Juan Aguilar

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.

Noradrenergic Activation Amplifies Bottom-Up and Top-Down Signal-to-Noise Ratios in Sensory Thalamus

Thalamocortical cells receive sensory signals via primary sensory afferents and cortical signals via corticothalamic afferents. These signals are influenced by a variety of neuromodulators that are released in the thalamus during specific behavioral states. Hence, different neuromodulators may set different thalamic modes of sensory information processing. We found that noradrenergic activation affects sensory and corticothalamic signals in the whisker thalamus differently than cholinergic activation. Whereas cholinergic activation increases the spontaneous firing (noise) and enlarges the receptive fields of ventroposterior medial thalamus (VPM) cells, noradrenergic activation decreases spontaneous firing and focuses receptive fields. Consequently, for sensory signals, noradrenergic activation sets bottom-up thalamic processing to a focused and noise-free excitatory receptive field, which contrasts with the broad and noisy excitatory receptive field characteristic of cholinergic activation. For corticothalamic signals, noradrenergic activation sets top-down processing to a noise-free high-frequency signal detection mode, whereas cholinergic activation produces a noisy broadband signal detection mode. The effects of noradrenergic activation on signal-to-noise ratios of VPM cells were found to be mediated by nucleus reticularis thalamic (nRt) cells. Hence, a major role of nRt cells is to regulate the noise level of thalamocortical cells during sensory processing. In conclusion, different modulators establish distinct modes of bottom-up and top-down information processing in the sensory thalamus.

Spatiotemporal Gating of Sensory Inputs in Thalamus during Quiescent and Activated States

The main role of the thalamus is to relay sensory inputs to the neocortex according to the regulations dictated by behavioral state. Hence, changes in behavioral state are likely to transform the temporal and spatial properties of thalamocortical receptive fields. We compared the receptive fields of single cells in the ventroposterior medial thalamus (VPM) of urethane-anesthetized rats during quiescent states and during aroused (activated) states. During quiescent states, VPM cells respond to stimulation of a principal whisker (PW) and may respond modestly to one or a few adjacent whiskers (AWs). During either generalized forebrain activation or selective thalamic activation caused by carbachol infusion in the VPM, the responses to AWs enhance so that VPM receptive fields become much larger. Such enlargement is not observed at the level of the principal trigeminal nucleus, indicating that it originates within the thalamus. Interestingly, despite the increase in AW responses during activation, simultaneous deflection of the PW and AWs produced VPM responses that resembled the PW response, as if the AWs were not stimulated. This nonlinear summation of sensory responses was present during both quiescent and activated states. In conclusion, the thalamus suppresses the excitatory surround (AWs) of the receptive field during quiescent states and enlarges this surround during arousal. But, thalamocortical cells represent only the center (PW) of the receptive field when the center (PW) and surround (AWs) are stimulated simultaneously.

Transcranial static magnetic field stimulation of the human motor cortex

Non‐Technical Summary  Non‐invasive neuromodulation of the human brain – with pulsed magnetic fields or small direct currents – is becoming increasingly popular for treating a variety of neurological and neuropsychiatric disorders. In the present work we investigated in healthy humans the possibility of a non‐invasive modulation of motor cortex excitability by the application of static magnetic fields through the scalp. We found that transcranial static magnetic field stimulation (tSMS) can reduce the excitability of the motor cortex for a period that outlasts the time of the application of the magnetic field. Moreover, we demonstrated that these excitability changes take origin at the cortical level. These results suggest that tSMS using small static magnets may be a promising tool to modulate cerebral excitability in a non‐invasive, painless and reversible way.

Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples

Sharp-wave ripples represent a prominent synchronous activity pattern in the mammalian hippocampus during sleep and immobility. GABAergic interneuronal types are silenced or fire during these events, but the mechanism of pyramidal cell (PC) participation remains elusive. We found opposite membrane polarization of deep (closer to stratum oriens) and superficial (closer to stratum radiatum) rat CA1 PCs during sharp-wave ripples. Using sharp and multi-site recordings in combination with neurochemical profiling, we observed a predominant inhibitory drive of deep calbindin (CB)-immunonegative PCs that contrasts with a prominent depolarization of superficial CB-immunopositive PCs. Biased contribution of perisomatic GABAergic inputs, together with suppression of CA2 PCs, may explain the selection of CA1 PCs during sharp-wave ripples. A deep-superficial gradient interacted with behavioral and spatial effects to determine cell participation during sleep and awake sharp-wave ripples in freely moving rats. Thus, the firing dynamics of hippocampal PCs are exquisitely controlled at subcellular and microcircuit levels in a cell type–selective manner.

Spatial and cortical influences exerted on cuneothalamic and thalamocortical neurons of the cat

This work aimed to study the responses of cuneothalamic and thalamocortical cells to electrical stimulation of the body surface in α‐chloralose‐anaesthetized cats. It was found that both classes of cells had a central excitatory receptive field, an edge overlapping the field centre whose stimulation elicited inhibitory–excitatory (cuneothalamic cells) and excitatory–inhibitory (thalamocortical cells) sequences, and a surrounding or peripheral area usually being inhibitory. Manipulating the descending corticofugal activity by removing the fronto‐parietal cortex, electrical stimulation, or by placing picrotoxin or muscimol over the sensorimotor cortex demonstrated that the cortical feedback potentiated effects driven from the field centre and the surround. In particular this potentiated centre‐driven excitation and surround‐driven inhibition, but some of the data points to more complex patterns. The inhibition elicited in cuneothalamic cells from the edge and the surround of the field was faster than the excitation induced from the field centre. Effects at the edge of the field centre included late excitatory responses relayed via the cerebral cortex. There were also direct corticofugal excitatory inputs to the field centre. Excitatory surrounds were occasionally observed, the assumption being that in most cases these were suppressed by the enhanced inhibition driven from the cortex. The data indicate that the cortico‐subcortical feedback contributes not only to enhance the surround antagonism of a centre response but also to increase the time resolution of thalamic and cuneate relay somesthetic neurons.

Spinal direct current stimulation modulates the activity of gracile nucleus and primary somatosensory cortex in anaesthetized rats

Non‐Technical Summary  Stimulation of the human brain with direct current is a simple but effective neuromodulation technique that is becoming increasingly popular due to its potentiality for non‐invasively treating a variety of neurological and neuropsychiatric disorders. Recently, this neuromodulation technique has been extended to the stimulation of the human spinal cord. Here we investigated the mechanisms of action of spinal direct current stimulation (sDCS) in anaesthetized rats. We found that sDCS can selectively modulate the spontaneous activity entering the brain through the spinal cord via the somatosensory system, consequently modulating both the internal state of the brain and its responsiveness to external somatosensory stimuli. These findings have at least two levels of significance: from a physiological perspective, they remark on the importance of the spinal cord in regulating the state of the brain; from a clinical perspective, they offer a mechanistic rationale for the development of sDCS as an effective bottom‐up neuromodulation technique.

Spike Timing, Spike Count, and Temporal Information for the Discrimination of Tactile Stimuli in the Rat Ventrobasal Complex

The aim of this work was to investigate the role of spike timing for the discrimination of tactile stimuli in the thalamic ventrobasal complex of the rat. We applied information-theoretic measures and computational experiments on neurophysiological data to test the ability of single-neuron responses to discriminate stimulus location and stimulus dynamics using either spike count (40 ms bin size) or spike timing (1 ms bin size). Our main finding is not only that spike timing provides additional information over spike count alone, but specifically that the temporal aspects of the code can be more informative than spike count in the rat ventrobasal complex. Virtually all temporal information—i.e., information exclusively related to when the spikes occur—is conveyed by first spikes, arising mostly from latency differences between the responses to different stimuli. Although the imprecision of first spikes (i.e., the jitter) is highly detrimental for the information conveyed by latency differences, jitter differences can contribute to temporal information, but only if latency differences are close to zero. We conclude that temporal information conveyed by spike timing can be higher than spike count information for the discrimination of somatosensory stimuli in the rat ventrobasal complex.

Lemniscal recurrent and transcortical influences on cuneate neurons

Intracellular recordings were obtained from cuneate neurons of chloralose-anesthetized, paralysed cats to study the synaptic responses induced by electrical stimulation of the contralateral medial lemniscus. From a total of 178 cells sampled, 109 were antidromically fired from the medial lemniscus, 82 of which showed spontaneous bursting activity. In contrast, the great majority (58/69) of the non-lemniscal neurons presented spontaneous single spike activity. Medial lemniscus stimulation induced recurrent excitation and inhibition on cuneolemniscal and non-lemniscal cells. Some non-lemniscal neurons were activated by somatosensory cortex and inhibited by motor cortex stimulation. Some other non-lemniscal cells that did not respond to medial lemniscus stimulation in control conditions were transcortically affected by stimulating the medial lemniscus after inducing paroxysmal activity in the sensorimotor cortex. These findings indicate that different sites in the sensorimotor cortex can differentially influence the sensory transmission through the cuneate, and that the distinct available corticocuneate routes are selected within the cerebral cortex. From a total of 92 cells tested, the initial effect induced by low-frequency stimulation of the sensorimotor cortex was inhibition on most of the cuneolemniscal neurons (32/52) and excitation on the majority of the non-lemniscal cells (25/40). The fact that a substantial proportion of cuneolemniscal and non-lemniscal cells was excited and inhibited, respectively, suggests that the cerebral cortex may potentiate certain inputs by exciting and disinhibiting selected groups of cuneolemniscal cells. Finally, evidence is presented demonstrating that the tendency of the cuneolemniscal neurons to fire in high-frequency spike bursts is due to different mechanisms, including excitatory synaptic potentials, recurrent activation through lemniscal axonal collaterals, and via the lemnisco-thalamo-cortico-cuneate loop.A corticocuneate network circuit to explain the results is proposed.