Marcello Massimini

Marcello Massimini
University of Milan | UNIMI · Department of Biomedical and Clinical Sciences "Luigi Sacco"

MD, PhD

About

189
Publications
431,077
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17,376
Citations
Additional affiliations
January 2009 - present
University of Liège
January 2004 - December 2011
University of Wisconsin–Madison
January 2001 - December 2002
Laval University

Publications

Publications (189)
Article
Full-text available
Objective Validating objective, brain‐based indices of consciousness in behaviorally unresponsive patients represents a challenge due to the impossibility of obtaining independent evidence through subjective reports. Here we address this problem by first validating a promising metric of consciousness—the Perturbational Complexity Index (PCI)—in a b...
Article
Full-text available
A common endpoint of general anesthetics is behavioral unresponsiveness [1], which is commonly associated with loss of consciousness. However, subjects can become disconnected from the environment while still having conscious experiences, as demonstrated by sleep states associated with dreaming [2]. Among anesthetics, ketamine is remarkable [3] in...
Article
Full-text available
During non-rapid eye movement (NREM) sleep (stage N3), when consciousness fades, cortico-cortical interactions are impaired while neurons are still active and reactive. Why is this? We compared cortico-cortical evoked-potentials recorded during wakefulness and NREM by means of time-frequency analysis and phase-locking measures in 8 epileptic patien...
Article
Full-text available
One challenging aspect of the clinical assessment of brain-injured, unresponsive patients is the lack of an objective measure of consciousness that is independent of the subject's ability to interact with the external environment. Theoretical considerations suggest that consciousness depends on the brain's ability to support complex activity patter...
Article
Full-text available
Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some d...
Preprint
Full-text available
Human studies employing intracerebral and transcranial perturbations suggest that the input-output properties of cortical circuits are dramatically affected during sleep in healthy subjects as well as in awake patients with multifocal and focal brain injury. In all these conditions, cortical circuits react to direct stimulation with an initial acti...
Article
Background Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of t...
Article
Interpreting empirical measures of integration and differentiation as indices of cortical performance and memory consolidation during wakefulness rather than consciousness per se is inconsistent with the literature. Recent studies show that these theory-inspired measures can dissociate from such processes and reliably index the brain's capacity for...
Article
Full-text available
Objective Quantitative Electroencephalography (qEEG) can capture changes in brain activity following stroke. qEEG metrics traditionally focus on oscillatory activity, however recent findings highlight the importance of aperiodic (power-law) structure in characterizing pathological brain states. We assessed neurophysiological alterations and recove...
Article
Full-text available
Consciousness can be defined by two components: arousal (wakefulness) and awareness (subjective experience). However, neurophysiological consciousness metrics able to disentangle between these components have not been reported. Here, we propose an explainable consciousness indicator (ECI) using deep learning to disentangle the components of conscio...
Article
Background Coupling transcranial magnetic stimulation with electroencephalography (TMS-EEG) allows recording the EEG response to a direct, non-invasive cortical perturbation. However, obtaining a genuine TMS-evoked EEG potential requires controlling for several confounds, among which a main source is represented by the auditory evoked potentials (A...
Article
Full-text available
Dissociated cortical neurons in vitro display spontaneously synchronized, low-frequency firing patterns, which can resemble the slow wave oscillations characterizing sleep in vivo. Experiments in humans, rodents, and cortical slices have shown that awakening or the administration of activating neuromodulators decrease slow waves, while increasing t...
Preprint
Full-text available
Background The impact of transcranial magnetic stimulation (TMS) on cortical neurons is currently hard to predict based on a priori biophysical and anatomical knowledge alone. This problem can hamper the reliability and reproducibility of protocols aimed at measuring electroencephalographic (EEG) responses to TMS. New Method We introduce and releas...
Preprint
Full-text available
Background Coupling transcranial magnetic stimulation with electroencephalography (TMS-EEG) allows recording the EEG response to a direct, non-invasive cortical perturbation. However, obtaining a genuine TMS-evoked EEG potential requires controlling for several confounds, among which a main source is represented by the auditory evoked potentials (A...
Article
Full-text available
Over the last years, a surge of empirical studies converged on complexity-related measures as reliable markers of consciousness across many different conditions, such as sleep, anesthesia, hallucinatory states, coma, and related disorders. Most of these measures were independently proposed by researchers endorsing disparate frameworks and employing...
Preprint
Full-text available
Background Quantitative EEG (qEEG) can capture changes in brain activity that follow a stroke. Accordingly, EEG metrics could be used to monitor patients’ state and recovery. Although qEEG metrics traditionally focus on oscillatory activity, recent findings highlight the importance of aperiodic (power-law) structure in characterizing pathological b...
Article
Full-text available
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...
Preprint
Full-text available
Background Cortical excitability changes across conscious states, being higher in unconsciousness compared to normal wakefulness. Anaesthesia offers controlled manipulation to investigate conscious processes and underlying brain dynamics. Among commonly used anaesthetic agents, dexmedetomidine (DEX) effects are not completely known. In this study,...
Article
Full-text available
Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The cha...
Article
Full-text available
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 ov...
Chapter
Developing biomarkers for psychiatric disorders represents a major challenge. Indeed, the identification of dependable brain-based measures, such as those derived from electrophysiological techniques, would represent a key step toward better profiling of patients with major psychiatric disorders. A principled neurophysiological approach would also...
Article
Full-text available
The analysis of spontaneous EEG activity and evoked potentials is a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). The past few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury, opening up...
Article
Full-text available
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...
Article
Full-text available
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 paramete...
Preprint
Full-text available
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 paramete...
Preprint
Full-text available
Background: The perturbational complexity index (PCI) is a useful measure of consciousness that combines transcranial magnetic stimulation (TMS) with electroencephalography (EEG). However, the PCI has not been assessed for reliability between sessions nor is there a clear best stimulation target to acquire a PCI. Objective/Hypothesis: We assessed t...
Preprint
Full-text available
The functional consequences of brain injury are known to depend on neuronal alterations extending beyond the area of structural damage. Although a lateralized EEG slowing over the injured hemisphere was known since the early days of clinical neurophysiology, its electrophysiological mechanisms were not systematically investigated. In parallel, basi...
Article
Introduction Peripheral as well as direct cortical stimulations have been classically used to probe the reactivity of thalamocortical circuits across brain states, showing consistent state-dependent modifications. Methods Here we aim at directly comparing state-dependent changes across the wake/sleep cycle of the electroencephalographic (EEG) resp...
Article
Background Direct cortical perturbations had been used to study state-dependent changes in thalamocortical network. TMS combined with EEG has demonstrated consistent modifications among wakefulness, NREM sleep, and anesthesia; furthermore, these measurements resulted useful in the diagnosis and pathophysiological stratification of patients with dis...
Article
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 restric...
Article
Full-text available
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....
Article
Background and objective: Knowing whether a subject is conscious or not is a current challenge with a deep potential clinical impact. Recent theoretical considerations suggest that consciousness is linked to the complexity of distributed interactions within the corticothalamic system. The fractal dimension (FD) is a quantitative parameter that has...
Article
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 th...
Article
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 multivariari...
Article
Full-text available
Unresponsive wakefulness syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and reactive to sensory stimuli but fail to engage in complex causal interactions, resulting in loss of consciousness. Here, we show that loss of brain complexity after severe injuries is due to a pathological tend...
Preprint
Full-text available
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...
Article
Background: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. Methods...
Book
Sizing up Consciousness explores, at an introductory level, the potential practical, clinical, and ethical implications of a general principle about the nature of consciousness. Using information integration theory (IIT) as a guiding principle, the book takes the reader along a scientific trajectory to face fundamental questions about the relations...
Conference Paper
Full-text available
Providing objective metrics of conscious state is of great theoretical and practical interest. The Luminous project [1] aims to develop information-based metrics of consciousness and methods for its alteration using non-invasive brain stimulation (NIBS). We provide here a consensus overview on the scientific foundations, goals and methods of the pr...
Article
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...
Preprint
Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) also reveals preserved cortical reactivity, but in most cases, the residual...
Article
Full-text available
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 philoso...
Preprint
Background Impaired consciousness has been associated with impaired cortical signal propagation following transcranial magnetic stimulation (TMS). Herein we hypothesized that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy....
Article
Full-text available
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 st...
Article
Full-text available
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.
Article
Full-text available
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 largel...
Data
Comparison of 5 second (top panels) and 3 second ISI (bottom panels) in one representative subject. For both ISIs, the distribution of peak-to-peak MEP amplitude of all artifact free trials (left top) and the corresponding average MEP (left bottom), the butterfly plots of all channels (right top, grey traces), the TEPs recorded at the channel close...
Data
(A) Grand-average of GMFP for each stimulated area. Thick traces indicate the grand-average GMFP across subjects (±SE, color-coded shaded regions). Responses recorded after the stimulation of different cortical areas are color coded as follows: motor in black, prefrontal in yellow, premotor in red, parietal in green. (B) For each stimulated area, t...
Data
For each stimulated area, the LMFP values, calculated using all artifact free trials (panel A) and the same number of trials across stimulation site (panel B), and then averaged between 8 and 350 ms post-TMS are shown in the bar histogram (mean ± SE). Asterisks indicate statistically significant differences (* p<0.05, Wilcoxon signed rank test). Ba...
Data
Top and bottom panels show, for one representative subject, the average MEPs of the quadriceps and APB muscles, the butterfly plot of all channels (grey lines), the TEP of the channel closest to the stimulation site (black line) and the corresponding ERSP obtained by stimulating the medial M1 (leg motor cortex) respectively at 100% RMTAPB and 100%...
Chapter
Measuring electroencephalographic responses to nTMS/EEG harbors a huge potential to investigate cortico-cortical connectivity. In the present chapter, we address one major application of nTMS/EEG in neurosurgery: the problem of objectively estimating the brain’s capacity for consciousness in severely brain-injured patients who show little or no int...
Article
Slow oscillations have been suggested as the default emergent activity of the cortical network. This is a low complexity state that integrates neuronal, synaptic, and connectivity properties of the cortex. Shaped by variations of physiological parameters, slow oscillations provide information about the underlying healthy or pathological network. We...
Article
Full-text available
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 sl...