Guglielmo Foffani

Reduced Spike-Timing Reliability Correlates with the Emergence of Fast Ripples in the Rat Epileptic Hippocampus

Ripples are sharp-wave-associated field oscillations (100-300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200-600 Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern.

Movement-related frequency modulation of beta oscillatory activity in the human subthalamic nucleus

Event‐related changes of brain electrical rhythms are typically analysed as amplitude modulations of local field potential (LFP) oscillations, like radio amplitude modulation broadcasting. In telecommunications, frequency modulation (FM) is less susceptible to interference than amplitude modulation (AM) and is therefore preferred for high‐fidelity transmissions. Here we hypothesized that LFP rhythms detected from deep brain stimulation (DBS) electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinsons disease could represent movement‐related activity not only in AM but also in FM. By combining adaptive autoregressive identification with spectral power decomposition, we were able to show that FM of low‐beta (13–20 Hz) and high‐beta (20–35 Hz) rhythms significantly contributes to the involvement of the human STN in movement preparation, execution and recovery, and that the FM patterns are regulated by the dopamine levels in the system. Movement‐related FM of beta oscillatory activity in the human subthalamic nucleus therefore provides a novel informational domain for rhythm‐based pathophysiological models of cortico‐basal ganglia processing.

Dopamine‐dependent non‐linear correlation between subthalamic rhythms in Parkinson's disease

The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non‐linearly correlated, thus leading to a loss of segregation between rhythms. Non‐linear correlation was particularly consistent between the low‐beta rhythm (13–20 Hz) and the high‐beta rhythm (20–35 Hz). Levodopa administration significantly decreased these non‐linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non‐linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms.

Emergent Dynamics of Fast Ripples in the Epileptic Hippocampus

Fast ripples are a type of transient high-frequency oscillations recorded from the epileptogenic regions of the hippocampus and the temporal cortex of epileptic humans and rodents. These events presumably reflect hypersynchronous bursting of pyramidal cells. However, the oscillatory spectral content of fast ripples varies from 250 to 800 Hz, well above the maximal firing frequency of most hippocampal pyramidal neurons. How such high-frequency oscillations are generated is therefore unclear. Here, we combine computational simulations of fast ripples with multisite and juxtacellular recordings in vivo to examine the underlying mechanisms in the hippocampus of epileptic rats. We show that populations of bursting cells firing individually at 100–400 Hz can create fast ripples according to two main firing regimes: (1) in-phase synchronous firing resulting in “pure” fast ripples characterized by single spectral peaks that reflect single-cell behavior and (2) out-of-phase firing that results in “emergent” fast ripples. Using simulations, we found that fast ripples generated under these two different regimes can be quantitatively separated by their spectral characteristics, and we took advantage of this separability to examine their dynamics in vivo. We found that in-phase firing can reach frequencies up to 300 Hz in the CA1 and up to 400 Hz in the dentate gyrus. The organization of out-of-phase firing is determined by firing delays between cells discharging at low frequencies. The two firing regimes compete dynamically, alternating randomly from one fast ripple event to the next, and they reflect the functional dynamic organization of the different regions of the hippocampus.

Prefrontal hemodynamic changes produced by anodal direct current stimulation.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been investigated for the treatment of many neurological or neuropsychiatric disorders. Its main effect is to modulate the cortical excitability depending on the polarity of the current applied. However, understanding the mechanisms by which these modulations are induced and persist is still an open question. A possible marker indicating a change in cortical activity is the subsequent variation in regional blood flow and metabolism. These variations can be effectively monitored using functional near-infrared spectroscopy (fNIRS), which offers a noninvasive and portable measure of regional blood oxygenation state in cortical tissue. We studied healthy volunteers at rest and evaluated the changes in cortical oxygenation related to tDCS using fNIRS. Subjects were tested after active stimulation (12 subjects) and sham stimulation (10 subjects). Electrodes were applied at two prefrontal locations; stimulation lasted 10 min and fNIRS data were then collected for 20 min. The anodal stimulation induced a significant increase in oxyhemoglobin (HbO(2)) concentration compared to sham stimulation. Additionally, the effect of active 10-min tDCS was localized in time and lasted up to 8-10 min after the end of the stimulation. The cathodal stimulation manifested instead a negligible effect. The changes induced by tDCS on HbO(2), as captured by fNIRS, agreed with the results of previous studies. Taken together, these results help clarify the mechanisms underlying the regional alterations induced by tDCS and validate the use of fNIRS as a possible noninvasive method to monitor the neuromodulation effect of tDCS.

Spinal Cord Injury Immediately Changes the State of the Brain

Spinal cord injury can produce extensive long-term reorganization of the cerebral cortex. Little is known, however, about the sequence of cortical events starting immediately after the lesion. Here we show that a complete thoracic transection of the spinal cord produces immediate functional reorganization in the primary somatosensory cortex of anesthetized rats. Besides the obvious loss of cortical responses to hindpaw stimuli (below the level of the lesion), cortical responses evoked by forepaw stimuli (above the level of the lesion) markedly increase. Importantly, these increased responses correlate with a slower and overall more silent cortical spontaneous activity, representing a switch to a network state of slow-wave activity similar to that observed during slow-wave sleep. The same immediate cortical changes are observed after reversible pharmacological block of spinal cord conduction, but not after sham. We conclude that the deafferentation due to spinal cord injury can immediately (within minutes) change the state of large cortical networks, and that this state change plays a critical role in the early cortical reorganization after spinal cord injury.

Effects of simultaneous bilateral tDCS of the human motor cortex

BACKGROUND Transcranial direct current stimulation (tDCS) is a noninvasive technique that has been investigated as a therapeutic tool for different neurologic disorders. Neuronal excitability can be modified by application of DC in a polarity-specific manner: anodal tDCS increases excitability, while cathodal tDCS decreases excitability. Previous research has shown that simultaneous bilateral tDCS of the human motor cortex facilitates motor performance in the anodal stimulated hemisphere much more than when the same hemisphere is stimulated using unilateral anodal motor cortex tDCS. OBJECTIVE The main purpose of this study was to determine whether simultaneous bilateral tDCS is able to increase cortical excitability in one hemisphere whereas decreasing cortical excitability in the contralateral hemisphere. To test our hypothesis, cortical excitability before and after bilateral motor cortex tDCS was evaluated. Moreover, the effects of bilateral tDCS were compared with those of unilateral motor cortex tDCS. METHODS We evaluated cortical excitability in healthy volunteers before and after unilateral or bilateral tDCS using transcranial magnetic stimulation. RESULTS We demonstrated that simultaneous application of anodal tDCS over the motor cortex and cathodal tDCS over the contralateral motor cortex induces an increase in cortical excitability on the anodal-stimulated side and a decrease in the cathodal stimulated side. We also used the electrode montage (motor cortex-contralateral orbit) method to compare the bilateral tDCS montage with unilateral tDCS montage. The simultaneous bilateral tDCS induced similar effects to the unilateral montage on the cathode-stimulated side. On the anodal tDCS side, the simultaneous bilateral tDCS seems to be a slightly less robust electrode arrangement compared with the placement of electrodes in the motor cortex-contralateral orbit montage. We also found that intersubject variability of the excitability changes that were induced by the anodal motor cortex tDCS using the bilateral montage was lower than that with the unilateral montage. CONCLUSIONS This is the first study in which cortical excitability before and after bilateral motor cortex tDCS was extensively evaluated, and the effects of bilateral tDCS were compared with unilateral motor cortex tDCS. Simultaneous bilateral tDCS seems to be a useful tool to obtain increases in cortical excitability of one hemisphere whereas causing decreases of cortical excitability in the contralateral hemisphere (e.g.,to treat stroke).

Subthalamic local field potential oscillations during ongoing deep brain stimulation in Parkinson's disease

How deep brain stimulation (DBS) acts and how the brain responds to it remains unclear. To investigate the mechanisms involved, we analyzed changes in local field potentials from the subthalamic area (STN-LFPs) recorded through the deep brain macroelectrode during monopolar DBS of the subthalamic nucleus area (STN-DBS) in a group of eight patients (16 nuclei) with idiopathic Parkinsons disease. Monopolar STN-DBS was delivered through contact 1 and differential LFP recordings were acquired between contacts 0 and 2. The stimulating contact was 0.5 mm away from each recording contact. The power spectral analysis of STN-LFPs showed that during ongoing STN-DBS whereas the power of beta oscillations (8-20 Hz) and high beta oscillations (21-40 Hz) remained unchanged, the power of low-frequency oscillations (1-7 Hz) significantly increased (baseline=0.37+/-0.22; during DBS=7.07+/-15.10, p=0.0003). Despite comparable low-frequency baseline power with and without levodopa, the increase in low-frequency oscillations during STN-DBS was over boosted by pretreatment with levodopa. The low-frequency power increase in STN-LFPs during ongoing STN-DBS could reflect changes induced at basal ganglia network level similar to those elicited by levodopa. In addition, the correlation between the heart beat and the low-frequency oscillations suggests that part of the low-frequency power increase during STN-DBS arises from polarization phenomena around the stimulating electrode. Local polarization might in turn also help to normalize STN hyperactivity in Parkinsons disease.

Role of Spike Timing in the Forelimb Somatosensory Cortex of the Rat

The aim of this study was to test the hypothesis that the significance of spike timing in somatosensory processing is not a specific feature of the whisker cortex but a more general characteristic of the primary somatosensory cortex. We recorded ensembles of neurons using microwire arrays implanted in the deep layers of the forelimb region of the rat primary somatosensory cortex in response to step stimuli delivered to the cutaneous surface of the contralateral body. We used a recently developed peristimulus time histogram (PSTH)-based classification method to investigate the temporal precision of the code by evaluating how changing the bin size (from 40 to 1 msec) would affect the ability of the ensemble responses to discriminate stimulus location on a single-trial basis. The information related to the discrimination was redundantly distributed within the ensembles, and the ability to discriminate stimulus location increased when decreasing the bin size, reaching a maximum at 4 msec. In our experiment, at 4 msec bin size the first spike per neuron after the stimulus conveyed almost as much information as the entire responses, so the temporal precision of the code was preserved in the first spikes. Subsequent spikes were less frequent but conveyed more information per spike. Finally, not only the trials correctly classified but also the trials incorrectly classified conveyed information about stimulus location with a similar temporal precision. We conclude that the role of spike timing in cortical somatosensory processing is not an exclusive feature of the highly specialized rat trigeminal system, but a more general property of the rat primary somatosensory cortex.

Modulation of beta oscillations in the subthalamic area during action observation in Parkinson's disease.

Mapping observed actions into the onlookers motor system seems to provide the neurofunctional mechanisms for action understanding. Subthalamic nucleus (STN) local field potential (LFP) recordings in patients with movement disorders disclosed that network oscillations in the beta range are involved in conveying motor and non-motor information across the cortico-basal ganglia-thalamo-cortical loop. This evidence, together with the existence of connections between the STN and cortical areas active during observation of actions performed by other people, suggests that the STN oscillatory activity in specific frequency bands could encode not only motor information, but also information related to action observation. To test this hypothesis we directly recorded STN oscillations through electrodes for deep brain stimulation in patients with Parkinsons disease during observation of actions and of static objects. We found selective action-related oscillatory modulations in two functionally distinct beta bands: whereas low-beta oscillations (10-18 Hz) selectively desynchronized only during action-observation, high-beta oscillations (20-30 Hz) synchronized both during the observation of action and action-related objects. Low-beta modulations are therefore specific to action observation and high-beta modulations are related to the action scene. Our findings show that in the basal ganglia there are functional changes spreading to the action environment, probably presetting the motor system in relation to the motor context and suggesting that the dynamics of beta oscillations can contribute to action understanding mechanisms.