Meccanismi neurofisiologici dei disturbi degli stati di coscienza
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di Paolo M. Rossini Clinica Neurologica, Università Cattolica, Policlinico . Gemelli, Roma Convegno "Le neuroscienze incontrano le altre discipline" Padova, Palazzo del Bo 5 maggio 2011 Il convegno è promosso dall’Università di Padova e dal Dipartimento di Psicologia generale della stessa università, con il sostegno della Fondazione Sigma Tau e della Fondazione Giannino Bassetti.
![[object Object],[object Object],[object Object],[object Object],[object Object],Consciousness: a simplified neurological vision The level of consciusness is the degree of wafefulness or arousal, wich ranges from alertness through drowsiness to coma. It depends on the integrity of ascending ponto-mesodiencephalic reticular pathways and widespread thalamocortical projections and can be quantified through assessment of an individual’s motor and verbal responses to external stimuli (GCS).](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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Meccanismi neurofisiologici dei disturbi degli stati di coscienza
- 1. Meccanismi neurofisiologici dei disturbi degli stati di coscienza Paolo M. Rossini Clinica Neurologica, Università Cattolica, Policlinico . Gemelli, Roma
- 4. Coherence analysis of the EEG-MEG signals have been used to estimate the degree of functional connectivity among cortical areas. It represents the covariance of the EEG spectral activity at two recording sites and can be considered as a measure of temporal synchronization of signals recorded at pairs of sites. Ideally, coherence estimates temporal synchronization or functional coupling of the two cortical populations generating signals collected at the two scalp sites. Decreased coherence reflects reduced functional connection. This analysis only measure the linear component of the functional coupling of the brain oscillations when compared to modern nonlinear approaches.
- 6. Disorders of consciousness The assessment of persons with disorders of consciousness is fraught with difficulties and challenges. Disorders of consciousness are not distinguished by a particular pathology or quantifiable marker. Instead, the diagnostic decision-making process is informed by the clinical team’s interpretation of the behaviours exhibited by a patient over a period of observation. The interpretation of exhibited behaviours is complicated by the fact that we currently have an incomplete knowledge of consciousness and there remains debate as to whether behaviours should be classified as conscious. In a review of 40 patients referred to a specialist rehabilitation unit, Andrews and colleagues considered 17 (43%) of the patients as having been misdiagnosed .
- 8. Is neurophysiology able to evaluate perception and consciousness? Some recent examples…
- 10. Volume 8, Number 10, October 2005
- 11. Electroencephalography and Clinical Neurophysiology Volume 1, Issues 1-4, 1949 , Pages 455-473 Neurophysiology and consciousness: n ot only diagnosis Therapeutic aspects: f rom 1949…cat’s brain…
- 12. John Hughlings Jackson’s “Highest Centers”: he proposed that consciousness was impaired when higher cortical function became disorganized and lacked integrative ability Consciousness: what can we learn from neurophysiology and epilepsy Penfield and Jasper’s Centrencephalic Theory: From the 1930s to the 1950 they posited that a system existed within the brain that could be responsible for integrating the actions of the two hemispheres of the brain. They saw that epileptic patients who had had large portions of cerebral cortex or corpus callosum removed suffered little to no impairment of consciousness, while pressure applied to the brainstem resulted in immediate and reversible loss of consciousness Penfield Jasper
- 14. Englot et al. Complex partial seizure Simple partial seizure (Impaired consciousness) (Unimpaired consciousness)
- 15. Preserved consciousness Profound alteration of consciousness Variation of synchronization indices Profound alteration of consciousness Preserved consciousness synchronization indices. Statistical variations by comparing groups C and A
- 16. The Network Inhibition Hypothesis Following Moruzzi & Magoun 1949
- 17. SEPs- median nerve stimulation PSV patient with preserved peripheral and primary cortical responses Laureys et al.
- 19. ERP Primary cortical components N1–P2—however, without any differentiation between frequent and rare stimuli, in a male patient, 51, anoxic brain injury Apart of the primary complex, a delayed P3 to rare stimuli in a female, 29, subarachnoidal hemorrhage A long-latency, significant positive deflection (‘P600’) to the counted word category (animals) in the semantic oddball, a female, 19, PVS after a postoperative intraventricular hemorrhage. An N400 in the Word pair experiment to semantically unrelated words, in contrast to a positivity to related words, in a male, 42, head injury. An N400 to incongruent end words in the Sentence experiment, in a male, 61, MCS following bilateral infarcts in basal ganglia. Only one lead (Cz) is presented
- 20. Luauté et al.,
- 21. Wijnen et al.
- 24. A woman, unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context T1 horizontal MRI image FDG-PET isolated regions in the left hemisphere expressing higher levels of metabolism T1 MRI image of sagittal sections through the brainstem from right hemisphere revealing total destruction of the thalamus
- 26. fMRI…and EEG??
- 27. 50 PSV patients and 30 cognitively normal subjects Eye closed EEG- LORETA analysis; Rec group: recovery group (3 months); Non Rec: non recovery group (3 months)
- 28. Prognosis in patients in a persistent vegetative state (VS) consciousness may be regarded as complex systems whose outputs show a degree of unpredictability experimentally quantifiable by means of nonlinear parameters such as approximate entropy (ApEn). - 38 Vegetative patients and 40 controls - Nonlinear dynamics applied to EEG DYNAMIC CORRELATES OF NEURAL REDISUAL COMPLEXITY MIGHT HELP IN PREDICTING OUTCOMES IN VS Controls VS
- 30. … or lost in connection? GRAZIE PER L’ATTENZIONE
Editor's Notes
- When a flashed stimulus is followed by a backward mask, subjects fail to perceive it unless the target-mask interval exceeds a threshold duration of about 50 ms. Models of conscious access postulate that this threshold is associated with the time needed to establish sustained activity in recurrent cortical loops, but the brain areas involved and their timing remain debated. We used high-density recordings of event-related potentials (ERPs) and cortical source reconstruction to assess the time course of human brain activity evoked by masked stimuli and to determine neural events during which brain activity correlates with conscious reports. Target-mask stimulus onset asynchrony (SOA) was varied in small steps, allowing us to ask which ERP events show the characteristic nonlinear dependence with SOA seen in subjective and objective reports. The results separate distinct stages in mask-target interactions, indicating that a considerable amount of subliminal processing can occur early on in the occipito-temporal pathway (<250 ms) and pointing to a late (>270 ms) and highly distributed fronto-parieto-temporal activation as a correlate of conscious reportability.
- In the phenomenon of attentional blink, identical visual stimuli are sometimes fully perceived and sometimes not detected at all. This phenomenon thus provides an optimal situation to study the fate of stimuli not consciously perceived and the differences between conscious and nonconscious processing. We correlated behavioral visibility ratings and recordings of event-related potentials to study the temporal dynamics of access to consciousness. Intact early potentials (P1 and N1) were evoked by unseen words, suggesting that these brain events are not the primary correlates of conscious perception. However, we observed a rapid divergence around 270 ms, after which several brain events were evoked solely by seen words. Thus, we suggest that the transition toward access to consciousness relates to the optional triggering of a late wave of activation that spreads through a distributed network of cortical association areas.
- Transitions from sleep to wakefulness, or from the less extreme states of relaxation and drowsiness to alertness and attention, are all characterized by an apparent breaking up of the synchronization of discharge of elements of the cerebral cortex, an alteration marked in the EEG by the replacement of high-voltage slow waves with low-voltage fast activity. The magnitude of the electrical change parallels the degree of transition, and that most commonly observed in clinical electroencephalography is a minimal one. consisting of an alpha-wave blockade during attention to visual stimulation. Such activation of the EEG may be produced by any type of afferent stimulus that arouses the subject to alertness, or it may be centrally generated, but the basic processes underlying it, like those involved in waking from sleep, have remained obscure. Recent experimental findings which may contribute to tlais subject have stemmed from the observation that EEG changes seemingly identical with those in the physiological arousal reactions can be produced by direct stimulation of the reticular formation of the brain stem. The following account describes such features of the response and its excitable substrate as have been determined, provides an analysis of changes in cortical and thalamic activity associated with it, and explores the relations of this reticular activating system to the arousal reaction to natural stimuli. Alterations produced by acute lesions in this system are presented in a succeeding paper. The effects of chronic lesions within it are under investigation.
- EEG patterns for different seizure types. a. in generalized tonic-clonic seizures, diffuse high frequency and high amplitude spikes are apparent. B. Absence seizures are characterized by diffuse 3-4 Hz spike-and-wave complexes. C. In complex partial seizures, localized abnormal rhythmic activity usually arises in the temporal lobe
- Fig1 complex partial seizure. Fig 2 simple partial seizure
- Loss of consciousness (LOC) is a dramatic clinical manifestation of temporal lobe seizures. Its underlying mechanism could involve altered coordinated neuronal activity between the brain regions that support conscious information processing. The consciousness access hypothesis assumes the existence of a global workspace in which information becomes available via synchronized activity within neuronal modules, often widely distributed throughout the brain. Re-entry loops and, in particular, thalamo-cortical communication would be crucial to functionally bind different modules together. In the present investigation, we used intracranial recordings of cortical and subcortical structures in 12 patients, with intractable temporal lobe epilepsy (TLE), as part of their presurgical evaluation to investigate the relationship between states of consciousness and neuronal activity within the brain. The synchronization of electroencephalography signals between distant regions was estimated as a function of time by using non-linear regression analysis. We report that LOC occurring during temporal lobe seizures is characterized by increased long-distance synchronization between structures that are critical in processing awareness, including thalamus (Th) and parietal cortices. The degree of LOC was found to correlate with the amount of synchronization in thalamocortical systems. We suggest that excessive synchronization overloads the structures involved in consciousness processing, preventing them from treating incoming information, thus resulting in LOC. FIG: Figure 1 (A) Intracerebral recordings used multiple contacts electrodes placed according to Talairach’s stereotactic method (Talairach et al., 1992). (Upper part) = sinistra: schematic diagram of SEEG electrodes placement on a lateral view of Talairach’s basic referential system in a patient with MTLE. A: Electrode exploring the amygdala (medial leads) and the anterior part of the MTG (lateral leads), B: electrode exploring the anterior hippocampus (medial leads) and the mid part of MTG (lateral leads); Tb: Electrode exploring the entorhinal cortex (internal contacts) and the anterior part of the inferior temporal gyrus (external contacts); C: electrode exploring the posterior hippocampus (medial leads) and the posterior part of MTG (lateral leads); H: electrode exploring the thalamus (medial leads) and the superior temporal gyrus (lateral leads), P: electrode exploring the posterior cingulated gyrus (medial leads) and inferior parietal lobe (lateral leads); parietal electrode. (Lower part)= destra : estimation of interdependencies using non-linear regression (h2 estimation) between pair-wise signals in a Group C seizure and in a Group A seizure. Increase in h2 values is particularly marked for seizure from Group C affecting not only the mesial temporal interactions (EC-Hip, red line) but also the other interactions represented. Seizure from Group A is mainly characterized by increase in h2 values between entorhinal cortex and hippocampus (red line). Note that a discharge affecting the parietal lobe is visible in the two cases (with and without LOC), being more marked in seizures with LOC.
- Blumenfeld, H. & J. Taylor. 2003. Why do seizures cause loss of consciousness? Neuroscientist 9: 301–310 Figure 1 Network inhibition hypothesis for loss of consciousness in complex partial seizures. ( A ) Under normal conditions, the upper brain stem–diencephalic activating systems interact with the cerebral cortex to maintain normal consciousness (yellow represents normal activity). ( B ) A focal seizure (red) involving the mesial temporal lobe unilaterally. ( C ) Propagation of seizure activity from the mesial temporal lobe to midline subcortical structures. ( D ) Disruption of the normal activating functions of the midline subcortical structures leads to depressed activity (blue) in bilateral regions of the fronto–parietal association cortex, leading to loss of consciousness.
- The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. We used positron emission tomography to assess the central processing of noxious somatosensory stimuli in the PVS. Changes in regional cerebral blood flow were measured during high-intensity electrical stimulation of the median nerve compared with rest in 15 nonsedated patients and in 15 healthy controls. Evoked potentials were recorded simultaneously. The stimuli were experienced as highly unpleasant to painful in controls. Brain glucose metabolism was also studied with [18F]fluorodeoxyglucose in resting conditions. In PVS patients, overall cerebral metabolism was 40% of normal values. Nevertheless, noxious somatosensory stimulation-activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. Secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices did not show activation in any patient. Moreover, in PVS patients, the activated primary somatosensory cortex was functionally disconnected from secondary somatosensory, bilateral posterior parietal, premotor, polysensory superior temporal, and prefrontal cortices. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices
- Initial conceptualisation about the nature of vegetative state (VS) assumed at least temporary loss of the entire cortical functioning. Since a broad range of stimulus-related cortical activations was demonstrated in VS patients, this simplified idea is not tenable any longer, but no alternative concept emerges instead. Two recent hypotheses, empirically testable and well grounded, could fill this vacuum: (1) In VS, isolated cortical areas may work, but their integration into a distributed network is lacking. (2) In VS, complex stimulus processing is limited to primary sensory and motor areas; the co-ordination between them and the secondary and tertiary areas is lacking. To test these hypotheses, we estimated the frequency of occurrence of late event-related potential components P3 and N400, presumably indicating activity of complex distributed networks including high-level sensory and associative areas. Both components occurred in VS with above-chance frequencies, but less frequently than in two control groups. Besides these frequent normal brain activations, some VS patients exhibit highly significant but abnormal activations, whose functional meaning remains unclear. A methodological analysis leads to the conclusion that any neurophysiological assessment of VS patients is biased toward under-, rather than over-estimation, of their remaining information processing abilities.
- Objective: To study the presence of electrophysiological indicators of remaining cortical functions in patients with persistent vegetative state (PVS) and minimally conscious state (MCS). Previous electrophysiological and PET data indicated that some PVS patients have partially intact cortical processing functions. However, it remains unclear whether the reported patients were representative for PVS population or just some exceptional cases. Methods: Event-related brain responses to stimuli of different complexity levels, recorded in 98 patients with extremely severe diffuse brain injuries, 50 of which in PVS. Four main indicators of cortical functions were: (i) N1–P2 complex as an index of simple, undifferentiated cortical processing; (ii) mismatch negativity as an index of pre-attentive, probably unconscious, cortical orientation; (iii) P3 wave as an index of deep cortical analysis of physical stimuli, and (iv) brain responses to semantic stimuli. Results: Cortical responses were found in all PVS patients with a background EEG activity O4 Hz. All responses investigated, including those to semantic stimuli that indicated comprehension of meaning, occurred significantly above chance, though less frequently than in patients with severe brain injuries who were conscious. Conclusions: Cortical responses were lacking in most patients with severe EEG slowing (!4 Hz). Follow-up data revealed that the presence of a mismatch negativity, a short disease duration, and the traumatic etiology were related to a better outcome. Significance: The data show that in a subpopulation of PVS patients with preserved thalamocortical feedback connections, remaining cortical information processing is a consistent finding and may even involve semantic levels of processing. Fig. 2. Examples of various ERP phenomena in patients with severe brain damage. (A): Primary cortical components N1–P2—however, without any differentiation between frequent and rare stimuli, in a male patient, 51, anoxic brain injury. (B): Apart of the primary complex, a delayed P3 to rare stimuli in a female, 29, subarachnoidal hemorrhage. (C): A long-latency, significant (PZ0.014) positive deflection (‘P600’) to the counted word category (animals) in the semantic oddball, a female, 19, PVS after a postoperative intraventricular hemorrhage. (D): An N400 in the Word pair experiment to semantically unrelated words, in contrast to a positivity to related words, in a male, 42, head injury. (E): An N400 to incongruent end words in the Sentence experiment, in a male, 61, MCS following bilateral infarcts in basal ganglia. For simplicity only one lead (Cz) is presented. Ticks on the amplitude axis indicate: 5 mV on A and B, 2 mV on C, D, and E. Ticks on the time axis indicate 200 ms in all graphics. The negativity is plotted upwards.
- Objective: To investigate whether late auditory and eventrelated potentials, and in particular N100 and mismatch negativity, together with clinical parameters, can help to predict good functional outcome in comatose patients. Design: Prospective cohort study. Setting: Hospital. Participants: Consecutively sampled comatose patients (N346) whose etiologies of coma were stroke (125 patients), brain injury (96 patients), anoxia (64 patients), complication of neurosurgery (54 patients), and encephalitis (7 patients). Interventions: Not applicable. Main Outcome Measures: Glasgow Outcome Scale score at 1 year postonset. Patients in a minimally conscious state and those who awoke and died during the follow-up period were classified separately. Results: Univariate analysis showed that all variables studied, except brainstem auditory evoked potentials, correlated significantly with functional outcome. Mismatch negativity showed the highest positive predictive value for good outcome. A validated model was obtained with multivariate logistic analysis, including pupillary light reflex, N100, mismatch negativity, etiology, and age. Conclusions: Late auditory and event-related potentials, and particularly N100 and mismatch negativity, provide strong prognostic factors for good functional outcome. Furthermore, these components may enhance the accuracy of prognosis when associated with other clinical parameters available at the early stage of coma.
- Abstract Objective: Mismatch negativity (MMN) is an automatic event related brain response, well investigated in the acute phase after severe brain injury: the presence of a MMN is often found to predict the emergence from coma, and the exclusion of shifting into a vegetative state (VS). In the present study MMN was examined during recovery from VS. Methods: Ten vegetative patients were repeatedly examined every 2 weeks for an average period of 3.5 months. Amplitudes and latencies were related to the patients’ recovery from VS to consciousness, and to a healthy norm group. In addition, MMN was examined on its prognostic value in VS patients, in predicting recovery to consciousness and long-term functional outcome. Results: With recovery to consciousness MMN-amplitudes increased. A sudden increase was seen in MMN amplitude when patients started to show inconsistent behavioural responses to simple commands. At this level MMN resembled the MMN response as was seen in the norm group. In addition, the MMN-amplitude and latency during the first measurement predicted the patients’ outcome on recovery to consciousness. Conclusions: With recovery from VS to consciousness the ability to process auditory stimulus deviance increases. A sudden enhancement in MMN-amplitude preceded overt communication with the environment. This might be indicative of the consolidation of neural networks underlying overt communication. Moreover, MMN can be helpful in identifying the ability to recover from VS. Significance: MMN can be used to track recovery from the vegetative state in the post-acute phase after severe brain injury. In addition, MMN can be used to predict the ability to recover from the vegetative state.
- Can conscious processing be inferred from neurophysiological measurements? Some models stipulate that the active maintenance of perceptual representations across time requires consciousness. Capitalizing on this assumption, we designed an auditory paradigm that evaluates cerebral responses to violations of temporal regularities that are either local in time or global across several seconds. Local violations led to an early response in auditory cortex, independent of attention or the presence of a concurrent visual task, whereas global violations led to a late and spatially distributed response that was only present when subjects were attentive and aware of the violations. We could detect the global effect in individual subjects using functional MRI and both scalp and intracerebral event-related potentials. Recordings from 8 noncommunicating patients with disorders of consciousness confirmed that only conscious individuals presented a global effect. Taken together these observations suggest that the presence of the global effect is a signature of conscious processing, although it can be absent in conscious subjects who are not aware of the global auditory regularities. This simple electrophysiological marker could thus serve as a useful clinical tool.
- A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinás, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation.
- Objective: High power of pre-stimulus cortical alpha rhythms (about 8–12 Hz) underlies conscious perception in normal subjects. Here we tested the hypothesis that these rhythms are abnormal in persistent vegetative state (PVS) patients, who are awake but not aware of self and environment. Methods: Clinical and resting-state, eyes-closed electroencephalographic (EEG) data were taken from a clinical archive. These data were recorded in 50 PVS subjects (level of cognitive functioning – LCF score: I–II) and in 30 cognitively normal subjects. Rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). Cortical sources were estimated by low-resolution electromagnetic tomography (LORETA). Based on LCF score at 3-months follow-up, PVS patients were retrospectively divided into three groups: 30 subjects who did not recover (NON-REC patients; follow-up LCF: I–II), 8 subjects classified as minimally conscious state patients (MCS patients; follow-up LCF: III–IV), and 12 subjects who recovered (REC patients; follow-up LCF: V–VIII). Results: Occipital source power of alpha 1 and alpha 2 was high in normal subjects, low in REC patients, and practically null in NON-REC patients. A Cox regression analysis showed that the power of alpha source predicted the rate of the follow up recovery, namely the higher its power, the higher the chance to recover consciousness. Furthermore, the MCS patients showed intermediate values of occipital alpha source power between REC and NON-REC patients. Conclusions: These results suggest that cortical sources of alpha rhythms are related to the chance of recovery at a 3-months follow-up in patients in persistent vegetative state. Significance: Cortical sources of resting alpha rhythms might predict recovery in PVS patients
- Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases1,2. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS)3,4, a condition that is characterized by intermittent evidence of awareness of self or the environment5. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.