Article

A human brain network derived from coma-causing brainstem lesions

Authors:
  • Max Planck Institute for Biological Cybernetics & Center for Integrative Neuroscience, Tuebingen, Germany
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Abstract

Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

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... The lateral columns mediate reward-seeking behavior (Tyron and Mizumori, 2018) and the ventrolateral are related to the homeostatic regulation of pain (Lane et al., 2005). There is also evidence that the insular VEN area is connected with the parabrachial nuclei in humans, though they may not be direct (Fischer et al., 2016). The evidence in humans comes from a remarkable (Evrard et al., 2014). ...
... The section is from the same plane as Fig. 2E and corresponds to insular VEN connection with Idm labeled in turquoise in Fig. 2E. study in which the lesions that caused coma in 12 patients were compared with 24 patients with brain stem lesions that did not cause coma; the net coma-causing area largely overlapped with the parabrachial nuclei (Fischer et al., 2016). Then, in normal subjects, the authors mapped functional connectivity between the pontine coma area and the forebrain and found that the connected areas closely corresponded to the VEN areas in the anterior insula and anterior cingulate cortex suggesting that the VEN areas may be related to consciousness (Fischer et al., 2016). ...
... study in which the lesions that caused coma in 12 patients were compared with 24 patients with brain stem lesions that did not cause coma; the net coma-causing area largely overlapped with the parabrachial nuclei (Fischer et al., 2016). Then, in normal subjects, the authors mapped functional connectivity between the pontine coma area and the forebrain and found that the connected areas closely corresponded to the VEN areas in the anterior insula and anterior cingulate cortex suggesting that the VEN areas may be related to consciousness (Fischer et al., 2016). In our earlier analysis of magnetic resonance diffusion data from gorilla 2 we reported connections with the thalamus, amygdala and hippocampus (Allman et al., 2010), but the methods employed in the current analysis provide overall more finely differentiated pathways that more clearly match the experimental findings in macaque monkeys for most brain structures. ...
Article
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We mapped the connections of the insular von Economo neuron (VEN) area in ex vivo brains of a bonobo, an orangutan and two gorillas with high angular resolution diffusion MRI imaging acquired in 36 h imaging sessions for each brain. The apes died of natural causes without neurological disorders. The localization of the insular VEN area was based on cresyl violet-stained histological sections from each brain that were coregistered with structural and diffusion images from the same individuals. Diffusion MRI tractography showed that the insular VEN area is connected with olfactory, gustatory, visual and other sensory systems, as well as systems for the mediation of appetite, reward, aversion and motivation. The insular VEN area in apes is most strongly connected with frontopolar cortex, which could support their capacity to choose voluntarily among alternative courses of action particularly in exploring for food resources. The frontopolar cortex may also support their capacity to take note of potential resources for harvesting in the future (prospective memory). All of these faculties may support insight and volitional choice when contemplating courses of action as opposed to rule-based decision-making.
... 1. There are specific sites critical for consciousness, but the absence of activation of these sites on functional imaging of patients with DoC (e.g., under propofol anesthesia [28]) does not reliably correlate with absent function [26,27]. Rostral brainstem, midline thalamic nuclei, and anterior insula have emerged as possible key sites critical for consciousness [28][29][30]. ...
... There are specific sites critical for consciousness, but the absence of activation of these sites on functional imaging of patients with DoC (e.g., under propofol anesthesia [28]) does not reliably correlate with absent function [26,27]. Rostral brainstem, midline thalamic nuclei, and anterior insula have emerged as possible key sites critical for consciousness [28][29][30]. Yet, it is unclear whether all of these sites, in isolation, are both necessary and sufficient. 2. There are systems and connections that subserve consciousness. ...
Article
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This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.
... A jumping-off point for multimodal integration in DOC may be to overlay the structural correlates of DOC with the healthy human connectome (both structural and functional) to derive likely locations for a diaschisis effect, a method that avoids the often challenging process of multimodal data collection within patients themselves [59,60]. Such an approach could be used to build wholebrain computational models, including the known structural correlates of DOC and known large-scale functional correlates (Box 2). ...
... Similarly, critical insights at the microscopic systems level are to be gained from the brainstem neuromodulatory nuclei, which have been extensively studied in animals by using anesthetic and lesion approaches [99][100][101]. Their associated transmitter systems and brain-wide neuromodulatory projections have been variously implicated as causing coma [60,102,103]. In healthy patients, they have been found to possibly drive both tonic and phasic large-scale in vivo brain activity [104][105][106]. ...
Article
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Aim In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. Methods To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. Results We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. Conclusion In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a “virtuous cycle,” leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.
... 1,2 Disruptions in this thalamocortical network have been implicated in disorders of consciousness (DoCs) following severe brain injury. [3][4][5][6] Tools that assay thalamocortical network integrity may therefore allow for more precise tracking of neurological recovery than is possible with behavioural assessments alone. ...
... The 'A' category (no spectral peak above the delta [<4 Hz] range) corresponds to a completely disconnected thalamocortical network that can be likened to the 'cortical slab preparation,' wherein neocortical neurons are markedly hyperpolarized and exclusively produce low frequency oscillations. 8 The 'B' category (spectral peak in the theta [4][5][6][7][8] range) corresponds to a severely disconnected system wherein cortical neurons are comparatively more depolarized resulting in theta frequency bursting. 9 The 'C' category (spectral peaks in the theta and beta [13][14][15][16][17][18][19][20][21][22][23][24] ranges) corresponds to a moderately disconnected system wherein thalamic neuron bursting produces coexisting theta and beta frequency oscillations in connected cortex. ...
Preprint
Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma. We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework: A = no peaks above delta (<4 Hz) range (complete thalamocortical disruption); B = theta (4-8 Hz) peak (severe thalamocortical disruption); C = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or D = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). We assessed behavioural level of consciousness with the Coma Recovery Scale-Revised or neurological examination and, in 12 patients, performed repeat EEG and behavioural assessments at ≥6-months post-injury. Acutely, 95% of patients demonstrated D signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent D signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent D signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (P<0.05), providing electrophysiological evidence for the effectiveness of this commonly performed technique. ABCD classification did not correspond with behavioural level of consciousness acutely, where patients demonstrated substantial within-session temporal variability in ABCD classifications. However, ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (P<0.01). Patients also demonstrated significant longitudinal improvement in EEG dynamics along the ABCD scale (median change in D signals: 37%, P<0.05). These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.
... Starting from the experiments ran in cats by Moruzzi andMagoun in 1949 (Moruzzi andMagoun, 1949), the respective contributions of all these nuclei have extensively been studied in animals through lesional and stimulation experiments (Fuller et al., 2011;Qiu et al., 2016;Kroeger et al., 2017;Gao et al., 2019). The observation of coma-causing lesions in MRI and histopatho- logical studies allowed to largely extend this knowledge to humans, by displaying a very similar complex system subserving arousal (Parvizi 2003;Edlow et al. 2012;Fischer et al. 2016;Snider et al. 2019 and Figure 1.2B). ...
... They all assessed the efficacy of 20 Hz rTMS over the left M1 in comparison to a sham control condition. None of them demonstrated consciousness improvement by stimulation, regardless of whether the protocol consisted in a single session (Liu et al., 2016) or in daily sessions over 5 days (Cincotta et al., 2015;He et al., 2018;Liu et al., 2018). These studies only showed some minor EEG changes in power spectra or hemodynamic parameters monitored by transcranial doppler. ...
Thesis
Accurate diagnosis and treatment of consciousness disorders (DoC) remains a challenging issue. In this work, we introduced a new behavioral scale for DoC capitalizing on the wisdom of the crowd phenomenon, we validated the FDG-PET metabolic index of the best preserved hemisphere as one of the best neuro-imaging technique for minimally conscious state (MCS) diagnosis and proposed a new and reliable clinical sign of MCS, the habituation of auditory startle reflex. In addition to enriching and refining our repertoire of diagnostic procedures available for DoC diagnosis, our results support the interpretation of the generic and elusive MCS as a cortically-mediated state, which reflects the preservation of activity within specialized cortical networks and could include both conscious and non-conscious states. On the therapeutic side, by investigating the effects of prefrontal transcranial direct current stimulation (tDCS) on behavior and brain activity of patients suffering from DoC, we provided evidence for a genuine and direct cortical effect of the stimulation on consciousness through the modulation of residual cortical activity and cortico-cortical connectivity. Finally, in an attempt to develop theory-driven stimulation paradigms, we used tDCS and transcranial alternative stimulation to test predictions of the global neuronal workspace theory on conscious access in healthy subjects, with heterogeneous stimulation responses. Taken together, our results advocate for the systematic investigation of stimulation effect on brain activity and for the future development of more powerful and targeted stimulation procedures.
... Parvizi and Damasio (2003) analyzed patients with brainstem lesions to identify the region necessary for wakefulness, and found that the maximum overlap between coma-causing lesions was in the upper pontine tegmentum ( Figure 1G). Fischer et al. (2016) refined this approach by comparing comatose patients to a control group with lesions that did not produce coma and found that comatose patients were significantly more likely to have damage to a focal area of the pontine tegmentum in or near the medial PB ( Figure 1H). ...
... Second, human coma-causing lesions likewise localize to a small area of the upper brainstem tegmentum. These findings support the idea that a focal group of neurons in this area maintains wakefulness (Parvizi and Damasio, 2003;Fischer et al., 2016). Presumably, neurons here exert their influence via output connectivity to arousal centers in the forebrain, including the basal forebrain and cerebral cortex. ...
Article
Full-text available
Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse “reticular activating system,” the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.
... It has also been shown that impaired communication between AI and pACC is observed in patients with impaired consciousness. Logically, it was concluded that a neural network heavily based on neurons von Economo based in the cortical regions of AI and pACC may play an important role in maintaining human consciousness [103]. ...
... It turns out that damage to a small area on the left side of the bridge, next to the medial parabrachial nucleus, causes a coma [121]. This region of the brainstem, like other areas affected by coma, is associated with the left agranular, anterior insula (AI), and the pregenual anterior cingulate cortex (pACC) [103]. These areas of the cortex correspond to the distribution of von Economo neurons (VENs). ...
Article
There are at least two approaches to the definition of consciousness. In the first case, certain aspects of consciousness, called qualia, are considered inaccessible for research from a third person and can only be described through subjective experience. This approach is inextricably linked with the so-called "hard problem of consciousness", that is, the question of why consciousness has qualia or how any physical changes in the environment can generate subjective experience. With this approach, some aspects of consciousness, by definition, cannot be explained on the basis of external observations and, therefore, are outside the scope of scientific research. In the second case, a priori constraints do not constrain the field of scientific investigation, and the best explanation of the experience in the first person is included as a possible subject of empirical research. Historically, in the study of cause-and-effect relationships in biology, it was customary to distinguish between proximate causation and ultimate causation existing in biological systems. Immediate causes are based on the immediate influencing factors [1]. Proximate causation has evolutionary explanations. When studying biological systems themselves, such an approach is undoubtedly justified, but it often seems insufficient when studying the interaction of consciousness and the brain [2], [3]. Current scientific communities proceed from the assumption that the physical substrate for the generation of consciousness is a neural network that unites various types of neurons located in various brain structures. Many neuroscientists attach a key role in this process to the cortical and thalamocortical neural networks. This question is directly related to experimental and clinical research in the field of disorder of consciousness. Progress in this area of medicine depends on advances in neuroscience in this area and is also a powerful source of empirical information. In this area of consciousness research, a large amount of experimental data has been accumulated, and in this review an attempt was made to generalize and systematize.
... Несмотря на очевидные достоинства, фМРТ с заданием имеет свои методологические особенности и затратна с точки зрения временнóго и трудового ресурсов. В том числе и по этой причине в последнее время имеет место смещение фокуса исследовательского внимания в сторону использования фМРТ покоя (регистрация спонтанной активности мозга в отсутствие задания или какой-либо стимуляции (Курганский, 2018)) (Sinitsyn et al., 2018;Wu et al., 2015;Demertzi et al., 2015;Fischer et al., 2016;P. et al., 2015 и др.) С помощью фМРТ покоя были получены данные о наиболее типичных паттернах функциональной нейросетевой реорганизации мозга при ХНС. ...
... et al., 2015 и др.) С помощью фМРТ покоя были получены данные о наиболее типичных паттернах функциональной нейросетевой реорганизации мозга при ХНС. Так, были выявлены изменения в работе сети по умолчанию/сети пассивного режима работы мозга (DMN-default mode network) (Silva et al., 2015), сети управляющих функций Demertzi et al., 2014b), сети салиентности (считается ответственной за выделение значимого стимула из окружающей среды) (Qin et al., 2015;Fischer et al., 2016), сенсомоторной сети (Yao et al., 2015), слуховой сети (Yao et al., 2015), зрительной сети (Demertzi et al., 2014a) и в подкорковых сетях (He et al., 2015). ...
Article
This review analyzes the literature on studies of states of pathological disorders (suppression) of consciousness based on the use of neuroimaging, electrophysiological, and other noninvasive methods for assessing nervous system activity. Problems of making diagnoses and prognosticating the recovery of patients with chronic disorders of consciousness are assessed. Neuroimaging, electrophysiological, physiological, and other correlates of chronic disorders of consciousness, such as the minimally conscious state and unresponsive wakefulness syndrome, are assessed. Pathways to resolving problems in diagnosis and prognostication of chronic disorders of consciousness are discussed.
... Lesion locations from originally published figures were manually traced onto a standard template brain as described previously (Boes et al., 2015;Darby et al., 2017;Fasano et al., 2017;Fischer et al., 2016;Joutsa et al., 2018;Laganiere et al., 2016). Neuroanatomical landmarks were used to ensure accurate transfer onto the template. ...
... The analysis steps of this technique have been described in the Introduction (see also Boes et al., 2015;Corp et al., 2019;Darby et al., 2017; C Feng et al. Clinical Psychology Review xxx (xxxx) 102189 Darby, Horn, et al., 2018;Fischer et al., 2016;Laganiere et al., 2016). ...
Article
Motivational dysfunction constitutes one of the fundamental dimensions of psychopathology cutting across traditional diagnostic boundaries. However, it is unclear whether there is a common neural circuit responsible for motivational dysfunction across neuropsychiatric conditions. To address this issue, the current study combined a meta-analysis on psychiatric neuroimaging studies of reward/loss anticipation and consumption (4308 foci, 438 contrasts, 129 publications) with a lesion network mapping approach (105 lesion cases). Our meta-analysis identified transdiagnostic hypoactivation in the ventral striatum (VS) for clinical/at-risk conditions compared to controls during the anticipation of both reward and loss. Moreover, the VS subserves a key node in a distributed brain network which encompasses heterogeneous lesion locations causing motivation-related symptoms. These findings do not only provide the first meta-analytic evidence of shared neural alternations linked to anticipatory motivation-related deficits, but also shed novel light on the role of VS dysfunction in motivational impairments in terms of both network integration and psychological functions. Particularly, the current findings suggest that motivational dysfunction across neuropsychiatric conditions is rooted in disruptions of a common brain network anchored in the VS, which contributes to motivational salience processing rather than encoding positive incentive values.
... Las manifestaciones clínicas más frecuentes en los abscesos cerebrales se incluyen en la tríada de fiebre, dolor de cabeza y déficit neurológico, si bien la presentación completa ocurre en menos de la mitad de los casos (5). Además, recientemente, Fischer et al. (6) encontraron que las lesiones localizadas en una pequeña área del tegmento dorsolateral de la protuberancia (sobre todo izquierda) se asocian significativamente al estado de coma, lo que se ha atribuido a la desconexión entre dicha región y dos áreas corticales implicadas en la consciencia, la ínsula anterior y el córtex cingular anterior pregenual. El caso presentado sería un ejemplo paradigmático de lesión en dicha área y justificaría el estado de coma tras la desintubación de la paciente, en consonancia con los hallazgos de dicho estudio. ...
Article
Brain stem abscesses are rare entities that predominantly affect the pons. A wide variety of microorganisms may be implied, depending on the focus of dissemination. We present the case of a female patient with multiple comorbidities who developed multi-lobar pneumonia due to influenza A(H1N1)pdm09 virus during the postoperative period after an emergent cholecystectomy, requiring mechanical ventilation (MV). Following clinical improvement and withdrawal of MV, the patient did not recover consciousness. Forty-eight hours later, imaging exams showed an abscess in the left pontine dorsolateral tegmentum –a region recently associated with coma-. Despite the administration of broad-spectrum antibiotics, the patient died five days later. This case illustrates the importance of considering pontine abscesses as a cause of poor neurological course in critically ill patients, as well as the need for doing imaging exams to rule out intracranial lesions, particularly in coma-associated areas.
... Based on the concept of diaschisis and the finding that symptoms are not attributed solely to the lesion itself but also to regions functionally connected to the lesion (Fasano et al., 2017), this technique utilizes normative connectome data to identify the networks associated with focal brain lesions without the need for special imaging sequences. This approach has been increasingly used to investigate the networks responsible for various neurological symptoms, including visual/auditory hallucinations, central post-stroke pain, subcortical aphasia (Boes et al., 2015), hemi-choreahemiballismus (Laganiere et al., 2016), Capgras syndrome (Darby et al., 2017), coma (Fischer et al., 2016), impaired decision making (Sutterer et al., 2016), freezing of gait (Fasano et al., 2017), and the rubber hand illusion (Wawrzyniak et al., 2018). Employing this unique methodology, we tested the hypothesis that lesions causing FAS would be connected to a common network of sites involved in motor speech function. ...
Article
Full-text available
Background Foreign accent syndrome (FAS) is a rare acquired speech disorder wherein an individual’s spoken accent is perceived as “foreign.” Most reported cases involve left frontal brain lesions, but it is known that various other lesions can also cause FAS. To determine whether heterogeneous FAS-causing lesions are localized to a common functional speech network rather than to a single anatomical site, we employed a recently validated image analysis technique known as “lesion network mapping.” Methods We identified 25 published cases of acquired neurogenic FAS without aphasia, and mapped each lesion volume onto a reference brain. We next identified the network of brain regions functionally connected to each FAS lesion using a connectome dataset from normative participants. Network maps were then overlapped to identify common network sites across the lesions. Results Classical lesion overlap analysis showed heterogeneity in lesion anatomical location, consistent with prior reports. However, at least 80% of lesions showed network overlap in the bilateral lower and middle portions of the precentral gyrus and in the medial frontal cortex. The left lower portion of the precentral gyrus is suggested to be the location of lesions causing apraxia of speech (AOS), and the middle portion is considered to be a larynx-specific motor area associated with the production of vowels and stop/nasal consonants and with the determination of pitch accent. Conclusions The lesions that cause FAS are anatomically heterogeneous, but they share a common functional network located in the bilateral posterior region of the frontal lobe. This network specifically includes not only the lower portion of the central gyrus, but also its middle region, which is referred to as the larynx motor cortex and is known to be associated with phonation. Our findings suggest that disrupted networks in FAS might be anatomically different from those in AOS.
... This is consistent with the theoretical framework of top-down and bottom-up mechanisms of general anesthetics mapping on to disruptions of content and level of consciousness, respectively ( Mashour and Hudetz, 2017 ). Second, the abrupt boost of subcorticocortical connectivity upon emergence (ROR) involved the brain stem, basal ganglia and thalamic nuclei that participate in the brainstemthalamocortical axis of arousal ( Akeju et al., 2014 ;Fischer et al., 2016 ;Giacino et al., 2014 ;Gili et al., 2013 ;Halassa et al., 2014 ;Halassa and Kastner, 2017 ;Hindman et al., 2018 ;Mhuircheartaigh et al., 2010 ;Song et al., 2017 ). The basal ganglia are also involved in regulating thalamocortical signal transmission ( Mhuircheartaigh et al., 2010 ;Schiff, 2010 ;Schiff et al., 2007 ) with the dorsal pallidum, in particular, regulating voluntary movement ( Gillies et al., 2017 ). ...
Article
Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.
... Two prerequisites for consciousness is the feeling of arousal and awareness. The part of the brainstem that allows one to retain consciousness is the rostral dorsolateral pontine tegmentum (at least in a study conducted by Harvard researchers) (Fischer et al. 2016). If this view is adopted, the difference between an artificial intelligence system and a human being is the concept of "consciousness". ...
Article
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This article discusses some of the issues surrounding artificial intelligence systems and whether artificial intelligence systems should be granted legal personhood. The first part of the article discusses whether current artificial intelligence systems should be granted rights and obligations, akin to a legal person. The second part of the article deals with imposing liability on artificial intelligence beings by analogising with incorporation and veil-piercing principles in company law. It examines this by considering that a future board may be replaced entirely by an artificial intelligence director managing the company. It also explores the possibility of disregarding the corporate veil to ascribe liability on such artificial intelligence beings and the ramifications of such an approach in the areas of fraud and crime.
... Il joue un rôle important dans l'éveil car une lésion de cette région induit un état végétatif irréversible [396]. Les neurones glutamatergiques présents dans ce noyau sont essentiels à la genèse de l'éveil, si l'on considère qu'ils innervent densément le télencéphale basal. ...
Thesis
Toxoplasma gondii est un parasite intra-cellulaire infectant près d’un tiers de la population mondiale. Généralement asymptomatique, la toxoplasmose est associée à une symptomatologie grave chez les patients immunodéprimés et dans le cas d’infection congénitale. Négligée par les pouvoirs publics, la phase chronique de l’infection a longtemps été sous-estimée. Cette méconnaissance entraîne donc des questions telles que quel est le meilleur protocole thérapeutique ? quelle est la meilleure stratégie diagnostique ? Récemment une stratégie de dissémination très avancée a été suspectée, sur la base de la théorie de la manipulation comportementale de l’hôte. Chez l’Homme, une telle manipulation peut avoir des effets majeurs cérébraux, neurologiques ou psychologiques. Quoi qu’il en soit, son impact sur le sommeil, qui constitue un index particulièrement sensible des fonctions cérébrales, est pour le moment inconnu. C’est pourquoi nous avons établi un modèle murin expérimental afin d’étudier les effets de Toxoplasma gondii sur le cycle éveil-sommeil. Nous avons montré que l’infection chronique par T. gondii était associée de manière persistante avec une augmentation de l’éveil et une diminution du sommeil, ce qui cadre avec la stratégie du parasite pour faciliter sa dissémination grâce à la prédation de son hôte. Nos résultats montrent pour la première fois les conséquences directes de l’infection toxoplasmique sur le comportement, pouvant avoir un impact majeur sur l’apparition de pathologies neuropsychiatriques et neurodégénératives.
... 19-97), where, in a state of flow, system one, dedicated to fast and unconscious processing of information, is rather active than system two, which is usually used for slow, effortful, and conscious tasks. Neuroscientific findings could also suggest that system one is generally representing arousal, while system two is representing awareness, and for the experience of consciousness, both have to be active (Fischer, et al., 2016). Lastly, markers seven and eight are directly referencing two of the three basic psychological needs, as described by White's effectance motivation theory (1959), Hunt's theory of optimal incongruity (1965), de Charms' personal causation theory (1968), and synthesized by Deci and Ryan (1980). ...
Thesis
DOWNLOAD HERE: https://nbn-resolving.org/urn:nbn:de:hbz:992-opus4-8362 Research on motivation may be alive and vital, but it is highly fragmented. This thesis discusses the most prevalent motivation theories and compares their ideas and concepts to introduce two new fields of research in this area: neurology and cardiology. The next era of motivation research will conflate concepts derived from behavioral approaches with organic substructure and elevate our understanding of motivation. A sound understanding of motivation allows organizational scholars to solve the motivational problem in the context of the organizational problem. To make proper use of promising novel insights in organizational contexts, we will revisit the current state of performance evaluation and their ability to coordinate and motivate individuals. By reconsidering how rewards crowd out intrinsic motivation via complex moods, and how superior intrinsic motivation increases performance compared to extrinsic motivation, this thesis introduces the motivation-potential model of feedback. Using a case study on a feedback-based management control system at a European e-commerce company based in Germany, we test how self-determination theory could be expanded by neurological concepts and quantitatively applied to design performance evaluation systems under the consideration of the motivation-potential model of feedback. In its entirety, this thesis attempts to build common ground for the future of motivation research and provides in-depth examples of theorization upon the aggregation of the field of research, as well as practical application and execution.
... Studies have reported that the presence of VENs in these two brain regions is associated with the capability of more complex cognition features. These neurons are important in selfregulation, self-awareness, and consciousness [20]. VENs have been suggested to be involved in the pathophysiology of several neuropsychiatric disorders that all show social-emotional deficits; a feature also present in MDD. ...
Article
Depression is the second leading cause of disability in the world. Despite developing some efficacious treatments, many patients do not respond to the treatment well due to the complexity of depression and unknown mechanisms involved in its pathogenesis. It has been reported that patients with major depressive disorder (MDD) experience autonomic dysfunctions in different aspects. Evidence suggests that modulation of the autonomic nervous system may improve depression. Von economo neurons (VENs) are shown to be involved in the pathophysiology of some of the neurological and psychological diseases. VENs are also important for the “ego” formation, sense of empathy, intuition, and cognition. These neurons express a high level of adrenoreceptor alpha 1a, which confirms their role in the autonomic function. Here, based on some evidence, I propose the hypothesis that these neurons may play a role in depression, possibly through being involved in the autonomic function. More focused studies on VENs and their possible role in depression is suggested in future. This pathway may open a new window in the treatment of depression.
... It has been theorized that the rmPFC and AI may comprise key neurocircuitry for visceromotor prediction or allostatic regulatory control (Stephan et al., 2016;Kleckner et al., 2017). These two regions are known to communicate directly with the midbrain homeostatic control system in the brainstem (Fischer et al., 2016), possibly via von Economo neurons, which are known to support rapid brain-body communications (Allman et al., 2010(Allman et al., , 2011. According to this view, the function of the rmPFC and AI would be to predict potential future homeostatic imbalance and prompt preventive physiological responses or behavioral actions. ...
Article
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People often engage in impression management by presenting themselves and others as socially desirable. However, specific behavioral manifestations and underlying neural mechanisms of impression management remain unknown. In this study, we investigated the neural mechanism of impression management during self-and friend-evaluation. Only participants assigned to the observation (OBS) group, not the control (CON) group, were informed that their responses would be monitored. They answered how well positive and negative trait adjectives described themselves or their friends. The behavioral results showed that the OBS group was more likely to reject negative traits for self-evaluation and to accept positive traits for friend-evaluation. An independent study revealed that demoting negative traits for oneself and promoting positive traits for a friend helps manage one's impression. In parallel with the behavioral results, in the OBS vs. the CON group, the rostromedial prefrontal cortex (RMPFC) and anterior insula (AI) activity showed a greater increase as the negativity of negatively valenced adjectives increased during self-evaluation and also showed a greater increase as the positivity of positively valenced adjectives increased during friend-evaluation. The present study suggests that RMPFC and AI are critically involved in impression management, promoting socially desirable target evaluations under social observation.
... Fischer et al identified and characterized a human brain network derived from coma-causing brainstem lesions and they found that a small region in the pontine was functionally connected to the insula and anterior cingulate cortex. [21] This demonstrated that there did exist a connectivity network between these areas. Hence, the brainstem damage may lead structure changes of the insula and anterior cingulate cortex. ...
Article
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The study aimed to explore the cortical thickness and gyrification abnormalities in acute brainstem ischemic patients in both the ipsilateral and contralateral hemisphere compared with healthy controls. Structural magnetic resonance imaging data were prospectively acquired in 48 acute brainstem ischemic patients, 21 patients with left lesion and 27 with right lesion, respectively. Thirty healthy controls were recruited. Cortical morphometry based on surface-based data analysis driven by CAT12 toolbox implemented in SPM12 was used to compare changes in cortical thickness and gyrification. Significant decreases of cortical thickness loss were found in bilateral cerebral hemispheres of the brainstem ischemic patients compared to the healthy controls (P < .05, family-wise error (FWE)-corrected). We also found significant gyrification decreases in the insula, transverse temporal, supramarginal of the ipsilateral on hemisphere in the right brainstem ischemic patients compared to the healthy controls (P < .05, FWE-corrected). Brainstem ischemic patients have widely morphological changes in the early phase and may be helpful in designing individualized rehabilitative strategies for these patients.
... More broadly, it is a generalpurpose method to estimate functional network deficits from clinical scans. [17][18][19][20][21][22] ...
Article
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Lesion network mapping estimates functional network abnormalities caused by a focal brain lesion. The method requires embedding the volume of the lesion into a normative functional connectome and using the average functional magnetic resonance imaging signal from that volume to compute the temporal correlation with all other brain locations. Lesion network mapping yields a map of potentially functionally disconnected regions. Although promising, this approach does not predict behavioral deficits well. We modified lesion network mapping by using the first principal component of the functional magnetic resonance imaging signal computed from the voxels within the lesioned area for temporal correlation. We measured potential improvements in connectivity strength, anatomical specificity of the lesioned network, and behavioral prediction in a large cohort of first-time stroke patients at 2-weeks post-injury (n = 123). This principal component functional disconnection approach localized mainly cortical voxels of high signal-to-noise; and it yielded networks with higher anatomical specificity, and stronger behavioral correlation than the standard method. However, when examined with a rigorous leave-one-out machine learning approach, principal component functional disconnection approach did not perform better than the standard lesion network mapping in predicting neurological deficits. In summary, even though our novel method improves the specificity of disconnected networks and correlates with behavioral deficits post-stroke, it does not improve clinical prediction. Further work is needed to capture the complex adjustment of functional networks produced by focal damage in relation to behavior.
... We didn't repeat our analysis using normative connectome without global signal regression because many lesion network mapping studies have already made comparisons between the results with global signal regression and those without. They found that results are robust to this preprocessing difference, and the identified networks are highly similar under both conditions (Boes et al. 2015;Ferguson et al. 2021;Cohen et al. 2019;Snider et al. 2020;Fischer et al. 2016). ...
Article
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Functional neuroimaging techniques have been widely used to probe the neural substrates of facial emotion processing in healthy people. However, findings are largely inconsistent across studies. Here, we introduce a new technique termed activation network mapping to examine whether heterogeneous functional magnetic resonance imaging findings localize to a common network for emotion processing. First, using the existing method of activation likelihood estimation meta-analysis, we showed that individual-brain-based reproducibility was low across studies. Second, using activation network mapping, we found that network-based reproducibility across these same studies was higher. Validation analysis indicated that the activation network mapping-localized network aligned with stimulation sites, structural abnormalities and brain lesions that disrupt facial emotion processing. Finally, we verified the generality of the activation network mapping technique by applying it to another cognitive process, that is, rumination. Activation network mapping may potentially be broadly applicable to localize brain networks of cognitive functions. Gong et al. introduce a new method, activation network mapping, for integration of neuroimaging findings.
... a | EEG was recorded for 10 s following alternating instructions of "keep opening and closing your right hand" (green) and "stop opening and closing your right hand" (red). b | Power spectral density (PSD) analysis was applied to the EEG recorded from each electrode in four frequency bands: delta (1-3 Hz), theta (4-7 Hz), alpha (8-13 Hz) and beta (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). c | Resulting features were used to train and test a machine learning algorithm (support vector machine). ...
Article
Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15–20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC.
... Regardless of the cause of the lesion, its size or precise location, evidence has accumulated over recent years in favor of the connectome hypothesis whereby the specific network(s) the lesion affects can predict many of the patient's responses across behavioral, cognitive or sensory-motor domains . A computational solution to map the lesion-driven disconnectivity to behavior was developed recently 1 , and it has been successfully applied to several conditions and pathologies 4,5,[7][8][9][10][11][12][13]15,16,18,19,[21][22][23] . Due to the simplicity of this method to correlate behavioral outcomes with the extent of lesion-driven disconnection, the strategy was referred to as Lesion Network Mapping (LNM). ...
Preprint
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Lesion network mapping (LNM) has proved to be a successful technique to map symptoms to brain networks after acquired brain injury. Beyond the characteristics of a lesion, such as its etiology, size or location, LNM has shown that common symptoms in patients after injury may reflect the effects of their lesions on the same circuits, thereby linking symptoms to specific brain networks. Here, we extend LNM to its multimodal form, using a combination of functional and structural connectivity maps drawn from data from 1000 healthy participants in the Human Connectome Project. We applied the multimodal LNM to a cohort of 54 stroke patients with the aim of predicting sensorimotor behavior, as assessed through a combination of motor and sensory tests. Test scores were predicted using a Canonical Correlation Analysis with multimodal brain maps as independent variables, and cross-validation strategies were employed to overcome overfitting. The results obtained led us to draw three conclusions. First, the multimodal analysis reveals how functional connectivity maps contribute more than structural connectivity maps in the optimal prediction of sensorimotor behavior. Second, the maximal association solution between the behavioral outcome and multimodal lesion connectivity maps suggests an equal contribution of sensory and motor coefficients, in contrast to the unimodal analyses where the sensory contribution dominates in both structural and functional maps. Finally, when looking at each modality individually, the performance of the structural connectivity maps strongly depends on whether sensorimotor performance was corrected for lesion size, thereby eliminating the effect of larger lesions that produce more severe sensorimotor dysfunction. By contrast, the maps of functional connectivity performed similarly irrespective of any correction for lesion size. Overall, these results support the extension of LNM to its multimodal form, highlighting the synergistic and additive nature of different types of imaging modalities, and the influence of their corresponding brain networks on behavioral performance after acquired brain injury.
... Plasticity in the brainstem is crucial for recovery from DOCs, especially from a coma. A comparison between focal brainstem lesions causing or not causing coma in humans identified a specific region significantly associated with coma in the left rostral dorsolateral pontine tegmentum near the medial parabrachial nucleus (Fischer et al., 2016). This region was affected in 10/12 brainstem lesions causing coma, and the lesions that spared this region involved the midbrain immediately rostral to it. ...
Chapter
Disorders of consciousness (DOCs), i.e., coma, vegetative state, and minimally conscious state are the consequences of a severe brain injury that disrupts the brain ability to generate consciousness. Recovery from DOCs requires functional and structural changes in the brain. The sites where these plastic changes take place vary according to the pathophysiology of the DOC. The ascending reticular activating system of the brainstem and its complex connections with the thalamus and cortex are involved in the pathophysiology of coma. Subcortical structures, such as the striatum and globus pallidus, together with thalamocortical and corticothalamic projections, the basal forebrain, and several networks among different cortical areas are probably involved in vegetative and minimally conscious states. Some mechanisms of plasticity that allegedly operate in each of these sites to promote recovery of consciousness will be discussed in this chapter. While some mechanisms of plasticity work at a local level, others produce functional changes in complex neuronal networks, for example by entraining neuronal oscillations. The specific mechanisms of brain plasticity represent potential targets for future treatments aiming to restore consciousness in patients with severe DOCs.
... First, despite a relatively large hemorrhage -dissecting through the right pons-midbrain tegmentum, with edema extending partly across the midline and well into the midbrain -he never lost consciousness. Hemorrhages and other lesions in the pons-midbrain tegmentum frequently produce coma [4,5], but loss of consciousness may be more common after bilateral or leftsided lesions [8,9]. ...
Article
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The upper brainstem tegmentum is dense and complex, making it difficult to localize functions to specific subregions. In particular, the precise location and possible laterality of subregions supporting basic functions like consciousness and urinary continence remain unclear. Here, we describe a patient who presented with a right pontine tegmental syndrome caused by intraparenchymal hemorrhage. Despite hemorrhage extension into the fourth ventricle and expansion of both hemorrhage and edema into a large region of the caudal midbrain and right-sided pontine tegmentum, this patient did not lose consciousness. Instead, he developed new and total urinary retention, with residual bladder volumes of more than 1,000 mL. We conclude that injury to the right pontine tegmentum is sufficient to disrupt the micturition reflex pathway.
... In the present case, widespread white matter tracts, cortical, subcortical, and pontin regions were damaged. Interestingly some lesions were localised on regions identified as a potential key neural structure necessary to awareness, the posterior brainstem that includes the ascending reticular system and the subinsular regions that includes the claustrum, a narrow grey matter structure massively connected to distant associative cortices [45][46][47]. Here, brainstem dysfunction was confirmed both by an alteration of the brainstem auditory evoked potentials and by clinical evidence (skew deviation and left internuclear ophthalmoplegia). ...
Article
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Predicting the functional recovery of patients with severe neurological condition due to coronavirus disease 2019 (COVID-19) is a challenging task. Only limited outcome data are available, the pathophysiology is poorly understood, and the time-course of recovery is still largely unknown. Here, we report the case of a patient with COVID-19 associated encephalitis presenting as a prolonged state of unresponsiveness for two months, who finally fully recovered consciousness, functional communication, and autonomy after immunotherapy. In a multimodal approach, a high-density resting state EEG revealed a rich brain activity in spite of a severe clinical presentation. Using our previously validated algorithms, we could predict a possible improvement of consciousness in this patient. This case report illustrates the value of a multimodal approach capitalizing on advanced brain-imaging and bedside electrophysiology techniques to improve prognosis accuracy in this complex and new aetiology.
... What is more, localized microinjection of minute quantities of opiates into the brainstem PAG yields selective whole-body analgesia and microinjecting GABAergic anesthetics into the brainstem MPTA (mesopontine tegmental anesthesia area) yields LOC including insensitivity to noxious stimuli [96][97][98][99]. Most telling of all, localized lesions in the dorsal mesopontine tegmentum readily induce LOC in animals and humans, and lesions limited to the MPTA render animals relatively insensitive to otherwise clinically effective doses of anaesthetics delivered systemically [90,91,[100][101][102]. ...
Article
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Doubtless, the conscious brain integrates masses of information. But declaring that consciousness simply "emerges" when enough has accumulated, doesn't really explain how first person experience is implemented by neurons. Moreover, empirical observations challenge integrated information theory's (IIT) reliance on thalamo-cortical interactions as the information integrator. More likely, the cortex streams processed information to a still-enigmatic consciousness generator, one perhaps located in the brainstem.
... What is more, localized microinjection of minute quantities of opiates into the brainstem PAG yields selective whole-body analgesia and microinjecting GABAergic anesthetics into the brainstem MPTA (mesopontine tegmental anesthesia area) yields LOC including insensitivity to noxious stimuli [96][97][98][99]. Most telling of all, localized lesions in the dorsal mesopontine tegmentum readily induce LOC in animals and humans, and lesions limited to the MPTA render animals relatively insensitive to otherwise clinically effective doses of anaesthetics delivered systemically [90,91,[100][101][102]. ...
Article
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It is nearly axiomatic that pain, among other examples of conscious experience, is an outcome of still-uncertain forms of neural processing that occur in the cerebral cortex, and specifically within thalamo-cortical networks. This belief rests largely on the dramatic relative expansion of the cortex in the course of primate evolution, in humans in particular, and on the fact that direct activation of sensory representations in the cortex evokes a corresponding conscious percept. Here we assemble evidence, drawn from a number of sources, suggesting that pain experience is unlike the other senses and may not, in fact, be an expression of cortical processing. These include the virtual inability to evoke pain by cortical stimulation, the rarity of painful auras in epileptic patients and outcomes of cortical lesions. And yet, pain perception is clearly a function of a conscious brain. Indeed, it is perhaps the most archetypical example of conscious experience. This draws us to conclude that conscious experience, at least as realized in the pain system, is seated subcortically, perhaps even in the “primitive” brainstem. Our conjecture is that the massive expansion of the cortex over the course of evolution was not driven by the adaptive value of implementing consciousness. Rather, the cortex evolved because of the adaptive value of providing an already existing subcortical generator of consciousness with a feed of critical information that requires the computationally intensive capability of the cerebral cortex.
... During dreamless sleep, the brainstem prevents the free energy that is available to the cortical areas through a variety of neural transmitters [171]. Likewise, arousal and awareness disruptions of consciousness in the cortical regions, specifically the left, ventral, anterior insula, and anterior cingulate cortex regions of comatose patients, is regulated by the brainstem through the rostral dorsolateral pontine tegmentum [172]. Similar events take place during diabetic conditions and head trauma, where the loss of metabolic energy, due to the disturbance of the synthesis of adenosine triphosphoric acid (ATP), can result in free energy changes. ...
Chapter
It is a century-old view that experiential philosophies are not compatible with materialism. In the contextual inconsistency with the reality, that matter is inertly acquiring only a single physical state, philosophers have gained ground in metaphysical beliefs, including dualism, monism, and idealism. We show that a new foundational self-referential identity theory of the mind is needed to bridge the explanatory gap. Panexperiential materialism is a new materialistic framework originating in the spectral domain of matter-wave energy quanta transcending the barrier of thermoquantal information, isomorphically aligning with consciousness. The holistic nature of its instantiation is panexperiential due to the composite states of non-inert matter, depending crucially on their interrelations without embracing essentialist ontology, further entwined with epistemic teleofunctionalism and informational relationalism, and based on the research agenda, concepts, and shared values of quantum chemistry. Panexperiential materialism is characterized by a spectral matter-wave structure, which is conjugate to the prescriptive structural properties of the spacetime domain. Yet panexperiential materialism is not contrary to ordinary materialism, although the latter may be fundamentally grounded in molecular networks. The phenomenology of consciousness is not merely a mental reification in the first-person perspective. The proper guideline should be the reduction of conscious processes to nonreductive physical correlates in the brain. The wet and hot environment of the brain affords quantum-thermal correlations in a transcending energy processing zone where quantum and classical fluctuations are fused to thermoquantal information. The quantum chemical basis incorporates non-self-adjoint analytic extensions in Liouville space and associated Fourier-Laplace transforms that conjoin energy, time, entropy, and temperature. The transformation across hierarchical thermodynamical domains is caused by the negentropic gain wholly implicated by the entropy production arising in the energy exchange resulting in the transformation of information forming informational holarchies, driven by nonlocal teleological mechanisms. The information transformation from the objective to the subjective is a process that is quantum in nature. The process of non-integrated information, actualizing the information-based action as a teleological process of cognition in the entailment of preconscious experientialities, should not be conflated with the experience itself, but rather as an isomorphic connection between mind and brain via the Fourier-Laplace transformation. Our holistic viewpoint denies the existence of integrated information as an emergentist ontology, instead advocating the canonical transformations B and B† as the syntax or universal grammar for intrinsic information (proto-communication). The irreducible character of an informational holarchy where the whole is affected non-synergistically by the non-integrated information is how intrinsic information encapsulates the energy transformation from fusing thermal and quantum fluctuations that result in long-range correlations (phase wave) that constitutes the fundamental dynamics of physical feelings. In panexperiential materialism, there is no issue dividing holists and reductionists, concerning the issue whether the whole or the discrete parts are primary, but rather their interrelations. This relationalism is pivotal in understanding how non-integrated information holistically concresce. Although we consider matter waves to be fundamental, one might say, avoiding the trap of eliminative materialism, that the brain is conjugate to the mind and vice versa.
... For those remining in DoC recovery will continue for several years, but the odds of substantive recovery incrementally decreasing each year thereafter [7]. Recovery from DoC is described by a gradient of consciousness where less consciousness is associated with more disruption of functional and structural neural connectivity [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. While the gradient is delineated clinically as the vegetative state (VS), minimally conscious state (MCS), and emergence from MCS (eMCS) recovery [22][23][24][25], is not necessarily a linear progression along this gradient [13,[26][27][28]. ...
Article
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The purpose of this study is to describe the clinical lifeworld of rehabilitation practitioners who work with patients in disordered states of consciousness (DoC) after severe traumatic brain injury (TBI). We interviewed 21 practitioners using narrative interviewing methods from two specialty health systems that admit patients in DoC to inpatient rehabilitation. The overarching theme arising from the interview data is "Experiencing ambiguity and uncertainty in clinical reasoning about consciousness" when treating persons in DoC. We describe practitioners' practices of looking for consistency, making sense of ambiguous and hard to explain patient responses, and using trial and error or "tinkering" to care for patients. Due to scientific uncertainty about diagnosis and prognosis in DoC and ambiguity about interpretation of patient responses, working in the field of DoC disrupts the canonical meaning-making processes that practitioners have been trained in. Studying the lifeworld of rehabilitation practitioners through their story-making and story-telling uncovers taken-for-granted assumptions and normative structures that may exist in rehabilitation medical and scientific culture, including practitioner training. We are interested in understanding these canonical breaches in order to make visible how practitioners make meaning while treating patients.
... With the advent of sophisticated functional neuroimaging and electroencephalography (EEG)-based technologies [12][13][14][15][16][17][18][19][20][21], new states have been described that defy established neurological paradigms [7]. These include cognitive motor dissociation (CMD), that is, the presence of brain modulation in response to verbal commands during functional magnetic resonance imaging (fMRI) and EEG despite the absence of volitional responsiveness at the bedside [22], and higher-order cortex motor dissociation, also termed "covert cortical processing" [23], that is, fMRI and EEG evidence of association cortex activity to passive stimuli in clinically low or unresponsive patients [22]. ...
Article
Background Consciousness in patients with brain injury is traditionally assessed based on semiological evaluation at the bedside. This classification is limited because of low granularity, ill-defined and rigid nomenclatures incompatible with the highly fluctuating nature of consciousness, failure to identify specific brain states like cognitive motor dissociation, and neglect for underlying biological mechanisms. Here, the authors present a pragmatic framework based on consciousness endotypes that combines clinical phenomenology with all essential physiological and biological data, emphasizing recovery trajectories, therapeutic potentials and clinical feasibility.Methods The Neurocritical Care Society’s Curing Coma Campaign identified an international group of experts who convened in a series of online meetings between May and November 2020 to discuss and propose a novel framework for classifying consciousness.ResultsThe expert group proposes Advanced Classification of Consciousness Endotypes (ACCESS), a tiered multidimensional framework reflecting increasing complexity and an aspiration to consider emerging and future approaches. Tier 1 is based on clinical phenotypes and structural imaging. Tier 2 adds functional measures including EEG, PET and functional MRI, that can be summarized using the Arousal, Volition, Cognition and Mechanisms (AVCM) score (where “Volition” signifies volitional motor responses). Finally, Tier 3 reflects dynamic changes over time with a (theoretically infinite) number of physiologically distinct states to outline consciousness recovery and identify opportunities for therapeutic interventions.Conclusions Whereas Tiers 1 and 2 propose an approach for low-resource settings and state-of-the-art expertise at leading academic centers, respectively, Tier 3 is a visionary multidimensional consciousness paradigm driven by continuous incorporation of new knowledge while addressing the Curing Coma Campaign’s aspirational goals.
Article
Purpose of review: In the study of brain-injured patients with disorders of consciousness (DoC), structural and functional MRI seek to provide insights into the neural correlates of consciousness, identify neurophysiologic signatures of covert consciousness, and identify biomarkers for recovery of consciousness. Recent findings: Cortical volume, white matter volume and integrity, and structural connectivity across many grey and white matter regions have been shown to vary with level of awareness in brain-injured patients. Resting-state functional connectivity (rs-FC) within and between canonical cortical networks also correlates with DoC patients' level of awareness. Stimulus-based and motor-imagery fMRI paradigms have identified some behaviorally unresponsive DoC patients with cortical processing and activation patterns that mirror healthy controls. Emerging techniques like dynamic rs-FC have begun to identify temporal trends in brain-wide connectivity that may represent novel neural correlates of consciousness. Summary: Structural and functional MRI will continue to advance our understanding of brain regions supporting human consciousness. Measures of regional and global white matter integrity and rs-FC in particular networks have shown significant improvement over clinical features in identifying acute and chronic DoC patients likely to recover awareness. As they are refined, functional MRI paradigms may additionally provide opportunities for interacting with behaviorally unresponsive patients.
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Background Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients. Methods This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < −3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU). Results A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, p = 0.034) and cough reflexes (OR 5.12, p = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92–14.1], p = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64–30.0], p = 0.0004). Conclusion Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation.
Chapter
DESCRIPTION Scientists continue to delve on sure grounds into the secrets of the mind and, finishing this essay, we return to consider a few significant novel observations. These advances steered us to assemble and refine the image we have been sketching, then confirmed how the result is a perfectly consistent and useful theoretical framework, from which the latest experiments certainly suggest new paths. Furthermore, this chapter plays the role of an epilogue, finally emphasizing how the facts strongly endorse that, like systems in a traditional physics laboratory, the brain displays phases conforming to mental states; it moves—naturally and irregularly—through and between them, and it continually looks for criticality.
Article
Background In patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (“arousal nuclei”) are implicated in coma pathogenesis and are compatible with coma recovery. Methods We mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 Tesla susceptibility-weighted images (SWI) in twelve patients with acute severe TBI who presented in coma and recovered consciousness within six months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at six months. Results There was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%) and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within non-arousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale-Extended scores. Conclusions These results suggest resilience of arousal mechanisms in the human brain after severe TBI.
Chapter
Despite the prevalence of anhedonia across multiple psychiatric disorders, its relevance to treatment selection and prognostication can be unclear (Davey et al., Psychol Med 42(10):2071-81, 2012). Given the challenges in pharmacological and psychosocial treatment, there has been increasing attention devoted to neuroanatomically-targeted treatments. This chapter will present a brief introduction to circuit-targeted therapeutics in psychiatry (Sect. 1), an overview of brain mapping as it relates to anhedonia (Sect. 2), a review of existing studies on brain stimulation for anhedonia (Sect. 3), and a description of emerging approaches to circuit-based neuromodulation for anhedonia (Sect. 4).
Article
Spontaneous intracranial hypotension typically manifests with orthostatic headaches and is caused by spinal dural tears, ruptured meningeal diverticula, or CSF-venous fistulas. While most patients are diagnosed and treated in the outpatient setting, some patients will occasionally present in the emergent ICU setting due to subdural hematomas, coma, or downward brain herniation. In this review paper, we will discuss the diagnostic and treatment steps that intensivists can undertake to coordinate a team approach to successfully manage these patients. A brief general overview of spontaneous intracranial hypotension will also be discussed.
Article
Major advances have been made over the past few decades in identifying and managing disorders of consciousness (DOC) in patients with acquired brain injury (ABI), bringing the transformation from a conceptualized definition to a complex clinical scenario worthy of scientific exploration. Given the continuously-evolving framework of precision medicine that integrates valuable behavioral assessment tools, sophisticated neuroimaging, and electrophysiological techniques, a considerably higher diagnostic accuracy rate of DOC may now be reached. During the treatment of patients with DOC, a variety of intervention methods are available, including amantadine and transcranial direct current stimulation, which have both provided class II evidence, zolpidem, which is also of high quality, and non-invasive stimulation, which appears to be more encouraging than pharmacological therapy. However, heterogeneity is profoundly ingrained in study designs, and only rare schemes have been recommended by authoritative institutions. There is still a lack of an effective clinical protocol for managing patients with DOC following ABI. To advance future clinical studies on DOC, we present a comprehensive review of the progress in clinical identification and management as well as some challenges in the pathophysiology of DOC. We propose a preliminary clinical decision protocol, which could serve as an ideal reference tool for many medical institutions.
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In this paper, I review the case of Jahi McMath, who was diagnosed with brain death (BD). Nonetheless, ancillary tests performed nine months after the initial brain insult showed conservation of intracranial structures, EEG activity, and autonomic reactivity to the “Mother Talks” stimulus. She was clinically in an unarousable and unresponsive state, without evidence of self-awareness or awareness of the environment. However, the total absence of brainstem reflexes and partial responsiveness rejected the possibility of a coma. Jahi did not have uws because she was not in a wakefulness state and showed partial responsiveness. She could not be classified as a LIS patient either because LIS patients are wakeful and aware, and although quadriplegic, they fully or partially preserve brainstem reflexes, vertical eye movements or blinking, and respire on their own. She was not in an MCS because she did not preserve arousal and preserved awareness only partially. The CRS-R resulted in a very low score, incompatible with MCS patients. mcs patients fully or partially preserve brainstem reflexes and usually breathe on their own. MCS has always been described as a transitional state between a coma and UWS but never reported in a patient with all clinical BD findings. This case does not contradict the concept of BD but brings again the need to use ancillary tests in BD up for discussion. I concluded that Jahi represented a new disorder of consciousness, non-previously described, which I have termed “reponsive unawakefulness syndrome” (RUS).
Chapter
Brain lesions, such as the ones caused by stroke or tumors, disrupt normal brain function and cause a wide spectrum of neurological and psychiatric symptoms. Studying brain lesions has formed the foundation for localization of symptoms throughout the history of neurology, providing unique causal evidence. In exceedingly rare cases, spontaneous brain lesions can improve pre-existing symptoms, which is referred to as paradoxical functional facilitation. Iatrogenic brain lesions can provide similar functional benefit. Both types of lesions have helped lead to identification of deep brain stimulation targets. However, paradoxical functional facilitation is rare and lesions improving similar symptoms can occur in multiple different neuroanatomical locations, leaving the optimal treatment target unclear. Emerging new techniques combining causal and beneficial brain lesions with the human connectome have opened the door for systematic search of new and improved therapeutic targets for functional neurosurgery.
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How do we incorporate contextual information to infer others’ emotional state? Here we employed a naturalistic context-dependent facial expression estimation task where participants estimated pleasantness levels of others’ ambiguous expression faces when sniffing different contextual cues (e.g., urine, fish, water, and rose). Based on their pleasantness rating data, we placed participants on a context-dependency continuum and mapped the individual variability in the context-dependency onto the neural representation using a representational similarity analysis. We found that the individual variability in the context-dependency of facial expression estimation correlated with the activity level of the pregenual anterior cingulate cortex (pgACC) and the amygdala and was also decoded by the neural representation of the ventral anterior insula (vAI). A dynamic causal modeling revealed that those with higher context-dependency exhibited a greater degree of the modulation from vAI to the pgACC. These findings provide novel insight into the neural circuitry associated with the individual variability in context-dependent facial expression estimation and the first empirical evidence for individual variability in the predictive accounts of affective states.
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Preprint
The substantial individual heterogeneity that characterizes mental illness is often ignored by classical case-control designs that rely on group mean comparisons. Here, we present a comprehensive, multiscale characterization of individual heterogeneity of brain changes in 1294 cases diagnosed with one of six conditions and 1465 matched healthy controls. Normative models identified that person-specific deviations from population expectations for regional grey matter volume were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience/ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia, and ADHD. Our findings indicate that while phenotypic differences between cases assigned the same diagnosis may arise from heterogeneity in the location of regional deviations, phenotypic similarities are attributable to dysfunction of common functional circuits and networks.
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Mapping human brain function is a long-standing goal of neuroscience that promises to inform the development of new treatments for brain disorders. Early maps of human brain function were based on locations of brain damage or brain stimulation that caused a functional change. Over time, this approach was largely replaced by technologies such as functional neuroimaging, which identify brain regions in which activity is correlated with behaviours or symptoms. Despite their advantages, these technologies reveal correlations, not causation. This creates challenges for interpreting the data generated from these tools and using them to develop treatments for brain disorders. A return to causal mapping of human brain function based on brain lesions and brain stimulation is underway. New approaches can combine these causal sources of information with modern neuroimaging and electrophysiology techniques to gain new insights into the functions of specific brain areas. In this Review, we provide a definition of causality for translational research, propose a continuum along which to assess the relative strength of causal information from human brain mapping studies and discuss recent advances in causal brain mapping and their relevance for developing treatments. In this Review, Siddiqi et al. examine causal approaches to mapping human brain function. They provide a definition of causality for translational research, propose a framework for assessing causality strength in brain mapping studies and cover advances in techniques and their use in developing treatments for brain disorders.
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A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liège) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 ± 18 years, range 11-87; 16 traumatic, 32 non-traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post-insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each network's capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale-Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Objective: Neuroimaging studies using a variety of techniques have been conducted in sleep to explore the changes in brain activity during the different sleep stages. The current study employed a quantitative meta-analytic technique in an attempt to integrate the findings from such studies. Methods: Using an updated version of the Activation Likelihood Estimation (ALE) method, individual meta-analyses were carried out on: 1) studies contrasting REM sleep and wake-fulness, and 2) studies contrasting NREM sleep and wakefulness. Results: Based on the results of the current meta-analyses, a number of cortical and subcortical brain regions appear to be involved in sleep and sleep processes, with both decreases and increases noted across NREM and REM sleep. Specifically, areas of decreased activity comprised thalamic structures (pulvinar, dorsomedial thalamus) and frontal regions (inferior, superior, and middle frontal gyrus). Furthermore, increased and decreased activity was noted in the anterior cingulate during sleep. Conclusions: Despite limited overlap across these sleep stages among regions identified, consistent decreases were revealed in NREM sleep (thalamus) and REM sleep (frontal cortex) when compared to wakefulness. Such findings suggest that these regions may ultimately play a key role in the loss of consciousness characteristic of sleep. Further research is needed to determine if and how such activity may be related to dreaming.
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In resting-state functional magnetic resonance imaging (fMRI), functional connectivity measures can be influenced by the presence of a strong global component. A widely used pre-processing method for reducing the contribution of this component is global signal regression, in which a global mean time series signal is projected out of the fMRI time series data prior to the computation of connectivity measures. However, the use of global signal regression is controversial because the method can bias the correlation values to have an approximately zero mean and may in some instances create artifactual negative correlations. In addition, while many studies treat the global signal as a non-neural confound that needs to be removed, evidence from electrophysiological and fMRI measures in primates suggests that the global signal may contain significant neural correlates. In this study, we used simultaneously acquired fMRI and electroencephalographic (EEG) measures of resting-state activity to assess the relation between the fMRI global signal and EEG measures of vigilance in humans. We found that the amplitude of the global signal (defined as the standard deviation of the global signal) exhibited a significant negative correlation with EEG vigilance across subjects studied in the eyes-closed condition. In addition, increases in EEG vigilance due to the ingestion of caffeine were significantly associated with both a decrease in global signal amplitude and an increase in the average level of anti-correlation between the default mode network and the task-positive network.
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A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.
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It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his "autobiographical self", the patient's SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices.
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Intrinsic functional connectivity detected by functional MRI (fMRI) provides a useful but indirect approach to study the organization of human brain systems. An unresolved question is whether functional connectivity measured by resting-state fMRI reflects anatomical connections. In this study, we used the well-characterized anatomy of cerebrocerebellar circuits to directly test whether intrinsic functional connectivity is associated with an anatomic pathway. Eleven first-episode stroke patients were scanned five times during a period of 6 months, and 11 healthy control subjects were scanned three times within 1 month. In patients with right pontine strokes, the functional connectivity between the right motor cortex and the left cerebellum was selectively reduced. This connectivity pattern was reversed in patients with left pontine strokes. Although factors beyond anatomical connectivity contribute to fMRI measures of functional correlation, these results provide direct evidence that functional connectivity depends on intact connections within a specific polysynaptic pathway.
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Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.
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Human anterior cingulate and frontoinsular cortices participate in healthy social-emotional processing. These regions feature 2 related layer 5 neuronal morphotypes, the von Economo neurons and fork cells. In this paper, we review the historical accounts of these neurons and provide a German-to-English translation of von Economo's seminal paper describing the neurons which have come to bear his name. We close with a brief discussion regarding the functional and clinical relevance of these neurons and their home regions.
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Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a 'network inhibition hypothesis' in which temporal lobe seizures disrupt brainstem-diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1-2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
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The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex in great apes and humans, but not other primates. We performed stereological counts of the VENs in FI and LA (limbic anterior, a component of anterior cingulate cortex) in great apes and in humans. The VENs are more numerous in humans than in apes, although one gorilla approached the lower end of the human range. We also examined the ontological development of the VENs in FI and LA in humans. The VENs first appear in small numbers in the 36th week post-conception, are rare at birth, and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than in the left in FI and LA in postnatal brains of apes and humans. This asymmetry in VEN numbers may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, which contains FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. The VENs appear to be projection neurons, although their targets are unknown. We made a preliminary study of the connections of FI cortex based on diffusion tensor imaging in the brain of a gorilla. The VEN-containing regions connect to the frontal pole as well as to other parts of frontal and insular cortex, the septum, and the amygdala. It is likely that the VENs in FI are projecting to some or all of these structures and relaying information related to autonomic control, decision-making, or awareness. The VENs selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing peptide (GRP) which are also expressed in another population of closely related neurons, the fork cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations may be related to the VEN and fork cells and may be involved in the regulation of appetite. The loss of these cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. We found that the protein encoded by the gene DISC1 (disrupted in schizophrenia) is preferentially expressed by the VENs. DISC1 has undergone rapid evolutionary change in the line leading to humans, and since it suppresses dendritic branching it may be involved in the distinctive VEN morphology.
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There is now a wealth of evidence that anterior insular and anterior cingulate cortices have a close functional relationship, such that they may be considered together as input and output regions of a functional system. This system is typically engaged across cognitive, affective, and behavioural contexts, suggesting that it is of fundamental importance for mental life. Here, we review the literature and reinforce the case that these brain regions are crucial, firstly, for the production of subjective feelings and, secondly, for co-ordinating appropriate responses to internal and external events. This model seeks to integrate higher-order cortical functions with sensory representation and autonomic control: it is argued that feeling states emerge from the raw data of sensory (including interoceptive) inputs and are integrated through representations in conscious awareness. Correspondingly, autonomic nervous system reactivity is particularly important amongst the responses that accompany conscious experiences. Potential clinical implications are also discussed.
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The 'default network' is defined as a set of areas, encompassing posterior-cingulate/precuneus, anterior cingulate/mesiofrontal cortex and temporo-parietal junctions, that show more activity at rest than during attention-demanding tasks. Recent studies have shown that it is possible to reliably identify this network in the absence of any task, by resting state functional magnetic resonance imaging connectivity analyses in healthy volunteers. However, the functional significance of these spontaneous brain activity fluctuations remains unclear. The aim of this study was to test if the integrity of this resting-state connectivity pattern in the default network would differ in different pathological alterations of consciousness. Fourteen non-communicative brain-damaged patients and 14 healthy controls participated in the study. Connectivity was investigated using probabilistic independent component analysis, and an automated template-matching component selection approach. Connectivity in all default network areas was found to be negatively correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative then coma patients. Furthermore, precuneus connectivity was found to be significantly stronger in minimally conscious patients as compared with unconscious patients. Locked-in syndrome patient's default network connectivity was not significantly different from controls. Our results show that default network connectivity is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment. Future prospective studies in a larger patient population are needed in order to evaluate the prognostic value of the presented methodology.
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The claustrum is a thin, irregular, sheet-like neuronal structure hidden beneath the inner surface of the neocortex in the general region of the insula. Its function is enigmatic. Its anatomy is quite remarkable in that it receives input from almost all regions of cortex and projects back to almost all regions of cortex. We here briefly summarize what is known about the claustrum, speculate on its possible relationship to the processes that give rise to integrated conscious percepts, propose mechanisms that enable information to travel widely within the claustrum and discuss experiments to address these questions.
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Seven cases of the "locked-in" syndrome are described. This is a disorder in which a conscious, mute patient is completely paralysed apart from some form of eye movement, usually as a result of an infarct in the ventral pons. Such patients are often assumed to be in coma and as a result may be distressed by inappropriate conversation around the bedside.
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The projection from the parabrachial nucleus (PB) to the cerebral cortex in the rat was studied in detail using the autoradiographic method for tracing anterograde axonal transport and the wheat germ agglutinin-horseradish peroxidase (WGA-HRP) method for both anterograde and retrograde tracing. PB innervates layers I, V and VI of a continuous sheet of cortex extending from the posterior insular cortex caudally, through the dorsal agranular and the granular anterior insular cortex and on rostrally into the lateral prefrontal cortex. Within the prefrontal area, PB fibers innervate primarily layer V of the ventrolateral cortex caudally, but more rostrally the innervated region includes progressively more dorsal portions of the prefrontal area, until by the frontal pole the entire lateral half of the hemisphere is innervated. This projection originates for the most part in a cluster of neurons in the caudal ventral part of the medial PB subdivision, although a few neurons in the adjacent parts of the PB, the Kolliker-Fuse nucleus and the subcoeruleus region also participate. After injection of WGA-HRP into the PB region, retrogradely labeled neurons were found in layer V of the same cortical areas which receive PB inputs. The importance of this monosynaptic reciprocal brainstem-cortical projection as a possible anatomical substrate for the regulation of cortical arousal is discussed.
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Hypertension intracerebral hemorrhages are caused by leakage from small penetrating branches of larger cerebral vessels. In the brainstem, these vessels penetrate in a median, paramedian, and more lateral orientation. As illustrated by three patients reported here, hemorrhage from the lateral vessels may be limited to the lateral tegmentum, or spread to the dorsal basis pontis. The syndrome is relatively consistent and includes (1) ipsilateral conjugate gaze palsy, (2) ipsilateral internuclear ophthalmoplegia, (3) small reactive pupils with a smaller pupil ipsilateral to the lesion, (4) limb ataxia of the cerebellar type (often greater ipsilaterally), (5) contralateral hemiplegia, and (6) contralateral severe hemisensory loss. Patients frequently survive after lateral tegmental hemorrhages, which can be diagnosed by CT.
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The efferent connections of the parabrachial nucleus have been analyzed in the rat using the anterograde autoradiographic method. Fibers originating from the lateral parabrachial nucleus (PBI) ascend in the periventricular system, the dorsal tegmental bundle and the central tegmental tract. The PBl projects to the dorsal raphe nucleus, the superior central raphe nucleus, and the Edinger-Westphal nucleus. It also innervates the intralaminar (centromedian, centrolateral, paracentral, parafascicular), the midline (paraventricular, reuniens), and the ventromedial basal (VMb) thalamic nuclei as well as much of the hypothalamus, including the dorsomedial, the ventromedial, the arcuate and the paraventricular nuclei, the lateral hypothalamic and the lateral preoptic areas. The PBl sends fibers via the ansa peduncularis into the amygdala, innervating the anterior, the central, the medial, the basomedial, and the posterior basolateral nuclei. In addition, it projects to the lateral part of the bed nucleus of the stria terminalis. Descending PBl fibers travel mainly through the ventrolateral medulla, passing through the region of the A1 and A5 catecholamine cell groups, the ventrolateral reticular formation and the region that contains parasympathetic preganglionic neurons. A small component travels in Probst's bundle to the ventral part of the nucleus of the solitary tract. Only a few PBl axons continue caudally into the lateral funiculus of the spinal cord, but these could not be followed beyond the first few cervical segments.
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To evaluate changes in arousal and their impact on memory performance during the intracarotid amobarbital test (IAT). Along with memory measures, level of arousal was evaluated through clinical ratings and nonverbal self-ratings in epilepsy patients undergoing IAT before anterior temporal lobectomy. Irrespective of seizure focus, left-sided amobarbital injection resulted in decreased objective and subjective arousal more often than right-side injection. Impaired objective arousal was greater when the left hemisphere was injected second, because of the presumed additive effects of systemic amobarbital residual from the first injection. Decreased objective arousal was related to poorer performance on memory testing following left-hemisphere injection. The IAT, as practiced in most centers, is biased, so patients with right temporal lobe seizure focus are more likely to "pass" the test, whereas patients with left seizure focus are more likely to "fail" the test. The significant impact of changes in arousal on memory testing needs to be considered when using IAT results to select patients for temporal lobectomy.
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ONE ASPECT of the relation of the brain to the mind which may be contributed to by experimental study is concerned with the neural management of wakefulness. The waking state is certainly not essential to mental activity, for in the lighter stages of sleep vivid impressions may be experienced as dreams. In states of deep sleep, unconsciousness, or coma, however, mental activity seems practically in abeyance, and interrelations of the two have been expressed succinctly by Sherrington, in concluding a moving account of arousal from sleep, with the statement, "The brain is awakening and, with it, the mind returning." The waking state has generally been thought to depend in an important fashion upon the arousing influence at the cerebral cortex of afferent messages initiated by sensory stimulation. It is a commonplace observation that afferent impulses from within or without can arouse a sleeping subject, and reduction of sensory impressions is