Andrea Pigorini

EEG Responses to TMS Are Sensitive to Changes in the Perturbation Parameters and Repeatable over Time

Background High-density electroencephalography (hd-EEG) combined with transcranial magnetic stimulation (TMS) provides a direct and non-invasive measure of cortical excitability and connectivity in humans and may be employed to track over time pathological alterations, plastic changes and therapy-induced modifications in cortical circuits. However, the diagnostic/monitoring applications of this technique would be limited to the extent that TMS-evoked potentials are either stereotypical (non-sensitive) or random (non-repeatable) responses. Here, we used controlled changes in the stimulation parameters (site, intensity, and angle of stimulation) and repeated longitudinal measurements (same day and one week apart) to evaluate the sensitivity and repeatability of TMS/hd-EEG potentials. Methodology/Principal Findings In 10 volunteers, we performed 92 single-subject comparisons to evaluate the similarities/differences between pairs of TMS-evoked potentials recorded in the same/different stimulation conditions. For each pairwise comparison, we used non-parametric statistics to calculate a Divergence Index (DI), i.e., the percentage of samples that differed significantly, considering all scalp locations and the entire post-stimulus period. A receiver operating characteristic analysis showed that it was possible to find an optimal DI threshold of 1.67%, yielding 96.7% overall accuracy of TMS/hd-EEG in detecting whether a change in the perturbation parameters occurred or not. Conclusions/Significance These results demonstrate that the EEG responses to TMS essentially reflect deterministic properties of the stimulated neuronal circuits as opposed to stereotypical responses or uncontrolled variability. To the extent that TMS-evoked potentials are sensitive to changes and repeatable over time, they may be employed to detect longitudinal changes in the state of cortical circuits.

Stratification of unresponsive patients by an independently validated index of brain complexity

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 benchmark population who could confirm the presence or absence of consciousness through subjective reports, and then applying the same index to patients with disorders of consciousness (DOCs).

Local aspects of sleep: observations from intracerebral recordings in humans.

Human sleep is considered a global phenomenon, orchestrated by central specialized neuronal networks modulating the whole-brain activity. However, recent studies point to a local regulation of sleep. Sleep disorders, such as sleepwalking, suggest that electroencephalographic (EEG) features of sleep and wakefulness might be simultaneously present in different cerebral regions. Recently, intracranial EEG recording techniques, mainly applied for the presurgical evaluation of drug-resistant epileptic patients, have provided new and interesting information on the activity of different cortical and subcortical structures during sleep in humans. In particular, it has been observed that the thalamus, during the transition between wake and sleep undergoes a deactivation process that precedes the one occurring within the cortex, with extensive cortical territories maintaining an activated pattern for several minutes after the thalamic deactivation. Very recent intracerebral EEG studies have also shown that human NREM sleep can be characterized by the coexistence of wake-like and sleep-like EEG patterns in different cortical areas. Moreover, unit-firing recordings in multiple brain regions of neurosurgical patients evidenced that most sleep slow waves and the underlying active and inactive neuronal states do occur locally. These findings add a new dimension to the concept of local sleep regulation and opens new perspectives in the interpretation of the substrates underlying behavioral states of vigilance. The implications for sleep medicine are also discussed.

Bistability breaks-off deterministic responses to intracortical stimulation during non-REM sleep

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 patients undergoing intra-cerebral stimulations/recordings for clinical evaluation. We observed that, while during wakefulness electrical stimulation triggers a chain of deterministic phase-locked activations in its cortical targets, during NREM the same input induces a slow wave associated with an OFF-period (suppression of power>20Hz), possibly reflecting a neuronal down-state. Crucially, after the OFF-period, cortical activity resumes to wakefulness-like levels, but the deterministic effects of the initial input are lost, as indicated by a sharp drop of phase-locked activity. These findings suggest that the intrinsic tendency of cortical neurons to fall into a down-state after a transient activation (i.e. bistability) prevents the emergence of stable patterns of causal interactions among cortical areas during NREM. Besides sleep, the same basic neurophysiological dynamics may play a role in pathological conditions in which thalamo-cortical information integration and consciousness are impaired in spite of preserved neuronal activity.

Local aspects of sleep

Human sleep is considered a global phenomenon, orchestrated by central specialized neuronal networks modulating the whole-brain activity. However, recent studies point to a local regulation of sleep. Sleep disorders, such as sleepwalking, suggest that electroencephalographic (EEG) features of sleep and wakefulness might be simultaneously present in different cerebral regions. Recently, intracranial EEG recording techniques, mainly applied for the presurgical evaluation of drug-resistant epileptic patients, have provided new and interesting information on the activity of different cortical and subcortical structures during sleep in humans. In particular, it has been observed that the thalamus, during the transition between wake and sleep undergoes a deactivation process that precedes the one occurring within the cortex, with extensive cortical territories maintaining an activated pattern for several minutes after the thalamic deactivation. Very recent intracerebral EEG studies have also shown that human NREM sleep can be characterized by the coexistence of wake-like and sleep-like EEG patterns in different cortical areas. Moreover, unit-firing recordings in multiple brain regions of neurosurgical patients evidenced that most sleep slow waves and the underlying active and inactive neuronal states do occur locally. These findings add a new dimension to the concept of local sleep regulation and opens new perspectives in the interpretation of the substrates underlying behavioral states of vigilance. The implications for sleep medicine are also discussed.

Hippocampal sleep spindles preceding neocortical sleep onset in humans

The coexistence of regionally dissociated brain activity patterns -with some brain areas being active while other already showing sleep signs- may occur throughout all vigilance states including the transition from wakefulness to sleep and may account for both physiological as well as pathological events. These dissociated electrophysiological states are often characterized by multi-domain cognitive and behavioral impairment such as amnesia for events immediately preceding sleep. By performing simultaneous intracerebral electroencephalographic recordings from hippocampal as well as from distributed neocortical sites in neurosurgical patients, we observed that sleep spindles consistently occurred in the hippocampus several minutes before sleep onset. In addition, hippocampal spindle detections consistently preceded neocortical events, with increasing delays along the cortical antero-posterior axis. Our results support the notion that wakefulness and sleep are not mutually exclusive states, but rather part of a continuum resulting from the complex interaction between diffuse neuromodulatory systems and intrinsic properties of the different thalamocortical modules. This interaction may account for the occurrence of dissociated activity across different brain structures characterizing both physiological and pathological conditions.

Assessing the Effects of Electroconvulsive Therapy on Cortical Excitability by Means of Transcranial Magnetic Stimulation and Electroencephalography

Electroconvulsive therapy (ECT) has significant short-term antidepressant effects on drug-resistant patients with severe major depression. Animal studies have demonstrated that electroconvulsive seizures produce potentiation-like synaptic remodeling in both sub-cortical and frontal cortical circuits. However, the electrophysiological effects of ECT in the human brain are not known. In this work, we evaluated whether ECT induces a measurable change in the excitability of frontal cortical circuits in humans. Electroencephalographic (EEG) potentials evoked by transcranial magnetic stimulation (TMS) were collected before and after a course of ECT in eight patients with severe major depression. Cortical excitability was measured from the early and local EEG response to TMS. Clinical assessment confirmed the beneficial effects of ECT on depressive symptoms at the group level. TMS/EEG measurements revealed a clear-cut increase of frontal cortical excitability after ECT as compared to baseline, that was significant in each and every patient. The present findings corroborate in humans the idea that ECT may produce synaptic potentiation, as previously observed in animal studies. Moreover, results suggest that TMS/EEG may be employed in depressed patients to monitor longitudinally the electrophysiological effects of different therapeutic neuromodulators, e.g. ECT, repetitive TMS, and sleep deprivation. To the extent that depression involves an alteration of frontal cortical excitability, these measurements may be used to guide and evaluate treatment progression over time at the single-patient level.

Time–frequency spectral analysis of TMS-evoked EEG oscillations by means of Hilbert–Huang transform

A single pulse of Transcranial Magnetic Stimulation (TMS) generates electroencephalogram (EEG) oscillations that are thought to reflect intrinsic properties of the stimulated cortical area and its fast interactions with other cortical areas. Thus, a tool to decompose TMS-evoked oscillations in the time-frequency domain on a millisecond timescale and on a broadband frequency range may help to understand information transfer across cortical oscillators. Some recent studies have employed algorithms based on the Wavelet Transform (WT) to study TMS-evoked EEG oscillations in healthy and pathological conditions. However, these methods do not allow to describe TMS-evoked EEG oscillations with high resolution in time and frequency domains simultaneously. Here, we first develop an algorithm based on Hilbert-Huang Transform (HHT) to compute statistically significant time-frequency spectra of TMS-evoked EEG oscillations on a single trial basis. Then, we compared the performances of the HHT-based algorithm with the WT-based one by applying both of them to a set of simulated signals. Finally, we applied both algorithms to real TMS-evoked potentials recorded in healthy or schizophrenic subjects. We found that the HHT-based algorithm outperforms the WT-based one in detecting the time onset of TMS-evoked oscillations in the classical EEG bands. These results suggest that the HHT-based algorithm may be used to study the communication between different cortical oscillators on a fine time scale.

Changes of cortical excitability as markers of antidepressant response in bipolar depression: preliminary data obtained by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG)

It is still unclear which biological changes are needed to recover from a major depressive episode. Current perspectives focus on cortical synaptic neuroplasticity. Measures of cortical responses evoked by transcranial magnetic stimulation (TMS) change with sleep homeostasic pressure in humans and approximate measures of synaptic strength in animal models. Using repeated total sleep deprivation as a model of antidepressant treatment, we aimed to correlate recovery from depression with these measures of cortical excitability.

Transcranial magnetic stimulation-evoked EEG/cortical potentials in physiological and pathological aging.

The frontal cortex undergoes macrostructural and microstructural changes across the lifespan. These changes can be entirely physiological, such as the ones occurring in elderly individuals who are cognitively intact, or pathological, such as the ones occurring in patients with Alzheimers disease. Here, we use simultaneous electroencephalography (EEG) and transcranial magnetic stimulation (TMS) to study how the excitability of the frontal cortex changes during healthy and pathological aging. Hence, we compared the TMS-evoked EEG potentials collected in healthy elderly individuals with the ones collected in healthy young individuals, and in patients with Alzheimers disease. We have shown that the EEG response to TMS of the left superior frontal cortex is not affected by physiological aging but is markedly altered by cognitive impairment.