Reorganisation of Brain Hubs across Altered States of Consciousness.

Patterns of functional interactions across distributed brain regions are suggested to provide a scaffold for the conscious processing of information, with marked topological alterations observed in loss of consciousness. However, establishing a firm link between macro-scale brain network organisation and conscious cognition requires direct investigations into neuropsychologically-relevant architectural modifications across systematic reductions in consciousness. Here we assessed both global and regional disturbances to brain graphs in a group of healthy participants across baseline resting state fMRI as well as two distinct levels of propofol-induced sedation. We found a persistent modular architecture, yet significant reorganisation of brain hubs that formed parts of a wider rich-club collective. Furthermore, the reduction in the strength of rich-club connectivity was significantly associated with the participants' performance in a semantic judgment task, indicating the importance of this higher-order topological feature for conscious cognition. These results highlight a remarkable interplay between global and regional properties of brain functional interactions in supporting conscious cognition that is relevant to our understanding of clinical disorders of consciousness.

Brain network disintegration during sedation is mediated by the complexity of sparsely connected regions.

The precise mechanism of anaesthetic action on a neural level remains unclear. Recent approaches suggest that anaesthetics attenuate the complexity of interactions (connectivity) however evidence remains insufficient. We used tools from network and information theory to show that, during propofol-induced sedation, a collection of brain regions displayed decreased complexity in their connectivity patterns, especially so if they were sparsely connected. Strikingly, we found that, despite their low connectivity strengths, these regions exhibited an inordinate role in network integration. Their location and connectivity complexity delineated a specific pattern of sparse interactions mainly involving default mode regions while their connectivity complexity during the awake state also correlated with reaction times during sedation signifying its importance as a reliable indicator of the effects of sedation on individuals. Contrary to established views suggesting sedation affects only richly connected brain regions, we propose that suppressed complexity of sparsely connected regions should be considered a critical feature of any candidate mechanistic description for loss of consciousness.

Angular default mode network connectivity across working memory load.

Initially identified during no-task, baseline conditions, it has now been suggested that the default mode network (DMN) engages during a variety of working memory paradigms through its flexible interactions with other large-scale brain networks. Nevertheless, its contribution to whole-brain connectivity dynamics across increasing working memory load has not been explicitly assessed. The aim of our study was to determine which DMN hubs relate to working memory task performance during an fMRI-based n-back paradigm with parametric increases in difficulty. Using a voxel-wise metric, termed the intrinsic connectivity contrast (ICC), we found that the bilateral angular gyri (core DMN hubs) displayed the greatest change in global connectivity across three levels of n-back task load. Subsequent seed-based functional connectivity analysis revealed that the angular DMN regions robustly interact with other large-scale brain networks, suggesting a potential involvement in the global integration of information. Further support for this hypothesis comes from the significant correlations we found between angular gyri connectivity and reaction times to correct responses. The implication from our study is that the DMN is actively involved during the n-back task and thus plays an important role related to working memory, with its core angular regions contributing to the changes in global brain connectivity in response to increasing environmental demands. Hum Brain Mapp 38:41-52, 2017. © 2016 Wiley Periodicals, Inc.

Default mode network connectivity during task execution.

Initially described as task-induced deactivations during goal-directed paradigms of high attentional load, the unresolved functionality of default mode regions has long been assumed to interfere with task performance. However, recent evidence suggests a potential default mode network involvement in fulfilling cognitive demands. We tested this hypothesis in a finger opposition paradigm with task and fixation periods which we compared with an independent resting state scan using functional magnetic resonance imaging and a comprehensive analysis pipeline including activation, functional connectivity, behavioural and graph theoretical assessments. The results indicate task specific changes in the default mode network topography. Behaviourally, we show that increased connectivity of the posterior cingulate cortex with the left superior frontal gyrus predicts faster reaction times. Moreover, interactive and dynamic reconfiguration of the default mode network regions' functional connections illustrates their involvement with the task at hand with higher-level global parallel processing power, yet preserved small-world architecture in comparison with rest. These findings demonstrate that the default mode network does not disengage during this paradigm, but instead may be involved in task relevant processing.

Clinical decision-making augmented by simulation training: neural correlates demonstrated by functional imaging: a pilot study.

BACKGROUND: Investigation of the neuroanatomical basis of clinical decision-making, and whether this differs when students are trained via online training or simulation training, could provide valuable insight into the means by which simulation training might be beneficial. METHODS: The aim of this pilot prospective parallel group cohort study was to investigate the neural correlates of clinical decision-making, and to determine if simulation as opposed to online training influences these neural correlates. Twelve third-year medical students were randomized into two groups and received simulation-based or online-based training on anaphylaxis. This was followed by functional magnetic resonance imaging scanning to detect brain activation patterns while answering multiple choice questions (MCQs) related to anaphylaxis, and unrelated non-clinical (control) questions. Performance in the MCQs, salivary cortisol levels, heart rate, and arterial pressure were also measured. RESULTS: Comparing neural responses to clinical and non-clinical questions (in all participants), significant areas of activation were seen in the ventral anterior cingulate cortex and medial prefrontal cortex. These areas were activated in the online group when answering action-based questions related to their training, but not in the simulation group. The simulation group tended to react more quickly and accurately to clinical MCQs than the online group, but statistical significance was not reached. CONCLUSIONS: The activation areas seen could indicate increased stress when answering clinical questions compared with general non-clinical questions, and in the online group when answering action-based clinical questions. These findings suggest simulation training attenuates neural responses related to stress when making clinical decisions.

Altered functional connectivity in the motor network after traumatic brain injury.

BACKGROUND: A large proportion of survivors of traumatic brain injury (TBI) have persistent cognitive impairments, the profile of which does not always correspond to the size and location of injuries. One possible explanation could be that TBI-induced damage extends beyond obvious lesion sites to affect remote brain networks. We explored this hypothesis in the context of a simple and well-characterized network, the motor network. The aim of this cross-sectional study was to establish the residual integrity of the motor network as an important proof of principle of abnormal connectivity in TBI. METHODS: fMRI data were obtained from 12 right-handed patients and 9 healthy controls while they performed the finger-thumb opposition task with the right hand. We used both conventional and psychophysiologic interaction (PPI) analyses to examine the integrity of functional connections from brain regions we found to be activated in the paradigm we used. RESULTS: As expected, the analysis showed significant activations of the left primary motor cortex (M1), right cerebellum (Ce), and bilateral supplementary motor area (SMA) in controls. However, only the activation of M1 survived robust statistical thresholding in patients. In controls, the PPI analysis revealed that left M1, SMA, and right Ce positively interacted with the left frontal cortex and negatively interacted with the right supramarginal gyrus. In patients, we observed no negative interaction and reduced interhemispheric interactions from these seed regions. CONCLUSIONS: These observations suggest that patients display compromised activation and connectivity patterns during the finger-thumb opposition task, which may imply functional reorganization of motor networks following TBI.

Complementary hemispheric asymmetries in object naming and recognition: a voxel-based correlational study.

Cognitive neuroscientific research proposes complementary hemispheric asymmetries in naming and recognising visual objects, with a left temporal lobe advantage for object naming and a right temporal lobe advantage for object recognition. Specifically, it has been proposed that the left inferior temporal lobe plays a mediational role linking conceptual information with word forms and vice versa, while the right inferior temporal lobe supports the retrieval of conceptual knowledge from visual input. To test these hypotheses, we administered four behavioural tasks to fifteen patients with temporal lobe brain damage, and correlated their behavioural scores with voxel-based measures of neuronal integrity (signal intensities) in whole-brain analyses. The behavioural paradigms included four tasks. Two were verbal tasks: (a) picture naming requiring the mapping of conceptual knowledge to word forms, (b) semantic categorisation of words requiring the reverse mapping of word forms to conceptual knowledge, and two were visual object tasks with no verbal component, both of which required the retrieval of conceptual information from visual objects, i.e., (c) visual object categorisation and (d) normal and chimera object decisions. Performance on the verbal tasks correlated with the neural integrity of partially overlapping left inferior and anterior temporal lobe regions, while performance on the object tasks correlated with the neural integrity of overlapping regions in right inferior and anterior temporal lobe. These findings support the notion of complementary hemispheric advantages for object naming and recognition, and further suggest that the classical language model emphasising posterior regions in the mapping between word forms and conceptual knowledge should be extended to include left inferior temporal lobe.

Longitudinal studies of semantic dementia: the relationship between structural and functional changes over time.

The pattern of brain atrophy in semantic dementia and its associated cognitive effects have attracted a considerable body of research, but the nature of core impairments remains disputed. A key issue is whether the disease encompasses one neurocognitive network (semantics) or two (language and semantics). In order to address these conflicting perspectives, we conducted a longitudinal investigation of two semantic dementia patients, in which behavioural performance across a range of measures of language and semantic performance was assessed and interpreted in the context of annually acquired MRI scans. Our results indicated a core semantic impairment in early stages of the disease, associated with atrophy of the inferior, anterior temporal cortex. Linguistic impairments emerged later, and were contingent on atrophy having spread into areas widely believed to subserve core language processes (left posterior perisylvian, inferior frontal and insular cortex). We claim, therefore, that phonological, syntactic and morphological processing deficits in semantic dementia reflect damage to core language areas. Further, we propose that much of the current controversy over the nature of deficits in semantic dementia reflect a tendency in the literature to adopt a static perspective on what is a progressive disease. An approach in which the relationship between progressive neural changes and behavioural change over time is carefully mapped, offers a more constraining data-set from which to draw inferences about the relationship between language, semantics and the brain.

Cortical differentiation for nouns and verbs depends on grammatical markers.

Here we address the contentious issue of how nouns and verbs are represented in the brain. The co-occurrence of noun and verb deficits with damage to different neural regions has led to the view that they are differentially represented in the brain. Recent neuroimaging evidence and inconsistent lesion-behavior associations challenge this view. We have suggested that nouns and verbs are not differentially represented in the brain, but that different patterns of neural activity are triggered by the different linguistic functions carried by nouns and verbs. We test these claims in a functional magnetic resonance imaging study using homophones -- words which function grammatically as nouns or verbs but have the same form and meaning -- ensuring that any neural differences reflect differences in grammatical function. Words were presented as single stems and in phrases in which each homophone was preceded by an article to create a noun phrase (NP) or a pronoun to create a verb phrase (VP), thus establishing the word's functional linguistic role. Activity for single-word homophones was not modulated by their frequency of usage as a noun or verb. In contrast, homophones marked as verbs by appearing in VPs elicited greater activity in the left posterior middle temporal gyrus (LpMTG) compared to homophones marked as nouns by occurring in NPs. Neuropsychological patients with grammatical deficits had lesions which overlapped with the greater LpMTG activity found for VPs. These results suggest that nouns and verbs do not invariably activate different neural regions; rather, differential cortical activity depends on the extent to which their different grammatical functions are engaged.

Grammatical categories in the brain: the role of morphological structure.

The current study addresses the controversial issue of how different grammatical categories are neurally processed. Several lesion-deficit studies suggest that distinct neural substrates underlie the representation of nouns and verbs, with verb deficits associated with damage to left inferior frontal gyrus (LIFG) and noun deficits with damage to left temporal cortex. However, this view is not universally shared by neuropsychological and neuroimaging studies. We have suggested that these inconsistencies may reflect interactions between the morphological structure of nouns and verbs and the processing implications of this, rather than differences in their neural representations (Tyler et al. 2004). We tested this hypothesis using event-related functional magnetic resonance imaging, to scan subjects performing a valence judgment on unambiguous nouns and verbs, presented as stems ('snail, hear') and inflected forms ('snails, hears'). We predicted that activations for noun and verb stems would not differ, whereas inflected verbs would generate more activation in left frontotemporal areas than inflected nouns. Our findings supported this hypothesis, with greater activation of this network for inflected verbs compared with inflected nouns. These results support the claim that form class is not a first-order organizing principle underlying the representation of words but rather interacts with the processes that operate over lexical representations.

Repetition suppression and semantic enhancement: an investigation of the neural correlates of priming.

The priming of a stimulus by another has become an important tool for exploring the neural underpinnings of conceptual representations. However, priming effects can derive from many different types of relationships and it is important to distinguish between them in order to be able to develop theoretical accounts of the representation of conceptual knowledge. While it is well known that repetition priming (the repeated presentation of the same stimulus) is associated with a reduced neural response, called repetition suppression (RS), the neural correlates of semantic priming (when two stimuli are related in meaning but not identical) are not so well established. We compared the neural correlates of repetition and semantic priming using written words, independently manipulating form and meaning. In an fMRI study, subjects saw single words and made a concrete-abstract decision. Two consecutive words were identical (town-town) or varied along a continuum of semantic relatedness, from highly related (cord-string) to unrelated (face-sail). We found distinct patterns of activation for repetition and semantic priming. Repetition priming was associated with RS in LIFG, bilateral parahippocampal gyrus and R fusiform gyrus. We also observed increased activation for word repetition in the RMFG and RMTG/STG, which may reflect recognition of item's earlier presentation. There was no evidence of suppression for semantic relatedness. Semantic priming was associated with enhanced activation in multiple bilateral fronto-temporal areas, i.e. semantic enhancement. The results suggest that repetition and semantic priming in visual word recognition depend on distinct cognitive processes and neural substrates.

Cingulate control of fronto-temporal integration reflects linguistic demands: a three-way interaction in functional connectivity.

In a recent fMRI language comprehension study, we asked participants to listen to word-pairs and to make same/different judgments for regularly and irregularly inflected word forms [Tyler, L.K., Stamatakis, E.A., Post, B., Randall, B., Marslen-Wilson, W.D., in press. Temporal and frontal systems in speech comprehension: an fMRI study of past tense processing. Neuropsychologia, available online.]. We found that a fronto-temporal network, including the anterior cingulate cortex (ACC), left inferior frontal gyrus (LIFG), bilateral superior temporal gyrus (STG) and middle temporal gyrus (MTG), is preferentially activated for regularly inflected words. We report a complementary re-analysis of the data seeking to understand the behavior of this network in terms of inter-regional covariances, which are taken as an index of functional connectivity. We identified regions in which activity was predicted by ACC and LIFG activity, and critically, by the interaction between these two regions. Furthermore, we determined the extent to which these inter-regional correlations were influenced differentially by the experimental context (i.e. regularly or irregularly inflected words). We found that functional connectivity between LIFG and left MTG is positively modulated by activity in the ACC and that this effect is significantly greater for regulars than irregulars. These findings suggest a monitoring role for the ACC which, in the context of processing regular inflected words, is associated with greater engagement of an integrated fronto-temporal language system.

Differentiating lexical form, meaning, and structure in the neural language system.

A technique for studying the relationship between brain and language, which involves correlating scores on two continuous variables, signal intensity across the entire brains of brain-damaged patients and behavioral priming scores, was used to investigate a central issue in cognitive neuroscience: Are the components of the neural language system organized as a single undifferentiated process, or do they respond differentially to different types of linguistic structure? Differences in lexical structure, in the form of the regular and irregular past tense, have proven to be critical in this debate by contrasting a highly predictable rule-like process (e.g., jump-jumped) with an unpredictable idiosyncratic process typified by the irregulars (e.g., think-thought). The key issue raised by these contrasts is whether processing regular and irregular past tense forms differentially engages different aspects of the neural language system or whether they are processed within a single system that distinguishes between them purely on the basis of phonological and semantic differences. The correlational analyses provide clear evidence for a functional differentiation between different brain regions associated with the processing of lexical form, meaning, and morphological structure.

Anteromedial temporal cortex supports fine-grained differentiation among objects.

Patients with damage to left anteromedial temporal cortex often show a striking deficit: they fail to recognize animals and other living things. This failure of recognition presents an important challenge to theories of the neural representation of conceptual knowledge. Here we propose that this lesion-behaviour association arises because polymodal neurons in anteromedial temporal cortex integrate simple features into complex feature conjunctions, providing the neural infrastructure for differentiating among objects.

Processing objects at different levels of specificity.

How objects are represented and processed in the brain is a central topic in cognitive neuroscience. Previous studies have shown that knowledge of objects is represented in a feature-based distributed neural system primarily involving occipital and temporal cortical regions. Research with nonhuman primates suggest that these features are structured in a hierarchical system with posterior neurons in the inferior temporal cortex representing simple features and anterior neurons in the perirhinal cortex representing complex conjunctions of features (Bussey & Saksida, 2002; Murray & Bussey, 1999). On this account, the perirhinal cortex plays a crucial role in object identification by integrating information from different sensory systems into more complex polymodal feature conjunctions. We tested the implications of these claims for human object processing in an event-related fMRI study in which we presented colored pictures of common objects for 19 subjects to name at two levels of specificity - basic and domain. We reasoned that domain-level naming requires access to a coarser-grained representation of objects, thus involving only posterior regions of the inferior temporal cortex. In contrast, basic-level naming requires finer-grained discrimination to differentiate between similar objects, and thus should involve anterior temporal regions, including the perirhinal cortex. We found that object processing always activated the fusiform gyrus bilaterally, irrespective of the task, whereas the perirhinal cortex was only activated when the task required finer-grained discriminations. These results suggest that the same kind of hierarchical structure, which has been proposed for object processing in the monkey temporal cortex, functions in the human.

Neural processing of nouns and verbs: the role of inflectional morphology.

Dissociations of nouns and verbs following brain damage have been interpreted as evidence for distinct neural substrates underlying different aspects of the language system. Some neuroimaging studies have supported this claim by finding neural differentiation for nouns and verbs [Brain 122 (1999) 2337] while others have argued against neural specialisation [Brain 119 (1996) 159; Brain 124 (2001) 1619]. We suggest that one reason why these inconsistencies may have arisen is because the morphological structure of nouns and verbs has been ignored. In an event-related functional magnetic resonance imaging (fMRI) study we test the hypothesis that the neural processing of nouns and verbs differs when they are inflected. We contrasted the processing of regularly inflected nouns (dogs) with regularly inflected verbs (hitting), and found that the LIFG was more strongly activated in processing regularly inflected verbs compared to regularly inflected nouns. Moreover, regions of LIFG that were more active in the fMRI study for inflected verbs partially overlapped with the lesions in patients who have particular problems with verb morphology. Taken together with previous studies, these results suggest that noun and verb stems do not differ in terms of their representation, but when verbs are morphologically complex they differentially engage those neural systems which are involved in processes of morpho-phonology and syntax.

Objects and their actions: evidence for a neurally distributed semantic system.

An influential model of conceptual knowledge claims that objects are represented in a distributed network of cortical areas that store information about different types of attributes, such as form, colour, and motion (A. Martin et al., 2000, in: The Cognitive Neurosciences, 2nd ed., MIT Press, Cambridge). Two specific claims of this account are that (a) the motions and actions associated with objects (along with other attributes) are automatically activated whenever the object concept is evoked and (b) topographically distinct neural regions are responsible for motion/action attributes pertaining to objects in the categories of tools and animals. We used fMRI to examine the neural activation associated with conceptual processing of nouns referring to animals and tools and for verbs referring to tool-associated actions (e.g., drilling, painting) and biological actions (e.g., walking, jumping). We found that object names and their associated actions activated the same set of neural regions (left fusiform gyrus, superior and middle temporal cortex) consistent with the claim that word tool and animal concepts implicitly activate the actions associated with them. However, there was no evidence of category specificity for either objects or actions, with essentially the same activations for the form and motion attributes of both living and nonliving categories.

Spatial normalization of lesioned HMPAO-SPECT images.

We investigated the effect of nonlinear alignment on SPECT images with lesions. Linear alignment produces reliable results but the introduction of nonlinear methods can improve matching by accounting for global brain shape. We examined the hypothesis that nonlinear alignment can introduce unwanted image distortions when lesions are present. We set out to quantify possible distortions by constructing artificial lesions in order to obtain images with controllable characteristics. We examined the use of basis functions (in SPM96 and SPM99) and other nonlinear models (in AIR3.08) designed to achieve optimum alignment between image and template. We found that the use of models with high degrees of nonlinearity will result in unwanted deformations and that the safest way to align images with lesions is to use 12-point linear affine transformations. Masking was examined as a remedy to distortions caused by nonlinear methodologies and produced significantly improved results.

Analysis of HMPAO SPECT scans in head injury using Statistical Parametric Mapping.

The paper examines the ability of Statistical Parametric Mapping (SPM) to contribute towards the quantitative analysis of HMPAO SPECT images containing lesions. A validation study is described in which SPECT images were created that contained synthetic lesions and were analysed with SPM. The study established a set of guidelines concerning the alignment, smoothing, and statistical analysis of images. These were then applied to analysis of SPECT scans from head injured patients. A demonstration is given of the use of SPM to identify localised blood flow abnormalities associated with cognitive deficits after head injury. Correlations between blood flow abnormalities and a test of visual memory are illustrated.

Validation of statistical parametric mapping (SPM) in assessing cerebral lesions: A simulation study.

Simulated abnormalities were introduced in a normal SPECT with known and controllable characteristics (abnormality size and depth) in an attempt to provide validation for the analysis of SPECT lesion studies using SPM. Two simulations were carried out. The first determined the minimum hypoperfusion depth detectable using SPM by altering mean local intensity while keeping the size of the lesion constant. This was done by changing the mean local intensity in percentile increments of 10 down to -100 and up to 50. The second simulation determined the cluster size that SPM can detect by keeping the mean intensity of the lesion constant while altering its size from 4 voxels to 63,000 voxels in a total brain volume of 300, 000 voxels. Both simulations determined which method of normalization is most appropriate, what level of grey matter thresholding should be used, and at what statistical probability peak threshold (u) the results should be determined. Proportional scaling was found to be the most appropriate normalization method. ANCOVA was useful where very large abnormalities were present and normalization external to SPM was not available. In those cases, ANCOVA was used in conjunction with measurement of an unaffected part of the brain (in this case medial occipital lobe). For better results statistical probability peak threshold was set to p(u) = 0. 01 and grey matter threshold was set to a value below 0.5. SPM produced best results when the abnormality represented a decrease of about -50% from the normal or more and detected other decreases in an acceptable manner.