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Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinsons disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.

Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

BackgroundPrior studies have shown that the auditory N1 event-related potential component elicited by self-generated vocalizations is reduced relative to played back vocalizations, putatively reflecting a corollary discharge mechanism. Schizophrenia patients and psychosis risk syndrome (PRS) youth show deficient N1 suppression during vocalization, consistent with corollary discharge dysfunction. Because N1 is an admixture of theta (4-7 Hz) power and phase synchrony, we examined their contributions to N1 suppression during vocalization, as well as their sensitivity, relative to N1, to corollary discharge dysfunction in schizophrenia and PRS individuals.MethodsTheta phase and power values were extracted from electroencephalography data acquired from PRS youth (n = 71), early illness schizophrenia patients (ESZ; n = 84), and healthy controls (HCs; n = 103) as they said "ah" (Talk) and then listened to the playback of their vocalizations (Listen). A principal component analysis extracted theta intertrial coherence (ITC; phase consistency) and event-related spectral power, peaking in the N1 latency range. Talk-Listen suppression scores were analyzed.ResultsTalk-Listen suppression was greater for theta ITC (Cohen's d = 1.46) than for N1 in HC (d = 0.63). Both were deficient in ESZ, but only N1 suppression was deficient in PRS. When deprived of variance shared with theta ITC suppression, N1 suppression no longer differentiated ESZ and PRS individuals from HC. Deficits in theta ITC suppression were correlated with delusions (P = .007) in ESZ. Theta power suppression did not differentiate groups.ConclusionsTheta ITC-suppression during vocalization is a more sensitive index of corollary discharge-mediated auditory cortical suppression than N1 suppression and is more sensitive to corollary discharge dysfunction in ESZ than in PRS individuals.

The receptive field of a neuron describes the regions of a stimulus space where the neuron is consistently active. Sparse spiking outside of the receptive field is often considered to be noise, rather than a reflection of information processing. Whether this characterization is accurate remains unclear. We therefore contrasted the sparse, temporally isolated spiking of hippocampal CA1 place cells to the consistent, temporally adjacent spiking seen within their spatial receptive fields ("place fields"). We found that isolated spikes, which occur during locomotion, are strongly phase coupled to hippocampal theta oscillations and transiently express coherent nonlocal spatial representations. Further, prefrontal cortical activity is coordinated with and can predict the occurrence of future isolated spiking events. Rather than local noise within the hippocampus, sparse, isolated place cell spiking reflects a coordinated cortical-hippocampal process consistent with the generation of nonlocal scenario representations during active navigation.

Theta-band (∼6 Hz) rhythmic activity within and over the medial PFC ("midfrontal theta") has been identified as a distinctive signature of "response conflict," the competition between multiple actions when only one action is goal-relevant. Midfrontal theta is traditionally conceptualized and analyzed under the assumption that it is a unitary signature of conflict that can be uniquely identified at one electrode (typically FCz). Here we recorded simultaneous MEG and EEG (total of 328 sensors) in 9 human subjects (7 female) and applied a feature-guided multivariate source-separation decomposition to determine whether conflict-related midfrontal theta is a unitary or multidimensional feature of the data. For each subject, a generalized eigendecomposition yielded spatial filters (components) that maximized the ratio between theta and broadband activity. Components were retained based on significance thresholding and midfrontal EEG topography. All of the subjects individually exhibited multiple (mean 5.89, SD 2.47) midfrontal components that contributed to sensor-level midfrontal theta power during the task. Component signals were temporally uncorrelated and asynchronous, suggesting that each midfrontal theta component was unique. Our findings call into question the dominant notion that midfrontal theta represents a unitary process. Instead, we suggest that midfrontal theta spans a multidimensional space, indicating multiple origins, but can manifest as a single feature at the sensor level because of signal mixing.SIGNIFICANCE STATEMENT "Midfrontal theta" is a rhythmic electrophysiological signature of the competition between multiple response options. Midfrontal theta is traditionally considered to reflect a single process. However, this assumption could be erroneous because of "mixing" (multiple sources contributing to the activity recorded at a single electrode). We investigated the dimensionality of midfrontal theta by applying advanced multivariate analysis methods to a multimodal MEG/EEG dataset. We identified multiple topographically overlapping neural sources that drove response conflict-related midfrontal theta. Midfrontal theta thus reflects multiple uncorrelated signals that manifest with similar EEG scalp projections. In addition to contributing to the cognitive control literature, we demonstrate both the feasibility and the necessity of signal demixing to understand the narrowband neural dynamics underlying cognitive processes.

Working memory (WM) relies on the prioritization of relevant information and suppression of irrelevant information [1, 2]. Prioritizing relevant information has been linked to theta frequency neural oscillations in lateral prefrontal cortex and suppressing irrelevant information has been linked to alpha oscillations in occipito-parietal cortex [3,11]. Here, we used a retrospective-cue WM paradigm to manipulate prioritization and suppression task demands designed to drive theta oscillations in prefrontal cortex and alpha oscillations in parietal cortex, respectively. To causally test the role of these neural oscillations, we applied rhythmic transcranial magnetic stimulation (TMS) in either theta or alpha frequency to prefrontal and parietal regions identified using functional MRI. The effect of rhythmic TMS on WM performance was dependent on whether the TMS frequency matched or mismatched the expected underlying task-driven oscillations of the targeted region. Functional MRI in the targeted regions predicted subsequent TMS effects across subjects supporting a model by which theta oscillations are excitatory to neural activity, and alpha oscillations are inhibitory. Together, these results causally establish dissociable roles for prefrontal theta oscillations and parietal alpha oscillations in the control of internally maintained WM representations.

Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per ∼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by "bottom-up" enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Many genes have been linked to autism. However, it remains unclear what long-term changes in neural circuitry result from disruptions in these genes, and how these circuit changes might contribute to abnormal behaviors. To address these questions, we studied behavior and physiology in mice heterozygous for Pogz, a high confidence autism gene. Pogz+/- mice exhibit reduced anxiety-related avoidance in the elevated plus maze (EPM). Theta-frequency communication between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) is known to be necessary for normal avoidance in the EPM. We found deficient theta-frequency synchronization between the vHPC and mPFC in vivo. When we examined vHPC-mPFC communication at higher resolution, vHPC input onto prefrontal GABAergic interneurons was specifically disrupted, whereas input onto pyramidal neurons remained intact. These findings illustrate how the loss of a high confidence autism gene can impair long-range communication by causing inhibitory circuit dysfunction within pathways important for specific behaviors.

When viewing familiar stimuli (e.g., common words), processing is highly automatized such that it can interfere with the processing of incompatible sensory information. At least two mechanisms may help mitigate this interference. Early selection accounts posit that attentional processes filter out distracting sensory information to avoid conflict. Alternatively, late selection accounts hold that all sensory inputs receive full semantic analysis and that frontal executive mechanisms are recruited to resolve conflict. To test how these mechanisms operate to overcome conflict induced by highly automatized processing, we developed a novel version of the color-word Stroop task, where targets and distractors were simultaneously flickered at different frequencies. We measured the quality of early sensory processing by assessing the amplitude of steady-state visually evoked potentials (SSVEPs) elicited by targets and distractors. We also indexed frontal executive processes by assessing changes in frontal theta oscillations induced by color-word incongruency. We found that target- and distractor-related SSVEPs were not modulated by changes in the level of conflict whereas frontal theta activity increased on high compared to low conflict trials. These results suggest that frontal executive processes play a more dominant role in mitigating cognitive interference driven by the automatic tendency to process highly familiar stimuli.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ∼350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ∼5 s on average, whereas ripples on successive SSR peaks are separated by only ∼80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.SIGNIFICANCE STATEMENT Rodent hippocampal neurons replay waking events during sharpwave ripples (SWRs) in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces SWRs, but spindle ripples predominate in posterior. Whereas SWRs typically occur as cortex emerges from inactivity, spindle ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle ripples can recur within a second, whereas SWRs are separated by ∼5 s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindle ripples may support a related function in humans.

Origin and functions of intermittent transitions among sleep stages, including short awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing the sleep-wake cycle results from an underlying non-equilibrium critical dynamics, bridging collective behaviors across spatio-temporal scales. We investigate θ and δ wave dynamics in control rats and in rats with lesions of sleep-promoting neurons in the parafacial zone. We demonstrate that intermittent bursts in θ and δ rhythms exhibit a complex temporal organization, with long-range power-law correlations and a robust duality of power law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, typical features of non-equilibrium systems self-organizing at criticality. Crucially, such temporal organization relates to anti-correlated coupling between θ- and δ-bursts, and is independent of the dominant physiologic state and lesions, a solid indication of a basic principle in sleep dynamics.

Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.

Theta oscillations (4-8 Hz) provide an organizing principle of cognitive control, allowing goal-directed behavior. In adults, theta power over medial-frontal cortex (MFC) underlies conflict/error monitoring, whereas theta connectivity between MFC and lateral-frontal regions reflects cognitive control recruitment. However, prior work has not separated theta responses that occur before and immediately after a motor response, nor explained how medial-lateral connectivity drives different kinds of control behaviors. Theta's role during adolescence, a developmental window characterized by a motivation-control mismatch also remains unclear. As social observation is known to influence motivation, this might be a particularly important context for studying adolescent theta dynamics. Here, adolescents performed a flanker task alone or under social observation. Focusing first on the nonsocial context, we parsed cognitive control into dissociable subprocesses, illustrating how theta indexes distinct components of cognitive control working together dynamically to produce goal-directed behavior. We separated theta power immediately before/after motor responses, identifying behavioral links to conflict monitoring and error monitoring, respectively. MFC connectivity was separated before/after responses and behaviorally-linked to reactive and proactive control, respectively. Finally, distinct forms of post-error control were dissociated, based on connectivity with rostral/caudal frontal cortex. Social observation was found to exclusively upregulate theta measures indexing post-response error monitoring and proactive control, as opposed to conflict monitoring and reactive control. Linking adolescent cognitive control to theta oscillations provides a bridge between non-invasive recordings in humans and mechanistic studies of neural oscillations in animal models; links to social observation provide insight into the motivation-control interactions that occur during adolescence.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P

How do we remember emotional events? While emotion often leads to vivid recollection, the precision of emotional memories can be degraded, especially when discriminating among overlapping experiences in memory (i.e., pattern separation). Communication between the amygdala and the hippocampus has been proposed to support emotional memory, but the exact neural mechanisms remain unclear. Here, we used intracranial recordings in pre-surgical epilepsy patients to show that successful pattern separation of emotional stimuli is associated with theta band (3-7 Hz)-coordinated bidirectional interactions between the amygdala and the hippocampus. In contrast, discrimination errors (i.e., failure to discriminate similar stimuli) were associated with alpha band (7-13 Hz)-coordinated unidirectional influence from the amygdala to the hippocampus. These findings imply that alpha band synchrony may impair discrimination of similar emotional events via the amygdala-hippocampal directional coupling, which suggests a target for treatments of psychiatric conditions such as post-traumatic stress disorder, in which aversive experiences are often overgeneralized.

The theta rhythm during waking has been associated with voluntary motor activity and learning processes involving the hippocampus. Theta also occurs continuously during rapid eye movement (REM) sleep where it likely serves memory consolidation. Theta amplitude builds across wakefulness and is the best indicator of the homeostatic need for non-REM (NREM) sleep. Although REM sleep is homeostatically regulated independently of NREM sleep, the drivers of REM sleep regulation are under debate. The dynamics of theta within REM sleep bouts have not been thoroughly explored. We equipped 20 male rats with sleep instrumentation and hippocampal electrodes to measure theta across normal sleep/waking periods over the first 4 h of the sleep phase on two consecutive days. We found that theta power decreased by a third, on average, within individual REM sleep bouts, but recovered between bouts. Thus, there was no general decline in theta power across the duration of the recording period or between days. The time constant of theta power decline within a REM sleep bout was the same whether the bout was short, midlength, or long, and did not predict the behavioral state immediately following the REM sleep bout. Interestingly, the more time spent in NREM sleep prior to REM sleep, the larger the decline in theta power during REM sleep, indicating that REM sleep theta may be homeostatically driven by NREM sleep just as NREM delta power is driven by the length of prior waking and by waking theta. Potential causes and implications for this phenomenon are discussed.

BackgroundAutism spectrum disorder (ASD) is a complex neurodevelopmental condition, and multiple theories have emerged concerning core social deficits. While the social motivation hypothesis proposes that deficits in the social reward system cause individuals with ASD to engage less in social interaction, the overly intense world hypothesis (sensory over-responsivity) proposes that individuals with ASD find stimuli to be too intense and may have hypersensitivity to social interaction, leading them to avoid these interactions.MethodsEEG was recorded during reward anticipation and reward processing. Reward anticipation was measured using alpha asymmetry, and post-feedback theta was utilized to measure reward processing. Additionally, we calculated post-feedback alpha suppression to measure attention and salience. Participants were 6- to 8-year-olds with (N = 20) and without (N = 23) ASD.ResultsChildren with ASD showed more left-dominant alpha suppression when anticipating rewards accompanied by nonsocial stimuli compared to social stimuli. During reward processing, children with ASD had less theta activity than typically developing (TD) children. Alpha activity after feedback showed the opposite pattern: children with ASD had greater alpha suppression than TD children. Significant correlations were observed between behavioral measures of autism severity and EEG activity in both the reward anticipation and reward processing time periods.ConclusionsThe findings provide evidence that children with ASD have greater approach motivation prior to nonsocial (compared to social) stimuli. Results after feedback suggest that children with ASD evidence less robust activity thought to reflect evaluation and processing of rewards (e.g., theta) compared to TD children. However, children with ASD evidence greater alpha suppression after feedback compared to TD children. We hypothesize that post-feedback alpha suppression reflects general cognitive engagement-which suggests that children with ASD may experience feedback as overly intense. Taken together, these results suggest that aspects of both the social motivation hypothesis and the overly intense world hypothesis may be occurring simultaneously.

Cognitive control refers to the ability to produce flexible, goal-oriented behavior in the face of changing task demands and conflicting response tendencies. A classic cognitive control experiment is the Stroop-color naming task, which requires participants to name the color in which a word is written while inhibiting the tendency to read the word. By comparing stimuli with conflicting word-color associations to congruent ones, control processes over response tendencies can be isolated. We assessed the spatial specificity and temporal dynamics in the theta and gamma bands for regions engaged in detecting and resolving conflict in a cohort of 13 patients using a combination of high-resolution surface and depth recordings. We show that cognitive control manifests as a sustained increase in gamma band power, which correlates with response time. Conflict elicits a sustained gamma power increase but a transient theta power increase, specifically localized to the left cingulate sulcus and bilateral dorsolateral prefrontal cortex (DLPFC). Additionally, activity in DLPFC is affected by trial-by-trial modulation of cognitive control (the Gratton effect). Altogether, the sustained local neural activity in dorsolateral and medial regions is what determines the timing of the correct response.

Sleep is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity that is necessary to incorporate new information into pre-existing memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2 Hz during sleep, we reduced sleep spindle occurrence, as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories.

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. These results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. These results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

In Parkinson's disease (PD), subthalamic nucleus beta band oscillations are decreased by therapeutic deep-brain stimulation (DBS) and this has been proposed as important to the mechanism of therapy. The globus pallidus is a common alternative target for PD with similar motor benefits as subthalamic DBS, but effects of pallidal stimulation in PD are not well studied, and effects of pallidal DBS on cortical function in PD are unknown. Here, in 20 PD and 14 isolated dystonia human patients of both genders undergoing pallidal DBS lead implantation, we recorded local field potentials from the globus pallidus and in a subset of these, recorded simultaneous sensorimotor cortex ECoG potentials. PD patients had elevated resting pallidal low beta band (13-20 Hz) power compared with dystonia patients, whereas dystonia patients had elevated resting pallidal theta band (4-8 Hz) power compared with PD. We show that this results in disease-specific patterns of interaction between the pallidum and motor cortex: PD patients demonstrated relatively elevated phase coherence with the motor cortex in the beta band and this was reduced by therapeutic pallidal DBS. Dystonia patients had greater theta band phase coherence. Our results support the hypothesis that specific motor phenomenology observed in movement disorders are associated with elevated network oscillations in specific frequency bands, and that DBS in movement disorders acts in general by disrupting elevated synchronization between basal ganglia output and motor cortex.SIGNIFICANCE STATEMENT Perturbations in synchronized oscillatory activity in brain networks are increasingly recognized as important features in movement disorders. The globus pallidus is a commonly used target for deep-brain stimulation (DBS) in Parkinson's disease (PD), however, the effects of pallidal DBS on basal ganglia and cortical oscillations are unknown. Using invasive intraoperative recordings in patients with PD and isolated dystonia, we found disease-specific patterns of elevated oscillatory synchronization within the pallidum and in coherence between pallidum and motor cortex. Therapeutic pallidal DBS in PD suppresses these elevated synchronizations, reducing the influence of diseased basal ganglia on cortical physiology. We propose a general mechanism for DBS therapy in movement disorders: functional disconnection of basal ganglia output and motor cortex by coherence suppression.

Biological oscillations can be controlled by a small population of rhythmic pacemaker cells, or in the brain, they also can emerge from complex cellular and circuit-level interactions. Whether and how these mechanisms are combined to give rise to oscillatory patterns that govern cognitive function are not well understood. For example, the activity of hippocampal networks is temporally coordinated by a 7- to 9-Hz local field potential (LFP) theta rhythm, yet many individual cells decouple from the LFP frequency to oscillate at frequencies ∼1 Hz higher. To better understand the network interactions that produce these complex oscillatory patterns, we asked whether the relative frequency difference between LFP and individual cells is retained when the LFP frequency is perturbed experimentally. We found that rhythmic optogenetic stimulation of medial septal GABAergic neurons controlled the hippocampal LFP frequency outside of the endogenous theta range, even during behavioral states when endogenous mechanisms would otherwise have generated 7- to 9-Hz theta oscillations. While the LFP frequency matched the optogenetically induced stimulation frequency, the oscillation frequency of individual hippocampal cells remained broadly distributed, and in a subset of cells including interneurons, it was accelerated beyond the new base LFP frequency. The inputs from septal GABAergic neurons to the hippocampus, therefore, do not appear to directly control the cellular oscillation frequency but rather engage cellular and circuit mechanisms that accelerate the rhythmicity of individual cells. Thus, theta oscillations are an example of cortical oscillations that combine inputs from a subcortical pacemaker with local computations to generate complex oscillatory patterns that support cognitive functions.

How do we rapidly process incoming streams of information in working memory, a cognitive mechanism central to human behavior? Dominant views of working memory focus on the prefrontal cortex (PFC), but human hippocampal recordings provide a neurophysiological signature distinct from the PFC. Are these regions independent, or do they interact in the service of working memory? We addressed this core issue in behavior by recording directly from frontotemporal sites in humans performing a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. Theta band oscillations drove bidirectional interactions between the PFC and medial temporal lobe (MTL; including the hippocampus). MTL theta oscillations directed the PFC preferentially during the processing of spatiotemporal information, while PFC theta oscillations directed the MTL for all types of information being processed in working memory. These findings reveal an MTL theta mechanism for processing space and time and a domain-general PFC theta mechanism, providing evidence that rapid, dynamic MTL-PFC interactions underlie working memory for everyday experiences.

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed "task engagement," may enable context-dependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision-making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4-7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.SIGNIFICANCE STATEMENT When rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated compared with task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex and thus represents a form of "top-down" regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task-dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing.

The goal of this study was to investigate the neural dynamics of error processing and post-error adjustments in cognitive control and attention to a cognitive task in schizophrenia. We adopted a time-frequency approach in order to examine activity in the theta and alpha frequency bands as indices of cognitive control and attentional engagement. The results showed that error processing was characterized by increases in theta-band activity, accompanied by decreases in alpha-band activity, in both healthy control participants and participants with schizophrenia. However, both the theta and alpha effects were significantly reduced in participants with schizophrenia. Post-error increases in theta activity were associated with improved accuracy on subsequent trials in control participants but not in participants with schizophrenia. In addition, increases in alpha-band activity were found in the prestimulus period before partial attention lapses, but only for control participants and participants with schizophrenia with relatively low positive symptom severity. These results provide evidence for a deficit in cognitive control mechanisms mediated by midfrontal theta activity in schizophrenia, and suggest a particularly pronounced deficit in patients' ability to engage adaptive control mechanisms following errors. Our results also indicate that partial attention lapses can be indexed in both control participants and participants with schizophrenia by increases in alpha activity, but that in schizophrenia this varies as a function of positive symptom severity. We suggest that disrupted theta-band function represents a key deficit of schizophrenia, whereas disruptions in the alpha band may be the byproduct of atypically regulated attention.

The theta rhythm-a slow (6-12 Hz) oscillatory component of the local field potential-plays a critical role in spatial navigation and memory by coordinating the activity of neuronal ensembles within the medial temporal lobe (MTL). Although theta has been extensively studied in freely moving rodents, its presence in humans has been elusive and primarily investigated in stationary subjects. Here we used a unique clinical opportunity to examine theta within the human MTL during untethered, real-world ambulatory movement. We recorded intracranial electroencephalographic activity from participants chronically implanted with the wireless NeuroPace responsive neurostimulator (RNS) and tracked their motion with sub-millimeter precision. Our data revealed that movement-related theta oscillations indeed exist in humans, such that theta power is significantly higher during movement than immobility. Unlike in rodents, however, theta occurs in short bouts, with average durations of ∼400 ms, which are more prevalent during fast versus slow movements. In a rare opportunity to study a congenitally blind participant, we found that both the prevalence and duration of theta bouts were increased relative to the sighted participants. These results provide critical support for conserved neurobiological characteristics of theta oscillations during ambulatory spatial navigation, while highlighting some fundamental differences across species in these oscillations between humans and rodents.

BackgroundFew patients recover full hand dexterity after an acquired brain injury such as stroke. Repetitive somatosensory electrical stimulation (SES) is a promising method to promote recovery of hand function. However, studies using SES have largely focused on gross motor function; it remains unclear if it can modulate distal hand functions such as finger individuation.ObjectiveThe specific goal of this study was to monitor the effects of SES on individuation as well as on cortical oscillations measured using EEG, with the additional goal of identifying neurophysiological biomarkers.MethodsEight participants with a history of acquired brain injury and distal upper limb motor impairments received a single two-hour session of SES using transcutaneous electrical nerve stimulation. Pre- and post-intervention assessments consisted of the Action Research Arm Test (ARAT), finger fractionation, pinch force, and the modified Ashworth scale (MAS), along with resting-state EEG monitoring.ResultsSES was associated with significant improvements in ARAT, MAS and finger fractionation. Moreover, SES was associated with a decrease in low frequency (0.9-4 Hz delta) ipsilesional parietomotor EEG power. Interestingly, changes in ipsilesional motor theta (4.8-7.9 Hz) and alpha (8.8-11.7 Hz) power were significantly correlated with finger fractionation improvements when using a multivariate model.ConclusionsWe show the positive effects of SES on finger individuation and identify cortical oscillations that may be important electrophysiological biomarkers of individual responsiveness to SES. These biomarkers can be potential targets when customizing SES parameters to individuals with hand dexterity deficits.Trial registrationNCT03176550; retrospectively registered.

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake-sleep regulatory system.

Event related oscillations (EROs) are heritable measures of neurocognitive function that have served as useful phenotype in genetic research. A recent family genome-wide association study (GWAS) by the Collaborative Study on the Genetics of Alcoholism (COGA) found that theta EROs during visual target detection were associated at genome-wide levels with several single nucleotide polymorphisms (SNPs), including a synonymous SNP, rs702859, in the KCNJ6 gene that encodes GIRK2, a G-protein inward rectifying potassium channel that regulates excitability of neuronal networks. The present study examined the effect of the KCNJ6 SNP (rs702859), previously associated with theta ERO to targets in a visual oddball task, on theta EROs during reward processing in a monetary gambling task. The participants were 1601 adolescent and young adult offspring within the age-range of 17-25years (800 males and 801 females) from high-dense alcoholism families as well as control families of the COGA prospective study. Theta ERO power (3.5-7.5Hz, 200-500ms post-stimulus) was compared across genotype groups. ERO theta power at central and parietal regions increased as a function of the minor allele (A) dose in the genotype (AA>AG>GG) in both loss and gain conditions. These findings indicate that variations in the KCNJ6 SNP influence magnitude of theta oscillations at posterior loci during the evaluation of loss and gain, reflecting a genetic influence on neuronal circuits involved in reward-processing. Increased theta power as a function of minor allele dose suggests more efficient cognitive processing in those carrying the minor allele of the KCNJ6 SNPs. Future studies are needed to determine the implications of these genetic effects on posterior theta EROs as possible "protective" factors, or as indices of delays in brain maturation (i.e., lack of frontalization).

The capacity for using external cues to guide behavior ("cue detection") constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta-gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection.SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding ("cue detection") is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.

Recent research suggests that prosocial outcomes in sharing games arise from prefrontal control of self-maximizing impulses. We used continuous theta burst stimulation (cTBS) to disrupt the functioning of two prefrontal areas, the right dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex (DMPFC). We used cTBS in the right MT/V5, as a control area. We then tested subjects' prosocial inclinations with an unsupervised Dictator Game in which they allocated real money anonymously between themselves and low and high socioeconomic status (SES) players. cTBS over the two prefrontal sites made subjects more generous compared to MT/V5. More specifically, cTBS over DLPFC increased offers to high-SES players, while cTBS over DMPFC caused increased offers to low-SES players. These data, the first to demonstrate an effect of disruptive neuromodulation on costly sharing, suggest that DLPFC and MPFC exert inhibitory control over prosocial inclinations during costly sharing, though they may do so in different ways. DLPFC may implement contextual control, while DMPFC may implement a tonic form of control. This study demonstrates that humans' prepotent inclination is toward prosocial outcomes when cognitive control is reduced, even when prosocial decisions carry no strategic benefit and concerns for reputation are minimized.

One of the most firmly established factors determining the speed of human behavioral responses toward action-critical stimuli is the spatial correspondence between the stimulus and response locations. If both locations match, the time taken for response production is markedly reduced relative to when they mismatch, a phenomenon called the Simon effect. While there is a consensus that this stimulus-response (S-R) conflict is associated with brief (4-7 Hz) frontal midline theta (fmθ) complexes generated in medial frontal cortex, it remains controversial (1) whether there are multiple, simultaneously active theta generator areas in the medial frontal cortex that commonly give rise to conflict-related fmθ complexes; and if so, (2) whether they are all related to the resolution of conflicting task information. Here, we combined mental chronometry with high-density electroencephalographic measures during a Simon-type manual reaching task and used independent component analysis and time-frequency domain statistics on source-level activities to model fmθ sources. During target processing, our results revealed two independent fmθ generators simultaneously active in or near anterior cingulate cortex, only one of them reflecting the correspondence between current and previous S-R locations. However, this fmθ response is not exclusively linked to conflict but also to other, conflict-independent processes associated with response slowing. These results paint a detailed picture regarding the oscillatory correlates of conflict processing in Simon tasks, and challenge the prevalent notion that fmθ complexes induced by conflicting task information represent a unitary phenomenon related to cognitive control, which governs conflict processing across various types of response-override tasks.SIGNIFICANCE STATEMENT Humans constantly monitor their environment for and adjust their cognitive control settings in response to conflicts, an ability that arguably paves the way for survival in ever-changing situations. Anterior cingulate-generated frontal midline theta (fmθ) complexes have been hypothesized to play a role in this conflict-monitoring function. However, it remains a point of contention whether fmθ complexes govern conflict processing in a unitary, paradigm-nonspecific manner. Here, we identified two independent fmθ oscillations triggered during a Simon-type task, only one of them reflecting current and previous conflicts. Importantly, this signal differed in various respects (cortical origin, intertrial history) from fmθ phenomena in other response-override tasks, challenging the prevalent notion of conflict-induced fmθ as a unitary phenomenon associated with the resolution of conflict.

Low-Frequency Oscillations (LFO) in the range of 7-9 Hz, or theta rhythm, has been recorded in rodents ambulating in the real world. However, intra-hippocampus EEG recordings during virtual navigation in humans have consistently reported LFO that appear to predominate around 3-4 Hz. Here we report clear evidence of 7-9 Hz rhythmicity in raw intra-hippocampus EEG traces during real as well as virtual movement. Oscillations typically occur at a lower frequency in virtual than real world navigation. This study highlights the possibility that human and rodent hippocampal EEG activity are not as different as previously reported and this difference may arise, in part, due to the lack of actual movement in previous human navigation studies, which were virtual.

Language is classically thought to be supported by perisylvian cortical regions. Here we provide intracranial evidence linking the hippocampal complex to linguistic processing. We used direct recordings from the hippocampal structures to investigate whether theta oscillations, pivotal in memory function, track the amount of contextual linguistic information provided in sentences. Twelve participants heard sentences that were either constrained ("She locked the door with the") or unconstrained ("She walked in here with the") before presentation of the final word ("key"), shown as a picture that participants had to name. Hippocampal theta power increased for constrained relative to unconstrained contexts during sentence processing, preceding picture presentation. Our study implicates hippocampal theta oscillations in a language task using natural language associations that do not require memorization. These findings reveal that the hippocampal complex contributes to language in an active fashion, relating incoming words to stored semantic knowledge, a necessary process in the generation of sentence meaning.

ObjectiveElectrocorticography (ECoG) has become an important tool in human neuroscience and has tremendous potential for emerging applications in neural interface technology. Electrode array design parameters are outstanding issues for both research and clinical applications, and these parameters depend critically on the nature of the neural signals to be recorded. Here, we investigate the functional spatial resolution of neural signals recorded at the human cortical surface. We empirically derive spatial spread functions to quantify the shared neural activity for each frequency band of the electrocorticogram.ApproachFive subjects with high-density (4 mm center-to-center spacing) ECoG grid implants participated in speech perception and production tasks while neural activity was recorded from the speech cortex, including superior temporal gyrus, precentral gyrus, and postcentral gyrus. The cortical surface field potential was decomposed into traditional EEG frequency bands. Signal similarity between electrode pairs for each frequency band was quantified using a Pearson correlation coefficient.Main resultsThe correlation of neural activity between electrode pairs was inversely related to the distance between the electrodes; this relationship was used to quantify spatial falloff functions for cortical subdomains. As expected, lower frequencies remained correlated over larger distances than higher frequencies. However, both the envelope and phase of gamma and high gamma frequencies (30-150 Hz) are largely uncorrelated (

Modulations in alpha oscillations (∼10 Hz) are typically studied in the context of anticipating upcoming stimuli. Alpha power decreases in sensory regions processing upcoming targets compared to regions processing distracting input, thereby likely facilitating processing of relevant information while suppressing irrelevant. In this electroencephalography study using healthy human volunteers, we examined whether modulations in alpha power also occur after the onset of a bilaterally presented target and distractor. Spatial attention was manipulated through spatial cues and feature-based attention through adjusting the color-similarity of distractors to the target. Consistent with previous studies, we found that informative spatial cues induced a relative decrease of pretarget alpha power at occipital electrodes contralateral to the expected target location. Interestingly, this pattern reemerged relatively late (300-750 ms) after stimulus onset, suggesting that lateralized alpha reflects not only preparatory attention, but also ongoing attentive stimulus processing. Uninformative cues (i.e., conveying no information about the spatial location of the target) resulted in an interaction between spatial attention and feature-based attention in post-target alpha lateralization. When the target was paired with a low-similarity distractor, post-target alpha was lateralized (500-900 ms). Crucially, the lateralization was absent when target selection was ambiguous because the distractor was highly similar to the target. Instead, during this condition, midfrontal theta was increased, indicative of reactive conflict resolution. Behaviorally, the degree of alpha lateralization was negatively correlated with the reaction time distraction cost induced by target-distractor similarity. These results suggest a pivotal role for poststimulus alpha lateralization in protecting sensory processing of target information.

When we respond to a stimulus, our decisions are based not only on external stimuli but also on our ongoing performance. If the response deviates from our goals, monitoring and decision-making brain areas interact so that future behavior may change. By taking advantage of natural variation in error salience, as measured by the RT taken to correct an error (RTEC), here we argue that an evidence accumulation framework provides a potential underlying mechanism for this variable process of error identification and correction, as evidenced by covariation of frontal monitoring and parietal decision-making processes. We study two early EEG signals linked to monitoring within medial PFC-the error-related negativity (ERN) and frontocentral theta activity-and a third EEG signal, the error positivity (Pe), that is thought to share the same parietal substrates as a signal (the P3b) proposed to reflect evidence accumulation. As predicted, our data show that on slow RTEC trials, frontal monitoring resources are less strongly employed, and the latency of the Pe is longer. Critically, the speed of the RTEC also covaries with the magnitude of subsequent neural (intertrial alpha power) and behavioral (post-error slowing) adjustments following the correction. These results are synthesized to describe a timing diagram for adaptive decision-making after errors and support a potential evidence accumulation mechanism in which error signaling is followed by rapid behavioral adjustments.

The switch between automatic action selection and more controlled forms of decision-making is a dynamic process thought to involve both cortical and subcortical structures. During sensory conflict, medial pFC oscillations in the theta band (

Long-term potentiation (LTP) shows memory-like consolidation and thus becomes increasingly resistant to disruption by low-frequency stimulation (LFS). However, it is known that nicotine application during LFS uniquely depotentiates consolidated LTP. Here, we investigated how nicotine contributes to the disruption of stabilized LTP in the hippocampal CA1 region. We found that nicotine-induced depotentiation is not due to masking LTP by inducing long-term depression and requires the activation of GluN2A-containing NMDARs. We further examined whether nicotine-induced depotentiation involves the reversal of LTP mechanisms. LTP causes phosphorylation of Ser-831 on GluA1 subunits of AMPARs that increases the single-channel conductance of AMPARs. This phosphorylation remained unchanged after depotentiation. LTP involves the insertion of new AMPARs into the synapse and the internalization of AMPARs is associated with dephosphorylation of Ser-845 on GluA1 and caspase-3 activity. Nicotine-induced depotentiation occurred without dephosphorylation of the Ser-845 and in the presence of a caspase-3 inhibitor. LTP is also accompanied by increased filamentous actin (F-actin), which controls spine size. Nicotine-induced depotentiation was prevented by jasplakinolide, which stabilizes F-actin, suggesting that nicotine depotentiates consolidated LTP by destabilizing F-actin. α7 nicotinic acetylcholine receptor (nAChR) antagonists mimicked the effect of nicotine and selective removal of hippocampal cholinergic input caused depotentiation in the absence of nicotine, suggesting that nicotine depotentiates consolidated LTP by inducing α7 nAChR desensitization. Our results demonstrate a new role for nicotinic cholinergic systems in protecting potentiated synapses from depotentiation by preventing GluN2A-NMDAR-mediated signaling for actin destabilization.

Study objectivesTo examine nonrapid eye movement (NREM) sleep in insomnia using high-density electroencephalography (EEG).MethodsAll-night sleep recordings with 256 channel high-density EEG were analyzed for 8 insomnia subjects (5 females) and 8 sex and age-matched controls without sleep complaints. Spectral analyses were conducted using unpaired t-tests and topographical differences between groups were assessed using statistical non-parametric mapping. Five minute segments of deep NREM sleep were further analyzed using sLORETA cortical source imaging.ResultsThe initial topographic analysis of all-night NREM sleep EEG revealed that insomnia subjects had more high-frequency EEG activity (> 16 Hz) compared to good sleeping controls and that the difference between groups was widespread across the scalp. In addition, the analysis also showed that there was a more circumscribed difference in theta (4-8 Hz) and alpha (8-12 Hz) power bands between groups. When deep NREM sleep (N3) was examined separately, the high-frequency difference between groups diminished, whereas the higher regional alpha activity in insomnia subjects persisted. Source imaging analysis demonstrated that sensory and sensorimotor cortical areas consistently exhibited elevated levels of alpha activity during deep NREM sleep in insomnia subjects relative to good sleeping controls.ConclusionsThese results suggest that even during the deepest stage of sleep, sensory and sensorimotor areas in insomnia subjects may still be relatively active compared to control subjects and to the rest of the sleeping brain.

The establishment of reference is essential to language comprehension. The goal of this study was to examine listeners' sensitivity to referential ambiguity as a function of individual variation in attention, working memory capacity, and verbal ability. Participants listened to stories in which two entities were introduced that were either very similar (e.g., two oaks) or less similar (e.g., one oak and one elm). The manipulation rendered an anaphor in a subsequent sentence (e.g., oak) ambiguous or unambiguous. EEG was recorded as listeners comprehended the story, after which participants completed tasks to assess working memory, verbal ability, and the ability to use context in task performance. Power in the alpha and theta frequency bands when listeners received critical information about the discourse entities (e.g., oaks) was used to index attention and the involvement of the working memory system in processing the entities. These measures were then used to predict an ERP component that is sensitive to referential ambiguity, the Nref, which was recorded when listeners received the anaphor. Nref amplitude at the anaphor was predicted by alpha power during the earlier critical sentence: Individuals with increased alpha power in ambiguous compared with unambiguous stories were less sensitive to the anaphor's ambiguity. Verbal ability was also predictive of greater sensitivity to referential ambiguity. Finally, increased theta power in the ambiguous compared with unambiguous condition was associated with higher working-memory span. These results highlight the role of attention and working memory in referential processing during listening comprehension.

Traumatic brain injury (TBI) often results in persistent attention and memory deficits that are associated with hippocampal dysfunction. Although deep brain stimulation (DBS) is used to treat neurological disorders related to motor dysfunction, the effectiveness of stimulation to treat cognition remains largely unknown. In this study, adult male Harlan Sprague-Dawley rats underwent a lateral fluid percussion or sham injury followed by implantation of bipolar electrodes in the medial septal nucleus (MSN) and ipsilateral hippocampus. In the first week after injury, there was a significant decrease in hippocampal theta oscillations that correlated with decreased object exploration and impaired performance in the Barnes maze spatial learning task. Continuous 7.7 Hz theta stimulation of the medial septum significantly increased hippocampal theta oscillations, restored normal object exploration, and improved spatial learning in injured animals. There were no benefits with 100 Hz gamma stimulation, and stimulation of sham animals at either frequency did not enhance performance. We conclude, therefore, that there was a theta frequency-specific benefit of DBS that restored cognitive function in brain-injured rats. These data suggest that septal theta stimulation may be an effective and novel neuromodulatory therapy for treatment of persistent cognitive deficits following TBI.

Theta may play a central role during language understanding and other extended cognitive processing, providing an envelope for widespread integration of participating cortical areas. We used linear microelectrode arrays in epileptics to define the circuits generating theta in inferotemporal, perirhinal, entorhinal, prefrontal and anterior cingulate cortices. In all locations, theta was generated by excitatory current sinks in middle layers which receive predominantly feedforward inputs, alternating with sinks in superficial layers which receive mainly feedback/associative inputs. Baseline and event-related theta were generated by indistinguishable laminar profiles of transmembrane currents and unit-firing. Word presentation could reset theta phase, permitting theta to contribute to late event-related potentials, even when theta power decreases relative to baseline. Limited recordings during sentence reading are consistent with rhythmic theta activity entrained by a given word modulating the neural background for the following word. These findings show that theta occurs spontaneously, and can be momentarily suppressed, reset and synchronized by words. Theta represents an alternation between feedforward/divergent and associative/convergent processing modes that may temporally organize sustained processing and optimize the timing of memory formation. We suggest that words are initially encoded via a ventral feedforward stream which is lexicosemantic in the anteroventral temporal lobe; its arrival may trigger a widespread theta rhythm which integrates the word within a larger context.

The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC.

Key pointsExtended trains of theta rhythm afferent activity lead to a biphasic response facilitation in field CA1 but not in the lateral perforant path input to the dentate gyrus. Processes that reverse long-term potentiation in field CA1 are not operative in the lateral perforant path: multiple lines of evidence indicate that this reflects differences in adenosine signalling. Adenosine A1 receptors modulate baseline synaptic transmission in the lateral olfactory tract but not the associational afferents of the piriform cortex. Levels of ecto-5'-nucleotidase (CD73), an enzyme that converts extracellular ATP into adenosine, are markedly different between regions and correlate with adenosine signalling and the efficacy of theta pulse stimulation in reversing long-term potentiation. Variations in transmitter mobilization, CD73 levels, and afferent divergence result in multivariate differences in signal processing through nodes in the cortico-hippocampal network.AbstractThe present study evaluated learning-related synaptic operations across the serial stages of the olfactory cortex-hippocampus network. Theta frequency stimulation produced very different time-varying responses in the Schaffer-commissural projections than in the lateral perforant path (LPP), an effect associated with distinctions in transmitter mobilization. Long-term potentiation (LTP) had a higher threshold in LPP field potential studies but not in voltage clamped neurons; coupled with input/output relationships, these results suggest that LTP threshold differences reflect the degree of input divergence. Theta pulse stimulation erased LTP in CA1 but not in the dentate gyrus (DG), although adenosine eliminated potentiation in both areas, suggesting that theta increases extracellular adenosine to a greater degree in CA1. Moreover, adenosine A1 receptor antagonism had larger effects on theta responses in CA1 than in the DG, and concentrations of ecto-5'-nucleotidase (CD73) were much higher in CA1. Input/output curves for two connections in the piriform cortex were similar to those for the LPP, whereas adenosine modulation again correlated with levels of CD73. In sum, multiple relays in a network extending from the piriform cortex through the hippocampus can be differentiated along three dimensions (input divergence, transmitter mobilization, adenosine modulation) that potently influence throughput and plasticity. A model that incorporates the regional differences, supplemented with data for three additional links, suggests that network output goes through three transitions during the processing of theta input. It is proposed that individuated relays allow the circuit to deal with different types of behavioural problems.

BackgroundIndividuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism.MethodsEROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups.ResultsHR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects.ConclusionsAs theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders.

Previous studies have rarely examined how temporal dynamic patterns, event-related coherence, and phase-locking are related to each other. This study assessed reaction-time-sorted spectral perturbation and event-related spectral perturbation in order to examine the temporal dynamic patterns in the frontal midline (F), central parietal (CP), and occipital (O) regions during a chemistry working memory task at theta, alpha, and beta frequencies. Furthermore, the functional connectivity between F-CP, CP-O, and F-O were assessed by component event-related coherence (ERCoh) and component phase-locking (PL) at different frequency bands. In addition, this study examined whether the temporal dynamic patterns are consistent with the functional connectivity patterns across different frequencies and time courses. Component ERCoh/PL measured the interactions between different independent components decomposed from the scalp EEG, mixtures of time courses of activities arising from different brain, and artifactual sources. The results indicate that the O and CP regions' temporal dynamic patterns are similar to each other. Furthermore, pronounced component ERCoh/PL patterns were found to exist between the O and CP regions across each stimulus and probe presentation, in both theta and alpha frequencies. The consistent theta component ERCoh/PL between the F and O regions was found at the first stimulus and after probe presentation. These findings demonstrate that temporal dynamic patterns at different regions are in accordance with the functional connectivity patterns. Such coordinated and robust EEG temporal dynamics and component ERCoh/PL patterns suggest that these brain regions' neurons work together both to induce similar event-related spectral perturbation and to synchronize or desynchronize simultaneously in order to swiftly accomplish a particular goal. The possible mechanisms for such distinct component phase-locking and coherence patterns were also further discussed.

Fast spiking, parvalbumin (PV) expressing hippocampal interneurons are classified into basket, axo-axonic (chandelier), and bistratified cells. These cell classes play key roles in regulating local circuit operations and rhythmogenesis by releasing GABA in precise temporal patterns onto distinct domains of principal cells. In this study, we show that each of the three major PV cell classes further splits into functionally distinct sub-classes during fast network events in vivo. During the slower (90 Hz) oscillations, within-class differences in PV interneuron discharges emerged, which segregated along specific features of dendritic structure or somatic location. Functional divergence of PV sub-classes during fast but not slow network oscillations effectively doubles the repertoire of spatio-temporal patterns of GABA release available for rapid circuit operations.