386 | Nature | Vol 577 | 16 January 2020
Article
Cortical pattern generation during
dexterous movement is input-driven
Britton A. Sauerbrei1,3, Jian-Zhong Guo1,3, Jeremy D. Cohen1,3, Matteo Mischiati^1 , Wendy Guo^1 ,
Mayank Kabra^1 , Nakul Verma^2 , Brett Mensh^1 , Kristin Branson^1 & Adam W. Hantman^1 *The motor cortex controls skilled arm movement by sending temporal patterns of
activity to lower motor centres^1. Local cortical dynamics are thought to shape these
patterns throughout movement execution^2 –^4. External inputs have been implicated in
setting the initial state of the motor cortex^5 ,^6 , but they may also have a pattern-
generating role. Here we dissect the contribution of local dynamics and inputs to
cortical pattern generation during a prehension task in mice. Perturbing cortex to an
aberrant state prevented movement initiation, but after the perturbation was
released, cortex either bypassed the normal initial state and immediately generated
the pattern that controls reaching or failed to generate this pattern. The difference in
these two outcomes was probably a result of external inputs. We directly investigated
the role of inputs by inactivating the thalamus; this perturbed cortical activity and
disrupted limb kinematics at any stage of the movement. Activation of
thalamocortical axon terminals at different frequencies disrupted cortical activity
and arm movement in a graded manner. Simultaneous recordings revealed that both
thalamic activity and the current state of cortex predicted changes in cortical activity.
Thus, the pattern generator for dexterous arm movement is distributed across
multiple, strongly interacting brain regions.Reaching, grasping and object manipulation have a central role in the
lives of mammals with prehensile forelimbs. Motor cortex is a key brain
hub involved in the control of skilled movements of the arm and hand.
In primates and rodents, lesions of motor cortex can impair dexterity^7 –^9 ,
stimulation of cortical neurons evokes movements^10 –^15 , the activity
of these neurons is closely linked to movement parameters^1 ,^16 –^25 , and
optogenetic perturbations have a range of effects on different forelimb
behaviours^14 ,^22 ,^26 –^28. Recent work has emphasized that the motor cortex
is a dynamical system in which neural firing rates evolve over time as
a result of both the local cortical dynamics and external inputs from
other areas, such as the thalamus and other cortical regions^2 ,^3 (Fig. 1a).
The dynamical principles governing the cortical system, however,
remain largely unknown.
External inputs to motor cortex carry sensory information about the
arm^29 as well as signals from the cerebellum, basal ganglia and higher
cortical areas. The inputs are known to be important for movement
preparation^5 ,^6 ,^30 –^33 and sensory-based corrections^29 , but how do these
inputs work together with local dynamics to produce motor corti-
cal output during the execution of an unperturbed movement? One
possibility is that once motor cortex has been set to the appropriate
initial condition by external input, strong local dynamics generate
the output during execution, whereas external inputs are weak; that
is, the motor cortical dynamical system is largely autonomous dur-
ing movement^4 (Fig. 1b, left). However, previous studies have shown
movement-locked patterns in many brain areas providing input to
motor cortex, coherence between motor cortex and these regions^34 ,^35 ,
and disrupted cortical activity following cerebellar cooling^36 or in ani-
mal models of Parkinson’s disease^37. A second possibility is that exter-
nal inputs are needed to maintain the motor cortical dynamics in a
pattern-generating regime, but the precise temporal pattern of these
inputs is not critical to producing the correct output pattern^38. A third
possibility is that local dynamics within motor cortex must receive a
strong, time-varying input pattern to produce the appropriate output
(Fig. 1b, right). Although firing rates in thalamus are modulated on a
kinematic timescale^39 –^43 , the hypothesis that this temporal modulation
is required for the generation of time-varying output within cortex has
not been tested directly. Here we dissect the contribution of external
inputs to cortical dynamics controlling dexterous behaviour by com-
bining optogenetic perturbations of motor cortex and thalamus with
high-density electrophysiology and movement tracking.Recovery from perturbed initial states
To study cortical dynamics during dexterous movement, we trained
mice to perform a reach-to-grasp movement, which we have previ-
ously shown to depend on motor cortex^26 (Fig. 1c), and extracted arm
kinematics and behavioural waypoints from high-speed video (Fig. 1d,
Supplementary Video 1). Using silicon probes, we recorded activity
from neural ensembles in contralateral forelimb motor cortex (Fig. 1d).
Whereas the responses of individual cells were highly consistent across
trials, we observed a wide diversity of patterns across neurons, includ-
ing increases, decreases, and multi-phasic responses (Fig. 1e, f ). Thesehttps://doi.org/10.1038/s41586-019-1869-9
Received: 15 February 2018
Accepted: 29 October 2019
Published online: 25 December 2019
(^1) Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA. (^2) Department of Computer Science, Columbia University, New York, NY, USA. (^3) These authors contributed
equally: Britton A. Sauerbrei, Jian-Zhong Guo, Jeremy D. Cohen. *e-mail: [email protected]