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A
circuit
for
pupil
orienting
responses:
implications
for
cognitive
modulation
of
pupil
size
Chin-An
Wang
and
Douglas
P
Munoz
Pupil
size,
as
a
component
of
orienting,
changes
rapidly
in
response
to
local
salient
events
in
the
environment,
in
addition
to
its
well-known
illumination-dependent
modulation.
Recent
research
has
shown
that
visual,
auditory,
or
audiovisual
stimuli
can
elicit
transient
pupil
dilation,
and
the
timing
and
size
of
the
evoked
responses
are
systematically
modulated
by
stimulus
salience.
Moreover,
weak
microstimulation
of
the
superior
colliculus
(SC),
a
midbrain
structure
involved
in
eye
movements
and
attention,
evokes
similar
transient
pupil
dilation,
suggesting
that
the
SC
coordinates
the
orienting
response
which
includes
transient
pupil
dilation.
Projections
from
the
SC
to
the
pupil
control
circuitry
provide
a
novel
neural
substrate
underlying
pupil
modulation
by
various
cognitive
processes.
Address
Centre
for
Neuroscience
Studies,
Queen’s
University,
Kingston,
Ontario,
Canada
Corresponding
author:
Munoz,
Douglas
P
(doug.munoz@queensu.ca)
Current
Opinion
in
Neurobiology
2015,
33:134–140
This
review
comes
from
a
themed
issue
on
Motor
circuits
and
action
Edited
by
Ole
Kiehn
and
Mark
Churchland
http://dx.doi.org/10.1016/j.conb.2015.03.018
0959-4388/#
2015
Published
by
Elsevier
Ltd.
Introduction
Efficient
visual
coding
begins
in
the
eye.
Light
enters
the
eye
through,
and
is
controlled
by,
the
pupil.
The
pupil
constricts
in
response
to
an
increase
of
global
luminance
level,
which
is
typically
referred
to
as
the
pupillary
light
reflex,
and
it
dilates
for
a
global
luminance
decrease,
referred
to
as
the
darkness
reflex
[1].
The
quality
of
the
signal
projected
on
the
retina
is
already
under
the
control
of
this
simple
mechanism.
This
illumination-
dependent
pupil
modulation
is
well
understood,
and
thought
to
regulate
the
trade-off
between
sensitivity
and
sharpness
for
the
optimization
of
image
quality
[2,3].
Additionally,
pupil
dilation
has
been
linked
to
various
cognitive
processes
[4],
which
we
refer
to
as
cognition-related
pupil
responses.
Over
the
past
decade,
a
growing
body
of
research
has
used
pupil
size
to
investi-
gate
various
cognitive
processes,
demonstrating
correla-
tions
between
pupil
size
and
aspects
in
cognition
such
as
target
detection,
perception,
learning,
memory,
and
de-
cision
making
(e.g.
[5–12]).
Changes
in
pupil
size
have
also
been
associated
with
the
orienting
response
[13,14],
we
refer
to
these
responses
as
orienting-related
pupil
responses.
The
presentation
of
a
salient
stimulus
initiates
a
series
of
responses
to
orient
the
body
for
appropriate
action,
including
not
only
saccades
and
attentional
shifts
[15,16],
but
also
transient
pupil
dilation
[1,17
,18
,19
].
The
function
of
this
pupil
dila-
tion
is
thought
to
increase
visual
sensitivity
[13],
although
empirical
evidence
to
support
the
argument
is
lacking
[20].
The
superior
colliculus
(SC;
optic
tectum
in
non-
mammals),
one
of
most
important
structures
related
to
saccadic
eye
movements
and
spatial
attention
[21,22
],
may
also
play
a
central
role
in
coordinating
this
orienting-
related
pupil
response
[17
,18
,23,24
],
highlighting
a
novel
neural
substrate
to
possibly
coordinate
various
cognitive
processes
and
pupil
diameter.
Here,
we
review
the
evidence
supporting
the
link
of
the
SC
to
orienting-
related
pupil
responses,
focusing
on
recent
work
in
mon-
keys
and
humans.
Pupil
control
circuit
Pupil
size
is
controlled
by
the
balanced
activity
between
sympathetic
and
parasympathetic
pathways
(Figure
1)
that
have
been
identified
and
reviewed
in
detail
else-
where
[1,25].
Briefly,
in
the
parasympathetic
system,
reti-
nal
ganglion
cells
project
directly
to
the
pretectal
olivary
nucleus
(PON),
which
in
turn
projects
bilaterally
to
the
Edinger–Westphal
(EW)
nucleus
[26].
Preganglionic
para-
sympathetic
neurons
in
the
EW
project
to
the
ciliary
ganglion
to
control
pupillary
constriction
muscles
of
the
iris
[1].
Pupil
size
is
also
controlled
by
the
dilator
muscle
that
is
innervated
by
sympathetic
nerves
from
the
superior
cervical
ganglion
(SCG),
which
is
driven
by
a
circuit
originating
in
the
hypothalamus
via
the
spinal
cord
[1,25].
Although
the
neural
substrate
mediating
cognitive
state
and
pupil
dilation
is
less
clear,
the
locus
coeruleus-nor-
epinephrine
system
(LC-NE)
is
regularly
implicated
[70].
Anatomically,
the
LC
has
efferent
projections
to
the
EW
nucleus
and
the
spinal
cord
[25]
to
connect
with
both
parasympathetic
and
sympathetic
pathways,
respectively
(Figure
1).
Furthermore,
the
LC
has
been
associated
with
many
functions
related
to
cognition,
arguably
via
arousal
mechanisms
[27
].
One
important
preliminary
study
has
reported
a
correlation
between
pupil
size
and
LC
activity
in
monkey
single
cell
recording
[28
].
In
humans,
drugs
assumed
to
alter
arousal
level
via
modulating
LC
activity
Available
online
at
www.sciencedirect.com
ScienceDirect
Current
Opinion
in
Neurobiology
2015,
33:134–140
www.sciencedirect.com
also
change
pupil
size
accordingly
[29],
and
pupil
diame-
ter
is
linked
to
LC
activation
in
a
recent
fMRI
study
[30].
Behavioral
studies
have
shown
that
the
relationship
be-
tween
changes
in
pupil
size
and
task
performances
can
be
well
explained
by
assuming
that
pupil
size
reflects
LC
activity
[10,31,32].
Although
it
is
generally
accepted
that
pupil
size
is
modulated
by
activity
in
the
LC-NE
system
likely
via
changing
arousal
state,
there
is
likely
an
addi-
tional
pathway
that
also
mediates
cognition-related
pupil
responses.
The
superior
colliculus
(SC)
is
a
midbrain
structure
with
neurons
organized
into
a
retinotopically
coded
map
of
contralateral
visual
and
saccade
space.
The
SC
is
functionally
separated
into
superficial
visual-only
layers
(SCs)
that
receive
inputs
from
the
retina
and
visual
cortex,
and
intermediate
layers
(SCi)
that
receive
convergent
cognitive,
multi-sensory,
and
motor
inputs
[33,34].
Moreover,
the
SCi
projects
directly
to
the
brainstem
premotor
circuit
to
execute
orienting
responses.
An
increasing
number
of
studies
have
sug-
gested
that
the
SCi
encodes
both
stimulus
salience
and
relevance
to
coordinate
various
components
of
orienting
[35,36
,37,38],
including
not
only
shifts
of
gaze
and
attention,
but
also
pupil
dilation
[17
,18
,23,24
,39].
The
SC
has
direct
connections
to
the
pupil
pathways
(Figure
1).
The
SCs
projects
ipsilaterally
to
the
PON
[40].
The
SCi
receives
inputs
from
the
SCs,
frontal-parietal
areas,
and
the
basal
ganglia,
as
well
as
the
LC
[41].
The
SCi
projects
directly
and
indirectly
to
the
EW
[40,42,43],
possibly
activating
and
inhibiting
parasympathetic
path-
ways,
respectively.
The
SCi
could
modulate
the
sympa-
thetic
system
through
efferent
projections
to
the
mesencephalic
cuneiform
nucleus
(MCN)
[33,44,45],
a
brainstem
area
regulating
stress-related
and
defensive
responses
[46,47].
Stimulation
of
the
MCN
activates
sympathetic
vasomotor
outflow
[48],
including
modula-
tion
of
pupil
size
[1].
Therefore,
the
SC
has
the
necessary
connections
to
coordinate
orienting-related
pupil
responses
via
key
inputs
to
the
pupil
control
circuit.
Pupil
responses
to
salient
stimuli
Numerous
studies
have
identified
a
significant
effect
of
stimulus
saliency
on
shifts
of
gaze
and
attention
[15,16],
but
saliency
effects
on
the
orienting-related
pupil
response
are
less
understood.
Stimulus
contrast
is
one
of
the
most
primitive
saliency
components
[49],
and
has
been
imple-
mented
as
a
component
of
saliency
in
a
number
of
compu-
tational
models
[50].
Changing
the
contrast
of
a
target
has
dramatic
effects
on
sensory
responses
in
the
SCi
and
ensuing
saccadic
reaction
times
(SRT),
with
faster
and
greater
SCi
activity
and
faster
SRTs
for
higher
contrast
stimuli
[51–53].
Moreover,
auditory
stimuli
tend
to
induce
faster,
but
smaller
sensory
responses
in
the
SCi
com-
pared
to
those
produced
with
visual
stimuli
(Figure
2a)
[54
].
If
transient
pupil
dilation
is
linked
to
saliency
via
the
SCi,
it
should
occur
regardless
of
stimulus
modality,
particularly
on
a
salient
non-visual
(i.e.,
auditory)
stim-
ulus,
and
the
magnitude
and
timing
of
evoked
pupil
responses
should
scale
with
the
level
of
stimulus
con-
trast.
Recent
studies
have
shown
that
pupil
responses
were
induced
by
presentation
of
visual
stimuli,
and
evoked
responses
were
qualitative
similar
to
those
evoked
by
auditory
stimuli
(Figure
2b)
[18
],
suggest-
ing
that
these
responses
are
dissociable
from
illumina-
tion-dependent
pupil
responses.
Most
importantly,
the
transient
pupil
responses
scaled
with
stimulus
contrast,
with
faster
and
greater
responses
for
higher
visual
stim-
ulus
contrast
and
louder
auditory
stimuli.
Additionally,
auditory
stimuli
evoked
faster
pupil
responses
compared
Pupil
orienting
circuit
Wang
and
Munoz
135
Figure
1
C
ONSTRICTION
D
ILATION
P
ARASYMPATHETIC
S
YMPATHETIC
V1
EXTRA-
STRIATE
T
HALAMUS
BG
R
ETINA
SCs
SCi
F
RONTAL
P
ARIETAL
SCG
S
PINAL
M
EDULLA
H
YPOTH
LC
CG
EW
PON
MCN
Current Opinion in Neurobiology
Schematic
of
the
pupil
orienting
circuit.
See
text
for
details.
Abbreviations:
BG,
basal
ganglia;
CG,
ciliary
ganglion;
EW,
Edinger–
Westphal
nucleus;
Hypoth,
hypothalamus;
LC,
locus
coeruleus;
MCN,
mesencephalic
cuneiform
nucleus;
PON,
pretectal
olivary
nucleus;
SCi,
intermediate
layers
of
the
superior
colliculus;
SCs,
superficial
layers
of
the
superior
colliculus;
SCG,
superior
cervical
ganglion;
V1,
primary
visual
cortex.
www.sciencedirect.com
Current
Opinion
in
Neurobiology
2015,
33:134–140
to
visual
stimuli,
consistent
with
modality
effects
observed
in
SCi
neuronal
activity
[54
].
Overall,
these
results
suggest
that
transient
pupil
dilation,
as
one
component
of
orienting,
is
modulated
by
stimulus
contrast,
likely
mediated
via
the
SCi.
Pupil
responses
to
multisensory
stimuli
Salient
visual
and
auditory
stimuli,
when
presented
alone,
elicit
transient
pupil
dilation.
This
raises
an
intriguing
question
of
how
salient
signals
from
the
different
modal-
ities
(i.e.,
visual
and
auditory)
are
combined
to
influence
pupil
dynamics.
One
hallmark
of
SCi
processing
is
mul-
tisensory
integration
[55].
If
the
orienting-related
pupil
responses
are
coordinated
by
the
SCi,
salient
stimuli
presented
from
different
modalities
should
be
integrated
in
the
SCi
to
produce
coordinated
pupil
responses.
Be-
cause
response
onset
latencies
evoked
by
auditory
sti-
muli
in
the
SCi
are
faster
than
those
evoked
by
visual
stimuli
(Figure
2a)
[54
],
the
earliest
component
of
pupil
responses
induced
by
audiovisual
stimuli
should
be
similar
to
that
induced
by
auditory
stimuli,
and
pupil
response
magnitude
should
be
enhanced
in
the
audiovi-
sual
condition.
Consistently,
the
presentation
of
com-
bined
visual
and
auditory
stimuli
induced
similar
pupil
responses
in
monkeys
(Figure
3a),
with
greater
response
magnitude,
compared
to
single
modality
presentation
[18
].
Moreover,
response
latencies
in
the
audiovisual
condition
were
similar
to
those
in
the
auditory
alone
condition,
but
faster
than
those
in
the
visual
alone
con-
dition,
again
suggesting
that
the
SCi
is
involved
in
integrating
multisensory
stimuli
for
orienting-related
pupil
responses.
Effects
of
pupil
responses
evoked
by
the
presentation
of
salient
stimuli
have
also
been
demonstrated
in
humans
and
again,
the
size
and
magnitude
of
evoked
pupil
responses
scaled
with
the
level
of
stimulus
contrast
[19
].
Faster
pupil
responses
were
induced
by
auditory,
compared
to
visual
stimuli
(Figure
3b),
and
audiovisual
stimuli
evoked
larger
pupil
response
magnitude,
com-
pared
to
visual
or
auditory
alone
stimuli
[56].
In
sum-
mary,
qualitatively
similar
pupil
modulations
have
been
observed
in
both
humans
and
monkeys
(Figure
3).
Pupil
responses
to
SC
microstimulation
Although
the
central
role
of
the
SCi
on
shifts
of
gaze
and
attention
is
well-established
[21,22
],
its
role
is
less
clear
on
other
components
of
orienting
such
as
pupil
dilation.
SCi
microstimulation
evokes
saccades
and
deactivation
of
the
SCi
interrupts
saccades
toward
the
affected
location
of
the
visual
field
[21].
Studies
exploring
SCi
microsti-
mulation
on
the
shift
of
attention
demonstrate
facilitative
effects
for
stimuli
presented
in
the
stimulated
location
of
the
visual
field
and
neurons
recorded
in
the
SCi
are
also
modulated
by
covert
shifts
of
attention
[22
].
Recently,
it
has
shown
that
deactivation
of
the
SCi
diminishes
covert
136
Motor
circuits
and
action
Figure
2
0 250 500 750 1000
−0.04
−0.02
0
0.02
0.04
Normalized pupil diameter (mm)
VisLow
VisHigh
AudLow
AudHigh
Time from stimulus onset (ms)
30 sp/s
0 250 500
Visual
Auditory
SCi activity
0
250
500 750 1000
0
0.02
0.04
Time from SCi microstimulation (ms)
SCi-stim
(c)
(b)
(a)
Normalized pupil diameter (mm)
Current Opinion in Neurobiology
Effect
of
contrast-based
saliency
modulation
and
SCi
microstimulation
on
transiently
evoked
pupil
responses.
(a)
Population
activity
recorded
from
the
monkey
SCi
following
the
presentation
of
visual
(red
trace)
or
auditory
(blue
trace)
stimuli
(adapted
with
permission
[54
]).
(b)
Normalized
pupil
responses
following
the
presentation
of
visual
or
auditory
stimuli
with
two
different
levels
of
stimulus
contrast
(high-
visual
and
low-visual
contrast
or
high-auditory
and
low-auditory
intensity)
(adapted
with
permission
[18
]).
(c)
Normalized
pupil
responses
following
SCi
microstimulation
(adapted
with
permission
[24
]).
Gray
bar
on
X-axis
indicates
the
time
line
of
stimulation
(a:
50
ms;
b
and
c:
100
ms).
VisHigh:
high
contrast
visual
stimulus;
VisLow:
low
contrast
visual
stimulus;
AudHigh:
high
auditory
intensity
stimulus;
AudLow:
low
auditory
intensity
stimulus;
SCi:
intermediate
layers
of
the
superior
colliculus.
Current
Opinion
in
Neurobiology
2015,
33:134–140
www.sciencedirect.com
selection
of
task-required
information
on
the
affected
location
of
visual
field
[57],
establishing
a
causal
role
of
the
SC
on
attention.
Microstimulation
of
the
monkey
SCi,
subthreshold
for
saccade
initiation,
also
elicited
transient
pupil
dilation
(Figure
2c)
[24
].
Similar
pupil
dilation
was
also
evoked
by
microstimulation
in
the
deep
layers
of
the
optic
tectum
in
anesthetised
barn
owls
[17
].
Given
that
pupil
dilation
was
not
evoked
by
weak
microstimulation
of
the
SCs
[24
],
projections
from
the
SCi
to
the
EW
and
MCN
may
underlie
this
pupil
response
by
either
inhi-
biting
the
parasympathetic
pathway,
activating
the
sympathetic
pathway,
or
both.
Moreover,
the
pupil
response
latency
and
magnitude
evoked
by
SCi
stimu-
lation
was
similar
to
that
induced
by
salient
auditory
and
visual
stimuli
(compare
Figure
2b
and
c).
Although
there
were
differences
in
the
sustained
portion
of
the
pupil
response
between
salient
stimulus
presentation
versus
SCi
microstimulation,
the
initial
increase
of
pupil
dilation
was
comparable
and
in
line
with
the
suggested
role
of
the
SCi
in
driving
the
initial
orienting
response.
These
results
also
raise
one
intriguing
possibility
that
pupil
dilation
evoked
by
SCi
microstimulation
may
contribute
to
some
facilitative
effects
in
behavior.
How-
ever,
future
research
is
required
to
address
this
question
in
detail.
Modulation
of
pupil
responses
by
saccade
preparation
Pupil
responses
are
also
modulated
by
top-down
process-
es
[4],
and
some
of
these
modulations
may
be
associated
with
SC-mediated
pupil
pathways.
The
anti-saccade
task
is
frequently
used
to
examine
voluntary
control
because
subjects
are
instructed
prior
to
stimulus
appearance
to
either
generate
a
pro-saccade
(look
at
a
peripheral
stimu-
lus)
or
an
anti-saccade
(look
in
the
opposite
direction
of
the
stimulus).
Unlike
the
automatic
visuomotor
response
required
in
the
pro-saccade
condition,
to
complete
an
anti-saccade,
subjects
must
suppress
the
automatic
sac-
cade
and
generate
a
voluntary
response
in
the
opposite
direction
of
the
stimulus.
Distinct
neural
preparatory
activity
is
required
to
successfully
generate
pro-saccade
versus
anti-saccade
[58],
particularly
in
the
SC
and
frontal
eye
field
(FEF),
with
higher
inhibition-related
fixation
activity
(rostral
SC)
in
preparation
for
anti-saccade
com-
pared
to
pro-saccade.
Moreover,
the
level
of
preparatory
activity
(caudal
SC)
related
to
motor
preparation
negatively
correlated
with
SRTs
[59,60].
Similarly,
in
human
func-
tional
magnetic
resonance
imaging
studies,
there
is
higher
FEF
activation
during
preparation
for
anti-saccades
com-
pared
to
pro-saccades
[61–63],
and
this
preparatory
activity
in
the
FEF
negatively
correlates
with
SRTs
[64,65].
Because
pupil
dilation
is
evoked
by
microstimulation
of
both
rostral
and
caudal
SC
[24
],
pupil
size
should
reflect
both
types
of
preparatory
activity.
Consistently,
human
pupil
size
was
larger
in
preparation
for
correct
anti-
saccades,
compared
to
correct
pro-saccades
and
errone-
ous
pro-saccades
made
in
the
anti-saccade
condition
(Figure
4a
and
b)
[66
].
Furthermore,
larger
pupil
dila-
tion
prior
to
stimulus
appearance
accompanied
saccades
with
faster
reaction
times
(Figure
4c
and
d),
together
suggesting
that
pupil
size
is
an
effective
proxy
of
neural
activity
related
to
preparation
of
pro-saccade
and
anti-
saccade.
Pupil
orienting
circuit
Wang
and
Munoz
137
Figure
3
0 500 1000
−0.05
0
0.05
Time from stimulus onset (ms)
Normalized pupil diameter (mm)
0 500 1000 1500 2000
0
0.04
0.08 Auditory
Visual
Audiovisual
Auditory
Visual
Audiovisual
(a) (b)
Current Opinion in Neurobiology
Monkey Human
Multisensory
integration
of
orienting-related
pupil
responses.
(a)
Monkey
transient
pupil
responses
evoked
by
presentation
of
visual-alone
(red
traces),
auditory-alone
(blue
traces),
or
combined
audiovisual
stimulus
(purple
traces)
(adapted
with
permission
[18
]).
(b)
Human
transient
pupil
responses
evoked
by
presentation
of
visual-alone,
auditory-alone,
audiovisual
stimulus.
Gray
bar
on
X-axis
indicates
the
time
line
of
stimulation
(100
ms).
www.sciencedirect.com
Current
Opinion
in
Neurobiology
2015,
33:134–140
Conclusions
and
clinical
applications
The
orienting-related
pupil
response
has
the
potential
to
be
used
as
a
biomarker
for
clinical
investigation
because
of
the
proposed
link
of
top-down
processes
in
the
frontoparietal
cortex
and
basal
ganglia
to
the
pupil
control
circuit
via
the
SCi
(Figure
1).
We
propose
that
dysfunction
in
the
fronto-
parietal
cortex
and
basal
ganglia
can
lead
to
altered
pupil
responses
in
cognitive
tasks.
For
example,
the
ability
to
recognize
stimulus
saliency
is
impaired
among
patients
with
neurological
disorders
[67]
and
these
effects
could
be
medi-
ated
via
the
SCi.
It
has
been
suggested
that
low
salient
stimuli
could
induce
maximal
dopamine
released
as
high
salient
stimuli
in
schizophrenia
[68].
Therefore,
modulations
of
stimulus
salience
on
pupil
size
should
be
greatly
reduced
in
schizophrenia.
Because
autism
participants
show
less
interesting
to
eye-face
stimuli
[69],
pupil
responses
induced
by
the
presentation
of
eye-face
stimuli
should
also
be
attenuated
accordingly.
A
simple
orienting
task
requiring
no
saccadic
eye
movements
could
easily
be
completed
by
young
children
and
more
severely
affected
patients,
and
could
be
helpful
for
diagnoses
of
such
disorders.
The
SCi
receives
multisensory-related,
arousal-related,
cognition-related
signals
from
cortical
and
subcortical
structures,
and
projects
directly
to
the
brainstem
premo-
tor
circuit
to
coordinate
the
orienting
response
(Figure
1).
We
reviewed
a
compelling
set
of
results,
showing
tran-
sient
pupil
dilation
evoked
by
both
salient
sensory
stimuli
(visual,
auditory,
and
audiovisual)
and
SCi
microstimula-
tion,
and
we
argue
for
a
key
role
of
the
SCi
in
coordinating
138
Motor
circuits
and
action
Figure
4
0.03
0.04
0.05
−400 −200 0 90
0
0.04
0.08
Time from stimulus onset (ms)
Change in pupil diameter (mm)
Pro Anti Anti-Error
−400 −200 090
0
0.04
0.08
Express Pro
Regular-latency Pro
Time from stimulus onset (ms)
−400 −200 0 90
0
0.04
0.08
Short-latency Anti
Long-latency Anti
(b)
(a)
(d)
(c)
Current Opinion in Neurobiology
Effects
of
saccade
preparation
on
pupil
size
(adapted
with
permission
[66
].
(a)
Change
in
pupil
diameter
for
correct
pro-saccade
and
anti-
saccade
trials
before
stimulus
appearance.
(b)
Pupil
dilation
size
(50
ms
before
to
stimulus
presentation)
among
trials
with
correct
pro-saccade,
correct
anti-saccade,
or
erroneous
anti-saccade.
(c)
Pupil
response
for
correct
short-latency
express
and
regular-latency
pro-saccades
prior
to
stimulus
appearance.
(d)
Pupil
response
for
correct
short-
and
long-latency
anti-saccades
prior
to
stimulus
appearance.
In
(a,
c,
d),
the
shaded
colored
regions
surrounding
the
pupillary
response
represent
standard
error
range
(across
participants)
for
different
conditions.
In
(b),
the
error-
bar
represents
standard
error
across
participants.
Pro:
correct
pro-saccade
trials;
Anti:
correct
anti-saccade
trials;
Anti-error:
erroneous
anti-
saccade
trials.
Current
Opinion
in
Neurobiology
2015,
33:134–140
www.sciencedirect.com
the
orienting-related
pupil
response.
Moreover,
pupil
size
was
modulated
by
preparatory
activity
related
to
saccade
generation
(top-down
signal).
The
SCi
is
a
key
locus
for
convergence
of
bottom-up
sensory
information
and
top-
down
goal-directed
signals
that
are
critical
for
orienting
[36
,37].
The
SC-mediated
pupil
pathways
could
pro-
vide
the
substrate
required
for
pupil
size
modulation
by
various
cognitive
processes.
Conflict
of
interest
statement
Nothing
declared.
Acknowledgements
This
work
was
supported
by
Canadian
Institutes
of
Health
Research
Grant
(MOP-136972).
D.P.M.
was
supported
by
the
Canada
Research
Chair
Program.
References
and
recommended
reading
Papers
of
particular
interest,
published
within
the
period
of
review,
have
been
highlighted
as:
of
special
interest
of
outstanding
interest
1.
Loewenfeld
IE:
The
Pupil:
Anatomy,
Physiology,
and
Clinical
Applications.
Boston:
Butterworth-Heinemann;
1999.
2.
Campbell
FW,
Gregory
AH:
Effect
of
size
of
pupil
on
visual
acuity.
Nature
1960,
187:1121-1123.
3.
Laughlin
SB:
Retinal
information
capacity
and
the
function
of
the
pupil.
Ophthalmic
Physiol
Opt
1992,
12:161-164.
4.
Beatty
J:
Task-evoked
pupillary
responses,
processing
load,
and
the
structure
of
processing
resources.
Psychol
Bull
1982,
91:276-292.
5.
de
Gee
JW,
Knapen
T,
Donner
TH:
Decision-related
pupil
dilation
reflects
upcoming
choice
and
individual
bias.
Proc
Natl
Acad
Sci
USA
2014,
111:E618-E625.
6.
Einhauser
W,
Stout
J,
Koch
C,
Carter
O:
Pupil
dilation
reflects
perceptual
selection
and
predicts
subsequent
stability
in
perceptual
rivalry.
Proc
Natl
Acad
Sci
USA
2008,
105:1704-1709.
7.
Eldar
E,
Cohen
JD,
Niv
Y:
The
effects
of
neural
gain
on
attention
and
learning.
Nat
Neurosci
2013,
16:1146-1153.
8.
Goldinger
SD,
Papesh
MH:
Pupil
dilation
reflects
the
creation
and
retrieval
of
memories.
Curr
Dir
Psychol
Sci
2012,
21:90-95.
9.
Naber
M,
Frassle
S,
Rutishauser
U,
Einhauser
W:
Pupil
size
signals
novelty
and
predicts
later
retrieval
success
for
declarative
memories
of
natural
scenes.
J
Vis
2013,
13:1-20.
10.
Nassar
MR,
Rumsey
KM,
Wilson
RC,
Parikh
K,
Heasly
B,
Gold
JI:
Rational
regulation
of
learning
dynamics
by
pupil-linked
arousal
systems.
Nat
Neurosci
2012,
15:1040-1046.
11.
Privitera
CM,
Renninger
LW,
Carney
T,
Klein
S,
Aguilar
M:
Pupil
dilation
during
visual
target
detection.
J
Vis
2010,
10:1-14
3.
12.
Wierda
SM,
van
Rijn
H,
Taatgen
NA,
Martens
S:
Pupil
dilation
deconvolution
reveals
the
dynamics
of
attention
at
high
temporal
resolution.
Proc
Natl
Acad
Sci
USA
2012,
109:8456-8460.
13.
Lynn
R:
Attention,
arousal
and
the
orientation
reaction.
Oxford,
UK:
Pergamon
Press;
1966.
14.
Sokolov
EN:
Higher
nervous
functions;
the
orienting
reflex.
Annu
Rev
Physiol
1963,
25:545-580.
15.
Carrasco
M:
Visual
attention:
the
past
25
years.
Vis
Res
2011,
51:1484-1525.
16.
Kowler
E:
Eye
movements:
the
past
25
years.
Vis
Res
2011,
51:1457-1483.
17.
Netser
S,
Ohayon
S,
Gutfreund
Y:
Multiple
manifestations
of
microstimulation
in
the
optic
tectum:
eye
movements,
pupil
dilations,
and
sensory
priming.
J
Neurophysiol
2010,
104:108-118.
This
paper
showed
that
pupil
dilation,
as
a
component
of
orienting,
is
evoked
by
microstimulation
of
the
optic
tectum
in
barn
owls,
providing
converging
evidence
from
different
animals.
18.
Wang
CA,
Boehnke
SE,
Itti
L,
Munoz
DP:
Transient
pupil
response
is
modulated
by
contrast-based
saliency.
J
Neurosci
2014,
34:408-417.
This
paper
showed
that
transient
pupil
dilation
in
monkeys
is
evoked
by
presentation
of
visual,
auditory,
or
audiovisual
stimuli,
and
transient
component
of
pupil
responses
evoked
by
stimulus
presentation
is
similar
to
that
evoked
by
SCi
microstimulation,
together
suggesting
an
involve-
ment
of
the
SCi
on
evoked
pupil
responses.
19.
Wang
CA,
Munoz
DP:
Modulation
of
stimulus
contrast
on
the
human
pupil
orienting
response.
Eur
J
Neurosci
2014,
40:2822-2832.
This
paper
demonstrated
that
pupil
dilation
in
humans
is
transiently
evoked
by
presentation
of
visual
stimuli,
and
the
timing
and
the
size
of
evoked
responses
are
systematically
modulated
by
stimulus
contrast.
20.
Nieuwenhuis
S,
De
Geus
EJ,
Aston-Jones
G:
The
anatomical
and
functional
relationship
between
the
P3
and
autonomic
components
of
the
orienting
response.
Psychophysiology
2011,
48:162-175.
21.
Gandhi
NJ,
Katnani
HA:
Motor
functions
of
the
superior
colliculus.
Annu
Rev
Neurosci
2011,
34:205-231.
22.
Krauzlis
RJ,
Lovejoy
LP,
Zenon
A:
Superior
colliculus
and
visual
spatial
attention.
Annu
Rev
Neurosci
2013,
36:165-182.
This
paper
reviewed
recent
findings
that
highlight
a
causal
involvement
of
the
SC
on
spatial
attention,
independent
of
the
modulation
of
attention
in
visual
cortex,
suggesting
novel
possibilities
to
understand
the
brain
mechanisms
that
enable
spatial
attention.
23.
Netser
S,
Dutta
A,
Gutfreund
Y:
Ongoing
activity
in
the
optic
tectum
is
correlated
on
a
trial-by-trial
basis
with
the
pupil
dilation
response.
J
Neurophysiol
2014,
111:918-929.
24.
Wang
CA,
Boehnke
SE,
White
BJ,
Munoz
DP:
Microstimulation
of
the
monkey
superior
colliculus
induces
pupil
dilation
without
evoking
saccades.
J
Neurosci
2012,
32:3629-3636.
This
paper
demonstrated
that,
in
awake
monkeys
performed
the
task,
transient
pupil
dilation
is
evoked
by
weak
electrical
microstimulation
in
the
SCi,
but
not
in
the
SCs,
suggesting
a
coordinated
role
of
the
SCi
on
the
orienting
response
including
pupil
dilation.
25.
Szabadi
E:
Modulation
of
physiological
reflexes
by
pain:
role
of
the
locus
coeruleus.
Front
Integr
Neurosci
2012,
6:94.
26.
Gamlin
PD:
The
pretectum:
connections
and
oculomotor-
related
roles.
Prog
Brain
Res
2006,
151:379-405.
27.
Sara
SJ,
Bouret
S:
Orienting
and
reorienting:
the
locus
coeruleus
mediates
cognition
through
arousal.
Neuron
2012,
76:130-141.
This
review
argued
a
critical
role
of
the
locus
coeruleus
on
cognition
mediating
through
arousal.
28.
Rajkowski
J,
Kubiak
P,
Aston-Jones
G:
Correlations
between
locus
coeruleus
(LC)
neural
activity,
pupil
diameter
and
behavior
in
monkey
support
a
role
of
LC
in
attention.
Soc
Neurosci
Abstr
1993,
19:974.
This
is
the
first
study
to
provide
neurophysiological
evidence
on
the
correlation
between
pupil
size
and
activity
in
the
locus
coeruleus
in
nonhuman
primate
performed
behavioral
tasks.
29.
Hou
RH,
Freeman
C,
Langley
RW,
Szabadi
E,
Bradshaw
CM:
Does
modafinil
activate
the
locus
coeruleus
in
man?
Comparison
of
modafinil
and
clonidine
on
arousal
and
autonomic
functions
in
human
volunteers.
Psychopharmacology
(Berl)
2005,
181:537-549.
30.
Murphy
PR,
O’Connell
RG,
O’Sullivan
M,
Robertson
IH,
Balsters
JH:
Pupil
diameter
covaries
with
BOLD
activity
in
human
locus
coeruleus.
Hum
Brain
Mapp
2014,
35:4140-4154.
31.
Gilzenrat
MS,
Nieuwenhuis
S,
Jepma
M,
Cohen
JD:
Pupil
diameter
tracks
changes
in
control
state
predicted
by
the
adaptive
gain
theory
of
locus
coeruleus
function.
Cogn
Affect
Behav
Neurosci
2010,
10:252-269.
Pupil
orienting
circuit
Wang
and
Munoz
139
www.sciencedirect.com
Current
Opinion
in
Neurobiology
2015,
33:134–140
32.
Jepma
M,
Nieuwenhuis
S:
Pupil
diameter
predicts
changes
in
the
exploration-exploitation
trade-off:
evidence
for
the
adaptive
gain
theory.
J
Cogn
Neurosci
2011,
23:1587-1596.
33.
May
PJ:
The
mammalian
superior
colliculus:
laminar
structure
and
connections.
Prog
Brain
Res
2006,
151:321-378.
34.
White
BJ,
Munoz
DP:
The
superior
colliculus.
In
Oxford
Handbook
of
Eye
Movements.
Edited
by
Liversedge
S,
Gilchrist
I,
Everling
S.
Oxford
University
Press;
2011:195-213.
35.
Boehnke
SE,
Munoz
DP:
On
the
importance
of
the
transient
visual
response
in
the
superior
colliculus.
Curr
Opin
Neurobiol
2008,
18:544-551.
36.
Corneil
BD,
Munoz
DP:
Overt
responses
during
covert
orienting.
Neuron
2014,
82:1230-1243.
This
paper
reviewed
recent
findings
to
support
that
the
SCi
coordinates
various
components
of
the
orienting
response,
including
saccadic
eye
movements,
neck
and
limb
muscle
recruitment,
pupil
dilation,
and
micro-
saccade,
highlighting
potential
implications
to
provide
oculomotor
bio-
markers
in
health
and
disease.
37.
Fecteau
JH,
Munoz
DP:
Salience,
relevance,
and
firing:
a
priority
map
for
target
selection.
Trends
Cogn
Sci
2006,
10:382-390.
38.
Mysore
SP,
Knudsen
EI:
A
shared
inhibitory
circuit
for
both
exogenous
and
endogenous
control
of
stimulus
selection.
Nat
Neurosci
2013,
16:473-478.
39.
Dutta
A,
Gutfreund
Y:
Saliency
mapping
in
the
optic
tectum
and
its
relationship
to
habituation.
Front
Integr
Neurosci
2014,
8:1.
40.
Harting
JK,
Huerta
MF,
Frankfurter
AJ,
Strominger
NL,
Royce
GJ:
Ascending
pathways
from
the
monkey
superior
colliculus:
an
autoradiographic
analysis.
J
Comp
Neurol
1980,
192:853-882.
41.
Edwards
SB,
Ginsburgh
CL,
Henkel
CK,
Stein
BE:
Sources
of
subcortical
projections
to
the
superior
colliculus
in
the
cat.
J
Comp
Neurol
1979,
184:309-329.
42.
Edwards
SB,
Henkel
CK:
Superior
colliculus
connections
with
the
extraocular
motor
nuclei
in
the
cat.
J
Comp
Neurol
1978,
179:451-467.
43.
Grantyn
A,
Grantyn
R:
Axonal
patterns
and
sites
of
termination
of
cat
superior
colliculus
neurons
projecting
in
the
tecto-
bulbo-spinal
tract.
Exp
Brain
Res
1982,
46:243-256.
44.
Huerta
M,
Harting
J:
Connectional
organization
of
the
superior
colliculus.
Trends
Neurosci
1984,
7:286-289.
45.
Harting
JK:
Descending
pathways
from
the
superior
collicullus:
an
autoradiographic
analysis
in
the
rhesus
monkey
(Macaca
mulatta).
J
Comp
Neurol
1977,
173:583-612.
46.
Korte
SM,
Jaarsma
D,
Luiten
PG,
Bohus
B:
Mesencephalic
cuneiform
nucleus
and
its
ascending
and
descending
projections
serve
stress-related
cardiovascular
responses
in
the
rat.
J
Auton
Nerv
Syst
1992,
41:157-176.
47.
Dean
P,
Redgrave
P,
Westby
GW:
Event
or
emergency?
Two
response
systems
in
the
mammalian
superior
colliculus.
Trends
Neurosci
1989,
12:137-147.
48.
Verberne
AJ:
Cuneiform
nucleus
stimulation
produces
activation
of
medullary
sympathoexcitatory
neurons
in
rats.
Am
J
Physiol
1995,
268(3
Pt
2):R752-R758.
49.
Itti
L,
Koch
C:
Computational
modelling
of
visual
attention.
Nat
Rev
Neurosci
2001,
2:194-203.
50.
Borji
A,
Sihite
DN,
Itti
L:
Quantitative
analysis
of
human-model
agreement
in
visual
saliency
modeling:
a
comparative
study.
IEEE
Trans
Image
Process
2013,
22:55-69.
51.
Marino
RA,
Munoz
DP:
The
effects
of
bottom-up
target
luminance
and
top-down
spatial
target
predictability
on
saccadic
reaction
times.
Exp
Brain
Res
2009,
197:321-335.
52.
Marino
RA,
Levy
R,
Boehnke
S,
White
BJ,
Itti
L,
Munoz
DP:
Linking
visual
response
properties
in
the
superior
colliculus
to
saccade
behavior.
Eur
J
Neurosci
2012,
35:1738-1752.
53.
Stanford
TR,
Quessy
S,
Stein
BE:
Evaluating
the
operations
underlying
multisensory
integration
in
the
cat
superior
colliculus.
J
Neurosci
2005,
25:6499-6508.
54.
Bell
AH,
Fecteau
JH,
Munoz
DP:
Using
auditory
and
visual
stimuli
to
investigate
the
behavioral
and
neuronal
consequences
of
reflexive
covert
orienting.
J
Neurophysiol
2004,
91:2172-2184.
This
paper
showed
sensory
activities
induced
by
visual
or
auditory
stimuli
in
the
SCi,
with
faster
and
weaker
SCi
responses
evoked
by
auditory
compared
to
visual
stimuli.
55.
Stein
B,
Meredith
M:
The
Merging
of
the
Senses.
Cambridge,
MA:
MIT;
1993.
56.
Wang
CA,
Munoz
DP:
The
role
of
the
superior
colliculus
in
the
coordination
of
the
pupil
orienting
response.
Soc
Neurosc
Abstr
2014,
238:5054.
57.
Zenon
A,
Krauzlis
RJ:
Attention
deficits
without
cortical
neuronal
deficits.
Nature
2012,
489:434-437.
58.
Munoz
DP,
Everling
S:
Look
away:
the
anti-saccade
task
and
the
voluntary
control
of
eye
movement.
Nat
Rev
Neurosci
2004,
5:218-228.
59.
Everling
S,
Dorris
MC,
Munoz
DP:
Reflex
suppression
in
the
anti-
saccade
task
is
dependent
on
prestimulus
neural
processes.
J
Neurophysiol
1998,
80:1584-1589.
60.
Everling
S,
Dorris
MC,
Klein
RM,
Munoz
DP:
Role
of
primate
superior
colliculus
in
preparation
and
execution
of
anti-
saccades
and
pro-saccades.
J
Neurosci
1999,
19:2740-2754.
61.
Connolly
JD,
Goodale
MA,
Menon
RS,
Munoz
DP:
Human
fMRI
evidence
for
the
neural
correlates
of
preparatory
set.
Nat
Neurosci
2002,
5:1345-1352.
62.
DeSouza
JF,
Menon
RS,
Everling
S:
Preparatory
set
associated
with
pro-saccades
and
anti-saccades
in
humans
investigated
with
event-related
FMRI.
J
Neurophysiol
2003,
89:1016-1023.
63.
Manoach
DS,
Thakkar
KN,
Cain
MS,
Polli
FE,
Edelman
JA,
Fischl
B,
Barton
JJ:
Neural
activity
is
modulated
by
trial
history:
a
functional
magnetic
resonance
imaging
study
of
the
effects
of
a
previous
antisaccade.
J
Neurosci
2007,
27:1791-1798.
64.
Alahyane
N,
Brien
DC,
Coe
BC,
Stroman
PW,
Munoz
DP:
Developmental
improvements
in
voluntary
control
of
behavior:
effect
of
preparation
in
the
fronto-parietal
network?
Neuroimage
2014,
98:103-117.
65.
Connolly
JD,
Goodale
MA,
Goltz
HC,
Munoz
DP:
fMRI
activation
in
the
human
frontal
eye
field
is
correlated
with
saccadic
reaction
time.
J
Neurophysiol
2005,
94:605-611.
66.
Wang
CA,
Brien
DC,
Munoz
DP:
Pupil
size
reveals
preparatory
processes
in
the
generation
of
pro-
and
anti-saccades.
Eur
J
Neurosci
2015
http://dx.doi.org/10.1111/ejn.12883.
in
press.
This
paper
showed
modulation
of
pupil
size
by
active
preparation
for
pro-
saccade
versus
anti-saccade,
with
larger
pupil
dilation
in
preparation
for
correct
anti-saccades,
compared
to
correct
pro-saccades
and
erroneous
anti-saccades.
Larger
dilation
prior
to
stimulus
appearance
accompanied
saccades
with
faster
reaction
times,
together
suggesting
that
pupil
size
is
an
effective
proxy
of
neural
activity
related
to
saccade
preparation.
67.
Winton-Brown
TT,
Fusar-Poli
P,
Ungless
MA,
Howes
OD:
Dopaminergic
basis
of
salience
dysregulation
in
psychosis.
Trends
Neurosci
2014,
37:85-94.
68.
Grace
AA:
Ventral
hippocampus,
interneurons,
and
schizophrenia
a
new
understanding
of
the
pathophysiology
of
schizophrenia
and
its
implications
for
treatment
and
prevention.
Curr
Dir
Psychol
Sci
2010,
19:232-237.
69.
Klin
A,
Jones
W,
Schultz
R,
Volkmar
F:
The
enactive
mind,
or
from
actions
to
cognition:
lessons
from
autism.
Philos
Trans
R
Soc
Lond
B
Biol
Sci
2003,
358:345-360.
70.
Aston-Jones
G,
Cohen
JD:
An
integrative
theory
of
locus
coeruleus-norepinephrine
function:
adaptive
gain
and
optimal
performance.
Annu
Rev
Neurosci
2005,
28:403-450.
140
Motor
circuits
and
action
Current
Opinion
in
Neurobiology
2015,
33:134–140
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