Marco Sarà

Cortical sources of resting-state alpha rhythms are abnormal in persistent vegetative state patients.

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.

Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs?

Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). Coma is a condition of unarousability with a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. Patients in coma are unconscious because they lack both wakefulness and awareness. Patients in a VS are unconscious because, although they are wakeful, they lack awareness. Patients in a MCS show minimal but definite behavioural evidence of self and environmental awareness.Coma results from diffuse bilateral hemispheric lesions or selective damage to the ascending reticular system (which is functionally connected to the cerebral cortex by intralaminar thalamic nuclei). VS is a syndrome that is considered to be the result of a disconnection of different cortical networks rather than a dysfunction of a single area or a global reduction in cortical metabolism. As revealed by functional imaging studies, clinical recovery is often associated with a functional restoration of cortico-thalamo-cortical connections. Depending on the amount of network restored, patients may regain full consciousness or remain in a MCS. Molecular and neural mediators may indirectly contribute to the above restoration processes owing to their role in the phenomenon of neural synaptic plasticity. Therefore, there is growing interest in the possible effects of drugs that act at the level of the CNS in promoting emergence from DOC.Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. Analysis of the reported cases of recovery, with particular attention paid to the condition of the patients and to the association of their improvement with the start of drug administration, suggests that these treatments might have promoted the clinical improvement of some patients. These drugs are from various and diverging classes, but can be grouped into two main categories, CNS stimulants and CNS depressants. Some of these treatments seem to directly encourage a consciousness restoration, while others play a more determinant role in improving cognitive domains, especially in patients with residual cognitive impairment, than in the field of consciousness.Given the great interest recently generated in the scientific community by the increasing number of papers addressing this issue, further investigation of the above treatments, with particular attention paid to their mechanisms of action, the neurotransmitters involved and their effects on cortico-thalamocortical circuitry, is needed.

An unexpected recovery from permanent vegetative state

Primary objective: To challenge the Multi-Society Task Forces ruling that a persistent vegetative state (PVS) can be judged to be permanent for non traumatic brain injury after three months. Method: We report the case of a 44-year-old man who had recovery of consciousness with persistent severe disability 19 months after a non-traumatic brain injury at least in part triggered and maintained by intrathecal baclofen administration. Result: This unexpected and late recovery of consciousness raises an interesting hypothesis of possible effects of partially regained spinal cord outputs on reactivation of cognition. Conclusion: Considering that several ethical, legal, and socio-economic issues have been raised about the opportunity of withdrawing treatment and life support in patients with PVS the report of this case might add further documentation to the ongoing debate.

Functional isolation within the cerebral cortex in the vegetative state: A nonlinear method to predict clinical outcomes

Background. Establishing prognosis in patients in a persistent vegetative state (VS) is still challenging. Neural networks underlying 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). Objective. The authors propose that the VS might be the result of derangement of the above neural networks, with an ensuing decrease in complexity and mutual interconnectivity: this might lead to a functional isolation within the cerebral cortex and to a reduction in the chaotic behavior of its outputs, with monotony taking the place of unpredictability. To test this hypothesis, the authors investigated whether nonlinear dynamics methods applied to electroencephalography (EEG) recordings may be able to predict outcomes. Methods. A total of 38 vegetative patients and 40 matched healthy controls were investigated. At admission, all patients were assessed by means of the Extended Glasgow Outcomes Coma Scale (E-GOS) and the Coma Recovery Scale–Revised (CRS-R). At the same time an EEG recording was performed and used for time series analysis and ApEn computation. Patients were clinically reassessed at 6 months from the first evaluation. Results. Mean ApEn values (0.73, standard deviation [SD] = 0.12 vs 0.97, SD = 0.02; P < .001) were lower in patients than in controls. Patients with the lowest ApEn values either died (n = 14) or remained in a VS (n = 12), whereas patients with the highest ApEn values became minimally conscious (n = 5) or showed partial (n = 4) or full recovery (n = 3). Conclusions. These findings suggest that dynamic correlates of neural residual complexity might help in predicting outcomes in vegetative patients.

Action observation improves motor imagery: specific interactions between simulative processes

In the present study, we demonstrated that observation of hand rotation had specific facilitation effects on a classical motor imagery task, the hand-laterality judgement. In Experiment 1, we found that action observation improved subjects’ performance on the hand laterality but not on the letter rotation task (stimulus specificity). In Experiment 2, we demonstrated that this facilitation was not due to mere observation of a moving hand, because it was triggered by observation of manual rotation but not of manual prehension movements (motion specificity). In Experiment 3, this stimulus- and motion-specific effect was found to be right hand-specific, compatible with left-hemispheric specialization in motor imagery but not in action observation. These data provided direct support to the idea that different simulation states, such as action observation and motor imagery, share some common mechanisms but also show specific functional differences.

Resting state eyes-closed cortical rhythms in patients with locked-in-syndrome: an EEG study

OBJECTIVE Locked-in syndrome (LIS) is a state of complete paralysis, except for ocular movements, which results from ventral brainstem lesions. Patients typically are fully conscious. Here we tested the hypothesis that electroencephalographic (EEG) rhythms are abnormal in LIS patients, possibly due to an impaired neural synchronization between brainstem and cerebral cortex. METHODS Resting state eyes-closed EEG data were recorded in 13 LIS subjects and 15 cognitively normal control subjects. With reference to the individual alpha frequency (IAF), the bands of interest were delta (IAF-8 to IAF-6Hz), theta (IAF-6 to IAF-4Hz), alpha 1 (IAF-4 to IAF-2Hz), alpha 2 (IAF-2 to IAFHz), and alpha 3 (IAF to IAF+2Hz). Furthermore, beta 1 (13-20Hz) and beta 2 (20-30Hz) bands were also considered. Cortical EEG sources were estimated by low-resolution electromagnetic tomography (LORETA). RESULTS The power of alpha 2 and alpha 3 sources in all regions was lower in patients with LIS compared to controls. The power of delta sources in central, parietal, occipital and temporal regions was higher in patients with LIS compared to controls. CONCLUSIONS These results suggest that cortical sources of resting state eyes-closed alpha and delta rhythms are abnormal in LIS patients. SIGNIFICANCE LIS is accompanied by a functional impairment of cortical neuronal synchronization mechanisms in the resting state condition.

Heart rate non linear dynamics in patients with persistent vegetative state: a preliminary report

Primary objective: This study evaluated the hypothesis that neural networks derangement in patients with a vegetative state (VS) may cause an alteration of heart rate (HR) non-linear pattern. Methods and procedures: Fifteen consecutive patients with a persistent VS and 15 matched healthy control subjects were included in the study. A 6-hour continuous electrocardiographic recording was used for the time series analysis measuring the occurrence time of the intervals between consecutive normal sinus heart beats (RR’ intervals). Parameters evaluating linear and non-linear HR variability were studied. Approximate Entropy (ApEn), a non-linear parameter that quantifies the unpredictability of fluctuations in an instantaneous HR time series, was calculated from the average values of time series with fixed input variables. Main outcomes and results: All linear parameters, with the only exception being the percentage of RR’ intervals that were by at least 50 ms different from the previous interval (0.56, SD = 1.31 vs 10.35, SD = 12.58; p = 0.005) were similar in patients and in healthy control subjects. Mean ApEn values (0.68, SD = 0.24 vs 1.10, SD = 0.16; p = 0.0001) were lower in patients than in healthy control subjects. Conclusions: The findings support the hypothesis that derangement of neural networks may cause a reduction of non-linear behaviour in HR such as ApEn.

Management of pathologic laughter and crying in patients with locked-in syndrome: a report of 4 cases

Emotional lability and pathologic laughter and crying (PLC) have been frequently mentioned in patients with locked-in syndrome (LIS) without giving any detail about the clinical characteristics and possible consequences in terms of symptoms burden, functional impact, and recovery. In the present report, we describe our approach and management of 4 patients with LIS and PLC. PLC caused discomfort to the patients and hindered the different components of their rehabilitation program, limiting communication, the execution of swallowing testing and training, and the improvement of any residual motor function. PLC was unrelated to depression, did not ameliorate after pharmacologic treatment, and improved with cognitive-behavior treatment. Our findings suggest that, in LIS patients, laughter and crying alterations do not represent symptoms of a mood disorder but are the result of the same pontine lesion that causes LIS. In relation to the complex pathway regulating laughter and crying, we hypothesized that, in patients with LIS, PLC may be the result of a direct damage to the pontine center or of an alteration in the ponto-cerebellar pathway linking emotional behavior to contextual information. Presence of PLC in patients with LIS severely affects their intelligent adaptation to the environment. Direct explanation to the patients of the origin of PLC may be helpful as a cognitive-behavior treatment, with resulting benefits to the entire rehabilitation program.

Corticomotor Facilitation in Vegetative State: Results of a Pilot Study

OBJECTIVE To investigate whether corticomotor facilitation induced by transcranial magnetic stimulation (TMS-CF) could evoke a simple purposeful motor behavior in patients with a diagnosis of vegetative state. DESIGN Cross-sectional survey. SETTING Post-coma and rehabilitation care unit. PARTICIPANTS Patients (N=6) with a diagnosis of vegetative state. INTERVENTIONS A cascade of consecutive motor-evoked potentials (MEPs) was elicited under 3 different conditions: in the first condition, patients were at rest (Rest); in the second, they were asked to open and close the right hand (Execution); in the third, the examiner modeled a movement of abduction of the thumb in front of the patient who was encouraged in advance to imitate the action (Observation to Imitate). MAIN OUTCOME MEASURES Changes in MEP values from the abductor pollicis brevis muscle and improvement in scores on the Coma Recovery Scale-Revised. RESULTS TMS-CF alone or combined with verbal instructions did not yield any change; only the combination with imitation caused changes in MEPs (shorter latency and increased amplitude) associated with behavioral improvement in 4 patients. CONCLUSIONS Encouraging observation to imitate may favor the transformation of some perceived actions into motor images and performances, probably depending on the activation of mirror motor neurons. In our opinion, combining visual input with TMS-CF might have reinforced the coupling between movement planning and execution, promoting the recovery of elementary motor activities in some patients. The proposed protocol may contribute to unmasking signs of preserved consciousness in patients with latent capacities for recovery.

Inter-hemispheric functional coupling of eyes-closed resting EEG rhythms in adolescents with Down syndrome

OBJECTIVE We tested the hypothesis that inter-hemispheric directional functional coupling of eyes-closed resting EEG rhythms is abnormal in adolescents with Down syndrome (DS). METHODS Eyes-closed resting EEG data were recorded in 38 DS adolescents (18.7 years +/-0.67 SE, IQ=49+/-1.9 SE) and in 17 matched normal control subjects (NYoung=19.1 years +/-0.39 SE). The EEG data were recorded from 8 electrodes (Fp1, Fp2, C3, C4, T3, T4, O1, O2) referenced to vertex. EEG 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). Power of EEG rhythms was evaluated by FFT for control purposes, whereas inter-hemispheric directional EEG functional coupling was computed by directed transfer function (DTF). RESULTS As expected, alpha, beta, and gamma power was widely higher in NYoung than DS subjects, whereas the opposite was true for delta power. As a novelty, DTF (directionality) values globally prevailed from right to left occipital areas in NYoung subjects and in the opposite direction in DS patients. A control experiment showed that this DTF difference could not be observed in the comparison between DS adults with mild cognitive impairment and normal age-matched adults. CONCLUSIONS These results indicate a peculiar abnormal directional inter-hemispheric interplay in visual occipital areas of DS adolescents. SIGNIFICANCE Direction of inter-hemispheric EEG functional coupling unveils a new abnormal brain network feature in DS adolescents.