Modulation of hippocampal theta oscillations via deep brain stimulation of the parietal cortex depends on cognitive state.

The angular gyrus (AG) and posterior cingulate cortex (PCC) demonstrate extensive structural and functional connectivity with the hippocampus and other core recollection network regions. Consequently, recent studies have explored neuromodulation targeting these and other regions as a potential strategy for restoring function in memory disorders such as Alzheimer's Disease. However, determining the optimal approach for neuromodulatory devices requires understanding how parameters like selected stimulation site, cognitive state during modulation, and stimulation duration influence the effects of deep brain stimulation (DBS) on electrophysiological features relevant to episodic memory. We report experimental data examining the effects of high-frequency stimulation delivered to the AG or PCC on hippocampal theta oscillations during the memory encoding (study) or retrieval (test) phases of an episodic memory task. Results showed selective enhancement of anterior hippocampal slow theta oscillations with stimulation of the AG preferentially during memory retrieval. Conversely, stimulation of the PCC attenuated slow theta oscillations. We did not observe significant behavioral effects in this (open-loop) stimulation experiment, suggesting that neuromodulation strategies targeting episodic memory performance may require more temporally precise stimulation approaches.

Laser interstitial thermal therapy for new and recurrent meningioma: a prospective and retrospective case series.

OBJECTIVE: Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS: Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS: Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS: This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.

Stereo-electroencephalographic seizure localization in patients with mesial temporal sclerosis: A single center experience.

Objective: Epilepsy patients with mesial temporal sclerosis (MTS) on imaging who are drug-resistant usually undergo epilepsy surgery without previous invasive evaluation. However, up to one-third of patients are not seizure-free after surgery. Prior studies have identified risk factors for surgical failure, but it is unclear if they are associated with bilateral or discordant seizure onset. Methods: In this retrospective case series, we identified 17 epilepsy patients who had MRI-confirmed MTS but received invasive stereo-EEG (SEEG) evaluation before definitive intervention. We analyzed their presurgical risk factors in relation to SEEG seizure onset localization and MRI/SEEG concordance. Results: SEEG ictal onset was concordant with MTS localization (i.e. seizures started only from the hippocampus with MTS) in 5 out of 13 patients with unilateral MTS (UMTS) and in 3 out of 4 patients with bilateral MTS.No statistically significant association regarding concordance of SEEG ictal onset and MTS location was found in patients with such risk factors as a history of non-mesial temporal aura, frequent focal to bilateral tonic-clonic seizures, prior viral brain infection, or family history of epilepsy. Nine out of 13 UMTS patients had resective surgery only, 5 out of 9 (56 %) have Engel class I outcome at most recent follow-up (median 46.5 months, range 22-91 months). In Engel class I cohort, the SEEG ictal onset was concordant with MTS location in 3 out of 5 patients, and 2 patients had ipsilateral temporal neocortical ictal onset. Conclusions: Our findings suggest that patients with MTS might have discordant SEEG ictal onset (in 61.5% patients with UMTS in presented cohort), which may explain poor surgical outcome after destructive surgery in these cases. Significance: Although no statistically significant association was found in this under-powered study, these findings could be potentially valuable for future meta-analyses.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

Bibliometric Analysis and Applications of a Modified H-Index Examining the Research Productivity of Neurosurgery Faculty at High-Ranking Academic Institutions.

OBJECTIVE: A major critique of the h-index is that it may be inflated by noncritical authorship. We propose a modified h-index (hm), incorporating critical authorship, complementary to the h-index. We analyze its relationship to the traditional h-index, and how each varies across professional categories relevant to academic neurosurgery. This analysis is not meant to critique authorship decisions, affect career development, alter academic legacy, or imply that the concepts of team science or midlevel authorship contributions are not valuable. METHODS: H-indices and hms were gathered and computed for clinical neurosurgical faculty at the top 32 ranked academic neurosurgical programs based on the current literature. Hm was computed for faculty at each program, using articles in which the individual was first, second, last, or co-corresponding author. Individuals were further identified based on chair status, leadership status, neurosurgical subspecialty, and National Institutes of Health funding status. Further analysis was performed to determine factors influencing h-index and hm. RESULTS: The median h-index for the 225 physicians included in the final dataset is 48 (interquartile range [IQR], 39-61), whereas the median hm was 32 (IQR, 24-43). The median difference between h-index and hm is 15 (IQR, 10-23). The median hm/h was 64% (IQR, 57-74). National Institutes of Health funding and subspecialty (neurosurgical oncology, neurocritical care, and cerebrovascular) were associated with significant change from h to hm. CONCLUSIONS: The h-index can be influenced by noncritical authorship, and hm, using critical contributions, can be used as a complement reflecting critical academic output in neurosurgery. Leaders deciding on hiring or promotion should consider disparities in productivity predicated on noncritical authorship contributions.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Episodic boundaries affect neural features of representational drift in humans.

A core feature of episodic memory is representational drift, the gradual change in aggregate oscillatory features that supports temporal association of memory items. However, models of drift overlook the role of episodic boundaries, which indicate a shift from prior to current context states. Our study focuses on the impact of task boundaries on representational drift in the parietal and temporal lobes in 99 subjects during a free recall task. Using intracranial EEG recordings, we show boundary representations reset gamma band drift in the medial parietal lobe, selectively enhancing the recall of early list (primacy) items. Conversely, the lateral temporal cortex shows increased drift for recalled items but lacked sensitivity to task boundaries. Our results suggest regional sensitivity to varied contextual features: the lateral temporal cortex uses drift to differentiate items, while the medial parietal lobe uses drift-resets to associate items with the current context. We propose drift represents relational information tailored to a region's sensitivity to unique contextual elements. Our findings offer a mechanism to integrate models of temporal association by drift with event segmentation by episodic boundaries.

Neuromodulation of the anterior thalamus: Current approaches and opportunities for the future.

The role of thalamocortical circuits in memory has driven a recent burst of scholarship, especially in animal models. Investigating this circuitry in humans is more challenging. And yet, the development of new recording and stimulation technologies deployed for clinical indications has created novel opportunities for data collection to elucidate the cognitive roles of thalamic structures. These technologies include stereoelectroencephalography (SEEG), deep brain stimulation (DBS), and responsive neurostimulation (RNS), all of which have been applied to memory-related thalamic regions, specifically for seizure localization and treatment. This review seeks to summarize the existing applications of neuromodulation of the anterior thalamic nuclei (ANT) and highlight several devices and their capabilities that can allow cognitive researchers to design experiments to assay its functionality. Our goal is to introduce to investigators, who may not be familiar with these clinical devices, the capabilities, and limitations of these tools for understanding the neurophysiology of the ANT as it pertains to memory and other behaviors. We also briefly cover the targeting of other thalamic regions including the centromedian (CM) nucleus, dorsomedial (DM) nucleus, and pulvinar, with associated potential avenues of experimentation.

Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Acetylcholine modulates the temporal dynamics of human theta oscillations during memory.

The cholinergic system is essential for memory. While degradation of cholinergic pathways characterizes memory-related disorders such as Alzheimer's disease, the neurophysiological mechanisms linking the cholinergic system to human memory remain unknown. Here, combining intracranial brain recordings with pharmacological manipulation, we describe the neurophysiological effects of a cholinergic blocker, scopolamine, on the human hippocampal formation during episodic memory. We found that the memory impairment caused by scopolamine was coupled to disruptions of both the amplitude and phase alignment of theta oscillations (2-10 Hz) during encoding. Across individuals, the severity of theta phase disruption correlated with the magnitude of memory impairment. Further, cholinergic blockade disrupted connectivity within the hippocampal formation. Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation. These findings expand our mechanistic understanding of the neurophysiology of human memory and offer insights into potential treatments for memory-related disorders.

Biomarker-guided neuromodulation aids memory in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

Seizure onset patterns predict outcome after stereo-electroencephalography-guided laser amygdalohippocampotomy.

OBJECTIVE: Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom. METHODS: This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category. RESULTS: Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015). SIGNIFICANCE: Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Machine learning classifiers for electrode selection in the design of closed-loop neuromodulation devices for episodic memory improvement.

Successful neuromodulation approaches to alter episodic memory require closed-loop stimulation predicated on the effective classification of brain states. The practical implementation of such strategies requires prior decisions regarding electrode implantation locations. Using a data-driven approach, we employ support vector machine (SVM) classifiers to identify high-yield brain targets on a large data set of 75 human intracranial electroencephalogram subjects performing the free recall (FR) task. Further, we address whether the conserved brain regions provide effective classification in an alternate (associative) memory paradigm along with FR, as well as testing unsupervised classification methods that may be a useful adjunct to clinical device implementation. Finally, we use random forest models to classify functional brain states, differentiating encoding versus retrieval versus non-memory behavior such as rest and mathematical processing. We then test how regions that exhibit good classification for the likelihood of recall success in the SVM models overlap with regions that differentiate functional brain states in the random forest models. Finally, we lay out how these data may be used in the design of neuromodulation devices.

Stereo-EEG Evaluation and Surgical Treatment in Patients With Drug-Resistant Focal Epilepsy Associated With Nodular Heterotopia.

PURPOSE: Nodular heterotopia (NH) is a common cause of drug-resistant epilepsy. Only limited studies detail the treatment of NH with laser interstitial thermal therapy and none analyze the relation between epileptogenicity and NH location. METHODS: We retrospectively studied nine patients with drug-resistant epilepsy and NH who underwent stereoelectroencephalography and subsequent epilepsy surgery. Nodular heterotopia in the frontal lobes or along the bodies of the lateral ventricles was classified as anterior NH. Nodular heterotopia in the trigones, temporal or occipital horns, or temporal lobes was classified as posterior NH. Nodular heterotopia in both anterior and posterior locations was classified as diffuse NH. Interictal and ictal stereoelectroencephalography were analyzed, and patients were followed postoperatively to assess outcomes. RESULTS: Of the six patients who underwent nine laser interstitial thermal therapy procedures either in isolation or in combination with other surgical therapies, four patients were Engel Ia, one was Engel IIb, and one was Engel IIIa, with an average follow-up of 22.8 months. All patients with posterior NH had interictal epileptiform abnormalities and seizures originating from the posterior NH. None of the patients with anterior NH had epileptiform activity recorded from their NH. CONCLUSION: Laser interstitial thermal therapy alone or in combination with other surgical therapies is an effective treatment in those with drug-resistant epilepsy because of NH, even in those with extensive NH and broad seizure onset. We observed a trend suggesting that posterior NH are more likely to be epileptogenic compared with anterior NH and recommend that in patients with anterior NH, alternative epilepsy etiologies and stereoelectroencephalography implantation strategies be considered.

Single center outcomes of intracranial evaluation and surgical intervention in the elderly population.

Objective: The object of this case series is to report the effectiveness and complication rates of presurgical evaluation and surgical treatment among elderly epilepsy patients in our clinic. Methods: We reviewed patients charts from 2016 to 2020 and identified patients over the age of 55 years of age who underwent intracranial EEG, resection, and device placement. We compared the complications and post-intervention outcomes of 14 different patients. Results: The mean age of patients was 63.6 ± 4.13 years, and 6 (42.9 %) patients were female. 8 (57.1 %) patients underwent intracranial evaluation; 6 patients underwent SEEG, and 2 patients underwent SDE placement. 5/11 (45 %) patients reached seizure freedom with at least one year follow-up. Discussion: Intracranial evaluation could play an important role in the success of surgical intervention in the elderly epilepsy population. Prospective, multicenter studies are needed to determine the ideal candidate for a safe and effective intracranial evaluation and resection.

Flexibility of functional neuronal assemblies supports human memory.

Episodic memories, or consciously accessible memories of unique events, represent a key aspect of human cognition. Evidence from rodent models suggests that the neural representation of these complex memories requires cooperative firing of groups of neurons on short time scales, organized by gamma oscillations. These co-firing groups, termed "neuronal assemblies," represent a fundamental neurophysiological unit supporting memory. Using microelectrode data from neurosurgical patients, we identify neuronal assemblies in the human MTL and show that they exhibit consistent organization in their firing pattern based on gamma phase information. We connect these properties to memory performance across recording sessions. Finally, we describe how human neuronal assemblies flexibly adjust over longer time scales. Our findings provide key evidence linking assemblies to human episodic memory for the first time.

Vagus nerve stimulation paired with rehabilitation for stroke: Implantation experience from the VNS-REHAB trial.

OBJECTIVE: Vagus Nerve Stimulation (VNS) paired with rehabilitation delivered by the Vivistim® Paired VNS™ System was approved by the FDA in 2021 to improve motor deficits in chronic ischemic stroke survivors with moderate to severe arm and hand impairment. Vagus nerve stimulators have previously been implanted in over 125,000 patients for treatment-resistant epilepsy and the surgical procedure is generally well-tolerated and safe. In this report, we describe the Vivistim implantation procedure, perioperative management, and complications for chronic stroke survivors enrolled in the pivotal trial. METHODS: The pivotal, multisite, randomized, triple-blind, sham-controlled trial (VNS-REHAB) enrolled 108 participants. All participants were implanted with the VNS device in an outpatient procedure. Thrombolytic agents were temporarily discontinued during the perioperative period. Participants were discharged within 48 hrs and started rehabilitation therapy approximately 10 days after the Procedure. RESULTS: The rate of surgery-related adverse events was lower than previously reported for VNS implantation for epilepsy and depression. One participant had vocal cord paresis that eventually resolved. There were no serious adverse events related to device stimulation. Over 90% of participants were taking antiplatelet drugs (APD) or anticoagulants and no adverse events or serious adverse events were reported as a result of withholding these medications during the perioperative period. CONCLUSIONS: This study is the largest, randomized, controlled trial in which a VNS device was implanted in chronic stroke survivors. Results support the use of the Vivistim System in chronic stroke survivors, with a safety profile similar to VNS implantations for epilepsy and depression.

Riding brain "waves" to identify human memory genes.

While there is extensive research on memory-related oscillations and brain gene expression, the relationship between oscillations and gene expression has rarely been studied. Recently, progress has been made to identify specific genes associated with oscillations that are correlated with episodic memory. Neocortical regions, in particular the temporal pole, have been examined in this line of research due to their accessibility during neurosurgical procedures. By harnessing this accessibility, a unique and powerful study design has allowed gene expression and intracranial oscillatory data to be sourced from the same human patients. These studies have identified a plethora of understudied gene targets that should be further characterized with respect to human brain function. Future work should extend to other brain regions to increase our understanding of the genetic signatures of oscillations and, ultimately, human cognition.

A Control-Theoretical System for Modulating Hippocampal Gamma Oscillations Using Stimulation of the Posterior Cingulate Cortex.

Closed-loop stimulation for targeted modulation of brain signals has emerged as a promising strategy for episodic memory restoration. In parallel, closed-loop neuromodulation strategies have been applied to treat brain conditions including drug-resistant depression, Parkinson's Disease, and epilepsy. In this study, we seek to apply control theoretical principles to achieve closed loop modulation of hippocampal oscillatory activity. We focus on hippocampal gamma power, a signal with an established association for episodic memory processing, which may be a promising 'biomarker' for the modulation of memory performance. To develop a closed-loop stimulation paradigm that effectively modulates hippocampal gamma power, we use a novel data-set in which open-loop stimulation was applied to the posterior cingulate cortex and hippocampal gamma power was recorded during the encoding of episodic memories. The dataset was used to design and evaluate a linear quadratic integral (LQI) servo-controller in order to determine its viability for in-vivo use. In our simulation framework, we demonstrate that applying an LQI servo controller based on an autoregressive with exogenous input (ARX) plant model achieves effective control of hippocampal gamma power in 15 out of 17 experimental subjects. We demonstrate that we are able to modulate gamma power using stimulation thresholds that are physiologically safe and on time scales that are reasonable for application in a clinical system. We outline further experimentation to test our proposed system and compare our findings to emerging closed-loop neuromodulation strategies.

Temporal lobe interictal spikes disrupt encoding and retrieval of verbal memory: A subregion analysis.

OBJECTIVE: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall. METHODS: Seventy-eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre-encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed-effects logistic regression. RESULTS: IS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63-.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27-.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66-.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62-.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08-.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07-.8, p < .05) reduced the probability of recalling a word. SIGNIFICANCE: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory.