1. Neuroscience
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Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control

  1. Derek Evan Nee  Is a corresponding author
  2. Mark D'Esposito
  1. Florida State University, United States
  2. Helen Wills Neuroscience Institute, University of California, United States
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Cite this article as: eLife 2017;6:e28040 doi: 10.7554/eLife.28040


The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but how its interactions support cognitive control remains elusive. Previously (Nee and D'Esposito, 2016), dynamic causal modeling (DCM) indicated that mid LPFC integrates abstract, rostral and concrete, caudal influences to inform context-appropriate action. Here, we use continuous theta-burst transcranial magnetic stimulation (cTBS) to causally test this model. cTBS was applied to three LPFC sites and a control site in counterbalanced sessions. Behavioral modulations resulting from cTBS were largely predicted by information flow within the previously estimated DCM. However, cTBS to caudal LPFC unexpectedly impaired processes presumed to involve rostral LPFC. Adding a pathway from caudal to mid-rostral LPFC significantly improved the model fit and accounted for the observed behavioral findings. These data provide causal evidence for LPFC dynamics supporting cognitive control and demonstrate the utility of combining DCM with causal manipulations to test and refine models of cognition.

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Author details

  1. Derek Evan Nee

    Department of Psychology, Florida State University, Tallahassee, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7858-6871
  2. Mark D'Esposito

    Department of Psychology, Helen Wills Neuroscience Institute, University of California, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.


National Institute of Neurological Disorders and Stroke (F32 NS0802069)

  • Derek Evan Nee

National Institute of Neurological Disorders and Stroke (P01 NS040813)

  • Mark D'Esposito

National Institute of Mental Health (R01 MH063901)

  • Mark D'Esposito

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.


Human subjects: Informed consent was obtained in accordance with the Committee for Protection of Human Subjects at the University of California, Berkeley under protocol number 2010-02-781.

Reviewing Editor

  1. Lila Davachi, New York University, United States

Publication history

  1. Received: April 25, 2017
  2. Accepted: August 30, 2017
  3. Accepted Manuscript published: September 13, 2017 (version 1)
  4. Version of Record published: October 13, 2017 (version 2)


© 2017, Nee & D'Esposito

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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Further reading

    1. Neuroscience
    Derek Evan Nee, Mark D'Esposito
    Research Article

    Higher-level cognition depends on the lateral prefrontal cortex (LPFC), but its functional organization has remained elusive. An influential proposal is that the LPFC is organized hierarchically whereby progressively rostral areas of the LPFC process/represent increasingly abstract information facilitating efficient and flexible cognition. However, support for this theory has been limited. Here, human fMRI data revealed rostral/caudal gradients of abstraction in the LPFC. Dynamic causal modeling revealed asymmetrical LPFC interactions indicative of hierarchical processing. Contrary to dominant assumptions, the relative strength of efferent versus afferent connections positioned mid LPFC as the apex of the hierarchy. Furthermore, cognitive demands induced connectivity modulations towards mid LPFC consistent with a role in integrating information for control operations. Moreover, the strengths of these dynamics were related to trait-measured higher-level cognitive ability. Collectively, these results suggest that the LPFC is hierarchically organized with the mid LPFC positioned to synthesize abstract and concrete information to control behavior.

    1. Neuroscience
    Jenna Nagy et al.
    Research Article Updated

    Output signals of neural circuits, including the retina, are shaped by a combination of excitatory and inhibitory signals. Inhibitory signals can act presynaptically on axon terminals to control neurotransmitter release and regulate circuit function. However, it has been difficult to study the role of presynaptic inhibition in most neural circuits due to lack of cell type-specific and receptor type-specific perturbations. In this study, we used a transgenic approach to selectively eliminate GABAA inhibitory receptors from select types of second-order neurons – bipolar cells – in mouse retina and examined how this affects the light response properties of the well-characterized ON alpha ganglion cell retinal circuit. Selective loss of GABAA receptor-mediated presynaptic inhibition causes an enhanced sensitivity and slower kinetics of light-evoked responses from ON alpha ganglion cells thus highlighting the role of presynaptic inhibition in gain control and temporal filtering of sensory signals in a key neural circuit in the mammalian retina.