Single-pulse electrical stimulation artifact removal using the novel matching pursuit-based artifact reconstruction and removal method (MPARRM).

Objective.Single-pulse electrical stimulation (SPES) has been widely used to probe effective connectivity. However, analysis of the neural response is often confounded by stimulation artifacts. We developed a novel matching pursuit-based artifact reconstruction and removal method (MPARRM) capable of removing artifacts from stimulation-artifact-affected electrophysiological signals.Approach.To validate MPARRM across a wide range of potential stimulation artifact types, we performed a bench-top experiment in which we suspended electrodes in a saline solution to generate 110 types of real-world stimulation artifacts. We then added the generated stimulation artifacts to ground truth signals (stereoelectroencephalography signals from nine human subjects recorded during a receptive speech task), applied MPARRM to the combined signal, and compared the resultant denoised signal with the ground truth signal. We further applied MPARRM to artifact-affected neural signals recorded from the hippocampus while performing SPES on the ipsilateral basolateral amygdala in nine human subjects.Main results.MPARRM could remove stimulation artifacts without introducing spectral leakage or temporal spread. It accommodated variable stimulation parameters and recovered the early response to SPES within a wide range of frequency bands. Specifically, in the early response period (5-10 ms following stimulation onset), we found that the broadband gamma power (70-170 Hz) of the denoised signal was highly correlated with the ground truth signal (R=0.98±0.02, Pearson), and the broadband gamma activity of the denoised signal faithfully revealed the responses to the auditory stimuli within the ground truth signal with94%±1.47%sensitivity and99%±1.01%specificity. We further found that MPARRM could reveal the expected temporal progression of broadband gamma activity along the anterior-posterior axis of the hippocampus in response to the ipsilateral amygdala stimulation.Significance.MPARRM could faithfully remove SPES artifacts without confounding the electrophysiological signal components, especially during the early-response period. This method can facilitate the understanding of the neural response mechanisms of SPES.

A test of the social behavior network reveals differential patterns of neural responses to social novelty in bonded, but not non-bonded, male prairie voles.

The social behavior network (SBN) has provided a framework for understanding the neural control of social behavior. The original SBN hypothesis proposed this network modulates social behavior and should exhibit distinct patterns of neural activity across nodes, which correspond to distinct social contexts. Despite its tremendous impact on the field of social neuroscience, no study has directly tested this hypothesis. Thus, we assessed Fos responses across the SBN of male prairie voles (Microtus ochrogaster). Virgin/non-bonded and pair bonded subjects were exposed to a sibling cagemate or pair bonded partner, novel female, novel male, novel meadow vole, novel object, or no stimulus. Inconsistent with the original SBN hypothesis, we did not find profoundly different patterns of neural responses across the SBN for different contexts, but instead found that the SBN generated significantly different patterns of activity in response to social novelty in pair bonded, but not non-bonded males. These findings suggest that non-bonded male prairie voles may perceive social novelty differently from pair bonded males or that SBN functionality undergoes substantial changes after pair bonding. This study reveals novel information about bond-dependent, context-specific neural responsivity in male prairie voles and suggests that the SBN may be particularly important for processing social salience. Further, our study suggests there is a need to reconceptualize the framework of how the SBN modulates social behavior.

Rhesus monkeys with damage to amygdala or orbitofrontal cortex perform well on novelty-based memory tasks.

The amygdala and orbitofrontal cortex (OFC) are interconnected regions that serve as key nodes in brain circuits supporting social and affective behaviors. An important question that has come into focus is whether these regions also play a fundamental role in responding to novelty. One possibility is that these regions are important for discriminating novel from familiar stimuli. An alternative possibility is that these regions contribute to affective responses to stimuli in novelty-based tasks. For example, the amygdala and OFC could contribute to assessing novel stimuli as being threatening or previously selected stimuli as having reward value. The present study tested rhesus macaque monkeys with damage to the amygdala or OFC, along with sham-operated control monkeys, across six variants of novelty-based memory tasks. The results showed that monkeys with damage to the amygdala or OFC performed better overall than control monkeys across the tasks. The results indicated that neither region was essential for discriminating novel from familiar stimuli. Instead, the findings suggested that the improved performance observed in novelty-based tasks following damage to these regions was more likely attributable to influences on affect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Challenges facing fMRI studies of systems consolidation.

Tallman and colleagues (this issue) report fMRI findings in support of the classic view of memory consolidation over its main challenger, the multiple trace theory. The present commentary highlights some of the obstacles facing any fMRI study of memory consolidation and notes which challenges were tackled by Tallman and colleagues and which challenges might be insurmountable.

Reassessing Diabetes and APOE Genotype as Potential Interacting Risk Factors for Alzheimer's Disease.

Objective: To assess whether diabetes alone or in association with Apolipoprotein E (APOE) ε4 genotype increases the risk of Alzheimer's Disease (AD) diagnosis. Methods: A retrospective cohort study of 33,456 participants from the National Alzheimer's Coordinating Center database. Results: Participants with one or two APOE ε4 alleles had 2.71 (CI:2.55-2.88) and 9.37 (CI:8.14-10.78) times higher odds of AD diagnosis, respectively, relative to those with zero ε4 alleles. In contrast, diabetic participants showed 1.07 (CI:0.96-1.18) times higher odds of AD relative to nondiabetics. Diabetes did not exacerbate the odds of AD in APOE ε4 carriers. APOE ε4 carriage was correlated with declines in long-term memory and verbal fluency, which were strongly correlated with conversion to AD. However, diabetes was correlated with working memory decline, which had a relatively weak correlation with AD. Conclusions: Unlike APOE ε4, there was little evidence that diabetes was a risk factor for AD.

Delta-modulated cortical alpha oscillations support new knowledge generation through memory integration.

The ability to generate new knowledge depends on integration of separate information. For example, in one episode an individual may learn that apple seeds are called pips. In a separate episode, the individual may then learn that pips contain cyanide. Integration of the related facts in memory may then support derivation of the new knowledge that apple seeds contain cyanide. Past studies show that adults form relational memories that represent the commonalities among discrete events, and that such integrated representation supports the ability to infer new knowledge. Although these integrated representations are thought to result from linking separate memories to the same neuronal ensemble, the neural mechanisms that underlie formation of such linkages are not well understood. Here we examined whether self-derivation of new, integrated knowledge was supported by oscillatory coherence, a means of linking discrete neuronal ensembles. Cortical alpha coherence was greater when adults encoded new facts that could be integrated with existing knowledge, relative to encoding unrelated facts, particularly in participants who showed better performance on the subsequent test of knowledge generation via fact integration. In high performers, posterior alpha amplitude was also modulated by delta phase, a form of cross-frequency coupling previously implicated in coordinating information stored widely throughout the cortex. Examination of the timing and topography of these respective signatures suggested that these oscillatory dynamics work in concert to encode and represent new knowledge with respect to prior knowledge that is reactivated, thus revealing fundamental mechanisms through which related memories are linked into integrated knowledge structures.

Optogenetic stimulation of the basolateral amygdala accelerates acquisition of object-context associations.

The basolateral complex of the amygdala (BLA) is capable of modulating memory and is thought to do so via projections to regions such as the hippocampus. The present study used optogenetic stimulation of glutamatergic projection neurons in the BLA as rats learned object-context associations during a well-studied hippocampus-dependent memory task. Relative to a control condition, optogenetic BLA stimulation resulted in the accelerated acquisition of when stimulation was delivered following correct choices but not when it was delivered during the intertrial interval. These results extend prior examples of amygdala-mediated memory enhancement to a canonical example of hippocampus-dependent memory and provide an opportunity for future dissection of amygdalar modulation of object-context associative memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Prioritization of social information by the basolateral amygdala in rats.

The amygdala is a collection of nuclei that support adaptive social behavior and are implicated in disorders such as autism. The basolateral complex of the amygdala (BLA), a main subdivision of the amygdala, influences fear responses, motivated behavior, and memory of emotional events via its communication with other amygdalar nuclei and with other brain regions such as the prefrontal cortex, striatum, and hippocampus. The specific role of the BLA in responses to social stimuli is less clear. The present study of female rats investigated the role of the BLA in responding to socially-relevant information by asking how inactivation of the BLA with bilateral infusions of the GABA receptor agonist muscimol would affect spontaneous exploration of wood blocks scented either with conspecific male or female urine or with nonsocial odorants. Conspecific urine samples were used because urine conveys information about sex, health, social status, and reproductive state in rodents. The results revealed that BLA inactivation reduced female rats' spontaneous preference for social odors over nonsocial odors, specifically for female urine. However, BLA inactivation did not generally impair rats' ability to distinguish two odors from the same category (e.g., urine odors from two different male rats). The results indicate that the BLA is important for responding to salience of social stimuli but not for discriminating between different individuals, a result that has important implications for amygdalar modulation of downstream attention, motivation, and memory processes for social stimuli.

Amygdala Stimulation Leads to Functional Network Connectivity State Transitions in the Hippocampus.

Several studies have shown that direct brain stimulation can enhance memory in humans and animal models. Investigating the neurophysiological changes induced by brain stimulation is an important step towards understanding the neural processes underlying memory function. Furthermore, it paves the way for developing more efficient neuromodulation approaches for memory enhancement. In this study, we utilized a combination of unsupervised and supervised machine learning approaches to investigate how amygdala stimulation modulated hippocampal network activities during the encoding phase. Using a sliding window in time, we estimated the hippocampal dynamic functional network connectivity (dFNC) after stimulation and during sham trials, based on the covariance of local field potential recordings in 4 subregions of the hippocampus. We extracted different network states by combining the dFNC samples from 5 subjects and applying k-means clustering. Next, we used the between-state transition numbers as the latent features to classify between amygdala stimulation and sham trials across all subjects. By training a logistic regression model, we could differentiate stimulated from sham trials with 67% accuracy across all subjects. Using elastic net regularization as a feature selection method, we identified specific patterns of hippocampal network state transition in response to amygdala stimulation. These results offer a new approach to better understanding of the causal relationship between hippocampal network dynamics and memory-enhancing amygdala stimulation.

Optogenetic Stimulation of the Basolateral Amygdala Increased Theta-Modulated Gamma Oscillations in the Hippocampus.

The amygdala can modulate declarative memory. For example, previous research in rats and humans showed that brief electrical stimulation to the basolateral complex of the amygdala (BLA) prioritized specific objects to be consolidated into long term memory in the absence of emotional stimuli and without awareness of stimulation. The capacity of the BLA to influence memory depends on its substantial projections to many other brain regions, including the hippocampus. Nevertheless, how activation of the BLA influences ongoing neuronal activity in other regions is poorly understood. The current study used optogenetic stimulation of putative glutamatergic neurons in the BLA of freely exploring rats to determine whether brief activation of the BLA could increase in the hippocampus gamma oscillations for which the amplitude was modulated by the phase of theta oscillations, an oscillatory state previously reported to correlate with good memory. BLA neurons were stimulated in 1-s bouts with pulse frequencies that included the theta range (8 Hz), the gamma range (50 Hz), or a combination of both ranges (eight 50-Hz bursts). Local field potentials were recorded in the BLA and in the pyramidal layer of CA1 in the intermediate hippocampus. A key question was whether BLA stimulation at either theta or gamma frequencies could combine with ongoing hippocampal oscillations to result in theta-modulated gamma or whether BLA stimulation that included both theta and gamma frequencies would be necessary to increase theta-gamma comodulation in the hippocampus. All stimulation conditions elicited robust responses in BLA and CA1, but theta-modulated gamma oscillations increased in CA1 only when BLA stimulation included both theta and gamma frequencies. Longer bouts (5-s) of BLA stimulation resulted in hippocampal activity that evolved away from the initial oscillatory states and toward those characterized more by prominent low-frequency oscillations. The current results indicated that one mechanism by which the amygdala might influence declarative memory is by eliciting neuronal oscillatory states in the hippocampus that benefit memory.

Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy.

BACKGROUND: Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function. METHODS: In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity. RESULTS: The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient's anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in 2 patients with anatomically similar electrode placements localized to an approximately 1-cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum. CONCLUSIONS: The current study demonstrates a robust anxiolytic response to cingulum bundle stimulation in 3 patients with epilepsy. TRIAL REGISTRATION: The current study was not affiliated with any formal clinical trial. FUNDING: This project was supported by the American Foundation for Suicide Prevention and the NIH.

Hippocampal place cell dysfunction and the effects of muscarinic M1 receptor agonism in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.

Direct electrical stimulation of the amygdala enhances declarative memory in humans.

Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies.

Cortical dynamics of emotional autobiographical memory retrieval differ between women and men.

Retrieval of autobiographical memories entails periods of search, access, and elaboration. Women's reports of their memories feature more detail and emotional content relative to men's. A key question is how these gender differences relate to unfolding changes in cortical activity during retrieval. We recorded EEG activity from 32 scalp electrodes as women and men were cued to retrieve positive, negative, and neutral autobiographical memories. Alpha (9-12Hz) oscillations were prominent at all EEG channels. Alpha coherence between channels was calculated as a measure of ms-level cortical synchrony. Across participants and memory types, a frontal cluster showed pronounced decreases in coherence with other channels during the first second of autobiographical retrieval. In the following second, a left parietal-centered cluster showed increased coherence with other channels. This effect strengthened and spread in the third second of retrieval, perhaps reflecting trace elaboration and/or evaluation of the memory. Although women and men gave similar subjective ratings of their memories, the second-by-second pattern of alpha coherence during autobiographical retrieval differed by gender and memory type. Specifically, women sustained the increased pattern of left-parietal coherence throughout the trial, whereas for men, alpha coherence in this cluster returned to baseline by second two for neutral memories and by second three for emotional memories. Examination of the temporal dynamics of cortical oscillations provides novel insight into autobiographical memory retrieval processes and to gendered retrieval in particular, suggesting that women may persist with elaboration and/or evaluation to a greater extent than men.

Gamma Oscillations in Rat Hippocampal Subregions Dentate Gyrus, CA3, CA1, and Subiculum Underlie Associative Memory Encoding.

Neuronal oscillations in the rat hippocampus relate to both memory and locomotion, raising the question of how these cognitive and behavioral correlates interact to determine the oscillatory network state of this region. Here, rats freely locomoted while performing an object-location task designed to test hippocampus-dependent spatial associative memory. Rhythmic activity in theta, beta, slow gamma, and fast gamma frequency ranges were observed in both action potentials and local field potentials (LFPs) across four main hippocampal subregions. Several patterns of LFP oscillations corresponded to overt behavior (e.g., increased dentate gyrus-CA3 beta coherence during stationary moments and CA1-subiculum theta coherence during locomotion). In comparison, slow gamma (∼40 Hz) oscillations throughout the hippocampus related most specifically to object-location associative memory encoding rather than overt behavior. The results help to untangle how hippocampal oscillations relate to both memory and motion and single out slow gamma oscillations as a distinguishing correlate of spatial associative memory.

The amygdala and prioritization of declarative memories.

The present review highlights results from recent studies that delivered brief electrical stimulation to the basolateral complex of the amygdala in rats to reveal its capacity to prioritize declarative memories on a moment-to-moment basis even after the moment has passed. The results indicate that this memory enhancement depends on the hippocampus and elicits intrahippocampal gamma synchrony that possibly corresponds with sharpened hippocampal spike-timing dependent plasticity. These recent findings are discussed in relation to past studies of emotional memory in rodents and humans.

Effects of Selective M1 Muscarinic Receptor Activation on Hippocampal Spatial Representations and Neuronal Oscillations.

The muscarinic M1 acetylcholine receptor is a key target for drugs aimed at treating cognitive dysfunction, including the memory impairment in Alzheimer's disease. The overall question of the current study was to ask how systemic administration of the bitopic M1 agonist VU0364572, the M1 positive allosteric modulator BQCA, and the acetylcholinesterase inhibitor donepezil (current standard of care for Alzheimer's disease), would impact spatial memory-related hippocampal function in rats. Hippocampal pyramidal neuron spiking and local field potentials were recorded from regions CA1 and CA3 as rats freely foraged in a recording enclosure. To assess the relative stability versus flexibility of the rats' spatial representations, the walls of the recording enclosure were reshaped in 15-m intervals. As compared to the control condition, systemic administration of VU0364572 increased spatial correlations of CA1 and CA3 pyramidal neuron spiking across all enclosure shape comparisons, whereas BQCA and donepezil appeared to decrease these spatial correlations. Further, both VU0364572 and BQCA increased intrahippocampal synchrony as measured by CA3-CA1 field-field coherence in frequency ranges that tended to align with the prominence of those oscillations for the behavioral state (i.e., theta during locomotion and slow gamma during stationary moments). The results indicated that VU0364572 and BQCA influenced hippocampal function differently but in ways that might both be beneficial for treating memory dysfunction.

Memory-enhancing amygdala stimulation elicits gamma synchrony in the hippocampus.

Activation of the amygdala either during emotional arousal or by direct stimulation is thought to enhance memory in part by modulating plasticity in the hippocampus. However, precisely how the amygdala influences hippocampal activity to improve memory remains unclear. In the present study, brief electrical stimulation delivered to the basolateral complex of the amygdala (BLA) following encounters with some novel objects led to better memory for those objects 1 day later. Stimulation also elicited field-field and spike-field CA3-CA1 synchrony in the hippocampus in the low gamma frequency range (30-55 Hz), a range previously associated with spike timing and good memory. In addition, the hippocampal spiking patterns observed during BLA stimulation reflected recent patterns of activity in the hippocampus. Thus, the results indicate that amygdala activation can prioritize memory consolidation of specific object encounters by coordinating the precise timing of CA1 membrane depolarization with incoming CA3 spikes to initiate long-lasting spike-timing dependent plasticity at putative synapses between recently active neurons.

A temporal context repetition effect in rats during a novel object recognition memory task.

Recent research in humans has used formal models of temporal context, broadly defined as a lingering representation of recent experience, to explain a wide array of recall and recognition memory phenomena. One difficulty in extending this work to studies of experimental animals has been the challenge of developing a task to test temporal context effects on performance in rodents. The current study presents results from a novel object recognition memory paradigm that was adapted from a task used in humans and demonstrates a temporal context repetition effect in rats. Specifically, the findings indicate that repeating the first two objects from a once-encountered sequence of three objects incidentally cues memory for the third object, even in its absence. These results reveal that temporal context influences item memory in rats similar to the manner in which it influences memory in humans and also highlight a new task for future studies of temporal context in experimental animals.

Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats.

Acetylcholine signaling through muscarinic receptors has been shown to benefit memory performance in some conditions, but pan-muscarinic activation also frequently leads to peripheral side effects. Drug therapies that selectively target M1 or M4 muscarinic receptors could potentially improve memory while minimizing side effects mediated by the other muscarinic receptor subtypes. The ability of three recently developed drugs that selectively activate M1 or M4 receptors to improve recognition memory was tested by giving Long-Evans rats subcutaneous injections of three different doses of the M1 agonist VU0364572, the M1 positive allosteric modulator BQCA or the M4 positive allosteric modulator VU0152100 before performing an object recognition memory task. VU0364572 at 0.1 mg/kg, BQCA at 1.0 mg/kg and VU0152100 at 3.0 and 30.0 mg/kg improved the memory performance of rats that performed poorly at baseline, yet the improvements in memory performance were the most statistically robust for VU0152100 at 3.0 mg/kg. The results suggested that selective M1 and M4 receptor activation each improved memory but that the likelihood of obtaining behavioral efficacy at a given dose might vary between subjects even in healthy groups depending on baseline performance. These results also highlighted the potential of drug therapies that selectively target M1 or M4 receptors to improve memory performance in individuals with impaired memory.