Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

BackgroundHippocampal oscillations play a critical role in the ontogeny of allocentric memory in rodents. During the critical period for memory development, hippocampal theta is the driving force behind the temporal coordination of neuronal ensembles underpinning spatial memory. While known that hippocampal oscillations are necessary for normal spatial cognition, whether disrupted hippocampal oscillatory activity during the critical period impairs long-term spatial memory is unknown. Here we investigated whether disruption of normal hippocampal rhythms during the critical period have enduring effects on allocentric memory in rodents.Objective/hypothesisWe hypothesized that disruption of hippocampal oscillations via artificial regulation of the medial septum during the critical period for memory development results in long-standing deficits in spatial cognition.MethodsAfter demonstrating that pan-neuronal medial septum (MS) optogenetic stimulation (465 nm activated) regulated hippocampal oscillations in weanling rats we used a random pattern of stimulation frequencies to disrupt hippocampal theta rhythms for either 1Hr or 5hr a day between postnatal (P) days 21–25. Non-stimulated and yellow light-stimulated (590 nm) rats served as controls. At P50-60 all rats were tested for spatial cognition in the active avoidance task. Rats were then sacrificed, and the MS and hippocampus assessed for cell loss. Power spectrum density of the MS and hippocampus, coherences and voltage correlations between MS and hippocampus were evaluated at baseline for a range of stimulation frequencies from 0.5 to 110 Hz and during disruptive hippocampal stimulation. Unpaired t-tests and ANOVA were used to compare oscillatory parameters, behavior and cell density in all animals.ResultsNon-selective optogenetic stimulation of the MS in P21 rats resulted in precise regulation of hippocampal oscillations with 1:1 entrainment between stimulation frequency (0.5–110 Hz) and hippocampal local field potentials. Across bandwidths MS stimulation increased power, coherence and voltage correlation at all frequencies whereas the disruptive stimulation increased power and reduced coherence and voltage correlations with most statistical measures highly significant (p < 0.001, following correction for false detection). Rats receiving disruptive hippocampal stimulation during the critical period for memory development for either 1Hr or 5hr had marked impairment in spatial learning as measured in active avoidance test compared to non-stimulated or yellow light-control rats (p < 0.001). No cell loss was measured between the blue-stimulated and non-stimulated or yellow light-stimulated controls in either the MS or hippocampus.ConclusionThe results demonstrated that robust regulation of hippocampal oscillations can be achieved with non-selective optogenetic stimulation of the MS in rat pups. A disruptive hippocampal stimulation protocol, which markedly increases power and reduces coherence and voltage correlations between the MS and hippocampus during the critical period of memory development, results in long-standing spatial cognitive deficits. This spatial cognitive impairment is not a result of optogenetic stimulation-induced cell loss.     

Hippocampal Theta Oscillations Support Successful Associative Memory Formation

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2–5 Hz and 5–9 Hz theta oscillations, by which power increases in 2–5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2–5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5–9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.SIGNIFICANCE STATEMENT Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2–5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.     

Functional substrate for memory function differences between patients with left and right mesial temporal lobe epilepsy associated with hippocampal sclerosis

ObjectiveLittle is known about the functional substrate for memory function differences in patients with left or right mesial temporal lobe epilepsy (mTLE) associated with hippocampal sclerosis (HS) from an electrophysiological perspective. To characterize these differences, we hypothesized that hippocampal theta connectivity in the resting-state might be different between patients with left and right mTLE with HS and be correlated with memory performance.MethodsResting-state hippocampal theta connectivity, identified via whole-brain magnetoencephalography, was evaluated. Connectivity and memory function in 41 patients with mTLE with HS (left mTLE = 22; right mTLE = 19) were compared with those in 46 age-matched healthy controls and 28 patients with focal cortical dysplasia (FCD) but without HS.ResultsConnectivity between the right hippocampus and the left middle frontal gyrus was significantly stronger in patients with right mTLE than in patients with left mTLE. Moreover, this connectivity was positively correlated with delayed verbal recall and recognition scores in patients with mTLE. Patients with left mTLE had greater delayed recall impairment than patients with right mTLE and FCD. Similarly, delayed recognition performance was worse in patients with left mTLE than in patients with right mTLE and FCD. No significant differences in memory function between patients with right mTLE and FCD were detected. Patients with right mTLE showed significantly stronger hippocampal theta connectivity between the right hippocampus and left middle frontal gyrus than patients with FCD and left mTLE.ConclusionOur results suggest that right hippocampal–left middle frontal theta connectivity could be a functional substrate that can account for differences in memory function between patients with left and right mTLE. This functional substrate might be related to different compensatory mechanisms against the structural hippocampal lesions in left and right mTLE groups. Given the positive correlation between connectivity and delayed verbal memory function, hemispheric-specific hippocampal–frontal theta connectivity assessment could be useful as an electrophysiological indicator of delayed verbal memory function in patients with mTLE with HS.     

Prestimulus theta in the human hippocampus predicts subsequent recognition but not recall

Human theta (4?8 Hz) activity in the medial temporal lobe correlates with memory formation; however, the precise role that theta plays in the memory system remains elusive (Hanslmayr and Staudigl, 2014 ). Recently, prestimulus theta activity has been associated with successful memory formation, although its specific cognitive role remains unknown (e.g., Fell et al., 2011). In this report, we demonstrate that prestimulus theta in the hippocampus indexes encoding that supports old‐new recognition memory but not recall. These findings suggest that human hippocampal prestimulus theta may preferentially participate in the encoding of item information, as opposed to associative information. © 2014 Wiley Periodicals, Inc.     

Associative recognition in mild cognitive impairment: Relationship to hippocampal volume and apolipoprotein E

Associative memory involves remembering relations between items of information and is critically dependent on the hippocampus, a brain structure that shows early changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. We examined associative and item memory in aMCI with a focus on the role of medial-temporal lobe regions and genetic risk for Alzheimer's disease. Twenty-four individuals with aMCI and 21 demographically matched healthy older adults underwent associative recognition testing, structural brain imaging, and apolipoprotein E (ApoE) genotyping. A significant interaction between group and recognition type indicated poorer associative recognition than item recognition across tasks in the aMCI group relative to controls. Within the aMCI group, associative but not item recognition showed sizable and significant correlations with hippocampal volume (but not with other medial temporal-lobe structures) and with number of ApoE ε4 alleles. Correlations were smaller and generally not significant in the control group. Our findings replicate and extend previous studies by showing an associative recognition impairment in aMCI that is not accounted for by an item recognition deficit, is related to structural integrity of the hippocampus, and increases with genetic risk for Alzheimer's disease.     

Frequency‐specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity

Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal‐cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network‐targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta‐burst stimulation, intermittent theta‐burst stimulation, and beta‐frequency (20‐Hz) repetitive stimulation, and one sham condition. Resting‐state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta‐burst stimulation conditions would most strongly influence hippocampal‐HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta‐band activity for HCN memory function. Continuous theta‐burst stimulation improved item retrieval success relative to sham and relative to beta‐frequency stimulation, whereas intermittent theta‐burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta‐burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory‐related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta‐burst stimulation affected memory‐related hippocampal‐HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory‐related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta‐burst noninvasive stimulation.     

Theta band power increases in the posterior hippocampus predict successful episodic memory encoding in humans

Functional differences in the anterior and posterior hippocampus during episodic memory processing have not been examined in human electrophysiological data. This is in spite of strong evidence for such differences in rodent data, including greater place cell specificity in the dorsal hippocampus, greater sensitivity to the aversive or motivational content of memories in ventral regions, connectivity analyses identifying preferential ventral hippocampal connections with the amygdala, and gene expression analyses identifying a dorsal–ventral gradient. We asked if memory‐related oscillatory patterns observed in human hippocampal recordings, including the gamma band and slow‐theta (2.5–5 Hz) subsequent memory effects, would exhibit differences along the longitudinal axis and between hemispheres. We took advantage of a new dataset of stereo electroencephalography patients with simultaneous, robotically targeted anterior, and posterior hippocampal electrodes to directly compare oscillatory subsequent memory effects during item encoding. This same data set allowed us to examine left–right connectivity and hemispheric differences in hippocampal oscillatory patterns. Our data suggest that a power increase during successful item encoding in the 2.5–5 Hz slow‐theta frequency range preferentially occurs in the posterior hippocampus during the first 1,000 ms after item presentation, while a gamma band power increase is stronger in the dominant hemisphere. This dominant–nondominant pattern in the gamma range appears to reverse during item retrieval, however. Intrahippocampal phase coherence was found to be stronger during successful item encoding. Our phase coherence data are also consistent with existing reports of a traveling wave for theta oscillations propagating along the septotemporal (longitudinal) axis of the human hippocampus. We examine how our findings fit with theories of functional specialization along the hippocampal axis.     

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.     

Stimulation-induced reset of hippocampal theta in the freely performing rat

Previous research has suggested that visual and auditory stimuli in a working memory task have the ability to reset hippocampal theta, perhaps allowing an organism to encode the incoming information optimally. The present study examined two possible neural pathways involved in theta resetting. Rats were trained on a visual discrimination task in an operant chamber. At the beginning of a trial, a light appeared over a centrally located lever that the rat was required to press to receive a water reward. There was a 30-s intertrial interval before the next light stimulus appeared. After learning the task, all rats received surgical implantation of stimulating electrodes in both the fornix and the perforant path and recording electrodes, bilaterally in the hippocampus. After surgery, theta was recorded before and after the light stimulus to determine whether resetting to the visual stimulus occurred. During the intertrial interval, rats received single-pulse electrical stimulation of either the fornix or perforant path. Theta was recorded both before and after the electrical stimulation to determine whether resetting occurred. In this experiment, hippocampal theta was reset after all three stimulus conditions (light, perforant path, and fornix stimulation), with the greatest degree of reset occurring after the fornix stimulation. The results suggest that activation of the perforant path and fornix may underlie theta reset and provide a mechanism by which the hippocampus may enhance cognitive processing.     

Conditional associative learning and the hippocampal system

Rats with lesions of the fornix, the dorsal hippocampus, or a control operation were trained on a spatial-visual conditional associative learning task in which they had to learn to associate particular locations with specific visual stimuli. Animals with damage of the fornix were able to learn the task at a rate comparable to that of the control animals, but the performance of the hippocampal rats was significantly impaired in comparison with that of both the control and the fornix groups. In a second experiment, lesions to the fornix or the dorsal hippocampus significantly impaired performance on a spatial working memory task, the eight-arm radial maze. These findings suggest that the interaction between the hippocampus and subcortical structures via the fornix may be critical only for certain types of spatial learning and memory. Hippocampus 1998;8:131–137. © 1998 Wiley-Liss, Inc.     

Identifying the neurophysiological effects of memory-enhancing amygdala stimulation using interpretable machine learning

BackgroundDirect electrical stimulation of the amygdala can enhance declarative memory for specific events. An unanswered question is what underlying neurophysiological changes are induced by amygdala stimulation.ObjectiveTo leverage interpretable machine learning to identify the neurophysiological processes underlying amygdala-mediated memory, and to develop more efficient neuromodulation technologies.MethodPatients with treatment-resistant epilepsy and depth electrodes placed in the hippocampus and amygdala performed a recognition memory task for neutral images of objects. During the encoding phase, 160 images were shown to patients. Half of the images were followed by brief low-amplitude amygdala stimulation. For local field potentials (LFPs) recorded from key medial temporal lobe structures, feature vectors were calculated by taking the average spectral power in canonical frequency bands, before and after stimulation, to train a logistic regression classification model with elastic net regularization to differentiate brain states.ResultsClassifying the neural states at the time of encoding based on images subsequently remembered versus not-remembered showed that theta and slow-gamma power in the hippocampus were the most important features predicting subsequent memory performance. Classifying the post-image neural states at the time of encoding based on stimulated versus unstimulated trials showed that amygdala stimulation led to increased gamma power in the hippocampus.ConclusionAmygdala stimulation induced pro-memory states in the hippocampus to enhance subsequent memory performance. Interpretable machine learning provides an effective tool for investigating the neurophysiological effects of brain stimulation.     

Impaired hippocampal function during the detection of novel words in schizophrenia.

BACKGROUND: Patients with schizophrenia have smaller hippocampal volumes and perform abnormally on most declarative memory tasks. Although these findings are likely related, the impact of hippocampal pathology on cognitive performance in schizophrenia remains unclear. This study examined this relationship by measuring the volume of the hippocampus and its activation during memory task performance. METHODS: Participants included 15 patients with schizophrenia and 16 age-matched control subjects. Hippocampal volume was determined via three-dimensional volumetric analysis of high-resolution magnetic resonance images. Hippocampal activity was assessed by measuring changes in blood oxygen level-dependent signal during a recognition memory task. RESULTS: Patients with schizophrenia had smaller hippocampal volumes bilaterally and demonstrated poorer performance on the recognition memory task, largely because of a heightened rate of false alarms to novel stimuli. Both groups showed robust hippocampal activity to old and new items when compared with a low-level baseline task; however, direct comparison of hippocampal activity during recognition task performance revealed that healthy control, but not the schizophrenia, subjects showed significant right anterior hippocampal activation during the evaluation of novel items. CONCLUSIONS: The impaired ability to classify new items as previously not experienced is associated with decreased recruitment and smaller volume of the hippocampus in schizophrenia.     

Speed modulation of hippocampal theta frequency correlates with spatial memory performance

Hippocampal theta rhythm is believed to play a critical role in learning and memory. In animal models of temporal lobe epilepsy (TLE), there is evidence that alterations of hippocampal theta oscillations are involved in the cognitive impairments observed in this model. However, hippocampal theta frequency and amplitude at both the local field potential (LFP) and single unit level are strongly modulated by running speed, suggesting that the integration of locomotor information into memory processes may also be critical for hippocampal processing. Here, we investigate whether hippocampal speed‐theta integration influences spatial memory and whether it could account for the memory deficits observed in TLE rats. LFPs were recorded in both Control (CTR) and TLE rats as they were trained in a spatial alternation task. TLE rats required more training sessions to perform the task at CTR levels. Both theta frequency and power were significantly lower in the TLE group. In addition, speed/theta frequency correlation coefficients and regression slopes varied from session to session and were worse in TLE. Importantly, there was a strong relationship between speed/theta frequency parameters and performance. Our analyses reveal that speed/theta frequency correlation with performance cannot merely be explained by the direct influence of speed on behavior. Therefore, variations in the coordination of theta frequency with speed may participate in learning and memory processes. Impairments of this function could explain at least partially memory deficits in epilepsy. © 2013 Wiley Periodicals, Inc.     

Septal elicitation of hippocampal theta rhythm did not repair cognitive and emotional deficits resulting from vestibular lesions

Bilateral vestibular lesions cause atrophy of the hippocampus in humans and subsequent deficits in spatial memory and the processing of emotional stimuli in both rats and humans. Vestibular lesions also impair hippocampal theta rhythm in rats. The aim of the present study was to investigate whether restoring theta rhythm to the hippocampus of a rat, via stimulation of the medial septum, would repair the deficits caused by vestibular lesions. It was hypothesized that the restoration of theta would repair the deficits and the vestibular rats would exhibit behavior and EEG similar to that of the sham rats. Rats were given either sham surgery or bilateral vestibular deafferentation (BVD) followed in a later operation by electrode implants. Half of the lesioned rats received stimulation. Subjects were tested in open field, elevated T-maze and spatial nonmatching to sample tests. BVD caused a deficit in hippocampal theta rhythm. Stimulation restored theta power at a higher frequency in the vestibular-lesioned rats, however, the stimulation did not repair the cognitive and emotional deficits caused by the lesions. It was concluded that stimulation, at least in the form used here, would not be a viable treatment option for vestibular damaged humans.     

Recognition memory for single items and for associations in amnesic patients

Recognition memory performance reflects two distinct processes or types of memory referred to as recollection and familiarity. According to theoretical claims about the two types of memory, single item and associative recognition tasks can be used as an experimental method to distinguish recollection and familiarity processes. Associative recognition decisions can be used as an index of recollection while memory for single items is mostly based on familiarity judgement. We employed this procedure to examine a possible dissociation in the memory performance of amnesic patients between spared single item and impaired associative recognition. Twelve amnesic patients, six with damage confined to the hippocampus proper, and six with damage elsewhere in the brain, were recruited for the present study. The findings showed that hippocampal amnesics exhibit relative sparing of single item learning but are consistently deficient in the learning of all kinds of between-item associations. These results are consistent with the view that hippocampal formation contributes differently to declarative tasks that require recollective or familiarity processes.     

Inactivation of the rat dorsal striatum impairs performance in spatial tasks and alters hippocampal theta in the freely moving rat

We analysed the interaction between the dorsal striatum (motor coordination and planning) and the hippocampus (sensory information processing and integration) during performance of goal-directed tasks. The performance of rats that had been injected with different doses of the D(2)-antagonist Sulpiride into the dorsal striatum was tested in an egocentric 4-arm maze task that tests striatal functions. Furthermore, hippocampal EEGs were recorded before, during and after inactivation of the dorsal striatum via injections of Sulpiride of rats that were performing a continuous alternation task. Injection of 5 microl of 100 mM Sulpiride increased the number of errors committed in the egocentric 4-arm maze (p < 0.01), indicating that the dorsal striatum is involved in motor control and motor memory recall in such a task. In the recording study, the same dose of Sulpiride injected into the dorsal striatum had powerful effects on the hippocampal EEG. The main activity in the theta range (5-10 Hz) was shifted from higher frequencies in the 8-10 Hz range to lower frequencies in the 5-7 Hz range (p < 0.005). The impairment in the behavioural egocentric task after Sulpiride injection, and the effects of Sulpiride on hippocampal theta shows that there is a functional interaction between the dorsal striatum and the hippocampus. While the dorsal striatum coordinates the execution of complex motor programs, the hippocampus integrates spatial and other sensory information required for the planning and execution of goal-directed movements.     

Deep brain stimulation in the medial septum attenuates temporal lobe epilepsy via entrainment of hippocampal theta rhythm

AimsTemporal lobe epilepsy (TLE), often associated with cognitive impairment, is one of the most common types of medically refractory epilepsy. Deep brain stimulation (DBS) shows considerable promise for the treatment of TLE. However, the optimal stimulation targets and parameters of DBS to control seizures and related cognitive impairment are still not fully illustrated.MethodsIn the present study, we evaluated the therapeutic potential of DBS in the medial septum (MS) on seizures and cognitive function in mouse acute and chronic epilepsy models.ResultsWe found that DBS in the MS alleviated the severity of seizure activities in both kainic acid‐induced acute seizure model and hippocampal‐kindled epilepsy model. DBS showed antiseizure effects with a wide window of effective stimulation frequencies. The antiseizure effects of DBS were mediated by the hippocampal theta rhythm, as atropine, which reversed the DBS‐induced augmentation of the hippocampal theta oscillation, abolished the antiseizure effects of DBS. Further, in the kainic acid‐induced chronic TLE model, DBS in the MS not only reduced spontaneous seizures, but also improved behavioral performance in novel object recognition.ConclusionDBS in the MS is a promising approach to attenuate TLE probably through entrainment of the hippocampal theta rhythm, which may be therapeutically significant for refractory TLE treatment.     

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson’s disease: A pilot study

BackgroundThere is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson’s disease (PD).ObjectiveTo evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency.MethodsTwelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130–135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects.ResultsTheta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests.ConclusionIn this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.     

Anterior thalamic stimulation improves working memory precision judgments

BackgroundThe anterior nucleus of thalamus (ANT) has been suggested as an extended hippocampal system. The circuit of ANT and hippocampus has been widely demonstrated to be associated with memory function. Both lesions to each region and disrupting inter-regional information flow can induce working memory impairment. However, the role of this circuit in working memory precision remains unknown.ObjectiveTo test the role of the hippocampal-anterior thalamic pathway in working memory precision, we delivered intracranially electrical stimulation to the ANT. We hypothesize that ANT stimulation can improve working memory precision.MethodsPresurgical epilepsy patients with depth electrodes in ANT and hippocampus were recruited to perform a color-recall working memory task. Participants were instructed to point out the color they were supposed to recall by clicking a point on the color wheel, while the intracranial EEG data were synchronously recorded. For randomly selected half trials, a bipolar electrical stimulation was delivered to the ANT electrodes.ResultsWe found that compared to non-stimulation trials, working memory precision judgements were significantly improved for stimulation trials. ANT electrical stimulation significantly increased spectral power of gamma (30–100 Hz) oscillations and decreased interictal epileptiform discharges (IED) in the hippocampus. Moreover, the increased gamma power during the pre-stimulus and retrieval period predicted the improvement of working memory precision judgements.ConclusionANT electrical stimulation can improve working memory precision judgements and modulate hippocampal gamma activity, providing direct evidence on the role of the human hippocampal-anterior thalamic axis in working memory precision.     

Reduced specificity of hippocampal and posterior ventrolateral prefrontal activity during relational retrieval in normal aging

Neuroimaging studies of episodic memory in young adults demonstrate greater functional neural activity in ventrolateral pFC and hippocampus during retrieval of relational information as compared with item information. We tested the hypothesis that healthy older adults--individuals who exhibit behavioral declines in relational memory--would show reduced specificity of ventrolateral prefrontal and hippocampal regions during relational retrieval. At study, participants viewed two nouns and were instructed to covertly generate a sentence that related the words. At retrieval, fMRIs were acquired during item and relational memory tasks. In the relational task, participants indicated whether the two words were previously seen together. In the item task, participants indicated whether both items of a pair were previously seen. In young adults, left posterior ventrolateral pFC and bilateral hippocampal activity was modulated by the extent to which the retrieval task elicited relational processing. In older adults, activity in these regions was equivalent for item and relational memory conditions, suggesting a reduction in ventrolateral pFC and hippocampal specificity with normal aging.