[Current progress on characteristics of intracranial electrophysiology related to prolonged disorders of consciousness].

Prolonged disorders of consciousness (pDOC) are pathological conditions of alterations in consciousness caused by various severe brain injuries, profoundly affecting patients' life ability and leading to a huge burden for both the family and society. Exploring the mechanisms underlying pDOC and accurately assessing the level of consciousness in the patients with pDOC provide the basis of developing therapeutic strategies. Research of non-invasive functional neuroimaging technologies, such as functional magnetic resonance (fMRI) and scalp electroencephalography (EEG), have demonstrated that the generation, maintenance and disorders of consciousness involve functions of multiple cortical and subcortical brain regions, and their networks. Invasive intracranial neuroelectrophysiological technique can directly record the electrical activity of subcortical or cortical neurons with high signal-to-noise ratio and spatial resolution, which has unique advantages and important significance for further revealing the brain function and disease mechanism of pDOC. Here we reviewed the current progress of pDOC research based on two intracranial electrophysiological signals, spikes reflecting single-unit activity and field potential reflecting multi-unit activities, and then discussed the current challenges and gave an outlook on future development, hoping to promote the study of pathophysiological mechanisms related to pDOC and provide guides for the future clinical diagnosis and therapy of pDOC.

Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice.

Oscillations, a highly conserved brain function across mammalian species, play a pivotal role in both brain physiology and pathology. Traumatic brain injury (TBI) frequently results in subacute and chronic alterations in brain oscillations, which are often associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. We recently conducted longitudinal recordings of local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice and classical laboratory inbred C57BL/6 J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 h post-injury) and subacute (12-48 h post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced signal complexity that prevailed exclusively during the acute phase in CC031 mice, which later developed PTE. This characteristic early brain oscillatory alteration was absent in CC031 sham controls, as well as in other CC strains and reference C57BL/6 J mice that did not develop PTE after TBI. Our findings offer quantitative measures linking early hippocampal brain oscillation to PTE at a population level in mice. These insights enhance understanding of circuit mechanisms and suggest potential targets for neuromodulatory intervention.

Acute nicotine exposure attenuates neurological deficits, ischemic injury and brain inflammatory responses and restores hippocampal long-term potentiation in ischemic stroke followed by lipopolysaccharide-induced sepsis-like state.

Ischemic stroke is followed by an increased susceptibility to bacterial infections, which exacerbate histological stroke outcome, neurological deficits and memory impairment due to increased neuroinflammation and neurotransmitter dysfunction. Pharmacological activation of nicotinic acetylcholine receptors was suggested to mitigate brain inflammatory responses in ischemic stroke. The functional responses associated with nicotinic acetylcholine receptor activation were unknown. In this study, male NMRI mice subjected to transient intraluminal middle cerebral artery occlusion (MCAO) were intraperitoneally exposed to vehicle treatment or Escherichia coli lipopolysaccharide (LPS; 4 mg/kg)-induced sepsis-like state 24 h post-MCAO, followed by intraperitoneal administration of vehicle or nicotine (0.5 mg/kg) 30 min later. Over 96 h, rectal temperature, neurological deficits, spontaneous locomotor activity, working memory, ischemic injury, synaptic plasticity, and brain inflammatory responses were evaluated by temperature measurement, behavioral analysis, infarct volumetry, electrophysiological recordings, and polymerase-chain reaction analysis. LPS-induced sepsis induced hypothermia, increased general and focal neurological deficits, reduced spontaneous exploration behavior, reduced working memory, and increased infarct volume post-MCAO. Additional treatment with nicotine attenuated LPS-induced hypothermia, reduced neurological deficits, restored exploration behavior, restored working memory, and reduced infarct volume. Local field potential recordings revealed that LPS-induced sepsis decreased long-term potentiation (LTP) in the dentate gyrus post-MCAO, whereas concomitant nicotine exposure restored LTP in the contralateral dentate gyrus. LPS-induced sepsis increased microglial/ macrophage Iba-1 mRNA and astrocytic GFAP mRNA levels post-MCAO, whereas add-on nicotine treatment reduced astrocytic GFAP mRNA. Taken together, these findings indicate that acute nicotine exposure enhances functional stroke recovery. Future studies will have to evaluate the effects of (1) chronic nicotine exposure, a clinically relevant vascular risk factor, and (2) the cessation of nicotine exposure, which is widely recommended post-stroke, but might have detrimental effects in the early stroke recovery phase.

Electrophysiological and Behavioral Markers of Hyperdopaminergia in DAT-KO Rats.

Background/Objectives: Dopamine dysfunction (DA) is a hallmark of many neurological disorders. In this case, the mechanism of changes in dopamine transmission on behavior remains unclear. This study is a look into the intricate link between disrupted DA signaling, neuronal activity patterns, and behavioral abnormalities in a hyperdopaminergic animal model. Methods: To study the relationship between altered DA levels, neuronal activity, and behavioral deficits, local field potentials (LFPs) were recorded during four different behaviors in dopamine transporter knockout rats (DAT-KO). At the same time, local field potentials were recorded in the striatum and prefrontal cortex. Correlates of LFP and accompanying behavioral patterns in genetically modified (DAT-KO) and control animals were studied. Results: DAT-KO rats exhibited desynchronization between LFPs of the striatum and prefrontal cortex, particularly during exploratory behavior. A suppressive effect of high dopamine levels on the striatum was also observed. Wild-type rats showed greater variability in LFP patterns across certain behaviors, while DAT-KO rats showed more uniform patterns. Conclusions: The decisive role of the synchrony of STR and PFC neurons in the organization of motor acts has been revealed. The greater variability of control animals in certain forms of behavior probably suggests greater adaptability. More uniform patterns in DAT-KO rats, indicating a loss of striatal flexibility when adapting to specific motor tasks. It is likely that hyperdopaminergy in the DAT-KO rat reduces the efficiency of information processing due to less synchronized activity during active behavior.

Serotonin transporter knockout in rats reduces beta- and gamma-band functional connectivity between the orbitofrontal cortex and amygdala during auditory discrimination.

The orbitofrontal cortex and amygdala collaborate in outcome-guided decision-making through reciprocal projections. While serotonin transporter knockout (SERT-/-) rodents show changes in outcome-guided decision-making, and in orbitofrontal cortex and amygdala neuronal activity, it remains unclear whether SERT genotype modulates orbitofrontal cortex-amygdala synchronization. We trained SERT-/- and SERT+/+ male rats to execute a task requiring to discriminate between two auditory stimuli, one predictive of a reward (CS+) and the other not (CS-), by responding through nose pokes in opposite-side ports. Overall, task acquisition was not influenced by genotype. Next, we simultaneously recorded local field potentials in the orbitofrontal cortex and amygdala of both hemispheres while the rats performed the task. Behaviorally, SERT-/- rats showed a nonsignificant trend for more accurate responses to the CS-. Electrophysiologically, orbitofrontal cortex-amygdala synchronization in the beta and gamma frequency bands during response selection was significantly reduced and associated with decreased hubness and clustering coefficient in both regions in SERT-/- rats compared to SERT+/+ rats. Conversely, theta synchronization at the time of behavioral response in the port associated with reward was similar in both genotypes. Together, our findings reveal the modulation by SERT genotype of the orbitofrontal cortex-amygdala functional connectivity during an auditory discrimination task.

Photopharmacological modulation of hippocampal local field potential by caged-glutamate with MicroLED probe.

AIM: Photopharmacology is a new technique for modulating biological phenomena through the photoconversion of substances in a specific target region at precise times. Caged compounds are thought to be compatible with photopharmacology as uncaged ligands are released and function in a light irradiation-dependent manner. Here, we investigated whether a microscale light-emitting diode (MicroLED) probe is applicable for the photoconversion of caged-glutamate (caged-Glu) in vivo. METHODS: A needle-shaped MicroLED probe was fabricated and inserted into the mouse hippocampal dentate gyrus (DG) with a cannula for drug injection and a recording electrode for measuring the local field potential (LFP). Artificial cerebrospinal fluid (ACSF) or caged-Glu was infused into the DG and illuminated with light from a MicroLED probe. RESULTS: In the caged-Glu-injected DG, the LFP changed in the 10-20 Hz frequency ranges after light illumination, whereas there was no change in the ACSF control condition. CONCLUSION: The MicroLED probe is applicable for photopharmacological experiments to modulate LFP with caged-Glu in vivo.

Induction of seizures and initiation of epileptogenesis by pilocarpine in zebrafish larvae.

Objective: Preclinical models of seizures and epilepsy in rodents contributed substantially to the discovery of currently available antiseizure medications. These were also broadly used for investigation of processes of epileptogenesis. Nevertheless, rodent models pose some limitations, thus, new models using alternative species are in high demand. The aim of this study was to describe a new model of seizures/epilepsy induced by the cholinomimetic agent, pilocarpine (PILO), in larval zebrafish. Methods: Local field potential (LFP) recordings were conducted to analyze electroencephalographic discharges and correlate it with larval behavior. Hematoxylin and eosin (H&E) staining, as well as TUNEL staining were performed to analyze morphology and apoptosis, respectively. Real-time quantitative polymerase chain reaction (qRT-PCR) was undertaken for gene expression analysis. Results: Acute exposure to PILO, in a concentration-dependent manner, induces electroencephalographic discharges in larval zebrafish, which behaviorally manifest as decreased locomotion and moving time, but enhanced movement velocity. The PILO-induced seizure-like activity is behaviorally distinct from this induced by the application of chemoconvulsant pentylenetetrazole (PTZ). Zebrafish larvae previously exposed to PILO (2 h), after a washing out period, exhibit spontaneous, unprovoked discharges and apoptotic changes in their brains. Significance: Here, we comprehensively investigated a new model of PILO-induced seizures/epilepsy in larval zebrafish. We propose that this model may be used to study epileptogenesis and for antiseizure drug screening purposes.

Organotypic culture of post-mortem adult human brain explants exhibits synaptic plasticity.

BACKGROUND: Synaptic plasticity is an essential process encoding fine-tuned brain functions, but models to study this process in adult human systems are lacking. OBJECTIVE: We aim to test whether ex vivo organotypic culture of post-mortem adult brain explants (OPABs) retain synaptic plasticity. METHODS: OPABs were seeded on 3D microelectrode arrays to measure local field potential (LFP). Paired stimulation of distant electrodes was performed over three days to investigate our capacity to modulate specific neuronal connections. RESULTS: Long-term potentiation (LTP) or depression (LTD) did not occur within a single day. In contrast, after two and three days of training, OPABs showed a significant modulation of the paired electrodes' response compared to the non-paired electrodes from the same array. This response was alleviated upon treatment with dopamine. CONCLUSION: Our work highlights that adult human brain explants retain synaptic plasticity, offering novel approaches to neural circuitry in animal-free models.

A method for the synchronization of inertial sensor signals and local field potentials from deep brain stimulation systems.

Objective. Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication.Approach. Fourteen male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted neurostimulator, which produces artifacts in the LFPs that a nearby inertial sensor can simultaneously record.Main results. In 64% of the recruited subjects, induced artifacts were detected at least in one condition. Among those subjects, 83% of the recordings could be synchronized offline analyzing LFPs and wearables data. The remaining recordings were synchronized by video analysis.Significance. The proposed synchronization method does not require an external system (e.g., TENS electrodes) and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers.

Network resonance and the auditory steady state response.

The auditory steady state response (ASSR) arises when periodic sounds evoke stable responses in auditory networks that reflect the acoustic characteristics of the stimuli, such as the amplitude of the sound envelope. Larger for some stimulus rates than others, the ASSR in the human electroencephalogram (EEG) is notably maximal for sounds modulated in amplitude at 40 Hz. To investigate the local circuit underpinnings of the large ASSR to 40 Hz amplitude-modulated (AM) sounds, we acquired skull EEG and local field potential (LFP) recordings from primary auditory cortex (A1) in the rat during the presentation of 20, 30, 40, 50, and 80 Hz AM tones. 40 Hz AM tones elicited the largest ASSR from the EEG acquired above auditory cortex and the LFP acquired from each cortical layer in A1. The large ASSR in the EEG to 40 Hz AM tones was not due to larger instantaneous amplitude of the signals or to greater phase alignment of the LFP across the cortical layers. Instead, it resulted from decreased latency variability (or enhanced temporal consistency) of the 40 Hz response. Statistical models indicate the EEG signal was best predicted by LFPs in either the most superficial or deep cortical layers, suggesting deep layer coordinators of the ASSR. Overall, our results indicate that the recruitment of non-uniform but more temporally consistent responses across A1 layers underlie the larger ASSR to amplitude-modulated tones at 40 Hz.

Anterior thalamic nucleus local field potentials during focal temporal lobe epileptic seizures.

Objective: To analyze the local field potentials (LFPs) in patients with focal drug-resistant epilepsy (DRE) from the anterior nucleus of the thalamus (ANT) during inter-ictal state and seizure state. Method: ANT stereotactic EEG (SEEG) recordings were studied in four patients with focal temporal lobe epilepsy. SEEG data was classified as inter-ictal and ictal state and sub-categorized into electrographic (ESz), focal aware seizure (FAS), focal with impaired awareness (FIA), or focal to bilateral tonic-clonic seizure (FBTC). LFP was analyzed at 4 Hz, 8 Hz, 16 Hz, 32 Hz, high gamma (100 Hz), and ripples (200 Hz) using spectrogram analysis and a statistical comparison of normalized power spectral density (PSD) averaged during seizures versus pre-ictal baseline segments. Result: The LFP recordings were analyzed for 162 seizures (127 ESz, 23 FAS, 6 FIA, and 6 FBTC). Based on time-frequency data (spectrogram), a broad band of activity, occurring between 2 and 6 Hz and centered at 4 Hz, and thin-band activity occurring specifically at 8 Hz on the frequency spectrogram were observed during the inter-ictal state. Statistically significant changes in LFP-PSD were seen for FAS, FIA, and FBTC. We observed a significant gain in LFP at the lower frequency band during FAS at 4 Hz, FIA, and FBTC at 4, 8, and 16 Hz while also observing increases at higher frequencies during FBTC at 100 and 200 Hz and a decrease during FAS seizures at 32 Hz. In contrast, no significant change in LFP power was seen for electrographic seizures. Interpretation: Our observations from a limited dataset indicate that all clinical seizure types, but not electrographic seizures, caused a change in ANT-LFP based on the magnitude of the associated power spectral density (PSD). Future work will be needed to validate the use of ANT-LFP at these frequencies as accurate measurements of seizure occurrence and severity. This work represents a first step toward understanding ANT thalamic LFP patterns during focal seizures and developing adaptive DBS strategies.

NeoCoMM: A neocortical neuroinspired computational model for the reconstruction and simulation of epileptiform events.

BACKGROUND: Understanding the pathophysiological dynamics that underline Interictal Epileptiform Events (IEEs) such as epileptic spikes, spike-and-waves or High-Frequency Oscillations (HFOs) is of major importance in the context of neocortical refractory epilepsy, as it paves the way for the development of novel therapies. Typically, these events are detected in Local Field Potential (LFP) recordings obtained through depth electrodes during pre-surgical investigations. Although essential, the underlying pathophysiological mechanisms for the generation of these epileptic neuromarkers remain unclear. The aim of this paper is to propose a novel neurophysiologically relevant reconstruction of the neocortical microcircuitry in the context of epilepsy. This reconstruction intends to facilitate the analysis of a comprehensive set of parameters encompassing physiological, morphological, and biophysical aspects that directly impact the generation and recording of different IEEs. METHOD: a novel microscale computational model of an epileptic neocortical column was introduced. This model incorporates the intricate multilayered structure of the cortex and allows for the simulation of realistic interictal epileptic signals. The proposed model was validated through comparisons with real IEEs recorded using intracranial stereo-electroencephalography (SEEG) signals from both humans and animals. Using the model, the user can recreate epileptiform patterns observed in different species (human, rodent, and mouse) and study the intracellular activity associated with these patterns. RESULTS: Our model allowed us to unravel the relationship between glutamatergic and GABAergic synaptic transmission of the epileptic neural network and the type of generated IEE. Moreover, sensitivity analyses allowed for the exploration of the pathophysiological parameters responsible for the transitions between these events. Finally, the presented modeling framework also provides an Electrode Tissue Model (ETI) that adds realism to the simulated signals and offers the possibility of studying their sensitivity to the electrode characteristics. CONCLUSION: The model (NeoCoMM) presented in this work can be of great use in different applications since it offers an in silico framework for sensitivity analysis and hypothesis testing. It can also be used as a starting point for more complex studies.

Brain connectivity analysis in preictal phases of seizure induced by pentylenetetrazol in rats.

Abnormal patterns of brain connectivity characterize epilepsy. However, little is known about these patterns during the stages preceding a seizure induced by pentylenetetrazol (PTZ). To investigate brain connectivity in male Wistar rats during the preictal phase of PTZ-induced seizures (60 mg/kg), we recorded local field potentials in the primary motor (M1) cortex, the ventral anterior (VA) nucleus of the thalamus, the hippocampal CA1 area, and the dentate gyrus (DG) during the baseline period and after PTZ administration. While there were no changes in power density between the baseline and preictal periods, we observed an increase in directional functional connectivity in theta from the hippocampal formation to M1 and VA, as well as in middle gamma from DG to CA1 and from CA1 to M1, and also in slow gamma from M1 to CA1. These findings are supported by increased phase coherence between DG-M1 in theta and CA1-M1 in middle gamma, as well as enhanced phase-amplitude coupling of delta-middle gamma in M1 and delta-fast gamma in CA1. Interestingly, we also noted a slight decrease in phase synchrony between CA1 and VA in slow gamma. Together, these results demonstrate increased functional connectivity between brain regions during the PTZ-induced preictal period, with this increase being particularly driven by the hippocampal formation.

Clinical asymmetry in Parkinson's disease is characterized by prevalence of subthalamic pause-burst neurons and alpha-beta oscillations.

OBJECTIVE: We aimed to establish specific biomarkers of Parkinson's disease (PD) by comparing activity of more affected (MA) and less affected (LA) subthalamic nucleus (STN) of patients with prominent clinical asymmetry. METHODS: We recorded single unit activity and local field potentials (LFP) of the STN during deep brain stimulation surgeries. Neuronal firing patterns and discharge rate, as well as oscillatory features of both single cells and LFP, were analyzed. RESULTS: We observed notable differences in proportions of irregular-burst and pause-burst, but not tonic neurons, between the hemispheres. Oscillations of pause-burst neurons correlated significantly with the bradykinesia and rigidity scores of the corresponding hemibody. LFP derived from MA STN featured greater power in 12-15 Hz. CONCLUSIONS: Our results provide evidence that the increased proportion of units with prolonged pauses may be associated with PD. We also speculate that some of them may gain rhythmicity in the alpha-beta range in relation to hypokinetic symptoms, long-term disease, or both. SIGNIFICANCE: Our findings highlight the relation between specific oscillatory features of the STN, predominance of subthalamic pause-burst units and PD pathophysiology.

Intracranial neural representation of phenomenal and access consciousness in the human brain.

After more than 30 years of extensive investigation, impressive progress has been made in identifying the neural correlates of consciousness (NCC). However, the functional role of spatiotemporally distinct consciousness-related neural activity in conscious perception is debated. An influential framework proposed that consciousness-related neural activities could be dissociated into two distinct processes: phenomenal and access consciousness. However, though hotly debated, its authenticity has not been examined in a single paradigm with more informative intracranial recordings. In the present study, we employed a visual awareness task and recorded the local field potential (LFP) of patients with electrodes implanted in cortical and subcortical regions. Overall, we found that the latency of visual awareness-related activity exhibited a bimodal distribution, and the recording sites with short and long latencies were largely separated in location, except in the lateral prefrontal cortex (lPFC). The mixture of short and long latencies in the lPFC indicates that it plays a critical role in linking phenomenal and access consciousness. However, the division between the two is not as simple as the central sulcus, as proposed previously. Moreover, in 4 patients with electrodes implanted in the bilateral prefrontal cortex, early awareness-related activity was confined to the contralateral side, while late awareness-related activity appeared on both sides. Finally, Granger causality analysis showed that awareness-related information flowed from the early sites to the late sites. These results provide the first LFP evidence of neural correlates of phenomenal and access consciousness, which sheds light on the spatiotemporal dynamics of NCC in the human brain.

Exploring the local field potential signal from the subthalamic nucleus for phase-targeted auditory stimulation in Parkinson's disease.

BACKGROUND: Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, could potentially benefit patients with Parkinson's disease (PD) by improving sleep quality and slowing disease progression. Phase-targeted auditory stimulation (PTAS) is an approach to enhance slow waves, which are detected in real-time in the surface EEG signal. OBJECTIVE: We aimed to test whether the local-field potential of the subthalamic nucleus (STN-LFP) can be used to detect frontal slow waves and assess the electrophysiological changes related to PTAS. METHODS: We recruited patients diagnosed with PD and undergoing Percept™ PC neurostimulator (Medtronic) implantation for deep brain stimulation of STN (STN-DBS) in a two-step surgery. Patients underwent three full-night recordings, including one between-surgeries recording and two during rehabilitation, one with DBS+ (on) and one with DBS- (off). Surface EEG and STN-LFP signals from Percept PC were recorded simultaneously, and PTAS was applied during sleep in all three recording sessions. RESULTS: Our results show that during NREM sleep, slow waves of the cortex and STN are time-locked. PTAS application resulted in power and coherence changes, which can be detected in STN-LFP. CONCLUSION: Our findings suggest the feasibility of implementing PTAS using solely STN-LFP signal for slow wave detection, thus without a need for an external EEG device alongside the implanted neurostimulator. Moreover, we propose options for more efficient STN-LFP signal preprocessing, including different referencing and filtering to enhance the reliability of cortical slow wave detection in STN-LFP recordings.

Estrogen deficiency affects synchronized neural connectivity in the olfactory bulb-nucleus accumbens circuit: A local field potential study in ovariectomized mouse model.

Estrogen plays a crucial role in regulating various brain functions, including cognitive, emotional, and social behaviors. Menopausal women face a decline in estrogen levels, which has been linked to several physical and mental health issues. However, the impact of estrogen on the olfactory bulb-nucleus accumbens (OB-NAc) circuit, which is essential for regulating emotions and cognitive behaviors, remains poorly understood. To test the hypothesis that estrogen deficiency affects signal processing, we recorded local field potentials (LFPs) using intracranial electrodes implanted in four-week-old ovariectomized (OVX) mice during an open-field test (OFT). The results showed a decrease in locomotor activity and increase in anxiety-like behaviors in OVX mice. Furthermore, we found a decrease in high-gamma power in the OB. We analyzed coherence and inter-region phase-amplitude coupling (ir-PAC) to explore the connectivity between the OB and NAc. We observed a decrease in low-gamma and high-gamma coherence in OVX mice. Additionally, we found that the direction of connectivity from the NAc to the OB was disrupted in OVX mice. In summary, our study provides evidence that estrogen deficiency is linked to synchronized neural connectivity changes in the OB-NAc circuit. These findings have implications for our understanding of the roles played by the OB-NAc neural circuit and estrogen in the regulation of general exploratory behavior and anxiety-like behavior.

Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease.

Background: Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments.In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. Methods: We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept™ device), ON dopaminergic medication, with stimulation both ON or OFF; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles (ECoG) over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both ON or OFF.Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. Results: In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation OFF, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. Conclusion: We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms.

High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?

Despite advances in understanding the cellular and molecular processes underlying memory and cognition, and recent successful modulation of cognitive performance in brain disorders, the neurophysiological mechanisms remain underexplored. High frequency oscillations beyond the classic electroencephalogram spectrum have emerged as a potential neural correlate of fundamental cognitive processes. High frequency oscillations are detected in the human mesial temporal lobe and neocortical intracranial recordings spanning gamma/epsilon (60-150 Hz), ripple (80-250 Hz) and higher frequency ranges. Separate from other non-oscillatory activities, these brief electrophysiological oscillations of distinct duration, frequency and amplitude are thought to be generated by coordinated spiking of neuronal ensembles within volumes as small as a single cortical column. Although the exact origins, mechanisms and physiological roles in health and disease remain elusive, they have been associated with human memory consolidation and cognitive processing. Recent studies suggest their involvement in encoding and recall of episodic memory with a possible role in the formation and reactivation of memory traces. High frequency oscillations are detected during encoding, throughout maintenance, and right before recall of remembered items, meeting a basic definition for an engram activity. The temporal coordination of high frequency oscillations reactivated across cortical and subcortical neural networks is ideally suited for integrating multimodal memory representations, which can be replayed and consolidated during states of wakefulness and sleep. High frequency oscillations have been shown to reflect coordinated bursts of neuronal assembly firing and offer a promising substrate for tracking and modulation of the hypothetical electrophysiological engram.

Short-Term Preexposure to Novel Enriched Environment Augments Hippocampal Ripples in Urethane-Anesthetized Mice.

Learning and memory are affected by novel enriched environment, a condition where animals play and interact with a variety of toys and conspecifics. Exposure of animals to the novel enriched environments improves memory by altering neural plasticity during natural sleep, a process called memory consolidation. The hippocampus, a pivotal brain region for learning and memory, generates high-frequency oscillations called ripples during sleep, which is required for memory consolidation. Naturally occurring sleep shares characteristics in common with general anesthesia in terms of extracellular oscillations, guaranteeing anesthetized animals suitable to examine neural activity in a sleep-like state. However, it is poorly understood whether the preexposure of animals to the novel enriched environment modulates neural activity in the hippocampus under subsequent anesthesia. To ask this question, we allowed mice to freely explore the novel enriched environment or their standard environment, anesthetized them, and recorded local field potentials in the hippocampal CA1 area. We then compared the characteristics of hippocampal ripples between the two groups and found that the amplitude of ripples and the number of successive ripples were larger in the novel enriched environment group than in the standard environment group, suggesting that the afferent synaptic input from the CA3 area to the CA1 area was higher when the animals underwent the novel enriched environment. These results underscore the importance of prior experience that surpasses subsequent physical states from the neurophysiological point of view.