Neuronal sequences in population bursts encode information in human cortex.

Neural coding has traditionally been examined through changes in firing rates and latencies in response to different stimuli1-5. However, populations of neurons can also exhibit transient bursts of spiking activity, wherein neurons fire in a specific temporal order or sequence6-8. The human brain may utilize these neuronal sequences within population bursts to efficiently represent information9-12, thereby complementing the well-known neural code based on spike rate or latency. Here we examined this possibility by recording the spiking activity of populations of single units in the human anterior temporal lobe as eight participants performed a visual categorization task. We find that population spiking activity organizes into bursts during the task. The temporal order of spiking across the activated units within each burst varies across stimulus categories, creating unique stereotypical sequences for individual categories as well as for individual exemplars within a category. The information conveyed by the temporal order of spiking activity is separable from and complements the information conveyed by the units' spike rates or latencies following stimulus onset. Collectively, our data provide evidence that the human brain contains a complementary code based on the neuronal sequence within bursts of population spiking to represent information.

Neuronal Spiking Responses to Direct Electrical Microstimulation in the Human Cortex.

Microstimulation can modulate the activity of individual neurons to affect behavior, but the effects of stimulation on neuronal spiking are complex and remain poorly understood. This is especially challenging in the human brain where the response properties of individual neurons are sparse and heterogeneous. Here we use microelectrode arrays in the human anterior temporal lobe in 6 participants (3 female) to examine the spiking responses of individual neurons to microstimulation delivered through multiple distinct stimulation sites. We demonstrate that individual neurons can be driven with excitation or inhibition using different stimulation sites, which suggests an approach for providing direct control of spiking activity at the single-neuron level. Spiking responses are inhibitory in neurons that are close to the site of stimulation, while excitatory responses are more spatially distributed. Together, our data demonstrate that spiking responses of individual neurons can be reliably identified and manipulated in the human cortex.SIGNIFICANCE STATEMENT One of the major limitations in our ability to interface directly with the human brain is that the effects of stimulation on the activity of individual neurons remain poorly understood. This study examines the spiking responses of neurons in the human temporal cortex in response to pulses of microstimulation. This study finds that individual neurons can either be excited or inhibited depending on the site of stimulation. These data suggest an approach for modulating the spiking activity of individual neurons in the human brain.

Persistent GDNF Expression 45 Months after Putaminal Infusion of AAV2-GDNF in a Patient with Parkinson's Disease.

OBJECTIVE: Gene therapy by convection-enhanced delivery of type 2 adeno-associated virus-glial cell derived neurotrophic factor (AAV2-GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). METHODS: A 63-year-old man with advanced PD received AAV2-GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F-Fluorodopa (18F-FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2-GDNF infusion. RESULTS: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. CONCLUSION: After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD.

Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

Interictal discharges in the human brain are travelling waves arising from an epileptogenic source.

While seizure activity may be electrographically widespread, increasing evidence has suggested that ictal discharges may in fact represent travelling waves propagated from a focal seizure source. Interictal epileptiform discharges (IEDs) are an electrographic manifestation of excessive hypersynchronization of cortical activity that occur between seizures and are considered a marker of potentially epileptogenic tissue. The precise relationship between brain regions demonstrating IEDs and those involved in seizure onset, however, remains poorly understood. Here, we hypothesize that IEDs likewise reflect the receipt of travelling waves propagated from the same regions which give rise to seizures. Forty patients from our institution who underwent invasive monitoring for epilepsy, proceeded to surgery and had at least one year of follow-up were included in our study. Interictal epileptiform discharges were detected using custom software, validated by a clinical epileptologist. We show that IEDs reach electrodes in sequences with a consistent temporal ordering, and this ordering matches the timing of receipt of ictal discharges, suggesting that both types of discharges spread as travelling waves. We use a novel approach for localization of ictal discharges, in which time differences of discharge receipt at nearby electrodes are used to compute source location; similar algorithms have been used in acoustics and geophysics. We find that interictal discharges co-localize with ictal discharges. Moreover, interictal discharges tend to localize to the resection territory in patients with good surgical outcome and outside of the resection territory in patients with poor outcome. The seizure source may originate at, and also travel to, spatially distinct IED foci. Our data provide evidence that interictal discharges may represent travelling waves of pathological activity that are similar to their ictal counterparts, and that both ictal and interictal discharges emerge from common epileptogenic brain regions. Our findings have important clinical implications, as they suggest that seizure source localizations may be derived from interictal discharges, which are much more frequent than seizures.

Identifying sources of human interictal discharges with travelling wave and white matter propagation.

Interictal epileptiform discharges have been shown to propagate from focal epileptogenic sources as travelling waves or through more rapid white matter conduction. We hypothesize that both modes of propagation are necessary to explain interictal discharge timing delays. We propose a method that, for the first time, incorporates both propagation modes to identify unique potential sources of interictal activity. We retrospectively analysed 38 focal epilepsy patients who underwent intracranial EEG recordings and diffusion-weighted imaging for epilepsy surgery evaluation. Interictal discharges were detected and localized to the most likely source based on relative delays in time of arrival across electrodes, incorporating travelling waves and white matter propagation. We assessed the influence of white matter propagation on distance of spread, timing and clinical interpretation of interictal activity. To evaluate accuracy, we compared our source localization results to earliest spiking regions to predict seizure outcomes. White matter propagation helps to explain the timing delays observed in interictal discharge sequences, underlying rapid and distant propagation. Sources identified based on differences in time of receipt of interictal discharges are often distinct from the leading electrode location. Receipt of activity propagating rapidly via white matter can occur earlier than more local activity propagating via slower cortical travelling waves. In our cohort, our source localization approach was more accurate in predicting seizure outcomes than the leading electrode location. Inclusion of white matter in addition to travelling wave propagation in our model of discharge spread did not improve overall accuracy but allowed for identification of unique and at times distant potential sources of activity, particularly in patients with persistent postoperative seizures. Since distant white matter propagation can occur more rapidly than local travelling wave propagation, combined modes of propagation within an interictal discharge sequence can decouple the commonly assumed relationship between spike timing and distance from the source. Our findings thus highlight the clinical importance of recognizing the presence of dual modes of propagation during interictal discharges, as this may be a cause of clinical mislocalization.

Source-sink connectivity: a novel interictal EEG marker for seizure localization.

Over 15 million epilepsy patients worldwide have drug-resistant epilepsy. Successful surgery is a standard of care treatment but can only be achieved through complete resection or disconnection of the epileptogenic zone, the brain region(s) where seizures originate. Surgical success rates vary between 20% and 80%, because no clinically validated biological markers of the epileptogenic zone exist. Localizing the epileptogenic zone is a costly and time-consuming process, which often requires days to weeks of intracranial EEG (iEEG) monitoring. Clinicians visually inspect iEEG data to identify abnormal activity on individual channels occurring immediately before seizures or spikes that occur interictally (i.e. between seizures). In the end, the clinical standard mainly relies on a small proportion of the iEEG data captured to assist in epileptogenic zone localization (minutes of seizure data versus days of recordings), missing opportunities to leverage these largely ignored interictal data to better diagnose and treat patients. IEEG offers a unique opportunity to observe epileptic cortical network dynamics but waiting for seizures increases patient risks associated with invasive monitoring. In this study, we aimed to leverage interictal iEEG data by developing a new network-based interictal iEEG marker of the epileptogenic zone. We hypothesized that when a patient is not clinically seizing, it is because the epileptogenic zone is inhibited by other regions. We developed an algorithm that identifies two groups of nodes from the interictal iEEG network: those that are continuously inhibiting a set of neighbouring nodes ('sources') and the inhibited nodes themselves ('sinks'). Specifically, patient-specific dynamical network models were estimated from minutes of iEEG and their connectivity properties revealed top sources and sinks in the network, with each node being quantified by source-sink metrics. We validated the algorithm in a retrospective analysis of 65 patients. The source-sink metrics identified epileptogenic regions with 73% accuracy and clinicians agreed with the algorithm in 93% of seizure-free patients. The algorithm was further validated by using the metrics of the annotated epileptogenic zone to predict surgical outcomes. The source-sink metrics predicted outcomes with an accuracy of 79% compared to an accuracy of 43% for clinicians' predictions (surgical success rate of this dataset). In failed outcomes, we identified brain regions with high metrics that were untreated. When compared with high frequency oscillations, the most commonly proposed interictal iEEG feature for epileptogenic zone localization, source-sink metrics outperformed in predictive power (by a factor of 1.2), suggesting they may be an interictal iEEG fingerprint of the epileptogenic zone.

Travelling waves reveal a dynamic seizure source in human focal epilepsy.

Treatment of patients with drug-resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured by intracranial EEG has traditionally been interpreted to suggest that the underlying cortex is actively involved in seizures. Here, we hypothesize that such activity instead reflects propagated activity from a relatively focal seizure source, even during later time points when ictal activity is more widespread. We used the time differences observed between ictal discharges in adjacent electrodes to estimate the location of the hypothesized focal source and demonstrated that the seizure source, localized in this manner, closely matches the clinically and neurophysiologically determined brain region giving rise to seizures. Moreover, we determined this focal source to be a dynamic entity that moves and evolves over the time course of a seizure. Our results offer an interpretation of ictal activity observed by intracranial EEG that challenges the traditional conceptualization of the seizure source.

Dual processes in memory: Evidence from memory of time-of-occurrence of events.

Bastin et al. present a framework that draws heavily on existing ideas of dual processes in memory in order to make predictions about memory deficits in clinical populations. It has been difficult to find behavioral evidence for multiple memory processes but we offer some evidence for dual processes in a related domain: memory for the time-of-occurrence of events.

Signal Complexity of Human Intracranial EEG Tracks Successful Associative-Memory Formation across Individuals.

Memory performance is highly variable among individuals. Most studies examining human memory, however, have largely focused on the neural correlates of successful memory formation within individuals, rather than the differences among them. As such, what gives rise to this variability is poorly understood. Here, we examined intracranial EEG (iEEG) recordings captured from 43 participants (23 male) implanted with subdural electrodes for seizure monitoring as they performed a paired-associates verbal memory task. We identified three separate but related signatures of neural activity that tracked differences in successful memory formation across individuals. High-performing individuals consistently exhibited less broadband power, flatter power spectral density slopes, and greater complexity in their iEEG signals. Furthermore, within individuals across three separate time scales ranging from seconds to days, successful recall was positively associated with these same metrics. Our data therefore suggest that memory ability across individuals can be indexed by increased neural signal complexity.SIGNIFICANCE STATEMENT We show that participants whose intracranial EEG exhibits less low-frequency power, flatter power spectrums, and greater sample entropy overall are better able to memorize associations, and that the same metrics track fluctuations in memory performance across time within individuals. These metrics together signify greater neural signal complexity, which may index the brain's ability to flexibly engage with information and generate separable memory representations. Critically, the current set of results provides a unique window into the neural markers of individual differences in memory performance, which have hitherto been underexplored.

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

OBJECTIVE: To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS: Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 µL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002). CONCLUSION: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [18 F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.

Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein.

OBJECTIVES: Neuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology. METHODS: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video-electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1-weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral - contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (VT /fP ) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age-matched volunteers (5 high-affinity and 6 medium affinity) who had metabolite-corrected arterial input functions measured. RESULTS: Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured. SIGNIFICANCE: Our study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability.

Functional MRI and direct cortical stimulation: Prediction of postoperative language decline.

OBJECTIVE: To assess the ability of functional MRI (fMRI) to predict postoperative language decline compared to direct cortical stimulation (DCS) in epilepsy surgery patients. METHODS: In this prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline. RESULTS: Four of 17 patients (12 female; median [range] age, 43 [23-59] years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline. SIGNIFICANCE: Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone.

fMRI prediction of naming change after adult temporal lobe epilepsy surgery: Activation matters.

OBJECTIVE: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability. METHOD: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance. RESULTS: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r2  = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality). SIGNIFICANCE: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.

Cognitive control involves theta power within trials and beta power across trials in the prefrontal-subthalamic network.

There is increasing evidence that the medial prefrontal cortex participates in conflict and feedback monitoring while the subthalamic nucleus adjusts actions. Yet how these two structures coordinate their activity during cognitive control remains poorly understood. We recorded from the human prefrontal cortex and the subthalamic nucleus simultaneously while participants (n = 22) performed a novel task involving high conflict trials, complete response inhibition trials, and trial-to-trial behavioural adaptations to conflict and errors. Overall, we found that within-trial adaptions to both conflict and complete response inhibition involved changes in the theta band while across-trial behavioural adaptations to both conflict and errors involved changes in the beta band (P < 0.05). Yet the role each region's theta and beta oscillations played during the task differed significantly between the two sites. Trials that involved either within-trial conflict or complete response inhibition were associated with increased theta phase synchrony between the medial prefrontal cortex and the subthalamic nucleus (P < 0.05). Despite increased synchrony, however, increases in prefrontal theta power were associated with response inhibition, while increases in subthalamic theta power were associated with response execution (P < 0.05). In the beta band, post-response increases in prefrontal beta power were suppressed when the completed trial contained either conflict or an erroneous response (P < 0.05). Subthalamic beta power, on the other hand, was only modified during the subsequent trial that followed a conflict or error trial. Notably, these adaptation trials exhibited slower response times (P < 0.05), suggesting that both brain regions contribute to across-trial adaptations but do so at different stages of the adaptation process. Taken together, our data shed light on the mechanisms underlying within-trial and across-trial cognitive control and how disruption of this network can negatively impact cognition. More broadly, however, our data also demonstrate that the specific role of a brain region, rather than the frequency being utilized, governs the behavioural correlates of oscillatory activity.

Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex.

Converging evidence suggests that reinstatement of neural activity underlies our ability to successfully retrieve memories. However, the temporal dynamics of reinstatement in the human cortex remain poorly understood. One possibility is that neural activity during memory retrieval, like replay of spiking neurons in the hippocampus, occurs at a faster timescale than during encoding. We tested this hypothesis in 34 participants who performed a verbal episodic memory task while we recorded high gamma (62-100 Hz) activity from subdural electrodes implanted for seizure monitoring. We show that reinstatement of distributed patterns of high gamma activity occurs faster than during encoding. Using a time-warping algorithm, we quantify the timescale of the reinstatement and identify brain regions that show significant timescale differences between encoding and retrieval. Our data suggest that temporally compressed reinstatement of cortical activity is a feature of cued memory retrieval.SIGNIFICANCE STATEMENT We show that cued memory retrieval reinstates neural activity on a faster timescale than was present during encoding. Our data therefore provide a link between reinstatement of neural activity in the cortex and spontaneous replay of cortical and hippocampal spiking activity, which also exhibits temporal compression, and suggest that temporal compression may be a universal feature of memory retrieval.

Surface based electrode localization and standardized regions of interest for intracranial EEG.

Intracranial recordings captured from subdural electrodes in patients with drug resistant epilepsy offer clinicians and researchers a powerful tool for examining neural activity in the human brain with high spatial and temporal precision. There are two major challenges, however, to interpreting these signals both within and across individuals. Anatomical distortions following implantation make accurately identifying the electrode locations difficult. In addition, because each implant involves a unique configuration, comparing neural activity across individuals in a standardized manner has been limited to broad anatomical regions such as cortical lobes or gyri. We address these challenges here by introducing a semi-automated method for localizing subdural electrode contacts to the unique surface anatomy of each individual, and by using a surface-based grid of regions of interest (ROIs) to aggregate electrode data from similar anatomical locations across individuals. Our localization algorithm, which uses only a postoperative CT and preoperative MRI, builds upon previous spring-based optimization approaches by introducing manually identified anchor points directly on the brain surface to constrain the final electrode locations. This algorithm yields an accuracy of 2 mm. Our surface-based ROI approach involves choosing a flexible number of ROIs with different spatial resolutions. ROIs are registered across individuals to represent identical anatomical locations while accounting for the unique curvature of each brain surface. This ROI based approach therefore enables group level statistical testing from spatially precise anatomical regions.

Language functional MRI and direct cortical stimulation in epilepsy preoperative planning.

OBJECTIVE: Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for presurgical language mapping are functional MRI (fMRI) and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to help optimize noninvasive language localization and assess its validity. METHODS: We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed four language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether language positive electrode pairs intersected with significant fMRI activity clusters for language tasks. RESULTS: Sensitivity and specificity depended on electrode region of interest radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description decision task provided the best trade-off between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of excluding eloquent language processing. INTERPRETATION: Language fMRI is an effective tool for determining language lateralization before electrode implantation and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas by DCS. Ann Neurol 2017;81:526-537.

Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders.

OBJECTIVE: Refractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive-compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016. DESIGN: Here we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses. CONCLUSION: Interest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.