Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Human thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning.

Reinforcement-based adaptive decision-making is believed to recruit fronto-striatal circuits. A critical node of the fronto-striatal circuit is the thalamus. However, direct evidence of its involvement in human reinforcement learning is lacking. We address this gap by analyzing intra-thalamic electrophysiological recordings from eight participants while they performed a reinforcement learning task. We found that in both the anterior thalamus (ATN) and dorsomedial thalamus (DMTN), low frequency oscillations (LFO, 4-12 Hz) correlated positively with expected value estimated from computational modeling during reward-based learning (after outcome delivery) or punishment-based learning (during the choice process). Furthermore, LFO recorded from ATN/DMTN were also negatively correlated with outcomes so that both components of reward prediction errors were signaled in the human thalamus. The observed differences in the prediction signals between rewarding and punishing conditions shed light on the neural mechanisms underlying action inhibition in punishment avoidance learning. Our results provide insight into the role of thalamus in reinforcement-based decision-making in humans.

Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

Neural modulations in the auditory cortex during internal and external attention tasks: A single-patient intracranial recording study.

Brain sensory processing is not passive, but is rather modulated by our internal state. Different research methods such as non-invasive imaging methods and intracranial recording of the local field potential (LFP) have been used to study to what extent sensory processing and the auditory cortex in particular are modulated by selective attention. However, at the level of the single- or multi-units the selective attention in humans has not been tested. In addition, most previous research on selective attention has explored externally-oriented attention, but attention can be also directed inward (i.e., internal attention), like spontaneous self-generated thoughts and mind-wandering. In the present study we had a rare opportunity to record multi-unit activity (MUA) in the auditory cortex of a patient. To complement, we also analyzed the LFP signal of the macro-contact in the auditory cortex. Our experiment consisted of two conditions with periodic beeping sounds. The participants were asked either to count the beeps (i.e., an "external attention" condition) or to recall the events of the previous day (i.e., an "internal attention" condition). We found that the four out of seven recorded units in the auditory cortex showed increased firing rates in "external attention" compared to "internal attention" condition. The beginning of this attentional modulation varied across multi-units between 30-50 msec and 130-150 msec from stimulus onset, a result that is compatible with an early selection view. The LFP evoked potential and induced high gamma activity both showed attentional modulation starting at about 70-80 msec. As the control, for the same experiment we recorded MUA activity in the amygdala and hippocampus of two additional patients. No major attentional modulation was found in the control regions. Overall, we believe that our results provide new empirical information and support for existing theoretical views on selective attention and spontaneous self-generated cognition.

Hypoxemia following generalized convulsive seizures: Risk factors and effect of oxygen therapy.

OBJECTIVE: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS). METHODS: We reviewed the video-EEG recordings of 1,006 patients with drug-resistant focal epilepsy included in the REPO2MSE study to identify those with ≥1 GCS and pulse oximetry (SpO2) measurement. Factors determining recovery of SpO2 ≥ 90% were investigated using Cox proportional hazards models. Association between SpO2 nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS: A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 GCS (86%). Rate of GCS with SpO2 <70% dropped from 40% to 21% when oxygen was administered early (p = 0.046). Early recovery of SpO2 ≥90% was associated with early administration of oxygen (p = 0.004), absence of postictal generalized EEG suppression (PGES) (p = 0.014), and extratemporal lobe epilepsy (p = 0.001). Lack of early administration of O2 (p = 0.003), occurrence of PGES (p = 0.018), and occurrence of ictal hypoxemia during the focal phase (p = 0.022) were associated with lower SpO2 nadir. CONCLUSION: Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.

Self-induced intracerebral gamma oscillations in the human cortex.

Gamma oscillations play a pivotal role in multiple cognitive functions. They enable coordinated activity and communication of local assemblies, while abnormalities in gamma oscillations exist in different neurological and psychiatric diseases. Thus, a specific rectification of gamma synchronization could potentially compensate the deficits in pathological conditions. Previous experiments have shown that animals can voluntarily modulate their gamma power through operant conditioning. Using a closed-loop experimental setup, we show in six intracerebrally recorded epileptic patients undergoing presurgical evaluation that intracerebral power spectrum can be increased in the gamma frequency range (30-80 Hz) at different fronto-temporal cortical sites in human subjects. Successful gamma training was accompanied by increased gamma power at other cortical locations and progressively enhanced cross-frequency coupling between gamma and slow oscillations (3-12 Hz). Finally, using microelectrode targets in two subjects, we report that upregulation of gamma activities is possible also in spatial micro-domains, without the spread to macroelectrodes. Overall, our findings indicate that intracerebral gamma modulation can be achieved rapidly, beyond the motor system and with high spatial specificity, when using micro targets. These results are especially significant because they pave the way for use of high-resolution therapeutic approaches for future clinical applications.

Event-Related Potential, Time-frequency, and Functional Connectivity Facets of Local and Global Auditory Novelty Processing: An Intracranial Study in Humans.

Auditory novelty detection has been associated with different cognitive processes. Bekinschtein et al. (2009) developed an experimental paradigm to dissociate these processes, using local and global novelty, which were associated, respectively, with automatic versus strategic perceptual processing. They have mostly been studied using event-related potentials (ERPs), but local spiking activity as indexed by gamma (60-120 Hz) power and interactions between brain regions as indexed by modulations in beta-band (13-25 Hz) power and functional connectivity have not been explored. We thus recorded 9 epileptic patients with intracranial electrodes to compare the precise dynamics of the responses to local and global novelty. Local novelty triggered an early response observed as an intracranial mismatch negativity (MMN) contemporary with a strong power increase in the gamma band and an increase in connectivity in the beta band. Importantly, all these responses were strictly confined to the temporal auditory cortex. In contrast, global novelty gave rise to a late ERP response distributed across brain areas, contemporary with a sustained power decrease in the beta band (13-25 Hz) and an increase in connectivity in the alpha band (8-13 Hz) within the frontal lobe. We discuss these multi-facet signatures in terms of conscious access to perceptual information.