Domenica Veniero

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.

Paired Associative Stimulation Enforces the Communication between Interconnected Areas

Paired associative stimulation (PAS) protocols induce forms of spike-timing-dependent-plasticity (STDP) when paired pulses are repeatedly applied with different timing over interconnected cortical areas such as the posterior parietal cortex (PPC) and the primary motor cortex (M1). However, the assessment of PAS effects is usually limited to M1 through recording of motor-evoked potential (MEP) amplitude. Here, by combining transcranial magnetic stimulation (TMS) with EEG we aimed at investigating PAS effects over both areas (PPC, M1) and the modulation induced on their connectivity in humans. In different PAS conditions, PPC preceded or followed M1 TMS by 5 ms. We found that TMS-evoked potentials (TEPs) changed differently according to the long-term depression (LTD) or potentiation (LTP) after-effect assessed by MEPs, but did not vary at PPC level. Moreover, there was no change in local oscillatory power. However, there was a remarkable increase of coherence between the PPC and the M1 areas. When the PAS protocol induced LTD as revealed by MEPs, there was a specific increase of the coherence between PPC and M1 within the beta band. On the contrary, when PAS induced LTP, the coherence crucially increased in the alpha band. The same LTP results were confirmed when rotating the stimulating coil in M1 during the PAS protocol. In conclusion, we report new evidence that opposite STDP-like effects induced by corticocortical PAS are associated with increased communication between involved brain areas and that antithetic forms of STDP-like after-effects result in distinct cortical rhythms connectivity changes.

Lasting EEG/MEG Aftereffects of Rhythmic Transcranial Brain Stimulation: Level of Control Over Oscillatory Network Activity.

A number of rhythmic protocols have emerged for non-invasive brain stimulation (NIBS) in humans, including transcranial alternating current stimulation (tACS), oscillatory transcranial direct current stimulation (otDCS), and repetitive (also called rhythmic) transcranial magnetic stimulation (rTMS). With these techniques, it is possible to match the frequency of the externally applied electromagnetic fields to the intrinsic frequency of oscillatory neural population activity (“frequency-tuning”). Mounting evidence suggests that by this means tACS, otDCS, and rTMS can entrain brain oscillations and promote associated functions in a frequency-specific manner, in particular during (i.e., online to) stimulation. Here, we focus instead on the changes in oscillatory brain activity that persist after the end of stimulation. Understanding such aftereffects in healthy participants is an important step for developing these techniques into potentially useful clinical tools for the treatment of specific patient groups. Reviewing the electrophysiological evidence in healthy participants, we find aftereffects on brain oscillations to be a common outcome following tACS/otDCS and rTMS. However, we did not find a consistent, predictable pattern of aftereffects across studies, which is in contrast to the relative homogeneity of reported online effects. This indicates that aftereffects are partially dissociated from online, frequency-specific (entrainment) effects during tACS/otDCS and rTMS. We outline possible accounts and future directions for a better understanding of the link between online entrainment and offline aftereffects, which will be key for developing more targeted interventions into oscillatory brain activity.

The contribution of TMS-EEG coregistration in the exploration of the human cortical connectome.

Recent developments in neuroscience have emphasised the importance of integrated distributed networks of brain areas for successful cognitive functioning. Our current understanding is that the brain has a modular organisation in which segregated networks supporting specialised processing are linked through a few long-range connections, ensuring processing integration. Although such architecture is structurally stable, it appears to be flexible in its functioning, enabling long-range connections to regulate the information flow and facilitate communication among the relevant modules, depending on the contingent cognitive demands. Here we show how insights brought by the coregistration of transcranial magnetic stimulation and electroencephalography (TMS-EEG) integrate and support recent models of functional brain architecture. Moreover, we will highlight the types of data that can be obtained through TMS-EEG, such as the timing of signal propagation, the excitatory/inhibitory nature of connections and causality. Last, we will discuss recent emerging applications of TMS-EEG in the study of brain disorders.

Hebbian and Anti-Hebbian Spike-Timing-Dependent Plasticity of Human Cortico-Cortical Connections

Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)], but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (M1) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different M1 neuronal populations by applying transcranial magnetic stimulation over M1 with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti-Hebbian STDP in human long-range connections. The induction of bidirectional long-term potentiation or depression in M1 depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons.

Prefrontal control over motor cortex cycles at beta frequency during movement inhibition.

Summary A fully adapted behavior requires maximum efficiency to inhibit processes in the motor domain [1]. Although a number of cortical and subcortical brain regions have been implicated, converging evidence suggests that activation of right inferior frontal gyrus (r-IFG) and right presupplementary motor area (r-preSMA) is crucial for successful response inhibition [2, 3]. However, it is still unknown how these prefrontal areas convey the necessary signal to the primary motor cortex (M1), the cortical site where the final motor plan eventually has to be inhibited or executed. On the basis of the widely accepted view that brain oscillations are fundamental for communication between neuronal network elements [4–6], one would predict that the transmission of these inhibitory signals within the prefrontal-central networks (i.e., r-IFG/M1 and/or r-preSMA/M1) is realized in rapid, periodic bursts coinciding with oscillatory brain activity at a distinct frequency. However, the dynamics of corticocortical effective connectivity has never been directly tested on such timescales. By using double-coil transcranial magnetic stimulation (TMS) and electroencephalography (EEG) [7, 8], we assessed instantaneous prefrontal-to-motor cortex connectivity in a Go/NoGo paradigm as a function of delay from (Go/NoGo) cue onset. In NoGo trials only, the effects of a conditioning prefrontal TMS pulse on motor cortex excitability cycled at beta frequency, coinciding with a frontocentral beta signature in EEG. This establishes, for the first time, a tight link between effective cortical connectivity and related cortical oscillatory activity, leading to the conclusion that endogenous (top-down) inhibitory motor signals are transmitted in beta bursts in large-scale cortical networks for inhibitory motor control.

Potentiation of Short-Latency Cortical Responses by High-Frequency Repetitive Transcranial Magnetic Stimulation

It is generally accepted that low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability, but there is only indirect evidence of its effects despite a large number of studies employing different stimulation parameters. Typically the cortical modulations are inferred through indirect measurements, such as recording the change in electromyographic responses. Recently it has become possible to directly evaluate rTMS-induced changes at the cortical level using electronencephalography (EEG). The present study investigates the modulation induced by high-frequency rTMS via EEG by evaluating changes in the latency and amplitude of TMS-evoked responses. In this study, rTMS was applied to the left primary motor cortex (MI) in 16 participants while an EEG was simultaneously acquired from 29 scalp electrodes. The rTMS consisted of 40 trains at 20 Hz with 10 stimuli each (a total of 400 stimuli) that were delivered at the individual resting motor threshold. The on-line modulation induced by the high-frequency TMS was characterized by a sequence of EEG responses. Two of the rTMS-induced responses, P5 and N8, were specifically modulated according to the protocol. Their latency decreased from the first to the last TMS stimuli, while the amplitude values increased. These results provide the first direct, on-line evaluation of the effects of high-frequency TMS on EEG activity. In addition, the results provide a direct demonstration of cortical potentiation induced by rTMS in humans.

TMS evidence for a selective role of the precuneus in source memory retrieval

The posteromedial cortex including the precuneus (PC) is thought to be involved in episodic memory retrieval. Here we used continuous theta burst stimulation (cTBS) to disentangle the role of the precuneus in the recognition memory process in a sample of healthy subjects. During the encoding phase, subjects were presented with a series of colored pictures. Afterwards, during the retrieval phase, all previously presented items and a sample of new pictures were presented in black, and subjects were asked to indicate whether each item was new or old, and in the latter case to indicate the associated color. cTBS was delivered over PC, posterior parietal cortex (PPC) and vertex before the retrieval phase. The data were analyzed in terms of hits, false alarms, source errors and omissions. cTBS over the precuneus, but not over the PPC or the vertex, induced a selective decrease in source memory errors, indicating an improvement in context retrieval. All the other accuracy measurements were unchanged. These findings suggest a direct implication of the precuneus in successful context-dependent retrieval.

Cerebellar theta burst stimulation modulates the neural activity of interconnected parietal and motor areas

Voluntary movement control and execution are regulated by the influence of the cerebellar output over different interconnected cortical areas, through dentato-thalamo connections. In the present study we applied transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess the effects of cerebellar theta-burst stimulation (TBS) over the controlateral primary motor cortex (M1) and posterior parietal cortex (PPC) in a group of healthy volunteers. We found a TBS-dependent bidirectional modulation over TMS-evoked activity; specifically, cTBS increased whereas iTBS decreased activity between 100 and 200 ms after TMS, in a similar manner over both M1 and PPC areas. On the oscillatory domain, TBS induced specific changes over M1 natural frequencies of oscillation: TMS-evoked alpha activity was decreased by cTBS whereas beta activity was enhanced by iTBS. No effects were observed after sham stimulation. Our data provide novel evidence showing that the cerebellum exerts its control on the cortex likely by impinging on specific set of interneurons dependent on GABA-ergic activity. We show that cerebellar TBS modulates cortical excitability of distant interconnected cortical areas by acting through common temporal, spatial and frequency domains.

To the Other Side of the Neglected Brain The Hyperexcitability of the Left Intact Hemisphere

The human brain is characterized by the lateralization of cognitive functions. Multiple lines of evidence suggest the deployment of visuospatial attention is controlled by a frontoparietal network, with a right hemisphere dominance. Among cortical areas included in the network, the right posterior parietal cortex (PPC) has been proposed to be a crucial node and has also been implicated on clinical grounds. Here, the authors provide an overview of the existent literature giving evidence to a functional asymmetry of the parietal cortices in directing visuospatial attention, focusing on those studies seeking to characterize the causal role of PPC, applying transcranial magnetic stimulation and its combination with imaging techniques, such as electroencephalography and fMRI. First, the role of PPC and how this region exerts its control over remote areas of both hemispheres is discussed. The second part discusses studies involving neglect patients shedding light on the complex interplay between left and right PPC, strongly supporting the hemispheric rivalry theory. Finally, studies demonstrating changes of neglect disorders following the manipulation of the unaffected hemisphere activation will be discussed.