ITS 833 – INFORMATION GOVERNANCEChapter 7Dr. Omar Mohamed.docx

ITS 833 – INFORMATION GOVERNANCE
Chapter 7
Dr. Omar Mohamed
Copyright @ Omar Mohamed 2019
1
1
Chapter Goals and Objectives
What is the difference between structured
What is the difference between unstructured and semi-structured
information?
Why is unstructured data so challenging?
2
Generally, what is full cost accounting (FCA)?
What are the 10 key factors that drive the total cost of
ownership of unstructured data
How can we better manage information?
How would an IG enabled organization look different from one
that is not IG enabled?
2
The Business Case for
Information Governance

Difficult to Justify
Short term return on investment is nonexistent
Long term view is essential
Reduce exposure to risk over time
Improve quality and security of information
Streamlining information retention
Looking at Information Costs differently
3
3
The information environment
Challenges of Unstructured Information
Data volumes are growing
“Unstructured Information” is growing at a dramatic rate
Challenges unique to unstructured information
Horizontal nature
Lack of formality
Management location
Identification of ownership
Classification
4
Calculating Information Costs
Rising Storage Costs (Short sighted thinking)
Labor (particularly knowledge workers)
Overhead costs
Costs of e-discovery and litigation

Opportunity Costs
4
Full Cost Accounting for
Information Models
Total Cost of Ownership (TCO) Model
Return on Investment Model (ROI)
Full Cost Accounting Model (FCA)
Past, Present, Future Costs
Direct Costs
Indirect Costs
Flexible Application
Triple Bottom Line Accounting – Monetary, Environment,
Societal Costs
5
Full Cost Accounting
General and Administrative Costs
Productivity Gains and Losses
Legal and E-discovery costs
Indirect Costs
Up-Front Costs
Future Costs
5
The politics involved

Tools needed to establish facts about the information
environment
SOURCES OF Costs of owning unstructured information, cost
reducers, and cost enhancers
Giving unstructured information value
The IG enabled organization
The End
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Brain, Behavior, and Immunity 64 (2017) 59–64
Contents lists available at ScienceDirect
Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi
Short Communication
Constriction of the buccal branch of the facial nerve produces
unilateral
craniofacial allodynia
http://dx.doi.org/10.1016/j.bbi.2016.12.004
0889-1591/� 2016 Elsevier Inc. All rights reserved.
⇑ Corresponding author at: Department of Psychology, Campus
Box 345, Univer-
sity of Colorado at Boulder, Boulder, CO 80309-0345, USA.
E-mail address: [email protected] (L.R. Watkins).
1 Authors contributed equally to this work.
2 Current address: Department of Critical Care Research,
University of Texas MD
Anderson Cancer Center, Houston, USA.
Susannah S. Lewis a,1, Peter M. Grace a,b,1,2, Mark R.
Hutchinson b,c, Steven F. Maier a, Linda R. Watkins a,⇑
a Department of Psychology & Neuroscience, University of
Colorado, Boulder, USA
b School of Medicine, University of Adelaide, Adelaide,
Australia
c Australian Research Council Centre of Excellence for
Nanoscale BioPhotonics, Adelaide, Australia
a r t i c l e i n f o
Article history:
Received 27 October 2016
Received in revised form 2 December 2016
Accepted 5 December 2016
Available online 18 December 2016
Keywords:
Orofacial

Muscle
Glia
Hyperalgesia
Mirror-image pain
a b s t r a c t
Despite pain being a sensory experience, studies of spinal cord
ventral root damage have demonstrated
that motor neuron injury can induce neuropathic pain. Whether
injury of cranial motor nerves can also
produce nociceptive hypersensitivity has not been addressed.
Herein, we demonstrate that chronic con-
striction injury (CCI) of the buccal branch of the facial nerve
results in long-lasting, unilateral allodynia in
the rat. An anterograde and retrograde tracer (3000 MW
tetramethylrhodamine-conjugated dextran) was
not transported to the trigeminal ganglion when applied to the
injury site, but was transported to the
facial nucleus, indicating that this nerve branch is not composed
of trigeminal sensory neurons.
Finally, intracisterna magna injection of interleukin-1 (IL-1)
receptor antagonist reversed allodynia,
implicating the pro-inflammatory cytokine IL-1 in the
maintenance of neuropathic pain induced by facial
nerve CCI. These data extend the prior evidence that selective
injury to motor axons can enhance pain to
supraspinal circuits by demonstrating that injury of a facial
nerve with predominantly motor axons is
sufficient for neuropathic pain, and that the resultant pain has a
neuroimmune component.
� 2016 Elsevier Inc. All rights reserved.
1. Introduction
Peripheral nerve lesions or disease can initiate neuropathic
pain, which is responsible for chronic pain in up to 10% of the

gen-
eral population (Treede et al., 2008; van Hecke et al., 2014).
Due to
the fact that pain is a sensory experience, neuropathic pain is
fre-
quently assumed to only follow damage to sensory neurons.
How-
ever, recent studies have revealed that selective lesion of spinal
motor neurons by L5 ventral root transection induces
nociceptive
hypersensitivity and microglia activation in the spinal dorsal
horn,
which are both dependent on tumor necrosis factor (TNF)
signaling
(Li et al., 2002; Sheth et al., 2002; Xu et al., 2006, 2007). Such
neu-
roimmune signaling has a well-documented role in the develop-
ment of neuropathic pain after injury to mixed (sensory and
motor) peripheral nerves (Grace et al., 2014, 2016a).
Furthermore,
injury of the gastrocnemius-soleus (predominantly motor) nerve
results in nociceptive hypersensitivity, and both induces ectopic
activity and amplifies evoked action potentials of sciatic nerve
and DRG neurons (Kirillova et al., 2011; Michaelis et al., 2000;
Zhou et al., 2010). Thus, injury of spinal motor nerves is
sufficient
for peripheral neuropathic pain.
To date, several models of craniofacial neuropathic pain have
been developed, involving lesions of the sensory infraorbital
(Eriksson et al., 2005; Vos et al., 1994), or sensory inferior
alveolar
nerves (Sugiyama et al., 2013). However, it is not yet known
whether injury of cranial motor nerves is sufficient to induce
neu-
ropathic pain, similar to the spinal system. Uniformity cannot

be
assumed, given the documented pathophysiological differences
between the injured spinal and trigeminal systems. For example,
production of spinal dorsal horn interleukin (IL)-6 and
sprouting
of noradrenergic nerves within the dorsal root ganglia (DRG)
occurs after sciatic nerve injury (Latrémolière et al., 2008;
McLachlan et al., 1993), but neither occur within the trigeminal
ganglia after infraorbital nerve injury (Benoliel et al., 2001;
Latrémolière et al., 2008). Furthermore, triptans and calcitonin
gene-related peptide (CGRP) receptor antagonists are effective
in
reversing nociceptive hypersensitivity induced by injury of the
infraorbital nerve, but not of the sciatic nerve (Kayser et al.,
2002, 2011; Michot et al., 2012, 2015).
Therefore, the goal of this study was to determine whether
injury of a motor cranial nerve could produce neuropathic pain.
http://crossmark.crossref.org/dialog/?doi=10.1016/j.bbi.2016.12
.004&domain=pdf
mailto:[email protected]
http://www.sciencedirect.com/science/journal/08891591
http://www.elsevier.com/locate/ybrbi
60 S.S. Lewis et al. / Brain, Behavior, and Immunity 64 (2017)
59–64
The facial nerve (cranial nerve VII) of the rat is an excellent
candi-
date to address this question, as it is comprised of motor
efferent
neurons without a significant somatosensory nerve component
from the skin (Nerve, 2013), is readily accessible surgically and

there is a well-established protocol for demonstrating facial
allo-
dynia in the rat (Ren, 1999). Given the dimorphic role of pro-
inflammatory cytokines in craniofacial and spinal neuropathic
pain
(Latrémolière et al., 2008), the second goal of this study was to
determine whether allodynia induced by facial nerve injury
could
be attenuated by blocking IL-1 signaling.
Fig. 1. Approximate size and position of the incision with skin
retracted. Three
chromic gut ligatures are shown in red. The buccal branch of
the facial nerve
(straight black line) is readily visible upon skin incision. Area
for tactile testing is
shown in blue square. (For interpretation of the references to
color in this figure
legend, the reader is referred to the web version of this article.)
2. Methods
2.1. Animals
Adult, male, pathogen-free Sprague-Dawley rats (Harlan Labs,
Madison, WI) were used for all experiments. Rats (350–400 g at
time of surgery) were housed in temperature (23 ± 3 oC) and
light
(12 h:12 h light:dark; lights on 0700 h) controlled rooms with
water and food given ad libitum. All habituation and behavioral
testing procedures were performed during the light phase of the
daily cycle. All procedures were approved by the University of
Col-
orado Boulder Institutional Animal Care and Use Committee.
All
experimental groups have 6–9 rats per group.
2.2. Facial nerve chronic constriction injury surgery

This novel surgery constricted the buccal branch of the facial
nerve. The buccal branch of the facial nerve has the advantage
of
being readily accessible following a skin incision, allowing for
a
straightforward surgery with very little damage to tissues sur-
rounding the nerve. All surgical instruments were sterilized
prior
to use and all surgical procedures were conducted under
isoflurane
anesthesia.
The buccal branch of the facial nerve was aseptically exposed
through a 1 cm skin incision. Great care is necessary when
shaving
the skin, as damage to whiskers alters subsequent behavioral
responses. The buccal facial nerve branch is superficial and
visible
following a skin incision. The incision was made along the line
from the corner of the mouth to the ear, about two-thirds of the
way to the ear (Fig. 1). Once exposed, the nerve was kept moist
with sterile physiological saline drops and only touched with
glass
instruments to prevent damage through metal instruments.
Borosilicate 600 glass pipettes (Fisherbrand, Fisher Scientific,
Wal-
tham, MA) were molded into a curved ‘L’ shape approximately
8 mm long at the tip and used to gently manipulate the nerve.
These steps were undertaken to minimize the variability in
nerve
damage between rats.
To isolate the nerve, two nicks (each approximately 0.5 mm)
were made into the fascia and muscle surrounding the nerve
using
the tip of a #11 scalpel blade (Havel, Cincinnati, OH, USA).

These
small incisions were expanded using a pair of shaped glass
pipettes
in a spreading motion to gently separate the nerve completely
from the surrounding fascia and muscle. The spreading motion,
rather than additional scalpel incisions, separated the muscle
along
muscle fibers and minimized damage and bleeding. Care was
taken
not to stretch the nerve during the separation of the nerve and
musculature.
Once the nerve was isolated from surrounding muscle and con-
nective tissue, three 4-0 chromic gut (Ethicon, Somerville, NJ,
USA)
ligatures were tied around the nerve with a square knot.
Ligatures
were tied tightly enough so to not to move along the nerve when
gently pushed with forceps, but loose enough not to visibly
deform
the nerve and spaced approximately 1 mm apart. Again, care
was
taken not to stretch or deform the nerve during ligation. After
ligation, the chromic gut was cut close to the knot and the skin
was then sutured closed with 4-0 silk suture (Ethicon,
Somerville,
NJ, USA). Sham surgeries were as described above, with the
excep-
tion that no chromic gut sutures were tied around the isolated
nerve.
2.3. von Frey test for tactile sensitivity
Assessment of the development and persistence of tactile allo-
dynia was conducted as detailed (Ren, 1999). Briefly, rats were
habituated in two 5 min sessions to stand comfortably with their

forepaws in a leather glove. This method allows the rats to be
com-
pletely unrestrained. Calibrated microfilaments (von Frey hairs;
Stoelting, Wood Dale, IL, USA) were applied to the hairy skin
under
the eye by and experimental blind to treatment groups.
Microfila-
ments were applied in 5 quick up-down applications and the
num-
ber of brisk head withdrawals or aggravated paw swipes
recorded
as responses.
Microfilaments ranging logarithmically from 1.2 to 75.86 g
were applied starting with a mild stimulus of 3.63 g and
increasing
or decreasing to find the range from 0 out of 5, to 5 out of 5
responses from the rat. Assessments were made prior to and 3,
7,
10, 14, 21, 28, 35, 42 days following facial nerve CCI or sham
sur-
gery by an experimenter blind to treatment group. Responses
were
fitted to a Gaussian integral psychometric function using a
maximum-likelihood fitting method as described (Milligan et
al.,
2000).
2.4. Body weights
Body weights were measured prior to and 3, 7, 10, 14, 21, 28,
35,
42 days following facial nerve CCI or sham surgery by an
experi-
menter blind to treatment group. Measurements were made
between 0900 and 1100 h to reduce variability due to circadian

changes.
2.5. Neuronal tracing
Although the majority of the constricted nerve is efferent facial
nerve axons, it is possible that there may be a small component
of
afferent trigeminal axons also mixed within the nerve bundle. In
order to determine whether any increase in mechanical
sensitivity
could be due to damage of intermingled trigeminal afferents in
the
buccal nerve CCI site, a neuronal tracing study was conducted.
Anterograde and retrograde labeling of the facial and trigeminal
brainstem nuclei and trigeminal ganglia with the tracer 3000
MW
tetramethylrhodamine-conjugated dextran (Invitrogen, Carlsbad,
CA, USA) was used to determine origin/terminus of neurons in
S.S. Lewis et al. / Brain, Behavior, and Immunity 64 (2017) 59–
64 61
the constricted region. The nerve was first exposed and isolated
identically to that described above. Using a method adapted
from
May and Hill (2006), the nerve was then transected and parafilm
placed under the nerve to isolate it from surrounding tissues. A
Q-tip was used to apply DMSO to the cut end of the nerve to
increase dextran penetration. Dextran granules were then placed
on the nerve, held in place with a small dab of petroleum jelly
and the parafilm sealed around the nerve with superglue. This
method allowed the dextran to be applied to the nerve for an
extended period of time without contaminating nearby tissues,
which are innervated by other cranial nerves. By transecting the

nerve, all axons in the nerve were exposed to the retrograde
tracer.
At 1, 3, 4, 5, 6 or 7 days after dextran placement (n = 2/time-
point), rats were deeply anesthetized with sodium pentobarbital
(50 mg/kg i.p.) and transcardially perfused, first with a saline
flush,
and then with 4% paraformaldehyde to fix the tissue. Brains and
trigeminal ganglia were harvested and cryoprotected in 30%
sucrose. Brains and ganglia were then frozen in dry-ice chilled
isopentane and sliced in 50 lm sections in a cryostat. The entire
trigeminal ganglion was sectioned, and approximately one out
of
every 10 sections were stained. Sections were mounted on
gelatin
coated slides and fluorescence examined immediately on an
Olym-
pus BX61 fluorescence microscope (Olympus America, Center
Val-
ley, PA) using Microsuite software (Olympus America).
2.6. Drug administration
The effect of proinflammatory cytokines on facial nerve CCI
was
assessed using interleukin-1 receptor antagonist (IL-1ra,
Amgen,
Thousand Oaks, CA) administered intracisterna magna (i.c.m.).
IL-
1ra or equivolume sterile, endotoxin free saline was
administered
21 and 28 days after facial nerve CCI or sham surgery.
Mechanical
allodynia was assessed 45 min following i.c.m. injection to
account
for the relatively short cerebrospinal fluid half life of IL-1ra
(Milligan et al., 2005).

I.c.m. injections were percutaneously performed as previously
described (Frank et al., 2010), using polyethylene-60 (PE60)
tubing
attached to a 30 gauge 3/800 hypodermic needle. Each rat was
briefly anesthetized with isoflurane and a small patch at the
nape
of the neck was shaved and scrubbed with 70% ethyl alcohol.
The
rat was then placed in ventral recumbancy on a box with the
head
positioned beyond the end of the box such that the head bent
downward at a 90� angle to the body, allowing easier access to
the cisterna magna. The 30 gauge needle was percutaneously
inserted into the cisterna magna and a 10 ll injection of either
1 ll of 100 lg IL-1ra plus 8 ll saline vehicle separated by 1 ll
air, or 9 ll saline vehicle plus 1 ll air. Injections were given
slowly
over a 30 s period. A dose of 100 lg IL-1ra was chosen based on
prior reports that the same dose intrathecally reversed
neuropathic
pain induced by sciatic CCI (Grace et al., 2016b) and
inflammatory
neuropathy (Milligan et al., 2003), and this same dose i.c.m.
blocked stress-induced enhancement of pro-inflammatory
responses by brain nuclei (Johnson et al., 2004).
2.7. Statistics
Mechanical allodynia was analyzed as the interpolated 50%
thresholds (absolute threshold). One-way analysis of variance
fol-
lowed by the Tukey post hoc test was used to confirm that there
were no baseline differences in absolute thresholds between
treat-
ment groups. Differences between treatment groups were deter-
mined using 2-way analysis of variance, followed by the Sidak

post hoc test, with a correction for repeated measures for
mechan-
ical allodynia. P < 0.05 was considered significant, and all data
are
expressed as mean ± SEM.
3. Results
3.1. Buccal branch CCI produces unilateral craniofacial
allodynia
There were no pre-surgical baseline differences between the
either surgery group on either side of the face (F3,24 = 0.69,
P > 0.05). CCI of the buccal branch of the facial nerve produced
sig-
nificant orofacial allodynia ipsilateral to the site of injury from
day
10 through day 35 after surgery (Fig. 2; Time x Treatment:
F7,84 = 3.86, P < 0.01; Time: F7,84 = 4.99, P < 0.001;
Treatment:
F1,12 = 28.93, P < 0.001). Post hoc tests showed a significant
decrease in the CCI group compared to Shams ipsilateral to
facial
nerve CCI at every time point tested after surgery, until testing
was concluded at day 42 (P < 0.05). No significant allodynia
devel-
oped contralateral to the site of injury (Time x Treatment:
F7,96 = 0.53, P = 0.8).
At no point in the six week duration of allodynia was there a
significant difference in body weight gain between the facial
nerve
CCI and sham animals (Treatment: F8,95 = 0.58, P = 1.0, data
not
shown). No noticeable changes in whisking behavior or
eyeblink
reflex were subjectively observed following the ligation of the

facial nerve.
3.2. No trigeminal afferents were detected at the site of
constriction
To test whether injury of a small contingent of sensory nerves
in
the facial nerve could have accounted for the robust allodynia,
trigeminal afferents were labelled with the antero- and
retrograde
tracer 3kD tetramethylrhodamine-conjugated dextran. This dye
has previously produced robust central nervous system cell body
labeling of peripheral gustatory sensory nerves (May and Hill,
2006), and tibial and common fibular motor nerves (English
et al., 2009). Strong labeling of neurons in the facial nucleus
was
found 6 days following dextran placement (Fig. 3) with weaker
labeling present 5 and 7 days following dextran placement. At
no
time point (1, 3, 4, 5, 6 or 7 days following dextran placement
at
the site of transection) was fluorescent labeling detected in the
trigeminal ganglion or at any level of the brainstem trigeminal
nuclei beyond that seen in an animal without dextran placement.
These data indicate that there are no detected trigeminal sensory
afferents in the surgical site of the facial nerve.
3.3. IL-1ra reverses established allodynia following facial nerve
CCI
Numerous studies have convincingly shown that an increase in
neuroinflammation in the dorsal spinal cord importantly con-
tributes to allodynia following sciatic CCI (Grace et al., 2014,
2016a). One of the major neuroinflammatory mediators within
spinal cord implicated in creating allodynia is following injury
to
peripheral sensory/motor mixed nerves is IL-1beta (Grace et al.,
2014, 2016a). In contrast, IL-1 has never been implicated in

allody-
nia induced as a consequence of injury to motor axons, either
spin-
ally or supraspinally. To determine if IL-1 provides a
proinflammatory component necessary to maintain the craniofa-
cial allodynia seen following facial nerve CCI, tactile
sensitivity
was assessed 45 min after i.c.m. IL-1ra, in a within-subjects
design
described above. There were no baseline differences between
the
sham and CCI group on either side of the face (F3,23 = 1.10,
P > 0.05). There was a significant interaction between surgery
and drug treatment (Fig. 4; F3,48 = 4.74, P < 0.01), as well as a
main
effect of treatment (F3,48 = 13.57, P < 0.001), but not of time
(F1,48 = 1.42, P = 0.2). Post hoc tests showed that the facial
CCI sur-
gery produced a robust allodynia prior to the saline and IL-1ra
injections on day 21 and 28 post surgery compared to sham
treated
animals (P < 0.05). The allodynia remained unchanged after
Fig. 2. Chronic constriction injury of the facial nerve leads to
the development of
tactile allodynia ipsilateral to the surgery. No significant
allodynia was found
contralateral to injury. Animals with CCI maintained significant
allodynia from 10
to 35 days after surgery. Allodynia was no longer significant at
42 days post-
surgery. *P < 0.05, **P < 0.01, ***P < 0.001, relative to Sham
Ipsilateral. Mean ± SEM
are presented, n = 6–99/group.

59–64
an i.c.m. saline injection. However, IL-1ra reversed established
craniofacial allodynia, relative to control treatment after facial
CCI (P < 0.01), with no significant difference between CCI rats
trea-
ted with IL-1ra and sham treated animals. IL-1ra had no impact
on
contralateral mechanical thresholds, which were not altered by
facial nerve CCI (data not shown).
4. Discussion
These studies present the first evidence that constriction injury
to a cranial nerve with predominantly efferent motor neurons
can
produce reliable and prolonged tactile allodynia. Notably, con-
tralateral allodynia was absent after buccal branch CCI, which
con-
trasts with that reported for some models of sciatic nerve injury
(Grace et al., 2010; Milligan et al., 2003). The allodynia
measured
in this study was transiently reversed with an intracisterna
magna
injection of IL-1ra, suggesting a role for central nervous system
inflammation in the generation of the allodynia.
To our knowledge, all other craniofacial neuropathic pain mod-
els involve damage of sensory nerves (Eriksson et al., 2005;
Fig. 3. Representative micrographs from dextran staining
demonstrate that the injury sit
the trigeminal nucleus through the hindbrain as well as the
trigeminal ganglia were ex
fluorescence noted was in the facial nucleus 5, 6 and 7 days
following dextran placemen
position of the illuminated neurons in the facial nucleus (A,

4�), detailed morphology o
Sugiyama et al., 2013; Vos et al., 1994). The results obtained
here
demonstrate that injury to the facial nerve, which we show to be
devoid of detected trigeminal somatosensory afferents from the
skin, is also sufficient to create neuropathic pain. These data
paral-
lel and importantly extend studies performed in the motor
gastrocnemius-soleus nerve (Kirillova et al., 2011; Michaelis
et al., 2000; Zhou et al., 2010) and the motor ventral root (Li
et al., 2002; Sheth et al., 2002; Xu et al., 2006, 2007), and
highlight
a common consequence of damage of nerves that innervate mus-
cles in the cephalic and spinal systems. Injury of these motor
nerves also induces nociceptive hypersensitivity, and
spontaneous
activity in uninjured DRG sensory neurons (Kirillova et al.,
2011;
Michaelis et al., 2000; Xu et al., 2006, 2007; Zhou et al., 2010).
The facial region below the eye, where hypersensitivity was
detected, is innervated by the V2 branch of the trigeminal nerve
(Nerve, 2013). The trigeminal and facial nerves are not mixed,
but both project to the brainstem. This extra-territorial
allodynia
may therefore be mediated by central sensitization, rather than
by Wallerian degeneration of motor neurons, as occurs in the
spinal system (Gaudet et al., 2011; Xu et al., 2006, 2007).
Future
studies may seek to confirm these results in cephalic nerves
com-
posed solely of efferent fibers, such as the oculomotor nerve.
Our data also point to the involvement of pro-inflammatory
cytokines in neuropathic pain induced by facial nerve CCI.
While
TNF has previously been implicated in allodynia resultant from

injury to motor axons (Li et al., 2002; Sheth et al., 2002; Xu
et al., 2006, 2007), no prior study of allodynia in response to
motor
damage has examined IL-1. Here, IL-1ra reversed allodynia at
21
and 28 days post-surgery, indicating a role for IL-1 in
neuropathic
pain maintenance, most likely via release within brainstem
sites.
IL-1 may have a common role in mediating nociceptive
hypersen-
sitivity after craniofacial and sciatic nerve injury (Grace et al.,
2014), unlike IL-6 (Latrémolière et al., 2008). There are several
known mechanisms by which IL-1 may increase neuronal
excitability in nociceptive pathways (Grace et al., 2014, 2016a),
including phosphorylation of postsynaptic NR1 NMDA receptor
subunits (Zhang et al., 2008), and down-regulation of both the
astrocyte glutamate transporter GLT-1 (Yan et al., 2014) and
neu-
ronal G protein-coupled receptor kinase 2 (an enzymatic
regulator
of G protein-coupled receptor homologous desensitization, that
protects against overstimulation) (Kleibeuker et al., 2008). IL-1
is
elevated in the brainstem and contributes to extra-territorial
pain
after trigeminal nerve injury (Chai et al., 2012; Takahashi et al.,
2011), and this report adds to others demonstrating a causal role
for this cytokine in craniofacial neuropathic pain (Won et al.,
e did not contain trigeminal sensory afferents. Brain slices from
the caudal portion of
amined from 1 to 7 days following dextran placement at the
injury site. The only
t. Six days was optimal and shown in the above pictures.
Micrographs show relative
f illuminated neurons (B) and the lack of staining in the

trigeminal ganglia (C).
Fig. 4. Intracisterna magna IL-1 receptor antagonist (IL-1ra;
100 lg) significantly
attenuated the tactile allodynia that developed following facial
nerve constriction.
Assessments were made prior to (pre-treatment), and 45 min
after administration
(post-treatment). No significant change was noted following
i.c.m. saline injections.
*P < 0.05, **P < 0.01, ***P < 0.001. Mean ± SEM are
presented, n = 6–9/group.
S.S. Lewis et al. / Brain, Behavior, and Immunity 64 (2017) 59–
64 63
2014). Future studies may investigate whether activated glial
cells
or recruited immune cells are associated with this nerve injury
model, and are responsible for production of IL-1.
In conclusion, this study demonstrates that injury to the facial
nerve, which is predominantly composed of motor neurons, is
suf-
ficient to induce neuropathic pain in rat. This finding is also
sup-
ported by the clinical literature, as pain is a principal complaint
of Bell’s palsy—an idiopathic paralysis of the facial nerve (De
Seta
et al., 2014). Our data predict that neuroimmune signaling con-
tributes to nociceptive hypersensitivity after facial nerve injury,
and is a possible therapeutic target for craniofacial neuropathic
pain.
Acknowledgments

The authors declare that there are no conflicts of interest. Fund-
ing from NIH R01 DE021966. Peter M Grace was a NHMRC
(Aus-
tralia) CJ Martin Fellow [ID: 1054091] and American
Australian
Association Sir Keith Murdoch Fellow. Mark R. Hutchinson was
a
NHMRC (Australia) CJ Martin Fellow (ID 465423; 2007-2010)
and
an Australian Research Council Research Fellow
(DP110100297).
The authors are grateful to Drs. Dianna Bartel and Thomas
Finger
(University of Colorado Denver) for their assistance with the
neu-
ronal tracing protocol.
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http://dx.doi.org/10.1016/j.pain.2009.10.032Constriction of the
buccal branch of the facial nerve produces unilateral
craniofacial allodynia1 Introduction2 Methods2.1 Animals2.2
Facial nerve chronic constriction injury surgery2.3 von Frey test
for tactile sensitivity2.4 Body weights2.5 Neuronal tracing2.6
Drug administration2.7 Statistics3 Results3.1 Buccal branch
CCI produces unilateral craniofacial allodynia3.2 No trigeminal
afferents were detected at the site of constriction3.3 IL-1ra
reverses established allodynia following facial nerve CCI4
DiscussionAcknowledgmentsReferences
Eur J Neurosci. 2018;48:3171–3185.
wileyonlinelibrary.com/journal/ejn | 3171© 2018 Federation
of European Neuroscience Societies
and John Wiley & Sons Ltd
Received: 24 January 2018 | Revised: 24 July 2018 | Accepted:
27 July 2018
DOI: 10.1111/ejn.14121
R E V I E W A R T I C L E
Neuronal correlates of motion- defined shape perception in

primate dorsal and ventral streams
Takashi Handa1,2 | Akichika Mikami1,3
Edited by Dr. Helen Barbas. Reviewed by Georgia Gregoriou
and Arash Yazdanbaksh.
All peer review communications can be found with the online
version of the article.
Abbreviations: ITC, inferior temporal cortex; KB, kinetic
boundary; LGN, lateral geniculate nucleus; LOC, lateral
occipital complex; lSTS, lower bank of the
anterior superior temporal sulcus; MRI, magnetic resonance
imaging; MT, middle temporal area; PPC, posterior parietal
cortex; RF, receptive field; SFL, shape
from luminance; SFM, shape from motion; STP, superior
temporal polysensory area; uSTS, upper bank of the anterior
superior temporal sulcus; V1, primary
visual cortex.
1Department of Behavioral and Brain
Sciences, Primate Research Institute, Kyoto
University, Inuyama, Japan
2Department of Behavior and Brain
Organization, Center of Advanced European
Studies and Research (CAESAR), Bonn,
Germany
3Faculty of Nursing and
Rehabilitation, Chubu Gakuin University,
Seki, Japan
Correspondence
Takashi Handa, Department of Behavior
and Brain Organization, Center of
Advanced European Studies and Research

(CAESAR), Bonn, Germany.
Email: [email protected]
Abstract
Human and non- human primates can readily perceive the shape
of objects using
visual motion. Classically, shape, and motion are considered to
be separately pro-
cessed via ventral and dorsal cortical pathways, respectively.
However, many lines
of anatomical and physiological evidence have indicated that
these two pathways are
likely to be interconnected at some stage. For motion- defined
shape perception, these
two pathways should interact with each other because the
ventral pathway must uti-
lize motion, which the dorsal pathway processes, to extract
shape signal. However, it
is unknown how interactions between cortical pathways are
involved in neural mech-
anisms underlying motion- defined shape perception. We review
evidence from psy-
chophysical, lesion, neuroimaging and physiological research on
motion- defined
shape perception and then discuss the effects of behavioral
demands on neural activ-
ity in ventral and dorsal cortical areas. Further, we discuss
functions of two candidate
sets of levels: early and higher- order cortical areas. The
extrastriate area V4 and
middle temporal (MT) area, which are reciprocally connected, at
the early level are
plausible areas for extracting the shape and/or constituent parts
of shape from motion
cues because neural dynamics are different from those during
luminance- defined
shape perception. On the other hand, among other higher- order

visual areas, the an-
terior superior temporal sulcus likely contributes to the
processing of cue- invariant
shape recognition rather than cue- dependent shape processing.
We suggest that shar-
ing information about motion and shape between the early
visual areas in the dorsal
and ventral pathways is dependent on visual cues and behavioral
requirements, indi-
cating the interplay between the pathways.
K E Y W O R D S
dorsal stream, functional interaction, shape perception, ventral
stream, visual motion
www.wileyonlinelibrary.com/journal/ejn
http://orcid.org/0000-0003-3956-8077
mailto:[email protected]
3172 | HANDA AND MIKAMI
1 | I N T R O D U C T I O N
Among mammals, primates heavily rely on vision. The visual
systems of most primates have adapted evolutionally to diur-
nal activity. For diurnal primates, visual object recognition
plays pivotal roles in the judgment of good foods, such as ripe
fruits, and in appropriate action selection, such as catching
prey or escaping from predators (Barton, 1996, 1998; Kay &
Kirk, 2000). Accordingly, shape perception is a fundamen-
tal step in the processing of object recognition. Various vi-
sual features, including luminance, color, texture, depth, and
motion, enable human and non- human primates to perceive
the shape of an object. For instance, visual motion cues are
critical in detecting animals that camouflage themselves with
a similar color and texture to their surroundings while the
animals are still. Once they have moved, it becomes easier

for observers to recognize them (Curio, 1976; Eckert & Zeil,
2001; Julesz, 1971; Robinson, 1969) (Figure 1a). In humans,
relative motion is the most efficient cue for object segmenta-
tion from a visual scene (Nawrot, Shannon, & Rizzo, 1996).
How does the primate brain perform shape perception
using such motion cues? A classical view of the primate vi-
sual system is that shape and motion are processed through
distinct pathways. Visual information is first transmitted
from the retina to the cerebral cortex not only through the
lateral geniculate nucleus (LGN) in the thalamus (Leventhal,
Rodieck, & Dreher, 1981; Perry, Oehler, & Cowey, 1984;
Schiller & Logothetis, 1990) but also through the superior
colliculus and inferior pulvinar thalamic nucleus (Berman
& Wurtz, 2010; Lyon, Nassi, & Callaway, 2010). Visual
transmission through the retino- geniculo pathway has
been anatomically and physiologically classified into two
parallel pathways. The first is called the parvocellular (or
color- opponent) pathway, in which the small receptive
fields (RFs) of cells exhibit red- green color- opponent re-
sponse patterns and the cells convey sustained signals with
spatially fine resolution. A small lesion in the LGN par-
vocellular layer has been shown to impair the detection/
discrimination of color, texture, and fine patterns. The sec-
ond pathway is called the magnocellular (or broad- band)
pathway, in which cells have large RFs and convey achro-
matic, low spatial resolution, and more transient signals.
A small lesion in the LGN magnocellular layer has been
shown to impair motion perception (Derrington & Lennie,
1984; Schiller & Logothetis, 1990; Schiller, Logothetis, &
Charles, 1990; Shapley & Perry, 1986). Thus, the parvocel-
lular and magnocellular layers are capable of sending sig-
nals for processing shape/color and motion, respectively. In
the cerebral cortex, two visual pathways originating in the
primary visual cortex (V1) have also been characterized.

The parvocellular and magnocellular pathways are func-
tionally correlated to the ventral and dorsal cortical path-
ways, which have been considered to compute non- spatial
(shape and color) and spatial (motion and depth) visual
features, respectively (Ungerleider & Mishkin, 1982; Van
Essen & Gallant, 1994). Among early visual cortical areas,
the extrastriate area V4 in the ventral pathway and the mid-
dle temporal (MT) area in the dorsal pathway have been
extensively profiled. The V4 is critical for shape and color
vision (Pasupathy, 2015; Roe et al., 2012), whereas the
MT area is dedicated for processing visual motion (Born
& Bradley, 2005). Among higher visual cortical areas, the
ventral pathway terminates in the inferior temporal cortex
(ITC) (Connor, Brincat, & Pasupathy, 2007; Tanaka, 1996;
Tompa & Sáry, 2010), whereas the dorsal pathway is di-
vided into two side streams that are linked to the posterior
parietal cortex (PPC) (Goodale & Milner, 1992; Maunsell
& Van Essen, 1983) and anterior superior temporal sulcus
(Boussaoud, Ungerleider, & Desimone, 1990) (Figure 2).
For motion- defined shape perception, some corti-
cal areas must use motion to extract the boundary be-
tween the object and the background or shape of the
object. The ventral and dorsal pathways seem to not
be wholly independent; rather, they potentially inter-
act with each other. In the ventral and dorsal cortical
areas, neural inputs originating from the parvocellular
F I G U R E 1 A schematic illustration of motion- defined
shape
perception. (a) Left: A butterfly camouflaged by its surrounding
when still. Once it moves, the shape can be detected by the
primate
visual system. The white arrow indicates the direction of
movement
of the butterfly. The white dashed line contour indicates the

shape of
the butterfly. Right: Extended view around a circle in gray in
the left
panel. The boundary (white dashed line) is visible by the
movement of
dots (arrows) on the butterfly against the still dots background.
(b) In
the laboratory, some artificial motion- defined form stimuli
have been
used. Left: The kinetic boundary (KB), a visible oriented line
(dashed
line) at the boundary between the counter movements of dots.
Right:
Shape from motion (SFM). The relative motion between the
inside
and outside field of an object enables us to see the shape
(circle). Gray
arrows indicate the direction of the movement of dots
(a)
(b)
| 3173HANDA AND MIKAMI
and magnocellular pathways physiologically and ana-
tomically merge (Maunsell, 1992; Nassi & Callaway,
2009). Parvocellular layer inactivation reduces, but
not completely eliminates, visual responses in the V4.
Magnocellular layer inactivation comparably reduces
the firing rate of V4 neurons in response to an oscil-
lating white bar by approximately 40%. Thus, both
LGN pathways contribute to visual responses in V4
(Ferrera, Nealey, & Maunsell, 1992; Ferrera, Nealey, &

Maunsell, 1994). Moreover, non- direction- selective V4
neurons become tuned to the direction of random dot
movement after monkeys have adapted to a visual mo-
tion stimulus (Tolias, Keliris, Smirnakis, & Logothetis,
2005). Although the visual responses of MT neurons
strongly depend on magnocellular contribution, the
responsiveness of a few MT neurons reduced follow-
ing parvocellular layer inactivation (Maunsell, Nealey,
& DePriest, 1990). Rabies virus tracing has provided
further evidence of multisynaptic innervations, which
are disynaptic connections linking the magnocellu-
lar pathway to the V4 and disynaptic connections the
linking parvocellular pathway to the MT (Nassi, Lyon,
& Callaway, 2006; Ninomiya, Sawamura, Inoue, &
Takada, 2011). Taken together, these findings suggest
that the ventral and dorsal pathways can receive each
other’s information. This raises the question of how and
when such information is used for visual perception.
One possibility is that functional interactions between
the two pathways are required to achieve motion-
defined shape perception. Here we summarize the psy-
chophysical and single- cell physiological evidence of
motion- defined shape perception. We propose that the
coordinated activity between V4 and the MT contrib-
utes to the processing of motion- defined shape percep-
tion, and discuss future studies that can help uncover
the associated neural circuitry using recently developed
approaches.
2 | P S YC H O P H YS I C A L A N D
L E S I O N S T U D I E S : V I S UA L M O T I O N
I S T H E M O S T E F F I C I E N T C U E F O R
S H A P E P E RC E P T I O N A N D T H E
V E N T R A L A N D D O R S A L PAT H WAYS
A R E B O T H I M P L I C AT E D I N

P R O C E S S I N G
Visual motion cues are among the most efficient cues for
shape perception and segmentation of objects moving from
their background (Braddick, 1993; Nawrot et al., 1996). To
determine the efficiency of visual attributes for shape per-
ception, threshold levels for accurate shape perception were
compared among distinct cues, including luminance contrast,
motion, color, density, texture, and binocular disparity. The
threshold level for motion- defined shape perception was
lower than that for shape perception defined by luminance
contrast and color (Nawrot et al., 1996). Relative motion dif-
ferences, such as differences in speed or direction between an
object and its surrounding background, allow the perception
of the boundaries, edges, and contours of shapes (Figure 1b).
Psychophysical, electrophysiological and neuroimaging stud-
ies have utilized artificial motion- defined stimuli, in which
displaying computer- generated random dots at an identical
dot density and luminance contrast, but with coherent move-
ment of the dots. These conditions allow detection of bound-
ary, the so- called kinetic boundary (KB), or object contours,
the so- called two- (or three- ) dimensional shape (or structure)
from motion (SFM) (Figure 1b). In this review, we specifi-
cally refer to two- dimensional motion- defined stimuli. These
artificial visual stimuli are useful for investigating the extent
F I G U R E 2 The ventral and dorsal visual pathways in the
cerebral cortex of macaque monkeys. Left: The ventral pathway
(gray) starts from
the V1 and goes to ITC, whereas the dorsal pathway (black)
goes to the MT and medial superior temporal (MST) area and
then separates into the
PPC and uSTS. Right: A coronal section of the brain (indicated
by the vertical dashed line in the right panel) showing the uSTS
and lSTS where
neural activity was recorded (Unno et al. 2014; Handa et al.

2017). The black arrowhead indicates the location of
microlesions made after the
recordings. A scale bar: 1 cm, sts: superior temporal sulcus, lf:
lateral fissure, ips: intraparietal sulcus
lSTS/IT
uSTS
PPC
MST
V1V1 MTV4
sts
ips
lSTS
uSTS
lf
D
V
L M
IT
to which their physical features influence perception of ob-
servers or responsiveness of neurons by controlling the orien-

tations of boundaries, shape of objects, dot density, direction,
speed, and coherence of moving dots. Humans and mon-
keys are quite good at discriminating the orientations of KB
and shapes under the SFM condition (Regan, 1989; Regan
& Hamstra, 1991; Schiller, 1993; Sáry, Vogels, & Orban,
1994; Nawrot et al., 1996; Unno, Kuno, Inoue, Nagasaka, &
Mikami, 2003). Like humans, macaque monkeys can recog-
nize shapes under the SFM condition. The effects of changes
in the speed and density of moving dots on SFM perception
by monkeys are similar to the effects observed in humans
(Unno et al., 2003).
There is increasing evidence from lesion studies to suggest
that the ventral and dorsal cortical areas are essential for SFM
perception. Damage to the ventral or dorsal cortical regions
in humans is related to SFM perception deficits (Mercier,
Schwartz, Spinelli, Michel, & Blanke, 2017; Schenk & Zihl,
1997). Deficits in SFM recognition (motion- defined letter)
have been found in humans with lesions in parietotempo-
ral white matter, which corresponds to Brodmann areas 18,
19, 37, 39, 21, and 22. Some patients have also shown loss
of ability in detecting motion and discriminate its direction
(Regan, Giaschi, Sharpe, & Hong, 1992). Patients suffering
from acute brain damage in the ventral occipitotemporal
cortex, in proximity to area MT+/V5, or the lateral occipital
complex (LOC) have shown severe SFM perception deficits
(Blanke et al., 2007), suggesting that the human ventral and
dorsal cortical areas contribute to the processing of motion-
defined stimulus perception. In the ventral pathway, the ITC
of monkeys plays a pivotal role in recognizing objects (re-
tention) and learning new objects (Tanaka, 1996; Tompa &
Sáry, 2010). ITC lesions impaired the retention of learned
shapes defined by either motion or luminance cues, although
learning new object in SFM conditions was less impaired
than learning new luminance- defined shapes. Learning per-
formance in lesioned monkeys did not differ from perfor-

mance in the non- lesioned monkeys (Britten, Newsome, &
Saunders, 1992). This result suggests that the ITC plays a
role in the discrimination of shapes regardless of cues but that
the learning of SFM discrimination is processed by another
pathway without the contribution of the ITC. On the other
hand, ablation of the MT and adjacent areas in the dorsal
pathway impaired the performance of SFM discrimination,
but not the performance of luminance- defined shape discrim-
ination (Marcar & Cowey, 1992). Lesions in the V4, MT, or
both areas impaired accuracy in the judgment of the aspect
ratio of rectangles defined by motion cues (Schiller, 1993).
Taken together, lesion studies have suggested that the ventral
pathway could exclusively play a role in luminance- defined
shape perception, but not in SFM perception. In other words,
some functional interactions between the ventral and dorsal
pathways are required for motion- defined shape recognition.
3 | N E U R O N A L AC T I VAT I O N I N
R E S P O N S E T O M O T I O N - D E F I N E D
V I S UA L S T I M U L I I N PA S S I V E
V I E W I N G C O N D I T I O N S
A fundamental question is how visual cortical neurons in the
ventral and dorsal pathways respond to physical elements of
motion- defined shapes. Similar to the psychophysical ap-
proach, KB and SFM stimuli have been used to investigate
the nature of physiological responsiveness in single neurons
regarding the orientation of boundary, density, direction, and
speed of moving dots or shapes. For example, the KB, which
is made visible as a line by opposing directions of moving
dots (Figure 1b, left), may have an orientation orthogonal to
that of the axis of the direction of movement. In general, as
many visual cortical neurons selectively respond to either the
orientation or the direction of motion of conventional moving
bars or gratings, we can check if neurons selectively respond
to the orientation of the KB or to the direction of dot move-

ment. For this purpose, it is reasonable to examine single-
unit activity while awake monkeys gaze at a fixation spot
after various visual stimuli are presented because multiple
stimulus characteristics can be rapidly tested in sequence.
Electrophysiological recordings under anesthetized condi-
tions are also useful because various stimulus elements can
be tested while more stable isolation of the units lasts. Thus,
monkeys are passively presented visual stimuli under these
conditions.
Neurons in some cortical areas selectively respond to the
orientation of a boundary defined by relative motion rather
than to the direction of motion. In the ventral pathway, neu-
rons in the V2, V4, and ITC selectively responded to the same
orientations of the KB even when the directions of moving
dots have been orthogonally rotated (Marcar, Raiguel, Xiao,
& Orban, 2000; Mysore, Vogels, Raiguel, & Orban, 2006;
Sáry, Vogels, & Orban, 1995). A subset of neurons selec-
tively responded to motion- defined shapes (i.e., SFM), but
the shape selectivity tuning was clearer in the ITC than in
the V4 (Mysore, Vogels, Raiguel, & Orban, 2008; Mysore
et al., 2006; Sáry, Vogels, & Orban, 1993). In the dorsal path-
way, V3A neurons showed orientation selectivity for the KB
(Zeki, Perry, & Bartels, 2003). However, MT neurons did not
tune to the orientation of the boundary; rather, they tuned
to the direction of motion (Marcar, Xiao, Raiguel, Maes, &
Orban, 1995). These results suggest that ventral cortical neu-
rons primarily extract the KBs or contours of objects using
motion cues, while dorsal cortical neurons may partially pro-
cess such boundary extractions and mainly contribute to mo-
tion processing. However, we must account for other aspects
of passive visual stimulation. Even if animals are awake, it
is unclear that they actually perceived the given stimuli or
recognized the orientation of the KB or the shape of SFM.

Therefore, it is essential to determine the properties of neu-
ronal responses just when monkeys actually recognize pre-
sented boundaries and shapes.
4 | AC T I V E V I S I O N M O D U L AT E S
N E U R O N A L R E S P O N S E S T O
M O T I O N - D E F I N E D S T I M U L U S
It is important to note that the response properties of visual
cortical neurons are altered by various task demands (Gilbert
& Li, 2013), such as visual attention (McAdams & Maunsell,
2000; Motter, 1994; Ogawa & Komatsu, 2004; Reynolds,
Pasternak, & Desimone, 2000; Saruwatari, Inoue, & Mikami,
2008; Treue & Martinez- Trujillo, 1999), visual discrimina-
tion (Chelazzi, Duncan, Miller, & Desimone, 1998; Ferrera,
Rudolph, & Maunsell, 1994; Handa et al., 2008; Sáry,
Köteles, Chadaide, Tompa, & Benedek, 2006; Schlack &
Albright, 2007; Sheinberg & Logothetis, 1997), and per-
ceptual decision (Newsome, Britten, & Movshon, 1989;
Britten, Shadlen, Newsome, & Movshon, 1992; Leopold
& Logothetis, 1996; Bradley, Chang, & Andersen, 1998;
Nielsen, Logothetis, & Rainer, 2006; Kosai, El- Shamayleh,
Fyall, & Pasupathy, 2014; Unno, Handa, Nagasaka, Inoue,
& Mikami, 2014). Top- down modulation may enhance the
processing of behaviorally significant visual stimuli (Blatt,
Andersen, & Stoner, 1990; Schall, Morel, King, & Bullier,
1995; Moore & Armstrong, 2003; Buffalo, Fries, Landman,
Liang, & Desimone, 2010; Ninomiya, Sawamura, Inoue, &
Takada, 2012; Gregoriou, Rossi, Ungerleider, & Desimone,
2014).
Compared to the passive viewing condition, motion-
defined stimulus perception can alter neural activity in the

monkey V1. V1 neurons selective for orientation of KB were
scarce in anesthetized condition (Marcar et al., 2000). By con-
trast, when monkeys were required to detect the rotation of a
line, V1 neurons were more responsive to coherently moving
dots perceived as a line but less responsive to the incoherent
movement of dots not perceived as a line. The orientation
selectivity of V1 neurons for motion- defined lines correlated
to the perception of the monkeys, suggesting that the V1 en-
codes lines defined by coherent motion signals (Peterhans,
Heider, & Baumann, 2005). This discrepancy between pas-
sive viewing and visual discrimination conditions may arise
from differences in behavioral demands or wake states.
Similar to this comparison, we checked if neuronal acti-
vation in visual cortical areas during motion- defined shape
perception is different from that during passive viewing
and if behavioral demand modulates neuronal activity. To
this end, monkeys were required to discriminate motion-
defined shapes (SFM) and luminance- defined shapes (shape
from luminance, SFL) in a delayed matching- to- sample task
(Figure 3). This task paradigm enables us to infer whether
monkeys recognize shapes (Vogels & Orban, 1990; Unno
et al., 2003). Single- unit activity was extracellularly recorded
in the ventral and dorsal cortical areas during task perfor-
mance (Figure 4c). More than half of the V4 neurons (57%)
showed shape- selective responses to SFM (Figure 4a and d),
and the proportion of selective neurons in SFM was larger
during shape discrimination (Handa, Inoue, & Mikami, 2010)
than during passive viewing (approximately 30%) (Mysore
et al., 2008). There was a weak decreasing trend in the shape
selectivity of V4 neurons when monkeys made an erroneous
choice (Handa et al., 2010). In the MT, approximately 40%
of neurons showed shape- modulated activity in response to
SFM although their neuronal activity was strongly direction
F I G U R E 3 A delayed matching- to- sample task with

motion- defined and luminance- defined shapes. Each trial
begins with gazing at a
fixation point followed by a sample cue presentation. Monkeys
are required to retain the sample shape. After the pseudo-
random delay period, two
shapes, which are a target and a distractor, are presented during
continuous gaze fixation. After the fixation point disappears,
the target shape, which
is the same as the sample, is chosen by gaze shift (white arrow).
When the choice is correct, a reward is given. Otherwise, an
error alert is given.
Left: SFM condition. Right: Shape from luminance (SFL)
condition. Gray arrows indicate the direction of moving dots
Choice
Target
Time
SFM condition
or
Delay
Sample
Fixation
SFL condition
selective (Figure 4b and d). However, to our knowledge, there

is no evidence on the responsiveness of MT neurons to SFM
under the passive viewing condition although a paper re-
ported that MT neurons did not respond selectively to the ori-
entation of KB under the passive viewing condition (Marcar
et al., 1995). Thus, the extent to which shape discrimination
alters the neural activation in the MT compared with that in
the passive viewing condition is unknown.
Further, we addressed the question of whether the require-
ment of shape discrimination alters shape- modulated activity
in the MT. Neuronal responses to identical SFM stimuli were
compared between the requirement of shape discrimination
and that of motion discrimination. Of 68 MT neurons, 43%
and 24% showed shape- modulated responses when the task
required discrimination of shape and direction of motion, re-
spectively (Handa et al., 2008). Therefore, the requirement
of shape recognition may induce more frequently motion-
defined shape modulation in the MT.
We also found that some neurons in the upper bank of
the anterior superior temporal sulcus (uSTS), which is also
called anterior superior polysensory area (STP) (Baylis,
Rolls, & Leonard, 1987; Bruce, Desimone, & Gross, 1981;
Oram & Perrett, 1996), and the lower bank of the ante-
rior superior temporal sulcus (lSTS), which are areas TEa
and IPa in the ITC (Baylis et al., 1987; Boussaoud et al.,
1990), showed selective responses to the shape and motion
of SFM during shape discrimination (Unno et al., 2014).
The presence of SFM shape- selective uSTS neurons is
not consistent with the results of another study in which
monkeys were required to gaze at a fixation spot while
SFM stimuli were presented without the requirement of
shape discrimination. In this passive viewing condition,
neuronal modulation by shape in the SFM condition was
not observed in the STP (i.e., uSTS) (Anderson & Siegel,

1998). This discrepancy may arise from differences in task
demands. Taken together, differences in neural activity
between passive and active vison indicate that the recog-
nition of motion- defined stimuli can modulate neural re-
sponsiveness across the dorsal and ventral pathways. This
raises the question of whether enhanced neuronal repre-
sentation of motion- defined shapes (or orientations) by the
perception of observers in the dorsal and ventral pathways
is cue- dependent (i.e. motion or other visual features), or
a common neural modulation regardless of cues. Next,
F I G U R E 4 Single- unit activity in V4, MT, anterior
superior temporal sulcus during shape discrimination in the
SFM condition. Shape-
modulated neuronal activity of V4 (a) and MT (b) neurons. The
raster and histogram array consist of four shapes and two
directions of motion in
the SFM condition. This plot shows neural responses to a
stimulus presented within its RF. Time is aligned at stimulus
onset in target period. (c) A
schematic illustration of recording sites. (d) Population
histogram of responses to preferred (colored) and no- preferred
(gray) stimuli in functionally
classified group in V4 (top), MT (middle), and uSTS/lSTS
(bottom). (a), (b), and (d) are modified from (Handa et al.,
2010; Handa et al., 2008 and
Handa et al., 2017), respectively. [Colour figure can be viewed
at wileyonlinelibrary.com]
65
65
[Hz]
(a)

30
30
(b)
Motion direction Shape &motion direction Shape
(c)
(d)
N
or
m
al
iz
ed
fi
rin
g
ra
te
0
0.4
0

0.4
0
0.4
(n = 6) (n = 17) (n = 16)
0 0 0
0.6 0.4
0.6
(n = 8) (n = 36) (n = 21)
0 0
0.6
0.4 (n = 26) (n = 45)
MTV4 uSTS
lSTS
0.5 s
MT
V4
[Hz]
www.wileyonlinelibrary.com
we discuss cue- dependence of neuronal representation
of shape by comparison with motion- defined shape and

luminance- defined shape perception at different levels of
the cortical hierarchy.
5 | C A N D I DAT E A R E A S F O R
S H A R I N G O F I N F O R M AT I O N
A B O U T M O T I O N A N D S H A P E O N
M O T I O N - D E F I N E D S T I M U L I AT
E A R LY A N D H I G H E R - O R D E R
C O R T I C A L A R E A S
We hypothesize that an interplay between the ventral and
dorsal pathways must be required for motion- defined shape
(i.e., SFM) perception, but not for luminance- defined shape
(i.e., SFL) perception. This hypothesis is based on evidence
from lesion studies in which lesions in the dorsal or ventral
pathways resulted in distinct effects on the discrimination of
shapes defined by motion and luminance cues as discussed
above (Britten, Newsome, et al., 1992; Marcar & Cowey,
1992). To this end, we examined functional activity pat-
terns in early visual areas and at higher- order cortical areas,
which are likely to be candidate areas to share information
about motion and shape, based on the following rationale
(Figure 2).
At the lower level, the V4 and MT are candidate areas
because both areas have direct reciprocal innervations by
forming an intermediate connectivity pattern that is dif-
ferent from forward and feedback laminar projection pat-
terns (Maunsell & Van Essen, 1983; Ungerleider, Galkin,
Desimone, & Gattass, 2008). These monosynaptic connec-
tions can permit sending and/or receiving information about
motion and/or shape to process SFM. V4 can receive visual
motion signals through direct connections from MT as well
as V2 (Felleman, Burkhalter, & Van Essen, 1997; Maunsell
& Van Essen, 1983; Nassi et al., 2006; Ninomiya et al., 2011;
Ungerleider et al., 2008), and some V4 neurons encode mo-

tion signals (Desimone & Schein, 1987; Ferrera, Rudolph,
et al., 1994; Handa et al., 2010; Li et al., 2013; Tolias et al.,
2005) (Figure 4a and d). If neural activity is altered between
the SFM and SFL conditions, the difference in functional
activity may be attributed to differential neural mechanisms
underlying shape processing relying on cues. Approximately
50%–60% of shape- selective V4 neurons for SFM revealed
a similar shape preference to the SFL, suggesting cue-
invariant shape selectivity. However, the temporal properties
of shape- modulated neural activity differed between the two
cues (Handa, Unno, & Mikami, 2017; Handa et al., 2010;
Mysore et al., 2006, 2008). The visual response latency of
V4 neurons differed between the SFM and SFL conditions.
Delay to represent a shape signal in the V4 was longer in the
SFL condition (177 ms) than in the SFM condition (123 ms)
(Handa et al., 2017) (Figure 5). These results suggest that the
V4 encodes a specific shape and/or constituent parts of shape
regardless of cues, but that the underlying process for the ex-
traction of shape and/or its constituent part is dependent on
cues (motion vs. luminance). In the MT, the proportion of
shape- modulated neurons in the SFM condition (40%) was
significantly larger than that in the SFL condition (30%)
(Handa et al., 2008). Thus, shape modulation in the MT is
dependent on cues. The MT may interact with ventral cortical
areas (i.e., V4) in the SFM condition, but less so in the SFL
condition. Taken together, in the V4 and MT, shape modula-
tion differs depending on cues for shape recognition, indicat-
ing that distinct neural mechanisms or circuits are implicated
in the processing of shape. This result from the analysis of
functional activity supports the interpretation of results from
lesion studies (Britten, Newsome, et al., 1992; Marcar &
Cowey, 1992; Schiller, 1993).
Another candidate area for the processing of shape using
motion at the higher- order level is the anterior superior tem-

poral sulcus, where single neurons represent shape and mo-
tion signals, but functionally distinct neurons are spatially
F I G U R E 5 Comparison of temporal dynamics of shape-
modulated activity between SFM and SFL conditions. (a)
Comparison
of visual response latency between SFM (gray) and SFL (black)
conditions. (b) Comparison of time delay from response latency
to
emergence of shape representation between SFM and SFL
conditions.
(a) and (b) are modified from (Handa et al., 2017)
(a)
(b)
0
100
Response latency
Time (ms)
200 0
0
100
lSTS
Time from
response latency (ms)
Difference in time

200 0 400
V4
lSTS
V4
%
o
f c
el
l
%
o
f c
el
l
SFL
SFM
*
n.s.
*
n.s.

segregated (Baylis et al., 1987; Jastorff, Popivanov, Vogels,
Vanduffel, & Orban, 2012) (Figure 2). The uSTS in the
dorsal pathway has reciprocal connections with the medial
superior temporal area, which is another motion- sensitive
area (Boussaoud et al., 1990), and connections with the ITC
(including lSTS) (Saleem, Suzuki, Tanaka, & Hashikawa,
2000). In line with these anatomical connections, uSTS neu-
rons showed visually selective responses to moving objects
and complex objects such as faces and hands (Bruce et al.,
1981; Oram & Perrett, 1996). When monkeys discriminated
computer- generated rotating shapes, uSTS neurons selec-
tively altered their firing rates in response to the direction
of rotation and/or shape of objects (Tanaka, Koyama, &
Mikami, 2002). Therefore, the uSTS is considered to play a
role in the integration of motion and shape information. On
the other hand, in the lSTS, which is a subset of the ITC,
neurons responded to simple and complex visual objects
(Baylis et al., 1987; Kiani, Esteky, Mirpour, & Tanaka, 2007;
Mikami, Nakamura, & Kubota, 1994). A functional magnetic
resonance imaging (MRI) study revealed a motion- sensitive
subregion in the ITC which may correspond to the lSTS. The
SFM or KB induced stronger MRI signal in the lSTS than
transparent motion (Nelissen, Vanduffel, & Orban, 2006).
Therefore, an interaction between the uSTS and lSTS may
enable the areas to extract the SFM signal. In terms of re-
sponsiveness to SFM, uSTS neurons primarily showed se-
lectivity for the direction of motion, whereas lSTS neurons
frequently showed selectivity for the shape (Figure 4d). These
results are in accordance with the findings described above,
although a minor of uSTS and lSTS neurons showed both
shape and direction of motion selectivity (Unno et al., 2014).
lSTS neurons may be related to shape recognition regardless
of cues. Most lSTS neurons have a cue- invariant shape pref-

erence (Unno et al., 2014), as observed in the lateral convex-
ity of the ITC (Sáry et al., 1993; Tanaka, Uka, Yoshiyama,
Kato, & Fujita, 2001). Unlike V4 neurons, the temporal as-
pects of shape modulation in the lSTS were not significantly
different between SFM and SFL conditions (Handa et al.,
2017) (Figure 5). The shape selectivity of lSTS neurons sig-
nificantly correlated with the shape discrimination perfor-
mance of monkeys (Figure 6). At the population level, neural
responses to preferred shapes decreased when the shape was
a distractor, that is, one of two presented shapes, but not a
match to a sample shape. The shape selectivity of lSTS neu-
rons was enhanced when monkeys correctly chose shapes
matched to sample cues (Unno et al., 2014). Thus, these con-
stant neuronal properties of lSTS neurons in response to SFM
and SFL suggest that the lSTS plays a role in cue- invariant
shape recognition rather than in motion- cue- dependent shape
processing.
6 | E A R LY C O R T I C A L A R E A S
L I K E LY P R OV I D E A K E Y
F U N C T I O N T O S H A R E T H E
I N F O R M AT I O N O F T H E D O R S A L
A N D V E N T R A L PAT H WAYS
We suggest that interactions between the ventral and dor-
sal pathways can be carried out among early cortical areas
such as V4 and MT, particularly in the processing of motion-
defined shape (Figure 7). V4 is the most likely area because
the neuronal response preference for visual features is com-
plex; it is crucial for processing of shapes or their constituent
F I G U R E 6 Single- unit activity in
lSTS correlates to visual discrimination
performance. (a) Neural correlates with
shape discrimination performance when
the dot density of SFM varies. (b) The

rastergram of an lSTS neuron in response
to the preferred shape when the monkey
selected the correct (up) and incorrect
(bottom) shapes. (c) Group data of lSTS
neurons in comparison of shape preference
between correct and wrong choice trials.
(a–c) are modified from (Unno et al., 2014)
correct rate (recording exp.)
correct rate (behav exp.)
selectivity indices
Correct trials
Error trials
Distractor (n = 7)
Target (n = 5)
(a) (b)
C
or
re
ct
r
at
e
(%
)
Dot density (%)

40
20
1 5 10 20 40
0.8
0.6
0.4
0.2
0
60
80
100 1.0
S
electivity index
0
0 4020
0
40
20
Pref - NonPref

in error trials
P
re
f -
N
on
P
re
f
in
c
or
re
ct
tr
ia
ls
–20
–20
(c)
lSTS

parts and for transmitting signals to the posterior ITC (Connor
et al., 2007), even when visual motion cues are essential for
the shape perception (i.e., SFM) (Schiller, 1993). A primary
role of V4 may be to facilitate the figure- ground segregation
of visual scenes (Roe et al., 2012). Thus, under the SFM con-
dition, V4 may extract shape or constituent parts by utilizing
a motion signal. In V4, however, the mechanism underlying
extraction of shape using motion signals seems to be different
from the mechanism underlying the processing of luminance-
defined shape. The temporal dynamics of shape representa-
tion in V4 are different between the SFM and SFL conditions
(Handa et al., 2017). One may consider that V4 receives
information about motion or luminance to extract shape in-
formation via the dorsal or ventral pathways, respectively
(Figure 7). Motion information in V4 may be attributed to
that in MT because MT is essential for SFM discrimination.
Ablation of MT and adjacent areas has been shown to im-
pair SFM discrimination, but not luminance- defined shape
discrimination (Marcar & Cowey, 1992). In accordance with
this possibility, we found that the emergence of motion infor-
mation in V4 followed that in MT (Handa et al., 2017).
Another piece of evidence that supports the interaction be-
tween pathways is shape- modulated neuronal activity in the
MT. Shape modulation may be enhanced by the requirement
of shape discrimination by means of motion cues because
neural modulation by shapes has been observed when shapes
are related to motion signals (Handa et al., 2008; Schlack &
Albright, 2007). These lines of evidence indicate that the MT
receives shape signals from the ventral pathway.
An alternative neural mechanism underlying the pro-
cessing of SFM extraction is that V2 plays a role in some
interactive processing with V4 and MT. V2 consists of three

functionally different compartments called ‘thin- stripes’,
‘thick- stripes’, and ‘inter- stripes’, which are implicated in
the processing of color, motion, and orientation, respectively
(Van Essen & Gallant, 1994). Therefore, V2 is included in
both ventral and dorsal pathways. V2 reciprocally connects
with V4 and MT (Maunsell & Van Essen, 1983; Ungerleider
et al., 2008) and neuronal activation in V2 is influenced by
inactivation of V4 and MT. The orientation or direction se-
lectivity were sharpened or lost immediately after the phar-
macological inactivation of V4 (Jansen- Amorim, Fiorani, &
Gattass, 2012) and MT (Jansen- Amorim, Fiorani, & Gattass,
2011). When MT was inactivated by cooling, the neuronal
responses to a moving bar in V2 were modulated (decreased
in most cases) at the early (Hupé et al., 2001) and late (Hupé
et al., 1998) stages of the responses, indicating that this neu-
ral modulation was caused by interference of feedback signal
from MT (Hupé et al., 1998). Such a feedback motion signal
may be used for the processing of motion- defined stimulus.
Indeed, V2 neurons selectively responded to the orientation
of the KB and the response latency of the KB- orientation-
selective neurons was longer than in non- selective neurons.
This temporal difference indicates that the KB- orientation-
selective response is computed by using feedback inputs
from some areas (Marcar et al., 2000). A model study also
has suggested that V4 and MT neurons, which feed signals
back to V2 neurons, can play a crucial role in determining
figure surfaces distinct from the background using motion
cues (Layton & Yazdanbakhsh, 2015) (Figure 7).
At higher- order cortical areas, the uSTS and lSTS are un-
likely to work on the extraction of shapes or constituent parts
F I G U R E 7 Possible neural mechanisms across dorsal and
ventral pathways underlying SFM and SFL perception. Left:
Lateral view of
macaque cerebral cortex with labeling of cortical regions. Note

that superior temporal sulcus is unfolded in this illustration.
Right: A schematic
illustration of possible neural mechanism underlying shape
processing in SFM (top) and SFL (bottom) conditions with
major information flow.
Black and gray arrows indicate direction of transmission of
motion and shape information, respectively. Unarrowed line
indicates anatomical
connection on the basis of literature: a, Maunsell & Van Essen
(1983); b, Ungerleider et al. (2008); c, Boussaoud et al. (1990);
d, Saleem et al.
(2000). [Colour figure can be viewed at wileyonlinelibrary.com]
SFM
SFL
a,b
b
a c
d
a,b
b
a c
d
b
b
a

a
a
a
SFM
SFL
MST uSTS
lSTS
ITC
V1
V2
MT
V4
MST uSTS
lSTS
ITC
?
V1
MT
V4
V2
motion
shape/boundary

a,b
b
a c
d
a,b
b
a c
d
MT
uSTS
lSTS
V4
MST
V1
V2
PPC
ITC
b
b
a

a
a
a
www.wileyonlinelibrary.com
(boundaries) using motion cues. Rather, the lSTS encodes in-
variant shape information and can contribute to shape recog-
nition. Cue- invariant orientation selective neurons in the ITC
are less common than in the V4 (Mysore et al., 2006; Sáry
et al., 1995), whereas cue- invariant shape- selective neurons
are enriched (Sáry et al., 1993; Tanaka et al., 2001; Unno
et al., 2014). Shape selectivity for the SFM was correlated to
discrimination performance in monkeys (Unno et al., 2014).
The temporal dynamics of shape- selective responses in the
lSTS did not differ between SFM and SFL conditions (Handa
et al., 2017). Taken together, the lSTS and ITC contribute
to invariant shape recognition rather than to encoding cue-
dependent curvature or shape contours.
In our study, the uSTS may not have contributed to shape
processing under the SFM condition because few neurons
showed shape selectivity for the SFM. This result may be due
to the usage of simple shapes as uSTS neurons are more likely
to respond to complex objects, such as faces and hands, and
to body movements and biological motion, but not to sim-
ple shapes (Baylis et al., 1987; Bruce et al., 1981; Oram &
Perrett, 1996). In the uSTS and lSTS, the integration of mo-
tion and object information may be required to encode what
object is moving where (e.g., a human walking forward). In
addition to the previous single- unit electrophysiological find-
ings in the uSTS (Bruce et al., 1981; Oram & Perrett, 1996),
recent studies demonstrated that various sub- regions in su-

perior temporal sulcus, including the lSTS, were activated
by observing artificial biological motion (Vangeneugden,
Pollick, & Vogels, 2009) and observing action (Nelissen
et al., 2011). Human neuroimaging studies indicate that the
posterior superior temporal sulcus, which corresponds with
the monkey uSTS, is involved in the perception of biological
motion, and the function of this cortical area is implicated
in the integration/separation of shape and motion (Jastorff &
Orban, 2009). In the human ventral pathway, the extrastri-
ate body area, which is involved in the analysis of the static
human body form, was selectively activated by biological
motion displays (Peelen, Wiggett, & Downing, 2006). Thus,
interplay between the uSTS and lSTS may contribute to the
processing of higher cognitive functions such as action rec-
ognition (Keysers & Perrett, 2004).
Functional MRI and event- related potential mapping in
human brains have implicated the ventral and dorsal visual
pathways in motion- defined shape perception (for review, see
Kourtzi, Krekelberg, & Van Wezel, 2008). The dorsal visual
area MT+/V5, which corresponds with the monkey MT, as
well as ventral and lateral occipital areas such as the LOC and
ventral occipitotemporal cortex, which are considered to cor-
respond with the monkey ITC, showed SFM- related activa-
tion (Gulyas, Heywood, Popplewell, Roland, & Cowey, 1994;
Mercier et al., 2017; Schoenfeld et al., 2003; Wang et al.,
1999). Neuroimaging studies uncovered the involvement of
multiple cortical areas in dorsal and ventral pathways, such
as V3, the fundus of the superior temporal sulcus, and PPC
in addition to V2, V4 and MT, in the processing of three-
dimensional structure- from- motion (for review, see Orban,
2011). Thus, we should consider that the processing of two-
dimensional SFM involves a large scale network that includes
dorsal and ventral cortical areas.

7 | C O N C L U D I N G R E M A R K S A N D
F U T U R E P E R S P E C T I V E S
Considerable physiological and anatomical evidence as well
as lesion studies have indicated cooperation between the ven-
tral and dorsal cortical areas for visual perception (Maunsell,
1992; Gegenfurtner & Hawken, 1996; Perry & Fallah, 2014),
which is inconsistent with the classical concept, namely
the separation of the two visual pathways. A recent paper
revealed that shape- sensitive fMRI signals in the human
ventral and dorsal higher- order regions were correlated to
shape perception of observers, suggesting involvement of
both pathways in shape perception (Freud, Culham, Plaut, &
Behrmann, 2017). Not only the ventral pathway but also the
dorsal pathway may contribute to the processing of general
object recognition (Farivar, 2009).
The analysis of neuronal activity during shape recognition
has provided evidence that neural activation in the cortical
areas of the ventral and dorsal pathways is more modulated
by SFM discrimination than in the passive viewing condition.
The temporal dynamics of neuronal modulation by SFM is
different from those of neuronal modulation by luminance-
defined shape, suggesting that the underlying neural mech-
anisms are distinct for motion and luminance cues. There is
increasing anatomical and physiological evidence to support
the concept of an interactive mechanism between the MT
and V4. Motion- defined shape perception can be computed
via the ventral pathways with the cooperation of motion-
sensitive cortical areas such the MT. A KB or SFM can be
extracted at an early level such as V4. By contrast, higher-
order ventral cortical areas, such as the lSTS and ITC, encode
invariant shape information and directly contribute to shape
recognition, rather than the extraction of kinetic edges or sim-
ple shapes defined by motion.

Admittedly, there is so far no direct evidence to support
or refute the interactive neural computation between MT
and V4 in response to motion- defined shape. To determine
the presence of the interactive function at early visual cor-
tical areas, it is ideally required to identify neurons anatom-
ically connecting to other pathways, to analyze the encoded
signal (shape or motion) that the identified neurons convey,
and to investigate the effect of the inactivation of the iden-
tified neurons on neural representation at the other region.
Technical advances in rodent brain research, such as opto-
genetic manipulation (transient and reversal depolarization
or hyperpolarization) and large scale multiple- neuron re-
cordings, have enabled us to investigate the involvement
of a specific brain region, neural circuit, or pathway in a
specific behavior (Bolkan et al., 2017; Saiki et al., 2018).
Importantly, optogenetics can identify specific projection
neurons and can be used in primate brain research (Klein
et al., 2016; Stauffer et al., 2016). A combination of op-
togenetic manipulation in specific pathways with electro-
physiological recording (Cavanaugh et al., 2012; Inoue,
Takada, & Matsumoto, 2015) or functional MRI (Gerits
& Vanduffel, 2013) can be useful for understanding com-
prehensive networks relevant to specific processing (e.g.,
motion- defined shape perception) and the causality of per-
ception (Kahn et al., 2013). Future studies need to chal-
lenge the investigation of interactive functions at more
precise connection levels.
AC K N OW L E D G E M E N T S
We are grateful to all of our colleagues of primate research
institute for their supports.

C O N F L I C T O F I N T E R E S T
None declared.
AU T H O R C O N T R I B U T I O N S
AM designed and directed the project. TH performed experi-
ments, analyzed the data, and wrote the manuscript.
O RC I D
Takashi Handa http://orcid.org/0000-0003-3956-8077
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