Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring.

OBJECTIVE: Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short-term recording in an epilepsy monitoring unit (EMU) with altered antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long-term ambulatory intracranial recordings captured by the NeuroPace RNS System. METHODS: Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84-day period. We analyzed all detections and long device-detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE-SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi-square analysis was used to compare subjects grouped by region of seizure onset. RESULTS: In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE-SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model. SIGNIFICANCE: Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure-onset zone, with implications for treatment and safety, including SUDEP.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography.

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

A comparison of Granger causality and coherency in fMRI-based analysis of the motor system.

The ability of functional MRI to acquire data from multiple brain areas has spurred developments not only in voxel-by-voxel analyses, but also in multivariate techniques critical to quantifying the interactions between brain areas. As the number of multivariate techniques multiplies, however, few studies in any modality have directly compared different connectivity measures, and fewer still have done so in the context of well-characterized neural systems. To focus specifically on the temporal dimension of interactions between brain regions, we compared Granger causality and coherency (Sun et al., 2004, 2005: Neuroimage 21:647-658, Neuroimage 28:227-237) in a well-studied motor system (1) to gain further insight into the convergent and divergent results expected from each technique, and (2) to investigate the leading and lagging influences between motor areas as subjects performed a motor task in which they produced different learned series of eight button presses. We found that these analyses gave convergent but not identical results: both techniques, for example, suggested an anterior-to-posterior temporal gradient of activity from supplemental motor area through premotor and motor cortices to the posterior parietal cortex, but the techniques were differentially sensitive to the coupling strength between areas. We also found practical reasons that might argue for the use of one technique over another in different experimental situations. Ultimately, the ideal approach to fMRI data analysis is likely to involve a complementary combination of methods, possibly including both Granger causality and coherency.

Transient and sustained brain activity during anticipatory visuospatial attention.

In this study, we determined whether the visuospatial attention network of frontal, parietal, and occipital cortex can be parsed into two different subsets of active regions associated with transient and sustained processes within the same cue-to-target delay period of an endogenously cued visuospatial attention task. We identified regions with early transient activity and regions with later sustained activity during the same trials using a general linear model analysis of event-related BOLD functional MRI data with two timecourse covariates for the same cue-to-target delay period. During the delay between the cue and target, we observed significant transient activity in right frontal eye field and right occipital-parietal junction, and significant sustained activity in right ventral intraparietal sulcus and right dorsolateral and anterior prefrontal cortex.

Changes in the electrocorticogram after implantation of intracranial electrodes in humans: The implant effect.

OBJECTIVE: Subacute and long-term electrocorticographic (ECoG) changes in ambulatory patients with depth and cortical strip electrodes were evaluated in order to determine the length of the implant effect. METHODS: ECoG records were assessed in patients with medically intractable epilepsy who had depth and/or strip leads implanted in order to be treated with brain-responsive stimulation. Changes in total spectral power, band-limited spectral power, and spike rate were assessed. RESULTS: 121 patients participating in trials of the RNS® System had a total of 93994 ECoG records analyzed. Significant changes in total spectral power occurred from the first to second months after implantation, involving 55% of all ECoG channels (68% of strip and 47% of depth lead channels). Significant, but less pronounced, changes continued over the 2nd to 5th post-implant months, after which total power became more stable. Similar patterns of changes were observed within frequency bands and spike rate. CONCLUSIONS: ECoG spectral power and spike rates are not stable in the first 5 months after implantation, presumably due to neurophysiological and electrode-tissue interface changes. SIGNIFICANCE: ECoG data collected in the first 5 months after implantation of intracranial electrodes may not be fully representative of chronic cortical electrophysiology.

Day-Night Patterns of Epileptiform Activity in 65 Patients With Long-Term Ambulatory Electrocorticography.

PURPOSE: To characterize cyclic day-night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures. METHODS: Epileptiform events as defined by the physician (also termed more generally as "epileptiform activity" or EA) were recorded in 65 patients with partial onset (also referred to as "focal onset") seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed. RESULTS: There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets. CONCLUSIONS: This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patient's unique circadian pattern of EA.

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

OBJECTIVE: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. METHODS: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. RESULTS: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). CONCLUSIONS: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Closed-loop neurostimulation: the clinical experience.

Neurostimulation is now an established therapy for the treatment of movement disorders, pain, and epilepsy. While most neurostimulation systems available today provide stimulation in an open-loop manner (i.e., therapy is delivered according to preprogrammed settings and is unaffected by changes in the patient's clinical symptoms or in the underlying disease), closed-loop neurostimulation systems, which modulate or adapt therapy in response to physiological changes, may provide more effective and efficient therapy. At present, few such systems exist owing to the complexities of designing and implementing implantable closed-loop systems. This review focuses on the clinical experience of four implantable closed-loop neurostimulation systems: positional-adaptive spinal cord stimulation for treatment of pain, responsive cortical stimulation for treatment of epilepsy, closed-loop vagus nerve stimulation for treatment of epilepsy, and concurrent sensing and stimulation for treatment of Parkinson disease. The history that led to the development of the closed-loop systems, the sensing, detection, and stimulation technology that closes the loop, and the clinical experiences are presented.

The RNS System: responsive cortical stimulation for the treatment of refractory partial epilepsy.

The RNS(®) System is the first commercially available device to provide closed-loop responsive brain stimulation. The system includes a cranially implanted neurostimulator that continually monitors the electrocorticogram through one or two depth and/or subdural cortical strip leads that are placed at the seizure focus. When abnormal electrographic activity is detected, the neurostimulator delivers brief pulses of electrical stimulation to the seizure focus through the implanted leads. In November 2013, the US FDA approved the RNS System as an adjunctive therapy for patients with drug resistant, partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci. Safety and effectiveness of the RNS System for the indicated patient population was demonstrated in a multicenter, randomized, sham-stimulation controlled 2-year pivotal study. An ongoing, prospective, long-term treatment study is currently gathering an additional 7 years of prospective safety and effectiveness data of the RNS System.

Responsive neurostimulation suppresses synchronized cortical rhythms in patients with epilepsy.

Deep brain stimulation (DBS) is an established treatment for Parkinson's disease, and is increasingly used for other neuropsychiatric conditions including epilepsy. Nevertheless, neural mechanisms for DBS and other forms of neurostimulation remain elusive. The authors measured effects of responsive neurostimulation on intracranially recorded activity from participants in a clinical investigation to assess the safety of an implantable responsive neurostimulation system in epilepsy (RNS™ System, NeuroPace, Inc.). Neurostimulation acutely suppressed gamma frequency (35-100 Hz) phase-locking. This may represent a therapeutic mechanism by which responsive neurostimulation can suppress epileptiform activity and disconnect stimulated regions from downstream targets in epilepsy and other neuropsychiatric conditions.

Responsive cortical stimulation for the treatment of epilepsy.

Epilepsy is a common chronic neurological disorder affecting approximately 1-2% of the population. Despite the available treatment options (pharmacotherapy, surgery, and vagus nerve stimulation), a large percentage of patients continue to have seizures. With the success of deep brain stimulation for treatment of movement disorders, brain stimulation has received renewed attention as a potential treatment option for epilepsy. Responsive stimulation aims to suppress epileptiform activity by delivering stimulation directly in response to electrographic activity. Animal and human data support the concept that responsive stimulation can abort epileptiform activity, and this modality may be a safe and effective treatment option for epilepsy. Responsive stimulation has the advantage of specificity. In contrast to the typically systemic administration of pharmacotherapy, with the concomitant possibility of side effects, electrical stimulation can be targeted to the specific brain regions involved in the seizure. In addition, responsive stimulation provides temporal specificity. Treatment is provided as needed, potentially reducing the likelihood of functional disruption or habituation due to continuous treatment. Here we review current animal and human research in responsive brain stimulation for epilepsy and then discuss the NeuroPace RNS System, an investigational implantable responsive neurostimulator system that is being evaluated in a multicenter, randomized, double-blinded trial to assess the safety and efficacy of responsive stimulation for the treatment of medically refractory epilepsy.

Automated seizure onset detection for accurate onset time determination in intracranial EEG.

OBJECTIVE: A novel algorithm for automated seizure onset detection is presented. The method allows for precise identification of electrographic seizure onset times within large databases of electrographic data. METHODS: The patient-specific algorithm extracts salient spectral and temporal features in five frequency bands within a sliding window of an electrographic recording. Feature windows are classified as containing or not containing a seizure onset via support vector machines. A clustering and regression analysis is utilized to accurately localize seizure onsets in time. User-adjustable parameters allow for tuning of detection sensitivity, false positive rate, and latency. The method was tested on intracranial electrographic data recorded from six patients with a total of 1792 recorded seizure onsets from 8246 total electrographic recordings. RESULTS: Testing of algorithm performance via cross-validation resulted in sensitivities between 80% and 98%, false positive rates from 0.002 to 0.046 per minute (0.12-2.8 per hour), and median detection time within 100ms of the electrographic onset for all patients. In five of the six patients, more than 90% of all detected onsets were less than 3s from the electrographic onset. CONCLUSIONS: The detection system was able to detect seizure onset times in a temporally unbiased fashion with low latency while maintaining reasonable sensitivities and false positive rates. The regression algorithm for temporal localization of onsets confers a considerable benefit in terms of detection latency. SIGNIFICANCE: With the use of our algorithm, large databases of electrographic data can be rapidly processed and seizure onset times accurately marked, facilitating research and analyses of peri-onset events that require precise seizure onset alignment.

Functional connectivity of the hippocampus in elderly with mild memory dysfunction carrying the APOE epsilon4 allele.

The purpose of the present study was to evaluate functional connectivity of the hippocampus during a fMRI face-name learning task in a group of elders with mild memory impairment on the basis of the presence or absence of the APOE epsilon4 allele. Twelve epsilon4 carriers and 20 non-carriers with mild memory dysfunction and exhibiting equivalent performance in clinical evaluations of global cognitive function and memory were studied. Subjects underwent a fMRI session consisting of a face-name encoding memory task. Following scanning, subjects were asked to pair faces with their corresponding proper name. Functional connectivity of the hippocampus was measured by using coherence analysis to evaluate the activity of brain circuits related to memory encoding processes. In contrast to non-APOE epsilon4 allele bearers, APOE epsilon4 carriers showed enhanced connectivity with the anterior cingulate, inferior parietal/postcentral gyrus region and the caudate nucleus. Enhanced hippocampal connectivity with additional brain regions in APOE epsilon4 allele carriers during the performance of an associative memory task may reveal the existence of additional activity in the cortico-subcortical network engaged during memory encoding in subjects carrying this genetic variant.

Functional connectivity of cortical networks involved in bimanual motor sequence learning.

Motor skill learning requires the involvement and integration of several cortical and subcortical regions. In this study, we focus on how the functional connectivity of cortical networks changes with the acquisition of a novel motor skill. Using functional magnetic resonance imaging, we measured the localized blood oxygenation level-dependent (BOLD) signal in cortical regions while subjects performed a bimanual serial reaction time task under 2 conditions: 1) explicitly learning a novel sequence (NOVEL) and 2) playing a previously learned sequence (LEARNED). To investigate stages of learning, each condition was further divided into nonoverlapping early and late conditions. Functional connectivity was measured using a task-specific low-frequency coherence analysis of the data. We show that within the cortical motor network, the sensorimotor cortex, premotor cortex, and supplementary motor area have significantly greater inter- and intrahemispheric coupling during the early NOVEL condition compared with the late NOVEL condition. Additionally, we observed greater connectivity between frontal regions and cortical motor regions in the early versus late NOVEL contrast. No changes in functional connectivity were observed in the LEARNED condition. These results demonstrate that the functional connectivity of the cortical motor network is modulated with practice and suggest that early skill learning is mediated by enhanced interregional coupling.

Automated template-based PET region of interest analyses in the aging brain.

The definition of regions of interest for PET data analysis poses a number of complex problems. While studies have shown that regions drawn on a template can be appropriate for extracting data for normal healthy subjects, it is unclear how these results can be applied to different populations. In this study, we focused on the aging population and examined how different parameters in the template data-extraction process may affect the accuracy of the results. We first present an automated method for extracting PET counts using a region-of-interest approach within a template framework. Then, we discuss two studies in which we measure the effects of varying specific parameters in this process. In study 1 we examined three parameters that may influence this process: choice of template, region, and threshold. In study 2 we focused on the hippocampus. We considered 6 different templates, and examined how well the subject-specific hippocampal masks overlapped with each other and with the template hippocampal masks after normalization. While the data in the older cohort are more variable than the normal population, the results suggest that using an appropriate template and selecting the correct parameters for the template-based ROI method can provide template-extracted counts that are highly correlated to counts extracted using subject-specific ROIs.

Measuring temporal dynamics of functional networks using phase spectrum of fMRI data.

We present a novel method to measure relative latencies between functionally connected regions using phase-delay of functional magnetic resonance imaging data. Derived from the phase component of coherency, this quantity estimates the linear delay between two time-series. In conjunction with coherence, derived from the magnitude component of coherency, phase-delay can be used to examine the temporal properties of functional networks. In this paper, we apply coherence and phase-delay methods to fMRI data in order to investigate dynamics of the motor network during task and rest periods. Using the supplementary motor area (SMA) as a reference region, we calculated relative latencies between the SMA and other regions within the motor network including the dorsal premotor cortex (PMd), primary motor cortex (M1), and posterior parietal cortex (PPC). During both the task and rest periods, we measured significant delays that were consistent across subjects. Specifically, we found significant delays between the SMA and the bilateral PMd, bilateral M1, and bilateral PPC during the task condition. During the rest condition, we found that the temporal dynamics of the network changed relative to the task period. No significant delays were measured between the SMA and the left PM and left M1; however, the right PM, right M1, and bilateral PPC were significantly delayed with respect to the SMA. Additionally, we observed significant map-wise differences in the dynamics of the network at task compared to the network at rest. These differences were observed in the interaction between the SMA and the left M1, left superior frontal gyrus, and left middle frontal gyrus. These temporal measurements are important in determining how regions within a network interact and provide valuable information about the sequence of cognitive processes within a network.

Functional interactions between oculomotor regions during prosaccades and antisaccades.

Human behavior reflects a continual negotiation of automatic and directed actions. The oculomotor network is a well-characterized neural system in which to study this balance of behavioral control. For instance, saccades made toward and away from a flashed visual stimulus (prosaccades and antisaccades, respectively) are known to engage different cognitive processes. Brain regions important for such controlled execution include the presupplementary motor area (pre-SMA), frontal eye fields (FEF), and intraparietal sulcus (IPS). Recent work has emphasized various elements of this network but has not explored the functional interactions among regions. We used event-related fMRI to image human brain activity during performance of an interleaved pro/antisaccade task. Since traditional univariate statistics cannot address issues of functional connectivity, a multivariate technique is necessary. Coherence between fMRI time series of the pre-SMA with the FEF and IPS was used to measure functional interactions. The FEF, but not IPS, showed significant differential coherence between pro- and antisaccade trials with pre-SMA. These results suggest that the pre-SMA coordinates with FEF to maintain a controlled, preparatory set for task-appropriate oculomotor execution.

Coherence between fMRI time-series distinguishes two spatial working memory networks.

Widespread and distributed brain regions are thought to form networks that together support working memory. We recently demonstrated that different cortical areas maintain relatively different codes across a memory delay (Curtis et. al., J Neurosci, 2004; 24:3944-3952). The frontal eye fields (FEF), for example, were more active during the delay when the direction of the memory-guided saccade was known compared to when it was not known throughout the delay. Other areas showed the opposite pattern. Despite these task-dependent differences in regional activity, we could only assume but not address the functional interactions between the identified nodes of the putative network. Here, we use a bivariate technique, coherence, to formally characterize functional interactions between a seed region and other brain areas. We find that the type of representational codes that are being maintained in working memory biases frontal-parietal interactions. For example, coherence between FEF and other oculomotor areas was greater when a motor representation was an efficient strategy to bridge the delay period. However, coherence between the FEF and higher-order heteromodal areas, e.g., dorsolateral prefrontal cortex, was greater when a sensory representation must be maintained in working memory.