OPEN Prefrontal cortical microcircuits bind

SUBJECT AREAS:
perception to executive control
COGNITIVE CONTROL Ioan Opris1, Lucas Santos1, Greg A. Gerhardt2, Dong Song3, Theodore W. Berger3, Robert E. Hampson1
EXPERIMENTAL MODELS OF & Sam A. Deadwyler1
DISEASE
BIOMEDICAL ENGINEERING
1
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 2Department of
NEUROPHYSIOLOGY Anatomy and Neurobiology, University of Kentucky, Lexington, KY, 3Department of Biomedical Engineering, University of Southern
California, LA, CA.

Received
18 April 2013 During the perception-to-action cycle, our cerebral cortex mediates the interactions between the
environment and the perceptual-executive systems of the brain. At the top of the executive hierarchy,
Accepted prefrontal cortical microcircuits are assumed to bind perceptual and executive control information to guide
3 July 2013 goal-driven behavior. Here, we tested this hypothesis by comparing simultaneously recorded neuron firing
Published in prefrontal cortical layers and the caudate-putamen of rhesus monkeys, trained in a spatial-versus-object,
29 July 2013 rule-based match-to-sample task. We found that during the perception and executive selection phases, cell
firing in the localized prefrontal layers and caudate-putamen region exhibited similar location preferences
on spatial-trials, but less on object- trials. Then, we facilitated the perceptual-executive circuit by stimulating
the prefrontal infra-granular-layers with patterns previously derived from supra-granular-layers, and
Correspondence and produced stimulation-induced spatial preference in percent correct performance on spatial trials, similar to
requests for materials neural tuning. These results show that inter-laminar prefrontal microcircuits play causal roles to the
should be addressed to perception-to-action cycle.
I.O. (ioopris@wfubmc.

A
edu) or S.A.D. broad range of brain functions, from perceptual to executive actions encode, represent, monitor and
(sdeadwyl@ select information that is either spatial- and/or object-specific for effective behavioral performance1–7.
wakehealth.edu) Such constellations of brain abilities use large scale neural circuits consisting of thalamo-cortical loops
and cortical microcircuits with functional roles in the integration and selection of information8–10. The term
‘‘cognit’’ was coined by Fuster8 for such distributed functions in which the same neurons participate in several
different circuits (‘bottom-up’ in parietal/temporal-to-frontal and ‘top-down’ in frontal-to-caudate/putamen or
other subcortical regions)8.
It has been previously shown that dorsal visual stream of neural projections from the striate cortex to the
posterior parietal region carries the spatial information (Figure 1A) required for sensorimotor transformations in
visually guided actions, while the ventral stream projections from the striate cortex to the inferior temporal cortex
is primarily responsible for perceptual identification of objects11,12. Thus, a visual object’s qualities and its spatial
location depend on the processing of different types of visual information in the inferior temporal and posterior
parietal cortex, respectively. However, object and spatial information carried in these two separate pathways has
been shown to be integrated into a unified ‘visual percept’ in prefrontal cortex which receives connections from
both circuits11–13.
Several lines of evidence indicate that the basal ganglia participates in multiple parallel segregated circuits or
‘thalamo-cortical loops’ that make connections with motor, sensory and cognitive areas of the cerebral cor-
tex9,14,15. Prefrontal cortical areas seem to be the target of extensive, topographically organized outputs from the
basal ganglia14. Such thalamo-cortical projections from basal ganglia to the superficial and deep prefrontal cortical
layers can directly activate specific inputs to the re-entrant loop16,17. Thus, the outputs from the inter-laminar
microcircuits of prefrontal cortex are in ideal position to support the decision to act via the synchronous
excitation of the constellation of circuits in the executive hierarchy1,8.
Executive control is a fundamental function of the brain that mediates the integration of perception and action
during behaviorally relevant environmental events. It has been proposed that executive control involves a broad
network of brain areas, including frontal and parietal/temporal cortex, as well as striatum and other subcortical
structures8. These structures have been consistently associated with roles in sensorimotor integration and selec-
tion of task specific behavioral responses, commonly considered to be the regions necessary for ‘executive
decisions’18,19. However, what is not known is how such areas are synchronously activated via the inter-laminar

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Figure 1 | The perception-to-action cycle with the behavioral paradigm. (A). The illustration of the perception-to-action cycle. The diagram depicts the
flow of spatial and object signals during perceptual and executive selection of target stimuli in a rhesus macaque brain. In visual cortical area V2 visual
information splits into dorsal (spatial signals) and ventral (object signals) pathways that send signals to the top of executive hierarchy in prefrontal cortex,
and then top-down through the cortico-striatal-thalamo-cortical loops. Blue arrows depict the perceptual flow of information while red arrows indicate
the action (executive) signal flow from prefrontal cortical layer 5 to dorsal striatum, with the red dotted arrow indicating the thalamo-cortical projection
in the cortico-striatal-thalamo-cortical loop. The two adjacent cortical minicolumns with red and blue filled circles indicate inter-laminar simultaneous
recordings, while caudate-putamen recording are shown in green and pink circles. PFC-prefrontal cortex layers L2/3 and L5, and V2-secondary visual
cortex region. (B). Behavioral paradigm showing the sequence of events in the rule-based DMS task. Each trial begins with ‘trial start images’ (‘ring’ or
‘box’) to initiate an ‘object’ or ‘spatial’ trial, respectively. Then, presentation of the ‘Sample Target’ image is accompanied by a ‘Sample Response’,
followed by a variable ‘Delay’ period of 1–40 sec, with blank screen; followed by presentation of the ‘Match’ screen with Sample image accompanied by 1–
6 Non-match (distracter) images, requiring movement of the cursor into the correct Match target determined by ‘trial start’ screen (Spatial trial 5 same
location on the screen, or Object trial 5 same image-irrespective of position, responded to in the Sample phase) after presentation to receive a juice
reward, via an accessible sipper tube. Placement of the cursor into a Non-match target (.0.5 s) caused the screen to blank without reward delivery. Inter-
trial interval (ITI) 5 10.0 s. (C). Behavioral performance in the DMS task. Behavioral performance (% correct trials) is shown separately for spatial trials
(blue) vs. object trials (red) for trials ranging from 2–4 images (F(1,239) 5 12.54; p , 0.001) and 1–40 sec delays (F(1,239) 5 12.32; p , 0.001). Asterisks:
**p , 0.001, ANOVA.

microcircuits that operate to segregate information in a manner role in linking the perceptual and executive control signals is the fact
consistent with control of movements necessary during the percep- that the disruption of cortical minicolumns is present in post mortem
tion-to-action cycle that defines executive decision making in beha- cortical tissue from humans that suffered from autism29, dementia30
vioral tasks. or other psychiatric disorders.
Our approach to examine neural responses relevant to the percep-
Results tion-to-action information cycle1,8 involves determining the integ-
Prior evidence suggests that a critical role in this mechanism is played rative role of prefrontal layer 2/310,31, the role in target selection18 of
by inter-laminar microcircuits20–24 consisting of prefrontal cortical prefrontal layer 5 and the involvement of caudate in goal directed
minicolumns17,25–28 which receive converging inputs in the supra- behavior. An intriguing aspect of this approach is the involvement of
granular layers and send top-down outputs via columnar connec- the prefrontal inter-laminar microcircuit that links the perceptual
tions with sub-granular layers to dorsal striatum (caudate nucleus and executive/action related circuits as we have previously demon-
and putamen) to provide parallel cortico-striatal-thalamo-cortical strated19 in nonhuman primates. To examine how perception and
loops6,9,14,15 for different types of sensory inputs. However, the man- executive selection of visual information operate in prefrontal cor-
ner in which these local groups of neurons embedded in cortico- tico-striatal loops (Fig. 1A) we recorded simultaneously cell firing in
striatal loops dynamically encode and transform population codes the prefrontal cortical cell layers 2/3 and 5, with cell activity in the
across cortical layers to select spatial or object information for the caudate/putamen in rhesus macaques. A multi-electrode array with
executive control of behavior, remains a mystery. The evidence pre- recording locations that conformed to the microanatomy of the cor-
sented here shows that these brain structures are part of functional tex when inserted into the supra-granular and infra-granular layers
loops (Figure 1A) in which inter-laminar microcircuits or ‘minicol- in PFC was used. This allowed simultaneous recordings from mini-
umns’ in dorsolateral prefrontal cortex ‘bind’ perception and exec- columnar pyramidal cells in PFC cortical layers 2/3 & 518,19. This was
utive selection of spatial targets to guide goal-specific behavior. As combined with a tetrode array32 positioned to record simultaneously
stated in the past, it is only natural that the ‘critical link’ for this cells in the caudate-putamen while animals performed a DMS short-
process, is in the operation of prefrontal minicolumns8. Figure 1A term memory task (Fig. 1S Supplemental Information).
illustrates this perception-to-action cycle which consists of bottom- Four nonhuman primates (rhesus monkeys) were trained to per-
up visual pathways (dorsal visual stream for spatial and ventral form a delayed match to sample (DMS) task with the instruction to
stream for object information) with the associated inter-laminar select either 1) the remembered image on the screen (object trial) or
prefrontal microcircuits on top of hierarchy, and top-down cor- 2) the spatial location of the image on the screen (spatial trial), each
tico-striatal-pallidal-thalamo-cortical loops. presented in the Sample phase of the task (Fig. 1C). In both versions
One reason that supports the view that prefrontal cortical inter- of the task (Object or Spatial), subjects made hand tracking move-
laminar microcircuits at the top of executive hierarchy play an active ments to the appropriate visual targets for rewards in the Match

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Figure 2 | Neural firing in prefrontal cortical layers and striatum on spatial vs. object trials. (A–F). Example of simultaneous individual activity
(individual trial rasters and peri-event histograms) of single neurons recorded in prefrontal cortical layers L2/3 (A, D: blue) and L5 (B, E: red) with the
conformal MEA and caudate n. (C, E: green) during Sample (A,B,C) and Match (D,E,F) target presentation on Spatial (left panels) and Object (center
panels) trials during a single session (n 5 120 trials). The purple marks in the rasters represent the time when the target was reached. Directional tuning
plots (A, B, C for perception and C, D, E for executive selection, right panels) depict firing preference, measured by the radial eccentricity (in spike/sec or
Hz) in the polygonal contour for the eight different target locations on the screen where images appear. The overlay tuning plots compare firing
preferences on Spatial (black arrow) vs. Object (pink arrow) trials for the same cells. The same tuning vectors also show the magnitude of firing for
preferred locations during the encoding (left panel) and selection (right panel) phases of the task on Spatial and Object trials. Spatial trials tuning vectors
(black) show the same preferred directionality (i.e. 270u) during the encoding and selection phases in both PFC layers and in caudate nucleus, suggesting
parallel processing streams/loops through cortical minicolumns and striatum and likely through the entire thalamo-cortical loop. But when processing
object information directional preference changes in the three cells tuning plots, suggesting that object information processing does not follow in the same
‘‘foot prints’’ as processing by the same cells on Spatial trials. The radius of polar plots is represented in Hz and tuning amplitude is measured in Hz, as
well. Asterisks: **p , 0.001, ANOVA.

phase of the task (Fig. 1C). The DMS task incorporated key features The polar plots in Figure 2 show that neurons in layer 2/3 and 5
like the number of distracter images (2–4) which could appear in any fired similarly with caudate neurons and were synchronized and
of eight locations on the screen in the Match phase after variable spatially tuned to the same screen locations (black arrows).
durations of the intervening delay period (1 to 40 sec). These factors However, when the same neurons fired on object trials (blue arrows)
were reflected in the animal’s behavioral performance levels during either a decrease or a direction change in tuning (firing to preferred
encoding and selection of spatial or object stimuli as shown in location) occurred between the same 3 areas. When compared dur-
Figure 1D. ing match phase presentation (Match Tuning) neural tuning direc-
Neurons were recorded simultaneously in PFC (n 5 58 cells in tions for the 3 regions were again similar on spatial trials (black
layer L2/3 and n 5 49 cells in layer L5) and in the striatum (n 5 52 arrows), but not on object trials (blue arrows), as shown previously19.
cells, caudate and putamen) while the animals performed the DMS This feature is extremely important because it dissociates spatial
task. Only prefrontal cortical pyramidal cells with excitatory (no preference33 under these two trial conditions and indicates that
inhibitory) firing correlates to sample and match DMS task events, increased firing in these particular microcircuit connections was
and that demonstrated significant spatial tuning, were included in sensitive to particular spatial locations where task-dependent res-
analyses. Consistent with previous reports18,19 firing of cells in pre- ponses are performed.
frontal layers and minicolumns reflected differential encoding of Figure 3A compares the average firing response during sample
spatial and object trials in the DMS task. Figure 2A–F shows raster presentation (spatial perception) in PFC layers 2/3 and 5 with sim-
and peri-event histograms of cells recorded in prefrontal cortical ultaneous cell firing in the striatum. In Figure 3B average firing
layers 2/3 (A&D) and 5 (B&E), together with cells recorded simulta- responses of the same cells are compared during target selection in
neously in caudate/putamen (C&F caudate). For each of these cells the match phase. Significant increases in firing rates of cells in PFC
(Figure 2 and Figure 2S Supplementary Information) firing patterns layers and striatum were obtained during spatial trials in both the
were compared on object and spatial trials recorded during encoding perception (layer 2/3: F(1,1159) 5 21.63, p , 0.001, n 5 58; layer 5:
of sample target’s location of sample presentation on the screen F(1,979) 5 6.73, p , 0.01, n 5 49 cells; caudate: F(1,1039) 5 7.32, p
(Perception), and during: a) the selection of the matching image , 0.01, n 5 52 cells; ANOVA) and selection (layer 2/3: F(1,1159) 5
(object trials), or b) selection of the spatial location of the sample 22.47, p , 0.001, n 5 58; layer 5: F(1,979) 5 15.56, p , 0.001, n 5 49
image presentation on the screen (spatial trials), in the Match phase cells; caudate: F(1,1039) 5 9.13, p , 0.01, n 5 52 cells; ANOVA)
of the task (Selection). As indicated, both types of trials produced phases of the task (Fig. 3A&B), however, firing in these same areas
differential firing associated with Match phase selection behavior. was less during the perception phase on object trials (Fig. 3 A&C).

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Figure 3 | Mean firing responses and population tuning of prefrontal cortical and striatal cells during Spatial and Object trials. (A&B) Spatial trials.
Comparison of mean firing rates of neurons during encoding (A) and selection (B) across prefrontal cortical layers (L23 and L5 and Striatum (Caudate
nucleus) during ‘‘Spatial’’ trials. Prefrontal cortical L2/3 cells (n 5 58) showed elevated firing during encoding and selection on spatial trials. Striatal
(Caudate nucleus) cells (n 5 52) showed a higher firing rates at the trial start when the spatial rule entered in effect. PFC layer 5 cells (n 5 49) displayed
moderate involvement in perception and selection. (C&D) Object trials. Comparison of mean firing rates of the same cells during encoding (C) and
selection (D) is shown during Object trials. Cells in both prefrontal layers and striatum had much lower firing rates during Object (image) encoding and
higher rates during the match, target selection, phase. The F values for (PFC layer 2/3, PFC layer L5, caudate) in (A) Sample-Spatial (F(1,1159) 5 21.63,
p , 0.001; F(1,979) 5 6.73, p , 0.01; F(1,1039) 5 7.32, p , 0.01), (B) Match-Spatial (F(1,1159) 5 22.47; p , 0.001; F(1,979) 5 15.56; p , 0.001;
F(1,1039) 5 9.13; p , 0.01), (C) Sample-Object (F(1,1159) 5 1.46; p . 0.5; F(1,979) 5 1.27; p . 0.5; F(1,1039) 5 1.23; p . 0.5) and (D) Match-Object
(F(1,1159) 5 18.67; p , 0.001; F(1,979) 5 16.51; p , 0.001; F(1,1039) 5 14.31; p , 0.001). (E&F) Selection Phase. Comparison of neural tuning in
prefrontal cortical layers and striatum during target selection on Spatial and Object trials. In (F) the arrangement of spatial locations/directions has been
rotated so that the highest firing rates for all trials within the session correspond to 0u location/direction for every neuron. Error bars represent SEMs.
Asterisks: **p , 0.001 ANOVA.

Figure 4 | Distribution of preferred prefrontal-striatal cell firing at each target selection location. (A–C). Polar plots showing the distribution of
preferred firing directions for ‘‘Spatial’’ and ‘‘Object’’ trials in PFC layer 2/3 (A), layer 5 (B) and caudate nucleus (C) recoded simultaneously during the
executive selection (match) phase of the DMS task. The average % of cell firing for each cell type tuning vector direction (in Figure 2) is represented by the
corresponding target location in a circular histogram. The polar plot measures the percentage of cells with highest firing rates at those locations (tuning
vectors) and the asterisks indicate the highest percentage of cells from the total population with firing rates at that particular location/direction. Asterisks:
**p , 0.001, Rayleigh test.

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Figure 3D shows significant increases (layer 2/3: F(1,1159) 5 18.67, patterned stimulation previously shown to facilitate performance
layer 5: F(1,979) 5 16.51, caudate: F(1,1039) 5 14.31, p , 0.001, of the same task19,35. This is shown in Fig. 5 as a functional diagram
ANOVA) in the firing of neurons in both PFC layers and in striatum in which neural firing in PFC layer 2/3 was recorded with a multi-
for object trials during the target selection phase. Figure 3E&F shows electrode array18,19 and fed into a nonlinear multi-input–multi-out-
a direct comparison of overall firing in the Perception and Selection put (MIMO) math model (Fig. 5A & Fig. 3S Supplemental
phases across all 3 areas clearly indicating higher mean firing rates for Information), which processed and simultaneously delivered a pat-
spatial vs. object trials (F(1,1271) 5 10.96; p , 0.001, n 5 159, tern of electrical pulses from a multi-channel stimulator that mim-
ANOVA; p , 0.001; Rayleigh test). icked the correlated firing of PFC layer 5 cells on successful trials35.
Figure 4A–C shows the polar distribution of the proportion of MIMO stimulation methods and associated control procedures
tuned firing across the population of cells (PFC layer 2/3, 5 and proving columnar activation have been previously published in
caudate) shown in Figure 3E&F, for the tuning vectors during spatial detail18,35. These controls included delivery of stimulation pulse pat-
vs. object selection. Each cell’s tuning vector (see Fig 2) is mapped to terns that were different than what the MIMO model derived for
the corresponding target location/direction in a polar plot histogram. correct trials. In this case the intensity and the number of pulses, plus
The overall distribution of spatial tuning shows a general preference the area (L5) that was stimulated were identical, however the only
(layer 2/3: p , 0.001, n 5 58; layer 5: p , 0.001, n 5 49; caudate: p , factor that was different was the pattern that did not match the
0.001, n 5 52, Rayleigh test) for the contralateral targets with only a effective MIMO derived output shown in Supplementary Figure 3S.
few cells showing ipsilateral preference, as expected34. In addition, Figure 5B shows a peri-event multigram the spatial preference
this distribution on signaled spatial trials was clearly distinct from firing of a PFC layer 2/3 cell during the selection phase in which
that when object selection was the rule, which is consistent with the the cell fired highest for spatial match targets located at 315u.
perceptual dissociation of the task33. Figure 5C shows behavioral tuning across stimulation sessions under
To further test whether inter-laminar firing links spatial percep- spatial and object rules. Spatial trials showed improved accuracy
tion to executive selection we applied a novel type of closed loop when MIMO stimulation was delivered, but performance was

Figure 5 | Relations of preferred target selection location to stimulation induced enhancement of cognitive performance. (A). Application of
previously employed multi-input multi-output (MIMO) nonlinear model combined with the conformal MEA probe to extract the configuration of
electrical (bipolar) stimulation pulses (50 uA and 1 ms) delivered to columnar recording locations in PFC layer 535. (B). Peri-event multigram of a PFC
layer 2/3 cell with tuning plot showing preference for the 315u target location. (C). Distribution of MIMO-stimulation facilitated correct performance
locations for spatial vs. object trials across multiple sessions. Tuning vectors of percentage of correct responses on Spatial and Object trials show improved
performance by the MIMO stimulation was delivered on Spatial trials in which the target was in the same position as shown in Fig. 4, for the preferred
firing location (315u) of PFC and caudate neurons on nonstimulation trials. (D). Comparison of the facilitation effect of MIMO stimulation (Stim) with
control (no-stim) conditions on Spatial (n 5 40 sessions) and Object (n 5 50 sessions) locations with the highest performance levels on Stim trials with
locations of the highest performance levels on no-stim trials (Facilitated: F(1,319) 5 15.34, p , 0.001 on spatial and F(1,399) 5 12.68, p , 0.001 on
object). These selective changes in performance produced by MIMO stimulation are shown compared with overall changes across all types of trials (ALL:
F(1,319) 5 6.82, p , 0.01 on spatial and F(1,399) 5 9.51, p , 0.01 on object trials) in the same sessions. The differences in tuning reflected as highest %
correct performance indicate that MINO stimulation also enhanced the directional preference (spatial tuning bias around 315u) of the PFC layer 2/3
recorded minicolumn (Figure 4). Error bars represent SEMs. Asterisks: **p , 0.001, ANOVA.

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enhanced more on trials in which the target was in the preferred neurons in the same recorded minicolumns and that is what
firing location (315u) on the screen (p , 0.001; Rayleigh test). This improved spatial target selection in this phase of the task.
puts neural (Fig. 4) with behavioral ‘tuning’ in good agreement as it is The unique feature of these experiments is that they allow us to tap
necessary for causal relation to the perception-to-action cycle. into the perception-to-action cycle1. As a final validation of microcir-
The effectiveness of MIMO stimulation delivered to this particular cuit tuning in PFC and caudate we compared polar firing across the
region of PFC is shown in Figure 5D where the preference effect on same three nodes in the perception and selection phases on spatial
stimulated (Stim) vs. nonstim trials is compared for all Spatial (n 5 trials in which MIMO stimulation induced increases in performance.
40 sessions) and Object type trials (n 5 50 sessions) within the same Figure 6 A–C shows nearly complete overlap (between 81% and 91%)
session. The difference in mean % correct performance for all stim vs. in spatially tuned firing indicating that the majority of neural tuning
nonstim trials (ALL) is shown in comparison to stim vs. nonstim vectors for the preferred microcircuit target location (315u) facilitated
trials in which performance at locations was significantly above that task performance when subjected to MIMO stimulation during spatial
at all other locations (Facilitated). The marked difference (F(1,319) trials. The anatomic link between prefrontal cortex and striatum is
5 13.59, p , 0.001; ANOVA) in the degree of increase in % correct demonstrated physiologically normalized cross-correlations pairs of
trials produced by MIMO stimulation at preferred vs. non-preferred cells in PFC layer 5 and Caudate displaying synchronized firing during
(ALL) locations indicates that in addition to facilitating performance Match target presentation epoch (0, 2 s; red) compared to the pre-
at all response locations, the stimulation enhanced the innate dir- Match epoch (22 s, 0; blue). Therefore, such synchronized firing of
ectional preference (spatial tuning) which corresponded to the ana- PFC and Caudate neurons during the match phase (dealing with
tomic location of the PFC layer 2/3 minicolumn. This demonstrated target selection and executive control; Fig. 6E) is telling us that these
that the MIMO stimulation delivered during the match/selection key nodes in the prefrontal cortical striatal loop show the modulation
phase of the task was likely to have facilitated discharge of Layer 5 of executive control signals in the cortical-striatal executive loop9.

Figure 6 | Overlap of preferred firing and stimulation induced performance tuning during the perception-to-action cycle. (A), (B). Polar plots showing
the distribution of preferred firing direction for ‘‘Spatial’’ trials in PFC layer 2/3, layer 5 and caudate during the perception phase (A), and the executive
selection phase (B) as shown in Figure 4A–C. (C). Distribution of facilitated correct performance for spatial selection during MIMO stimulation sessions
(Figure 5D). The red dotted contour of tuned activity of the neurons from PFC layer 5 is overlaid to indicate similar preferred locations for columnar
tuning and MIMO-stimulation facilitated performance. (D). Prefrontal-striatal correlation. Normalized cross-correlations (overlay) between n 5 54
pairs of cells in PFC layer 5 and Caudate depict synchronized firing during Match target presentation (0, 2 s; red) compared to the pre-Match epoch
(22 s, 0; blue). There was a marked difference between CCHs in Match vs Pre-Match conditions; F(1,107) 5 21.82, p , 0.001; ANOVA. (E). Functional
diagram showing a representation of the flow of information in the PFC-caudate tuned spatial relationship across brain regions and behavior in the
perception-to-action cycle. Same symbols apply as in Fig. 1 A. Asterisks: **p , 0.001, ANOVA.

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Discussion in a broad spectrum of diseases like schizophrenia43, dementia30,

These novel findings demonstrate a robust involvement of cortical autism29,44, ADHD45, addiction46, aging47 and executive dysfunc-
layers and striatum in the perception-to-action cycle1,8. This is sup- tion48,49 in which inter-laminar processing is likely disrupted due to
ported by implementation of the MIMO model which extracts the cortical tissue damage or malfunction18,44,48,49.
percept from prefrontal layer 2/3 and imparts the appropriate signal
to columnar related layer 5 cells, thereby strengthening activation via Methods
the executive loop through the caudate nucleus (shown in Fig. 6D) to Four male rhesus monkeys (Macaca mulatta) were utilized as subjects in all DMS
manifest selection of a particular target location. Given these find- sessions. Single neuron activity was recorded simultaneously from PFC and striatum
ings, the functional specificity of the perceptual circuit is likely (Caudate) using our tetrode microdrive32 and a costumed-designed multi-electrode
array (MEA) specifically designed for this purpose (Center for Microelectrode
determined via ‘‘tuned’’ inter-laminar microcircuits connected to Technology – CenMet, Lexington, KY)50. Each nonhuman primate was trained to
executive prefrontal cortico-striatal, thalamo-cortical loops, that perform a complex DMS task for juice rewards18,19. Assessment of neuron activity
are translated into action via ‘‘cognits’’ that coordinate information within different PFC cortical layers and striatum was performed using recording
in large scale networks8,9,36. activity (Figs. 1S & 2S Supplementary Information) and MIMO stimulation35 (Fig. 3S
Supplementary Information) related to Match phase image presentation up until
The enhancement in cognitive performance by the MIMO stimu- completion of the motor target selection response, as shown in Figs. 2, 3, 5 and 2S
lation may be explained by induced changes in the balance between (Supplementary Information). All surgical and animal care procedures were per-
excitation and inhibition in cortical-striatal loop35,37 and by the tem- formed in accordance with National Institutes of Health guidelines and were
poral specificity of the PFC layered L2/3–L5 firing pattern35, since approved by the Wake Forest University Animal Care and Use Committee. Full
stimulation in a ‘‘scrambled’’ (random) pattern with the same pulses Methods and associated citations are available in the Supplementary Material file
associated with this manuscript.
impaired performance in prior studies18,35. The microstimulation
current activates the neighboring minicolumns around the micro-
electrode pad/tip causing the preference of this group of minicol- 1. Quintana, J. & Fuster, J. M. From perception to action: Temporal integrative
umns to win the competition for the behavioral output37. functions of prefrontal and parietal neurons. Cerebral Cortex 19, 213–221 (1999).
2. Goldman-Rakic, P. S. The prefrontal landscape: implications of functional
Consequently, the memory attractor for the encoded target may architecture for understanding human mentation and the central executive.
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mulated control trials38. This view is supported by the fact that in the 3. Posner, M. & Snyder, C. Attention and cognitive control. In Information
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4. Shallice,T. & Burgess, P. The domain of supervisory processes and temporal
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Furthermore, perception and action seem consistent with a lam- of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey:
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