Human hippocampal theta activity during virtual navigation

This study examines whether 4-8-Hz theta oscillations can be seen in the human hippocampus, and whether these oscillations increase during virtual movement and searching, as they do in rodents. Recordings from both hippocampal and neocortical depth electrodes were analyzed while six epileptic patients played a virtual taxi-driver game. During the game, the patients alternated between searching for passengers, whose locations were random, and delivering them to stores, whose locations remained constant. In both hippocampus and neocortex, theta increased during virtual movement in all phases of the game. Hippocampal and neocortical theta activity were also significantly correlated with each other, but this correlation did not differ between neocortex and hippocampus and within disparate neocortical electrodes. Our findings demonstrate the existence of movement-related theta oscillations in human hippocampus, and suggest that both cortical and hippocampal oscillations play a role in attention and sensorimotor integration.     

Two generators of hippocampal theta activity in rabbits.

Spontaneous and hypothalamically induced theta activity was studied in rabbits lightly anaesthetized with urethane or urethane-chloralose. Well-developed theta activity was found over a large area of the dorsal part of the hippocampal formation, roughly corresponding to the CA1 field. Cross-correlation analysis between a stationary and a moving electrode showed that a large sheet of tissue oscillated in remarkable synchrony. This region was at least 8 mm along the longitudinal axis of the hippocampus and 6 mm in a plane transverse to this axis, thus comprising the whole of the rostro-caudal extension of the CA1 region. For technical reasons the temporal half was not explored. Depth recordings showed two foci of theta activity, one in the basal part of CA1 (stratum oriens) and a second, separate region with considerably larger amplitudes in the dentate region, having its maximum in the molecular layer. Due to the folded nature of the dentate fascia, an electrode often recorded two maxima corresponding to its upper and lower blades. Wave form analysis showed that the dentrate and CA1 rhythmic activity was roughly 180 degrees out of phase. The dentate theta activity remained in conditions where the CA1 theta activity was absent, either spontaneously or due to experimental interference. Systematic micro-electrode tracking showed absence of theta activity in the CA3 region. Nor was convincing theta activity found in the subiculum, parasubiculum, presubiculum or entohinal areas.     

Alpha 2-noradrenergic modulation of hippocampal theta activity.

The purpose of the present study was to determine the role of norepinephrine in the generation of hippocampal theta activity. Experiments were performed on urethane-anesthetized rats, implanted with recording electrodes in the dentate gyrus and stimulating electrodes in the dorso-medial posterior hypothalamus. The effects of norepinephrine on hippocampal theta activity was studied by directly infusing norepinephrine and other noradrenergic agents into the hippocampus. Norepinephrine microinfusion produced a decrease in the amplitude of theta activity as observed in the polygraph chart record. Subsequent spectral analyses demonstrated a decrease in power at peak theta frequencies, as well as a decrease in power at frequencies between 20-25 Hz (noise). The inhibitory effect of norepinephrine on hippocampal type 2 theta activity was found to be mediated by alpha 2-adrenergic receptors. Microinfusions of an alpha 2 agonist (detomidine) mimicked the effects produced by norepinephrine, whereas alpha 1 and beta agonists were ineffective. The inhibitory effect of detomidine was blocked by microinfusions of an alpha 2 antagonist (tolazoline), which indicates that the site of action was specific to the noradrenergic alpha 2 receptor.     

Role of hippocampal H1 receptors in radial maze performance and hippocampal theta activity in rats

Histamine H1 antagonists impaired the spatial memory performance. On the other hand, it is well recognized that the hippocampal theta rhythm plays a critical role in spatial memory. However, little work has been done the effect of H1 antagonists on the hippocampal theta rhythm which was associated with the memory performance. We investigated the effect of pyrilamine, a selective H1 receptor antagonist, on spatial memory performance as well as hippocampal theta rhythm during the memory task in rats. Effect of pyrilamine on spatial memory was measured using eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was recorded with a polygraph system with a telemetric technique. Intraperitoneal injection of pyrilamine resulted in impairments of both reference and working memory on the radial maze task. The working memory deficit induced by pyrilamine was antagonized by the intrahippocampal injection of histamine and 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT), a histamine H1 agonist. Intraperitoneal injection of pyrilamine decreased the hippocampal theta power at a dose that impaired reference and working memory. This effect was antagonized by the intrahippocampal injection of histamine and HTMT at a dose that ameliorated the working memory deficit. Intrahippocampal injection of pyrilamine impaired working memory and simultaneously decreased the hippocampal theta power. These results suggest that: (i) the hippocampal H1 receptors play an important role in the working memory processes on the radial maze performance and (ii) the decrease in the hippocampal theta power is associated with the working memory deficit induced by the blocking of H1 receptors.     

Task-dependent effects of intracranial hippocampal stimulation on human memory and hippocampal theta power

BackgroundDespite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance.ObjectiveWe hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity.MethodsTo investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks – a word pair associative memory task and a single item memory task.ResultsHippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance.ConclusionsWe show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.     

Timing and hippocampal theta in animals

All animals have at least two different internal clocks, one governing cognition of time of day, and the other concerning awareness of seconds and minutes. In the latter case, organisms show scalar properties. The timing mechanisms in the brain may function similarly throughout the animal kingdom, but this is not yet clear. Previous studies have shown that the hippocampus is intricately involved with the process of interval timing. Data concerning electrophysiological field potentials in the hippocampus show obviously rhythmic activity, known as hippocampal theta activity. An information-processing model of interval timing postulates three distinct stages: a clock, a memory, and a decision stage /11/. The timing process includes memory processing, which means that the hippocampus works together with working memory to estimate current time passing.     

Carbachol-induced rhythmic slow activity (theta) in cat hippocampal formation slices.

Application of the cholinergic agonist, carbachol, produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus in the cat hippocampal formation slices. This effect of carbachol was antagonized by atropine but not D-tubocurarine. These results provide first direct evidence that the hippocampal formation neuronal network in the cat is capable of producing synchronized slow wave activity when isolated from pulsed rhythmic inputs of the medial septum.     

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre‐clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety‐like responses in two models of anxiety, the elevated plus maze and novelty‐induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane‐anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study. © 2014 Wiley Periodicals, Inc.     

Distinct contributions of human hippocampal theta to spatial cognition and anxiety

Current views of the hippocampus assign this structure, and its prominent theta rhythms, a key role in both cognition and affect. We studied this duality of function in humans, where no direct evidence exists. Whole‐head magnetoencephalographic (MEG) data were recorded to measure theta activity while healthy participants (N = 25) navigated two virtual Morris water mazes, one in which they risked receiving aversive shocks without warning to induce anxiety and one in which they were safe from shocks. Results showed that threat of shock elevated anxiety level and enhanced navigation performance as compared to the safe condition. MEG source analyses revealed that improved navigation performance during threat was preferentially associated with increased left septal (posterior) hippocampal theta (specifically 4–8 Hz activity), replicating previous research that emphasizes a predominant role of the septal third of the hippocampus in spatial cognition. Moreover, increased self‐reported anxiety during threat was preferentially associated with increased left temporal (anterior) hippocampal theta (specifically 2–6 Hz activity), consistent with this region's involvement in mediating conditioned and innate fear. Supporting contemporary theory, these findings highlight simultaneous involvement of the human hippocampus in spatial cognition and anxiety, and clarify their distinct correlates. © 2012 Wiley Periodicals, Inc.     

Increase of the hippocampal theta activity in the Morris water maze reflects learning rather than motor activity

The change in the percentage of rat hippocampal high-frequency theta activity from being immobile and awake to swimming behaviour was calculated for three groups of rats, trained in either place learning, cue learning or egocentric learning in the Morris water maze. The place-learning-trained rats showed an increase in the percentage of theta activity, along with a significant reduction in escape latency over the last 3 days of training. No changes were observed in the other two groups. Because the motor activity displayed by the three groups of rats was similar, we suggest that the increase in the percentage of theta activity concomitant with place-learning training could be related to the processing of information by the hippocampus, rather than to the displayed motor activity.     

Comparison of spontaneous and septally driven hippocampal theta field and theta-related cellular activity

Experiments were carried out for the purpose of comparing the electrophysiological properties of spontaneously occurring hippocampal theta field activity with those of theta-like field activity elicited by 5-Hz and 7-Hz electrical stimulation of the medial septum in urethane-anesthetized rats. Experiment 1 compared the amplitude and phase depth profiles for the three conditions of spontaneously occurring theta, theta elicited by 5-Hz medial septal stimulation, and theta elicited by 7-Hz medial septal stimulation. The results supported the conclusion that septally elicited theta field activity exhibited characteristics similar to those of spontaneously occurring theta field activity. Experiment 2 compared the discharge properties of hippocampal theta-related cellular discharges during spontaneous and septally elicited theta field activity. In contrast to the results of Experiment 1, the findings of Experiment 2 supported the conclusion that electrical stimulation of medial septal nuclei did not produce typical responses of hippocampal theta-related cellular activity. During spontaneously occurring field conditions, HPC theta-ON cells increased their discharge rates during spontaneous theta field activity, relative to LIA, and theta-OFF cells decreased (often to zero) their discharge rates during theta field activity relative to LIA. During septally elicited theta-like activity, phasic and tonic theta-ON cells decreased their discharge rates (some were totally inhibited), and most tonic theta-OFF cells increased their discharge rates (although two were totally inhibited). In addition, the discharges (albeit reduced) of the majority of both phasic and tonic theta-ON cells during septal driving became entrained to the stimulation pulses and thus exhibited rhythmicity and strong phase relations with the field activity. Furthermore, both cell types discharged near the positive peak of the septally elicited theta field activity during 5-Hz stimulation and near the negative peak during 7-Hz stimulation. The discharges of most tonic theta-OFF cells also became entrained to the stimulation pulses and exhibited similar phase relations to theta-ON cells during the 5-Hz and 7-Hz driving frequencies. Thus, based on cellular evidence, electrical stimulation of the medial septum activates the hippocampal neural circuitry involved in the generation of theta field activity in a nonphysiological manner. The findings of the present paper provide an explanation for why electrical stimulation of the medial septum in freely moving rats elicits a theta-like field activity that is dissociated from the normal behavioral correlates, in contrast to those elicited by stimulation of the posterior nucleus of the hypothalamus (Bland and Oddie. 2001. Behav Brain Res 127:119-136).     

Phase precession of medial prefrontal cortical activity relative to the hippocampal theta rhythm

Theta phase-locking and phase precession are two related phenomena reflecting coordination of hippocampal place cell firing with the local, ongoing theta rhythm. The mechanisms and functions of both the phenomena remain unclear, though the robust correlation between firing phase and location of the animal has lead to the suggestion that this phase relationship constitutes a temporal code for spatial information. Recent work has described theta phase-locking in the rat medial prefrontal cortex (mPFC), a structure with direct anatomical and functional links to the hippocampus. Here, we describe an initial characterization of phase precession in the mPFC relative to the CA1 theta rhythm. mPFC phase precession was most robust during behavioral epochs known to be associated with enhanced theta-frequency coordination of CA1 and mPFC activities. Precession was coherent across the mPFC population, with multiple neurons precessing in parallel as a function of location of the animal. The existence of phase precession beyond the hippocampus implies a more global role for this phenomenon during theta rhythm-mediated coordination of neural activity.     

Dehydroepiandrosterone sulfate suppresses hippocampal recurrent inhibition and synchronizes neuronal activity to theta rhythm

Several neurosteroids have proconvulsant and memory-en-hancing properties and are potent modulators of the γ-amino butyric acid (GABA) receptor/chloride-ionophore complex. The effects of in situ microelectrophoretic application of the natural sulfate ester of the neurosteroid dehydroepiandrosterone (DHEAS) on evoked field responses and single-unit activity were evaluated in the dentate gyrus and CA1 hippocampal subfield of halothane-anesthetized rats. The effects of endogenous stimulation of DHEAS by in situ micropressure application of Trilostane ((4α, 5α, 17β)-4, 5-epoxy-3, 17-dihydroxyandrost-2-ene-2-carbonitrile (WIN24540)), an inhibitor of 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD), the enzyme that metabolizes DHEAS, on evoked responses and cellular activity in the hippocampus were also investigated. In situ microelectrophoretic application of DHEAS or micropressure application of Trilostane into CA1 markedly increased population excitatory postsynaptic potential (pEPSP) slopes and population spike (PS) amplitudes. Neither DHEAS nor Trilostane altered dentate pEPSP slopes or PS amplitudes, but both increased the amplitude of a late component of the pEPSP. Both DHEAS and Trilostane abolished GABA-mediated pairedpulse inhibition in both the dentate and CA1. In addition, both DHEAS and Trilostane markedly increased the spontaneous firing rate of dentate hilar interneurons (INTs: 256% and 185%), CA1 pyramidal cells (PCs: 95% and 105%), and CA1 oriens/alveus (O/A) interneurons (179% and 85%) and synchronized their firing to hippocampal theta rhythm induced by tail-pinch. These findings indicate that exogenous application and endogenous stimulation of DHEAS modulates hippocampal GABA inhibition in a physiologically relevant manner possibly by entraining hippocampal neurons to theta rhythm. © 1995 Wiley-Liss, Inc.     

Frontal midline theta activity and platelet MAO in human subjects

The distinctive theta rhythm that appears at the frontal midline during the performance of mental tasks has been designated as frontal midline theta (Fm theta). Fm theta shows individual differences and seems to be related to certain personality traits. In several studies, it has been indicated that low platelet monoamine oxidase (MAO) activity is also associated with certain personality traits. In the present study, we found a negative correlation between the appearance of Fm theta and platelet MAO activity. Subjects with marked extroversion show a high amount of Fm theta and low MAO activity. It is therefore suggested that Fm theta, an electrophysiological marker, may be useful in the investigation of monoamine functions in the central nervous system (CNS) by way of platelet MAO activity, a biochemical marker.     

Phase relations of hippocampal projection cells and interneurons to theta activity in the anesthetized rat

The correlation between cell firing and hippocampal theta activity was studied with the spike-triggered averaging method in rats anesthetized with urethane. Projection cells in the CA1 region and the dentate gyrus fired with highest probability on the negative phase of the theta waves recorded from the corresponding regions. CA1 interneurons discharged mainly on the positive phase. In the dentate gyrus about half of the interneurons fired on the negative phase, while the remaining half discharged preferentially on the positive phase of the locally derived theta waves. It was suggested that septal theta ‘pacemaker’ cells directly excite hippocampal interneurons which in turn rhythmically inhibit a large number of projection cells.     

Rat hippocampal theta rhythm during sensory mismatch

It has been suggested that sensory mismatch induces motion sickness, but its neural mechanisms remain unclear. To investigate this issue, theta waves in the hippocampal formation (HF) were studied during sensory mismatch by backward translocation in awake rats. A monopolar electrode was implanted into the dentate gyrus in the HF, from which local field potentials were recorded. The rats were placed on a treadmill affixed to a motion stage translocated along a figure 8-shaped track. The rats were trained to run forward on the treadmill at the same speed as that of forward translocation of the motion stage (a forward condition) before the experimental (recording) sessions. In the experimental sessions, the rats were initially tested in the forward condition, and then tested in a backward (mismatch) condition, in which the motion stage was turned around by 180 degrees before translocation. That is, the rats were moved backward by translocation of the stage although the rats ran forward on the treadmill. The theta (6-9 Hz) power was significantly increased in the backward condition compared with the forward condition. However, the theta power gradually decreased by repeated testing in the backward condition. Furthermore, backward translocation of the stage without locomotion did not increase theta power. These results suggest that the HF might function as a comparator to detect sensory mismatch, and that alteration in HF theta activity might induce motion sickness.