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1.
Brain ; 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33188680

RESUMO

The functional consequences of focal brain injury are thought to be contingent on neuronal alterations extending beyond the area of structural damage. This phenomenon, also known as diaschisis, has clinical and metabolic correlates but lacks a clear electrophysiological counterpart, except for the long-standing evidence of a relative EEG slowing over the injured hemisphere. Here, we aim at testing whether this EEG slowing is linked to the pathological intrusion of sleep-like cortical dynamics within an awake brain. We used a combination of transcranial magnetic stimulation and electroencephalography (TMS/EEG) to study cortical reactivity in a cohort of 30 conscious awake patients with chronic focal and multifocal brain injuries of ischaemic, haemorrhagic and traumatic aetiology. We found that different patterns of cortical reactivity typically associated with different brain states (coma, sleep, wakefulness) can coexist within the same brain. Specifically, we detected the occurrence of prominent sleep-like TMS-evoked slow waves and off-periods-reflecting transient suppressions of neuronal activity-in the area surrounding focal cortical injuries. These perilesional sleep-like responses were associated with a local disruption of signal complexity whereas complex responses typical of the awake brain were present when stimulating the contralesional hemisphere. These results shed light on the electrophysiological properties of the tissue surrounding focal brain injuries in humans. Perilesional sleep-like off-periods can disrupt network activity but are potentially reversible, thus representing a principled read-out for the neurophysiological assessment of stroke patients, as well as an interesting target for rehabilitation.

2.
Brain Stimul ; 13(5): 1426-1435, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32717393

RESUMO

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

3.
4.
Sci Data ; 7(1): 127, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345974

RESUMO

Precisely localizing the sources of brain activity as recorded by EEG is a fundamental procedure and a major challenge for both research and clinical practice. Even though many methods and algorithms have been proposed, their relative advantages and limitations are still not well established. Moreover, these methods involve tuning multiple parameters, for which no principled way of selection exists yet. These uncertainties are emphasized due to the lack of ground-truth for their validation and testing. Here we present the Localize-MI dataset, which constitutes the first open dataset that comprises EEG recorded electrical activity originating from precisely known locations inside the brain of living humans. High-density EEG was recorded as single-pulse biphasic currents were delivered at intensities ranging from 0.1 to 5 mA through stereotactically implanted electrodes in diverse brain regions during pre-surgical evaluation of patients with drug-resistant epilepsy. The uses of this dataset range from the estimation of in vivo tissue conductivity to the development, validation and testing of forward and inverse solution methods.


Assuntos
Encéfalo/fisiologia , Estimulação Encefálica Profunda , Eletroencefalografia , Algoritmos , Mapeamento Encefálico/métodos , Epilepsia Resistente a Medicamentos , Eletrodos Implantados , Humanos
5.
Trends Neurosci ; 43(1): 6-16, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31836316

RESUMO

Ordinary human experience is embedded in a web of causal relations that link the brain to the body and the wider environment. However, there might be conditions in which brain activity supports consciousness even when that activity is fully causally isolated from the body and its environment. Such cases would involve what we call islands of awareness: conscious states that are neither shaped by sensory input nor able to be expressed by motor output. This Opinion paper considers conditions in which such islands might occur, including ex cranio brains, hemispherotomy, and in cerebral organoids. We examine possible methods for detecting islands of awareness, and consider their implications for ethics and for the nature of consciousness.

6.
Brain Stimul ; 12(5): 1280-1289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31133480

RESUMO

BACKGROUND: The Perturbational Complexity Index (PCI) was recently introduced to assess the capacity of thalamocortical circuits to engage in complex patterns of causal interactions. While showing high accuracy in detecting consciousness in brain-injured patients, PCI depends on elaborate experimental setups and offline processing, and has restricted applicability to other types of brain signals beyond transcranial magnetic stimulation and high-density EEG (TMS/hd-EEG) recordings. OBJECTIVE: We aim to address these limitations by introducing PCIST, a fast method for estimating perturbational complexity of any given brain response signal. METHODS: PCIST is based on dimensionality reduction and state transitions (ST) quantification of evoked potentials. The index was validated on a large dataset of TMS/hd-EEG recordings obtained from 108 healthy subjects and 108 brain-injured patients, and tested on sparse intracranial recordings (SEEG) of 9 patients undergoing intracranial single-pulse electrical stimulation (SPES) during wakefulness and sleep. RESULTS: When calculated on TMS/hd-EEG potentials, PCIST performed with the same accuracy as the original PCI, while improving on the previous method by being computed in less than a second and requiring a simpler set-up. In SPES/SEEG signals, the index was able to quantify a systematic reduction of intracranial complexity during sleep, confirming the occurrence of state-dependent changes in the effective connectivity of thalamocortical circuits, as originally assessed through TMS/hd-EEG. CONCLUSIONS: PCIST represents a fundamental advancement towards the implementation of a reliable and fast clinical tool for the bedside assessment of consciousness as well as a general measure to explore the neuronal mechanisms of loss/recovery of brain complexity across scales and models.


Assuntos
Encéfalo/fisiologia , Estado de Consciência/fisiologia , Eletroencefalografia/métodos , Pesquisa Empírica , Estimulação Magnética Transcraniana/métodos , Adulto , Feminino , Humanos , Masculino , Sono/fisiologia , Fatores de Tempo , Vigília/fisiologia
9.
Neuroimage ; 189: 631-644, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30639334

RESUMO

Despite the absence of responsiveness during anesthesia, conscious experience may persist. However, reliable, easily acquirable and interpretable neurophysiological markers of the presence of consciousness in unresponsive states are still missing. A promising marker is based on the decay-rate of the power spectral density (PSD) of the resting EEG. We acquired resting electroencephalogram (EEG) in three groups of healthy participants (n = 5 each), before and during anesthesia induced by either xenon, propofol or ketamine. Dosage of each anesthetic agent was tailored to yield unresponsiveness (Ramsay score = 6). Delayed subjective reports assessed whether conscious experience was present ('Conscious report') or absent/inaccessible to recall ('No Report'). We estimated the decay of the PSD of the resting EEG-after removing oscillatory peaks-via the spectral exponent ß, for a broad band (1-40 Hz) and narrower sub-bands (1-20 Hz, 20-40 Hz). Within-subject anesthetic changes in ß were assessed. Furthermore, based on ß, 'Conscious report' states were discriminated against 'no report' states. Finally, we evaluated the correlation of the resting spectral exponent with a recently proposed index of consciousness, the Perturbational Complexity Index (PCI), derived from a previous TMS-EEG study. The spectral exponent of the resting EEG discriminated states in which consciousness was present (wakefulness, ketamine) from states where consciousness was reduced or abolished (xenon, propofol). Loss of consciousness substantially decreased the (negative) broad-band spectral exponent in each subject undergoing xenon or propofol anesthesia-indexing an overall steeper PSD decay. Conversely, ketamine displayed an overall PSD decay similar to that of wakefulness-consistent with the preservation of consciousness-yet it showed a flattening of the decay in the high-frequencies (20-40 Hz)-consistent with its specific mechanism of action. The spectral exponent was highly correlated to PCI, corroborating its interpretation as a marker of the presence of consciousness. A steeper PSD of the resting EEG reliably indexed unconsciousness in anesthesia, beyond sheer unresponsiveness.


Assuntos
Anestésicos Gerais/farmacologia , Estado de Consciência/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Ketamina/farmacologia , Propofol/farmacologia , Inconsciência/fisiopatologia , Xenônio/farmacologia , Adolescente , Adulto , Ondas Encefálicas/efeitos dos fármacos , Feminino , Humanos , Masculino , Inconsciência/induzido quimicamente , Adulto Jovem
10.
J Neurosci Methods ; 313: 37-43, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571989

RESUMO

Our own experiences with disturbances to sleep demonstrate its crucial role in the recovery of cognitive functions. This importance is likely enhanced in the recovery from stroke; both in terms of its physiology and cognitive abilities. Decades of experimental research have highlighted which aspects and mechanisms of sleep are likely to underlie these forms of recovery. Conversely, damage to certain areas of the brain, as well as the indirect effects of stroke, may disrupt sleep. However, only limited research has been conducted which seeks to directly explore this bidirectional link between both the macro and micro-architecture of sleep and stroke. Here we describe a series of semi-independent approaches that aim to establish this link through observational, perturbational, and interventional experiments. Our primary aim is to describe the methodology for future clinical and translational research needed to delineate competing accounts of the current data. At the observational level we suggest the use of high-density EEG recording, combined analysis of macro and micro-architecture of sleep, detailed analysis of the stroke lesion, and sensitive measures of functional recovery. The perturbational approach attempts to find the causal links between sleep and stroke. We promote the use of transcranial magnetic stimulation combined with EEG to examine the cortical dynamics of the peri-infarct stroke area. Translational research should take this a step further using optogenetic techniques targeting more specific cell populations. The interventional approach focuses on how the same clinical and translational perturbational techniques can be adapted to influence long-term recovery of function.


Assuntos
Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Sono/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Humanos , Estudos Observacionais como Assunto
11.
J Neurosci Methods ; 312: 93-104, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30439389

RESUMO

BACKGROUND: The basic mechanisms underlying the electroencephalograpy (EEG) response to transcranial magnetic stimulation (TMS) of the human cortex are not well understood. NEW METHOD: A state-space modeling methodology is developed to gain insight into the network nature of the TMS/EEG response. Cortical activity is modeled using a multivariariate autoregressive model with exogenous stimulation parameters representing the effect of TMS. An observation equation models EEG measurement of cortical activity. An expectation-maximization algorithm is developed to estimate the model parameters. RESULTS: The methodology is used to assess two different hypotheses for the mechanisms underlying TMS/EEG in wakefulness and sleep. The integrated model hypothesizes that recurrent interactions between cortical regions are the source of TMS/EEG, while the segregated model hypothesizes that the TMS/EEG results from excitation of independent cortical oscillators. The results show that the relatively simple EEG response to TMS recorded during non-rapid-eye-movement sleep is described equally well by either the integrated or segregated model. However, the integrated model fits the more complex TMS/EEG of wakefulness much better than the segregated model. COMPARISON WITH EXISTING METHOD(S): Existing methods are limited to small numbers of cortical regions of interest or do not represent the effect of TMS. Our results are consistent with previous studies contrasting the complexity of TMS/EEG in wakefulness and sleep. CONCLUSION: The new method strongly suggests that effective feedback connections between cortical regions are required to produce the TMS/EEG in wakefulness.


Assuntos
Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Modelos Neurológicos , Estimulação Magnética Transcraniana/métodos , Interpretação Estatística de Dados , Humanos , Análise Multivariada , Vias Neurais/fisiologia , Análise de Regressão , Processamento de Sinais Assistido por Computador
14.
Neuroimage ; 175: 354-364, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29604455

RESUMO

Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18-30 yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29 h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well-rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies.


Assuntos
Nível de Alerta/fisiologia , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Lobo Frontal/fisiologia , Lobo Parietal/fisiologia , Privação do Sono/fisiopatologia , Vigília/fisiologia , Adolescente , Adulto , Lobo Frontal/fisiopatologia , Humanos , Masculino , Lobo Parietal/fisiopatologia , Estimulação Magnética Transcraniana , Adulto Jovem
15.
J Med Ethics ; 44(9): 606-610, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29491041

RESUMO

Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self-organise mimicking real organs with organ-specific cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to those of different organs, such as the retina, the intestines, the kidneys, the pancreas, the liver and the inner ear. Organoids are considered a great resource for biomedical research, as they allow for a detailed study of the development and pathologies of human cells; they also make it possible to test new molecules on human tissue. Furthermore, organoids have helped research take a step forward in the field of personalised medicine and transplants. However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids (ie, human embryos) and their properties. In particular, there are new, relevant and so-far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains as developed as a few-months-old fetus, albeit smaller and with many structural and functional differences. However, cerebral organoids exhibit neural connections and electrical activity, raising the question whether they are or (which is more likely) will one day be somewhat sentient. In principle, this can be measured with some techniques that are already available (the Perturbational Complexity Index, a metric that is directly inspired by the main postulate of the Integrated Information Theory of consciousness), which are used for brain-injured non-communicating patients. If brain organoids were to show a glimpse of sensibility, an ethical discussion on their use in clinical research and practice would be necessary.


Assuntos
Encéfalo/fisiologia , Ética em Pesquisa , Organoides/fisiologia , Células-Tronco/fisiologia , Estado de Consciência/fisiologia , Células-Tronco Fetais/fisiologia , Humanos
16.
Cereb Cortex ; 28(7): 2233-2242, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28525544

RESUMO

Measuring the spatiotemporal complexity of cortical responses to direct perturbations provides a reliable index of the brain's capacity for consciousness in humans under both physiological and pathological conditions. Upon loss of consciousness, the complex pattern of causal interactions observed during wakefulness collapses into a stereotypical slow wave, suggesting that cortical bistability may play a role. Bistability is mainly expressed in the form of slow oscillations, a default pattern of activity that emerges from cortical networks in conditions of functional or anatomical disconnection. Here, we employ an in vitro model to understand the relationship between bistability and complexity in cortical circuits. We adapted the perturbational complexity index applied in humans to electrically stimulated cortical slices under different neuromodulatory conditions. At this microscale level, we demonstrate that perturbational complexity can be effectively modulated by pharmacological reduction of bistability and, albeit to a lesser extent, by enhancement of excitability, providing mechanistic insights into the macroscale measurements performed in humans.


Assuntos
Estado de Consciência/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia , Algoritmos , Animais , Biofísica , Estimulação Elétrica , Entropia , Furões , Técnicas In Vitro , Análise Espectral
17.
Brain Stimul ; 11(2): 358-365, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29162503

RESUMO

BACKGROUND: Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity. The global fractional anisotropy (FA) is a marker of structural integrity. Little is known about how these parameters are related to each other. OBJECTIVE: We aimed at testing the relationship between structural integrity and effective connectivity. METHODS: We assessed 23 patients with severe brain injury more than 4 weeks post-onset, leading to DOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity. Structural integrity was measured using the global FA, derived from diffusion weighted imaging. We used linear regression modelling to test our hypothesis, and computed the correlation between PCI and FA in different groups. RESULTS: Global FA could predict 74% of PCI variance in the whole sample and 56% in the patients' group. No other predictors (age, gender, time since onset, behavioural score) improved the models. FA and PCI were correlated in the whole population (r = 0.86, p < 0.0001), the patients, and the healthy subjects subgroups. CONCLUSION: We here demonstrated that effective connectivity correlates with structural integrity in brain-injured patients. Increased structural damage level decreases effective connectivity, which could prevent the emergence of consciousness.


Assuntos
Lesões Encefálicas/fisiopatologia , Conectoma , Transtornos da Consciência/fisiopatologia , Adulto , Idoso de 80 Anos ou mais , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico por imagem , Transtornos da Consciência/diagnóstico por imagem , Transtornos da Consciência/etiologia , Imagem de Tensor de Difusão , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Magnética Transcraniana
18.
J Neurosci ; 37(45): 10882-10893, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-29118218

RESUMO

How consciousness (experience) arises from and relates to material brain processes (the "mind-body problem") has been pondered by thinkers for centuries, and is regarded as among the deepest unsolved problems in science, with wide-ranging theoretical, clinical, and ethical implications. Until the last few decades, this was largely seen as a philosophical topic, but not widely accepted in mainstream neuroscience. Since the 1980s, however, novel methods and theoretical advances have yielded remarkable results, opening up the field for scientific and clinical progress. Since a seminal paper by Crick and Koch (1998) claimed that a science of consciousness should first search for its neural correlates (NCC), a variety of correlates have been suggested, including both content-specific NCCs, determining particular phenomenal components within an experience, and the full NCC, the neural substrates supporting entire conscious experiences. In this review, we present recent progress on theoretical, experimental, and clinical issues. Specifically, we (1) review methodological advances that are important for dissociating conscious experience from related enabling and executive functions, (2) suggest how critically reconsidering the role of the frontal cortex may further delineate NCCs, (3) advocate the need for general, objective, brain-based measures of the capacity for consciousness that are independent of sensory processing and executive functions, and (4) show how animal studies can reveal population and network phenomena of relevance for understanding mechanisms of consciousness.


Assuntos
Comportamento , Encéfalo/fisiopatologia , Transtornos da Consciência/fisiopatologia , Transtornos da Consciência/psicologia , Estado de Consciência , Animais , Comportamento Animal , Humanos , Psicofisiologia
19.
J Neurosci ; 37(40): 9603-9613, 2017 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-28978697

RESUMO

The role of the frontal cortex in consciousness remains a matter of debate. In this Perspective, we will critically review the clinical and neuroimaging evidence for the involvement of the front versus the back of the cortex in specifying conscious contents and discuss promising research avenues.Dual Perspectives Companion Paper: Should a Few Null Findings Falsify Prefrontal Theories of Conscious Perception?, by Brian Odegaard, Robert T. Knight, and Hakwan Lau.


Assuntos
Córtex Cerebral/fisiologia , Estado de Consciência/fisiologia , Rede Nervosa/fisiologia , Neuroimagem/métodos , Animais , Mapeamento Encefálico/métodos , Humanos
20.
PLoS One ; 12(9): e0184910, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28910407

RESUMO

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event-related desynchronization (ERD-peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.


Assuntos
Eletroencefalografia/métodos , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto , Potencial Evocado Motor , Feminino , Humanos , Masculino
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