Pearl and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part II.

This review focuses on new and/or less standardized event-related potentials methods, in order to improve their knowledge for future clinical applications. The olfactory event-related potentials (OERPs) assess the olfactory functions in time domain, with potential utility in anosmia and degenerative diseases. The transcranial magnetic stimulation-electroencephalography (TMS-EEG) could support the investigation of the intracerebral connections with very high temporal discrimination. Its application in the diagnosis of disorders of consciousness has achieved recent confirmation. Magnetoencephalography (MEG) and event-related fields (ERF) could improve spatial accuracy of scalp signals, with potential large application in pre-surgical study of epileptic patients. Although these techniques have methodological limits, such as high inter- and intraindividual variability and high costs, their diffusion among researchers and clinicians is hopeful, pending their standardization.

Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.

"Hit the missing stimulus". A simultaneous EEG-fMRI study to localize the generators of endogenous ERPs in an omitted target paradigm.

Event-Related Potentials (ERPs) occurring independently from any stimulus are purely endogenous (emitted potentials) and their neural generators can be unequivocally linked with cognitive processes. In the present study, the subjects performed two similar visual counting tasks: a standard two-stimulus oddball, and an omitted-target oddball task, characterized by the physical absence of the target stimulus. Our investigation aimed at localizing the neural sources of the scalp-recorded endogenous/emitted ERPs. To optimize the source localization, the high temporal resolution of electrophysiology was combined with the fine spatial information provided by the simultaneous recording of functional magnetic resonance (fMRI). Both tasks identified two endogenous ERP components in the 300 to 520 ms interval. An earlier component, pP2, showed a bilateral generator in the anterior Insula. A later P3 component (P3b) was generated bilaterally in the temporal-parietal junction, the premotor and motor area and the anterior intraparietal sulcus (this latter one only in the standard oddball). Anticipatory slow waves (beginning 900 to 500 ms pre-stimulus), also of endogenous nature, were produced by the inferior and middle frontal gyrus and the supplementary and cingulate motor areas. Our protocol disentangled pre- from post-stimulus fMRI activations and provided original clues to the psychophysiological interpretation of emitted/endogenous ERPs.

Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation.

The identification of signs of awareness in patients with prolonged disorders of consciousness (DoC) after severe brain injury is a challenging task for clinicians. Differentiating on behavioural examination the vegetative state (VS) from the minimally conscious state (MCS) can lead to a high misdiagnosis rate. Advanced neuroimaging and neurophysiological techniques can supplement clinical evaluation by providing physiological evidence of brain activity. However, an open issue remains whether these empirical results are directly or indirectly associated with covert consciousness and limitations emerge for their diagnostic application at the single-patient level. On the therapeutic side, the efficacy of both non-invasive and invasive brain stimulation/modulation trials is matter of debate. The present review provides an updated analysis of the diagnostic and prognostic impact that the different neurophysiological techniques of stimulation [including short-latency evoked potentials, long-latency event related potentials (ERPs), transcranial magnetic stimulation (TMS), TMS-EEG co-registration] offer in prolonged DoC. The results of the therapeutic stimulation techniques are also evaluated. It is concluded that TMS-EEG emerges as the most promising tool for differentiating VS from MCS whereas ERPs allow neurophysiologists to probe covert cognitive capacities of each patient. Significant behavioural improvements in prolonged DoC with brain stimulation techniques are still anecdotical and further treatment options are awaited.

Role of the dorsal premotor cortex in rhythmic auditory-motor entrainment: a perturbational approach by rTMS.

Synchronization of body movements to an external beat is a universal human ability, which has also been recently documented in nonhuman species. The neural substrates of this rhythmic motor entrainment are still under investigation. Correlational neuroimaging data suggest an involvement of the dorsal premotor cortex (dPMC) and the supplementary motor area (SMA). In 14 healthy volunteers, we more specifically investigated the neural network underlying this phenomenon using a causal approach by an established 1-Hz repetitive transcranial magnetic stimulation (rTMS) protocol, which produces a focal suppression of cortical excitability outlasting the stimulation period. Synchronization accuracy between rhythmic cues and right index finger tapping, as measured by the mean time lag (asynchrony) between motor and auditory events, was significantly affected when the right dPMC function was transiently perturbed by "off-line" focal rTMS, whereas the reproduction of the rhythmic sequence per se (inter-tap-interval) was spared. This approach affected metrical rhythms of different complexity, but not non-metrical or isochronous sequences. Conversely, no change in auditory-motor synchronization was observed with rTMS of the SMA, of the left dPMC or over a control site (midline occipital area). Our data strongly support the view that the right dPMC is crucial for rhythmic auditory-motor synchronization in humans.

Vegetative versus minimally conscious states: a study using TMS-EEG, sensory and event-related potentials.

Differential diagnoses between vegetative and minimally conscious states (VS and MCS, respectively) are frequently incorrect. Hence, further research is necessary to improve the diagnostic accuracy at the bedside. The main neuropathological feature of VS is the diffuse damage of cortical and subcortical connections. Starting with this premise, we used electroencephalography (EEG) recordings to evaluate the cortical reactivity and effective connectivity during transcranial magnetic stimulation (TMS) in chronic VS or MCS patients. Moreover, the TMS-EEG data were compared with the results from standard somatosensory-evoked potentials (SEPs) and event-related potentials (ERPs). Thirteen patients with chronic consciousness disorders were examined at their bedsides. A group of healthy volunteers served as the control group. The amplitudes (reactivity) and scalp distributions (connectivity) of the cortical potentials evoked by TMS (TEPs) of the primary motor cortex were measured. Short-latency median nerve SEPs and auditory ERPs were also recorded. Reproducible TEPs were present in all control subjects in both the ipsilateral and the contralateral hemispheres relative to the site of the TMS. The amplitudes of the ipsilateral and contralateral TEPs were reduced in four of the five MCS patients, and the TEPs were bilaterally absent in one MCS patient. Among the VS patients, five did not manifest ipsilateral or contralateral TEPs, and three of the patients exhibited only ipsilateral TEPs with reduced amplitudes. The SEPs were altered in five VS and two MCS patients but did not correlate with the clinical diagnosis. The ERPs were impaired in all patients and did not correlate with the clinical diagnosis. These TEP results suggest that cortical reactivity and connectivity are severely impaired in all VS patients, whereas in most MCS patients, the TEPs are preserved but with abnormal features. Therefore, TEPs may add valuable information to the current clinical and neurophysiological assessment of chronic consciousness disorders.

Atypical event-related potentials in patients with mild cognitive impairment: An identification-priming study.

BACKGROUND: Our goal was to verify whether behavioral and electrophysiological measures of visual object priming can differentiate between patients with mild cognitive impairment (MCI) and elderly control subjects. METHODS: An identification-priming paradigm with spatially filtered stimuli was used. Subjects were presented with complete forms of the stimuli in the study phase. In the subsequent test phase, studied items were repeated in an ascending sequence of spatially filtered stimuli, following a coarse-to-fine order. Event-related potentials and behavioral measures were recorded. RESULTS: Behavioral priming effects were observed in the elderly and in MCI participants. None of the well-known event-related potential indices of stimulus repetition emerged in the MCI group. In elderly controls, stimulus repetition was associated with a frontal modulation, likely indexing familiarity. Priming effects in the MCI group were probably based on memory mechanisms altered by degenerative pathology. CONCLUSIONS: Event-related potentials hold great potential for the early detection of subjects at risk for dementia, because they may reveal possible functional brain abnormalities that are not detectable at clinical or behavioral levels.

Temporal dynamics of memory-related effects in older and young adults: an event-related potential study.

Priming effects on the identification process were examined in young and older adults by using event-related potentials (ERPs). Animals and artifacts were presented in an ascending sequence of filtered images, half of which had been shown in their complete versions in a previous study phase. Each stimulus was represented by a progressively less filtered image (i.e., more complete) until the whole version was revealed in a sequence of frames. Such a paradigm allowed us to record ERPs prior to, and during, the identification of stimuli. Results showed a dynamic interplay between memory, category, and aging effects. At the moment of identification, young adults elicited larger positivity at parietal sites for previously studied stimuli and this effect was not observed for older adults. For stimuli previously studied, a striking effect was observed in both groups at the level just prior to overt identification. In addition, a frontally distributed priming effect was evident in the elderly. Category-related ERP differences emerged between the two age groups. In particular, younger participants elicited an early positive activation at anterior sites upon seeing stimuli of animals. These results are discussed in relation to current models of recognition memory, categorization, and age-related cognitive decline.

Surface electromyography shows increased mirroring in Parkinson's disease patients without overt mirror movements.

Patients with Parkinson's disease (PD) may present mirror movements (MM). Transcranial magnetic stimulation data indicate that these movements reflect an abnormal enhancement of the "physiological mirroring" that can be observed in healthy adults during complex and effortful tasks. It was hypothesized that, in PD, enhanced mirroring is caused by a failure of basal ganglia output to support the cortical network that is responsible for the execution of strictly unimanual movements. If so, it is likely that subtle alterations of voluntary unimanual motor control are also present in PD patients without overt MM. We tested this hypothesis by using surface electromyographic (EMG) techniques in 12 mildly to moderately affected PD patients without overt MM, and in 2 control groups (12 age-matched and 10 young healthy volunteers). Subjects performed unilateral phasic thumb abduction during a sustained tonic contraction of the opposite abductor pollicis brevis. All patients were tested on dopaminergic therapy. On a separate day, 7 of 12 patients were re-tested after withdrawal of medication. During this task, involuntary mirror-like increase in surface EMG of the tonically abducting thumb was significantly larger in PD patients than in age-matched or young healthy volunteers. Off therapy, mirroring was slightly greater than on medication, although this difference was not significant. Our findings suggest that dysfunction of unimanual motor control is a general feature of PD. It is likely that this deficient movement lateralization contributes to an impairment of nonsymmetrical bimanual movements in PD.

Mechanisms underlying mirror movements in Parkinson's disease: a transcranial magnetic stimulation study.

The neural mechanisms underlying unintended mirror movements (MMs) of one hand during unimanual movements of the other hand in patients with Parkinson's disease (PD) are largely unexplored. Here we used surface electromyographic (EMG) analysis and focal transcranial magnetic stimulation (TMS) to investigate the pathophysiological substrate of MMs in four PD patients. Surface EMG was recorded from both abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles. Cross-correlation EMG analysis revealed no common motor drive to the two APBs during intended unimanual tasks. Focal TMS of either primary motor cortex (M1) elicited normal motor-evoked potentials (MEPs) in the contralateral APB, whereas MEPs were not seen in the ipsilateral hand. During either mirror or voluntary APB contraction, focal TMS of the contralateral M1 produced a long-lasting silent period (SP), whereas stimulation of the ipsilateral M1 produced a short-lasting SP. During either mirror or voluntary finger tapping, 5 Hz repetitive TMS (rTMS) of the contralateral M1 disrupted EMG activity in the target FDI, whereas the effects of rTMS of the ipsilateral M1 were by far slighter. During either mirror or voluntary APB contraction, paired-pulse TMS showed a reduction of short-interval intracortical inhibition in the contralateral M1. These findings provide converging evidence that, in PD, MMs do not depend on unmasking of ipsilateral projections but are explained by motor output along the crossed corticospinal projection from the mirror M1.

Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome.

INTRODUCTION: Prognostic determination of patients in coma after resuscitation from cardiac arrest is both common and difficult. We explored clinical and electrophysiological testing to determine their associations with favorable and poor outcomes. METHODS: We studied 75 comatose patients resuscitated from cardiac arrest, excluding those who were brain dead or continuously sedated; none received hypothermia therapy. Clinical examinations were performed on day 1. RESULTS: The following proportions recovered awareness: 2 of 18 patients with absent pupillary reflexes; 18 of 57 with preserved pupillary reflexes (p = 0.08); 2 of 32 with absent corneal reflexes; 16 of 43 with preserved corneal reflexes (p = 0.001); 0 of 15 with absent oculovestibular reflexes; and 8 of 29 with preserved oculovestibular reflexes (p < 0.037). Purposeful movements were associated with a high probability of recovery, whereas other categories were unfavorable. Other categories of motor response were associated with an increased proportion of those who died without recovering awareness, but each category had some survivors. Somatosensory evoked potentials (SSEPs) were recorded from 47 patients. One of 21 patients with loss of the N20 component survived, compared with survival of 11 of 26 patients in whom it was present (p = 0.003). All 5 patients with preserved N70 responses recovered awareness in a subgroup of 33 patients. Sixteen of 22 subjects with mild electroencephalogram (EEG) abnormalities recovered consciousness, compared with the survival of 3 of 50 patients with malignant EEG patterns (p = 0.0000001). Combining SSEP with EEG findings produced even greater predictive value. CONCLUSION: It seems unlikely that any single test will prove to have 100% predictive value for outcome; further studies combining clinical, EEG, and SSEP testing are warranted.

Prediction of 'awakening' and outcome in prolonged acute coma from severe traumatic brain injury: evidence for validity of short latency SEPs.

OBJECTIVE: To evaluate the prognostic value of somatosensory evoked potentials (SEPs) in severe traumatic brain injury (TBI) considering both 'awakening' and disability. METHODS: SEPs were recorded in 60 severe TBI with duration of acute coma>7 days. N20-P25 amplitudes, their side-to-side asymmetry and CCT were measured. SEPs on each hemisphere were classified as normal (N), pathological (P) or absent (A). 'Awakening' and disability were assessed after at least 12 months using Glasgow Outcome Scale (GOS). SEP predictive value was compared with GCS and EEG reactivity RESULTS: Seventy-five percent regained consciousness. 29/60 had a good outcome (GOS 4-5) and 31/60 had a bad outcome (GOS 1-3). According to the ROC curve, SEP findings were classified in 3 grades. Grade I (NN, NP) had PPV of 93.1% for 'awakening' and 86.2% for good outcome. Grade III (AA) had PPV of 100% for bad outcome and 72.7% for 'awakening'. Grade II (PP, NA, PA) was associated with the wider range of outcome. A multivariate analysis including SEP grading, GCS and EEG reactivity did not increase the percentage of cases prognosticated by SEP alone. CONCLUSIONS: We confirm the high predictive value of SEPs in TBI, which is greater than GCS and EEG reactivity. Indeed, SEP grades I and III were able to predict the correct prognosis in more than 80% of severe TBI. Therefore, SEPs should be used more widely in the prognosis of severe TBI. SIGNIFICANCE: Differently from post-anoxic, in post-traumatic coma the presence of normal SEPs has a favourable predictive value both for 'awakening' and disability. We think that in literature enough attention has still not been paid to this finding.

Involvement of the human dorsal premotor cortex in unimanual motor control: an interference approach using transcranial magnetic stimulation.

Unilateral movements are enabled through a distributed network of motor cortical areas but the relative contribution from the parts of this network is largely unknown. Failure of this network potentially results in mirror activation of the primary motor cortex (M1) ipsilateral to the intended movement. Here we tested the role of the right dorsal premotor cortex (dPMC) in 11 healthy subjects by disrupting its activity with 20 Hz repetitive transcranial magnetic stimulation (rTMS) whilst the subjects exerted a unilateral contraction of the left first dorsal interosseous (FDI). We found that disruption of right dPMC enhanced mirror activation of the ipsilateral left M1, as probed by motor evoked potential (MEP) amplitude to the right FDI. This was not the case with sham rTMS, when rTMS was directed to the right M1, or with rTMS of the right dPMC but without contraction of the left FDI. Findings suggest that activity in the dPMC contributes to the suppression of mirror movements during intended unilateral movements.

Separate ipsilateral and contralateral corticospinal projections in congenital mirror movements: Neurophysiological evidence and significance for motor rehabilitation.

The neurophysiological hallmark of congenital mirror movements (MM) are fast-conducting corticospinal projections from the hand area of one primary motor cortex to both sides of the spinal cord. It is still unclear whether the abnormal ipsilateral projection originates through branching fibres from the normal contralateral projection or constitutes a separate ipsilateral projection. To clarify this question, we used focal paired-pulse transcranial magnetic stimulation to test task-related modulation of short-interval intracortical inhibition (SICI) in the abductor pollicis brevis (APB) muscles of a 15-year-old girl (Patient 1) and a 40-year-old woman (Patient 2) with congenital MM. In both patients, during intended unilateral APB contraction, SICI decreased markedly in the "task" APB but remained unchanged in the "mirror" APB when compared to muscle rest. In contrast, spinal excitability as tested with H reflexes increased similarly in the task and mirror flexor carpi radialis muscles. This dissociation of task-related SICI modulation strongly supports the existence of a separate ipsilateral fast-conducting corticospinal projection. In Patient 1, we tested the functional significance of this separate ipsilateral projection during 7 months of motor rehabilitation training, which was designed to facilitate unilateral finger movements. A marked reduction of MM was observed after training, suggesting that unwanted mirror activity in the ipsilateral pathway can be suppressed by learning.

Nonlinear EEG analysis during sleep in premature and full-term newborns.

OBJECTIVE: Recently it has been shown that the adult sleep EEG is mostly determined by high-dimensional, linear dynamics with the exception of the A phase of the cyclic alternating pattern which displays more synchronized nonlinear dynamics. It is not known how these two different types of brain dynamics develop in early life; for this reason the aim of this study was that to extend the nonlinear analysis to the EEG during sleep recorded in premature and full-term newborns. METHODS: EEG epochs were chosen from a total of 24 polygraphic recordings from 14 babies (9 males and 5 females) aged between 33 weeks 3 days and 4 months conceptional age. All subjects were neurologically normal and showed normal psychomotor development at follow-up. A total of 243 artifact-free epochs was chosen during active sleep (AS, 74 total epochs), quiet sleep (QS, 76 total epochs) and indeterminate sleep (IS, 93 total epochs). The dynamic properties of the EEG were assessed by means of the nonlinear cross prediction test which uses 3 different 'model' time series in order to predict nonlinearly the original data set (Pred, Ama, and Tir). Pred is a measure of the predictability of the time series, and Ama and Tir are measures of asymmetry, indicating nonlinear structure. RESULTS: Our results show that the structure of sleep EEG in newborns is significantly different from that of adults, it cannot be distinguished from that of high-dimensional noise in the majority of epochs, and shows a tendency to become nonlinear in nature, mostly during QS, in a small percentage of the epochs analyzed. CONCLUSIONS: These findings can be interpreted as the effect of immature synaptic interconnections between neurons in the newborn brain.