Theta oscillations vary with local response rate and are moderated by the dopamine-depleting agent, tetrabenazine, during effort-based behavior.

Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety

Hippocampal theta oscillations are postulated to support mnemonic processes in humans and rodents. Theta oscillations facilitate encoding and spatial navigation, but to date, it has been difficult to dissociate the effects of volitional movement from the cognitive demands of a task. Therefore, we examined whether volitional movement or cognitive demands exerted a greater modulating factor over theta oscillations during decision-making. Given the anatomical, electrophysiological, and functional dissociations along the dorsal-ventral axis, theta oscillations were simultaneously recorded in the dorsal and ventral hippocampus in rats trained to switch between place and motor-response strategies. Stark differences in theta characteristics were found between the dorsal and ventral hippocampus in frequency, power, and coherence. Theta power increased in the dorsal, but decreased in the ventral hippocampus, during the decision-making epoch. Interestingly, the relationship between running speed and theta power was uncoupled during the decision-making epoch, a phenomenon limited to the dorsal hippocampus. Theta frequency increased in both the dorsal and ventral hippocampus during the decision epoch, although this effect was greater in the dorsal hippocampus. Despite these differences, ventral hippocampal theta was responsive to the navigation task; theta frequency, power, and coherence were all affected by cognitive demands. Theta coherence increased within the dorsal hippocampus during the decision-making epoch on all three tasks. However, coherence selectively increased throughout the hippocampus (dorsal to ventral) on the task with new hippocampal learning. Interestingly, most results were consistent across tasks, regardless of hippocampal-dependent learning. These data indicate increased integration and cooperation throughout the hippocampus during information processing.

Decades of hippocampal neurophysiology research have linked the hippocampal theta rhythm to voluntary movement. A consistent observation has been a robust correlation between the amplitude (or power) and frequency of hippocampal theta and running speed. Recently, however, it has been suggested that acceleration, not running speed, is the dominating influence on theta frequency. There is an inherent interdependence among these two variables, as acceleration is the rate of change in velocity. Therefore, we investigated theta frequency and amplitude of the local-field potential recorded from the stratum pyramidale, stratum radiatum, and stratum lacunosum moleculare of the CA1 subregion, considering both speed and acceleration in tandem as animals traversed a circular task or performed continuous alternation. In male and female rats volitionally controlling their own running characteristics, we found that running speed carries nearly all of the variability in theta frequency and power, with a minute contribution from acceleration. These results contradicted a recent publication using a speed-clamping task, where acceleration and movement are compelled through the use of a bottomless car (Kropff et al., 2021a). Therefore, we reanalyzed the speed-clamping data replicating a transient increase in theta frequency during acceleration. Compared with track running rats, the speed-clamped animals exhibited lower velocities and acceleration values but still showed a stronger influence of speed on theta frequency relative to acceleration. As navigation is the integration of many sensory inputs that are not necessarily linearly related, we offer caution in making absolute claims regarding hippocampal physiology from correlates garnered from a single behavioral repertoire.SIGNIFICANCE STATEMENT A long-standing, replicable observation has been the increase of hippocampal theta power and frequency with increasing running speed. Recently, however, an experimental approach that clamps the running speed of an animal has suggested that acceleration is the dominant influence. Therefore, we analyzed data from freely behaving rats as well as data from the speed-clamping experiment. In unrestrained behavior, speed remains the dominant behavioral correlate to theta amplitude and frequency. Positive acceleration in the speed-clamp experiment induced a transient increase in theta frequency and power. However, speed retained the dominant influence over theta frequency, changing with velocity in both acceleration and deceleration conditions.

The goal of this study was to use theta and alpha electroencephalography (EEG) frequency power and self-report measures to examine performance monitoring, cognitive inhibition, and perceived effort required for speech understanding in noise. It was hypothesized that with a linear increase in word recognition task difficulty, there would be a linear increase in listening effort and word recognition performance would decrease in the challenging conditions. In addition, theta and alpha power would have an inverted U-shape across easy to challenging listening conditions. The inverted U-shape would reflect the neural underpinnings of listening effort that cannot be measured by task performance alone. EEG data were collected in 34 normal-hearing adults (18 to 33 years old) during the Words-In-Noise (WIN) test, which was presented in sound field. EEG frequency data were averaged and analyzed at three frontal channels for theta power (4 to 8 Hz), which is thought to reflect performance monitoring, and three parietal channels for alpha power (8 to 12 Hz), which is thought to reflect cognitive inhibition. A ten-point visual analog scale was administered after each WIN signal-to-noise ratio (SNR) condition to capture self-reported required and invested listening effort (RLE and ILE, respectively). The WIN SNR conditions were presented in descending and random order. The SNR presentation (descending or random SNR) had a null effect on word recognition performance; however, presentation did have an effect on theta power, alpha power, and ILE. When controlling for presentation, there were significant effects of SNR and presentation on both theta and alpha frequency power. Theta and alpha power had an inverted U-shape as a function of SNR from easy to challenging, with peak power in the moderate SNR conditions. RLE and ILE both significantly increased as task difficulty increased as expected; however, RLE showed a stronger relation to task performance than ILE. Alpha power was a significant predictor of RLE, ILE, and WIN performance when controlling for SNR. The elevated theta and alpha power in the easy to moderate SNRs and alpha power predicting self-reported listening effort suggest the activation of supportive neural systems during word recognition that could be considered a marker of listening effort. Moreover, the measures of neural support systems and listening effort were independent from task performance, which is a key element to further understanding the neural bases for listening effort. In the context of the broader literature, these results are consistent with (1) a parietal alpha role in supporting inhibitory control to suppress irrelevant information and (2) a frontal theta role in supporting performance monitoring in difficult listening conditions where speech recognition is feasible.

Instrumental behavior is a very complex and multifaceted process. Behavioral output during instrumental performance is influenced by a variety of factors, including associative conditioning, directional and activational aspects of motivation, affect, action selection and execution, and decision-making functions. Detailed assessments of instrumental behavior can focus on the temporal characteristics of instrumental behavior such as local frequency and response duration, and biophysical measures of response topography such as force output over time. Furthermore, engaging in motivated behavior can require exertion of effort and effort-based decision making. The present review provides an overview of research on the specific deficits in operant behavior induced by dopamine antagonism and depletion. Furthermore, it discusses research on effort-based decision making, and highlights the complexities and seeming paradoxes that are revealed when detailed analyses of operant behavior are conducted, and instrumental behavior is put in the context of factors such as primary or unconditioned food reinforcement, appetite, binge-like eating, and response choice. Although impairments in mesolimbic dopamine are sometimes labeled as being due to “anhedonia”, a detailed deconstruction of the findings in this area of research point to a much more complex and nuanced picture of the role that dopamine plays in regulating instrumental behavior. Low doses of DA antagonists and accumbens dopamine depletions blunt the exertion of physical effort as measured by several different challenges in animal studies (e.g., lever pressing, barrier climbing, wheel running), and yet leave fundamental aspects of hedonic reactivity, food motivation, and reinforcement intact. Continued research on the specific features of instrumental behaviors that regulate the sensitivity to impaired dopamine transmission across a number of contexts is important for resolving some of the complexities that are evident in this area of inquiry. These investigations can also provide insights into psychomotor and motivational dysfunctions that are seen in neuropsychiatric conditions such as depression, schizophrenia, and Parkinson’s disease.

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and cortical dysfunction. Resting‐state EEG provides insights into AD‐related neurophysiological changes. This study investigates the associations between 32‐channel resting‐state EEG and AD plasma biomarkers in patients from a Memory Clinic population.MethodThis cross‐sectional study consecutively included 193 patients with cognitive disturbances due to heterogeneous conditions from the tertiary Memory Clinic at San Raffaele Hospital, Milan, Italy. Resting‐state 32‐channel EEG and Lumipulse plasma biomarkers (pTau217, pTau181, NfL, Ab42/40 ratio) were collected. Patients were stratified into three groups based on dual pTau217 cutoffs, calculated on a sample of 184 individuals to achieve 97% sensitivity and specificity for identifying pathological CSF pTau181/Aβ42 ratios. Linear regression models, adjusted for age, sex, and disease duration, assessed associations between plasma biomarkers and EEG parameters, including alpha amplitude, alpha frequency, and relative power in delta, theta, alpha, beta, and gamma bands. ANCOVA compared EEG parameters across the three pTau217‐defined groups.ResultIn the full sample, pTau217, pTau181, and the pTau217/Ab42 ratio were positively associated with theta power (+0.34 to +0.45) and delta power (+0.24), and negatively with alpha amplitude, alpha power (‐0.20 to ‐0.32), and beta power (‐0.20). In group 1 (low pTau217), the pTau217/Abeta42 ratio was negatively associated with beta, gamma, and alpha power (‐0.27 to ‐0.32). In group 2 (intermediate pTau217), NfL was positively associated with theta power (+0.47) and negatively with beta power (‐0.35). In group 3 (high pTau217), pTau217, pTau181, and the pTau217/Abeta42 ratio were positively associated with theta (+0.39) and delta power (+0.30), and negatively with alpha amplitude and alpha power. ANCOVA showed reduced alpha amplitude and alpha power together with higher theta in groups 2 and 3 versus group 1.ConclusionThis study demonstrates that resting‐state EEG parameters, particularly theta and alpha power, are closely linked to AD plasma biomarkers. Stratification based on pTau217 revealed distinct EEG patterns across biomarker‐defined groups, emphasizing EEG's utility as a non‐invasive tool for capturing disease‐specific neurophysiological alterations. These findings underline the potential of EEG as an accessible, non‐invasive, and scalable method to support the diagnosis and monitoring of AD.Funding: Fujirebio Italia

Hippocampal theta oscillations regulate the timing of neurons to support navigation, memory formation, and sensorimotor integration. Theta is modulated by running speed, breathing, whisking, and jumping and increases in tasks involving memory encoding or retrieval. The positive relationship between theta frequency and running speed is believed stabilize hippocampal representations of space amid movement variability. Here, we incorporated a novel string-pulling task to determine if established relationships between movement and theta hold when progress to a reward is determined by the length of string pulled. This task eliminates many speed-associated inputs, such vestibular, visual, and hindlimb information, and allows an unprecedented level of precision in the analysis of individual paw movements. Given that animals move the string a fixed length to acquire a reward, we predicted that the positive relationship between theta frequency and speed would hold.ApproachFive Sprague Dawley rats (4 mo.) were trained to continuously pull a string a fixed distance of 208 cm using an automated string-pulling system and run on a track for food reward. Local-field data was acquired from electrodes in dorsal CA1.ResultsRelationships between theta and movement speed were distinct during string pulling and running. While theta was robust in both conditions, frequency was significantly reduced during string-pulling and showed no speed-frequency coupling, unlike running. This difference could result from the conflict between hindlimb and forelimb signals, with only forelimb movement signaling advancement. Fine-grained analysis of paw movements during string-pulling (lift, advance, grasp, pull, push) revealed that theta power and frequency peaked during the contralateral paw’s downward push despite paw speed being low during this action. This suggests that theta frequency and power could respond to effort rather than purely kinematic information. Notably, running-associated theta may similarly reflect both speed and effort as most locomotor tasks conflate these variables. Finally, theta phase aligned from one reach-pull cycle to the next during the downward pull motion - the first action that directly advances the string forward. Since phase-locking has been associated with sensorimotor gating, synchrony at this point could reflect the gating of inputs that are the most causally relevant for reaching the reward, potentially facilitating integration of action-outcome signals for memory encoding and navigation. Taken together, these data support a dual-scale view of hippocampal processing and theta-band activity where macroscale theta activity requires suprathreshold sensory, vestibular, and proprioceptive drive and microscale theta remains sensitive to subsecond limb movements.

Nitrous oxide (N2O) may elicit antidepressant effects after its elimination from the brain. We sought to investigate whether short-term administration of N2O triggers power within the delta (0.5-4 Hz) and/or theta (4-7 Hz) frequency ranges in the electroencephalogram (EEG) after it's administration, as we have recently seen such rebound effects to N2O in studies conducted on mice. Twenty healthy male participants were randomly allocated to receive 50% N2O either continuously for 20 min (continuous group) or in two 10-min inhalations (repeated group) with 19-channel EEG. Median-averaged power spectral densities (PSDs) were calculated subject-, electrode-, and state-wise. Group-level data are topographically plotted and significant changes within specific frequency ranges for each condition are highlighted. The subjective effects in response to N2O were studied with questionnaires. Fourteen participants completed the study (n = 7 participants/group). Spectrograms showed that the EEG transitions between N2O and its withdrawal were extremely rapid in both groups and the effects remained stationary during specific states. Power in high-frequency bands (gamma) generally enhanced during N2O administration along with power reductions in beta (and alpha) frequencies. Power in specific theta, but not delta, frequencies increase after the cessation of N2O in several electrodes. However, direct comparison of the rebound EEG between the two treatment groups revealed negligible differences. Short-term administration of N2O evokes increase of power in theta frequency, but not delta, band power upon gas withdrawal.NEW & NOTEWORTHY This study specifically addressed rebound EEG alterations within slow-wave frequency range upon withdrawal from N2O in awake healthy participants. Short-term administration of N2O increased power in theta, but not delta, frequency range upon gas withdrawal and this effect was readily reproduced with repeated dose.

Introduction: Transcranial pulsed current stimulation (tPCS) is an emerging noninvasive brain stimulation technique that has shown significant effects on cortical excitability. To date, electrophysiological measures of the efficiency of monophasic tPCS have not been reported. Objective: We aimed to explore the effects of monophasic anodal and cathodal-tPCS (a-tPCS/c-tPCS) at theta (4 Hz) and gamma (75 Hz) frequencies on theta and high gamma electroencephalography (EEG) oscillatory power. Methods: In a single-blind, randomized, sham-controlled crossover design, 15 healthy participants were randomly assigned into 5 experimental sessions in which they received a-PCS/c-tPCS at 4 and 75 Hz or sham stimulation over the left primary motor cortex (M1) for 15 min at an intensity of 1.5 mA. Changes in theta and high gamma oscillatory power were recorded at baseline, immediately after, and 30 min after stimulation using EEG at rest with eyes open. Results: a-tPCS at 4 Hz showed a significant increase in theta power compared with sham, whereas c-tPCS at 4 Hz had no significant effect on theta power. a-tPCS at 75 Hz produced no changes in high gamma power compared with sham. Importantly, c-tPCS at 75 Hz led to a significant reduction in high gamma power compared with baseline, as well as compared with c-tPCS at 4 Hz and sham stimulation. Conclusion: The results demonstrate the modulation of oscillatory brain activity by monophasic tPCS, and highlight the need for future studies on a larger scale to confirm these initial findings. Impact statement Transcranial pulsed current stimulation (tPCS) is a novel brain stimulation technique. Recently, tPCS has been introduced to directly modulate brain oscillations by applying pulsatile current over the target brain area. Using both anodal and cathodal monophasic tPCS at theta and gamma frequencies, we demonstrate the ability of the stimulation to modulate brain activity. The present findings are the first direct electroencephalography evidence of an interaction between tPCS and ongoing oscillatory activity in the human motor cortex. Our work recommends tPCS as a tool for investigating human brain oscillations and open more studies in this area.

The goal of this study was to examine the effect of hearing loss on theta and alpha electroencephalography (EEG) frequency power measures of performance monitoring and cognitive inhibition, respectively, during a speech-in-noise task. It was hypothesized that hearing loss would be associated with an increase in the peak power of theta and alpha frequencies toward easier conditions compared to normal hearing adults. The shift would reflect how hearing loss modulates the recruitment of listening effort to easier listening conditions. Nine older adults with normal hearing (ONH) and 10 older adults with hearing loss (OHL) participated in this study. EEG data were collected from all participants while they completed the words-in-noise task. It hypothesized that hearing loss would also have an effect on theta and alpha power. The ONH group showed an inverted U -shape effect of signal-to-noise ratio (SNR), but there were limited effects of SNR on theta or alpha power in the OHL group. The results of the ONH group support the growing body of literature showing effects of listening conditions on alpha and theta power. The null results of listening condition in the OHL group add to a smaller body of literature, suggesting that listening effort research conditions should have near ceiling performance.

Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Ecopipam (0.05-0.2mg/kg) and haloperidol (0.05-0.15mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0mg/kg, while females showed augmented immunoreactivity at 2.0mg/kg. The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.

AimsSchizophrenia is a chronic brain disorder characterised by distortion of thoughts and perception. Several studies have shown a key role of the hippocampal formation in the pathophysiology of schizophrenia. Patients show impaired theta coherence between medial temporal lobe and medial prefrontal cortex (mPFC), and impairment of knowledge structuring and inferential processes. Both the hippocampal formation and mPFC contain hexadirectional modulation of activity, indicative of grid cell populations. Grid cells play an important role in mapping the environment and are believed to represent the transition structure between task states. With other cell populations in the hippocampal formation, they play a fundamental role in inference, episodic memory, and spatial navigation. Here, we investigate whether schizophrenia is associated with disrupted grid firing patterns.MethodsTo test this hypothesis, we asked 18 participants with diagnoses of schizophrenia and 26 controls (matched for age, sex and IQ) to perform a spatial memory task in magnetoencephalography (MEG), while navigating a virtual reality environment. We first analysed theta (4–10 Hz) power during movement onset compared to stationary periods. We then source-localised the signal and looked for the hexadirectional modulation of theta band oscillatory activity by heading direction during movement onset. We also controlled for other symmetries in theta frequencies (four, five, and eight fold) and hexadirectional modulation in other frequencies. The same participants performed an inference task outside MEG, which we used for correlation analysis.ResultsThe peak of theta power during movement onset was stronger in controls compared to patients (p < 0.05). In the control group, we found hexadirectional modulation of theta power by movement direction in the right entorhinal cortex (p < 0.005). This effect was absent in patients with a significant difference between groups (p < 0.05), suggesting that their entorhinal grid firing patterns may be disrupted. No other symmetry modulated theta power significantly in controls or patients, and hexadirectional modulation during movement onset was found only in theta frequencies in controls. Performance in the inference task was significantly impaired in schizophrenic patients, and spatial memory performance in both controls and patients was positively correlated with their performance in the inference task.ConclusionThese results are consistent with the hypothesis that impairments in knowledge structuring and inference associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex. Although further work is needed to better understand the role of grid cells in health and disease, this work provides new insights into dysfunction of the hippocampal formation in schizophrenia.

Characterizing Cortical Oscillatory Responses in Major Depressive Disorder Before and After Convulsive Therapy: A TMS-EEG Study

In the present study, we investigated the cognitive processes underlying selective word learning in preschoolers. We measured rhythmic neural activity in the theta (4-8 Hz) and alpha frequency range (7-12 Hz) in 67 four-year-olds. EEG was recorded during anticipation and encoding of novel labeling events performed by a speaker who had previously shown either competence (correct) or incompetence (incorrect) in labeling familiar objects. In both groups, children selected the target object equally often upon recall. However, children observing the incompetent speaker revealed weaker representations of novel words indicated by an increased likelihood for selecting familiar but incorrect items upon recall. Modulations in theta and alpha power suggest differential processing of novel label-object pairs depending on the speakers' competence. In the incompetent, but not the competent, speaker condition, increases in prefrontal theta power during anticipation and encoding were related to increased recall success. Findings suggest that theta power in the present study reflects cognitive control. In both conditions, occipital alpha power-indicating attentional processes-reflected familiarity with novel items, but in opposite directions. In familiar item trials, alpha power was increased observing the incompetent and decreased observing the competent speaker. Thus, both cognitive control and attention processes during word learning are differentially affected by speaker characteristics.

The modulatory role of 5-HT neurons and a number of different 5-HT receptor subtypes has been well documented in the regulation of sleep-wake cycles and hippocampal activity. A high level of 5-HT(6) receptor expression is present in the rat hippocampus. Further, hippocampal function has been shown to be modulated by both 5-HT(6) agonists and antagonists. In the current study, the potential involvement of 5-HT(6) receptors in the control of hippocampal theta rhythms and sleep-wake cycles has been investigated. Hippocampal activity was recorded by intracranial hippocampal electrodes both in anesthetized (n = 22) and in freely moving rats (n = 9). Theta rhythm was monitored in different sleep-wake states in freely moving rats and was elicited by stimulation of the brainstem reticular formation under anesthesia. Changes in theta frequency and power were analyzed before and after injection of the 5-HT(6) antagonist (SAM-531) and the 5-HT(6) agonist (EMD386088). In freely moving rats, EMD386088 suppressed sleep for several hours and significantly decreased theta peak frequency, while, in anesthetized rats, EMD386088 had no effect on theta power but significantly decreased theta frequency, which could be blocked by coadministration of SAM-531. SAM-531 alone did not change sleep-wake patterns and had no effect on theta parameters in both unanesthetized and anesthetized rats. Decreases in theta frequency induced by the 5-HT(6) receptor agonist correspond to previously described electrophysiological patterns shared by all anxiolytic drugs, and it is in line with its behavioral anxiolytic profile. The 5-HT(6) antagonist, however, failed to potentiate theta power, which is characteristic of many pro-cognitive substances, indicating that 5-HT(6) receptors might not tonically modulate hippocampal oscillations and sleep-wake patterns.