The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.SIGNIFICANCE STATEMENTNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1–4, 4–10, and 30–90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one's own body.SIGNIFICANCE STATEMENTSpatial computations using environmental boundaries are an integral part of the brain's spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to functional neuroimaging studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions, we identified a neural marker of boundary representation in the human subiculum.

Processing of memory is supported by coordinated activity in a network of sensory, association, and motor brain regions. It remains a major challenge to determine where memory is encoded for later retrieval. Here, we used direct intracranial brain recordings from epilepsy patients performing free recall tasks to determine the temporal pattern and anatomical distribution of verbal memory encoding across the entire human cortex. High γ frequency activity (65–115 Hz) showed consistent power responses during encoding of subsequently recalled and forgotten words on a subset of electrodes localized in 16 distinct cortical areas activated in the tasks. More of the high γ power during word encoding, and less power before and after the word presentation, was characteristic of successful recall and observed across multiple brain regions. Latencies of the induced power changes and this subsequent memory effect (SME) between the recalled and forgotten words followed an anatomical sequence from visual to prefrontal cortical areas. Finally, the magnitude of the memory effect was unexpectedly found to be the largest in selected brain regions both at the top and at the bottom of the processing stream. These included the language processing areas of the prefrontal cortex and the early visual areas at the junction of the occipital and temporal lobes. Our results provide evidence for distributed encoding of verbal memory organized along a hierarchical posterior-to-anterior processing stream.

Idiopathic intracranial hypertension, also known as pseudotumor cerebri, is a disorder characterized by increased intracranial pressure of unclear pathogenesis in the absence of other structural and obstructive lesions that is predominantly, although not exclusively, seen in obese women of childbearing age. Patients with idiopathic intracranial hypertension commonly present with a headache, transient visual obscurations, and intracranial noises with some cranial nerves occasionally involved, most commonly CN VI. We report idiopathic intracranial hypertension presenting with isolated complete unilateral facial nerve palsy, as the sole cranial nerve involved, which is a presentation rarely reported in the literature. A 40-year-old Hispanic woman with a history of obesity and hypertension presented to our emergency department complaining of bifrontal headache for 3 days associated with nausea, vomiting, transient visual disturbances, and a picture of right-sided cranial nerve VII palsy. Her neurologic examination including other cranial nerves was otherwise normal, but a fundus examination revealed bilateral grade II papilledema. Imaging studies ruled out structural and obstructive lesions as possible causes of her symptoms and lumber puncture results were unremarkable except for an increased opening pressure. She was then started on prednisone and acetazolamide. Two days later, she reported a dramatic improvement in both headache and facial nerve palsy. Idiopathic intracranial hypertension should be suspected in obese young women presenting with headache and transient visual complaints and some cranial nerve abnormalities. Idiopathic intracranial hypertension is a diagnosis of exclusion and imaging studies should always be performed to rule out other structural and obstructive lesions. In this case report, we aimed to draw attention to the possibility of idiopathic intracranial hypertension presenting with unilateral cranial nerve VII palsy as the only cranial nerve involved, which needs a high index of suspicion by clinicians. The mechanisms of cranial nerve VII palsy in idiopathic intracranial hypertension are not well understood and prompt further investigation.

Clinical trials are conducted to evaluate the efficacy of new treatments. Clinical trials involving multiple treatments utilize the randomization of treatment assignments to enable the evaluation of treatment efficacies in an unbiased manner. Such evaluation is performed in post hoc studies that usually use supervised-learning methods that rely on large amounts of data collected in a randomized fashion. That approach often proves to be suboptimal in that some participants may suffer and even die as a result of having not received the most appropriate treatments during the trial. Reinforcement-learning methods improve the situation by making it possible to learn the treatment efficacies dynamically during the course of the trial, and to adapt treatment assignments accordingly. Recent efforts using multi-arm bandits, a type of reinforcement-learning method, have focused on maximizing clinical outcomes for a population that was assumed to be homogeneous. However, those approaches have failed to account for the variability among participants that is becoming increasingly evident as a result of recent clinical-trial-based studies. We present a contextual-bandit-based online treatment optimization algorithm that, in choosing treatments for new participants in the study, takes into account not only the maximization of the clinical outcomes as well as the patient characteristics. We evaluated our algorithm using a real clinical trial dataset from the International Stroke Trial. We simulated the online setting by sequentially going through the data of each participant admitted to the trial. Two bandits (one for each context) were created, with four choices of treatments. For a new participant in the trial, depending on the context, one of the bandits was selected. Then, we took three different approaches to choose a treatment: (a) a random choice (i.e., the strategy currently used in clinical trial settings), (b) a Thompson sampling-based approach, and (c) a UCB-based approach. Success probabilities of each context were calculated separately by considering the participants with the same context. Those estimated outcomes were used to update the prior distributions within the bandit corresponding to the context of each participant. We repeated that process through the end of the trial and recorded the outcomes and the chosen treatments for each approach. We also evaluated a context-free multi-arm-bandit-based approach, using the same dataset, to showcase the benefits of our approach. In the context-free case, we calculated the success probabilities for the Bernoulli sampler using the whole clinical trial dataset in a context-independent manner. The results of our retrospective analysis indicate that the proposed approach performs significantly better than either a random assignment of treatments (the current gold standard) or a multi-arm-bandit-based approach, providing substantial gains in the percentage of participants who are assigned the most suitable treatments. The contextual-bandit and multi-arm bandit approaches provide 72.63% and 64.34% gains, respectively, compared to a random assignment.