Luigi De Gennaro

Consensus paper: Combining transcranial stimulation with neuroimaging

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

The electroencephalographic fingerprint of sleep is genetically determined: a twin study.

Humans have an individual profile of the electroencephalographic power spectra at the 8 to 16Hz frequency during non–rapid eye movement sleep that is stable over time and resistant to experimental perturbations. We tested the hypothesis that this electroencephalographic “fingerprint” is genetically determined, by recording 40 monozygotic and dizygotic twins during baseline and recovery sleep after prolonged wakefulness. We show a largely greater similarity within monozygotic than dizygotic pairs, resulting in a heritability estimate of 96%, not influenced by sleep need and intensity. If replicated, these results will establish the electroencephalographic profile during sleep as one of the most heritable traits of humans. Ann Neurol 2008

Antero-posterior EEG changes during the wakefulness-sleep transition

OBJECTIVES To investigate the brain topography of the human sleep EEG along the antero-posterior axis during the wakefulness-sleep transition, by means of both a single Hz analysis and a grouped-frequency analysis of EEG changes. METHODS EEG power values were calculated across a 1-28 Hz frequency range in a 1 Hz resolution during the wakefulness-sleep transition of 7 normal subjects. Topographical changes were assessed from C3-A2, C4-A1, Fpz-A1, Fz-A1, Cz-A1, Pz-A1, Oz-A1 recordings, after averaging individual time series, aligned with respect to the onset of stage 2. RESULTS The single Hz analysis showed that before sleep onset (SO), the <7 Hz slow frequencies were more prominent at the more anterior scalp locations; this anterior prominence was counterbalanced by a reciprocal prevalence across the >8 Hz frequencies of EEG activity from the occipital areas; while the >13 Hz fast frequencies were not characterized by significant antero-posterior differences. After SO, more EEG power was found in the range of slow frequencies at the centro-frontal scalp locations and a second peak of EEG activity was also revealed within the range of the sigma frequency, higher at the centro-parietal scalp locations. No consistent topographical changes were observed within the range of faster EEG frequencies. Grouped-frequency analysis confirmed these results, also pointing to different changes in the alpha frequency as a function of the SO point. CONCLUSIONS The results suggest that: (a) the alpha rhythm spreads anteriorly as the transition progresses; (b) several anterior areas first synchronize EEG activity; (c) the functional meaning of the EEG bands during the SO period should be partially revised with regard at least to alpha rhythm; (d) SO coincides with the start of stage 2.

Mobile phone emissions and human brain excitability

To test—via Transcranial Magnetic Stimulation (TMS)—the excitability of each brain hemisphere after ‘real’ or ‘sham’ exposure to the electromagnetic field (EMF) generated by a mobile phone operating in the Global System for Mobile Communication (GSM).

Validity of the Italian version of the Pittsburgh Sleep Quality Index (PSQI)

The aim of this study is to validate the Italian version of the Pittsburgh Sleep Quality Index (PSQI), comparing five different groups of individuals (healthy young and elderly, sleep apnoea syndrome patients, depressed patients, individuals with dementia) by both questionnaire scores and polysomnographic measures. Fifty individuals (10 for each group) participated in the study. Each of them filled in the PSQI and slept for two consecutive nights in the sleep laboratory. The PSQI showed an overall reliability coefficient (Cronbach’s α) of 0.835, indicating a high degree of internal consistency. The mean PSQI global score showed significant differences between groups, with an impaired overall quality of sleep in patients’ groups with respect to both the healthy groups. Results also indicated that the best cut-off score (differentiating “good” from “bad” sleepers) is 5. Pittsburgh Sleep Quality Index is a useful, valid and reliable tool for the assessment of sleep quality, with an overall efficiency comparable to the mother language version and differentiate “good” from “bad” sleepers. The Italian version of the questionnaire provides a good and reliable differentiation between normal and pathological groups, with higher scores reported by people characterized by impaired objectively evaluated sleep quality.

The spontaneous K-complex during stage 2 sleep: is it the ‘forerunner’ of delta waves?

The hypothesis that K-complexes (KCs) contribute to the process of synchronization leading to Slow-Wave Sleep (SWS) was evaluated by measuring their dynamic evolution across sleep cycles and before transitions to rapid eye movement (REM) or to SWS. KC density and inter-KC intervals respectively decreased and increased across the sleep cycles, revealing linear trends. Comparisons among transitions from stage 2 to SWS or to REM sleep showed a prevalence of KCs before the shift to SWS as compared to REM. Changes in KC density before the shift to SWS were fitted by a linear regression, at variance with the transition to REM sleep. Intra-night variations of KCs, paralleling the well-known decrease of slow waves across sleep cycles, and intracycle variations before shifting to SWS, both converge to indicate that KCs can be considered as the forerunner of delta waves.

Handedness is mainly associated with an asymmetry of corticospinal excitability and not of transcallosal inhibition

OBJECTIVE The study aims to compare transcallosal inhibition (TI), as assessed by the paired-pulse transcranial magnetic stimulation (TMS) technique, in a sample of right-handed subjects (RH) and left-handed subjects (LH). Motor thresholds (MTs) and motor evoked potential (MEP) amplitudes were also measured in the two groups, as an index of corticospinal activity. METHODS Thirty-two normal subjects (16 RH and 16 LH) were recorded with a paired-pulse TMS paradigm (intensity of both pulses=120% of MT). The inter-stimulus intervals (ISIs) were 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 ms for both motor cortices, and MEP responses were recorded from the abductor digiti minimi muscles. RESULTS Both groups showed a clear TI centred around the 12 ms ISI, but no difference was found as a function of handedness or of hemisphere. On the other hand, the two groups differed in terms of corticospinal activity, since the hand motor dominant hemisphere had lower MTs than the non-dominant one in LH, and larger MEP amplitudes for the right hand were found in RH. CONCLUSIONS Results point to a functional asymmetry of the motor cortex on the hand-dominant versus the non-dominant hemisphere, while handedness does not seem associated with functional differences in callosal inhibition, as measured by the inter-hemispheric paired-pulse TMS technique.

Neurophysiological correlates of sleepiness: A combined TMS and EEG study

Changes of cortical and corticospinal excitability as a function of sleep deprivation have been studied, using EEG power maps and several TMS measures in 33 normal subjects before and after a 40-h sleep deprivation (SD). The effects of SD were independently assessed by subjective and EEG measures of sleepiness, the latter being represented in terms of cortical maps for different frequency bands. Short intracortical facilitation (SICF) and inhibition (SICI) were measured by the paired-pulse TMS technique with different inter-stimulus intervals. Besides standardized motor threshold (MT), lower threshold (LT) and upper threshold (UT) were also determined. Subjective sleepiness severely increased as a consequence of SD, paralleled by a drastic decrease of alertness. EEG topography showed large increases in delta and theta activity, mainly evident at fronto-central areas. Standard MTs, as well as LTs and UTs, all increased as a consequence of SD. SICF also showed a significant increase as compared to pre-deprivation values, but only in females. The increase of theta activity was strongly associated in the left frontal and prefrontal cortex to a smaller decrease of corticospinal excitability, expressed by MTs, and a larger increase of intracortical facilitation, expressed by SICF. TMS and EEG measures converge in indicating that SD has severe effects on both cortical and corticospinal excitability, as shown respectively by the increases of slow-frequency EEG power and MTs. The SICF enhancement in females and the results of the combined topographical analysis of EEG and TMS changes are coherent with the hypothesis that cortical TMS-evoked responses are higher as a consequence of a longer wakefulness. However, the lack of an increase in cortical excitability after prolonged wakefulness in males suggests some caution in the generalization of these effects, that deserve further investigation.

The effects of sleep and sleep deprivation on task-switching performance

Neural systems of the prefrontal cortex (PFC) involved in executive functions are particularly vulnerable to sleep deprivation (SD). In this study, we investigated whether SD selectively affects specific components of the executive control processes involved in task‐switching performance. Two different tasks are performed in rapid and random succession in this procedure, so that the to‐be‐executed task may change from one trial to the next (switch trial), or may be repeated (repetition trial). Task‐switches are usually slower than task repetitions, giving way to the ‘switch cost’. One hundred and eight university students were assigned randomly to the sleep (S) or the SD group. Each of them was tested on a task‐switching paradigm before and after an experimental night (S or SD), and after one recovery night. SD impaired both task‐switching accuracy and speed. A higher proportion of errors and increased switch costs after SD have been observed, compared to normal sleep. Control analyses on switch and repetition trials showed that the SD group was significantly worse only on the switch trials. The effects of SD are reverted by one night of recovery sleep. It is concluded that the ability to adjust behaviour rapidly and flexibly to changing environmental demands, which relies on the functional integrity of the PFC, is impacted negatively by sleep loss.

Dissociated wake-like and sleep-like electro-cortical activity during sleep.

Sleep is traditionally considered a global process involving the whole brain. However, recent studies have shown that sleep depth is not evenly distributed within the brain. Sleep disorders, such as sleepwalking, also suggest that EEG features of sleep and wakefulness might be simultaneously present in different cerebral regions. In order to probe the coexistence of dissociated (wake-like and sleep-like) electrophysiological behaviors within the sleeping brain, we analyzed intracerebral electroencephalographic activity drawn from sleep recordings of five patients with pharmacoresistant focal epilepsy without sleep disturbances, who underwent pre-surgical intracerebral electroencephalographic investigation. We applied spectral and wavelet transform analysis techniques to electroencephalographic data recorded from scalp and intracerebral electrodes localized within the Motor cortex (Mc) and the dorso-lateral Prefrontal cortex (dlPFc). The Mc showed frequent Local Activations (lasting from 5 to more than 60s) characterized by an abrupt interruption of the sleep electroencephalographic slow waves pattern and by the appearance of a wake-like electroencephalographic high frequency pattern (alpha and/or beta rhythm). Local activations in the Mc were paralleled by a deepening of sleep in other regions, as expressed by the concomitant increase of slow waves in the dlPFc and scalp electroencephalographic recordings. These results suggest that human sleep can be characterized by the coexistence of wake-like and sleep-like electroencephalographic patterns in different cortical areas, supporting the hypothesis that unusual phenomena, such as NREM parasomnias, could result from an imbalance of these two states.