Clinical Theranostics in Recurrent Gliomas: A Review.

Gliomas represent the most commonly occurring tumors in the central nervous system and account for approximately 80% of all malignant primary brain tumors. With a high malignancy and recurrence risk, the prognosis of high-grade gliomas is poor, with a mean survival time of 12-18 months. While contrast-enhanced MRI serves as the standard diagnostic imaging modality for gliomas, it faces limitations in the evaluation of recurrent gliomas, failing to distinguish between treatment-related changes and tumor progression, and offers no direct therapeutic options. Recent advances in imaging modalities have attempted to address some of these limitations, including positron emission tomography (PET), which has demonstrated success in delineating tumor margins and guiding the treatment of recurrent gliomas. Additionally, with the advent of theranostics in nuclear medicine, PET tracers, when combined with therapeutic agents, have also evolved beyond a purely diagnostic modality, serving both diagnostic and therapeutic roles. This review will discuss the growing involvement of theranostics in diagnosing and treating recurrent gliomas and address the associated impact on quality of life and functional recovery.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Noradrenaline tracks emotional modulation of attention in human amygdala.

The noradrenaline (NA) system is one of the brain's major neuromodulatory systems; it originates in a small midbrain nucleus, the locus coeruleus (LC), and projects widely throughout the brain.1,2 The LC-NA system is believed to regulate arousal and attention3,4 and is a pharmacological target in multiple clinical conditions.5,6,7 Yet our understanding of its role in health and disease has been impeded by a lack of direct recordings in humans. Here, we address this problem by showing that electrochemical estimates of sub-second NA dynamics can be obtained using clinical depth electrodes implanted for epilepsy monitoring. We made these recordings in the amygdala, an evolutionarily ancient structure that supports emotional processing8,9 and receives dense LC-NA projections,10 while patients (n = 3) performed a visual affective oddball task. The task was designed to induce different cognitive states, with the oddball stimuli involving emotionally evocative images,11 which varied in terms of arousal (low versus high) and valence (negative versus positive). Consistent with theory, the NA estimates tracked the emotional modulation of attention, with a stronger oddball response in a high-arousal state. Parallel estimates of pupil dilation, a common behavioral proxy for LC-NA activity,12 supported a hypothesis that pupil-NA coupling changes with cognitive state,13,14 with the pupil and NA estimates being positively correlated for oddball stimuli in a high-arousal but not a low-arousal state. Our study provides proof of concept that neuromodulator monitoring is now possible using depth electrodes in standard clinical use.

Co-occurrence of dural arteriovenous fistula and meningioma: A rare case and systematic review.

Background: The coexistence of meningioma and dural arteriovenous fistula (dAVF) is a rare, but highly complex condition. Various pathophysiological mechanisms underlie intracranial meningiomas with continuous or distant dAVFs. We describe a case of coexisting meningioma and dAVF with a systematic review of the literature. Result: Including the present case, there are 21 reported cases of coexisting intracranial dAVF and meningioma. The patients' ages ranged from 23 to 76 years, with a mean age of 61 years. The most common presenting symptom was headache. The dAVFs were commonly located at the transverse-sigmoid sinus (43%) and superior sagittal sinus (24%). The most common meningioma locations were the tentorium and parietal convexity. In 76% of the cases, the meningioma occluded the sinus. The most common dAVF treatment was transcatheter arterial embolization, followed by tumor resection (52%). Among the 20 cases with available outcome data, 90% reported favorable outcomes. Conclusion: This report highlights some of the features of coexisting dAVF and meningioma and presents a systematic review of other reports on this phenomenon. Through an in-depth analysis of the literature, we highlight some of the leading theories regarding the causes of concomitant dAVF and meningiomas. Our report supports one of the leading theories that impaired venous return, whether through the occlusion of sinuses or sinus manipulation during surgery, plays a role in the development of dAVF. Further understanding may help guide future clinical decision-making and surgical planning.

Spinal Intradural Arachnoid Cysts in Adults: An Institutional Experience and Literature Review.

BACKGROUND: Adult spinal intradural arachnoid cysts are rare pathologic entities with an unclear etiopathogenesis. These lesions can be dichotomized into primary (idiopathic) or secondary (related to inflammation, intradural surgery, or trauma) etiologies. Limited series have depicted optimal management strategies and clinical outcomes. OBJECTIVE: To illustrate our experience with spinal intradural arachnoid cysts and to present a literature review of surgically treated cysts to elucidate the clinical and anatomic differences between etiologies. METHODS: Institutional review revealed 29 patients. Various data were extracted from the medical record. Initial and follow-up symptomatologies of the surgical cohort were compared. The literature review included case series describing cysts managed surgically. RESULTS: From patients treated surgically at our institution (22), there was a significant reduction in thoracic back pain postoperatively ( P = .034). A literature review yielded 271 additional cases. Overall, primary and secondary lesions accounted for 254 and 39 cases, respectively. Cysts of secondary origin were more likely localized ventral to the spinal cord ( P = .013). The rate of symptomatic improvement after surgical intervention for primary cysts was more than double than that of secondary cysts ( P < .001). Compared with primary etiologies, the rates of radiographic progression ( P = .032) and repeat surgery ( P = .041) were each more than double for secondary cysts. CONCLUSION: Surgical intervention for spinal intradural arachnoid cysts improves thoracic back pain. The literature supports surgical intervention for symptomatic primary spinal intradural arachnoid cysts with improved clinical outcomes. Surgery should be cautiously considered for secondary cysts given worse outcomes.

Supratentorial cortical ependymoma: A systematic literature review and case illustration.

Cortical ependymomas are currently not considered a subgroup of supratentorial ependymomas; however, there is a growing body of literature investigating the natural history of these lesions compared to supratentorial ependymomas. We performed a systematic literature review of cortical ependymomas with a focus on the natural history, clinical characteristics, and clinical outcomes of these lesions as compared to supratentorial ependymomas. Our search revealed 153 unique cases of cortical ependymomas. The mean age on presentation was 21.2 years. Males and females comprised 58.8% (90/153) and 41.2% (63/153) of cases, respectively. The most common presenting symptom was seizure activity occurring in 44.4% of the cohort (68/153). The recently recognized C11orf95-RELA fusion was identified in 13.7% of the cohort (21/153) and 95.5% of cases (21/22) reporting molecular characterization. World Health Organization grades 2 and 3 were reported in 52.3% (79/151) and 47.7% (72/151) of cases, respectively. The frontal lobe was involved in the majority of cases (54.9%, 84/153). Gross total resection was achieved in 80.4% of cases (123/153). Tumor recurrence was identified in 27.7% of cases (39/141). Mean clinical follow-up was 41.3 months. Mean overall survival of patients who expired was 27.4 months whereas mean progression-free survival was 15.0 months. Comparatively, cortical ependymomas with C11orf95-RELA fusions and supratentorial ependymomas with C11orf95 RELA fusions exhibited differing clinical outcomes. Further studies with larger sample sizes are necessary to investigate the significance of RELA fusions on survival in cortical ependymomas and to determine whether cortical ependymomas with C11orf95-RELA fusions should be classified as a distinct entity.

Monocyte Count on Admission Is Predictive of Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage.

The authors sought to evaluate whether immunologic counts on admission were associated with shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage. A retrospective analysis of 143 consecutive patients with aneurysmal subarachnoid hemorrhage over a 9-year period was performed. A stepwise algorithm was followed for external ventricular drain weaning and determining the necessity of shunt placement. Data were compared between patients with and without shunt-dependent hydrocephalus. Overall, 11.19% of the cohort developed shunt-dependent hydrocephalus. On multivariate logistic regression analysis, acute hydrocephalus (OR: 61.027, 95% CI: 3.890-957.327; p = 0.003) and monocyte count on admission (OR: 3.362, 95% CI: 1.024-11.037; p = 0.046) were found to be independent predictors for shunt dependence. Receiver operating characteristic curve analysis for the prediction of shunt-dependent hydrocephalus confirmed that monocyte count exhibited an acceptable area under the curve (AUC = 0.737, 95% CI: 0.601-0.872; p < 0.001). The best predictive cutoff value to discriminate between successful external ventricular drain weaning and shunt-dependent hydrocephalus was identified as a monocyte count ≥0.80 × 103/uL at initial presentation. These preliminary data demonstrate that a monocyte count ≥0.80 × 103/uL at admission predicts shunt-dependent hydrocephalus in patients with aneurysmal subarachnoid hemorrhage; however, further large-scale prospective trials and validation are necessary to confirm these findings.

Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors.

Introduction: Positron emission tomography (PET) imaging with prostate-specific membrane antigen- (PSMA-) binding tracers has been found incidentally to demonstrate uptake in CNS tumors. Following the encouraging findings of several such case reports, there is a growing interest in the potential application of PSMA-targeted PET imaging for diagnostics, theranostics, and monitoring of CNS tumors. This is a systematic literature review on PSMA-binding tracers in CNS tumors. Methods: A PubMed search was conducted, including preclinical and clinical reports. One hundred and twelve records were identified, and after screening, 56 were included in the final report. Results: Tissue studies demonstrated PSMA expression in tumor vascular endothelial cells, without expression in normal brain tissue, though the extent and intensity of staining varied by anti-PSMA antibody and methodology. Most included studies reported on gliomas, which showed strong PSMA ligand uptake and more favorable tumor to background ratios than other PET tracers. There are also case reports demonstrating PSMA ligand uptake in prostate cancer brain metastases, nonprostate cancer brain metastases, and meningiomas. We also review the properties of the various PSMA-binding radiotracers available. Therapeutic and theranostic applications of PSMA-binding tracers have been studied, including labeled alpha- and beta-ray emitting isotopes, as well as PSMA targeting in directing MRI-guided focused ultrasound. Conclusions: There is a potential application for PSMA-targeted PET in neuro-oncology as a combination of diagnostic and therapeutic use, as a theranostic modality for managing CNS tumors. Further research is needed regarding the mechanism(s) of PSMA expression in CNS tumors and its differential performance by tumor type.

Successful Treatment of a Balamuthia mandrillaris Cerebral Abscess in a Pediatric Patient With Complete Surgical Resection and Antimicrobial Therapy.

Cerebral amebic encephalitis due to Balamuthia mandrillaris is a rare yet typically fatal disease. As such, identification of the clinical characteristics, appropriate diagnostic workup and commencement of treatment is frequently delayed. Here, we present a case of a 4-year-old male with a B. mandrillaris cerebral abscess successfully treated with expedited neurosurgical resection and broad-spectrum antimicrobial therapy.

Neutrophil Count on Admission Predicts Acute Symptomatic Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To investigate the association between immunologic counts on admission and acute symptomatic hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 143 consecutive patients with aSAH. Patient demographics, clinical parameters, laboratory values, and radiographic imaging were obtained. Univariate and multivariate logistic regression analyses were performed to investigate parameters independently associated with acute symptomatic hydrocephalus. Receiver operating characteristic (ROC) curve analysis determined the best threshold value of neutrophil count to differentiate patients with and without hydrocephalus. RESULTS: Overall, acute symptomatic hydrocephalus developed in 39.16% of patients. In an adjusted multivariate logistic regression model, Hunt and Hess grade 4-5 (odds ratio [OR]: 16.052, 95% confidence interval [CI]: 1.188-216.983; P = 0.037), modified Fisher score 3-4 (OR: 10.107, 95% CI: 1.715-59.572; P = 0.011), intraventricular hemorrhage (OR: 4.578, 95% CI: 1.417-14.788; P = 0.011), neutrophil count (OR: 1.183, 95% CI: 1.033-1.354; P = 0.015), and prior ischemic stroke (OR: 7.003, 95% CI: 1.293-37.929; P = 0.024) were significantly associated with hydrocephalus. ROC analysis for neutrophil count confirmed an acceptable area under the curve (AUC 0.780, 95% CI: 0.701-0.859; P < 0.001). The best threshold value of neutrophil count to predict hydrocephalus was ≥9.80 × 103/mL. Overall, 81.25% of patients who developed shunt dependence had a neutrophil count ≥9.80 × 103/mL on admission (P = 0.003). CONCLUSIONS: Neutrophil count ≥9.80 × 103/mL on admission predicts acute symptomatic hydrocephalus after aSAH in an adjusted multivariate logistic regression model. Moreover, shunt dependence was associated with higher neutrophil counts.

Pineal Gland Metastasis From Poorly Differentiated Carcinoma of Unknown Primary Origin.

Pineal metastasis is an exceedingly rare finding in patients with systemic malignancies. Such lesions are typically the manifestation of a primary lung cancer; nonetheless, a variety of malignancies have been reported to disseminate to the pineal gland including gastrointestinal, endocrine, and skin cancers, among others. However, to our knowledge, pineal gland metastasis without a primary origin has yet to be described. Carcinoma of unknown primary origin is a heterogeneous group of cancers characterized by the presence of metastatic disease without an identifiable primary tumor on metastatic workup. Here, we present a case of a 65-year-old male found to have a heterogeneously enhancing lesion of the pineal gland as well as an enhancing lesion of the left cerebellar hemisphere. Comprehensive metastatic workup demonstrated multifocal metastatic adenopathy without an identifiable primary lesion. Stereotactic biopsy of the pineal lesion revealed poorly differentiated carcinoma with an immunophenotype most consistent with gastrointestinal origin. To our knowledge, this is the first case to describe a pineal gland metastasis without a primary origin. We discuss the relevant literature on pineal gland metastases as well as carcinoma of unknown primary origin.

Idiopathic fourth ventricular outlet obstruction misdiagnosed as normal pressure hydrocephalus: A cautionary case.

BACKGROUND: Fourth ventricular outlet obstruction is an infrequent but well-established cause of tetraventricular hydrocephalus characterized by marked dilatation of the ventricular system with ballooning of the foramina of Monro, Magendie, and Luschka. Multiple processes including inflammation, infection, hemorrhage, neoplasms, or congenital malformations are known to cause this pathological obstruction. However, true idiopathic fourth ventricular outlet obstruction is a rare phenomenon with only a limited number of cases reported in the literature. CASE DESCRIPTION: A 61-year-old female presented with several months of unsteady gait, intermittent headaches, confusion, and episodes of urinary incontinence. Conventional magnetic resonance imaging demonstrated tetraventricular hydrocephalus without transependymal flow, but with ventral displacement of the brainstem and dorsal displacement of the cerebellum without an obvious obstructive lesion on pre- or post-contrast imaging prompting a diagnosis of normal pressure hydrocephalus. However, constructive interference in steady state (CISS) and half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences followed by fluoroscopic dynamic cisternography suggested encystment of the fourth ventricle with thin margins of arachnoid membrane extending through the foramina of Luschka bilaterally into the pontocerebellar cistern. Operative intervention was pursued with resection of an identified arachnoid web. Postoperative imaging demonstrated marked reduction in the size of ventricular system, especially of the fourth ventricle. The patient's symptomatology resolved a few days after the procedure. CONCLUSION: Here, we describe an idiopathic case initially misdiagnosed as normal pressure hydrocephalus. The present case emphasizes the necessity of CISS sequences and fluoroscopic dynamic cisternography for suspected cases of fourth ventricular outlet obstruction as these diagnostic tests may guide surgical management and lead to superior patient outcomes.

Hippocampal CA1 and CA3 neural recording in the human brain: validation of depth electrode placement through high-resolution imaging and electrophysiology.

OBJECTIVE: Intracranial human brain recordings typically utilize recording systems that do not distinguish individual neuron action potentials. In such cases, individual neurons are not identified by location within functional circuits. In this paper, verified localization of singly recorded hippocampal neurons within the CA3 and CA1 cell fields is demonstrated. METHODS: Macro-micro depth electrodes were implanted in 23 human patients undergoing invasive monitoring for identification of epileptic seizure foci. Individual neurons were isolated and identified via extracellular action potential waveforms recorded via macro-micro depth electrodes localized within the hippocampus. A morphometric survey was performed using 3T MRI scans of hippocampi from the 23 implanted patients, as well as 46 normal (i.e., nonepileptic) patients and 26 patients with a history of epilepsy but no history of depth electrode placement, which provided average dimensions of the hippocampus along typical implantation tracks. Localization within CA3 and CA1 cell fields was tentatively assigned on the basis of recording electrode site, stereotactic positioning of the depth electrode in comparison with the morphometric survey, and postsurgical MRI. Cells were selected as candidate CA3 and CA1 principal neurons on the basis of waveform and firing rate characteristics and confirmed within the CA3-to-CA1 neural projection pathways via measures of functional connectivity. RESULTS: Cross-correlation analysis confirmed that nearly 80% of putative CA3-to-CA1 cell pairs exhibited positive correlations compatible with feed-forward connection between the cells, while only 2.6% exhibited feedback (inverse) connectivity. Even though synchronous and long-latency correlations were excluded, feed-forward correlation between CA3-CA1 pairs was identified in 1071 (26%) of 4070 total pairs, which favorably compares to reports of 20%-25% feed-forward CA3-CA1 correlation noted in published animal studies. CONCLUSIONS: This study demonstrates the ability to record neurons in vivo from specified regions and subfields of the human brain. As brain-machine interface and neural prosthetic research continues to expand, it is necessary to be able to identify recording and stimulation sites within neural circuits of interest.

Factors affecting R01 grant funding among academic neurosurgeons over the last decade.

BACKGROUND: Recent studies have reported a gender and medical degree disparity for those receiving Research Project Grants in surgical specialties. The aim of the present study is to analyze factors among academics neurosurgeons that correlate to higher amounts of R01 grant monies awarded. MATERIALS AND METHODS: The National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results database was queried for neurosurgery funding between 2008 and 2018. Grant recipients were categorized among type of degree, secondary degree(s), professorship, gender, and h - index. Statistical analysis was performed. RESULTS: The National Institutes of Health awarded 480 R01 grants totaling $182,482,644 to 81 allopathic neurosurgeons between 2008 and 2018. No osteopathic neurosurgeons were awarded an R01 grant during this timeframe. There was a significant difference for type of professorship on the total awarded amount at the p < 0.05 level for the three types of professorship [F (2,78) = 4.85, p < 0.01)]. There was a significant difference for magnitude of h - index on total R01 monies (p < 0.00001). Males accounted for the majority of R01 monies (93.99%); however, no significant difference between average amount awarded and gender was identified (p = 0.86). A secondary degree was without significant difference for R01 amount awarded (p = 0.75). CONCLUSIONS: The present study establishes a medical degree disparity for academic neurosurgeons who receive an R01 grant. Statistically significant factors found to affect amount of R01 grant monies awarded were limited to type of professorship and magnitude of h - index.

N-butyl cyanoacrylate embolization of a traumatic pseudoaneurysm and arteriovenous fistula of the middle meningeal artery.

We report a case of combined traumatic pseudoaneurysm and arteriovenous fistula of the middle meningeal artery, which presented clinically 1 year after initial head trauma. A 39-year-old male presented with seizure activity after a closed head injury from a fall. He was hospitalized for multiple intraparenchymal hemorrhages and ultimately discharged 2 weeks later without neurologic deficits. One year later, he presented with a new right anterior temporal intraparenchymal hemorrhage after a syncopal event. Selective angiography of the right external carotid artery demonstrated a chronic appearing traumatic laceration of the proximal middle meningeal artery with a 6 × 10 mm pseudoaneurysm and a single fistula with venous varix draining into the lateral pterygoid veins. The pseudoaneurysm and arteriovenous fistula were successfully embolized with n-butyl cyanoacrylate.

Meckel Cave Epidermoid Cyst Presenting as Multiple Cranial Nerve Deficits Due to Indirect Tumoral Compression of the Cavernous Sinus: A Case Report and Literature Review.

BACKGROUND: Epidermoid cysts in Meckel cave are exceedingly rare. Since 1971, only 17 cases have been reported in the literature, with most patients presenting with trigeminal hypesthesia. However, outgrowth of these lesions from Meckel cave can rarely lead to compression of the proximate cavernous sinus and the neurovascular structures contained within. To date, 2 cases have reported a Meckel cave epidermoid cyst presenting clinically as an intracavernous cranial nerve palsy, presumably a clinical manifestation of cavernous sinus compression from the lesion. CASE DESCRIPTION: We describe a case involving a 51-year-old woman presenting with unilateral refractory trigeminal neuralgia, facial hypesthesia, abducens palsy, plus new-onset partial ptosis. Magnetic resonance imaging revealed a mass in the left Meckel cave that was T1 hypointense, T2 hyperintense, peripherally enhancing, and restricting diffusion. A stereotactic left subtemporal extradural approach was used to resect the lesion, which alleviated most of the patient's symptomatology except for minimal intermittent left-sided facial hypesthesia that remained at her 1-year postoperative visit. CONCLUSIONS: This is a unique report depicting an epidermoid cyst in the Meckel cave causing numerous cranial nerve deficits because of indirect tumoral compression of cranial nerves within the cavernous sinus.

A Novel Approach for Responsive Neural Stimulator Implantation With Infraclavicular Placement of the Internal Pulse Generator.

INTRODUCTION: The Responsive Neurostimulation System (RNS, Neuropace, Mountain View, California) has been proven to be effective at reducing seizures in patients with partial-onset epilepsy. The system incorporates a skull-mounted neurostimulator that requires a cranial incision for replacement. Although integral to the functioning of the system, in some circumstances, such as in the setting of infection, this can be disadvantageous. At present, there are no alternatives to cranial implantation of the RNS System. METHODS: We describe a novel procedure enabling implantation of the neurostimulator within the chest wall, using components from a peripheral nerve stimulator. In a patient who achieved complete seizure freedom with the use of the RNS System, distant site implantation provided a viable means of continuing therapy in a setting where device explantation would have otherwise been inevitable as a result of cranial infection. We present continuous electrocorticographic data recorded from the device documenting the performance of the system with the subclavicular neurostimulator. RESULTS: Band pass detection rates increased by 50%, while line length detection rates decreased by 50%. The number of detections decreased from 1046 to 846, with a resultant decrease in stimulations. Although there was some compromise of function due to the elevated noise floor, more than 2 yr following the procedure the patient remains free of seizures and infection. CONCLUSION: The salvage procedure we describe offered an alternative therapeutic option in a patient with a complicated cranial wound issue, using heterogeneous components with marginal compromises in device functionality and no sacrifice in patient outcome.

Designing Patient-Specific Optimal Neurostimulation Patterns for Seizure Suppression.

Neurostimulation is a promising therapy for abating epileptic seizures. However, it is extremely difficult to identify optimal stimulation patterns experimentally. In this study, human recordings are used to develop a functional 24 neuron network statistical model of hippocampal connectivity and dynamics. Spontaneous seizure-like activity is induced in silico in this reconstructed neuronal network. The network is then used as a testbed to design and validate a wide range of neurostimulation patterns. Commonly used periodic trains were not able to permanently abate seizures at any frequency. A simulated annealing global optimization algorithm was then used to identify an optimal stimulation pattern, which successfully abated 92% of seizures. Finally, in a fully responsive, or closed-loop, neurostimulation paradigm, the optimal stimulation successfully prevented the network from entering the seizure state. We propose that the framework presented here for algorithmically identifying patient-specific neurostimulation patterns can greatly increase the efficacy of neurostimulation devices for seizures.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall.

OBJECTIVE: We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient's own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. APPROACH: We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. MAIN RESULTS: MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. SIGNIFICANCE: These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.

The Protective Action Encoding of Serotonin Transients in the Human Brain.

The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of 14 brains of human patients with Parkinson's disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.