A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)–thalamocortical (TC) network, more specifically on CT 5–9-Hz and TC spindle (10–16-Hz) oscillations. Two to three successive 5–9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5–9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5–9-Hz depolarizing wave–hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately −70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5–9-Hz waves can trigger TC spindles.
A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit‐level mechanisms responsible for EtOH‐dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration‐dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U‐shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH‐induced boost in the Ih and AMPA currents in the DA firing‐rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well‐established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.
Pain processing is associated with neural activity in a number of wide-spread brain regions. Here, we investigated whether functional connectivity at rest between these brain regions is associated with individual and sex-related differences in thermal pain and relief responsiveness. Twenty healthy volunteers (ten females) were scanned with functional magnetic resonance imaging in resting condition. Half an hour after scanning, we administered thermal pain on the back of their right hand, and collected pain and relief ratings in two separate runs of twelve stimulations each. Across the whole group, mean pain ratings were associated with decreased connectivity at rest between brain regions belonging to the default mode and the visual resting-state network. In men, pain measures correlated with increased connectivity within the visual resting-state network. In women instead, decreased connectivity between this network and parietal and prefrontal brain regions implicated in affective cognitive control were associated with both pain and relief ratings. Our findings indicate that the well documented individual variability and sex-differences in pain sensitivity may be explained, at least in part, by network dynamics at rest in these brain regions.
Neuronal activity in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) is characterised by excessive neuronal synchronization, particularly in the beta frequency range. However, less is known about the temporal dynamics of neuronal oscillations in PD. In this respect long-range temporal correlations (LRTC) are of special interest as they quantify the neuronal dynamics on different timescales and have been shown to be relevant for optimal information processing in the brain. While the presence of LRTC has been demonstrated in cortical data, their existence in deep brain structures remains an open question. We investigated (i) whether LRTC are present in local field potentials (LFP) recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and (ii) whether LRTC can be modulated by levodopa treatment (ON). Detrended fluctuation analysis was utilised in order to quantify the temporal dynamics in the amplitude fluctuations of LFP oscillations. We demonstrated for the first time the presence of LRTC (extending up to 50 s) in the STN. Importantly, the ON state was characterised by significantly stronger LRTC than the OFF state, both in beta (13-35 Hz) and high-frequency (> 200 Hz) oscillations. The existence of LRTC in subcortical structures such as STN provides further evidence for their ubiquitous nature in the brain. The weaker LRTC in the OFF state might indicate limited information processing in the dopamine-depleted basal ganglia. The present results implicate LRTC as a potential biomarker of pathological neuronal processes in PD.
Cognitive control during conflict monitoring, error processing, and post-error adjustment appear to be associated with the occurrence of midfrontal theta (MFϴ). While this association is supported by correlational EEG studies, much less is known about the possible causal link between MFϴ and error and conflict processing. In the present study, we aimed to explore the role of band-specific effects in modulating the error system during a conflict resolution. In turn, we delivered transcranial alternating current stimulation (tACS) at different frequency bands (delta δ, theta θ, alpha α, beta β, gamma γ) and sham stimulation over the medial frontal cortex (MFC) in 36 healthy participants performing a modified version of the Flanker task. Task performance and reports about the sensations (e.g. visual flickering, cutaneous burning) induced by the different frequency bands, were also recorded. We found that online θ-tACS increased the response speed to congruent stimuli after error execution with respect to sham stimulation. Importantly, the accuracy following the errors did not decrease because of speed-accuracy trade off. Moreover, tACS evoked visual and somatosensory sensations were significantly stronger at α-tACS and β-tACS compared to other frequencies. Our findings suggest that theta activity plays a causative role in modulating behavioural adjustments during perceptual choices in a stimulus-response conflict task.
Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30–80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomofunctional mechanisms remain elusive. Clinical and experimental evidence suggests that these deficits result from a hyporegulation of glutamate N-methyl-D-aspartate receptors. Here we modeled these deficits in rats with ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore, we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus. A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensory-evoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders.