Spatiotemporal coupling between hippocampal acetylcholine release and theta oscillations in vivo.

Both acetylcholine (ACh) and theta oscillations are important for learning and memory, but the dynamic interaction between these two processes remains unclear. Recent advances in amperometry techniques have revealed phasic ACh releases in vivo. However, it is unknown whether phasic ACh release co-occurs with theta oscillations. We investigated this issue in the CA1 region of urethane-anesthetized male rats using amperometric and electrophysiological recordings. We found that ACh release was highly correlated with the appearance of both spontaneous and induced theta oscillations. Moreover, the maximal ACh release was observed around or slightly above the pyramidal layer. Interestingly, such release lagged behind theta initiation by 25-60 s. The slow ACh release profile was matched by the slow firing rate increase of a subset of medial-septal low-firing-rate neurons. Together, these results establish, for the first time, the in vivo coupling between phasic ACh release and theta oscillations on spatiotemporal scales much finer than previously known. These findings also suggest that phasic ACh is not required for theta initiation and may instead operate synergistically with theta oscillations to promote neural plasticity in the service of learning and memory.

Theta oscillations reflect the dynamics of interference in episodic memory retrieval.

Selectively retrieving episodic information from a cue often induces interference from related episodes. To promote successful retrieval of the target episode, such interference is resolved by inhibition, causing retrieval-induced forgetting of the related but irrelevant information. Passively studying the episodic information again (reexposure) does not show this effect. This study examined the hypothesis that brain oscillations in the theta band (5-9 Hz) reflect the dynamics of interference in selective memory retrieval, analyzing EEG data from 24 healthy human subjects (21 women, 3 men). High versus low levels of interference were investigated by comparing the effects of selective retrieval with the effects of reexposure of material, with the former, but not the latter, inducing interference. Moreover, we analyzed repeated cycles of selective retrieval and reexposure, assuming that interference is reduced by inhibition across retrieval cycles, but not across reexposure cycles. We found greater theta band activity in selective retrieval than in reexposure, and a reduction in theta amplitude from the first to the second cycle of retrieval predicting the amount of retrieval-induced forgetting; the sources of theta amplitude reduction across retrieval cycles were located in the anterior cingulate cortex. No difference in theta activity was found across repeated cycles of reexposure. The results suggest that higher levels of interference in episodic memory are indexed by more theta band activity, and that successful interference resolution via inhibition causes a reduction in theta amplitude. Thus, theta band activity can serve as a neural marker of the dynamics of interference in selective episodic retrieval.

Combining theta burst stimulation with training after subcortical stroke.

BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation of the primary motor cortex (M1) may improve outcomes after stroke. The aim of this study was to determine the effects of M1 theta burst stimulation (TBS) and standardized motor training on upper-limb function of patients with chronic stroke. METHODS: Ten patients with chronic subcortical stroke and upper-limb impairment were recruited to this double-blind, crossover, sham-controlled study. Intermittent TBS of the ipsilesional M1, continuous TBS of the contralesional M1, and sham TBS were delivered in separate sessions in conjunction with standardized training of a precision grip task using the paretic upper limb. RESULTS: Training after real TBS improved paretic-hand grip-lift kinetics, whereas training after sham TBS resulted in deterioration of grip-lift. Ipsilesional M1 excitability increased after intermittent TBS of the ipsilesional M1 but decreased after continuous TBS of the contralesional M1. Action Research Arm Test scores deteriorated when training followed continuous TBS of the contralesional M1, and this was correlated with reduced ipsilesional corticomotor excitability. CONCLUSIONS: Generally, TBS and training led to task-specific improvements in grip-lift. Specifically, continuous TBS of the contralesional M1 led to an overall decrement in upper-limb function, indicating that the contralesional hemisphere may play a pivotal role in recovery after stroke.

The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments.

UNLABELLED: The aim of the study was to examine whether the reduction of theta prefrontal quantitative EEG (QEEG) cordance after one week of bupropion administration is a predictor of response to a 4-week treatment in patients that had failed to respond to previous antidepressant treatments. METHOD: EEG data of 18 inpatients were monitored at baseline and after one week. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz). Response to treatment was defined as a >/=50% reduction of MADRS score. RESULTS: Nine of the eleven responders and one of the seven non-responders showed decreased prefrontal cordance value after the first week of treatment (p=0.01). Positive and negative predictive values of cordance reduction for the prediction of response to the treatment were 0.9 and 0.75, respectively. CONCLUSION: Similar to other antidepressants, the reduction of prefrontal QEEG cordance might be helpful in the prediction of the acute outcome of bupropion treatment.

Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety.

The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.

Frontal theta links prediction errors to behavioral adaptation in reinforcement learning.

Investigations into action monitoring have consistently detailed a frontocentral voltage deflection in the event-related potential (ERP) following the presentation of negatively valenced feedback, sometimes termed the feedback-related negativity (FRN). The FRN has been proposed to reflect a neural response to prediction errors during reinforcement learning, yet the single-trial relationship between neural activity and the quanta of expectation violation remains untested. Although ERP methods are not well suited to single-trial analyses, the FRN has been associated with theta band oscillatory perturbations in the medial prefrontal cortex. Mediofrontal theta oscillations have been previously associated with expectation violation and behavioral adaptation and are well suited to single-trial analysis. Here, we recorded EEG activity during a probabilistic reinforcement learning task and fit the performance data to an abstract computational model (Q-learning) for calculation of single-trial reward prediction errors. Single-trial theta oscillatory activities following feedback were investigated within the context of expectation (prediction error) and adaptation (subsequent reaction time change). Results indicate that interactive medial and lateral frontal theta activities reflect the degree of negative and positive reward prediction error in the service of behavioral adaptation. These different brain areas use prediction error calculations for different behavioral adaptations, with medial frontal theta reflecting the utilization of prediction errors for reaction time slowing (specifically following errors), but lateral frontal theta reflecting prediction errors leading to working memory-related reaction time speeding for the correct choice.

Mechanisms and applications of theta-burst rTMS on the human motor cortex.

Theta-burst Stimulation (TBS) is a novel form of repetitive transcranial magnetic stimulation (rTMS). Applied over the primary motor cortex it has been successfully used to induce changes in cortical excitability. The advantage of this stimulation paradigm is that it is able to induce strong and long lasting effects using a lower stimulation intensity and a shorter time of stimulation compared to conventional rTMS protocols. Since its first description, TBS has been used in both basic and clinical research in the last years and more recently it has been expanded to other domains than the motor system. Its capacity to induce synaptic plasticity could lead to therapeutic implications for neuropsychiatric disorders. The neurobiological mechanisms of TBS are not fully understood at present; they may involve long-term potentiation (LTP)- and depression (LTD)-like processes, as well as inhibitory mechanisms modulated by GABAergic activity. This article highlights current hypotheses regarding the mechanisms of action of TBS and some central factors which may influence cortical responses to TBS. Furthermore, previous and ongoing research performed in the field of TBS on the motor cortex is summarized.

Complementary theta resonance filtering by two spatially segregated mechanisms in CA1 hippocampal pyramidal neurons.

Synaptic input to a neuron may undergo various filtering steps, both locally and during transmission to the soma. Using simultaneous whole-cell recordings from soma and apical dendrites from rat CA1 hippocampal pyramidal cells, and biophysically detailed modeling, we found two complementary resonance (bandpass) filters of subthreshold voltage signals. Both filters favor signals in the theta (3-12 Hz) frequency range, but have opposite location, direction, and voltage dependencies: (1) dendritic H-resonance, caused by h/HCN-channels, filters signals propagating from soma to dendrite when the membrane potential is close to rest; and (2) somatic M-resonance, caused by M/Kv7/KCNQ and persistent Na(+) (NaP) channels, filters signals propagating from dendrite to soma when the membrane potential approaches spike threshold. Hippocampal pyramidal cells participate in theta network oscillations during behavior, and we suggest that that these dual, polarized theta resonance mechanisms may convey voltage-dependent tuning of theta-mediated neural coding in the entorhinal/hippocampal system during locomotion, spatial navigation, memory, and sleep.

Differential effects of long and short train theta burst stimulation on LTP induction in rat anterior cingulate cortex slices: multi-electrode array recordings.

OBJECTIVE: There is substantial evidence supporting the notion that the anterior cingulate cortex (ACC) is an important limbic structure involved in multiple brain functions such as sensory perception, motor conflict monitoring, memory, emotion and cognition. It has been shown that long term potentiation (LTP) is an important synaptic model of neural plasticity in the ACC, however, little is known about the spatiotemporal properties of ACC at network level. The present study was designed to see the LTP induction effects across different layers of the ACC by using different conditioning stimuli (CS) protocols. METHODS: A unique multi-electrode array recording technique was used in the acutely-dissociated ACC slices of rats. Long and short train theta burst stimulation (TBS) paradigms were applied in layer V-VI as the CS and the LTP induction effects were compared across different layers of the ACC. Briefly, both long and short train TBS are composed of bursts (4 pulses at 100 Hz) with a 200 ms interval, however, the former (TBS1) was with 10 trains and the latter (TBS2) was with 5 trains. After test stimulation at layer V-VI in the ACC, network field potentials (FPs) could be simultaneously recorded across all layers of the ACC. RESULTS: The waveforms of FPs were different across different layers. Namely, positive-going waveforms were recorded in layer I and negative-going waveforms were recorded in layers V-VI, in contrast, complex waveforms were localized mainly in layers II-III. Following application of two CS protocols, the induction rate of LTP was significantly different between TBS1 and TBS2 regardless of the spatial properties. TBS1 had more than 60% success, while TBS2 was less than 25% in induction of LTP. Moreover, both the 2 CS protocols could induce LTP in layers II-III and layers V-VI without layer-related difference. However, no LTP was inducible in layer I. CONCLUSION: The present findings indicate that stimulation protocols may, at least in part, account for a large portion of variations among previous LTP studies, and hence highlight the importance of selecting the best LTP induction protocol when designing such experiments. Moreover, the present results demonstrate the prominent superiority of multi-electrode array recording in revealing the network properties of synaptic activities in the ACC, especially in comparing the spatiotemporal characteristics between different layers of this structure.

One session of repeated parietal theta burst stimulation trains induces long-lasting improvement of visual neglect.

BACKGROUND AND PURPOSE: Visual neglect is a frequent disability in stroke and adversely affects mobility, discharge destination, and length of hospital stay. It is assumed that its severity is enhanced by a released interhemispheric inhibition from the unaffected toward the affected hemisphere. Continuous theta burst transcranial magnetic stimulation (TBS) is a new inhibitory brain stimulation protocol which has the potential to induce behavioral effects outlasting stimulation. We aimed to test whether parietal TBS over the unaffected hemisphere can induce a long-lasting improvement of visual neglect by reducing the interhemispheric inhibition. METHODS: Eleven patients with left-sided visual neglect attributable to right hemispheric stroke were tested in a visual perception task. To evaluate the specificity of the TBS effect, 3 conditions were tested: 2 TBS trains over the left contralesional posterior parietal cortex, 2 trains of sham stimulation over the contralesional posterior parietal cortex, and a control condition without any intervention. To evaluate the lifetime of repeated trains of TBS in 1 session, 4 trains were applied over the contralesional posterior parietal cortex. RESULTS: Two TBS trains significantly increased the number of perceived left visual targets for up to 8 hours as compared to baseline. No significant improvement was found with sham stimulation or in the control condition without any intervention. The application of 4 TBS trains significantly increased the number of perceived left targets up to 32 hours. CONCLUSIONS: The new approach of repeating TBS at the same day may be promising for therapy of neglect.

Comparison of mapping quantitative theta encephalograms during directed and required visual-verbal activity and passive period in children with different disorders of speech-language functioning.

Aim of the research was to examine similarities and differences between the periods of experiencing visually stimulated directed speech-language information and periods of undirected attention. The examined group comprised N = 64 children, aged 4-5, with different speech-language disorders (developmental dysphasia, hyperactive syndrome with attention disorder, children with borderline intellectual abilities, autistic complex). Theta EEG was registered in children in the period of watching and describing the picture ("task"), and in the period of undirected attention ("passive period"). The children were recorded in standard EEG conditions, at 19 points of EEG registration and in longitudinal bipolar montage. Results in the observed age-operative theta rhythm indicated significant similarities and differences in the prevalence of spatial engagement of certain regions between the two hemispheres at the input and output of processing, which opens the possibility for more detailed analysis of conscious control of speech-language processing and its disorders.

Behavior-dependent coordination of multiple theta dipoles in the hippocampus.

Theta (4-10 Hz) oscillations in the hippocampus are thought to be important for plasticity, temporal coding, learning, and memory. The hippocampal system has been postulated to have two (or more) rhythmic sources of theta oscillations, but little is known about the behavior-dependent interplay of theta oscillations in different subregions and layers of the hippocampus. We tested rats in a hippocampus-dependent delayed spatial alternation task on a modified T-maze while simultaneously recording local field potentials from dendritic and somatic layers of the dentate gyrus, CA3, and CA1 regions using high-density, 96-site silicon probes. We found that while theta oscillations were generally coherent throughout the hippocampus, the power, coherence, and phase of theta oscillations fluctuated in a layer-specific manner, confirming the presence of multiple interdependent dipoles. Layer-dependent changes in the power and coherence of theta oscillations varied with aspects of both the memory and control (non-mnemonic) tasks, but only a small fraction of the variance could be explained by running speed or acceleration. Furthermore, the phase lag between theta oscillations in the CA3 and CA1 pyramidal layers was significantly smaller on the maze arm approaching the T-junction than on other arms of the alternation task or on comparable segments of control tasks. Overall, our findings reveal a consortium of layer-specific theta dipoles (current sinks and sources) generated by the rhythmic flow of ions into and out of hippocampal cells. Moreover, our data suggest that these different theta generators flexibly coordinate hippocampal regions and layers to support behavioral task performance.

Coupling of theta oscillations between anterior and posterior midline cortex and with the hippocampus in freely behaving rats.

Theta oscillations in the hippocampus support cognitive processing. Theta-range rhythmicity has also been reported in frontal and posterior cortical areas--where it tends to show consistent phase-relations with hippocampal rhythmicity. Theta-range rhythmicity may, then, be important for cortico-cortical and/or cortico-hippocampal interactions. Here, we surveyed the rat frontal and posterior midline cortices for theta-related oscillations and examined their relationships with hippocampal activity in freely moving rats. Variation in electroencephalography across 4 general classes of spontaneous behavior demonstrated different profiles of theta-like activities through the rat midline cortices. Analysis of cortico-cortical and cortico-hippocampal coherences showed distinct, behavior-dependent, couplings of theta and delta oscillations. Increased theta coherence between structures was most obvious during nonautomatic behaviors and least during immobility or grooming. Extensive coupling of theta oscillations throughout the rat midline cortices and hippocampus occurred during rearing, and exploratory behavior. Such increases in coherence could reflect binding of cortico-hippocampal pathways into temporary functional units by behavioral demands. Extensive coupling of frontal delta, which lacked coherence with posterior areas (including the hippocampus), suggests that different frequencies of rhythmicity may act to bind groups of structures into different functional circuits on different occasions.

Training effects outweigh effects of single-session conventional rTMS and theta burst stimulation in PD patients.

BACKGROUND: Focal single-session repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been claimed to be capable of improving motor function in Parkinson's disease. OBJECTIVE: The authors sought to determine which type of rTMS protocol holds the highest potential for future therapeutic application. METHODS: Twenty-two patients with Parkinson's disease received 5 different rTMS protocols on 5 consecutive days in a pseudorandomized and counterbalanced order either in the defined OFF condition or with their usual medication. The protocols tested in the present study included 2 conventional rTMS protocols (0.5 and 10 Hz) as well as the recently introduced theta burst stimulation (cTBS, iTBS) and a sham condition. Cortical excitability, motor performance (pointing movement, pronation-supination, Purdue Pegboard Test, walking), and mood were assessed before and after each session. RESULTS: The authors observed motor training from days 1 to 4, particularly in the group on dopaminergic medication. None of the rTMS paradigms excelled placebo stimulation. The only exception was the Purdue Pegboard Test, in which all active stimulation paradigms yielded slightly stronger effects than sham stimulation. CONCLUSIONS: Within a single session, no clinically relevant difference in the rTMS protocols could be detected. Training effects outweigh and may have masked rTMS effects, particularly in the group on dopaminergic mediation.

Synchronous bursts of neuronal activity in the developing hippocampus: modulation by active sleep and association with emerging gamma and theta rhythms.

The neonatal hippocampus exhibits regularly recurring waves of synchronized neuronal activity in vitro. Because active sleep (AS), characterized by bursts of phasic motor activity in the form of myoclonic twitching, may provide conditions that are conducive to activity-dependent development of hippocampal circuits, we hypothesized that the waves of synchronous neuronal activity that have been observed in vitro would be associated with AS-related twitching. Using unanesthetized 1- to 12-d-old rats, we report here that the majority of neurons in CA1 and the dentate gyrus (DG) are significantly more active during AS than during either quiet sleep or wakefulness. Neuronal activity typically occurs in phasic bursts, during which most neurons are significantly cross-correlated both within and across the CA1 and DG fields. All AS-active neurons increase their firing rates during periods of myoclonic twitching of the limbs, and a subset of these neurons exhibit a burst of activity immediately after limb twitches, suggesting that the twitches themselves provide sensory feedback to the infant hippocampus, as occurs in the infant spinal cord and neocortex. Finally, the synchronous bursts of neuronal activity are coupled to the emergence of the AS-related hippocampal gamma rhythm during the first postnatal week, as well as the emergence of the AS-related theta rhythm during the second postnatal week. We hypothesize that the phasic motor events of active sleep provide the developing hippocampus with discrete sensory stimulation that contributes to the development and refinement of hippocampal circuits as well as the development of synchronized interactions between hippocampus and neocortex.

Lesions of the mammillary body region alter hippocampal movement signals and theta frequency: implications for path integration models.

Cells throughout the hippocampal formation are involved in processing spatial information. These same cells also show an influence of locomotor activity, and these movement signals are thought to be critical for the path integration abilities of these cells. Nuclei in the mammillary region provide ascending influences to the hippocampal formation and have been implicated in influencing both hippocampal spatial and theta signals. Here, we report the effects of mammillary lesions on movement-related signals in several hippocampal subregions. We find first, as predicted by earlier work, these lesions cause an approximately 1 Hz reduction in the frequency of theta modulation of cell firing. According to recent theoretical work, this might, in turn, be expected to influence the size of hippocampal place fields. Our data do not confirm this prediction for any of the hippocampal regions examined. Second, we report lesion effects on the relationship between firing rate and running speed for the hippocampal cells. These lesions caused a reduction in both the slope and intercept of rate-by-speed functions for cells in the hippocampus and postsubiculum. Surprisingly, cells in subiculum showed an opposite effect, so that the excitatory influence of locomotion was enhanced. Path integration theories predict that the speed at which path integration occurs is related to the strength of this movement signal. In remarkable accordance with this prediction, we report that the timing of the place cell signals is slowed following mammillary lesions for hippocampal and postsubicular cells, but, in contrast, is speeded up for subicular cells. In fact, the timing for place signals across lesion condition and brain region is predicted by a single linear function which relates timing to the strength of the running speed signal. Thus, these data provide remarkable support for some aspects of current path integration theory, while posing a challenge for other aspects of these same theories.

Entorhinal theta phase precession sculpts dentate gyrus place fields.

It is known that the hippocampus facilitates memory formation and spatial representation and that hippocampal place cells establish spatial representations with firing activity modulated in terms of 'theta phase precession'. Clarifying how these spatial and temporal activities interact to process information is essential for a more coherent understanding of the way the hippocampus works. Recently, it has been reported that layer II entorhinal cortical cells, which mediate the majority of the cortical inputs to the dentate gyrus (DG), located at the gate of the hippocampus, fire with theta phase precession according to a grid-like pattern. Here we hypothesize that the temporal code of entorhinal grid neurons firing with theta phase precession provides selectivity in input integration of dentate neurons to support the emergence of place fields. Our large-scale network model analyses demonstrated that, by assuming coincidence detection properties of dentate neurons, grid fields are reliably transformed to place fields in a novel environment. Furthermore, global remapping of place fields in sequential experiences of environments can be obtained in agreement with known experimental observation. These findings indicate a critical role of temporal coding for space computation in the entorhinal-hippocampal system.

Theta-mediated dynamics of spatial information in hippocampus.

In rodent hippocampus, neuronal activity is organized by a 6-10 Hz theta oscillation. The spike timing of hippocampal pyramidal cells with respect to the theta rhythm correlates with an animal's position in space. This correlation has been suggested to indicate an explicit temporal code for position. Alternatively, it may be interpreted as a byproduct of theta-dependent dynamics of spatial information flow in hippocampus. Here we show that place cell activity on different phases of theta reflects positions shifted into the future or past along the animal's trajectory in a two-dimensional environment. The phases encoding future and past positions are consistent across recorded CA1 place cells, indicating a coherent representation at the network level. Consistent theta-dependent time offsets are not simply a consequence of phase-position correlation (phase precession), because they are no longer seen after data randomization that preserves the phase-position relationship. The scale of these time offsets, 100-300 ms, is similar to the latencies of hippocampal activity after sensory input and before motor output, suggesting that offset activity may maintain coherent brain activity in the face of information processing delays.

Human hippocampal and parahippocampal theta during goal-directed spatial navigation predicts performance on a virtual Morris water maze.

The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4-8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation.

Neglect-like visual exploration behaviour after theta burst transcranial magnetic stimulation of the right posterior parietal cortex.

The right posterior parietal cortex (PPC) is critically involved in visual exploration behaviour, and damage to this area may lead to neglect of the left hemispace. We investigated whether neglect-like visual exploration behaviour could be induced in healthy subjects using theta burst repetitive transcranial magnetic stimulation (rTMS). To this end, one continuous train of theta burst rTMS was applied over the right PPC in 12 healthy subjects prior to a visual exploration task where colour photographs of real-life scenes were presented on a computer screen. In a control experiment, stimulation was also applied over the vertex. Eye movements were measured, and the distribution of visual fixations in the left and right halves of the screen was analysed. In comparison to the performance of 28 control subjects without stimulation, theta burst rTMS over the right PPC, but not the vertex, significantly decreased cumulative fixation duration in the left screen-half and significantly increased cumulative fixation duration in the right screen-half for a time period of 30 min. These results suggest that theta burst rTMS is a reliable method of inducing transient neglect-like visual exploration behaviour.