Davide Rossi Sebastiano

Altered resting state effective connectivity in long-standing vegetative state patients: An EEG study

OBJECTIVE Recent evidence mainly based on hemodynamic measures suggests that the impairment of functional connections between different brain areas may help to clarify the neuronal dysfunction occurring in patients with disorders of consciousness (DOC). The aim of this study was to evaluate effective EEG connectivity in a cohort of 18 patients in a chronic vegetative state (VS) observed years after the occurrence of hypoxic (eight) and traumatic or hemorrhagic brain insult. METHODS we analysed the EEG signals recorded under resting conditions using a frequency domain linear index of connectivity (partial directed coherence: PDC) estimated from a multivariate autoregressive model. The results were compared with those obtained in ten healthy controls. RESULTS Our findings indicated significant connectivity changes in EEG activities in delta and alpha bands. The VS patients showed a significant and widespread decrease in delta band connectivity, whereas the alpha activity was hyper-connected in the central and posterior cortical regions. CONCLUSION These changes suggest the occurrence of severe circuitry derangements probably due to the loose control of the subcortical connections. The alpha hyper-synchronisation may be due to simplified networks mainly involving the short-range connections between intrinsically oscillatory cortical neurons that generate aberrant EEG alpha sources. This increased connectivity may be interpreted as a reduction in information capacity, implying an increasing prevalence of stereotypic activity patterns. SIGNIFICANCE Our observations suggest a remarkable rearrangement of connectivity in patients with long-standing VS. We hypothesize that in persistent VS, after a first period characterized by a breakdown of cortical connectivity, neurodegenerative processes, largely independent from the type of initial insult, lead to cortex de-afferentation and to a severe reduction of possible cortical activity patterns and states.

Multimodal study of default-mode network integrity in disorders of consciousness

Understanding residual brain function in disorders of consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default‐mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting‐state functional magnetic resonance imaging (rs‐fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment.

Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations.

Purpose:  Unverricht‐Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype–phenotype relationships.

Cortical myoclonus in childhood and juvenile onset Huntington's disease.

OBJECTIVE Huntingtons disease (HD) appearing before the age of 20 years gives rise to a distinct phenotype with respect to the classical adult-onset disease. Here we describe three patients with childhood or juvenile HD onset presenting with action myoclonus. METHODS We performed jerk-locked back-averaging (JLBA), EEG-EMG coherence and phase analysis, long-loop reflexes (LLRs) and somatosensory evoked potentials (SSEPs). In one patient, we also performed transcranial magnetic stimulation (TMS) using single and paired pulses. RESULTS In all patients, the EMG features revealed movement activated quasi-rhythmic repetitive jerks; the JLBA and EEG-EMG spectral and coherence profiles indicated a cortical generator of the myoclonus. All patients had enhanced LLRs during muscle contraction, while none showed giant SSEPs. The evaluation of intracortical inhibition by means of TMS revealed reduced inhibition at short and long interstimulus intervals. CONCLUSIONS The rhythmic course of the action myoclonus and the characteristics of the LLRs suggest that myoclonus is due to a reverberant circuit involving the motor cortex, possibly because of an imbalance between excitatory and inhibitory cortical neuronal systems. SIGNIFICANCE Our findings suggest a similar cortical dysfunction in childhood and juvenile onset HD, which probably results from a specific circuitry impairment.

Sleep patterns associated with the severity of impairment in a large cohort of patients with chronic disorders of consciousness

OBJECTIVE We assessed sleep patterns in 85 patients with chronic disorders of consciousness (DOC) in order to reveal any relationship with the degree of the impairment. METHODS Nocturnal polysomnography (PSG) was scored in patients classified as being in an unresponsive wakefulness syndrome/vegetative state (UWS/VS; n = 49) or a minimally conscious state (MCS; n = 36) in accordance with the rules of the American Academy of Sleep Medicine. The PSG data in the two diagnostic groups were compared, and the PSG parameters associated with the degree of impairment were analysed. RESULTS In 19/49 UWS/VS patients, signal attenuation was the only EEG pattern detectable in sleep. Non-REM 2 (NREM2) and slow-wave sleep (SWS) (but not REM) stages were more frequent in the MCS patients. The presence of SWS was the most appropriate factor for classifying patients as UWS/VS or MCS, and the duration of SWS was the main factor that significantly correlated with revised Coma Recovery Scale scores. CONCLUSION The presence of NREM sleep (namely SWS) reflects better preservation of the circuitry and structures needed to sustain this stage of sleep in DOC patients. SIGNIFICANCE PSG is a simple and effective technique, and sleep patterns may reflect the degree of impairment in chronic DOC patients.

The neural correlates of lexical processing in disorders of consciousness

There is a growing interest in the use of functional imaging to assess brain activity in the absence of behavioural responses in patients with disorders of consciousness (DOC). In the present study, we applied a hierarchical auditory stimulation paradigm to functional magnetic resonance (fMRI) in a group of long-term DOC adult patients. Brain response to pairs of pseudowords, of unrelated words and of semantically related words, i.e. stimuli differing in lexical status (words vs. pseudowords) and semantic relatedness (related vs. unrelated) was assessed. The former contrast was considered to reflect the automatic brain response to the passive presentation of meaningful real words, while the latter aimed to assess the response to meaning relationships. The results of the study indicate that automatic lexical processing can be observed in minimally conscious state (MCS), but also in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, as indicated by increase in blood oxygenation level dependent (BOLD) activity in the linguistic networks. DOC patients, for some task conditions, recruited additional areas in comparison to healthy participants. Furthermore this study provides additional evidence of the potential role of fMRI in the assessment of residual cognitive processing in some of these patients, which may not be evident at the clinical level.

Is Period3 Genotype Associated With Sleep and Recovery in Patients With Disorders of Consciousness

Background. Sleep evaluation is increasingly being used as prognostic tool in patients with disorders of consciousness, but, surprisingly, the role of Period3 (Per3) gene polymorphism has never been evaluated. Objective. The aim of this study was to investigate the contribution of Per3 genotype on sleep quantity and consciousness recovery level in patients with disorders of consciousness (DOC). Methods. In this observational study, we evaluated 71 patients with DOC classified as vegetative state/unresponsive wakefulness syndrome or minimally conscious state. Demographic and clinical data were collected and a standardised diagnostic workup, including a polysomnographic record, was applied. After informed consent provided by proxy, genomic DNA was obtained and Per3 polymorphism was analysed by polymerase chain reaction to identify 5/5, 4/5, or 4/4 genotype. Results. Per35/5 genotype was found in 12.7% of our DOC patients. The median total Coma Recovery Scale–revised score in Per35/5 carriers was significantly higher than 4/4 genotype (10, range 5-16 vs 7, range 4-11; post hoc P = .036). Moreover, total sleep time seemed to be higher in 5/5 genotype (5/5, 221 minutes, range 88-515 minutes; 4/4, 151.5 minutes, range 36-477 minutes; and 4/5, 188 minutes, range 44-422 minutes). Conclusion. For the first time we have shown a possible association between Per3 polymorphism and consciousness recovery level in DOC patients. Even though the exact molecular mechanism has not been defined, we speculate that its effect is mediated by higher total sleep time and slow wave sleep, which would improve the preservation of main cerebral connections.

Multimodality fNIRS-EEG, fMRI-EEG and TMS Clinical Study on Cortical Response During Motor Task in Adult Volunteers and Epileptic Patients with Movement Disorders

A multimodality fNIRS-EEG, fMRI-EEG and TMS clinical study was performed on adult volunteers and epileptic patients with movement disorders to assess cortical response during motor tasks

Effect of repetitive transcranial magnetic stimulation on action myoclonus: A pilot study in patients with EPM1

OBJECTIVE The objective of this study was to explore the short-term effects of repetitive transcranial magnetic stimulation (rTMS) on action myoclonus. METHODS Nine patients with Unverricht-Lundborg (EPM1) progressive myoclonus epilepsy type underwent two series of 500 stimuli at 0.3Hz through round coil twice a day for five consecutive days. Clinical and neurophysiological examinations were performed two hours before starting the first rTMS session and two hours after the end of the last rTMS session. RESULTS Eight patients completed the protocol; one discontinued because of a transient increase in spontaneous jerks. The unified myoclonus rating scale indicated a 25% reduction in posttreatment myoclonus with action score associated with an increase in the cortical motor threshold and lengthening of the cortical silent period (CSP). The decrease in the myoclonus with action scores correlated with the prolongation of CSP. CONCLUSIONS Repetitive transcranial magnetic stimulation can be safely used in patients with EPM1, improves action myoclonus, and partially restores deficient cortical inhibition.

Epileptic spikes in Rasmussen’s encephalitis: Migratory pattern and short-term evolution. A MEG study

OBJECTIVE We aimed this study at identifying cortical areas involved in the generation of interictal spikes in Rasmussens Encephalitis (RE) patients using magnetoencephalography (MEG), at comparing spike localization with the degree of cortical atrophy detected by MRI, and at identifying short-term changes during the follow-up. METHODS Five patients with RE underwent two MEG and magnetic resonance imaging (MRI) (six months interval). The sources of visually detected spikes were estimated using equivalent current dipoles technique; these were then superimposed on individual MRI and clustered; the locations of the clusters were related to the MRI stage of cortical atrophy. RESULTS All patients showed spikes and clusters located in different cortical areas in both recordings; the locations had a limited correspondence with cortical atrophy. The second recordings showed changes in the localisation of spikes and clusters, and confirmed the dissimilarities with neuroradiological abnormalities. CONCLUSIONS The presence of clusters of spikes of variable localisation suggests that RE progresses in a multifocal and fluctuating manner. The cortical areas most involved in epileptogenesis did not completely coincide with the most atrophic areas. SIGNIFICANCE MEG can contribute to evaluating multifocal hemispheric spikes in RE and to better understand the time course of epileptogenic process.