Download Functional circuitry underlying visual neglect

doi:10.1093/brain/awl140
Brain (2006), 129, 1803–1821
Functional circuitry underlying visual neglect
R. Jarrett Rushmore,1 Antoni Valero-Cabre,1 Stephen G. Lomber,2 Claus C. Hilgetag3 and
,
Bertram R. Payne1 y
1
Laboratory of Cerebral Dynamics, Plasticity and Rehabilitation Department of Anatomy and Neurobiology, Boston
University School of Medicine, Boston, MA, 2Centre for Brain and Mind, Departments of Physiology and Psychology,
University of Western Ontario, London, Ontario, Canada and 3School of Engineering and Science, International University
Bremen, Bremen, Germany
Correspondence to: R. Jarrett Rushmore, PhD, Laboratory of Cerebral Dynamics, Plasticity and Rehabilitation, Department of
Anatomy and Neurobiology, Boston University School of Medicine, 700 Albany Street, W702, Boston, MA 02118, USA
E-mail: [email protected]
y
The death of Dr Bertram Payne occurred during the preparation of this manuscript.
Visuospatial neglect is a common neurological syndrome caused by unilateral brain damage to the posterior
and inferior parietal cerebral cortex, and is characterized by an inability to respond or orient to stimuli
presented in the contralesional hemifield. Neglect has been elicited in experimental models of the rat, cat
and monkey, and is thought to result in part from a pathological state of inhibition exerted on the damaged
hemisphere by the hyperexcited intact hemisphere. We sought to test this theory by assessing neural activity
levels in multiple brain structures during neglect using 2-deoxyglucose (2DG) as a metabolic marker of neural
activity. Neglect was induced in two ways: (i) by cooling deactivation of posterior parietal cortex or (ii) in
conjunction with broader cortical blindness produced by unilateral lesion of all contiguous visual cortical areas
spanning occipital, parietal and temporal regions. The direction and magnitude of changes in 2DG uptake were
measured in cerebral cortex and midbrain structures. Finally, the 2DG uptake was assessed in a group of cats in
which the lesion-induced neglect component of blindness was cancelled by cooling of either the contralateral
posterior parietal cortex or the contralateral superior colliculus (SC). Overall, we found that (i) both lesion- and
cooling-induced neglect are associated with decreases in 2DG uptake in specific ipsilateral cortical and midbrain
regions; (ii) levels of 2DG uptake in the intermediate and deep layers of the SC contralateral to both cooling and
lesion deactivations are increased; (iii) changes in 2DG uptake were not identified in the contralateral cortex;
and (iv) reversal of the lesion-induced neglect component of blindness is associated with a reduction of contralesional 2DG uptake to normal or subnormal levels. These data are in accord with theories of neglect that
include mutually suppressive mechanisms between the two hemispheres, and we show that these mechanisms
operate at the level of the SC, but are not apparent at the level of cortex. These results suggest that the most
effective therapies for visual neglect will be those that act to decrease neural activity in the intermediate layers
of the SC contralateral to the brain damage.
Keywords: visuospatial neglect; superior colliculus; animal models; parietal cortex; visual perception
Abbreviations: 2DG = 2-deoxyglucose; MSs = middle suprasylvian sulcus; pMS = posterior middle suprasylvian; SC = superior
colliculus; SGI = stratum griseum intermediale; SGP = stratum griseum profundum; SGS = stratum griseum superficiale;
SO = stratum opticum
Received March 7, 2006. Revised April 24, 2006. Accepted April 26, 2006. Advance Access publication May 26, 2006
Introduction
Visual neglect is a neurological syndrome most
commonly caused by unilateral brain damage to the
posterior and inferior parietal cerebral cortex and is
characterized by an inability to detect or orient to
stimuli or objects presented in the contralesional visual
hemifield (Heilman and Valenstein, 1993; Mesulam, 1999;
Driver and Vuilleumier, 2001; Kerkhoff, 2001; Mort et al.,
2003).
Patients with neglect behave as if one half of visual space
does not exist and typically deny the presence of a defect.
However, neglect is usually not a sensorial problem of absent
or impoverished visual signals from the neglected field
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Brain (2006), 129, 1803–1821
because a variety of treatments such as the application of
cold water to the ear canal ipsilateral to the neglected field
(‘caloric stimulation’) or vibration of the dorsal neck musculature causes the patient to once again become aware of
stimuli in the neglected hemifield (Pierce and Buxbaum,
2002; Schindler et al., 2002; Kerkhoff, 2003). Such treatments
for neglect have only transitory or incomplete efficacy. These
phenomena inform us that sufficient neural circuitry exists
both for detection of stimuli in the neglected hemifield and
for producing orienting responses to the stimuli, but that
the circuits are prevented from acting. As a consequence, a
potential cure may be effected if the secondary circuits were
identified and reactivated through interventional therapy or
training. However, precise dissection of circuits in humans
with neglect has proven difficult owing to lesion variations
and the emergence of neural and behavioural compensations
following neglect-inducing damage to posterior parietal cortex. The detailed study of neglect requires a stable experimental model of the syndrome.
To that end, we have studied the cat model of neglect. Just
as in humans, damage to the posterior and inferior portion
of the cerebral cortex in the cat results in a syndrome with
the same features as neglect (Hardy and Stein, 1988; Lomber
and Payne, 1996; Payne et al., 1996a). Stable versions of
neglect are induced either through unilateral cooling deactivation of posterior parietal cortex (Payne et al., 1996a) or
in conjunction with the generation of a broader cortical
hemianopia in which all contiguous visually responsive cortex is removed (Lomber et al., 2002). In the cat model, lesion
and reversible deactivation studies have allowed for the generation of a hypothesis of neglect (Payne and Rushmore,
2004). This hypothesis suggests that neglect arises because
of an imposed interhemispheric imbalance of the orienting
system, which works to bias the system towards orienting to
stimuli in the intact visual hemifield, and skews the system
against stimuli presented in the neglected field.
The neglect-inducing lesion or deactivation of posterior–
inferior parietal cortex has been hypothesized to cause an
imbalance in activity between brain hemispheres through
imposed disruption of two main circuits.
(i) Cortical circuits: The neglect-inducing injury or deactivation of posterior parietal cortex silences or denervates
transcortical commissural projections to the homologous
cerebral region. In a functional sense, the injury is thought
to release the contralateral homologous parietal cortex from
inhibition and result in an elevated level of activity—an
excitability that then is translated along efferent projections
to overactivate the cerebral and subcortical orienting circuitry in the intact hemisphere (Payne and Rushmore, 2004).
(ii) Corticocollicular circuits: The neglect-inducing
manipulation of parietal cortex removes a major source of
input to the superficial visual layers of the superior colliculus
(SC; Harting et al., 1992), an action that feeds forward and
decreases excitability in efferent collicular circuits. Most
notably, efferent and inhibitory projections to the contralateral SC become deactivated, resulting in a disinhibition of
R. J. Rushmore et al.
the contralateral SC, a heightened state of activity that feeds
back to the ipsilateral SC as a higher inhibitory tone
(Kinsbourne, 1974, 1987, 1993; Hilgetag et al., 1999;
Payne and Rushmore, 2004). The end result is that the
ipsilateral SC is deactivated more than would be expected
than on the basis of simple denervation of parietal inputs,
and the contralateral SC becomes more active than normal.
Accordingly, our hypothesis is that the neglect-inducing
lesion of parietal cortex induces interhemispheric asymmetry
both in the cerebral cortex and in the SC. To address this
hypothesis, we prepared three groups of cats. In one group
(Group A), we induced neglect by unilateral cooling deactivation of parietal cortex. Cooling does not induce neural
compensations, and a stable neglect state is generated for the
duration of cooling (Lomber and Payne, 1996; Payne et al.,
1996a). In another group (Group B), we made large unilateral visual cortex lesions. While small lesions of posterior
parietal cortex produce only transient deficits in visual spatial attention (Payne et al., 1996b), lesions of all contiguous
visual areas prevent intrinsic neuroplastic mechanisms from
mediating recovery (Wallace et al., 1989). These cats displayed permanent visual neglect in conjunction with a
broader cortical blindness. Finally, in a third group of cats
with large unilateral visual cortical lesions (Group C), we
reversed the neglect by cooling contralateral parietal cortex
or the SC (Lomber et al., 2002). In all cats, we assessed the
functional state of the brain by injecting radiolabelled 2deoxyglucose (2DG) as a measure of neural activity during
the cooling-induced neglect (Group A), during the lesioninduced neglect (Group B) or during cooling-induced cancellation of the lesion-induced neglect (Group C). Our
results have implications for understanding the syndrome
of neglect, and for its treatment.
Material and methods
Animals and animal care
All cats were purchased from a licensed cat breeder and were grouphoused in an enriched environment with a 12 h daylight cycle. Cats
were provided with water ad libitum and were fed dry Purina Cat
Chow for 1 h per day. Animals were treated according to the
National Research Council’s Guidelines for the Care and Use of
Mammals in Neuroscience and Behavioral Research (2003), and
with the approval of the Institutional Animal Care and Use Committee of the Boston University School of Medicine.
Sixteen cats were used in this study. Ten cats were divided into
three experimental groups:
Group A: Unilateral cooling loops within the posterior middle
suprasylvian (pMS) sulcus (n = 4).
Group B: Unilateral lesion of all contiguous visual areas (n = 3).
Group C: Unilateral lesion of all contiguous visual areas with
(i) contralateral pMS cooling loop (n = 2); (ii) contralateral SC
cooling loop (n = 1).
Behavioural results for Group C have been reported previously
(Lomber et al., 2002), and will be repeated here in textual form. Six
additional cats were used as controls: four were unoperated and two
additional cats underwent cooling of temporal cortex. This cooling
Functional circuitry of neglect
did not have an impact on contralateral structures, and the contracooled hemispheres were included as control data. [Control
group same as in Rushmore et al. (2005)].
Cooling loop construction
Cooling loops were constructed from 23 gauge hypodermic tubing
(Small Parts, Inc., Miami Lakes, FL, USA) and shaped to conform
to the contour of the pMS sulcal cortex or the surface of the
SC (Lomber et al., 1999, 2001). A microthermocouple was constructed by soldering the bared ends of twisted copper/constantine
wire (30 gauge, Teflon insulated) to the union of the loop using
silver solder. The hypodermic tubing was trimmed at the ends
and led through a custom-made outside-threaded stainless steel
length of tubing. The microthermocouple wire was passed to
a thermocouple miniature connector. Dental acrylic was used
to hold the hypodermic tubing and the thermocouple wires
together, and a threaded cap was screwed on the outside-threaded
tubing for protection against inadvertent damage to the hypodermic
tubing. Each loop was tested for adequate flow rates and for proper
microthermocouple function before sterilization with ethylene
oxide.
Brain (2006), 129, 1803–1821
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was used to remove the marginal and suprasylvian gyri to A-P 14,
the posterolateral and posterior suprasylvian gyri in their entirety
and the cortex in the middle and posterior limbs of the suprasylvian
sulcus. Gelatin surgical sponges (Ethicon, Somerville, NJ, USA)
were placed in the cortical defect to assist haemostasis and the
bone piece was replaced.
Closing and postoperative care
Muscle and skin planes were re-approximated and sutured with
chrome gut and silk, respectively. Lidocaine (1%) was injected
locally into skin and muscle before suturing.
Cats were placed in a recovery cage with heating pads and were
closely monitored. Animals were given fluids (2.5% dextrose in
half-strength lactated Ringer solution, s.c.) and antibiotic
(Ambipen, 300 000 units, i.m.) was administered prophylactically.
Buprenorphine (0.01 mg/kg, s.c.) was injected to reduce potential
postoperative pain, and soft food and water was provided.
Cats were monitored several times per day and sutures were
removed 10 days after surgery. For cats with cooling loops, the
margin of the implant was cleaned several times a week with saline
and hydrogen peroxide, and topical triple antibiotic ointment was
applied to guard against infection.
Surgical procedures
Surgery was performed to implant cooling loops, for unilateral
removal of all contiguous visual cortical areas, or both. Surgery
employed sterile surgical technique and was carried out in an
aseptic environment.
General procedures
On the day before surgery, a catheter was inserted into the cephalic
vein under ketamine sedation (10 mg/kg, i.m.). The next day,
the cat was anaesthetized with sodium pentobarbital (25 mg/kg
i.v., and to effect). Atropine sulphate (0.03 mg/kg, s.c.) was injected
to decrease potential alimentary secretions, and dexamethasone
sulphate (1.0 mg/kg, i.m.) was given to reduce potential
swelling. Antibiotic ophthalmic ointment was applied to prevent
corneal drying. The cat’s head was secured in a stereotaxic
apparatus and centred in Horsley–Clarke coordinates (ReinosoSuarez, 1961). Core temperature, pulse rate, presence of reflexes
and respiratory rate were monitored and anaesthesia adjusted as
needed.
Cooling loop implantation
Stainless steel screws (Small Parts, Inc., Miami Lakes, FA, USA.)
were tapped into the skull and covered with dental acrylic to provide a base to secure and attach the loop. A cooling loop was
selected that best conformed to the individual brain contour and
was held in place by dental acrylic. The dura was substituted with
Gelfilm (Pharmacia & Upjohn, Kalamazoo, MI, USA), and the bone
piece was replaced and covered with dental acrylic.
Removal of contiguous visual areas
Mannitol (1.5 g/kg in 25% aqueous solution; i.v.) was administered
to harden the brain and make it more amenable to manipulation.
A large unilateral craniotomy was made to expose the marginal,
posterolateral, suprasylvian and ectosylvian gyri. Subpial aspiration
Perimetry testing
Perimetry testing was performed as described previously
(Lomber and Payne, 1996; Payne et al., 1996a; Lomber et al.,
2002). The perimetry testing apparatus consisted of a semicircular
table (88 cm diameter) with a 30-cm-high wall enclosing the
semicircle and holes in the floor at 15 intervals from left 90 to
right 90 (Fig. 2A). All testing occurred at photopic illumination
levels (85 cd/m2).
Cats were initially trained to fixate a target introduced through
the 0 hole (cynosure). The lateral canthi of the eyes were aligned
with a line connecting the left 90 and right 90 holes. Upon correct
fixation as deemed by the experimenter presenting the fixation
target, the cat was allowed to proceed forward and claim a dry
food reward at the cynosure. The cat was required to complete
50 consecutive trials to proceed with the next phase of the task.
Any non-fixation behaviour in response to target presentation was
not rewarded.
Following completion of the fixation task, the full perimetry task
was performed. The cat was required to fixate a target at the cynosure. Subsequently, a high-contrast stimulus was introduced
through a peripheral opening. A correct response was scored if
the cat broke fixation and quickly oriented to the peripheral
stimulus. The cat was then allowed to approach the stimulus and
was given a high-incentive wet food reward. A failure to detect the
peripheral stimulus was signalled by movement of the cat forward
to the cynosure, and the cat received a dry, low-incentive food
reward. Stimuli were introduced throughout the visual field in a
pseudorandom sequence equally balanced for eccentricity and
visual hemispace. Slow orienting responses or scanning behaviours
were scored as mistrials and not rewarded.
Cats with lesions were tested 3 weeks postoperatively, and at
3-week intervals. No signs of spontaneous recovery were ever noted
in any of the three cats. Lesion cats survived for 3 months after
surgery to allow degenerative effects of the lesion to run to completion. Cats with lesion and cooling were tested as detailed in
Lomber et al. (2002).
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Cooling
Following successful training, cats with cooling loops were acclimatized to wearing a harness connected via a tether to a stage over
the perimetry arena. The stage held the cooling pump, a methanol
bath and a methanol reservoir. For a cooling experiment, the protective cap was removed from the cooling loop and Teflon tubing
was attached to the inlet and outlet of the cooling loop. The tubes
were attached to the tether and connected to the cooling circuit.
Cats were tested for freedom of movement in the arena, and a precooling set of trials was performed to twice sample every visual field
location.
Cooling was effected by circulating chilled methanol through the
implanted cooling loop. Room temperature methanol was drawn
from the methanol reservoir by a peristaltic pump, circulated
through a cold methanol bath and pumped through the cooling
loop. The outlet of the cooling loop led to the methanol reservoir.
The temperature of the loop depended on the temperature of
methanol in the cooling loop, the rate of flow of the methanol
and the ability of the brain vasculature to counteract the cooling.
Loop temperature was monitored and was changed to the desired
temperature by adjusting flow rate. Typically, trials began 5 min
after the start of cooling and every visual field position was sampled
at least twice.
After the cooling trials were over, the cooling pump was turned
off, the coolant tubes were disconnected from the implant, the
protective cap reapplied and 5 min allowed before post-cool
(re-warm) control data were collected.
2DG administration and euthanasia
For 5–8 days before final procedures, the cat was trained to remain
calm for 30–45 min in a nylon veterinary cat sack. On the penultimate day, a venous catheter was inserted into the cephalic vein.
On the day of the 2DG experiment, the cat was put in the nylon
sack and the loop was cooled for 5 min to obtain a stable temperature of 1 6 3 C. The cat was then injected with four boluses of
2-deoxy-[14C]-glucose separated by 5 min (i.v., total 2DG dosage =
100 mCi/kg; specific activity = 310 mCi/mmol) (Vanduffel et al.,
1995, 1997, 1998; Rushmore and Payne, 2003; Rushmore et al.,
2005). Fifteen minutes later, cats were injected with the anticoagulant heparin (1000 units, i.v.) and the vasodilator sodium nitrite
(1% w/v, i.v.), and finally deeply anaesthetized with sodium pentobarbital (65 mg/kg, i.v.). Intact cats and cats with lesions underwent the same procedure without the presence of cooling.
The vascular system of the cat was perfused through the heart
with a flush solution [15% sucrose in 0.1 M phosphate buffer (PB),
pH = 7.4] for 1 min, followed by a fixative solution (2% paraformaldehyde and 15% sucrose in 0.1 M PB, pH = 7.4) for 5 min.
Cooling was discontinued when fixative had entered the brain.
The brain was quickly removed, blocked and photographed.
It was covered with albumin and submerged in a 30 C bath of
2-methylbutane for 30 min. The brain was then transferred to a
80 C freezer until cutting.
Histological procedures
Brains were cut into 23-mm thick coronal sections using a Bright OTF
cryostat (Hacker Instruments, Inc., Fairfield, NJ, USA) that was set at
23 C. Every fifth section was picked up with a 0.1% gelatin-chrome
alum subbed coverslip, heated to 60 C and glued to Bristol board.
Bristol boards with subbed coverslips applied to them were
apposed to high-resolution X-ray film (Structurix D7, Agfa,
R. J. Rushmore et al.
Mortsel, Belgium) along with 14C calibration strips (Amersham,
Piscataway, NJ, USA) and exposed at 80 C for 9 days. Films
were developed for 10 min (Kodak D19 Developer at 5 C) and
fixed (Kodak Fixer) in red light. Sections were transilluminated
and digitized (MCID, Imaging Research, Ste. Catherines, Ontario).
For each film, points in the calibration curve were joined by linear
interpolation and extended with linear extrapolation. Care was
taken not to over-expose or approach the saturation level of the
film. Distance was calibrated to each image by measuring the number of pixels per millimetre.
Adjacent sections were collected with subbed slides and processed for cytochome oxidase (Wong-Riley, 1979), acetyl thiocholinesterase (Geneser-Jensen and Blackstad, 1971) myelin (Schmued,
1990) or stained for Nissl substance. These sections were used to
demarcate extent of primary and secondary degenerative effects of
lesion.
Analysis
Lesion/cooling reconstruction
The extent of the cortical defect or of the cooling deactivation was
charted onto stereotyped coronal sections through the cat visual
cortex and transferred to a whole brain image (Rosenquist, 1985).
Secondary independent measures of the lesion were obtained by an
assessment of the retrograde degeneration of the lateral geniculate
nucleus and of the lateral posterior thalamic nucleus. Degeneration
was straightforward to assess because successful lesions induce a
retrograde degeneration with profound gliosis and subsequent collapse of the lateral geniculate nucleus, lateral posterior and pulvinar
nuclei.
2DG analysis
Two main regions were sampled: the SC and the contralateral pMS
cortex. Analysis of the SC was similar to previous approaches
(Rushmore and Payne, 2003; Rushmore et al., 2005) and consisted
of a mediolateral sampling of 2DG uptake in the following major
collicular sublaminae: stratum griseum superficiale (SGS), the stratum opticum (SO), the stratum griseum intermediale (SGI) and the
stratum griseum profundum (SGP) (Fig. 1A; Kanaseki and Sprague,
1974). Profiles for each collicular sublamina were obtained by
sampling at the midline outside the SC at a point overlying the
collicular commissure and then sequentially progressing into the
particular sublamina. This approach confers the advantage that
each 2DG profile is spatially calibrated and collicular profiles can
be overlaid and compared regardless of hemisphere or animal. Also,
an impact on specific visual field representation in the SC can be
assessed, rather than be diluted by using a gross structural sampling
approach. Moreover, this sampling strategy provided embedded
control measures of 2DG uptake in extra-collicular sites, which
did not change with condition. 2DG profiles from the middle
SC were generated from sampling from the middle 10 coronal
sections of the SC. For each section, the 2DG profiles were normalized to sectional white matter values (Sharp et al., 1983; Rushmore
et al., 2005) and averaged across the 10 sections. This ratio approach
controls for variations in glucose uptake between animals, and
allowed for a control of intersectional variability.
Uptake of 2DG in the contracooled pMS sulcus was measured in
sections from approximately AP0 to A1 by sequential sampling
(250 mm diameter circular samples) from the lateral crest of the
posterior aspect of the middle suprasylvian sulcus (MSs) via the
Functional circuitry of neglect
Brain (2006), 129, 1803–1821
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Fig. 1 (A) Dorsocaudal view of the SC showing sampling strategy. The left SC shows the retinotopic map and anatomical arrangement: Lat:
lateral, Med: medial; the dashed line represents the horizontal meridian and the dotted line represents the vertical meridian. The right SC
has been cut away in the coronal plane to show the sampling strategy. For each section, sampling (sampling circle: 300 mm diameter) began
on the midline, and outside of the SC. Sequential sampling from this midline point took the sampling into the different sublaminae and
maintained spatial calibration. SGS: stratum griseum superficiale; SO: stratum opticum; SGI: stratum griseum intermediale; SGP: stratum
griseum profundum. Figure modified from Rushmore et al. (2005). (B) A dorsolateral view of the cat cerebrum (left) showing the
demarcation of visual cortical areas (17: Area 17; 18: Area 18; 19: Area 18; 21: Area 21; 20: Area 20) and of select anatomical landmarks
(MSg: middle suprasylvian gyrus; MSs: middle suprasylvian sulcus; pESg: posterior ectosylvian gyrus). Also shown (middle) is a higher
magnification and unfolded view of the posterior terminus of the MSs (middle), illustrating the posterior aspect of the middle suprasylvian
region (pMS). The right portion shows a further inset showing the sampling strategy in which 250 mm samples were sequentially collected
from the crest of the lateral bank (#1) to the crest of the medial bank (#29). Other abbreviations: M: Medial; A: anterior; P: posterior;
L: lateral; D: dorsal.
fundus to the medial crest, in superficial, middle and deep layers
(Fig. 1B). Data from each section were normalized to the white
matter average. The average 2DG profiles for each animal were
generated from 10 sections.
Significant results between relative 2DG uptake in each neglect
group and the normative group were qualified at a P < 0.05 level
using non-parametric Mann–Whitney U-tests. Upon comparison of
two cases with pMS cooling opposite lesion, we assigned significance at a P < 0.1 level based on the limited sample size. In one
instance, we compared the 2DG uptake profile of normal cats with a
single case of unilateral SC deactivation opposite a cortical lesion;
since comparison of groups was not possible here, we assigned
significance when the 2DG uptake values from the deactivation/
lesion case exceeded 0.0001 confidence intervals of the control mean.
Results
Group A: neglect induced by cooling
Behaviour
All four cats demonstrated proficient behaviour in the perimetry task when the cortex was warm. During unilateral
cooling of the pMS loop to 0 6 3 C, cats neglected stimuli
moved into the contracooled visual hemispace. Performance
in the ipsicooled visual hemispace was unaffected by cooling
(e.g. Fig. 2B). These results were comparable with earlier
studies using identical techniques (Lomber and Payne,
1996; Payne et al., 1996a).
Deactivation
Coronal 2DG radiographs exhibited a decrease in 2DG
uptake in the cooled pMS cortex in the vicinity of the
loop (Fig. 2C). The extent of deactivation varied from cat
to cat but always included the medial bank of the pMS
sulcus. In most cats, the effects of cooling was observed
to flow dorsally and medially and resulted in diminished
2DG uptake in various portions of the middle suprasylvian
gyrus (MSg) (Fig. 3). This has been previously reported
following pMS cooling (Lomber et al., 1999; Lomber and
Payne, 2001) and represents an export of the cooling by
vascular elements. In two of the cats, the loop caused damage
to the pMS cortex (Fig. 3B, iii, iv, black). However, in both
instances, the cats were able to perform the orienting
task perfectly in the absence of cooling, and cooling deactivation selectively induced deficits in the visual field contralateral to the loop. The patterns of 2DG uptake, therefore,
represent the neglect state independent of local damage to
the cortex.
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R. J. Rushmore et al.
Fig. 2 The impact of unilateral cooling deactivation of pMS cortex on the ability to detect and orient to moving stimuli in the contracooled
hemifield. (A) The perimetry task. Cats were trained to fixate (A ii) a stimulus (A i) appearing at the 0 position. Upon successful fixation, a
high-contrast stimulus (B i) appeared at a position in either the left or the right visual hemifield. A correct response was recorded if the
cat oriented to the second stimulus (B ii). A soft food reward was given for a correct orienting response. An incorrect response was
recorded if the cat did not orient to the stimulus and instead moved ahead to the fixation point (A i)—in this case, the cat received a dry,
low-incentive food reward. Figure modified from Lomber and Payne (1996). (B) Representative performance of one cat on the
perimetry task with cooling loop at normal brain temperature (left) and during cooling of the left pMS loop (right). The brain icons beneath
the radial graphs represent the state of the pMS cooling loop. During normal brain temperature, the cat was highly proficient and
successfully responded to all secondary stimuli in both visual hemifields. During cooling deactivation of the left pMS cooling loop (grey), the
cat ceased to respond to introduction of the high-contrast stimulus to positions in the right, but not left, visual hemifield. (C) A 2DG
radiograph showing the position of the cooling loop (black circles) in the left pMS sulcus (pMSs) and the associated deactivation of primarily
the medial pMS bank. Notice the cooling was exported to the surface of the MSg.
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Brain (2006), 129, 1803–1821
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Fig. 3 Reconstruction of deactivation extents in cats with cooling of pMS cortex. (A) A dorsolateral view of the cat cerebrum (left)
and inset of cropped area with sulci opened to show the location of the pMS cortex. Medial: medial bank of the MSs; Lateral: lateral
bank of the MSs. Scale bar represents 1 mm. (B) Deactivation extents from the four cats with unilateral cooling loops (i–iv). The extents of
deactivation (grey) were taken from coronal 2DG radiographs and represent a 50% or greater decrease in 2DG uptake. Estimates from
damage from the cooling loop are derived from Nissl-stained sections and are shown as black regions. Abbreviations as in Fig. 1.
Functional impact of deactivation
1. Ipsilateral SC. The SGS and the SO of the SC receive
projections from layer 5 neurons of the pMS sulcus (Segal
and Beckstead, 1984; Harting et al., 1992). Accordingly, cooling silenced neurons in pMS sulcal cortex and resulted in a
decrease in 2DG uptake in the ipsilateral SGS and SO layers
(Fig. 4). This decrease was relatively localized and on the
basis of the visual maps of the SC (Feldon and Kruger, 1970)
roughly corresponded to the representations of the area
centralis and horizontal meridian, a finding concordant with
the retinotopy of cooled pMS cortex (Palmer et al., 1978;
Rosenquist, 1985). Thus, as in previous studies (Rushmore
and Payne, 2003; Rushmore et al., 2005) the focal decrease in
2DG uptake in the SC was probably communicated via
corticotectal projections from the deactivated cortex.
The pMS cortex sends more limited projections to the
ipsilateral intermediate grey level (SGI) of the SC, and no
projections to the deep grey lamina (SGP; Harting et al.,
1992). Correspondingly, these layers were largely unaffected
by cooling (Fig. 4).
2. Contralateral SC. The contralateral SGS was unaffected
by cooling of the pMS sulcus, whereas the SO exhibited an
increase in 2DG uptake. 2DG uptake levels in the contralateral SGI and SGP were also significantly higher than
normal levels (Fig. 4).
3. Contralateral pMS cortex. Cooling of pMS cortex did
not consistently alter 2DG uptake within any layer of the
contralateral pMS cortex (Fig. 5). In the middle layers, two
points of significant (P < 0.05) deviation from the intact
mean were noted, but consistent statistically significant differences were not observed.
Group B: neglect induced by large
cortical lesions
Behaviour
All cats neglected stimuli in the contralesional visual
field (Fig. 6A). Orienting to stimuli moved into the
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R. J. Rushmore et al.
Fig. 4 The impact of unilateral cooling deactivation of pMS cortex (grey) on 2DG uptake in the ipsilateral and contralateral superior colliculi.
2DG profiles for each collicular layer in the cooling group (filled symbols, n = 4) are compared with 2DG profiles of intact cats (open
diamonds, n = 6). Measures began at a midline point (M) outside of the colliculus and extended laterally in 300 mm increments to maintain
spatial calibration from the midline point. The approximate point at which sampling entered the SC laminae is represented by vertical lines.
Error bars represent the standard error of the mean. Statistical significance is set at a P < 0.05 level and is denoted by asterisks.
Abbreviations: SGS: stratum griseum superficiale; SO: stratum opticum; SGI: stratum griseum intermediale; SGP: stratum griseum
profundum.
Functional circuitry of neglect
Brain (2006), 129, 1803–1821
1811
A.
B.
C.
D.
Fig. 6 (A) Representative perimetry behaviour following lesion.
Behavioural performance was identical for all three subjects and
cats did not respond to stimuli in the contralesional visual
hemifield. (B) Lesion reconstructions for cats L1, L2 and L3—black
represents the visual cortex that was removed by the ablation.
Grey represents portions of visual cortex that were spared by the
lesion. The star and coronal line in L1 represent approximate
position of the radiograph in C. (C) A pseudocolour 2DG
radiograph showing the midbrain and cerebral hemispheres from
cat L1. The star represents the location of the lesion. Notice the
difference between the two SC. Scale bar: 1 mm.
ipsilesional visual hemifield was highly proficient. No
signs of spontaneous recovery were noted in any of the
three cats.
Lesion
Fig. 5 The impact of pMS cooling on 2DG uptake in the
contralateral pMS cortex. (A) Representation of the sampling
strategy applied to cortex (see Fig. 1): 250 mm samples were
sequentially collected from the crest of the lateral bank (#1) to the
crest of the medial bank (#29). Samples were collected from the
superficial (B), middle (C) and deep (D) layers in cats with pMS
cooling (filled squares, n = 4) and compared with values from intact
cats (open circles, n = 6). Error bars represent the standard error
of the mean. Asterisks denote significance level of P < 0.05.
The completeness of each cortical lesion was estimated at the
time of brain removal and the lesion borders were subsequently reconstructed from brain sections stained for Nissl
substance (Fig. 6B). Also, secondary measures of the lesion
size were assessed by examining retrograde degeneration in
the thalamus.
In all three cats, the vast majority of intended cortex was
judged to be removed and the assessment was confirmed by
massive retrograde degeneration in connected thalamic
1812
Brain (2006), 129, 1803–1821
nuclei leading to gliotic infiltration and nuclear collapse. The
retrograde degeneration was also evident in 2DG radiographs, which showed a profound reduction in 2DG uptake
within the LP/pulvinar complex. A variable amount of
spared cortex was present in the most ventral visuotemporal
region, which corresponded to neuronal sparing and preserved 2DG signal in the most medial fringe of the lateral
posterior nucleus (Fig. 6B, grey). Overall, any cortical sparing was minimal, and is probably irrelevant for the study
because none of the cats responded to stimuli presented in
the visual hemispace contralateral to the lesion.
Functional impact of lesion
1. Ipsilateral SC. The unilateral ablation of visual cortex
resulted in a profound decrease in 2DG uptake in the superficial layers (SGS and SO) of the ipsilateral SC (Fig. 7, left).
2DG uptake values in the SGI were at normal levels. In the
deep SGP layer, 2DG uptake was increased at mid-collicular
levels.
2. Contralateral SC. The contralateral SO, SGI and SGP
layers displayed heightened 2DG uptake values relative
to control measures, but 2DG uptake values in the contralesional SGS were not different from control measures
(Fig. 7, right).
3. Contralateral pMS cortex. 2DG profiles from the contralateral pMS cortex showed that the pMS cortex contralateral to a large lesion did not differ reliably from normal
2DG uptake profiles (Fig. 8). In the middle layers, two points
on the lateral bank were significantly decreased relative to
normal values.
Group C: reversal of neglect by pMS
deactivation opposite a large
cortical lesion
To this point, we have shown that the presence of
neglect for contralateral stimuli, either through unilateral
cooling deactivation of pMS cortex (Group A) or from
a large unilateral cortical lesion (Group B), corresponds to
a specific and bilateral pattern of changes in 2DG uptake
in the layers of the superior colliculi (Fig. 9). The pattern was
similar in sign and distribution, but not magnitude; the
pattern after lesion produced a larger impact in both the
ipsilateral and contralateral SC. Regions of the SC in receipt
of projections from the lesioned cortex or the deactivated
cortex show a decrease in 2DG uptake; these decreases represent the functional removal of efferent projections from the
lesioned or deactivated cortex. However, changes observed in
the contralateral SC were inconsistent with known direct
projections of the resected or deactivated cortex. These
changes included heightened 2DG uptake in the contralateral
R. J. Rushmore et al.
intermediate and deep layers of the SC. Since these
alterations cannot result from direct synaptic influence of
the deactivated or lesioned cortex, they must represent
secondary impacts promulgated by the initial lesion or
deactivation.
These results are in general agreement with theoretical
predictions that suggest that the induction of neglect influences crossed circuitry to produce a heightened activation of
the contralateral SC (Hilgetag et al., 1999). To determine
whether the heightened activation of the contralateral SC
co-varies with the presence of neglect, large unilateral cortical lesions were made to induce the heightened activation
of the contralesional SC and induce enduring hemineglect; in
the same animals, cooling loops were implanted either in the
contralateral pMS cortex (n = 2) or in contact with the
contralateral SC (n = 1). The purpose of these loops was
to reduce the activity of the SC contralateral to lesion, either
directly in the case of the SC loop or indirectly by deactivating the large corticotectal projection from the pMS cortex.
The behavioural results and lesion analysis have been
reported previously (Lomber et al., 2002), and will be reproduced in textual form below.
Behaviourally, cooling of the pMS loop to 8 C or the
SC loop to a temperature of 12 C produced a restoration of
orienting responses to stimuli in the formerly blind hemifield
(Lomber et al., 2002), which lasted only for the duration of
the cooling. The restoration of visual responses in the formerly neglected field disappeared and the neglect became
reinstated upon the cessation of cooling (Lomber et al.,
2002).
For the final section of the results, we report on the patterns of activity in the SC of the three cats who had an initial
lesion-induced neglect for stimuli that was cancelled by subsequent deactivation of either the contralateral pMS cortex
or the contralateral SC.
Analysis of 2DG uptake patterns in the SC of
cats with restored orienting ability
1. Cooling of pMS cortex opposite a large visual
cortex lesion. Deactivation of the pMS cortex opposite
a large lesion of visual cortex resulted in a reinstatement
of the ability to respond to stimuli in the formerly
blind visual field. Analysis of the pattern of 2DG
uptake in the SC during the reinstatement indicated that
the intermediate and deep layers of the ipsilesional or the
ipsicooled SC were not different from 2DG uptake in
normal cats (Fig. 10). Thus, the addition of pMS cooling
opposite lesion eliminated the lesion-induced heightened
activations in the contralesional SO, SGI and SGP, and in
the ipsilesional SGP.
A further comparison between 2DG uptake levels in
the SC of lesioned cats and lesioned cats with pMS
cooling showed that the SO on the side of the lesion,
but not the SGS or SGI, displayed a larger decrease in
Functional circuitry of neglect
Brain (2006), 129, 1803–1821
1813
Fig. 7 The impact of unilateral lesion (black) of all contiguous visual cortical areas on 2DG uptake in the ipsilateral and contralateral superior
colliculi. 2DG profiles for each collicular layer in the lesion group (filled symbols, n = 3) are compared with 2DG profiles of intact cats (open
diamonds, n = 6). Abbreviations and conventions as in Fig. 4.
2DG uptake than could be accounted for strictly by the
impact of the lesion. This difference was not a result of
different lesion extents, but a result of the interaction of
the pMS cooling with the extant lesion effects. Thus,
we conclude that the addition of pMS cooling caused a
further decrease in 2DG uptake in the ipsilesional SO, a
decrease that was superimposed on the lesion-induced
decrease.
In these cases, 2DG uptake in the SGI and the SGP on both
sides were comparable both with each other and with levels
measured in intact cats. Activity patterns in the SO and SGS
were asymmetrical.
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Brain (2006), 129, 1803–1821
2. Cooling of SC opposite a large visual cortex
lesion. Similar to the results of adding the contralateral
deactivation of pMS cortex to lesion, cooling the SC opposite
lesion enabled the animals to respond to stimuli in the
contralesional hemifield. Also similar to the effects of the
pMS cooling opposite lesion, the addition of the SC cooling
eliminated any evidence of heightened activity levels in the
contralesional SO, SGI and SGP, and in the ipsilesional SGP
(Fig. 11). In addition, direct collicular cooling also induced
changes in 2DG uptake throughout the colliculus that were
superimposed on the effects of lesion per se. For instance, the
decrease in 2DG uptake within the ipsilesional SGS and the
SO was clearly accentuated when the SC was cooled opposite
lesion. In addition, the ipsilesional SGI measured in lesion
cats exhibited no difference from control cats, but displayed
a decrease in 2DG uptake when the contralesional SC was
cooled (Fig. 12).
Finally, analysis of relative activity levels showed that
SC cooling opposite lesion induced symmetry in the SO
lamina, but symmetry was not present, and was even more
accentuated in the intermediate (SGI) and deep (SGP) laminae. However, it should be noted that in these layers the
asymmetry was between activity levels that were both below
normal. In no cases with SC cooling opposite lesion was the
activity higher than normal. Thus, it appears that symmetry
between the intermediate and deep layers is not necessary
for the re-establishment of visual orienting responses.
R. J. Rushmore et al.
A.
B.
C.
Discussion
Our results show that the presence of neglect, induced either
through unilateral cooling of pMS cortex or in conjunction
with cortical blindness, is associated with (i) a diminished
uptake of 2DG within the superficial laminae of the ipsilateral SC and (ii) a heightened level of 2DG uptake in the
intermediate and deeper layers of the contralateral SC. The
concordance of collicular 2DG uptake patterns across the
two separate groups of animals with similar visual defects
lends credence to our claim that neglect is associated with
alterations in activity at the level of the SC. Furthermore,
when the heightened level of activity in the contralesional SC
is diminished, either through deactivation of the colliculus
itself or via deactivation of contralateral parietal cortex,
the neglect was eliminated. These data indicate that alterations in circuitry in the SC is the major mechanism through
which neglect is manifested and reversed and suggest a
re-evaluation of current theories of hemispheric asymmetry
in the pathogenesis of neglect and in the design and application of therapeutic strategies
Neglect has been understood to be intricately tied to the
function of the human cerebral cortex, and in particular, the
function of the posterior parietal cortex. However, neglect is
not exclusive to the human condition, nor exclusive to insult
of the parietal cortical area. Multiple animal models of
neglect exist, and visuospatial neglect is also observed following damage to the cingulate cortex, to the superior temporal
Fig. 8 The impact of unilateral lesion of all contiguous visual areas
on 2DG uptake in the superficial (A), middle (B) and deep (C)
layers of the contralateral pMS cortex. Conventions and
abbreviations as in Fig. 5.
cortex or to the frontal eye field in most species studied
(Mesulam, 1999; Karnath et al., 2004; Lomber and Payne.,
2004; Payne and Rushmore, 2004). While the precise symptomology of neglect is likely to vary with cortical site of
damage (Mesulam, 1999), the disparate distribution of
these neglect-inducing foci suggests that neglect may result
not solely from lesion-induced disruption of processing
within these locations alone, but that the processing of a
more distal and downstream site may serve as a final common structure in the manifestation of neglect. All regions
whose disruption induces neglect maintain strong projections to the SC (Harting et al., 1992), and indeed, lesion
of SC in humans also produces neglect-like symptoms
(Weddell, 2004). As a consequence, the primary induction
of neglect may result from a diaschetic impact of lesion along
Functional circuitry of neglect
Fig. 9 Summary of results from cats with neglect. (A) Behavioural
results from cats with unilateral cooling of pMS sulcus (left) and
cats with unilateral lesions of all contiguous visual cortical regions
(right). (B) Schematic representation of cooling (grey, left) and
lesion (black, right) cats. (C) Representation of impact of
manipulation on 2DG uptake in SC. Note concordance of pattern,
but not magnitude in the two preparations. (One arrow represents
between 5 and 10% change from intact values, two arrows
represent a 10–20% change, three arrows represent a 20–30%
change, 0 represents no change).
efferent projections to the midbrain. This would explain the
convergence of symptoms from disparate cortical regions
and would suggest that the SC functions as a final common
structure mediating and/or exacerbating the effects of
neglect.
In this interpretation, permanent or reversible deactivation of parietal, frontal or cingulate cortical fields results in a
condition of reduced excitability in the ipsilesional SC
(Payne and Rushmore, 2004). This condition then initiates
a disinhibition of the contralateral SC by reducing the activity of intertectal inhibitory fibres. Finally, the disinhibited
contralateral SC exerts a higher inhibitory tone on the ipsilesional SC and inhibits it further (Hilgetag et al., 1999; Payne
and Rushmore, 2004). Thus, the visual deficit observed after
lesion or deactivation of cortex is a consequence of two
factors: the removal of parietal cortex processing and the
cascade of interactions arising from the subsequent disruption of collicular activity.
The origin of these ideas lies in findings that a cortical
lesion-induced visual deficit could be reversed by aspiration
lesion of the contralateral SC or after division of the intertectal commissure (Sprague, 1966); to explain these results,
Brain (2006), 129, 1803–1821
1815
Sprague suggested that the SC contralateral to lesion exerted
a compounding inhibitory influence on the ipsilesional SC
(Sprague, 1966, 1996). Other results suggested that inhibitory influences may arise from an extrinsic source whose
axons passed through the superficial layers of the SC to
access the intertectal commissure (Wallace et al., 1989).
As such, ibotenic acid lesions of the SC, which damaged
cells but not axons, were insufficient to reinstate behaviour
in the heminanopic field, whereas adding a transection of the
caudal intertectal commissure did restore visual orienting
(Wallace et al., 1989). Subsequent studies identified the
substantia nigra pars reticulata (SNpr; Wallace et al.,
1990) and the pendunculopontine tegmentum (PPT;
Durmer and Rosenquist, 2001) as providing anatomical
sources of the inhibitory influence; ibotenic acid lesions of
either structure were sufficient to restore visual orienting
following a cortical lesion (Wallace et al., 1990; Durmer
and Rosenquist, 2001).
These findings cannot be easily brought to terms with the
present behavioural and functional findings (Lomber et al.,
2002; present results) and with anatomical results (Appell
and Behan, 1990; Olivier et al., 1998; Takahashi et al., 2006).
As such, the heightened activation of the contralateral SC
may be due to the deactivation of a projection that courses in
the intertectal commissure and arises from the ipsilesional
SNpr (Harting et al., 1988; Jiang et al., 2003), the contralateral SC (Edwards, 1977; Olivier et al., 1998) or both. In
any case, the requirements for involvement are a relatively
tight coupling of activity with parietal cortex, a requirement
that fits both proposed structures. Unfortunately, we could
not examine the SNpr in the current study owing to methodological constraints: neurons of the nigrocollicular pathway are interspersed with other cell types (Jiang et al., 2003),
and the presence of the perforating fibres of the cerebral
peduncle makes accurate detection of changes difficult at
best with the 2DG method. As a consequence, we cannot
exclude or include an involvement of the substantia nigra as
a component in the functional circuitry.
Regardless, our data show that the presence of neglect is
associated with a hyperexcitability in the contralesional SO,
SGI and SGP layers of the SC, but not in the SGS layer.
In addition, there does not seem to be any lesion-related
inhibition of the ipsilateral SC apart from that expected
following the functional removal of corticotectal projections;
we expected a diminished 2DG uptake signal throughout SGI
and SGP, but found none. Moreover, we found that by
reducing the hyperexcitability of the contralesional collicular
layers, either directly or by deactivating highly connected
distant regions, the capacity to respond to moving stimuli
in the contralesional visual field was restored.
Unexpected findings in SC patterns after
induction of visual deficits
Previous investigation into the functional organization of
this system suggested that the initial cortical lesion-induced
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Brain (2006), 129, 1803–1821
R. J. Rushmore et al.
Fig. 10 The impact of adding cooling deactivation of pMS cortex (grey, right hemisphere) to a unilateral lesion of all contiguous visual areas
(black, left hemisphere) on 2DG uptake in the SC. Open diamonds represent intact (n = 6) values and filled symbols represent cats with
unilateral lesion of all contiguous visual areas combined with contralateral pMS cooling deactivation (n = 2; filled squares: ipsilesional, filled
triangles: ipsicooled). Abbreviations and conventions as in Fig. 4. Significance for this comparison was set at P < 0.10 and denoted by ‘+’
symbols.
Functional circuitry of neglect
Brain (2006), 129, 1803–1821
1817
Lesion
Fig. 11 The impact of adding cooling deactivation of SC (grey, right SC) to a unilateral lesion of all contiguous visual areas (black, left
hemisphere) on 2DG uptake in the SC. Open symbols represent intact (n = 6) values and filled symbols represent a single case with
unilateral lesion of all contiguous visual areas combined with contralateral SC cooling deactivation. Error bars represent 0.0001
confidence interval of the mean and · symbols indicate points in which values from the experimental case did not fall within the confidence
interval of the intact group and was thus considered to be significantly different. All other conventions and abbreviations as in Fig. 4.
1818
Brain (2006), 129, 1803–1821
R. J. Rushmore et al.
A.
B.
C.
Fig. 12 Summary of experimental results. The first row (A) represents orienting behaviour in cats with lesion (left), cats with lesion and
contralateral pMS cooling (middle) and cats with lesion and contralateral SC cooling (right). (B) The experimental preparation of each of the
three groups—black represents resected cortex and grey indicates cooling deactivation. (C) The impact of different conditions on the layers
of the superior colliculus. (One arrow represents between a 5 and 10% change from intact values, two arrows represents a 10–20% change,
three arrows represents a 20–30% change, four arrows represents >30% change from intact values; 0 represents no change). (A) redran
from Lomber et al. (2002).
neglect was maintained and compounded by a suddenly
unbalanced midbrain system (Kinsbourne, 1987; Hilgetag
et al., 1999; Payne and Rushmore, 2004) via induction of
asymmetry between the cortical hemispheres and between
the midbrain SC. Our findings provide a test of this idea
and force several modifications.
The contralateral pMS cortex
Contrary to speculations that the initial neglect-inducing
lesion would reduce or elevate excitability in the homotypic
contralateral cortical region and thus on the contralateral
SC (Hilgetag et al., 2001; Payne and Rushmore, 2004), we
found no consistent or statistically reliable evidence to suggest that the pMS contralateral to lesion or cooling was
affected by the deactivation of the contralateral homotypic
region. Thus, despite the large anatomical callosal projection
(Keller and Innocenti, 1981; Segraves and Rosenquist, 1982),
lesion or cooling do not appear to have an impact on
the contralateral pMS cortex. These findings are supported
by the presence of the multiple kinds of axons in the
corpus callosum (Peters et al., 1990) and the spectrum of
functional impacts of callosal projections (Payne et al., 1991).
Finally, behavioural data from Sherman (Sherman, 1974)
indicate that the contralateral cerebral cortex is not necessary
for recovery. Overall, our data show that contralateral
parietal cortex is not affected by a neglect-inducing manipulation of the contralateral homologue.
The ipsilesional SGI
A strong decrease in 2DG uptake in the ipsilesional/
ipsicooled SC was expected on the basis of two arguments.
First, we anticipated a functional denervation of cortical
inputs would decrease the excitability of superficial collicular
layers and vertically telegraph to the intermediate (SGI) and
deep (SGP) collicular layers (Behan and Appell, 1992) and
render the entire SC hypoexcitable. Second, the impact of a
lesion on crossed inhibitory mechanisms between the two SC
would be expected to feed back and further inhibit the ipsilesional intermediate and deeper layers (Hilgetag et al.,
1999). In the present study, however, we found a decrease
in 2DG uptake in the superficial layers SGS and SO, but 2DG
uptake in intermediate layers was not different from normal.
This constancy of SGI activity confirms previous data that
indicate that the superficial layers are functionally isolated
from the deeper layers (Wickelgren and Sterling, 1969;
Rizzolatti et al., 1970; Stein and Arigbede, 1972; Berman
and Cynader, 1975; Ogasawara et al., 1984); alternatively,
the normal activity level of the ipsilesional SGI may represent
functional compensation by non-visual inputs, which provide substantial inputs to SGI neurons (Huerta and Harting,
Functional circuitry of neglect
1984; Harting et al., 1992; Meredith and Stein, 1993; Harting,
2004).
Experimental models of visual neglect
Both large visual cortical lesions and focal cooling deactivations of pMS cortex are presented as models of neglect, and
here we discuss the suitability and limitations of each as
appropriate models of neglect. Restricted cooling deactivation of pMS cortex in the cat silences neurons under the
cooling loop and produces visual deficits consistent with
neglect (Lomber and Payne, 1996, 2004; Payne et al.,
1996a). Cooling is a focal manipulation and neurons are
functionally silenced, but structurally intact (Lomber,
1999); as such, adaptive or maladaptive mechanisms following cortical damage are not invoked.
Comparable functional deficits cannot simply be created
by focal permanent lesions of pMS, since in such cases visual
orienting spontaneously recovers within a matter of days,
presumably as adjacent cortical regions compensate for
the function of the damaged pMS cortex (Payne et al.,
1996b). Large lesions incorporating pMS and regions of
cortex that potentially compensate are required to produce
a stable form of neglect. This model is more similar to the
human condition, wherein neglect is elicited by brain
damage that is frequently quite extensive, and in which
case neglect and hemianopia often co-occur. However, the
experimental model involving large cortical lesion suffers
from a lack of specificity.
Overall, we are confident that the cooling and lesion
approaches are comparable for three reasons. First, the
cancellation of visual deficits argues that we are examining
recovery from neglect, and not hemianopia, because unlike
neglect, hemianopia cannot be reversed—the grain of analysis that striate cortex exerts on the visual field appears
irreplaceable. Second, visual deficits induced by a unilateral
pMS cooling or by a large visual cortex lesion can both be
reversed by cooling precisely the same region of cortex in the
intact side (Lomber and Payne, 1996; Lomber et al., 2001).
Finally, both approaches produce a pattern on the SC that is
similar in sign, but not magnitude, a result concordant with
the extent of the cortical manipulation.
We should also note that there is a piece of the puzzle
remaining to completely establish this comparison between
the two models: the impact of bilateral cooling deactivation
of pMS on 2DG uptake in the SC has not yet been performed. While on the basis of the current data and from the
data of Lomber and Payne (1996) we would expect the
second cooling to reduce 2DG uptake levels to normal or
subnormal levels, at this point we can only speculate.
Brain (2006), 129, 1803–1821
1819
the SC, orienting to stimuli in the previously neglected
hemifield returns (Fig. 12; Lomber et al., 2002).
These findings are in broad agreement with models of
midbrain function (Hilgetag et al., 1999; Payne and
Rushmore, 2004), but several features do not reflect theoretical predictions. In particular, we did not find any evidence
that the ipsilateral SC is being inhibited beyond the inhibition expected by functional denervation of corticotectal
inputs. Indeed, cancelling neglect is associated with a further
decrease in 2DG uptake in the ipsilesional SO layer, and
unchanged activity profiles in the SGI.
Thus, the simplest explanation we can proffer is that the
hyperexcitability of the contralesional SC is sufficient in itself
to produce symptoms of neglect. As such, ameliorative
manipulations taken previously, including transection of
the collicular commissure, ablation of the contralateral SC
(Sprague, 1966), as well as the recent findings using cooling
(Lomber et al., 2002) were effective because they eliminated
the excitability generated in contralateral SC. This mechanism also suggests that therapies that transiently eliminate
symptoms of neglect, such as caloric stimulation or neck
vibration treatments, may produce their effects by temporarily diminishing excitability in the contralesional SC. It is
important to note, however, that this interpretation is germane for the understanding of spatial neglect, but unlikely to
account for more complex features or forms of neglect, such
as representational neglect (e.g. Bisiach and Luzzatti, 1978).
Summary
We found evidence that the presence of neglect is associated
with a specific pattern of activity in the SC, a pattern that
indicates a hypoactivity of the layers of the ipsilateral SC
receiving input from the deactivation or lesion, and a hyperactivity of the contralateral SC. Depressing the hyperactivity
in the intact side with cooling resulted in a cancellation of
neglect. Our results encourage a relatively straightforward
approach to the treatment of neglect in humans: the
moderation of excitability in the contralesional SC. Owing
to the deep location of the SC, and the tendency of neglect to
naturally ameliorate in humans, an invasive approach is
counterindicated. Instead, since we have shown that neglect
may be reversed by modulating activity in strongly coupled
cerebral structures, it follows that non-invasive methods
such as transcranial magnetic stimulation or electrical stimulation may serve to diminish the activity in the SC through
long-range connections (Oliveri et al., 2001; Brighina et al.,
2003; Valero-Cabre et al., 2005). Obvious candidate
regions would be the frontal eye fields and the parietal cortex.
Neglect and its restoration
Acknowledgements
Our findings suggest that neglect is associated with an
increase in excitability in the contralateral SC; when that
excitability is diminished, either indirectly through cooling
deactivation of the pMS cortex or directly through cooling of
We thank the following people who read and made valuable
comments on previous versions of this manuscript: Mark
Moss, Julie Sandell, Álvaro Pascual-Leone, Alan Peters and
Louis Toth. This work was supported by grants NIH
1820
Brain (2006), 129, 1803–1821
NS044624 (R.J.R.), NS032137 and NS47754 (B.R.P., S.G.L.
and A.V.C.), NSF IBM9906443 (S.G.L.) and the Wellcome
Trust (C.C.H.).
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