Bio


Corey Keller, MD, PhD, is a Resident in Psychiatry and Postdoctoral Research Fellow in Neuroscience at Stanford University Medical Center. Corey received his MD and PhD in neuroscience from the Medical Scientist Training Program at Albert Einstein College of Medicine. Using neuroimaging and electrophysiological techniques, his research focuses on improving brain stimulation treatment for neurological and psychiatric disease. Corey's work suggests that brain-based biomarkers may be used to predict non-responders to TMS treatment, monitor brain networks during intervention, and be used to propose novel targets and treatment paradigms.

Clinical Focus


  • Residency
  • Interventional Neuropsychiatry

Honors & Awards


  • NIMH T32 Postdoctoral Fellowship, Stanford University (2018)
  • Alpha Omega Alpha Medical Honor Society, Alpha Omega Alpha (2018)
  • Collaborative Research Fellowship, Stanford Society of Physician Scholars (2018)
  • Career Development Institute for Psychiatry, Stanford University (2018)
  • Outstanding Resident Award, NIMH (2017)
  • New Investigator Award, American Society of Clinical Psychopharmacology (2017)
  • Travel Fellowship, Winter Conference on Brain Research (2016)
  • Early Career Investigator Travel Award, Society of Biological Psychiatry (2016)
  • Postgraduate Research Award, Alpha Omega Alpha (2016)
  • Fellowship for Clinical Trials, American Society of Clinical Psychopharmacology (2016)
  • Collaborative Research Fellowship, Stanford Society of Physician Scholars (2015)
  • Medical School Scholar, Society of Biological Psychiatry (2015)
  • Senior Research Fellowship, Albert Einstein College of Medicine (2014)
  • Combining Clinical and Research Careers in Neuroscience Travel Award, NINDS (2014)
  • Endowed Scholarship Fund, Neural Systems and Behavior Course (2013)
  • Medical Scientist Training Program Pre-Doctoral Fellowship, Ruth L. Kirschstein National Research Service Award (2011-2015)
  • Pre-Doctoral Research Training Fellowship, Epilepsy Foundation (2010-2011)
  • Grant for Summer Research, Albert Einstein College of Medicine (2009)
  • Master’s Thesis Highest Honors, Tufts University (2009)
  • Magna Cum Laude and Senior Thesis Highest Honors, Tufts University (2007)
  • Eta Kappa Nu – Electrical Engineering Honors Society, Tufts University (2007)
  • Dean’s List Honors, Tufts University (2004-2007)

Boards, Advisory Committees, Professional Organizations


  • Research and Grant Chair, Alpha Omega Alpha Medical Honor Society (2018 - Present)
  • Research and Scientific Oversight, International Neuromodulation Society (2016 - Present)
  • Research Committee Member, Clinical TMS Society (2017 - Present)

Professional Education


  • Post-doctoral Fellowship, Stanford University, Neuroscience (2019)
  • Residency, Stanford University, Psychiatry (2019)
  • MD, Albert Einstein College of Medicine, Medicine (2015)
  • PhD, Albert Einstein College of Medicine, Neuroscience (2015)
  • MS, Tufts University, Biomedical Engineering (2009)
  • BS, Tufts University, Electrical Engineering (2007)

Patents


  • Corey Keller, Amit Etkin, Wei Wu. "United States Patent 41243-520P01US, Patent Pending Use of a brain-based signal for predicting and guiding brain stimulation treatment in depression"
  • Corey Keller, Amit Etkin, Wei Wu. "United States Patent 41243-520P02US, Patent Pending Artifact Rejection for Transcranial Magnetic Stimulation Electroencephalogram Data."

Current Research and Scholarly Interests


The overarching goal of my research is to identify and apply individualized stimulation protocols to elicit precise and predictable long-term plasticity in order to alleviate psychiatric suffering. Repetitive transcranial magnetic stimulation (TMS) was FDA approved for treatment-resistant depression over 10 years ago as a circuit-based, targeted intervention that complements traditional psychiatric treatments. Remission rates, however, remain at 15% at worst and 40% at best. TMS trials using identical treatment settings are currently underway for bipolar disorder, PTSD, OCD, and addiction. The low efficacy and one-size-fits-all treatment (with respect to timing, site, and intensity) stems from our lack of understanding of how TMS induces brain changes. It is reasonable to expect that we can improve the efficacy of TMS. By selecting the optimal parameters based on the stimulation timing, location, intensity, and duration of the TMS pulses, we can customize treatment to maximize an individual’s clinical response. My 10 year research aims are to obtain this level of specificity and treatment response by:

1) Developing an integrated translational clinical research program.
2) Identifying the specific neural mechanisms underlying repetitive stimulation-induced plasticity.
3) Creating novel treatments with TMS based on experimentally-driven computational models of plasticity.

This three-pronged approach has the expected outcome of producing novel stimulation treatments with enhanced specificity, plasticity, and efficacy. By increasing our understanding of the underlying mechanism and monitoring of brain changes during TMS, we will markedly increase the utility of these powerful techniques. Together, this work will help transform interventional psychiatry from an isolated (from a clinic perspective), one-size-fits-all treatment approach to one that focuses on targeting objective biomarkers and that is collaborative, large-scale, and automated, pushing the field into the age of personalized neuromodulation.

All Publications


  • Induction and Quantification of Excitability Changes in Human Cortical Networks JOURNAL OF NEUROSCIENCE Keller, C. J., Huang, Y., Herrero, J. L., Fini, M. E., Du, V., Lado, F. A., Honey, C. J., Mehta, A. D. 2018; 38 (23): S384–S398

    Abstract

    How does human brain stimulation result in lasting changes in cortical excitability? Uncertainty on this question hinders the development of personalized brain stimulation therapies. To characterize how cortical excitability is altered by stimulation, we applied repetitive direct electrical stimulation in eight human subjects (male and female) undergoing intracranial monitoring. We evaluated single-pulse corticocortical-evoked potentials (CCEPs) before and after repetitive stimulation across prefrontal (n = 4), temporal (n = 1), and motor (n = 3) cortices. We asked whether a single session of repetitive stimulation was sufficient to induce excitability changes across distributed cortical sites. We found a subset of regions at which 10 Hz prefrontal repetitive stimulation resulted in both potentiation and suppression of excitability that persisted for at least 10 min. We then asked whether these dynamics could be modeled by the prestimulation connectivity profile of each subject. We found that cortical regions (1) anatomically close to the stimulated site and (2) exhibiting high-amplitude CCEPs underwent changes in excitability following repetitive stimulation. We demonstrate high accuracy (72-95%) and discriminability (81-99%) in predicting regions exhibiting changes using individual subjects' prestimulation connectivity profile, and show that adding prestimulation connectivity features significantly improved model performance. The same features predicted regions of modulation following motor and temporal cortices stimulation in an independent dataset. Together, baseline connectivity profile can be used to predict regions susceptible to brain changes and provides a basis for personalizing brain stimulation.SIGNIFICANCE STATEMENT Brain stimulation is increasingly used to treat neuropsychiatric disorders by inducing excitability changes at specific brain regions. However, our understanding of how, when, and where these changes are induced is critically lacking. We inferred plasticity in the human brain after applying electrical stimulation to the brain's surface and measuring changes in excitability. We observed excitability changes in regions anatomically and functionally closer to the stimulation site. Those in responsive regions were accurately predicted using a classifier trained on baseline brain network characteristics. Finally, we showed that the excitability changes can potentially be monitored in real-time. These results begin to fill basic gaps in our understanding of stimulation-induced brain dynamics in humans and offer pathways to optimize stimulation protocols.

    View details for DOI 10.1523/JNEUROSCI.1088-17.2018

    View details for Web of Science ID 000435412100012

    View details for PubMedID 29875229

    View details for PubMedCentralID PMC5990984

  • ARTIST: A fully automated artifact rejection algorithm for single-pulse TMS-EEG data. Human brain mapping Wu, W., Keller, C. J., Rogasch, N. C., Longwell, P., Shpigel, E., Rolle, C. E., Etkin, A. 2018

    Abstract

    Concurrent single-pulse TMS-EEG (spTMS-EEG) is an emerging noninvasive tool for probing causal brain dynamics in humans. However, in addition to the common artifacts in standard EEG data, spTMS-EEG data suffer from enormous stimulation-induced artifacts, posing significant challenges to the extraction of neural information. Typically, neural signals are analyzed after a manual time-intensive and often subjective process of artifact rejection. Here we describe a fully automated algorithm for spTMS-EEG artifact rejection. A key step of this algorithm is to decompose the spTMS-EEG data into statistically independent components (ICs), and then train a pattern classifier to automatically identify artifact components based on knowledge of the spatio-temporal profile of both neural and artefactual activities. The autocleaned and hand-cleaned data yield qualitatively similar group evoked potential waveforms. The algorithm achieves a 95% IC classification accuracy referenced to expert artifact rejection performance, and does so across a large number of spTMS-EEG data sets (n = 90 stimulation sites), retains high accuracy across stimulation sites/subjects/populations/montages, and outperforms current automated algorithms. Moreover, the algorithm was superior to the artifact rejection performance of relatively novice individuals, who would be the likely users of spTMS-EEG as the technique becomes more broadly disseminated. In summary, our algorithm provides an automated, fast, objective, and accurate method for cleaning spTMS-EEG data, which can increase the utility of TMS-EEG in both clinical and basic neuroscience settings.

    View details for DOI 10.1002/hbm.23938

    View details for PubMedID 29331054

  • Tuning face perception with electrical stimulation of the fusiform gyrus. Human brain mapping Keller, C. J., Davidesco, I., Megevand, P., Lado, F. A., Malach, R., Mehta, A. D. 2017; 38 (6): 2830-2842

    Abstract

    The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. []: J Neurosci 32:14915-14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event-related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 μs) electrical pulses to the FG and non-face-selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face-selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face-selective but not place-selective sites. Furthermore, ES applied to face-selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face-selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face-selective areas and signify an important link between electrophysiology and behavior in face perception. Hum Brain Mapp 38:2830-2842, 2017. © 2017 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.23543

    View details for PubMedID 28345189

  • The Clinical Applicability of Functional Connectivity in Depression: Pathways Toward More Targeted Intervention. Biological psychiatry. Cognitive neuroscience and neuroimaging Fischer, A. S., Keller, C. J., Etkin, A. 2016; 1 (3): 262–70

    Abstract

    Resting-state functional magnetic resonance imaging provides a noninvasive method to rapidly map large-scale brain networks affected in depression and other psychiatric disorders. Dysfunctional connectivity in large-scale brain networks has been consistently implicated in major depressive disorder (MDD). Although advances have been made in identifying neural circuitry implicated in MDD, this information has yet to be translated into improved diagnostic or treatment interventions. In the first section of this review, we discuss dysfunctional connectivity in affective salience, cognitive control, and default mode networks observed in MDD in association with characteristic symptoms of the disorder. In the second section, we address neurostimulation focusing on transcranial magnetic stimulation and evidence that this approach may directly modulate circuit abnormalities. Finally, we discuss possible avenues of future research to develop more precise diagnoses and targeted interventions within the heterogeneous diagnostic category of MDD as well as the methodological limitations to clinical implementation. We conclude by proposing, with cautious optimism, the future incorporation of neuroimaging into clinical practice as a tool to aid in more targeted diagnosis and treatment guided by circuit-level connectivity dysfunction in patients with depression.

    View details for DOI 10.1016/j.bpsc.2016.02.004

    View details for PubMedID 29560882

  • The Limited Utility of Multiunit Data in Differentiating Neuronal Population Activity PLOS ONE Keller, C. J., Chen, C., Lado, F. A., Khodakhah, K. 2016; 11 (4)

    Abstract

    To date, single neuron recordings remain the gold standard for monitoring the activity of neuronal populations. Since obtaining single neuron recordings is not always possible, high frequency or 'multiunit activity' (MUA) is often used as a surrogate. Although MUA recordings allow one to monitor the activity of a large number of neurons, they do not allow identification of specific neuronal subtypes, the knowledge of which is often critical for understanding electrophysiological processes. Here, we explored whether prior knowledge of the single unit waveform of specific neuron types is sufficient to permit the use of MUA to monitor and distinguish differential activity of individual neuron types. We used an experimental and modeling approach to determine if components of the MUA can monitor medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) in the mouse dorsal striatum. We demonstrate that when well-isolated spikes are recorded, the MUA at frequencies greater than 100Hz is correlated with single unit spiking, highly dependent on the waveform of each neuron type, and accurately reflects the timing and spectral signature of each neuron. However, in the absence of well-isolated spikes (the norm in most MUA recordings), the MUA did not typically contain sufficient information to permit accurate prediction of the respective population activity of MSNs and FSIs. Thus, even under ideal conditions for the MUA to reliably predict the moment-to-moment activity of specific local neuronal ensembles, knowledge of the spike waveform of the underlying neuronal populations is necessary, but not sufficient.

    View details for DOI 10.1371/journal.pone.0153154

    View details for Web of Science ID 000374970600012

    View details for PubMedID 27111446

    View details for PubMedCentralID PMC4844128

  • The clinical applicability of functional connectivity in depression: Pathways toward more targeted intervention Journal of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Fischer, A. S., Keller, C. J., Etkin, A. 2016
  • Mapping human brain networks with cortico-cortical evoked potentials PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Keller, C. J., Honey, C. J., Megevand, P., Entz, L., Ulbert, I., Mehta, A. D. 2014; 369 (1653)

    Abstract

    The cerebral cortex forms a sheet of neurons organized into a network of interconnected modules that is highly expanded in humans and presumably enables our most refined sensory and cognitive abilities. The links of this network form a fundamental aspect of its organization, and a great deal of research is focusing on understanding how information flows within and between different regions. However, an often-overlooked element of this connectivity regards a causal, hierarchical structure of regions, whereby certain nodes of the cortical network may exert greater influence over the others. While this is difficult to ascertain non-invasively, patients undergoing invasive electrode monitoring for epilepsy provide a unique window into this aspect of cortical organization. In this review, we highlight the potential for cortico-cortical evoked potential (CCEP) mapping to directly measure neuronal propagation across large-scale brain networks with spatio-temporal resolution that is superior to traditional neuroimaging methods. We first introduce effective connectivity and discuss the mechanisms underlying CCEP generation. Next, we highlight how CCEP mapping has begun to provide insight into the neural basis of non-invasive imaging signals. Finally, we present a novel approach to perturbing and measuring brain network function during cognitive processing. The direct measurement of CCEPs in response to electrical stimulation represents a potentially powerful clinical and basic science tool for probing the large-scale networks of the human cerebral cortex.

    View details for DOI 10.1098/rstb.2013.0528

    View details for Web of Science ID 000341695200007

    View details for PubMedID 25180306

  • Corticocortical Evoked Potentials Reveal Projectors and Integrators in Human Brain Networks JOURNAL OF NEUROSCIENCE Keller, C. J., Honey, C. J., Entz, L., Bickel, S., Groppe, D. M., Toth, E., Ulbert, I., Lado, F. A., Mehta, A. D. 2014; 34 (27): 9152-9163

    Abstract

    The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks.

    View details for DOI 10.1523/JNEUROSCI.4289-13.2014

    View details for Web of Science ID 000339153400023

    View details for PubMedID 24990935

  • Neurophysiological Investigation of Spontaneous Correlated and Anticorrelated Fluctuations of the BOLD Signal JOURNAL OF NEUROSCIENCE Keller, C. J., Bickel, S., Honey, C. J., Groppe, D. M., Entz, L., Craddock, R. C., Lado, F. A., Kelly, C., Milham, M., Mehta, A. D. 2013; 33 (15): 6333-6342

    Abstract

    Analyses of intrinsic fMRI BOLD signal fluctuations reliably reveal correlated and anticorrelated functional networks in the brain. Because the BOLD signal is an indirect measure of neuronal activity and anticorrelations can be introduced by preprocessing steps, such as global signal regression, the neurophysiological significance of correlated and anticorrelated BOLD fluctuations is a source of debate. Here, we address this question by examining the correspondence between the spatial organization of correlated BOLD fluctuations and correlated fluctuations in electrophysiological high γ power signals recorded directly from the cortical surface of 5 patients. We demonstrate that both positive and negative BOLD correlations have neurophysiological correlates reflected in fluctuations of spontaneous neuronal activity. Although applying global signal regression to BOLD signals results in some BOLD anticorrelations that are not apparent in the ECoG data, it enhances the neuronal-hemodynamic correspondence overall. Together, these findings provide support for the neurophysiological fidelity of BOLD correlations and anticorrelations.

    View details for DOI 10.1523/JNEUROSCI.4837-12.2013

    View details for Web of Science ID 000317476300009

    View details for PubMedID 23575832

  • Intrinsic functional architecture predicts electrically evoked responses in the human brain PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Keller, C. J., Bickel, S., Entz, L., Ulbert, I., Milham, M. P., Kelly, C., Mehta, A. D. 2011; 108 (25): 10308-10313

    Abstract

    Adaptive brain function is characterized by dynamic interactions within and between neuronal circuits, often occurring at the time scale of milliseconds. These complex interactions between adjacent and noncontiguous brain areas depend on a functional architecture that is maintained even in the absence of input. Functional MRI studies carried out during rest (R-fMRI) suggest that this architecture is represented in low-frequency (<0.1 Hz) spontaneous fluctuations in the blood oxygen level-dependent signal that are correlated within spatially distributed networks of brain areas. These networks, collectively referred to as the brain's intrinsic functional architecture, exhibit a remarkable correspondence with patterns of task-evoked coactivation as well as maps of anatomical connectivity. Despite this striking correspondence, there is no direct evidence that this intrinsic architecture forms the scaffold that gives rise to faster processes relevant to information processing and seizure spread. Here, we demonstrate that the spatial distribution and magnitude of temporally correlated low-frequency fluctuations observed with R-fMRI during rest predict the pattern and magnitude of corticocortical evoked potentials elicited within 500 ms after single-pulse electrical stimulation of the cerebral cortex with intracranial electrodes. Across individuals, this relationship was found to be independent of the specific regions and functional systems probed. Our findings bridge the immense divide between the temporal resolutions of these distinct measures of brain function and provide strong support for the idea that the low-frequency signal fluctuations observed with R-fMRI maintain and update the intrinsic architecture underlying the brain's repertoire of functional responses.

    View details for DOI 10.1073/pnas.1019750108

    View details for Web of Science ID 000291857500057

    View details for PubMedID 21636787

  • Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex BRAIN Keller, C. J., Truccolo, W., Gale, J. T., Eskandar, E., Thesen, T., Carlson, C., Devinsky, O., Kuzniecky, R., Doyle, W. K., Madsen, J. R., Schomer, D. L., Mehta, A. D., Brown, E. N., Hochberg, L. R., Ulbert, I., Halgren, E., Cash, S. S. 2010; 133: 1668-1681

    Abstract

    Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

    View details for DOI 10.1093/brain/awq112

    View details for Web of Science ID 000278226700010

    View details for PubMedID 20511283

  • Reproducibility in TMS-EEG studies: A call for data sharing, standard procedures and effective experimental control. Brain stimulation Belardinelli, P., Biabani, M., Blumberger, D. M., Bortoletto, M., Casarotto, S., David, O., Desideri, D., Etkin, A., Ferrarelli, F., Fitzgerald, P. B., Fornito, A., Gordon, P. C., Gosseries, O., Harquel, S., Julkunen, P., Keller, C. J., Kimiskidis, V. K., Lioumis, P., Miniussi, C., Rosanova, M., Rossi, S., Sarasso, S., Wu, W., Zrenner, C., Daskalakis, Z. J., Rogasch, N. C., Massimini, M., Ziemann, U., Ilmoniemi, R. J. 2019

    View details for DOI 10.1016/j.brs.2019.01.010

    View details for PubMedID 30738777

  • Reliability of Transcranial Magnetic Stimulation EEG Evoked Potentials Kerwin, L., Keller, C., Wu, W., Narayan, M., Etkin, A. ELSEVIER SCIENCE INC. 2017: S131
  • Test-retest reliability of transcranial magnetic stimulation EEG evoked potentials. Brain stimulation Kerwin, L. J., Keller, C. J., Wu, W., Narayan, M., Etkin, A. 2017

    Abstract

    Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (TMS-EEG), offer a powerful tool for measuring causal interactions in the human brain. However, the test-retest reliability of TEPs, critical to their use in clinical biomarker and interventional studies, remains poorly understood.We quantified TEP reliability to: (i) determine the minimal TEP amplitude change which significantly exceeds that associated with simply re-testing, (ii) locate the most reliable scalp regions of interest (ROIs) and TEP peaks, and (iii) determine the minimal number of TEP pulses for achieving reliability.TEPs resulting from stimulation of the left dorsolateral prefrontal cortex were collected on two separate days in sixteen healthy participants. TEP peak amplitudes were compared between alternating trials, split-halves of the same run, two runs five minutes apart and two runs on separate days. Reliability was quantified using concordance correlation coefficient (CCC) and smallest detectable change (SDC).Substantial concordance was achieved in prefrontal electrodes at 40 and 60 ms, centroparietal and left parietal ROIs at 100 ms, and central electrodes at 200 ms. Minimum SDC was found in the same regions and peaks, particularly for the peaks at 100 and 200 ms. CCC, but not SDC, reached optimal values by 60-100 pulses per run with saturation beyond this number, while SDC continued to improve with increased pulse numbers.TEPs were robust and reliable, requiring a relatively small number of trials to achieve stability, and are thus well suited as outcomes in clinical biomarker or interventional studies.

    View details for DOI 10.1016/j.brs.2017.12.010

    View details for PubMedID 29342443

  • Test-retest reliability of transcranial magnetic stimulation EEG evoked potentials Brain Stimulation Kerwin, L. J., Keller, C., Wu, W., Narayan, M., Etkin, A. 2017

    Abstract

    Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (TMS-EEG), offer a powerful tool for measuring causal interactions in the human brain. However, the test-retest reliability of TEPs, critical to their use in clinical biomarker and interventional studies, remains poorly understood.We quantified TEP reliability to: (i) determine the minimal TEP amplitude change which significantly exceeds that associated with simply re-testing, (ii) locate the most reliable scalp regions of interest (ROIs) and TEP peaks, and (iii) determine the minimal number of TEP pulses for achieving reliability.TEPs resulting from stimulation of the left dorsolateral prefrontal cortex were collected on two separate days in sixteen healthy participants. TEP peak amplitudes were compared between alternating trials, split-halves of the same run, two runs five minutes apart and two runs on separate days. Reliability was quantified using concordance correlation coefficient (CCC) and smallest detectable change (SDC).Substantial concordance was achieved in prefrontal electrodes at 40 and 60 ms, centroparietal and left parietal ROIs at 100 ms, and central electrodes at 200 ms. Minimum SDC was found in the same regions and peaks, particularly for the peaks at 100 and 200 ms. CCC, but not SDC, reached optimal values by 60-100 pulses per run with saturation beyond this number, while SDC continued to improve with increased pulse numbers.TEPs were robust and reliable, requiring a relatively small number of trials to achieve stability, and are thus well suited as outcomes in clinical biomarker or interventional studies.

    View details for DOI 10.1016/j.brs.2017.12.010

  • Cotard Delusion in the Context of Schizophrenia: A Case Report and Review of the Literature FRONTIERS IN PSYCHOLOGY Bott, N., Keller, C., Kuppuswamy, M., Spelber, D., Zeier, J. 2016; 7

    Abstract

    The Cotard delusion (CD) is one of a variety of narrowly defined monothematic delusions characterized by nihilistic beliefs about the body's existence or life itself. The presence of CD within the context of schizophrenia is rare (<1%), and remains understudied.'Mr. C' is a 58-year-old veteran with a prior diagnosis of schizophrenia, who presented with CD in the context of significant depression, suicidal ideation, violence, and self-harm behavior. He perseverated in his belief that he was physically dead and possessed by demons for several weeks. This delusion was reinforced by his religious belief that life was an attribute of God, and by inference, he as a human, was dead. His condition gradually improved over the course of treatment with Divalproex and quetiapine with discussions about the rationale for his belief. Upon discharge, Mr. C. demonstrated awareness of his fixation on death and an ability to redirect himself.This case highlights the need to better understand the co-occurrence of CD in schizophrenia, their differentiation, the increased risk of violence and self-harm behavior in this presentation, and how specific events and religious factors can influence delusional themes of CD. Pharmacotherapy and aspects of cognitive-behavioral therapy may be effective in ameliorating these symptoms in CD.

    View details for DOI 10.3389/fpsyg.2016.01351

    View details for Web of Science ID 000382720900001

    View details for PubMedID 27656159

    View details for PubMedCentralID PMC5013050

  • A case of butane hash oil (marijuana wax)-induced psychosis SUBSTANCE ABUSE Keller, C. J., Chen, E. C., Brodsky, K., Yoon, J. H. 2016; 37 (3): 384-386

    Abstract

    Marijuana is one of the most widely used controlled substances in the United States. Despite extensive research on smoked marijuana, little is known regarding the potential psychotropic effects of marijuana "wax," a high-potency form of marijuana that is gaining in popularity.The authors present a case of "Mr. B," a 34-year-old veteran who presented with profound psychosis in the setting of recent initiation of heavy, daily marijuana wax use. He exhibited incoherent speech and odd behaviors and appeared to be in a dream-like state with perseverating thoughts about his combat experience. His condition persisted despite treatment with risperidone 4 mg twice a day (BID), but improved dramatically on day 8 of hospitalization with the return of baseline mental function. Following discharge, Mr. B discontinued all marijuana use and did not exhibit the return of any psychotic symptoms.This study highlights the need for future research regarding the potential medical and psychiatric effects of new, high-potency forms of marijuana. Could cannabis have a dose-dependent impact on psychosis? What other potential psychiatric effects could emerge heretofore unseen in lower potency formulations? Given the recent legalization of marijuana, these questions merit timely exploration.

    View details for DOI 10.1080/08897077.2016.1141153

    View details for Web of Science ID 000382769800003

    View details for PubMedID 26820171

  • Evoked Effective Connectivity of the Human Neocortex HUMAN BRAIN MAPPING Entz, L., Toth, E., Keller, C. J., Bickel, S., Groppe, D. M., Fabo, D., Kozak, L. R., Eross, L., Ulbert, I., Mehta, A. D. 2014; 35 (12): 5736-5753

    Abstract

    The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6-BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies.

    View details for DOI 10.1002/hbm.22581

    View details for Web of Science ID 000344398900002

    View details for PubMedID 25044884

  • Exemplar Selectivity Reflects Perceptual Similarities in the Human Fusiform Cortex CEREBRAL CORTEX Davidesco, I., Zion-Golumbic, E., Bickel, S., Harel, M., Groppe, D. M., Keller, C. J., Schevon, C. A., McKhann, G. M., Goodman, R. R., Goelman, G., Schroeder, C. E., Mehta, A. D., Malach, R. 2014; 24 (7): 1879-1893

    Abstract

    While brain imaging studies emphasized the category selectivity of face-related areas, the underlying mechanisms of our remarkable ability to discriminate between different faces are less understood. Here, we recorded intracranial local field potentials from face-related areas in patients presented with images of faces and objects. A highly significant exemplar tuning within the category of faces was observed in high-Gamma (80-150 Hz) responses. The robustness of this effect was supported by single-trial decoding of face exemplars using a minimal (n = 5) training set. Importantly, exemplar tuning reflected the psychophysical distance between faces but not their low-level features. Our results reveal a neuronal substrate for the establishment of perceptual distance among faces in the human brain. They further imply that face neurons are anatomically grouped according to well-defined functional principles, such as perceptual similarity.

    View details for DOI 10.1093/cercor/bht038

    View details for Web of Science ID 000338110900016

    View details for PubMedID 23438448

  • Dominant frequencies of resting human brain activity as measured by the electrocorticogram NEUROIMAGE Groppe, D. M., Bickel, S., Keller, C. J., Jain, S. K., Hwang, S. T., Harden, C., Mehta, A. D. 2013; 79: 223-233

    Abstract

    The brain's spontaneous, intrinsic activity is increasingly being shown to reveal brain function, delineate large scale brain networks, and diagnose brain disorders. One of the most studied and clinically utilized types of intrinsic brain activity are oscillations in the electrocorticogram (ECoG), a relatively localized measure of cortical synaptic activity. Here we objectively characterize the types of ECoG oscillations commonly observed over particular cortical areas when an individual is awake and immobile with eyes closed, using a surface-based cortical atlas and cluster analysis. Both methods show that [1] there is generally substantial variability in the dominant frequencies of cortical regions and substantial overlap in dominant frequencies across the areas sampled (primarily lateral central, temporal, and frontal areas), [2] theta (4-8 Hz) is the most dominant type of oscillation in the areas sampled with a mode around 7 Hz, [3] alpha (8-13 Hz) is largely limited to parietal and occipital regions, and [4] beta (13-30 Hz) is prominent peri-Rolandically, over the middle frontal gyrus, and the pars opercularis. In addition, the cluster analysis revealed seven types of ECoG spectral power densities (SPDs). Six of these have peaks at 3, 5, 7 (narrow), 7 (broad), 10, and 17 Hz, while the remaining cluster is broadly distributed with less pronounced peaks at 8, 19, and 42 Hz. These categories largely corroborate conventional sub-gamma frequency band distinctions (delta, theta, alpha, and beta) and suggest multiple sub-types of theta. Finally, we note that gamma/high gamma activity (30+ Hz) was at times prominently observed, but was too infrequent and variable across individuals to be reliably characterized. These results should help identify abnormal patterns of ECoG oscillations, inform the interpretation of EEG/MEG intrinsic activity, and provide insight into the functions of these different oscillations and the networks that produce them. Specifically, our results support theories of the importance of theta oscillations in general cortical function, suggest that alpha activity is primarily related to sensory processing/attention, and demonstrate that beta networks extend far beyond primary sensorimotor regions.

    View details for DOI 10.1016/j.neuroimage.2013.04.044

    View details for Web of Science ID 000320412200023

    View details for PubMedID 23639261

  • Individualized localization and cortical surface-based registration of intracranial electrodes NEUROIMAGE Dykstra, A. R., Chan, A. M., Quinn, B. T., Zepeda, R., Keller, C. J., Cormier, J., Madsen, J. R., Eskandar, E. N., Cash, S. S. 2012; 59 (4): 3563-3570

    Abstract

    In addition to its widespread clinical use, the intracranial electroencephalogram (iEEG) is increasingly being employed as a tool to map the neural correlates of normal cognitive function as well as for developing neuroprosthetics. Despite recent advances, and unlike other established brain-mapping modalities (e.g. functional MRI, magneto- and electroencephalography), registering the iEEG with respect to neuroanatomy in individuals-and coregistering functional results across subjects-remains a significant challenge. Here we describe a method which coregisters high-resolution preoperative MRI with postoperative computerized tomography (CT) for the purpose of individualized functional mapping of both normal and pathological (e.g., interictal discharges and seizures) brain activity. Our method accurately (within 3mm, on average) localizes electrodes with respect to an individual's neuroanatomy. Furthermore, we outline a principled procedure for either volumetric or surface-based group analyses. We demonstrate our method in five patients with medically-intractable epilepsy undergoing invasive monitoring of the seizure focus prior to its surgical removal. The straight-forward application of this procedure to all types of intracranial electrodes, robustness to deformations in both skull and brain, and the ability to compare electrode locations across groups of patients makes this procedure an important tool for basic scientists as well as clinicians.

    View details for DOI 10.1016/j.neuroimage.2011.11.046

    View details for Web of Science ID 000301090100052

    View details for PubMedID 22155045

  • Parallel versus serial processing dependencies in the perisylvian speech network: A Granger analysis of intracranial EEG data BRAIN AND LANGUAGE Gow, D. W., Keller, C. J., Eskandar, E., Meng, N., Cash, S. S. 2009; 110 (1): 43-48

    Abstract

    In this work, we apply Granger causality analysis to high spatiotemporal resolution intracranial EEG (iEEG) data to examine how different components of the left perisylvian language network interact during spoken language perception. The specific focus is on the characterization of serial versus parallel processing dependencies in the dominant hemisphere dorsal and ventral speech processing streams. Analysis of iEEG data from a large, 64-electrode grid implanted over the left perisylvian region in a single right-handed patient showed a consistent pattern of direct posterior superior temporal gyrus influence over sites distributed over the entire ventral pathway for words, non-words, and phonetically ambiguous items that could be interpreted either as words or non-words. For the phonetically ambiguous items, this pattern was overlayed by additional dependencies involving the inferior frontal gyrus, which influenced activation measured at electrodes located in both ventral and dorsal stream speech structures. Implications of these results for understanding the functional architecture of spoken language processing and interpreting the role of the posterior superior temporal gyrus in speech perception are discussed.

    View details for DOI 10.1016/j.bandl.2009.02.004

    View details for Web of Science ID 000267098500006

    View details for PubMedID 19356793

  • Intracranial microprobe for evaluating neuro-hemodynamic coupling in unanesthetized human neocortex JOURNAL OF NEUROSCIENCE METHODS Keller, C. J., Cash, S. S., Narayanan, S., Wang, C., Kuzniecky, R., Carlson, C., Devinsky, O., Thesen, T., Doyle, W., Sassaroli, A., Boas, D. A., Ulbert, I., Halgren, E. 2009; 179 (2): 208-218

    Abstract

    Measurement of the blood-oxygen-level dependent (BOLD) response with fMRI has revolutionized cognitive neuroscience and is increasingly important in clinical care. The BOLD response reflects changes in deoxy-hemoglobin concentration, blood volume, and blood flow. These hemodynamic changes ultimately result from neuronal firing and synaptic activity, but the linkage between these domains is complex, poorly understood, and may differ across species, cortical areas, diseases, and cognitive states. We describe here a technique that can measure neural and hemodynamic changes simultaneously from cortical microdomains in waking humans. We utilize a "laminar optode," a linear array of microelectrodes for electrophysiological measures paired with a micro-optical device for hemodynamic measurements. Optical measurements include laser Doppler to estimate cerebral blood flow as well as point spectroscopy to estimate oxy- and deoxy-hemoglobin concentrations. The microelectrode array records local field potential gradients (PG) and multi-unit activity (MUA) at 24 locations spanning the cortical depth, permitting estimation of population trans-membrane current flows (Current Source Density, CSD) and population cell firing in each cortical lamina. Comparison of the laminar CSD/MUA profile with the origins and terminations of cortical circuits allows activity in specific neuronal circuits to be inferred and then directly compared to hemodynamics. Access is obtained in epileptic patients during diagnostic evaluation for surgical therapy. Validation tests with relatively well-understood manipulations (EKG, breath-holding, cortical electrical stimulation) demonstrate the expected responses. This device can provide a new and robust means for obtaining detailed, quantitative data for defining neurovascular coupling in awake humans.

    View details for DOI 10.1016/j.jneumeth.2009.01.036

    View details for Web of Science ID 000265585400008

    View details for PubMedID 19428529