provide individual brief motivational interventions (BMI) only for individuals who do not respond to an initial, low-intensity level of treatment such as Brief Advice (BA). However, how BMIs facilitate change in this higher-risk group of mandated students remains unclear. Perceived descriptive norms and alcohol-related expectancies are the most commonly examined mediators of BMI efficacy but have yet to be examined in the context of stepped care. Participants were mandated college students (N = 598) participating in a stepped care trial in which mandated students first received BA. Those who reported continued risky drinking 6 weeks following a BA session were randomized to either a single-session BMI (N = 163) or an assessment-only comparison condition (AO; N = 165). BMI participants reduced alcohol-related problems at the 9 month follow up significantly more than AO participants. Multiple mediation analyses using bootstrapping techniques examined whether perceived descriptive norms and alcohol-related expectancies mediated the observed outcomes. Reductions in perceptions of average student drinking (B = -.24; 95% CI [-.61, -.04]) and negative expectancies (B = -.13; 95% CI [-.38, -.01]) mediated the BMI effects. Furthermore, perceived average student norms were reduced after the BMI to levels approximating those of students who had exhibited lower risk drinking following the BA session. Findings highlight the utility of addressing perceived norms and expectancies in BMIs, especially for students who have not responded to less intensive prevention efforts.

Substance use among adolescents with one or more psychiatric disorders is a significant public health concern. In this study, 151 psychiatrically hospitalized adolescents, ages 13-17 with comorbid psychiatric and substance use disorders, were randomized to a two-session Motivational Interviewing intervention to reduce substance use plus treatment as usual (MI) vs. treatment as usual only (TAU). Results indicated that the MI group had a longer latency to first use of any substance following hospital discharge relative to TAU (36 days versus 11 days). Adolescents who received MI also reported less total use of substances and less use of marijuana during the first 6 months post-discharge, although this effect was not significant across 12 months. Finally, MI was associated with a significant reduction in rule-breaking behaviors at 6-month follow-up. Future directions are discussed, including means of extending effects beyond 6 months and dissemination of the intervention to community-based settings.

ObjectiveWe employed functional MRI (fMRI) to assess whether (1) patients with disorders of consciousness (DOC) retain the ability to willfully engage in top-down processing and (2) what neurophysiologic factors distinguish patients who can demonstrate this ability from patients who cannot.MethodsSixteen volunteers, 8 patients in vegetative state (VS), 16 minimally conscious patients (MCS), and 4 exit from MCS (eMCS) patients were enrolled in a prospective cross-sectional fMRI study. Participants performed a target detection task in which they counted the number of times a (changing) target word was presented amidst a set of distractors.ResultsThree of 8 patients diagnosed as being in a VS exhibited significant activations in response to the task, thereby demonstrating a state of consciousness. Differential activations across tasks were also observed in 6 MCS patients and 1 eMCS patient. A psycho-physiologic interaction analysis revealed that the main factor distinguishing patients who responded to the task from those who did not was a greater connectivity between the anterior section of thalamus and prefrontal cortex.ConclusionsIn our sample of patients, the dissociation between overt behavior observable in clinical assessments and residual cognitive faculties is prevalent among DOC patients (37%). A substantial number of patients, including some diagnosed with VS, can demonstrate willful engagement in top-down cognition. While neuroimaging data are not the same as observable behavior, this suggests that the mental status of some VS patients exceeds what can be appreciated clinically. Furthermore, thalamo-frontal circuits might be crucial to sustaining top-down functions.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.