Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept.

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.

Neural oscillations track recovery of consciousness in acute traumatic brain injury patients.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

Dissociating Language and Thought in Human Reasoning.

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.

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.

Longitudinal changes in blood-based biomarkers in chronic moderate to severe traumatic brain injury: preliminary findings.

Objectives: This longitudinal study aims at 1) providing preliminary evidence of changes in blood-based biomarkers across time in chronic TBI and 2) relating these changes to outcome measures and cerebral structure and activity.Methods: Eight patients with moderate-to-severe TBI (7 males, 35 ± 7.6 years old, 5 severe TBI, 17.52 ± 3.84 months post-injury) were evaluated at monthly intervals across 6 time-points using: a) Blood-based biomarkers (GFAP, NSE, S100A12, SDBP145, UCH-L1, T-tau, P-tau, P-tau/T-tau ratio); b) Magnetic Resonance Imaging to evaluate changes in brain structure; c) Resting-state electroencephalograms to evaluate changes in brain function; and d) Outcome measures to assess cognition, emotion, and functional recovery (MOCA, RBANS, BDI-II, and DRS).Results: Changes in P-tau levels were found across time [p = .007]. P-tau was positively related to functional [p < .001] and cognitive [p = .006] outcomes, and negatively related to the severity of depression, 6 months later [R = -0.901; p =.006]. P-tau and P-tau/T-tau ratio were also positively correlated to shape change in subcortical areas such as brainstem [T(7) = 4.71, p = .008] and putamen [T(7) = 3.25, p = .012].Conclusions: Our study provides preliminary findings that suggest a positive relationship between P-tau and the recovery of patients with chronic TBI.

Sedation-Induced Burst Suppression Predicts Positive Outcome Following Traumatic Brain Injury.

While electroencephalogram (EEG) burst-suppression is often induced therapeutically using sedatives in the intensive care unit (ICU), there is hitherto no evidence with respect to its association to outcome in moderate-to-severe neurological patients. We examined the relationship between sedation-induced burst-suppression (SIBS) and outcome at hospital discharge and at 6-month follow up in patients surviving moderate-to-severe traumatic brain injury (TBI). For each of 32 patients recovering from coma after moderate-to-severe TBI, we measured the EEG burst suppression ratio (BSR) during periods of low responsiveness as assessed with the Glasgow Coma Scale (GCS). The maximum BSR was then used to predict the Glasgow Outcome Scale extended (GOSe) at discharge and at 6 months post-injury. A multi-model inference approach was used to assess the combination of predictors that best fit the outcome data. We found that BSR was positively associated with outcomes at 6 months (P = 0.022) but did not predict outcomes at discharge. A mediation analysis found no evidence that BSR mediates the effects of barbiturates or propofol on outcomes. Our results provide initial observational evidence that burst suppression may be neuroprotective in acute patients with TBI etiologies. SIBS may thus be useful in the ICU as a prognostic biomarker.

Erratum: High-voltage, diffuse delta rhythms coincide with wakeful consciousness and complexity in Angelman syndrome.

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

Accounting for Changing Structure in Functional Network Analysis of TBI Patients.

Over the last 15 years, network analysis approaches based on MR data have allowed a renewed understanding of the relationship between brain function architecture and consciousness. Application of this approach to Disorders of Consciousness (DOC) highlights the relationship between specific aspects of network topology and levels of consciousness. Nonetheless, such applications do not acknowledge that DOC patients present with a dramatic level of heterogeneity in structural connectivity (SC) across groups (e.g., etiology, diagnostic categories) and within individual patients (e.g., over time), which possibly affects the level and quality of functional connectivity (FC) patterns that can be expressed. In addition, it is rarely acknowledged that the most frequently employed outcome metrics in the study of brain connectivity (e.g., degree distribution, inter- or intra-resting state network connectivity, and clustering coefficient) are interrelated and cannot be assumed to be independent of each other. We present empirical data showing that, when the two points above are not taken into consideration with an appropriate analytic model, it can lead to a misinterpretation of the role of each outcome metric in the graph's structure and thus misinterpretation of FC results. We show that failing to account for either SC or the inter-relation between outcome measures can lead to inflated false positives (FP) and/or false negatives (FN) in inter- or intra-resting state network connectivity results (defined, respectively, as a positive or negative result in network connectivity that is present when not accounting for SC and/or outcome measure inter-relation, but becomes not significant when accounting for all variables). Overall, we find that unconscious patients have lower rates of FP and FN for within cortical connectivity, lower rates of FN for cortico-subcortical connectivity, and lower rates of FP for within subcortical connectivity. These lower rates in unconscious patients may reflect differences in their triadic closure and SC metrics, which bias the interpretations of the inter- or intra-resting state network connectivity if the SC metrics and triadic closure are not modeled. We suggest that future studies of functional connectivity in DOC patients (i) incorporate where possible SC metrics and (ii) properly account for the intercorrelated nature of outcome variables.

Subcortical atrophy correlates with the perturbational complexity index in patients with disorders of consciousness.

BACKGROUND: The complexity of neurophysiological brain responses to direct cortical stimulation, referred to as the perturbational complexity index (PCI), has been shown able to discriminate between consciousness and unconsciousness in patients surviving severe brain injury as well as several other conditions (e.g., wake, dreamless sleep, sleep and ketamine dreaming, anesthesia). OBJECTIVE: This study asks whether, in patients with a disorder of consciousness (DOC), the complexity of the neurophysiological response to cortical stimulation is preferentially associated with atrophy within specific brain structures. METHODS: We perform a retrospective analysis of 40 DOC patients and correlate their maximal PCI to MR-based measurements of cortical thinning and subcortical atrophy. RESULTS: PCI was systematically and inversely associated with the degree of local atrophy within the globus pallidus, a region previously linked to electrocortical and behavioral arousal. Conversely, we fail to detect any association between variance in cortical ribbon thickness and PCI. CONCLUSION: These findings corroborate the previously reported association between pallidal atrophy and low behavioral arousal and suggest that this region's role in maintaining the overall balance of excitation and inhibition may critically affect the emergence of complex cortical interactions in chronic disorders of consciousness. This finding thus also suggests a target for potential neuromodulatory intervention in DOC patients.

High-voltage, diffuse delta rhythms coincide with wakeful consciousness and complexity in Angelman syndrome.

Abundant evidence from slow wave sleep, anesthesia, coma, and epileptic seizures links high-voltage, slow electroencephalogram (EEG) activity to loss of consciousness. This well-established correlation is challenged by the observation that children with Angelman syndrome (AS), while fully awake and displaying volitional behavior, display a hypersynchronous delta (1-4 Hz) frequency EEG phenotype typical of unconsciousness. Because the trough of the delta oscillation is associated with down-states in which cortical neurons are silenced, the presence of volitional behavior and wakefulness in AS amidst diffuse delta rhythms presents a paradox. Moreover, high-voltage, slow EEG activity is generally assumed to lack complexity, yet many theories view functional brain complexity as necessary for consciousness. Here, we use abnormal cortical dynamics in AS to assess whether EEG complexity may scale with the relative level of consciousness despite a background of hypersynchronous delta activity. As characterized by multiscale metrics, EEGs from 35 children with AS feature significantly greater complexity during wakefulness compared with sleep, even when comparing the most pathological segments of wakeful EEG to the segments of sleep EEG least likely to contain conscious mentation and when factoring out delta power differences across states. These findings (i) warn against reverse inferring an absence of consciousness solely on the basis of high-amplitude EEG delta oscillations, (ii) corroborate rare observations of preserved consciousness under hypersynchronization in other conditions, (iii) identify biomarkers of consciousness that have been validated under conditions of abnormal cortical dynamics, and (iv) lend credence to theories linking consciousness with complexity.

Age-related differences in the neural bases of phonological and semantic processes in the context of task-irrelevant information.

As we age we have increasing difficulty with phonological aspects of language production. Yet semantic processes are largely stable across the life span. This suggests a fundamental difference in the cognitive and potentially neural architecture supporting these systems. Moreover, language processes such as these interact with other cognitive processes that also show age-related decline, such as executive function and inhibition. The present study examined phonological and semantic processes in the presence of task-irrelevant information to examine the influence of such material on language production. Older and younger adults made phonological and semantic decisions about pictures in the presence of either phonologically or semantically related words, which were unrelated to the task. FMRI activation during the semantic condition showed that all adults engaged typical left-hemisphere language regions, and that this activation was positively correlated with efficiency across all adults. In contrast, the phonological condition elicited activation in bilateral precuneus and cingulate, with no clear brain-behavior relationship. Similarly, older adults exhibited greater activation than younger adults in several regions that were unrelated to behavioral performance. Our results suggest that as we age, brain-behavior relations decline, and there is an increased reliance on both language-specific and domain-general brain regions that are seen most prominently during phonological processing. In contrast, the core semantic system continues to be engaged throughout the life span, even in the presence of task-irrelevant information.

Network Analysis in Disorders of Consciousness: Four Problems and One Proposed Solution (Exponential Random Graph Models).

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.

Sources of disconnection in neurocognitive aging: cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume.

Age-related decline in fluid cognition can be characterized as a disconnection among specific brain structures, leading to a decline in functional efficiency. The potential sources of disconnection, however, are unclear. We investigated imaging measures of cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume as mediators of the relation between age and fluid cognition, in 145 healthy, community-dwelling adults 19-79 years of age. At a general level of analysis, with a single composite measure of fluid cognition and single measures of each of the 3 imaging modalities, age exhibited an independent influence on the cognitive and imaging measures, and the imaging variables did not mediate the age-cognition relation. At a more specific level of analysis, resting-state functional connectivity of sensorimotor networks was a significant mediator of the age-related decline in executive function. These findings suggest that different levels of analysis lead to different models of neurocognitive disconnection, and that resting-state functional connectivity, in particular, may contribute to age-related decline in executive function.

Frontoparietal activation during visual conjunction search: Effects of bottom-up guidance and adult age.

We conducted functional magnetic resonance imaging (fMRI) with a visual search paradigm to test the hypothesis that aging is associated with increased frontoparietal involvement in both target detection and bottom-up attentional guidance (featural salience). Participants were 68 healthy adults, distributed continuously across 19 to 78 years of age. Frontoparietal regions of interest (ROIs) were defined from resting-state scans obtained prior to task-related fMRI. The search target was defined by a conjunction of color and orientation. Each display contained one item that was larger than the others (i.e., a size singleton) but was not informative regarding target identity. Analyses of search reaction time (RT) indicated that bottom-up attentional guidance from the size singleton (when coincident with the target) was relatively constant as a function of age. Frontoparietal fMRI activation related to target detection was constant as a function of age, as was the reduction in activation associated with salient targets. However, for individuals 35 years of age and older, engagement of the left frontal eye field (FEF) in bottom-up guidance was more prominent than for younger individuals. Further, the age-related differences in left FEF activation were a consequence of decreasing resting-state functional connectivity in visual sensory regions. These findings indicate that age-related compensatory effects may be expressed in the relation between activation and behavior, rather than in the magnitude of activation, and that relevant changes in the activation-RT relation may begin at a relatively early point in adulthood. Hum Brain Mapp 38:2128-2149, 2017. © 2017 Wiley Periodicals, Inc.

Age-related differences in resolving semantic and phonological competition during receptive language tasks.

Receptive language (e.g., reading) is largely preserved in the aging brain, and semantic processes in particular may continue to develop throughout the lifespan. We investigated the neural underpinnings of phonological and semantic retrieval in older and younger adults during receptive language tasks (rhyme and semantic similarity judgments). In particular, we were interested in the role of competition on language retrieval and varied the similarities between a cue, target, and distractor that were hypothesized to affect the mental process of competition. Behaviorally, all participants responded faster and more accurately during the rhyme task compared to the semantic task. Moreover, older adults demonstrated higher response accuracy than younger adults during the semantic task. Although there were no overall age-related differences in the neuroimaging results, an Age×Task interaction was found in left inferior frontal gyrus (IFG), with older adults producing greater activation than younger adults during the semantic condition. These results suggest that at lower levels of task difficulty, older and younger adults engaged similar neural networks that benefited behavioral performance. As task difficulty increased during the semantic task, older adults relied more heavily on largely left hemisphere language regions, as well as regions involved in perception and internal monitoring. Our results are consistent with the stability of language comprehension across the adult lifespan and illustrate how the preservation of semantic representations with aging may influence performance under conditions of increased task difficulty.

Phonemic fluency and brain connectivity in age-related macular degeneration: a pilot study.

Age-related macular degeneration (AMD), the leading cause of blindness in developed nations, has been associated with poor performance on tests of phonemic fluency. This pilot study sought to (1) characterize the relationship between phonemic fluency and resting-state functional brain connectivity in AMD patients and (2) determine whether regional connections associated with phonemic fluency in AMD patients were similarly linked to phonemic fluency in healthy participants. Behavior-based connectivity analysis was applied to resting-state, functional magnetic resonance imaging data from seven patients (mean age=79.9±7.5 years) with bilateral AMD who completed fluency tasks prior to imaging. Phonemic fluency was inversely related to the strength of functional connectivity (FC) among six pairs of brain regions, representing eight nodes: left opercular portion of inferior frontal gyrus (which includes Broca's area), left superior temporal gyrus (which includes part of Wernicke's area), inferior parietal lobe (bilaterally), right superior parietal lobe, right supramarginal gyrus, right supplementary motor area, and right precentral gyrus. The FC of these reference links was not related to phonemic fluency among 32 healthy individuals (16 younger adults, mean age=23.5±4.6 years and 16 older adults, mean age=68.3±3.4 years). Compared with healthy individuals, AMD patients exhibited higher mean connectivity within the reference links and within the default mode network, possibly reflecting compensatory changes to support performance in the setting of reduced vision. These findings are consistent with the hypothesis that phonemic fluency deficits in AMD reflect underlying brain changes that develop in the context of AMD.

Global versus tract-specific components of cerebral white matter integrity: relation to adult age and perceptual-motor speed.

Although age-related differences in white matter have been well documented, the degree to which regional, tract-specific effects can be distinguished from global, brain-general effects is not yet clear. Similarly, the manner in which global and regional differences in white matter integrity contribute to age-related differences in cognition has not been well established. To address these issues, we analyzed diffusion tensor imaging measures from 52 younger adults (18-28) and 64 older adults (60-85). We conducted principal component analysis on each diffusion measure, using data from eight individual tracts. Two components were observed for fractional anisotropy: the first comprised high loadings from the superior longitudinal fasciculi and corticospinal tracts, and the second comprised high loadings from the optic radiations. In contrast, variation in axial, radial, and mean diffusivities yielded a single-component solution in each case, with high loadings from most or all tracts. For fractional anisotropy, the complementary results of multiple components and variability in component loadings across tracts suggest regional variation. However, for the diffusivity indices, the single component with high loadings from most or all of the tracts suggests primarily global, brain-general variation. Further analyses indicated that age was a significant mediator of the relation between each component and perceptual-motor speed. These data suggest that individual differences in white matter integrity and their relation to age-related differences in perceptual-motor speed represent influences that are beyond the level of individual tracts, but the extent to which regional or global effects predominate may differ between anisotropy and diffusivity measures.

Age-related differences in the neural bases of phonological and semantic processes.

Changes in language functions during normal aging are greater for phonological compared with semantic processes. To investigate the behavioral and neural basis for these age-related differences, we used fMRI to examine younger and older adults who made semantic and phonological decisions about pictures. The behavioral performance of older adults was less accurate and less efficient than younger adults' in the phonological task but did not differ in the semantic task. In the fMRI analyses, the semantic task activated left-hemisphere language regions, and the phonological task activated bilateral cingulate and ventral precuneus. Age-related effects were widespread throughout the brain and most often expressed as greater activation for older adults. Activation was greater for younger compared with older adults in ventral brain regions involved in visual and object processing. Although there was not a significant Age × Condition interaction in the whole-brain fMRI results, correlations examining the relationship between behavior and fMRI activation were stronger for younger compared with older adults. Our results suggest that the relationship between behavior and neural activation declines with age, and this may underlie some of the observed declines in performance.

Written distractor words influence brain activity during overt picture naming.

Language production requires multiple stages of processing (e.g., semantic retrieval, lexical selection), each of which may involve distinct brain regions. Distractor words can be combined with picture naming to examine factors that influence language production. Phonologically-related distractors have been found to speed picture naming (facilitation), while slower response times and decreased accuracy (interference) generally occur when a distractor is categorically related to the target image. However, other types of semantically-related distractors have been reported to produce a facilitative effect (e.g., associative, part-whole). The different pattern of results for different types of semantically-related distractors raises the question about how the nature of the semantic relation influences the effect of the distractor. To explore the nature of these semantic effects further, we used functional MRI to examine the influence of four types of written distractors on brain activation during overt picture naming. Distractors began with the same sound, were categorically-related, part of the object to be named, or were unrelated to the picture. Phonologically-related trials elicited greater activation than both semantic conditions (categorically-related and part-whole) in left insula and bilateral parietal cortex, regions that have been attributed to phonological aspects of production and encoding, respectively. Semantic conditions elicited greater activation than phonological trials in left posterior MTG, a region that has been linked to concept retrieval and semantic integration. Overall, the two semantic conditions did not differ substantially in their functional activation which suggests a similarity in the semantic demands and lexical competition across these two conditions.