Prefrontal Contributions To Visual Selective Attention

NE36CH20-Moore ARI 12 June 2013 12:52
ANNUAL
REVIEWS Further Prefrontal Contributions to
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Robert J. Schafer,1 and Tirin Moore1,2
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1
Department of Neurobiology and 2 Howard Hughes Medical Institute, Stanford University
School of Medicine, Stanford, California 94305; email: tirin@stanford.edu
Annu. Rev. Neurosci. 2013. 36:451–66 Keywords

The Annual Review of Neuroscience is online at
neuro.annualreviews.org cognition, neural circuitry, executive functions, visual perception
This article’s doi: Abstract
10.1146/annurev-neuro-062111-150439
The faculty of attention endows us with the capacity to process im-
Copyright c 2013 by Annual Reviews.
All rights reserved portant sensory information selectively while disregarding information
that is potentially distracting. Much of our understanding of the neural
circuitry underlying this fundamental cognitive function comes from
neurophysiological studies within the visual modality. Past evidence
suggests that a principal function of the prefrontal cortex (PFC) is se-
lective attention and that this function involves the modulation of sen-
sory signals within posterior cortices. In this review, we discuss recent
progress in identifying the specific prefrontal circuits controlling visual
attention and its neural correlates within the primate visual system. In
addition, we examine the persisting challenge of precisely defining how
behavior should be affected when attentional function is lost.
451
in low-frequency correlated variability across

Contents neuronal ensembles (Cohen & Maunsell 2009),
and increases in the phase locking of spiking re-
NEURAL CORRELATES OF
sponses with particular frequency components
VISUAL ATTENTION . . . . . . . . . . . 452
of local field potentials (LFPs) (Fries et al.
GAZE CONTROL, VISUAL
2001), as well as shifts and reductions in the
ATTENTION, AND THE FEF . . . 453
breadth of visual receptive fields (RFs) (Connor
CONTROL OF VISUAL
et al. 1997). Although we still need to determine
CORTICAL MODULATION BY
which (if any) of these parameters, including
FEF NEURONS . . . . . . . . . . . . . . . . . . 455
firing rate, is most strongly correlated with the
OPERANT CONTROL OF FEF
behavioral effects of attention, it is nonetheless
NEURONS AND VISUAL
clear that attentional deployment is associated
ATTENTION . . . . . . . . . . . . . . . . . . . . 458
with robust changes to the signaling properties
USING LOSS OF FUNCTION TO

of neurons within the visual system.

IDENTIFY SOURCES OF
Quite separate from the question of how
ATTENTIONAL CONTROL . . . . 461
attention changes the fidelity of visual signals
in the brain is the more basic question of which
mechanism initiates those changes. Although
it is overwhelmingly apparent that attention
NEURAL CORRELATES OF modulates the visual responses of neurons
VISUAL ATTENTION across many stages of the visual system, the
Attention describes the basic cognitive function neural circuits underlying that modulation
in which behaviorally relevant information remain unknown. The causal basis of visual
is selected in favor of irrelevant information selective attention has been an area of much re-
for further sensory processing and for the search for well over a century, primarily in the
guidance of behavioral responses. As William context of lesion studies, yet its origin continues
James (1890, pp. 403–4) classically described, to be one of the more fundamental unresolved
attention involves the “. . .withdrawal from questions. As we discuss in the closing section
some things in order to deal effectively with of this review, part of the reason for this
others.” Neurophysiological investigations missing information is the difficulty in defining
have established that in the visual modality, at- precisely what a loss of attention should look
tention involves the amplification of neuronal like. As a result, for example, competing hy-
representations corresponding to selected potheses of a critical role of the parietal cortex
targets at the expense of other representations (Bisley & Goldberg 2010), or of midbrain or
(Noudoost et al. 2010). Investigators have thalamic structures (e.g., Shipp 2004), or of the
observed attention-dependent modulation of prefrontal cortex (PFC) (Miller & Cohen 2001)
visually driven neural activity across multiple in visual attention have persisted in parallel,
stages of the primate visual system, primarily and almost in spite of one another, for decades.
in the form of increases in firing rate (Reynolds Given that attention has many forms (e.g.,
& Chelazzi 2004). In more recent years, spatial versus feature-based), these candidate
neurophysiological studies have found that, in structures may, in fact, contribute to these dif-
addition to increasing firing rates, attention ferent forms in complementary (e.g., Buschman
may enhance signaling efficacy for targets by & Miller 2007) or redundant ways. Yet, whether
changing other parameters of visually driven any one of them, or perhaps even some other
neural activity. These parameters include structure, is indeed a source of attentional
decreases in the trial-to-trial variability of modulation of visual signals remains to be de-
spiking activity (Mitchell et al. 2007), decreases termined. In this review, we focus on evidence
452 Squire et al.

that supports a causal role of PFC in visual Frontal

selective attention. Although it seems unlikely eye field
(FEF)
that PFC is both a necessary and a sufficient ip
p
source of attentional modulation in all its forms,
cs
recent work has nonetheless offered important
8/FEF
V2 MT 8r
46
F
new insights into what is likely a fundamental ps
contribution of PFC to visual attention. 45A
45B
The PFC consists of a multitude of frontal
V1 lu
u as
cortical areas anterior to primary and asso-
V4
ciation motor cortices, and it has long been st
sts
t ls
Anterior
implicated in high-level cognitive functions. ios
o
In humans, the PFC occupies a much larger TEO
proportion of the cerebral cortex than in other Posterior TE
species, which prompts the notion that it may

contribute more to cognitive capacities unique
to humans (Fuster 1995). Consistent with this
Figure 1
notion is the evidence that subregions within
The prefrontal cortex (PFC) of the macaque monkey and its connections with
the PFC play a crucial role in attention, includ- the posterior visual cortex. Shown in the lateral view of the monkey cerebral
ing visual attention. In particular, two regions, cortex (right hemisphere) are areas of the PFC with known involvement in
the dorsolateral prefrontal cortex (dlPFC) visual attention, particularly the frontal eye field (FEF, area 8) in the anterior
and the frontal eye field (FEF), comprising bank of the arcuate sulcus and the dorsolateral prefrontal cortex (dlPFC) in the
Brodmann areas 8, 45 and 46, have been im- principal sulcus (area 46). The arrow between the PFC and the posterior visual
cortex depicts the direct and indirect connections of the PFC to areas within
plicated (Figure 1). Beginning with the lesion the extrastriate cortex [V2, V4, MT (middle temporal), etc.]. Dotted lines
studies in monkeys conducted by David Ferrier denote cortical areas that are mostly buried within a sulcus. Abbreviations: as,
in the late nineteenth century, researchers arcuate sulcus; cs, central sulcus; ios, inferior occipital sulcus; ip, intraparietal
have known that damage to this region of the sulcus; lu, lunate sulcus; ls, lateral sulcus; ps, principal sulcus; sts, superior
PFC resulted in behavioral deficits believed to temporal sulcus. PFC areas are shown as defined in Gerbella et al. 2010.
be consistent with a loss of attentional control
(Ferrier 1876). More recently, studies in mon-
keys have yielded similar observations (Wardak (bottom-up) (Buschman & Miller 2007).
et al. 2006), as have studies of human subjects Combined with the lesion results, the evidence
with PFC damage (Knight et al. 1995, Rueckert of neural correlates in these areas has prompted
& Grafman 1996). Moreover, similar to what attempts to address the causal role of the PFC
is observed within the posterior visual cortex, in visual attention using more circuit-specific
neurophysiological studies of dlPFC and FEF approaches, particularly in the FEF.
have identified neural correlates of covert visual
attention in both of these areas. As in posterior
visual areas, visually driven responses in both GAZE CONTROL, VISUAL
areas are enhanced when attention is directed ATTENTION, AND THE FEF
to stimuli within the neuronal RF (Lebedev Before studies well established that covert
et al. 2004, Thompson et al. 2005, Buschman & attention involves a widespread modulation of
Miller 2007, Armstrong et al. 2009, Gregoriou visual activity, researchers knew that saccadic
et al. 2009). This enhancement is evident eye movements (overt attention) involve their
whether attention is directed voluntarily (top- own form of visual response modulation. In
down) (Buschman & Miller 2007, Armstrong their early studies of the visual and motor prop-
et al. 2009, Gregoriou et al. 2009) or shifted erties of neurons within the superficial layers of
to stimuli as the result of their greater salience the superior colliculus (SC) in alert monkeys,
www.annualreviews.org • Prefrontal Contributions to Attention 453

Wurtz & Goldberg (1972a,b) observed that et al. 1985). Subthreshold FEF stimulation, i.e.,
the neuronal responses elicited by visual stim- stimulation with currents below that required to
uli were enhanced when monkeys used those evoke a saccade, nonetheless increases the like-
stimuli as the targets of saccades. Similar effects lihood that an animal will subsequently initiate
were observed subsequently within the FEF the saccade represented by neurons at the stim-
(Goldberg & Bushnell 1981) and within ulation site. That is, subthreshold FEF stim-
the posterior parietal cortex (Mountcastle ulation can bias saccade planning (Schiller &
et al. 1975). Later studies demonstrated that Tehovnik 2001). The dynamics of FEF spiking
the presaccadic visual enhancement is also responses recorded during saccade tasks reveal
observed within the posterior visual cortex, a continuum of visual and movement functions
specifically in area V4 (Fischer & Boch 1981), among neurons within the FEF. Some neurons
and the inferior temporal cortex (Chelazzi et al. exhibit purely visual activity in response to
1993). These neurophysiological observations the onset of a stimulus (visual neurons), and
appear consistent with the long-appreciated others respond exclusively before a saccade
relationship between visual spatial attention is initiated (movement neurons), although
and gaze control. Gaze shifts, which are most most FEF neurons (visuomovement neurons)
often achieved by saccades, appear to occur in exhibit a combination of visual and movement
conjunction with shifts of visual attention, as properties (Bruce & Goldberg 1985, Sommer
shown by the decrement in target-detection & Wurtz 2000). The aforementioned finding
thresholds observed near the end points of of attentional modulation among FEF neurons
upcoming saccades (Hoffman & Subramaniam includes the observation that only visual and
1995, Peterson et al. 2004). In the 1980s, visuomovement neurons, and not movement
Rizzolatti and colleagues proposed a “premo- neurons, are modulated during covert atten-
tor theory of attention,” which hypothesized tion (Thompson et al. 2005, Gregoriou et al.
that the mechanisms responsible for spatial 2012).
attention and the mechanisms involved in Prompted by the psychophysical evidence of
programming saccades are the same, but that a link between saccades and attention, Moore
in the covert case “the eyes are blocked at and Fallah (Moore & Fallah 2001, Moore &
a certain peripheral stage” (Rizzolatti et al. Fallah 2004) examined whether manipulating
1987, p. 37). Subsequent studies demonstrated neural activity within the FEF could affect the
that visual detection and discrimination are in deployment of spatial attention. The authors
fact facilitated at the end points of saccades, stimulated FEF sites using subthreshold cur-
even when subjects are instructed to attend rents while monkeys monitored a target stimu-
elsewhere (Shepherd et al. 1986, Hoffman lus among distracters for a small change in lu-
& Subramaniam 1995, Deubel & Schneider minance. On trials in which microstimulation
1996). These results led to the hypothesis that occurred, monkeys were able to detect smaller
the selection of objects for perceptual process- luminance changes than they could on control
ing and the preparation of appropriate motor trials. This effect was spatially and temporally
responses are controlled by a common mech- specific: An increase in sensitivity was observed
anism. Later neurophysiological experiments only if the target location matched the end
provided crucial tests of that hypothesis. point of saccades evoked from the microstimu-
The FEF provides an interface between lation site, and the effect was strongest when on-
the saccadic system, the representation of set of microstimulation immediately preceded,
visual stimuli within posterior cortices, and the and temporally overlapped, the luminance
executive control functions of PFC. The FEF change. Moreover, the magnitude of the change
is the region from which contraversive saccadic in sensitivity produced by microstimulation
eye movements can be elicited with electrical was comparable to removing the distracters
stimulation (Robinson & Fuchs 1969, Bruce altogether.
454 Squire et al.

In addition to the behaviorally defined CONTROL OF VISUAL CORTICAL

effects of FEF microstimulation on attention, a MODULATION BY FEF NEURONS
series of related studies found that FEF micros- The fact that FEF microstimulation produces
timulation alters the visual responses of neurons attention-like modulation within area V4
within the posterior visual cortex, specifi- suggests that FEF neurons themselves are the
cally area V4. Moore & Armstrong (2003) source of that modulation. But such a conclu-
found that subthreshold microstimulation sion cannot be made. Electrical stimulation
of the FEF enhanced the visual responses in is known to antidromically activate neurons
V4 neurons at retinotopically corresponding within areas projecting to the stimulated site,
locations, whereas responses at other loca- in addition to orthodromic activation of down-
tions were suppressed. This modulation was stream neurons, and stimulation may even
stronger in the presence of distracters and was activate cells in remote regions whose axons
critically dependent on an overlap in the RF pass in proximity to the electrode tip (see Clark
of the V4 neuron and end point of saccades et al. 2011 for review). Thus, the possibility
evoked from the microstimulation site. The remains that neurons antidromically activated
enhancement also depended on the placement by stimulation, for example those within pari-
of the visual stimulus precisely at the end point etal area LIP (lateral intraparietal) (Bisley &
of evoked saccades and not merely anywhere Goldberg 2010), are in fact those directly
within the larger V4 receptive field (Armstrong responsible for producing the observed
et al. 2006). In addition, the microstimulation- modulation. In addition, the more recent
driven enhancement was larger for the V4 observation of an increased coupling of spiking
neuron’s preferred stimulus than for a non- and gamma-band local field activity between
preferred stimulus, resulting in an increase in the FEF and V4 during attention (Gregoriou
the ability of a V4 cell to discriminate between et al. 2009) has been interpreted by some as
preferred and nonpreferred stimuli (Armstrong evidence of a direct effect of FEF neurons on
& Moore 2007). Placing both a preferred and V4 (e.g., Anderson et al. 2011). Moreover,
nonpreferred stimulus within a V4 neuron’s a Granger causality analysis of the direction
RF produces a response that is intermediate of gamma-band local field potential increases
in magnitude between its responses to either suggests an early causal influence of the FEF
stimulus alone (Reynolds et al. 1999). The on V4 and a later causal influence of the latter
responses of V4 neurons to such competing RF on the former (Gregoriou et al. 2009). Though
stimuli could be biased toward one stimulus elegant, these results, like the stimulation
or the other with FEF microstimulation, results, leave open the possibility that neurons
depending on which stimulus was aligned with within one or more other structures not being
the stimulated FEF vector. This effect mirrors studied are in fact the ones driving modulation
the known influence of voluntary attention within both V4 and the FEF. Resolving the
on the responses of visual cortical neurons to question of a direct influence of FEF neurons
competing RF stimuli (Moran & Desimone on visual cortical modulation instead requires
1985, Reynolds et al. 1999). A subsequent study testing whether changes in FEF neuronal
by Ekstrom et al. 2009 examined the influence activity are sufficient to bring about that
of FEF microstimulation on visual cortical modulation. Such a test was recently carried
activity using functional magnetic resonance out by Noudoost & Moore (2011a).
imaging (fMRI), thus allowing them to see Experimental and clinical evidence suggests
effects in all visual areas. They observed mod- that dopamine (DA) within the PFC plays an
ulations in visually driven BOLD responses important role in cognitive functions, includ-
throughout the visual cortex, including V1, ing attention (Ernst et al. 1998, Castellanos
and found that the impact of microstimulation & Tannock 2002, Robbins & Arnsten 2009).
depended on the presence of distracters. Noudoost & Moore (2011a) exploited this

evidence and hypothesized that perhaps neuron activity are rather complex, evidence
DAergic activity within the FEF mediates the from a variety of experimental approaches
apparent influence that FEF neurons have on suggests that when acting via D1Rs, DA can
signals within the visual cortex. They reasoned alter the strength and reliability of converging
that if DA plays a role in visual attention, then excitatory (glutamatergic) synapses (Gao et al.
changes in DAergic activity within the FEF 2001). This property suggests a means by
should in some way alter signals within the which D1Rs could mediate the selection and
visual cortex. DAergic innervation of the PFC maintenance of particular FEF signals and the
originates from neurons within the ventral influence of those signals on other areas.
midbrain, including those within the ventral To address the direct role of FEF neuronal
tegmental area (VTA) (Björklund & Dunnett activity in the modulation of visual cortical
2007). Compared with other subtypes, D1 signals as well as the role of DA in medi-
receptors (D1Rs) are more abundant in the ating that modulation, Noudoost & Moore
PFC and are believed to play a more prominent (2011a) studied the impact of manipulating
role in regulating cognitive functions (Lidow D1R-mediated activity within the FEF on the
et al. 1991, Goldman-Rakic et al. 1992, Santana visual responses of extrastriate area V4 neurons
et al. 2009). Although the effects of DA on PFC (Figure 2a). Manipulation of D1R-mediated
a b Choice
c Fixation
Target
onset Δt
Fixation V4 RF
FEF RF
FEF
V4
Before After
Preferred
Proportion of RF choices
1.0
Nonpreferred
D1R antagonist
Control
0.5
50
Spikes/s
0 0
–40 40 120 200 280 0 0.5 1.0
RF later RF earlier Time from stimulus onset (s)
Target onset asynchrony (ms)
Figure 2
Dopamine-mediated frontal eye field (FEF) control of saccadic target selection and visual cortical responses. (a) Local manipulation of
D1 receptor (D1R)-mediated activity within the FEF during single-neuron electrophysiology in area V4. Lateral view of the macaque
brain depicts the location of a recording microinjectrode within the FEF and of recording sites within area V4. (b) A free-choice saccade
task was used to measure the monkey’s tendency to make saccades to targets within the part of visual space represented by neurons at
the drug infusion site (FEF RF) versus targets at a location in the opposite hemifield. In the task, the two targets appeared at varying
temporal onset asynchronies (t). The receptive field (RF) target appeared either earlier or later than the target outside the RF. The
monkey’s bias toward either target was measured as the asynchrony at which targets were chosen with equal probability (dotted arrows in
bottom plot). Following a local infusion of a D1R antagonist into the FEF, there was a leftward shift in the psychometric curve ( gold ),
indicating an increase in the tendency to make saccades to targets within the FEF RF. (c) Visual responses of a V4 neuron with an RF
within the FEF RF; responses were measured during passive fixation. The plot shows mean visual responses over time to oriented bar
stimuli presented at the preferred (solid lines) or nonpreferred (dotted lines) orientation both before (blue) and after (red ) the FEF D1R
manipulation. Adapted from Noudoost & Moore 2011a.
456 Squire et al.

FEF activity was achieved via small (a microliter In addition, the above effects show that DA,
or less) injections of the selective D1 antagonist acting via D1Rs, is involved in the FEF’s in-
SCH23390 into sites within the FEF. The fluence on visual cortical signals as well as its
authors then measured the spiking responses of influence on saccadic preparation. Because a
area V4 neurons that had RFs within the part of wealth of evidence implicates D1Rs in the neu-
space affected by the D1R manipulation. Thus, ral mechanisms of spatial working memory,
measurements of visually driven V4 activity specifically in regulating the persistent activ-
could be made before and after manipulating ity of neurons within the dlPFC (Williams &
the D1R-mediated activity of FEF neurons Goldman-Rakic 1995), the above results sug-
projecting to the recorded V4 neurons. In gest that D1Rs are part of a common mech-
addition, given the evidence mentioned above anism underlying spatial attention and spatial
that attentional deployment tends to coincide working memory (Noudoost & Moore 2011b).
with the preparation of saccades, the authors Like dlPFC neurons, FEF neurons also exhibit
also measured the effects of the D1R manipula- persistent, delay-period activity, even in tasks
tion on the selection of visual stimuli as targets not involving saccades (Armstrong et al. 2009)
for saccades (Figure 2b). They observed that (Figure 3). Persistent activity within the PFC
visual stimuli presented within the part of is thought to be generated by recurrent gluta-
space affected by the D1R manipulation were matergic connections between prefrontal pyra-
consistently more likely to be selected as midal neurons (Gao et al. 2001, Seamans &
saccadic targets compared with control trials. Yang 2004). DAergic modulation of persistent
Thus, the manipulation increased saccadic activity within the PFC appears to be achieved
target selection. Most importantly, within area by the influence of D1Rs on these recurrent
V4, the authors observed that responses to connections. The above results suggest a model
visual stimuli were altered in three important in which D1Rs contribute to signatures of at-
ways. First, the manipulation produced an tention within the visual cortex by a mechanism
enhancement in the magnitude of responses to similar to their influence on persistent activity,
visual stimulation (Figure 2c). Second, visual namely by modulating long-range, recurrent
responses became more stimulus selective. connections between the FEF and the visual
Third, visual responses became less variable cortex (Figure 4). Consistent with this idea is
across trials. Notably, all three of the observed the finding that FEF neurons exhibiting persis-
changes in V4 visual activity are known effects tent activity tend to exhibit greater attentional
of visual attention (Motter 1993, McAdams & modulation than do those without (Armstrong
Maunsell 1999, Mitchell et al. 2007). Moreover, et al. 2009). In the model, attention (and/or sac-
the magnitude of the observed modulation was cadic preparation) is directed toward particu-
nearly equal to that seen in attention studies. lar locations according to the pattern of activity
Thus, manipulation of D1R-mediated FEF across the map of visual space within the FEF,
activity not only increased saccadic target similar to what Bisley & Goldberg (2010) pro-
selection within the corresponding part of posed for parietal area LIP. Cortical columns
space but also increased the magnitude, selec- with greater activity would then correspond
tivity, and reliability of V4 visual responses. In to locations of greater attentional deployment
essence, the manipulation effectively elicited (and/or saccadic preparation) and consequently
correlates of covert attention within the ex- higher gain of spatially overlapping visual corti-
trastriate cortex in the absence of a behavioral cal signals, compared with nonoverlapping sig-
task. nals. A possible role of DA would be to control
The effects of the FEF D1R manipulation the extent of the FEF gain modulation, effec-
on V4 neurons show that changes to FEF neu- tively setting the breadth of the so-called at-
ronal activity are sufficient to exert a long-range tentional window. Thus, optimum DA levels
influence on signals within the visual cortex. would translate into larger differences between

Noudoost & Moore (2011a) also observed

Cue RF
that manipulation of D2 receptor (D2R)-
mediated activity increased saccadic target
Cue opposite
selection in a manner equivalent to the D1R
0.5 manipulation. However, only the D1R ma-
200 ms nipulation produced attention-like effects
within area V4; the D2R manipulation exerted
0.4
no measurable effects on the visual activity
Normalized response
of V4 neurons. Thus, in addition to being

0.3 dissociable at the level of functional subclasses
of FEF neurons (Thompson et al. 2005,
0.2
Gregoriou et al. 2009), the control of visual
attention and saccadic target selection appear
to be dissociable at the level of DA receptor

0.1 subtypes. This dissociability appears to result,
at least in part, from differing patterns of D1R
0
and D2R expression across cortical laminae
Cue Delay Delay Flash1 IFI Flash2 (Figure 4). Within the cortex, D1Rs exhibit
Figure 3 a bilaminar pattern of expression, appearing in
Modulation of frontal eye field (FEF) neuronal responses in monkeys both supragranular and infragranular layers. In
performing an attention task. In the task, monkeys fixated on a central fixation contrast, D2Rs are less abundant and tend to be
spot ( yellow dot in gray panels) and depressed a manual lever. The brief
expressed primarily within infragranular layers
appearance of a peripheral cue (white square, first panels) instructed the monkey
that, after a delay (∼1 s), a change in the orientation of a flashed grating (Lidow et al. 1991, Santana et al. 2009). In the
stimulus may occur at the cued location (50% of trials). During the grating FEF, the principal source of output to the brain
flash epoch that followed the delay, an array of six oriented gratings was flashed stem oculomotor nuclei and to the SC emanates
twice, and the monkey was rewarded for releasing the lever if the grating at the from pyramidal neurons in layer V (Segraves
cued location changed its orientation and for holding the lever if a change did
& Goldberg 1987), where both DA receptor
not occur. The diagram depicts trials without a change. The five remaining
gratings were distracters. The neuronal response histograms below show the subtypes are expressed. This finding proposes
average response of a population of 106 FEF neurons on correct trials in which how both the D1R and D2R manipulations
monkeys were cued to attend either to the location coinciding with the could have altered saccadic target selection.
receptive field (RF) of a FEF neuron (red ) or to a location in the opposite On the other hand, FEF neurons projecting
hemifield ( gray). The dotted half circle in each panel depicts the neuronal RF.
to the posterior visual cortex reside primarily
Note that the average neuronal response not only signals the visual appearance
of the brief cue but also continues to encode the attended location throughout within superficial layers II and III (Pouget et al.
the trial. Data are from only trials on which the grating orientation did not 2009), where D1Rs are the dominant receptor
change. Adapted from Armstrong et al. 2009. subtype and are thus more likely to mediate
the FEF’s influence on visual cortical activity.
attended and unattended stimuli, whereas sub-

OPERANT CONTROL OF FEF
optimal DA levels would mean small differ-
NEURONS AND VISUAL
ences and perhaps a less stable attentional fo-
ATTENTION
cus. At least superficially, such a role of DA
in attentional deployment would be consistent The aforementioned attention studies demon-
with the perceptual deficits characteristic of at- strate that when monkeys are engaged in
tention deficit hyperactivity disorder (ADHD) a learned task in which they must deploy
patients (Mason et al. 2003), who generally ex- attention, the activity of visual and visuo-
hibit abnormal PFC DA levels (Ernst et al. movement FEF neurons (as in many other
1998). areas) reflects that deployment. They do not,
458 Squire et al.

Saccade
Saccade
Supra
+ + D1Rs
D2Rs
+ +
FEF VTA
Infra
Superior
colliculus
Supra
V4
RF
RF
Figure 4
Possible influence of D1 receptors (D1Rs) on recurrent networks within the frontal eye field (FEF) and
between the FEF and V4. The diagram depicts two adjacent FEF or V4 columns representing different, but
adjacent, locations in saccadic or visual space, respectively. The columns are assumed to interact
competitively (black inhibitory neurons). Positive arrows between FEF neurons within the same column depict
the recurrent excitatory connections thought to underlie the persistence of spatial signals during
remembered saccades or locations. Recurrent activity between the FEF and V4 is proposed to underlie the
influence of FEF on the gain of visual inputs within V4. Diffuse dopaminergic input from the ventral
tegmental area (VTA) (input at right) to the FEF (all columns) may modulate recurrence both within the FEF
and between FEF and V4 through D1Rs and may influence competition between spatial representations. For
example, increases in recurrence in a particular column while remembering or attending to a corresponding
location (dotted rectangle, thicker arrows at left) may be modulated by dopamine levels. Biases in competitive
interactions between columns within the visual cortex can also be achieved by experimental manipulation of
D1R-mediated FEF activity. Also shown are the projections from infragranular FEF neurons to the superior
colliculus (SC). Red circles represent D1Rs, and blue circles indicate D2Rs. Note the localization of D2Rs
primarily in infragranular, SC-projecting, layers, which is consistent both with anatomical evidence and with
the observation that changes in D2R-mediated FEF activity affect only saccadic target selection and not
visual cortical activity. Adapted from Noudoost & Moore 2011b.

s
b 0m
1 ,50
0–
30
400 ms
FEF response field
Number of experiments
25
20 1.0 30
discrimination
% RF misses
20
Number of
15 10 0.5
neurons
10
Target
10 0 0
5 10
5 −0.5
20
0 0 −1.0 30
−0.3 −0.1 0 0.1 0.3 Up Down −200 0 200 400 −1 0 1
Control index Voluntary control Time from array Regression
condition onset (ms) coefficients
Figure 5
Operant control of frontal eye field (FEF) neurons and its effects on selective attention measured behaviorally and
neurophysiologically. (a) In the operant control task, the monkey fixated a central spot on an otherwise blank video display and was
rewarded for increasing or decreasing the firing rate of FEF neurons. The dotted circle shows the FEF receptive field (RF). Speaker
icon and musical notes depict auditory feedback of FEF neuronal activity (spike train) during a sliding 500-ms window ( gray rectangle).
Bottom plot shows a histogram of operant control indices across a population of FEF neurons. The control index measures the change
in FEF firing rate in the rewarded direction (UP or DOWN); positive values denote correct control. The light gray histogram shows all
experiments, the purple histogram shows experiments with individually significant positive control, and the dark gray histogram shows
experiments with significant negative control. (b) Behavioral and neurophysiological consequences of operant FEF control. (Top)
Visual-search probe trials, in which a search array appeared, the auditory feedback ceased (red “X” on speaker icon), and the monkey was
rewarded (blue droplet) for directing a saccade toward an oriented bar target. (Bottom left) Mean proportion of target misses opposite the
RF was increased during DOWN operant control of FEF activity in both monkeys (square and triangle symbols). (Bottom middle) Target
discrimination by FEF neurons was increased during upward (red ) operant control relative to downward (blue). (Bottom right)
Correlation of spontaneous activity with FEF responses to the target array. The direction of operant control determined the sign of the
relationship between baseline and target-driven FEF activity. Adapted from Schafer & Moore (2011).
however, show that changes in endogenously techniques to examine the impact of voluntary
generated neuronal activity in the absence of control of FEF activity on visually driven be-
an explicit task are sufficient to bring about that havior. Monkeys were given real-time auditory
deployment. Schafer & Moore (2011) tested feedback based on the firing rate of FEF activity
the hypothesis that behaviorally conditioned, and rewarded for either increasing or decreas-
voluntary changes in FEF neuronal activity ing that activity (in alternating UP and DOWN
are sufficient to bring about the deployment of blocks of trials), while maintaining central fix-
visual attention. The authors took advantage ation on a blank visual display (Figure 5a). In
of the evidence from previous studies that each behavioral trial that lasted several seconds,
demonstrated humans’ and monkeys’ ability to monkeys were rewarded every time neuronal
manipulate activity voluntarily within motor- activity measured within a moving time
related brain structures, even in the absence of window exceeded (for UP trials) or dropped
movement (Fetz & Finocchio 1975). Schafer below (for DOWN trials) an arbitrary spike
& Moore (2011) used similar operant training rate threshold. Reward therefore depended
460 Squire et al.

solely on the rate of neural activity during conditioning, demonstrating a dissociation

fixation and not on any explicit behavioral between the attention-related and motor-
task. preparatory effects of FEF activity. In addition,
The authors made several important ob- the authors found that FEF neurons could dis-
servations. First, monkeys were indeed able to criminate targets from distracters better during
alter the average firing rate of FEF neurons UP trials compared with DOWN trials. This
significantly in UP versus DOWN trials at a change in target discriminability was dependent
majority of recorded sites. Second, they found on the direction of operant control and not on
that the magnitude of voluntary modulation spontaneous fluctuations in firing rate. Lastly,
was uncorrelated with the visual or motor splitting UP and DOWN trials revealed a
properties of the individual FEF neurons being positive correlation between preprobe sponta-
recorded. That is, neurons that responded to neous firing rate and neuronal responses to the
visual stimuli, but not in advance of saccades, target in the RF during UP trials but revealed
were just as likely to be operantly controlled a negative correlation during DOWN trials.
as neurons with little or no visual activity but Thus, the direction of operant control seemed
with a great amount of saccade-related activity. to determine the nature of the relationship
Third, the authors observed significantly between spontaneous and target-driven neural
greater power in the gamma band of FEF local activity. Taken together, the above results
field potentials (LFPs). Fourth, and perhaps show that endogenous, voluntary changes in
most importantly, the authors probed the be- FEF neural activity are sufficient to bring about
havioral and neurophysiological consequences both the behavioral and the neurophysiological
of operant control of FEF activity. They effects of visual attention and that explicit
introduced probe trials in which the monkey learning of an attention task is not required.
performed a visual search task while exerting
operant control over FEF activity. Partway
through randomly chosen trials, the auditory USING LOSS OF FUNCTION TO
feedback would cease and a search array IDENTIFY SOURCES OF
appeared on the screen consisting of different ATTENTIONAL CONTROL
shapes of equal area. The monkey was then Understanding what controls a particular
rewarded for making a saccade to the oriented behavior ultimately requires demonstrating a
bar (the target) or withholding a saccade if specific loss in that behavior when the suspected
the search target was absent from the array underlying mechanism is damaged. But what
(Figure 5b). Saccades to other shapes were constitutes a loss of attention? Researchers
counted as incorrect and were not rewarded. have proposed a number of recent models to
The authors reasoned that if the monkeys’ account for the effects of attention on visual
strategy for altering FEF firing rates was one of signals (Desimone & Duncan 1995, Reynolds
general vigilance or arousal, any effects of UP et al. 2000, Reynolds & Heeger 2009, Lee &
versus DOWN modulation on behavior should Maunsell 2010). These models provide a useful
generalize across target locations. Instead, they framework for understanding the interaction
found behavioral effects of operant control of attentional control with the encoding of
that were limited to trials in which the target visual information, thus potentially allowing
appeared in the RF. Specifically, when the one to distinguish between deficits in either
target appeared in the RF, monkeys were less process. Attention is generally thought to affect
likely to detect the target (i.e., they had more the competitive interactions inherent in visual
misses) on the DOWN trials than they were on processing. For example, although a represen-
the UP trials. Unlike the effects on search per- tation with larger stimulus drive will tend to
formance, however, neither saccade probability exert greater suppression on its competitors
nor saccade metrics were affected by operant than one with lower stimulus drive, attention

This idea can be illustrated using one of the

above-mentioned models, for example, with the
normalization model described by Reynolds
& Heeger (2009). In their model, stimulus
drive combines with an attentional gain signal
(the “attention field”), and then competitive
1.0 interactions between multiple stimuli recipro-
cally inhibit one another as a function of their
activity (normalization). Using this model, we
simulated a lesion in the sensory drive indepen-
dent of attentional gain and examined its effects
Simulated response
on downstream encoding (Figure 6). The sim-

ulation shows that weakening the stimulus drive
0.5 can produce a deficit in the sensory encoding

that is dependent on the presence of other
competing stimuli. In the absence of competing
stimuli (distracters), there may be no observ-
Suprathreshold contrast, normal
Near threshold contrast, normal
able deficit in encoding, particularly when
Suprathreshold contrast, sensory lesion stimuli are sufficiently suprathreshold (e.g., at
Near threshold contrast, sensory lesion high contrast). But with multiple competing or
0
0 1 2 3 less salient stimuli, a significant deficit emerges.
Number of distracters Thus, even when attentional gain remains in-
tact, a diminution in the strength of visual input
could be sufficient to produce a distracter-
to one stimulus or the other is expected to dependent deficit. Unfortunately, distracter de-
mitigate (or exacerbate) that effect. However, pendency is often what is used to define a loss in
when attention is held constant, decreases in attentional function (e.g., De Weerd et al. 1999,
the strength of a representation can be brought Wardak et al. 2006, Lovejoy & Krauzlis 2010).
about not only by reduced competitiveness Such a definition may thus be overly broad in
with that of other stimuli, but also by reduced many cases (Desimone & Duncan 1995) and
stimulus drive, including reduced drive due may make it difficult to distinguish a role of
to brain damage. For example, cortical visual brain structures in visual attention and a role in
representations are distributed across a large visual processing, as in the case of area V4 (e.g.,
set of highly connected retinotopic maps, and Schiller & Lee 1991, De Weerd et al. 1999).
damage to a portion of one of them (e.g., V4) What then should an attention deficit look
should result in significant (yet incomplete) loss like? The answer to this question will only grow
of stimulus drive at retinotopically correspond- in importance as we contemplate future studies
ing portions in the others [e.g., V2, MT, MST investigating the neural mechanisms that are
(medial superior temporal area)]. This loss in causally related to the filtering and selection of
stimulus drive should result in a competitive behaviorally relevant sensory information (vi-
disadvantage at that spatial location within sual or otherwise). Carefully defined attention
the intact maps. As a result, because stimulus deficits are particularly important for studies
drive and attention both interact competitively, that employ cell- and circuit-specific experi-
the above models suggest that altering stimulus mental tools (Fenno et al. 2011) and for those
drive in such a way should affect the magnitude that employ animal models with more rudi-
of neural responses in a manner consistent mentary forms of attention-related behavior
with a loss of attention, even when attention is than primates (Muir et al. 1992). Subsequent at-
functioning normally. tempts to pinpoint the neurons, neural circuits,
462 Squire et al.

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 6
Distracter-dependent deficits from a loss of visual inputs in a normalization model of attention. (Top, left to
right) Schematic representations of a visual display with a target stimulus (Gabor grating) in isolation or with
one, two, or three distracters. In each display, the gray dot depicts the point of fixation during a covert
attention task. The dotted green line depicts the region of space affected by the lesion (the scotoma), the
attended location, and the receptive field of the simulated neuron. Both the location of attention and the
target stimulus are constant across the different distracter conditions, and the distracters have the same
contrast as the target. (Bottom) Responses of a simulated neuron as a function of the number of distracters in
the display. Without a lesion (blue and red solid lines), the responses remain nearly constant across the number
of distracters. With a visual lesion (dotted lines), which weakens the stimulus drive while leaving the attention
gain intact, responses become compromised as more distracters are added to the display. The distracter-
dependent deficits are less severe for high-contrast stimuli (red lines) than for near threshold, low-contrast
stimuli (blue lines). Model: The set of Matlab routines provided by the normalization model of attention
(NMA) (Reynolds & Heeger 2009) was used to implement the present simulation. In the NMA, stimulus-
driven inputs (stimulus drive) are multiplied by an attention gain signal (attention field), after which
competitive interactions between all units reciprocally inhibit one another as a function of their activities
(normalization) to yield the responses of the neurons in the model. Here, four significant additions were
made. First, the script for figure3F.m (Reynolds & Heeger 2009) was augmented to simulate multiple
distracters. Second, for more control over the spread and magnitude of the inhibition underlying the
competitive interactions between neurons (i.e., normalization), an additional variable, IxKernelHeight, was
added. IxKernelHeight allowed the user, along with the preexisting variable IxWidth, to independently
control the height and width of the Gaussian inhibition kernel, respectively. Third, to simulate a lesion in
the stimulus drive, independent of the attention gain, the stimulus drive was multiplied by a lesion matrix
before any other computations were performed. This produced a lesioned stimulus drive matrix that the
model used in place of the original stimulus drive. The lesion matrix consisted of values ranging between 0
and 1, and it can be visualized as an inverted Gaussian (specified by the variables lesionWidth and lesionDepth)
centered on the spatial center of the lesion. Multiplying the lesion matrix with the stimulus drive to create
the lesioned stimulus drive is equivalent to a gain down-modulation of the original stimulus drive. Fourth, to
simulate model neurons with saturating responses, final responses in the present simulation were computed
by passing the output of the NMA through a simple sigmoidal function: Final Response = 1/(1 +
∗
e(β (H−x)) ), where e is the natural number, β modifies the slope of the sigmoid, H is equal to the half-max
value of the sigmoid, and x is equal to the output of the NMA. Parameters: Apeak = 2; AxWidth = 7; β =
0.75; H = 7; IxKernelHeight = 0.0175; IxWidth = 100; lesionWidth = 7; lesionDepth = 0.5; stimWidth = 7.
and neural computations that confer a nervous separate from processing itself, appear to be
system with the unique capacity to distinguish what most specifically defines attention. We
a target from distracters will need to determine therefore suggest that the loss of function one
more definitively when a behavioral phenotype should expect when attentional mechanisms
reflects a loss in that capacity rather than a are absent is a loss of such benefits rather
loss in some other function. In this review of than a deficit in sensory processing per se. We
recent evidence for the PFC’s contribution to assume that independent of the absolute level
visual attention, we have highlighted studies of perceptual performance, or even the degree
that demonstrate experimentally produced of distracter dependency, a loss of attentional
benefits in visual processing, either by neurons control should result in performance that
(Noudoost & Moore 2011a, Schafer & Moore cannot be improved by attentional cues. Re-
2011) or in behavioral performance (Schafer markably, most, if not all, of the experimental
& Moore 2011). Such benefits in processing, literature is devoid of such results.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
This work was supported by NIH EY014924. The authors thank J.H. Reynolds, for discussion and
comments on our use of the normalization model, and members of the Moore lab, for insightful
discussions.
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Neuronal Computations in the Olfactory System of Zebrafish
Rainer W. Friedrich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 383
Transformation of Visual Signals by Inhibitory Interneurons in Retinal
Circuits
Pablo D. Jadzinsky and Stephen A. Baccus p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 403
Electrical Compartmentalization in Dendritic Spines

Rafael Yuste p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429

Prefrontal Contributions to Visual Selective Attention
Ryan F. Squire, Behrad Noudoost, Robert J. Schafer, and Tirin Moore p p p p p p p p p p p p p p p p 451
Gene Therapy for Blindness
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Translating Birdsong: Songbirds as a Model for Basic and Applied
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Transient Receptor Potential Channels and Mechanosensation
Niels Eijkelkamp, Kathryn Quick, and John N. Wood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519
The Molecular Basis of Self-Avoidance
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NE36CH20-Moore ARI 12 June 2013 12:52

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Annu. Rev. Neurosci. 2013. 36:451–66 Keywords

in low-frequency correlated variability across

USING LOSS OF FUNCTION TO

of neurons within the visual system.

452 Squire et al.

that supports a causal role of PFC in visual Frontal

species, which prompts the notion that it may

www.annualreviews.org • Prefrontal Contributions to Attention 453

454 Squire et al.

In addition to the behaviorally deﬁned CONTROL OF VISUAL CORTICAL

www.annualreviews.org • Prefrontal Contributions to Attention 455

456 Squire et al.

www.annualreviews.org • Prefrontal Contributions to Attention 457

Noudoost & Moore (2011a) also observed

of V4 neurons. Thus, in addition to being

to be dissociable at the level of DA receptor

attended and unattended stimuli, whereas sub-

458 Squire et al.

www.annualreviews.org • Prefrontal Contributions to Attention 459

460 Squire et al.

solely on the rate of neural activity during conditioning, demonstrating a dissociation

www.annualreviews.org • Prefrontal Contributions to Attention 461

This idea can be illustrated using one of the

on downstream encoding (Figure 6). The sim-

0.5 can produce a deﬁcit in the sensory encoding

462 Squire et al.

www.annualreviews.org • Prefrontal Contributions to Attention 463

464 Squire et al.

prefrontal and visual cortex during attention. Science 324:1207–10

www.annualreviews.org • Prefrontal Contributions to Attention 465

466 Squire et al.

Volume 36, 2013

Active Properties of Neocortical Pyramidal Neuron Dendrites

Developmental Mechanisms of Topographic Map Formation

Cortical Control of Arm Movements: A Dynamical

Electrical Compartmentalization in Dendritic Spines

Rafael Yuste p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429

Cumulative Index of Contributing Authors, Volumes 27–36 p p p p p p p p p p p p p p p p p p p p p p p p p p p 569

An online log of corrections to Annual Review of Neuroscience articles may be found at

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