Thalamic projections to visual and visuomotor areas (V6 and V6A) in

Brain Struct Funct
DOI 10.1007/s00429-015-0990-2
ORIGINAL ARTICLE
Thalamic projections to visual and visuomotor areas (V6
and V6A) in the Rostral Bank of the parieto-occipital sulcus
of the Macaque
Michela Gamberini • Sophia Bakola • Lauretta Passarelli •
Kathleen J. Burman • Marcello G. P. Rosa • Patrizia Fattori
Claudio Galletti
•
Received: 15 September 2014 / Accepted: 9 January 2015
Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The medial posterior parietal cortex of the
primate brain includes different functional areas, which
have been defined based on the functional properties, cytoand myeloarchitectural criteria, and cortico-cortical connections. Here, we describe the thalamic projections to two
of these areas (V6 and V6A), based on 14 retrograde
neuronal tracer injections in 11 hemispheres of 9 Macaca
fascicularis. The injections were placed either by direct
visualisation or using electrophysiological guidance, and
the location of injection sites was determined post mortem
based on cyto- and myeloarchitectural criteria. We found
that the majority of the thalamic afferents to the visual area
V6 originate in subdivisions of the lateral and inferior
pulvinar nuclei, with weaker inputs originating from the
central densocellular, paracentral, lateral posterior, lateral
geniculate, ventral anterior and mediodorsal nuclei. In
contrast, injections in both the dorsal and ventral parts of
the visuomotor area V6A revealed strong inputs from the
lateral posterior and medial pulvinar nuclei, as well as
smaller inputs from the ventrolateral complex and from the
central densocellular, paracentral, and mediodorsal nuclei.
These projection patterns are in line with the functional
M. Gamberini S. Bakola L. Passarelli P. Fattori C. Galletti (&)
Department of Pharmacy and Biotechnology, University of
Bologna, Piazza di Porta S. Donato, 2, 40126 Bologna, Italy
e-mail: claudio.galletti@unibo.it
S. Bakola K. J. Burman M. G. P. Rosa
Department of Physiology, Monash University, Clayton,
VIC 3800, Australia
S. Bakola M. G. P. Rosa
Australian Research Council, Centre of Excellence for
Integrative Brain Function, Monash University Node, Clayton,
VIC 3800, Australia
properties of injected areas: ‘‘dorsal stream’’ extrastriate
area V6 receives information from visuotopically organised subdivisions of the thalamus; whereas visuomotor area
V6A, which is involved in the sensory guidance of arm
movement, receives its primary afferents from thalamic
nuclei that provide high-order somatic and visual input.
Keywords Posterior parietal cortex Connectivity Primate Thalamus Superior parietal lobule Sensorimotor input
Abbreviations
Thalamic nuclei
AD
AM
AV
Bsc
Can
Cdc
CL
CM
Csl
GLvo
GLd
GMpc
LGN
Li
LP
MD
MDdc
MDmc
MDpc
MG
MGpc
Anterior dorsal
Anterior medial
Anterior ventral
Brachium of superior colliculus
Capsule of the anterior nuclei
Central densocellular
Central lateral
Centromedian
Centralis superior lateralis
Lateral geniculate, pars oralis
Lateral geniculate, dorsalis
Medial geniculate, pars parvocellularis
Lateral geniculate
Limitans
Lateral posterior
Mediodorsal
Mediodorsal, pars densocellularis
Mediodorsal, pars magnocellularis
Mediodorsal, pars parvocellularis
Medial geniculate
Medial geniculate, pars parvocellularis
123
Brain Struct Funct
PC/Pcn
Pul
PuI
PuL
PuM
SG
STN
R
VAmc
VAdc
VL
VLc
VLm
VLo
VLps
VPI
VPL
VPLo
VPLc
VPM
X
Paracentral
Pulvinar
Pulvinar, inferior subdivision
Pulvinar, lateral subdivision
Pulvinar, medial subdivision
Suprageniculatus
Subthalamic
Reticular
Ventral anterior, pars magnocellularis
Ventral anterior, pars densocellularis
Ventral lateral
Ventral lateral, pars caudalis
Ventral lateral, pars medialis
Ventral lateral, pars oralis
Ventral lateral, pars postrema
Ventral posterior inferior
Ventral posterior lateral
Ventral posterior lateral, pars oralis
Ventral posterior lateral, pars caudalis
Ventral posterior medial
Area X
Neuronal tracers and histological solutions
CTB-green
CTB-red
CTB-gold
DY
FB
WGA-HRP
PBS
Cholera toxin B subunit conjugated with
Alexa fluor 488
Cholera toxin B subunit conjugated with
Alexa fluor 594
Cholera toxin B subunit conjugated with
colloidal gold
Diamidino-yellow
Fast blue
Wheat germ agglutinin conjugated to
horseradish peroxidase
Phosphate buffered saline
Cortical areas
SPL
V6
V6Ad
V6Av
Superior parietal lobule
Area V6
Area V6A, dorsal portion
Area V6A, ventral portion
Introduction
The cortical areas located on the rostral bank of the parieto-occipital sulcus and adjacent portions of the superior
parietal lobule have been extensively studied in the
macaque monkey, particularly over the last two decades
(Galletti et al. 1996, 1999a, b, 2004; Breveglieri et al.
2002; Fattori et al. 2005; Luppino et al. 2005; for a
review see Gamberini et al. 2011). These studies have
reported the existence of two areas that are distinct in
123
terms of physiological properties, connections, and cytoarchitecture. From caudal to rostral (Fig. 1), they have
been designated as areas V6 and V6A, with V6A subdivided into ventral (V6Av) and dorsal (V6Ad) regions.
Area V6 is a visual extrastriate area, in which neurons
form a systematic representation of the entire contralateral
visual field, albeit with a much reduced emphasis on
central vision in comparison with the striate cortex
(Daniel and Whitteridge 1961; Galletti et al. 1999a). In
contrast, V6Av and V6Ad are better described as two
functionally related subdivisions of the same visuomotor
area, V6A, which have relatively complementary functions related to the integration of visual and somatic
signals for the control of arm and hand movements
towards targets in peripersonal space (Gamberini et al.
2011). Although the cortical connections of these regions
have been described in detail (Galletti et al. 2001; Gamberini et al. 2009; Passarelli et al. 2011), their thalamic
afferents have not yet been compared.
Previous studies in macaques (Yeterian and Pandya
1985; Schmahmann and Pandya 1990; Yeterian and
Pandya 1997) and New World owl and squirrel monkeys
(Gharbawie et al. 2010) have shown that posterior parietal
areas are preferentially connected with the lateral posterior
(LP), ventral lateral (VL), and medial pulvinar (PuM)
thalamic nuclei (see, Grieve et al. 2000). In addition, preliminary results obtained after injections in the V6/V6A
region indicated weak but consistent connections with the
medial and lateral subdivisions of the pulvinar complex
(Shipp et al. 1998). Finally, the dorsomedial visual area
(DM), an extrastriate region that has been considered the
New World monkey homologue of area V6 (Rosa et al.
2009; Paxinos et al. 2012), receives projections from the
lateral (PuL) and inferior (PuI) subdivisions of the pulvinar, as well as sparser connections from the lateral geniculate nucleus (LGN) and nucleus limitans (Li) (see, Beck
and Kaas 1998).
Since the precise cytoarchitectural and myeloarchitectural correlates of V6, V6Av, and V6Ad have been established in the macaque (Luppino et al. 2005), it has become
possible to achieve a more detailed understanding of their
afferent projections from specific thalamic nuclei. In the
present paper, we aimed to compare the relative numerical
weight of the projections from different thalamic nuclei to
areas V6 and V6A, to obtain further insights on the network activity that defines their neuronal function (e.g.
Burman et al. 2011).
Materials and methods
Experimental protocols were approved by the Bioethics
Committee of the University of Bologna and by the
Brain Struct Funct
A
pos
pos
ips
cs
B
cin
sts
ps
ars
ls
lf
CC
ios
ots
pom
V6Ad
V6Av
V6
cal
a
pcd
M
PE
v
PEc
pos
MIP V6Ad
S
cs
V6Av
PG
v
M
S
PE
PEc
V6Ad
cin
V6
PFG
ips
a
area
31
PGm
pos
V6Av
CC
PF
V6
pom
lf
sts
ls
Fig. 1 Anatomical localization of the areas of the rostral bank of
parieto-occipital sulcus. a Lateral view of macaque brain. The
enlargement in the bottom part of the figure highlights in colour the
location of areas V6A (subdivided into V6Ad and V6Av) and V6,
which are hidden on the depth of the parieto-occipital sulcus. The
intraparietal and parieto-occipital sulci are opened to show the areas
hidden within (grey surface). Dashed lines delimit other areas
reported in the literature (see below). b Mesial view of macaque
brain. The enlargement in the bottom part of the figure shows the
cortical areas located in the mesial wall of the hemisphere, with the
areas of interest shown in colour. ars arcuate sulcus, cal calcarine
sulcus, cin cingulate sulcus, cs central sulcus, ips intraparietal sulcus,
ios inferior occipital sulcus, lf lateral fissure, ls lunate sulcus, ots
occipito-temporal sulcus, pcd post central dimple, pos parietooccipital sulcus, pom medial parieto-occipital sulcus, ps principal
sulcus, sts superior temporal sulcus, a anterior, v ventral, CC corpus
callosum, M primary motor area, S primary somatosensory area; PE,
PEc, MIP, PG, PFG, PF, PGm, 31, V6, V6Ad, V6Av, areas PE, PEc,
MIP, PG, PFG, PF, PGm, area 31, V6, V6Ad, V6Av. (Galletti et al.
1996; Morecraft et al. 2004; Scheperjans et al. 2008)
Monash University Animal Experimentation Ethics
Committee, in accordance with the guidelines of the
European Directive 86/609/EEC, the revised Directive
2010/63/EU, and the Australian Code of Practice for the
Care and Use of Animals for Scientific Purposes. Fourteen
retrograde tracer injections were placed in 11 hemispheres
of 9 male adult monkeys (Macaca fascicularis, 3–7 kg).
Selection of injection sites was performed either by direct
visualisation of areas V6 and V6A (dorsal and ventral
subdivisions), based on sulcal morphology, or under
electrophysiological guidance, following previously
defined criteria (Galletti et al. 2001; Gamberini et al.
2009; Passarelli et al. 2011). The extent of each injection
site was reconstructed post mortem from cyto- and myeloarchitectural material. Figure 2a illustrates a schematic
of the extent of the injection sites relative to the boundaries of the different areas, projected onto a flat map
reconstruction of a reference macaque brain prepared with
the software CARET (http://www.nitrc.org/projects/caret/,
Van Essen et al. 2001). Table 1 presents details of individual injections.
Injections by direct visualisation of the cortex
Full details of the experimental procedures have been
described previously (Galletti et al. 1995, 1999b, 2001,
2005; Gamberini et al. 2009; Passarelli et al. 2011). In six
animals (cases A1R, A3R/A3L, A4R, MF1, MF2, and
11L), the target region was visualised during surgery under
aseptic conditions. Four of these animals were pre-treated
with atropine (0.05 mg/kg, i.m.) and anaesthetized with
ketamine hydrochloride (12 mg/kg, i.m.) followed, after
30 min, with sodium thiopental (8 mg/kg, i.v., with supplemental doses as required). To avoid oedema, mannitol
was administered intravenously (1 g/kg). A different protocol was used for animals MF1 and MF2, which were
premedicated with intramuscular injections of diazepam
(3.0 mg/kg) and atropine (0.2 mg/kg), with anaesthesia
being induced, 30 min later, with alfaxalone (10 mg/kg,
i.m.; supplemental doses of 5 mg/kg were administered
intravenously during surgery, as required). In all cases,
animals were secured to a stereotaxic frame and, after
craniotomy, the superior parietal lobule was exposed, the
123
Brain Struct Funct
A
ps
V6Ad
ips
A3aL
A3bL
A1R
M17R
ars
A3R
11L
cs
lf
M18L
A4aR
A4bR
MF2L
M21R
ips
sts
pos
ls
V6Ad
V6Av
V6
MF1L
V6
V6Av
pos
V6Ad
V6Av
ls
V6
pom
M17R
M17L
injection
core
B
ipsi
10°
contra
1
2
NV
pos
cin
V1
70°
V2
3
a
v
3
4
V6Av
6
4
8
5
2
NV
5mm
V6Ad
V6Av
1
250µm
6
5
7
7
NV
sts
ars
ps
cs ips
ls
8
NV
pos
80°
Fig. 2 Injection sites. a Injection sites are illustrated on the right on a
two-dimensional reconstruction of the rostral bank of parieto-occipital
sulcus of the left hemisphere of a reference monkey brain (http://
www.nitrc.org/projects/caret/, Van Essen et al. 2001) shown on the
left. The dashed contours represent the approximate cytoarchitectonic
borders of V6Ad, V6Av, and V6. The ‘‘halo’’ and ‘‘core’’ zones of
injection sites are shown as coloured and black areas, respectively,
with the name of cases reported (see also Table 1). b Reconstruction
of an injection performed under electrophysiological guidance (case
M21R). The recording site was in V6Av. The ‘‘halo’’ and ‘‘core’’
zones of the injection site are shown on the parasagittal section to the
left as white and black ovals, respectively. The enlargement to the
right of the section reports the type of cells encountered in V6Av
along the penetration. Black circles indicate non-visually responsive
(NV) cells, and white circles visually responsive cells. The receptive
fields of V6A visual cells are reported to the right, together with those
of cells recorded in the primary and second visual areas, while passing
through the occipital lobe. V1 primary visual area, V2 second visual
area, ipsi ipsilateral visual field, contra contralateral visual field.
Other abbreviations are as in Fig. 1
dura mater retracted, and neuronal tracers applied directly
to the cortex based on visualisation of the sulcal pattern.
The cortical midline and parieto-occipital sulcus were
retracted to expose the regions of interest, allowing injections through a Hamilton microsyringe, which had been
fitted with a glass micropipette attached to the needle. At
the end of the surgery, the exposed cortex was covered with
ophthalmic film (Gelfilm) and a thin layer of Gelfoam. The
bone was replaced, and the wound was sutured. Analgesics
(Ketorolac, 1 mg/kg, i.m., or Carprofen, 5 mg/kg, s.c., for
2–3 consecutive days) and antibiotics (Erythromycin,
1–1.5 ml/10 kg, or Norocillin, 0.1 ml) were administered
postoperatively. In all cases, the University veterinary staff
monitored physiological parameters during surgeries, as
well as the animal’s recovery in subsequent days.
123
Injections guided by electrophysiological recordings
In three animals (M17R and L, M18L and M21R), the
tracer injections were placed at the conclusion of longlasting (several months) single-unit recording experiments,
using a ‘recording syringe’ to target physiologically identified sites. During the recording sessions, the animals sat
in a primate chair performing fixation and motor tasks,
Brain Struct Funct
Table 1 Injection sites and neuronal tracers employed in the experiments
Animal
Cutting
plane
Injected
area
Tracer
Amount and
concentration
Functional
study
M17L
Parasagittal
V6
WGA-HRPa
0.10 ll, 4 % in distilled water
Yes
b
Total of cortical and
thalamic labelled cells
16,892
M17R
Parasagittal
V6 (V2 leakage)
FB
0.20 ll, 3 % in distilled water
Yes
5,151
M17R
Parasagittal
V6Av
CTB-goldc
0.8 ll, 0.5 % in distilled water
Yes
11,977
A4aR
Parasagittal
V6Av
CTB-redd
1.7 ll, 1 % in PBS
No
11,667
A4bR
Parasagittal
V6Av
CTB-greend
1.7 ll, 1 % in PBS
No
5,350
M21R
Parasagittal
V6Av
FBb
0.20 lL, 3 % in distilled water
Yes
2,162
No
No
11,695
4,546
b
MF1L
MF2L
Parasagittal
Parasagittal
V6Av/V6
V6Av/V6Ad
FB
FBb
1 crystal
1 crystal
11L
Coronal
V6Ad
WGA-HRPa
0.20 ? 0.28 ll, 4 % in distilled water
No
106,656
A1R
Parasagittal
V6Ad
CTB-redd
1.5 ll, 1 % in PBS
No
9,567
A3R
Parasagittal
V6Ad
FB2
0.20 ll, 3 % in distilled water
No
5,468
d
A3aL
Parasagittal
V6Ad
CTB-red
1.5 ll, 1 % in PBS
No
878
A3bL
Parasagittal
V6Ad
CTB-greend
1.5 ll, 1 % in PBS
No
4,599
M18L
Parasagittal
V6Ad/V6Av (V2 leakage)
WGA-HRPa
0.08 ll, 4 % in distilled water
Yes
4,333
a
Sigma Aldrich SrL
b
Polysciences Europe GmbH, Germany
c
List, Campbell, California
c
Molecular Probes
with the head restrained, while glass-coated Elgiloy
microelectrodes (Suzuki and Azuma 1976) were advanced
through the intact dura mater using a remote-controlled
microdrive. Eye position was recorded by an infrared oculometer (Bach et al. 1983). Visual stimuli of different
form, colour, size, orientation, direction, and speed of
movement were used for testing the visual responsiveness
of recorded cells, and for mapping visual receptive fields
(Fig. 2b). Areas V6 and V6A were identified using wellestablished physiological criteria (Galletti et al. 1996,
1999a, b), including the size and pattern of progression of
receptive fields, and pattern of activity during motor tasks.
Cells were assigned to the ventral or dorsal part of V6A
(V6Av, V6Ad) post mortem after microelectrode reconstructions from cyto- and myeloarchitectural material
(Luppino et al. 2005), as detailed by Gamberini and colleagues (Gamberini et al. 2011).
Histological procedures
After a variable survival period [14 days for fluorescent
tracers, 10 days for gold-conjugated cholera toxin subunit B
(CTB-gold), and 2 days for horseradish peroxidase (HRP)],
the animals were anaesthetized with ketamine hydrochloride (15 mg/kg, i.m.) or alfaxalone (10 mg/kg, i.m.). Following loss of consciousness, they received a lethal dose of
sodium thiopental (i.v.), and, upon cardiac arrest, were
perfused with 3 l of normal saline solution, followed by 5 l
of 4 % paraformaldehyde in 0.1 M phosphate buffer at pH
7.4 (3.5 % in the case of the HRP injection), and 4 l of 5 %
glycerol in the same buffer (except for cases MF1 and
MF2). The brains were removed from the skulls, photographed from all views, and cryoprotected by immersion in
0.1 M phosphate buffer solutions containing glycerol (10
and 20 %; most cases), or sucrose (10–30 %; MF1 and
MF2). The brains were then snap-frozen, and stored at 80 °C. Sections (50–60 lm) were obtained using a freezing
microtome or a cryostat. In most cases, the brain was sectioned in the parasagittal plane (only exception: case 11L in
coronal plane). This choice was dictated by the need to
determine the histological boundaries of V6, V6Av and
V6Ad, which are best visualised in parasagittal sections.
Five series of sections were obtained, one of which was
always stained for Nissl substance, and another for myelin
(Gallyas 1979). In animals MF1 and MF2 a third series was
stained for cytochrome oxidase (Wong-Riley 1979). The
other series were left unstained for fluorescence observation, processed to reveal CTB-gold by the silver-intensification protocol (Kritzer and Goldman-Rakic 1995), or
processed to reveal HRP using the tetra-methyl-benzidine
method (Mesulam and Rosene 1979). All sections were
coverslipped with DPX after quick steps of dehydration in
100 % ethanol, and clearing with xylene.
Data analysis
The sections were examined for labelled neurons using
microscopes (Zeiss Axioscope or Axio Imager) equipped
123
Brain Struct Funct
with 109 and 209 objectives. For each case, the entire
hemisphere ipsilateral to the injection site was examined
for retrograde label. Although anterograde label from some
of the injections was visualised, only the retrograde label
has been quantified for the purpose of the present report.
The section outlines and the location of labelled neurons
were plotted at 250–300 micron intervals, using a computerised system linked to X/Y transducers mounted on the
microscope stage.
The histological criteria used for the definition of the
boundaries of areas around the injection sites have been
fully described in previous studies (Galletti et al. 2001;
Luppino et al. 2005; Gamberini et al. 2009; Passarelli et al.
2011). The present report focuses on injections which were
found to be confined to a single architectonic area,
although data from injections that crossed areal boundaries
have been used as comparison and/or confirmation of
particular aspects of the data, as detailed in the ‘‘Results’’
section.
To identify the thalamic nuclei in coronal sections, we
used the atlas of Olszewski (1952), and for parasagittal
sections, we referred to Ilinsky and Kultas-Ilinsky (1987).
Figure 3a, b shows examples of data plotted on parasagittal
and coronal sections, respectively. For the nomenclature of
some thalamic nuclei, to harmonise the names and abbreviations between the two different planes of cutting, we
also referred to the review by Mai and Forutan (2012) (see
the details in Table 2). To define the labelled thalamic
nuclei, a camera lucida attachment was used to bring
stained histological sections into register with the corresponding drawings containing the positions of labelled
cells.
Results
We report on the results of tracer injections in areas V6 and
V6A (V6Av and V6Ad) of nine animals. As shown in
Fig. 2, two injections were placed in area V6. Based on the
location of visual receptive fields mapped with the
recording syringe (see ‘‘Materials and methods’’), and on
the location of labelled neurons in V1, these injections
covered different retinotopic regions of area V6: the nearperipheral part of the visual field in M17L (between 10°
and 20° from the fovea; see Fig. 4h), and the far-peripheral
part of the visual field in M17R (between 35° of eccentricity and the monocular crescents; see Fig. 4h). In case
M17R, leakage of tracer was observed along the needle
track in the posterior bank of the parieto-occipital sulcus at
the level of the second visual area (V2), where the lower
visual field approximately 10° from the fovea is represented (see Fig. 5c) (see also Gattass et al. 1981). Four
123
injection sites were entirely confined within the limits of
V6Av, and five injections within those of V6Ad. In animals
in which functional studies were carried out (see Table 1),
the visual field representation at the injection sites was
indicated by the location of receptive fields mapped with
the recording syringe (see example of Fig. 2b). Data from
injections that crossed the borders between V6Av and
V6Ad (two cases, Table 1) or between V6Av and V6 (one
case, Table 1) will only be briefly summarised.
In all cases, projecting cells were found in a relatively
small number of thalamic nuclei. In agreement with the
results of Markov et al. (2011) in other cortical areas, we
found that the number of labelled neurons in the thalamus
represented a small fraction of the overall cortical and
thalamic afferents to an area (V6, 3.4 ± 0.7 %; V6Av,
1.6 ± 0.9 %; V6Ad, 4.0 ± 3.4 %). For the present analyses, we considered input from a given thalamic nucleus to
an area as significant when it corresponded to at least 1 %
of all labelled cells in the thalamus; projections that did not
reach this threshold will not be discussed further.
Thalamic afferents to V6
Figure 4 illustrates the distribution of labelled cells in the
thalamus after V6 injections. In both cases, the majority of
labelled cells were found in two distinct clusters in the
visual nuclei of the pulvinar complex, that included the
PuL, dorsally, and the PuI, ventrally.
In the near-peripheral case, labelled cells were found in
the portion of both PuL and PuI that corresponds to the
visual field representation at the injected cortical region,
that is 10°–20° of the lower visual field representation,
between the representation of the horizontal and vertical
meridians (Fig. 5a). In the far-peripheral case (Fig. 5d),
labelled cells were also found in about the same portion of
PuL and PuI. This incongruence may derive from the low
magnification factor at peripheral representations, and/or
by the inherent imprecision in comparing results across
animals without direct electrophysiological recordings.
However, since the pulvinar region labelled in this case
included the part of the visual field represented in the
region of V2 involved by the leakage of neuronal tracer
(see Fig. 5c), some of these labelled cells could also be due
to the tracer leakage.
After V6 injections, labelled cells were also found in
the LGN (Figs. 4b, e, 5), mostly in the interlaminar layers. In the near-peripheral case, labelled cells were found
in the portion of LGN that corresponds to the nearperipheral visual field representation (see Fig. 5b), in
agreement with the region of V6 we injected. In the farperipheral case, labelled cells were only found in the
portion of LGN that corresponds to the paracentral lower
Brain Struct Funct
cs
A
a
ips
m
pos
v
pcs
v ips
ars
cin
ari
lf
ps
B
ps
cs
lf
cal
ips
cs
sts
sts
ots
cin
ls
pos
ios
V6Ad
V6Ad
ots
Case A3R
Case 11L
sts
ps
from Ilinsky & Kultas-Ilinsky, 1987
ips ls
ars
cs
R
VAdc
VLc
LP
Pcn
pos
VL
VPL
Pul
X
bsc
STN
MD
VLo
VPI
VLm
MGpc
7,25mm
VL
LP
PuM
VPL
LGN
Can AD
AV
AM Csl
VLc
Cdc
+ 9.3mm
R
VPI
Pcn MD
VLo
X
MGpc
VLm
GLvo
GLd
from Olszewski, 1952
Fig. 3 Assignment of labelled cells to thalamic nuclei. a Parasagittal
section of the brain taken at the level indicated on the brain silhouette
shown in the middle. The rectangle represents the thalamic region
enlarged on the bottom. Inset from the atlas (Ilinsky and KultasIlinsky 1987) shows thalamic nuclei at the same approximate level of
the section. Locations of labelled cells are shown as black circles.
b Coronal section of the brain taken at the level indicated on the brain
silhouette shown on the top right. The rectangle represents the
thalamic region enlarged in the centre. An inset from Olszewski atlas
(Olszewski 1952), bottom, shows the thalamic nuclei at the level of
the section. Labelled cells are shown as black dots. m medial. Other
details and abbreviations are as in Figs. 1 and 2 and in the list of
abbreviations
visual field representation (see Fig. 5e), which, as discussed above, is the part of the visual field represented in
the region of V2 where there was leakage of neuronal
tracer (see Fig. 5c).
Near-peripheral V6 also received dense projections from
the central densocellular nucleus of the thalamus (Cdc;
Fig. 4d, i), and moderate projections (\10 %) from other
thalamic nuclei (paracentral, PC; LP; ventral anterior pars
magnocellularis, VAmc; mediodorsal, MD; Fig. 4c, d, i).
These projections were not evident in the case of farperipheral field injection, suggesting that the peripheral
representation of V6 receives a less diverse set of thalamic
afferents than the central representation of this area.
Thalamic afferents to V6A
Thalamic afferents to V6Ad and V6Av showed a similar
pattern, although in our materials the afferents were generally sparser after injections in the ventral portion of V6A
(e.g. Fig. 6a, b, f, g). Figure 7 shows a quantitative comparison of the thalamic afferents after injections in the two
subdivisions of V6A.
After injections in V6Av, the majority of labelled
cells were located in the LP and PuM nuclei. Figure 7a shows the quantitative distribution of thalamic
labelled cells in three cases with injections restricted
to V6Av. The thalamic input was similar for the main
123
Brain Struct Funct
Table 2 Correspondence of
nomenclature of the thalamic
nuclei involved in this study
Ilinsky and Kultas-Ilinsky (1987)
Olszewski (1952)
Present study
MDdc
MDdc
MD
MDmc
MDmc
MDpc
MDpc
Cdc
Cdc
Cdc
Li
Li
Li
Lateral region
VAmc
VAmc
VAmc
Motor Thalamus
VL
Area X
VL
Medial region
VPLo
VLc
VLps
Intralaminar Formation
PC
Pcn
Anterior Group
CL
CL
Posterior region
For details see the list of
abbreviations
Pul
Pul. m
PuM
Pul
Pul. l
PuL
Puli
LG
Pul. i
GL
PuI
LGN
afferents (LP and PuM). Projections from the VL
nucleus were very weak and were found in only one
case (Fig. 7a).
Figure 3a shows the main afferents to V6Ad in a brain
that was cut in the parasagittal plane, while Figs. 6c–e and
3b show the distribution of labelled cells in another case,
which yielded coronal sections. The strongest connection
of V6Ad was with the LP nucleus (Figs. 3a, 6d). The
remaining labelled cells were nearly equally distributed
between the VL (Figs. 3b, 6c, d) and PuM (Fig. 6e) nuclei.
This connection pattern revealed similar afferents from the
LP to those observed in V6Av, but the projection from VL
to V6Ad was stronger than that to V6Av, whereas the
connection between the PuM and V6Ad seemed to be
relatively de-emphasised. The histogram in Fig. 7b shows
the fraction of labelled cells in various thalamic nuclei after
injections in lateral (case 11L, see also Figs. 3b and 6c–e),
central (average of cases A3L and A3R, see also Fig. 3a),
and medial (case A1R) parts of V6Ad (white, grey, dark
columns, respectively). In case 11L (Figs. 6c–e, 3b), we
also observed labelled cells in the MD, Li, Pcn (equivalent
to PC nucleus in the nomenclature of Ilinsky and KultasIlinsky 1987, see Table 2) and Cdc nuclei. The thalamic
projection patterns of V6Av and V6Ad were further supported by cases in which the injections sites partially
crossed into adjacent areas (3 cases, Fig. 7c).
Discussion
The aim of this study was to examine the thalamic
afferents to the areas that occupy the rostral bank of the
123
PC
parieto-occipital sulcus in the caudal-most part of the
superior parietal lobule, namely areas V6 and V6A (the
latter including ventral and dorsal subdivisions). Our
results show that each area receives input from a specific
set of thalamic nuclei. Conversely, several of the labelled
thalamic nuclei send projections to more than one area,
albeit with different strengths. This information is summarised in Fig. 8. The LP nucleus and the pulvinar
complex form the main projections in all cases, although
the connections to V6 and V6Ad/V6Av originate in different subdivisions of the pulvinar complex (PuI/PuL
versus PuM). We detected sparse projections from the
LGN only to V6, whereas V6A (in particular, the dorsal
subdivision) received additional inputs from the VL
nucleus. In addition, V6 and V6Ad received relatively
weak projections from other thalamic nuclei, including
those from the caudal part of the MD nucleus and intralaminar complex nuclei.
Overall, these results conform to the expectation that
the thalamo-cortical projections, as a whole, obey a
global topographic order, for example, with rostral
nuclei projecting to rostral areas, and caudal nuclei
projecting to caudal areas (e.g. Hohl-Abrahao and
Creutzfeldt 1991). As shown in Fig. 9, the percentage
of labelled neurons in nuclei located in the caudal third
of the thalamus increases progressively from V6Ad, to
V6Av, to V6. However, no trend is apparent along the
mediolateral dimension. As expected from the previous
literature on posterior occipital and parietal cortices, the
areas we studied mainly receive from the lateral and
posterior parts of the thalamus, (Adams et al. 1997;
Shipp 2003).
Brain Struct Funct
I
Thalamic
afferents to V6
Case M17L
40
10,5mm
PuL
cal
PuI
B
LGN
10mm
Case M17R
PuI
20
10
0
C
V6 far-peripheral
PuL
30
dc
M
D
VPL
M17L-V6
near-peripheral
cal
LP
P
uL
P
uI
LG
N
% Labelled thalamic cells
A
P
VA C
m
c
V6 near-peripheral
C
E
2mm
LGN
11mm
AM
PuL
PC
MD
cal
VAmc
LGN
D
F
0,3mm
10mm
VPL
AM
PuL
Cdc
cal
PuI
MD
PC
LGN
G
8,5mm
H
VL
ipsi contra
lf
30°
60°
ars
PuL
VPL
ips sts
ps
V6 near-peripheral
cal
cs
ls
A
pos
D
MG
V6 far-peripheral
lf
sts
ps
ars
cs
ips
ls
pos
E
G
70°
Fig. 4 Thalamic afferents to area V6. Four parasagittal sections (a–
d) from case M17L, with V6 injection in the near-peripheral visual
field representation. Three parasagittal sections (e–g) from case
M17R, with V6 injection in the far-peripheral representation. Sections
were taken at the levels indicated on the brain schematics shown on
the bottom. Bottom h Receptive fields of the cells recorded from the
injection sites (central and peripheral visual field representations of
V6) (Galletti et al. 2001). Top i Histogram of the relative percentage
of cells found in the different thalamic nuclei in the case injected in
the near-peripheral visual field representation of V6 (case M17L).
Other details and abbreviations are as in Figs. 1, 2 and 3, and the list
of abbreviations
123
Brain Struct Funct
V6 near-peripheral
ips sts
Case M17L
A
ps
PuL
10°
5°
2°
10,5mm
20°
lf
ars
A
B
pos
cs
ipsi
contra
30°
−
PuI
ls
V6 near-peripheral
+
30°
cal
LGN
B
from Bender, 1981
10mm
+
2°
5°
10°
20°
50°
PuI
LGN
2,5°
−
17°
from Malpeli & Baker, 1975
lf
V6 far-peripheral
sts
Case M17R
ps
ars
cs
ips
C
ipsi
core
halo
V2
V1
pn
V6 far-peripheral
a
V6
pom
cal
70°
VPL
123
10mm
LGN
5°
2°
+
LGN
E
PuL
20°
10°
PuI −
C
60°
v
D
E
V2 central
V1
10mm
pos
contra
pos
V6A
ls
cal
Brain Struct Funct
b Fig. 5 Distribution of labelled cells in pulvinar and LGN. a Parasag-
ittal section taken at the level of the pulvinar (see the brain silhouette
on the top) showing locations of labelled cells and the corresponding
visuotopic organisation of the pulvinar (modified from Fig. 12 by
Bender 1981). On the right, receptive fields of cells recorded from the
V6 injection site in case M17L (V6 near-peripheral) are reported.
b Parasagittal section taken at the level of the LGN (see the brain
silhouette on the top) showing locations of labelled cells and the
corresponding portion of the visual field represented in that part of the
LGN (modified from Fig. 12 by Malpeli and Baker 1975). On the left,
the insert shows schematically the representation of visual hemifield
with the symbols used by Bender 1981, on the left, and Malpeli and
Baker 1975, on the right. c Reconstruction on a parasagittal brain
section of the injection carried out with the recording syringe in case
M17R (V6 far-peripheral). Notice that there was a leakage of tracer in
the primary and second visual area (V1 and V2; grey areas). On the
right, receptive fields of cells recorded from the V2 region of leakage
and the V6 injection site are reported. pn penetration. d Parasagittal
section taken at pulvinar level (see the brain silhouette at the centre)
showing the locations of labelled cells and the corresponding
visuotopic organisation of the pulvinar (modified from Fig. 12 by
Bender 1981). e Parasagittal section taken at LGN level (see the brain
silhouette at the centre) showing the locations of labelled cells and the
corresponding portion of the visual field represented in that part of
LGN (modified from Fig. 12 by Malpeli and Baker 1975). Other
details and abbreviations are as in Figs. 1, 2 and 3, and the list of
abbreviations
Possible functional role of thalamic afferents
to the caudal superior parietal lobule
Thalamic afferents to V6 are largely typical of those to a
topographically organised visual area. Thus, major projections arrive from the two retinotopically organised
regions of the pulvinar complex (lateral and inferior pulvinar, respectively; see Fig. 8). The visuotopic organisation
of these two pulvinar regions is well established and it has
been shown that they both project to multiple extrastriate
areas with similar pattern of connections (Bender 1981;
Ungerleider et al. 1984; Shipp 2001; Soares et al. 2001;
Shipp 2003; Kaas and Lyon 2007). In our material, there
was little differentiation between the locations of patches
of labelled neurons from V6 injections in different parts of
the peripheral visual field (\30° versus [30°) in V6. In the
near-peripheral case labelled cells were found in the portions of pulvinar that are congruent with the part of the
visual field included in the injected region of V6 (see
Figs. 4h, 5a). In the far-peripheral case, labelled cells were
found more or less in the same part of the pulvinar.
Although we recognise the difficulty in reaching conclusions based on only two cases, it is possible that the
labelled cells in the same pulvinar region in this case
mainly reflect the low magnification factor in the pulvinar
at peripheral representations, or projections from V2, due
to the tracer leakage in the caudal bank of the parietooccipital sulcus. The comparison of our data with receptive
field maps (see Fig. 5a, d) seems reasonably consistent
with the interpretation that afferents to V6 (and/or V2)
originate in both of the two visual maps represented in PuL
and PuI (Bender 1981). In both V6 injection cases, the
more dorsal cluster of labelled cells could have included
the reported location of the vertical meridian representation
which forms the border between the two maps. However,
no firm conclusion can be reached in this respect given
individual variability, and the inexact correspondence
between our data and the parasagittal planes illustrated in
Bender’s (1981) study.
The paucity of projections from the pulvinar to the
topographically appropriate region of V6 in the farperipheral case could be a reflection of the marked
emphasis on central visual field representation, in the
pulvinar nuclei, as also apparent in studies of the marmoset
monkey, where injections in the far peripheral representation of the middle temporal area (MT) resulted in very
small numbers of labelled cells in the pulvinar complex
(Palmer and Rosa 2006). In addition, the same study
reported that injections in the far peripheral representation
of area MT result in label in a more restricted set of cortical
areas, in comparison with injections in the central representation. A similar trend was observed in our study, in
which a larger number of thalamic nuclei projected to the
near-peripheral injection site. Finally, it is worth noting
that the PuI region that projects to V6 is adjacent to the
LGN, in the rostral and lateral portion of ventral pulvinar.
This likely overlaps with the region that projects to area
MT (Shipp 2001, 2003; Soares et al. 2001).
The presence of labelled cells in the interlaminar layers
of the LGN after the near-peripheral field injection of V6
represents further evidence that area V6 is primarily a
visual area. The primary visual area was classically considered the main target of LGN in primates (Hubel and
Wiesel 1972), though there is currently considerable evidence of sparse connections from the LGN to extrastriate
areas (Wong-Riley 1976; Benevento and Yoshida 1981;
Yukie and Iwai 1981; Bullier and Kennedy 1983; Lysakowski et al. 1988; Hernandez-Gonzalez et al. 1994;
Sincich et al. 2004; Warner et al. 2010; Lyon and Rabideau
2012). Present results are in line with this evidence, which
may be important to explain the residual visual function
that remains in cases of cortical blindness after striate
cortex lesions (Schmid et al. 2010; Yu et al. 2013). Notice
that small numbers of neurons in the LGN have been found
in all studied primates after injections in DM (Beck and
Kaas 1998), the New World monkey homologue of area V6
(Rosa and Tweedale 2001), although the labelling was not
consistent, being found in less than half of the studied
cases. Projections from LGN neurons to V6 were also
inconsistent in our study; given that the number of labelled
cells in the LGN is small, these afferents could easily have
been missed due to methodological factors.
123
Brain Struct Funct
Fig. 6 Thalamic afferents to
area V6A. Left Injections in
V6Av. a, b Parasagittal sections
from case M21R. Right
Injections in V6Ad. c–e Coronal
sections from case 11L. Bottom
injections in V6Av. f,
g Parasagittal sections from case
A4R. Black circles represent
labelled cells after injections of
either CTB red or CTB green,
both within the limits of area
V6Av. Sections were taken at
the levels indicated on the brain
silhouettes shown on the centre.
Other details and abbreviations
are as in Figs. 1, 2 and 3, and
the list of abbreviations
A
C
7,25mm
VL
+ 8,1mm
LP
VLc
PuM
VPL
MD
Pcn
VPLo
MGpc
VPI
D
B
5,2mm
+ 4,5mm
VLps
MD
VL
VAdc
CL
VPLc
PuM
CM
LP
VPL
VPM
VPI
LGN
GMpc
lf
ars
sts
E
ls
cs ips
ps
A
B
pos
ari
V6Av
lf
Case M21R
MD
C
E
ips cs
sts
ls
PuM
PuL
cin
pos
SG
V6Av
V6Ad
Case A4R
sts
ars
F
G
+ 2,1mm
ps
ars
ls
ips
ps
cs
PuI
Case 11L
pos
F
G
6,7mm
LP
VL
VPM
6mm
VAdc
LP
VL
PuM
PuM
VPL
VPL
VPM
MGpc
Further input arrived in V6 from the VAmc, MD nucleus
and from the thalamic midline nuclei, in particular from
Cdc, and to a lesser degree, from the intralaminar paracentral nucleus (PC or Pcn). These inputs are similar to
those of DM of the New World monkey brain (Beck and
Kaas 1998; Rosa et al. 2009). To date, few studies have
focused on these thalamic nuclei and their specific
123
STN
VPI
functions are still not completely known (Hsu and Price
2007; Hsu et al. 2014). As suggested by Huerta and Kaas
(1990) for supplementary eye field, area V6 could use the
Cdc afferents to provide visual input for movement guidance, thanks to the connections with skeletomotor-related
areas, such as V6A and MIP, in addition to visual connections with extrastriate cortex (Galletti et al. 2001). A
Brain Struct Funct
80
A4aR
A4bR
M21R
70
% Labelled thalamic cells
80
Thalamic afferents to V6Av
60
70
% Labelled thalamic cells
A
50
40
30
20
VL
70
% Labelled thalamic cells
LP
PuM
40
30
20
Cdc
MD
PC
VAmc
VL
LP
PuM
PuL
PuI
LGN
Fig. 8 Summary of the thalamic afferents to areas V6, V6Av, and
V6Ad. Average percentages of labelled cells in thalamic nuclei after
tracer injections in V6, V6Av, and V6Ad. Vertical bar SD. For area
V6, only the case M17L (near-peripheral injection) is reported
because in the other case the injected tracer was not restricted to area
V6. Only labelling that represented[1 % of the thalamic afferents are
reported. Other details and abbreviations as for Fig. 7
Thalamic afferents to V6Ad
11L
A3R & A3L
A1R
60
50
0
0
80
60
10
10
B
V6
V6Av
V6Ad
Thalamic afferents to
50
40
30
20
10
0
Cdc
C
80
MD
Li
PC
VL
LP
PuM
Thalamic afferents in cases with
injections involving nearby areas
% Labelled thalamic cells
70
60
M18L V6Ad/V6Av inj, V2 leakage
MF1L V6Av/V6 inj
MF2L V6Av/V6Ad inj
50
40
30
20
10
0
Cdc
PC
VL
LP
PuM
PuL
PuI
LGN
Fig. 7 Thalamic afferents to areas V6Av and V6Ad. a Thalamic
afferents to V6Av in cases A4aR, A4bR and M21R. b Thalamic
afferences from cases with lateral (case 11L), central (cases A3R and
A3L) and mesial (A1R) injections in V6Ad. c Thalamic afferents
from three cases M18L, MF1L and MF2L with injection sites
partially crossed into adjacent areas. In all cases, only labelling that
represented [1 % of the thalamic afferents is reported. For other
details see the list of abbreviations
clear topographical organisation of central nuclei has not
been yet described. Schlag and Schlag-Rey (1984) and
Schlag-Rey and Schlag (1984) reported that the neurons of
the central thalamus show visual- and oculomotor-related
properties, while Wyder et al. (2003) have suggested that
the central thalamic nuclei integrate cortical and subcortical information related to eye movement. The MD nucleus
also seems to be involved in the control of eye movement
(Watanabe and Funahashi 2004), as well as VAmc nucleus,
which corresponds to the nigral input zone (Ilinsky et al.
1985). The pulvinar complex is known to contain neurons
which are modulated by eye position (Robinson et al.
1990). In summary, the present data support the view that
thalamic afferents could be part of the circuit responsible
for the high incidence of gaze modulation observed in V6
(Galletti et al. 1995).
Another aspect worthy of note is the similarity of the
thalamic pattern of connections of the two subdivisions of
V6A, which contrasts with the heterogeneity of their cortico-cortical connections: V6Av is preferentially connected
to visual areas (Passarelli et al. 2011), whereas V6Ad has
preferential connections with other parietal and premotor
areas (Gamberini et al. 2009). An analogous observation
was made by Boussaoud et al. (1992) in the medial superior
temporal area, where the two functionally distinct subregions of the area in terms of central versus peripheral
vision representation showed different cortico-cortical
patterns, but overlapping subcortical connections. Other
parietal areas show label in the same thalamic nuclei (e.g.
pulvinar complex, see Grieve et al. 2000), perhaps hinting
at a more general role of the thalamic circuit to caudal
123
Brain Struct Funct
rostral
caudal
medial
CORTEX
lateral
(left hemisphere)
medial
THALAMUS
caudal
lateral
medial
rostral
rostral
caudal
(left hemisphere)
lateral
Thalamic afferents
% Labelled thalamic cells
90
V6Ad
80
V6Av
70
V6
60
50
40
30
20
10
0
rostral
central
caudal
medial
lateral
Fig. 9 Gradients of thalamo-cortical afferents along the rostrocaudal
and mediolateral axes of the thalamus. Top Dorsal view of the left
hemisphere of a reference monkey brain (http://www.nitrc.org/
projects/caret/, Van Essen et al. 2001) and schematic representation
of the left thalamus. Note that the cortex is linked to the thalamus so
that the one (represented as a two-dimensional reconstruction of the
dorsal portion of the brain) forms a mirror image of the other with the
cortex turned 90° anticlockwise relative to the thalamus. Bottom
average percentages of labelled cells in topographical portions of the
thalamus, irrespective of nuclear thalamic boundaries, after tracer
injections in V6, V6Av, and V6Ad. Rostrocaudal axis of the thalamus
is represented in green, mediolateral one in red. Only labelling that
represented [1 % of the thalamic afferents are reported. Other details
and abbreviations as for Figs. 1 and 7
parietal areas in multimodal/sensorimotor integration. Our
recent work (Gamberini et al. 2011) has suggested that
V6Ad and V6Av have different functional emphases, but
are likely to work together as a single functional entity,
thereby presenting a sensory-motor gradient without sharp
segregation. The overlapping thalamic input to these V6A
territories highlights a possible common functional multimodal/sensorimotor role, such that they could be considered as a single functional area (Gamberini et al. 2011).
123
Strong thalamic projections to both subdivisions of area
V6A originated in the LP nucleus. It is believed that LP
provides information on somatic and attentional stimuli for
guiding motor acts towards targets of interest. In the rat, LP
is a key node in circuits involved in mediating directed
attention (Kamishina et al. 2008, 2009). In cats trained to
perform a reaching movement toward a moving target spot,
lesions localised in LP severely disrupt accuracy and reaction time (Fabre-Thorpe and Levesque 1991). V6A could
make use of different visual and somatosensory stimuli, as
well as attentional signals, for guiding intentional motor
acts. In this regard, it is worth noting that the activity of
V6A neurons can be modulated by both visual and
somatosensory stimuli (Breveglieri et al. 2002; Gamberini
et al. 2011), by prehension acts (Fattori et al. 2001, 2004,
2010; Gamberini et al. 2011), and by directional shifts of
attention (Galletti et al. 2010). The present data suggest that
these neuronal activities may derive from modulating signals that could reach V6A through LP afferents.
Area V6A also receives input from the PuM nucleus.
The pulvinar complex is traditionally subdivided into
medial, lateral, inferior, and anterior nuclei (Olszewski
1952). The medial subdivision is connected with the cingulate, posterior parietal and prefrontal cortices (for a
review, Grieve et al. 2000; Saalmann and Kastner 2009).
Whereas PuL is considered to be a visual nucleus, PuM is
viewed as a multimodal, associative nucleus (Ma et al.
1998). Several lines of evidence suggest that PuM is a
subcortical component of the brain attentional network
(Shipp 2003) and, accordingly, it has been reported that
lesions to this thalamic nucleus result in deficits of spatial
attention and neglect (Karnath et al. 2002). This attentional
role of the PuM agrees well with the strong influence of
attention reported in area V6A in monkeys and humans
(Galletti et al. 2010; Ciavarro et al. 2013).
Area V6A receives important input from the VL complex, which is regarded as having a primarily motor
function, sending fibres to the primary and secondary
motor areas (Ilinsky and Kultas-Ilinsky 2002; Kultas-Ilinsky et al. 2003; Burman et al. 2014). The strong input from
VL to V6Ad is in line with the proposed involvement of
V6Ad in the on-line control of motor acts (Gamberini et al.
2011).
Finally, minor inputs from the intralaminar and MD
nuclei were found after V6Av injections. The eye-related
neuronal activities that arise from these nuclei (Schlag and
Schlag-Rey 1984; Schlag-Rey and Schlag 1984; Wyder
et al. 2003; Watanabe and Funahashi 2004) agree well with
the functional properties found in visuomotor area V6A
(Galletti et al. 1995; Kutz et al. 2003; Hadjidimitrakis et al.
2011; Breveglieri et al. 2012), suggesting that this area
plays a critical role in the control of eye- and handmovements during the preparation and the execution of
Brain Struct Funct
actions focused on exploration of the world around us
(Galletti et al. 2003).
Concluding remarks
Thalamic afferents to the areas of the rostral bank of the
parieto-occipital sulcus in the caudal part of the superior
parietal lobule are in line with the functional roles suggested for these areas by a large series of electrophysiological experiments carried out on behaving animals, that
is, a visual role for area V6 (Galletti et al. 1999a, 2005),
and an associative and visuomotor role for area V6A
(Gamberini et al. 2011). The similarity of inputs to V6Ad
and V6Av further reinforces the view that these are best
regarded as subdivisions of the same cortical area. Thalamic afferents may contribute to the integration of visual,
somatosensory, attentional, and premotor information
needed for the guidance of motor acts.
Acknowledgments The authors wish to thank M. Verdosci, F.
Campisi and G. Placenti for the technical assistance, and R. Tweedale
for corrections to the manuscript. This research was supported by
European Union Grant FP7-PEOPLE-2011-IOF 300452, National
Health and Medical Research Council, grants 1020839 and 1082144,
Australian Research Council grant DP140101968, and by Ministero
dell’Università e della Ricerca and Fondazione del Monte di Bologna
e Ravenna, Italy.
Conflict of interest
of interest.
The authors declare that they have no conflict
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