EDITORIAL

published: 23 September 2014

doi: 10.3389/fncir.2014.00115

NEURAL CIRCUITS

Closed-loop neuroscience and neuroengineering

Steve M. Potter 1*, Ahmed El Hady 2 and Eberhard E. Fetz 3
1

Laboratory for Neuroengineering, Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
Department of Non Linear Dynamics, Max Planck Institute for Dynamics and Self Organization, Goettingen, Germany
3
Departments of Physiology and Biophysics and Bioengineering, Washington National Primate Research Center, University of Washington, Seattle, WA, USA
*Correspondence: steve.potter@bme.gatech.edu
2

Edited and reviewed by:

Florian Engert, Harvard University, USA
Keywords: feedback, real-time, BCI, microelectrode array, CMOS, DBS, stimulation

Feedback and closed-loop circuits exist in just about every part

of the nervous system. It is curious, therefore, that for decades
neuroscientists have been probing the nervous system in an openloop manner to understand it. Instead of the linear, reductionistic stimulate record response approach, a more modern
approach is taking hold: closed-loop neuroscience. It respects
the inherent loopiness of neural circuits, and the fact that
the nervous system is embodied, and embedded in an environment. Through active sensing, behaving animals can influence
their environment in ways that alter subsequent sensory inputs.
Therefore, loops abound not only in the nervous system itself,
but through its dynamic interactions with the world. By interposing our own technology in some of these loops, we can achieve
unprecedented control over the system being studied and explore
the functional consequences. This Research Topic, Closing the
Loop Around Neural Systems, presents a diverse set of recent
methodological, scientific and theoretical advances from neuroscientists and neuroengineers who are pioneering closed-loop
neuroscience.
As shown here, cutting-edge researchers are taking advantage
of real-time or on-line processing of large streams of neural
data. This has become feasible thanks to advances in computer
processing power, in electronics such as microprocessors and
field-programmable gate arrays (FPGAs), and in specialized and
open-source software. These advances have enabled a wide variety
of new neuroscience approaches to understanding, modulating,
and interfacing with the nervous systemapproaches in which
the variables being monitored can influence the experiment in
progress, just as active sensing can influence an animals next
input.
Our call for submissions to this Frontiers in Neural Circuits
Research Topic yielded an overwhelming response, indicating
that closing the loop around neural systems is an exciting and
rapidly expanding field. Perhaps this is because of the diversity
of ways in which closed-loops can be interpreted and implemented. This Research Topic presents seven Methods articles,
16 Original Research articles, and seven Reviews, Mini-Reviews,
and Perspectives, for a total of 30 accepted papers published in
Frontiers in Neural Circuits between April 2012 and October
2013. A map showing the locations of all the contributors1 reveals
1 See: https://mapsengine.google.com/map/edit?mid=zDBeK_5W8FVs.knb4_

z5h9NpQ

Frontiers in Neural Circuits

that most are in the USA and Europe, although researchers in

Russia, Japan, and Israel are also represented.
Several articles describe or review new technologies that
increase the options for closed-loop neuroscience. Two papers
by Bareket-Keren and Hanein (2013) and Robinson et al. (2013)
review the latest in carbon nanotube and nanowire multielectrode arrays (MEAs) for neural interfacing. Franke et al.
(2012) review high-density MEAs with many electrodes and realtime spike sorting. Mller et al. (2013) present sophisticated
hardware and software for very fast (sub-millisecond) closedloop recording and stimulation of cultured networks using their
CMOS array with 11,011 electrodes. Newman et al. (2013)
created an application programming interface (API) for their
open-source NeuroRighter electrophysiology system that greatly
enhances its ability to carry out closed-loop experiments in which
recorded signals trigger electrical stimulation or other hardware.
Five examples of closed loop experiments in vitro and in vivo are
described.
A number of articles present advances using acute or cultured networks in vitro. Bonifazi et al. (2013) present EU Brain
Bow project efforts in progress, to create and study bi-directional
neural interfaces. Their work includes both patterned dissociated
cultures and their responses to laser ablation, and a whole-brain
in vitro preparation and its response to focal ischemia. The goal is
to develop the closed-loop prostheses of the future. Tessadori et al.
(2012) present their Hybrain2 software for real-time control of
hybrid neural-robotic systems, consisting in this case of a virtual
wheeled robot interfaced to a living hippocampal network on an
MEA. Brewer et al. (2013) reconstructed a hippocampal trisynaptic loop in vitro on an MEA with small tunnels for neurites to grow
through. Pimashkin et al. (2013) used an adaptively enhanced
learning protocol to study learning in dissociated hippocampal
networks on MEAs.
Others studied the nervous systems of intact or semi-intact
animals with closed-loop approaches. Nishimura et al. (2013)
restored arm movements in a spinal cord-injured non-human
primate (NHP) with an artificial cortico-spinal connection and
an artificial musculo-spinal connection. This system allows volitional control and boosting of weak, residual muscle activity.
Opris et al. (2012) enhanced performance on a delayed match-tosample task in NHPs using cortical microstimulation contingent
on recordings that predict incorrect responses. Dhingra et al.
(2013) studied the role of the vagal mechanosensory feedback

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Potter et al.

Closing the loop around neural systems

loop for respiration in a perfused in situ brainstem preparation

of a mouse model for Rett syndrome. To help map the brains
feedback loops, Beier et al. (2013) demonstrate in the mouse a
new transsynaptic retrograde tracer, based on the vesicular stomatitis virus with a rabies virus coat. Egelhaaf et al. (2012) provide a
comprehensive review of work on insect vision, emphasizing the
importance of active sensing for interpreting optic flow to optimize flying. Ejaz et al. (2013) present closed-loop experiments to
study fly visual circuits in which recorded neural responses control a fast turntable on which the fly is mounted. Gollisch and
Herz (2012) review how the locust auditory system, salamander
retina, and the monkey visual cortex have been used to efficiently
explore a large parameter space of iso-response curves, via on-line
analysis of incoming data to generate the next stimuli.
The Model-in-the-loop paradigm is a powerful approach
to understanding complex neural network dynamics. Brookings
et al. (2012) interfaced an excised crab stomatogastric ganglion
(STG) to a dynamic clamp model neuron to help determine the
relative contributions of intrinsic and network properties of STG
neurons to network function. Hsiao et al. (2013) interfaced a dentate gyrus-CA1 model to an acute hippocampal slice preparation
on an MEA, with the goal of developing cognitive prostheses that
could someday replace damaged brain regions.
Theoretical advances are described in several modeling and
simulation papers. Witt et al. (2013) modeled the ability of
closed-loop optogenetic stimulation to control communication
between neural populations by altering their phase relationships.
DiMattina and Zhang (2013) reviewed the use of feedback to
optimize stimuli continuously during an experiment, for realtime model estimation. Hanuschkin et al. (2013) modeled the
sensory-motor loop by which birds learn to produce stereotyped
songs. Skocik and Kozhevnikov (2013) demonstrate a system
for real-time audio feedback to study birdsong learning. Little
and Sommer (2013) optimized exploration strategies in embodied agents based on information-theoretic analysis. Manoonpong
et al. (2013) demonstrate the value of adaptive forward models in developing a legged robot locomotion controller. Molkov
et al. (2013) modeled the roles of local (brainstem) and distal (lungs) feedback in mammalian respiratory circuits. Wallach
(2013) reviews the concept and implementation of a response
clamp, in which closed-loop control of a selected neural response
variable is used to uncover network properties in cultured
networks.
On the clinical side, Afshar et al. (2013) describe and test a new
platform for closed-loop deep brain stimulation (DBS). This is
the beginning of smart neuromodulators that tune themselves
to provide optimal benefit to those suffering from, for example, epilepsy or Parkinsons disease. Beverlin and Netoff (2013)
present theoretical analysis of a model neural network, aimed at
closed-loop seizure control with just such a smart DBS device.
Fernandez-Vargas et al. (2013) explored closed-loop optimization
of a flickering light display as part of a visually-evoked potential
(VEP) brain-computer interface that could be used by locked-in
patients to communicate. Walter et al. (2012, 2013) explored transcranial cortical magnetic stimulation (TMS) in a motor task in
3 paralyzed stroke patients wearing a mechatronic hand orthosis.
TMS was triggered by recorded brain states that were processed

Frontiers in Neural Circuits

in real time for spectral estimation and to deal with stimulation

artifacts.
The diversity of methods, experiments, tools, and analyses in
this Research Topic suggests that many more areas of neuroscience
research would benefit from adopting a closed-loop perspective.

ACKNOWLEDGMENTS
Many thanks to all the authors and to the many reviewers who
helped make this an outstanding set of articles!

REFERENCES
Afshar, P., Khambhati, A., Stanslaski, S., Carlson, D., Jensen, R., Linde, D., et al.
(2013). A translational platform for prototyping closed-loop neuromodulation
systems. Front. Neural Circuits 6:117. doi: 10.3389/fncir.2012.00117
Bareket-Keren, L., and Hanein, Y. (2013). Carbon nanotube-based multielectrode
arrays for neuronal interfacing: progress and prospects. Front. Neural Circuits
6:112. doi: 10.3389/fncir.2012.00122
Beier, K. T., Saunders, A. B., Oldenburg, I. A., Sabatini, B. L., and Cepko, C. L.
(2013). Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo. Front. Neural Circuits
7:11. doi: 10.3389/fncir.2013.00011
Beverlin, B. II., and Netoff, T. I. (2013). Dynamic control of modeled tonic-clonic
seizure states with closed-loop stimulation. Front. Neural Circuits 6:126. doi:
10.3389/fncir.2012.00126
Bonifazi, P., Difato, F., Massobrio, P., Breschi, G. L., Pasquale, V., Levi, T., et al.
(2013). In vitro large-scale experimental and theoretical studies for the realization of bi-directional brain-prostheses. Front. Neural Circuits 7:40. doi:
10.3389/fncir.2013.00040
Brewer, G. J., Boehler, M. D., Leondopulos, S., Pan, L., Alagapan, S., Demarse,
T. B., et al. (2013). Toward a self-wired active reconstruction of the hippocampal trisynaptic loop: DG-CA3. Front. Neural Circuits 7, 165165. doi:
10.3389/fncir.2013.00165
Brookings, T., Grashow, R., and Marder, E. (2012). Statistics of neuronal identification with open- and closed-loop measures of intrinsic excitability. Front. Neural
Circuits 6:19. doi: 10.3389/fncir.2012.00019
Dhingra, R. R., Zhu, Y., Jacono, F. J., Katz, D. M., Galan, R. F., and Dick, T. E.
(2013). Decreased hering-breuer input-output entrainment in a mouse model
of rett syndrome. Front. Neural Circuits 7:42. doi: 10.3389/fncir.2013.00042
DiMattina, C., and Zhang, K. (2013). Adaptive stimulus optimization for sensory systems neuroscience. Front. Neural Circuits 7:101. doi: 10.3389/fncir.2013.
00101
Egelhaaf, M., Boeddeker, N., Kern, R., Rafael, K., and Lindemann, J. P.
(2012). Spatial vision in insects is facilitated by shaping the dynamics of
visual input through behavioral action. Front. Neural Circuits 6:108. doi:
10.3389/fncir.2012.00108
Ejaz, N., Krapp, H. G., and Tanaka, R. J. (2013). Closed-loop response properties
of a visual interneuron involved in fly optomotor control. Front. Neural Circuits
7:50. doi: 10.3389/fncir.2013.00050
Fernandez-Vargas, J., Pfaff, H. U., Rodriguez, F. B., and Varona, P. (2013). Assisted
closed-loop optimization of SSVEP-BCI efficiency. Front. Neural Circuits 7:27.
doi: 10.3389/fncir.2013.00027
Franke, F., Jaeckel, D., Dragas, J., Mller, J., Radivojevic, M., Bakkum, D., et al.
(2012). High-density microelectrode array recordings and real-time spike sorting for closed-loop experiments: an emerging technology to study neural
plasticity. Front. Neural Circuits 6:105. doi: 10.3389/fncir.2012.00105
Gollisch, T., and Herz, A. V. M. (2012). The iso-response method: measuring neuronal stimulus integration with closed loop experiments. Front. Neural Circuits
6:104. doi: 10.3389/fncir.2012.00104
Hanuschkin, A., Ganguli, S., and Hahnloser, R. H. R. (2013). A hebbian learning
rule gives rise to mirror neurons and links them to control theoretic inverse
models. Front. Neural Circuits 7:106. doi: 10.3389/fncir.2013.00106
Hsiao, M.-C., Song, D., and Berger, T. W. (2013). Nonlinear dynamical model
based control of in vitro hippocampal output. Front. Neural Circuits 7:20. doi:
10.3389/fncir.2013.00020
Little, D. Y., and Sommer, F. T. (2013). Learning and exploration in actionperception loops. Front. Neural Circuits 7:37. doi: 10.3389/fncir.2013.00037

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Manoonpong, P., Parlitz, U., and Woergoetter, F. (2013). Neural control and
adaptive neural forward models for insect-like, energy-efficient, and adaptable locomotion of walking machines. Front. Neural Circuits 7:12. doi:
10.3389/fncir.2013.00012
Molkov, Y. I., Bacak, B. J., Dick, T. E., and Rybak, I. A. (2013). Control of breathing
by interacting pontine and pulmonary feedback loops. Front. Neural Circuits
7:16. doi: 10.3389/fncir.2013.00016
Mller, J., Bakkum, D. J., and Hierlemann, A. (2013). Sub-millisecond closed-loop
feedback stimulation between arbitrary sets of individual neurons. Front. Neural
Circuits 6:121. doi: 10.3389/fncir.2012.00121
Newman, J. P., Zeller-Townson, R., Fong, M.-F., Desai, S. A., Gross, R. E., and
Potter, S. M. (2013). Closed-loop, multichannel experimentation using the
open-source NeuroRighter electrophysiology platform. Front. Neural Circuits
6:98. doi: 10.3389/fncir.2012.00098
Nishimura, Y., Perlmutter, S. I., and Fetz, E. E. (2013). Restoration of upper
limb movement via artificial corticospinal and musculospinal connections
in a monkey with spinal cord injury. Front. Neural Circuits 7:57. doi:
10.3389/fncir.2013.00057
Opris, I., Fuqua, J. L., Huettl, P. F., Gerhardt, G. A., Berger, T. W., Hampson,
R. E., et al. (2012). Closing the loop in primate prefrontal cortex: interlaminar processing. Front. Neural Circuits 6:88. doi: 10.3389/fncir.2012.
00088
Pimashkin, A., Gladkov, A., Mukhina, I., and Kazantsev, V. (2013). Adaptive
enhancement of learning protocol in hippocampal cultured networks grown
on multielectrode arrays. Front. Neural Circuits 7:87. doi: 10.3389/fncir.2013.
00087
Robinson, J. T., Jorgolli, M., and Park, H. (2013). Nanowire electrodes for highdensity stimulation and measurement of neural circuits. Front. Neural Circuits
7:38. doi: 10.3389/fncir.2013.00038
Skocik, M., and Kozhevnikov, A. (2013). Real-time system for studies of the effects
of acoustic feedback on animal vocalizations. Front. Neural Circuits 6:111. doi:
10.3389/fncir.2012.00111
Tessadori, J., Bisio, M., Martinoia, S., and Chiappalone, M. (2012). Modular
neuronal assemblies embodied in a closed-loop environment: toward future

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integration of brains and machines. Front. Neural Circuits 6:99. doi:

10.3389/fncir.2012.00099
Wallach, A. (2013). The response clamp: functional characterization of neural systems using closed-loop control. Front. Neural Circuits 7:5. doi:
10.3389/fncir.2013.00005
Walter, A., Murguialday, A. R., Rosenstiel, W., Birbaumer, N., and Bogdan,
M. (2012). Coupling BCI and cortical stimulation for brain-state-dependent
stimulation: methods for spectral estimation in the presence of stimulation
after-effects. Front. Neural Circuits 6:87. doi: 10.3389/fncir.2012.00087
Walter, A., Murguialday, A. R., Spueler, M., Naros, G., Leao, M. T., Gharabaghi,
A., et al. (2013). Erratum: coupling BCI and cortical stimulation for brainstate-dependent stimulation: methods for spectral estimation in the presence
of stimulation after-effects (vol 6, pg 87, 2012). Front. Neural Circuits 7:6. doi:
10.3389/fncir.2013.00006
Witt, A., Palmigiano, A., Neef, A., EI Hady, A., Wolf, F., and Battaglia, D. (2013).
Controlling the oscillation phase through precisely timed closed-loop optogenetic stimulation: a computational study. Front. Neural Circuits 7:49. doi:
10.3389/fncir.2013.00049
Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Received: 03 December 2013; accepted: 01 September 2014; published online: 23
September 2014.
Citation: Potter SM, El Hady A and Fetz EE (2014) Closed-loop neuroscience and
neuroengineering. Front. Neural Circuits 8:115. doi: 10.3389/fncir.2014.00115
This article was submitted to the journal Frontiers in Neural Circuits.
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