effects of light deprivation on recovery from neglect and extinction

Research report

Effects of light deprivation on recovery from neglect and extinctioninduced by unilateral lesions of the medial agranular cortex and

dorsocentral striatum

T.M. Van Vleet a, S.A. Heldt a, B. Pyter a, J.V. Corwin a,*, R.L. Reep b

a Department of Psychology, Northern Illinois University, De Kalb, IL 60115, USAb Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA

Received 5 April 2002; received in revised form 6 August 2002; accepted 6 August 2002

Abstract

A number of previous studies have indicated that an environmental manipulation, 48 h of light deprivation (LD), produces

virtually complete and permanent behavioral recovery of function from neglect induced by medial agranular cortex (AGm) lesions.

LD-induced behavioral recovery from neglect is correlated with physiological changes in the dorsolateral striatum, an area that

contains the projection zone of AGm efferents in the dorsocentral striatum (DCS). In this study, the behavioral effects of 48 h of LD

on subjects with either unilateral DCS, AGm, or combined AGm/DCS lesions were investigated to examine whether the integrity of

the DCS is crucial for behavioral recovery from neglect and whether LD will have a therapeutic effect on extinction deficits. Subjects

were tested for extinction to bilateral simultaneous stimulation of the forepaws, and visual, auditory and tactile neglect. Forty-eight

hours of LD failed to produce behavioral recovery from neglect in rats with DCS lesions, or a therapeutic affect on extinction

deficits in any of the groups. The results of this study further support the crucial role of the DCS in recovery from neglect induced by

AGm lesions and suggests that the DCS may be the crucial site for the mechanisms leading to LD-induced recovery. Further, the

ineffectiveness of LD on extinction suggests that components of the neglect syndrome are dissociable and may require different

therapeutic interventions.

# 2002 Elsevier Science B.V. All rights reserved.

Keywords: Neglect; Light deprivation; Attention; Prefrontal; Extinction; Recovery

1. Introduction

Neglect is a complex and devastating human neurop-

sychological disorder characterized by a failure to attend

to novel or meaningful stimuli presented to the side

contralateral to a brain lesion, in the absence of a

primary sensory or motor dysfunction. Some manifesta-

tion of neglect is found in approximately 40% of all

cases of brain damage [22]. The vast majority (80�/90%)

of all cases of neglect are produced by destruction of one

of the three cortical regions: the dorsolateral prefrontal

cortex (area 8), the cingulate cortex, or the inferior

parietal lobule [22]. The disorder goes far beyond a lack

of responsiveness to contralesional stimuli to include

dramatic attentional and cognitive spatial deficits. The

failure to respond to contralesional stimuli has devastat-

ing effects for the patients’ abilities to demonstrate

independent daily living or to return to work, and the

presence of persistent neglect leads to a poor prognosis

[16,18,25]. Recovery, when it occurs, is spontaneous

over the course of weeks to months, but often it is

incomplete. Many patients continue to ignore or neglect

contralesional stimuli for months or years post-lesion

[20,23]. They are often unaware of their neurological

status (anosognosia), or are unconcerned and effectively

flat (anosodiaphoria) [22]. This lack of awareness and

changes in motivation interfere with successful physical

and occupational rehabilitation [40].

A rodent model of neglect has been developed to

examine the basic mechanisms of neglect and the

potential for recovery of function [2�/4,8,10]. The

* Corresponding author. Tel.: �/1-815-753-7088; fax: �/1-815-753-

8088

E-mail address: [email protected] (J.V. Corwin).

Behavioural Brain Research 138 (2003) 165�/178

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symptoms of neglect in rodents following unilateral

lesions of the medial agranular cortex (AGm), the

rodent analog of area 8, are similar to those found in

human neglect patients and include: severe neglect ofvisual, tactile, and auditory stimulation, extinction,

allesthesia/allokinesia, and disorders of spatial proces-

sing [1,8,14,15,27,28,45].

In rats, recovery from AGm-induced neglect has been

found to occur in three contexts: (1) as in humans,

dopamine (DA) agonists produce acute recovery of

function [10,17,19,24,26]; (2) as found in humans,

rodents with neglect demonstrate spontaneous althoughincomplete recovery over the course of weeks to months

[10,26,28]; and (3) exposure to 48 h of light deprivation

(LD) at 4 h post-surgery produces dramatic immediate

recovery [2,15].

Several recent studies in rodents strongly indicate that

the striatum may play a critical role in neglect, and both

drug-induced and spontaneous recovery from neglect

produced by unilateral AGm lesions [50,53�/55,58,59].Vargo and Marshall [53,54] using immediate early gene

expression (IEG) methods found that spontaneous

recovery from neglect was correlated with symmetrical

IEG expression in the dorsolateral striatum, and in a

subsequent study [55] correlated with changes in gluta-

mate receptors in the dorsolateral striatum. The im-

portance of the striatum in AGm lesion-induced neglect

was also suspected because apomorphine (a DA recep-tor agonist) can produce acute recovery [10,26], and

spiroperidol (a DA receptor antagonist) can reinstate

neglect [57]. The role of DA in cortical [10,12,26] and

subcortical neglect [30�/34], led Fleet et al. [17] and

Hurford et al. [24] to examine the effects of bromocrip-

tine, a D2 receptor agonist, in human patients with

chronic neglect. Bromocriptine produced recovery

across a range of measures. When treatment wasterminated, neglect worsened. Recently, Geminiani et

al. [19] found that apomorphine can also produce acute

recovery from neglect in humans.

These findings led to a series of studies designed to

investigate the role of the striatum in recovery from

neglect induced by unilateral destruction of the AGm.

Van Vleet et al. [50] examined the effects of unilateral

destruction of the striatal projection zone of the AGm inthe dorsocentral striatum (DCS) [38]. The results

indicated that unilateral axon-sparing DCS lesions

produced severe neglect and that the DCS operates did

not demonstrate spontaneous recovery, even in subjects

tested at 96 days post-lesion. Further, apomorphine did

not produce a therapeutic effect in the DCS operates. In

another study, Van Vleet et al. [49] examined the effects

of direct infusion of apomorphine into the DCS or alaterally adjacent region of the striatum in subjects with

severe neglect induced by unilateral AGm lesions. Direct

infusion of apomorphine into the DCS produced a

dramatic acute recovery, while infusion into the adjacent

region of the striatum did not produce recovery [49].

The results of these studies suggest that the DCS may be

a crucial region for recovery from neglect induced by

unilateral AGm destruction.Recovery from neglect produced by unilateral AGm

lesions can also be produced by an environmental

manipulation, 48 h of LD. LD produces dramatic,

accelerated recovery from severe neglect that lasts for

the duration of behavioral testing [2,9,14,15]. Vargo et

al. [59] examined the behavioral and neural correlates of

LD-induced recovery and found that recovery from

AGm-induced neglect was inversely correlated withbehavioral activity and with the degree of asymmetry

in c-fos expression in the right and left dorsolateral

striata. LD decreased the lesion-induced asymmetry in

the dorsolateral striatum and produced recovery. The

region described as the dorsolateral striatum in the

Vargo et al. [59] study encompassed much of the DCS.

The Vargo et al. [59] study pointed to the potential

importance of the DCS in LD-induced recovery fromneglect produced by unilateral AGm lesions, but the

data were correlational and included the entire dorso-

lateral striatum rather than the site of the AGm

projections to the DCS. In this study, we directly

examined the therapeutic effectiveness of LD on severe

neglect produced by unilateral AGm and/or DCS

lesions. In addition, we extended what is known about

LD-induced recovery by examining the effects of LD onone of the major deficits associated with the neglect

syndrome in humans, extinction to bilateral simulta-

neous stimulation. Examination of the effects of LD on

extinction deficits is important because extinction defi-

cits often persist in patients who have recovered from

neglect [25].

2. Methods

2.1. Subjects

Subjects were 43 male Long-Evans hooded rats bred

from stock purchased from Harlan Sprague�/Dawley.

Prior to the surgical procedures, the subjects were

handled daily (1�/2 min per day) for 21�/28 days to

gentle them for subsequent behavioral testing. Animalswere tested between 12:00 and 17:00 h. All procedures

conformed to institutional guidelines for the care and

use of animals.

2.2. Surgical groups

Prior to surgery, subjects were assigned to one of the

surgical groups. There were six groups. Five groupsreceived 48 h of LD: (1) a combined unilateral AGm and

DCS lesion group (AGm/DCS; n�/8); (2) a group with

combined AGm and control lesions of the area laterally

T.M. Van Vleet et al. / Behavioural Brain Research 138 (2003) 165�/178166

adjacent to the DCS (AGm/LSC; n�/6) which acted as a

control for extent of cortical and striatal damage; (3) a

unilateral DCS lesion group (n�/8); (4) a unilateral

AGm lesion group (AGm/LD; n�/5); and (5) a uni-lateral AGm lesion group that did not receive extinction

testing (AGm; n�/5). Prior studies have only examined

the effects of LD on neglect [2]; therefore, this AGm

group, which was taken from a prior study from our

laboratory [2], was used to control for the possible

effects of combined neglect and extinction testing on the

therapeutic effectiveness of LD. A sixth group which

received a unilateral AGm lesion was tested for bothneglect and extinction, but did not experience LD

(AGm/noLD; n�/8). This group was included in the

analysis of the extinction data only, and served as a

baseline comparison group to examine the affects of LD

on extinction. Finally, to examine the possibility that the

effective dose of LD may differ for the AGm and the

DCS, three additional unilateral DCS operates were

given 72 h of LD. A prior study has indicated that 72 hrather than 48 h of LD is necessary to consistently

produce recovery in 24-month-old AGm operates with

severe neglect [7].

2.3. Preoperative extinction testing

In order to assess for a preoperative paw preference,

subjects were given a test commonly used to examine

extinction to bilateral simultaneous stimulation[29,43,51]. The subjects, while still in their home cage,

were placed on a table in a room illuminated by dim red

light for 1 min of adaptation. After adaptation, round

adhesive-backed papers (1.3 cm diameter labels) (Avery

International) were attached bilaterally to the radial

aspect of the wrist. The distal part of the label covered

approximately 1 mm of the hairless part of the forepaw.

After both labels were attached, they were pressedsimultaneously, and the animal was replaced in its

home cage. Latency to contact and latency to remove

each label were recorded. If the animal failed to remove

one or both of the labels within 120 s of attachment, the

trial was terminated. Each animal was given five trials

per test session, with each trial separated by 1 min.

2.4. Surgical procedures

2.4.1. AGm lesions

A detailed description of the surgical procedures can

be found in Burcham et al. [2,4]. Briefly, animals were

anesthetized using sodium pentobarbital (50 mg/kg,

i.p.). Under aseptic conditions, a midline incision was

made and the skull revealed. A skull ‘‘window’’ extend-

ing from 5 mm rostral to �/2 mm caudal to bregma and2 mm lateral to the sagittal sinus was removed on the

intended side of the lesion. The AGm was then removed

via gentle subpial aspiration. Once hemostasis was

achieved, Gelfoam was placed in the wound and the

incision closed with sterile wound clips and treated with

Neomycin ointment. The subjects were kept warm and

monitored prior to behavioral testing.

2.4.2. DCS and LSC lesions

Animals were anesthetized using sodium pentobarbi-

tal (50 mg/kg, i.p.). When unresponsive (absence of

corneal reflex and responsiveness to a mild tail pinch),

the subjects were placed in a stereotaxic apparatus using

blunt-tipped ear bars. Under aseptic conditions, a small

hole was drilled in the skull at 0.5 mm rostral and 3.4mm lateral to bregma. Drugs were infused using a

programmable infusion pump (Stoelting) attached to a

0.5 ml, 26-gauge Hamilton syringe. For the DCS group,

the cannula was lowered 4.2 mm ventral to the dura. For

the LSC group, the hole was drilled at 0.5 mm rostral,

4.4 mm lateral relative to bregma, and the cannula

lowered to 5.2 mm ventral to the dura. The 0.1 ml dose

of NMDA was infused at a rate of 0.1 ml/2 min, andallowed to diffuse for an additional 4 min before the

syringe was removed. The incision was closed with

sterile wound clips, treated with neomycin ointment,

and the subjects kept warm and monitored prior to

being returned to the colony.

2.4.3. Combined lesions

In the AGm/DCS and AGm/LSC groups in which the

subjects received both surgeries in the same session, thesubjects received the appropriate striatal lesion first,

followed by subpial aspiration of the AGm as described

earlier for each of the individual procedures. The

subjects tolerated the combined procedures quite well,

and could be tested for neglect at 4 h post-injection.

2.5. Pre-LD behavioral testing

2.5.1. Circling behavior

The subject was placed in its home cage on the testing

platform, and the number of ipsi- and contralesional

turns was counted to the nearest 1/2 turn for a 2 min

period prior to behavioral testing for neglect [10,15]. A

1/2 turn was recorded when both of the subject’s hind

feet crossed over an imaginary line 908 from the starting

position.

2.5.2. Orientation testing

All testing were conducted during the light phase of

the light/dark cycle in a room with standard overhead

fluorescent lighting. Orientation testing was a modified

version of that developed by Crowne et al. [15] and was

designed to reflect simple bedside testing for neglect in

humans. These procedures have been used in a numberof studies from my laboratory [2,4,50] and others [59].

After the 2 min assessment of circling behavior, the

animal was taken out of its cage and placed directly on

T.M. Van Vleet et al. / Behavioural Brain Research 138 (2003) 165�/178 167

the test platform marked to delineate 08, 308, 458, and

608 angles in either direction from a central line running

the length of the testing board. The subject was gently

restrained by hand from behind without restricting headmovement, and aligned with the centerline. Stimuli were

presented only when there was no evidence of strug-

gling, no asymmetry of body posture, and when the

head was oriented in direct line with the body. Typically,

the animal’s body had to be realigned several times

during testing. The early extensive handling minimized

struggling and ‘‘freezing’’. Visual, tactile, and auditory

stimuli were presented in turn. The visual stimulusconsisted of the presentation of a silver metallic rod

10.0 cm in length (8 mm in width), which was waved in a

small circle (approximately 5.0 cm in diameter) five

times within the animal’s visual field at a distance of

7.5�/10.0 cm from the animal. Care was taken not to

contact the vibrissa while waving the metallic rod. The

auditory stimulus was a single 114 dB (SPL) click

generated by a clicking device held at mid-body,approximately 5 cm from the subject. The tactile

stimulus was a single caudal-to-rostral stroke through

the vibrissa with a 15 cm Puritan applicator (Harkwood

Products Co., No. 807). Although such stimulation has

a visual component, testing under red light conditions

yielded virtually identical results (Corwin, unpublished).

Three cycles of testing comprised one test session. One

cycle consisted of a single presentation of each of thethree stimuli to each body side in turn. Stimuli were

presented in the order: visual, tactile, and then auditory.

We have found that order of presentation does not

influence performance (Corwin, unpublished). The ex-

perimenter rated the degree of head turning toward or

away from (allesthetic responding) the stimuli as mea-

sured by the position of the tip of the snout over the test

platform markings. A head turn of less than 308 receiveda zero score, between 308 and 458 as 1.0, between 458and 608 as 1.5, and greater than 608 as 2.0. Orientations

later than 2 s after stimulus presentation received a zero

score. Orientations to the visual stimulus after the third

revolution (3 s) received a maximum score of 1.5. The

maximum score for each body side is 6.0 for each of the

three modalities, 18.0 in total. In prior studies, this

rating scale produced an interrator reliability of 1.0 forthe direction of orientation, and above 0.9 for the

magnitude of orientation [10]. The experimenter testing

the animals was blind with respect to the group

affiliation of the subjects.

A total neglect ratio was derived from the formula:

total contralesional responsiveness/total ipsilesional re-

sponsiveness, and collapsed across all modalities

[2,4,10]. The neglect ratio is a measure of relativeresponding to each body side and takes into account

total responsiveness; it indicates asymmetries in orienta-

tion behavior. Neglect ratios were also calculated to

compare the non-neglected to the neglected body side

for the visual, tactile, and auditory modalities. Because

neglect ratios give no indication of whether an asym-

metry in orientation results from lower contralesional

(non-neglect side), or higher ipsilesional (neglect side)scores separate analyses of raw scores for ipsi- and

contralesional responding was conducted to assess pre-

vs. post-manipulation responsiveness [57].

2.5.3. Allesthesia/allokinesia

Responses to the inappropriate side, away from the

side of stimulation (allesthetic responses), were rated

identically. All behavioral testing occurred between07:00 and 19:00 h of the light portion of the 12/12

day�/night cycle.

All LD subjects were tested for neglect 4 h after the

appropriate surgical procedures. As in prior studies, we

used animals with severe neglect: (total contralesional

responsiveness/total ipsilesional responsiveness)5/0.33,

in order to conservatively test the effects of LD [2,4,9].

The time post-injection when neglect is first assessed (4h) was chosen with two concerns in mind: (1) that as

short an interval post-surgery as possible be chosen that

would allow for behavioral assessment of neglect and (2)

severe neglect demonstrated at the first test would

predict severe neglect on subsequent tests. Both these

criteria have been met in previous studies of LD [2,4,9].

Severe neglect at 4 h post-injection has invariably

predicted severe neglect at 48 h post-surgery [2,9]. Inthe AGm and AGm/LSC groups, our criteria for severe

neglect was met by approximately 80% of all operates.

In contrast to prior studies [2,9], we have found that

DCS and AGm/DCS subjects consistently exhibit severe

chronic neglect at 48 h post-surgery regardless of the

severity of neglect during the Pre-LD test at 4 h post-

injection [51]. This may due to the possibility that the

neurotoxicity produced by NMDA requires a longertime course to produce severe neglect. In this study, only

50% of the subjects in the AGm/DCS and DCS groups

demonstrated severe neglect at 4 h post-injection.

2.6. Light deprivation

The environmental manipulation took place in a 3

m�/3 m windowless room. At any one time, one to

three animals were in the experimental room. Care wastaken to ensure that sufficient food and water was given

for the duration of the manipulation. The door was

sealed and all extraneous light was blocked. It was

typical that different groups experienced the environ-

mental manipulation together to prevent order effects.

2.7. Post-LD behavioral testing

2.7.1. Orientation testing

Following the environmental manipulation, the door

to the room was opened, the lights turned on, and the


subjects allowed at least 15 min of adaptation to the

lighted room. After adaptation, the subjects were tested

for neglect in a fashion identical to that described for the

orientation test at 4 h post-injection. Thereafter, allsubjects were kept in the colony under a 12:12 light/dark

cycle. The experimenter was blind with respect to the

subjects’ group affiliation. Subjects were tested twice per

week and the effects of LD on neglect were evaluated for

2 weeks.

2.7.2. Extinction testing

Extinction testing procedures were identical to those

given prior to surgery. Extinction was considered to be a

tendency to touch and/or remove the tab attached to the

ipsilesional wrist before touching and/or removing the

contralesionally applied tab during an individual trial.Therefore, analyses of data on the extinction task took

place on the following measures: (1) frequency of

touching the ipsilesional tab first, (2) frequency of

removing the ipsilesional tab first, (3) frequency of

touching the contralesional tab first, and (4) frequency

of removing the contralesional tab first. Extinction was

assessed on alternate days when the subjects were not

being tested for orientation (neglect) [29]. The experi-menter was blind with respect to the group affiliation of

the subjects.

2.8. Histological procedures

After behavioral testing was completed, the subjects

were given an overdose of sodium pentobarbital (65 mg)

and when totally unresponsive (absence of a corneal

reflex, unresponsiveness to tail pinch, and cessation of

respiration), intracardially perfused with normal saline,

followed by 10% formalin. The brain was removed from

the skull, placed in 10% formalin for at least 3 days, andthen into 30% sucrose�/formalin until the brain sank.

The brain was frozen and sectioned in the coronal plane

at 50 mm. For the AGm operates every tenth section

through the extent of the lesion and every fifth section

through the thalamus was saved, mounted, and stained

with cresyl-violet. All lesions were examined to deter-

mine the extent of damage to adjacent areas and the

AGm. The thalamus was examined for any signs ofcalcification, gliosis, or shrinkage of nuclei. For the

DCS and LSC operates every section through the extent

of the lesion was saved, mounted, and stained with

cresyl-violet. Lesion sizes were measured by tracing the

extent of lesion and areas of gliosis through an image

analysis program (Optimus, BioScan). Lesion extents

were traced onto standard brain diagrams [37]. All

brains were identified by an arbitrary number, and notassociated with a particular group. All histological

processing and analyses were performed prior to the

behavioral analyses in order to assure blindness.

3. Results

3.1. Histology

The histological analysis revealed that the unilateralAGm lesions were virtually identical to those in other

studies of neglect [2,4,10,14,26,56,57]. As indicated in

Fig. 1, in addition to the removal of AGm, typically

there was also some damage to the lateral agranular

cortex, the dorsal cingulate cortex, and the cingulum

bundle.

The size of the unilateral AGm lesions did not differ

among the groups and were virtually identical to thosein prior studies [2,4,9]. Likewise, DCS lesion size was

virtually identical across the groups and was virtually

identical to those in a prior study of the effects of DCS

lesions [50]. The DCS lesions in the AGm/DCS and the

DCS groups destroyed a significant portion of the

projection zone of the Agm; however, there was very

minor damage produced by the injection procedure

itself. The LSC lesions in the AGm/LSC group werevirtually identical in size to the DCS lesions. Image

analysis revealed no significant difference in lesion

extent between the AGm/DCS group and the AGm/

LSC group; therefore, any behavioral differences cannot

be explained by differences in lesion size.

3.2. Neglect

A total neglect ratio was derived from the formula:

contralateral total neglect/ipsilateral total neglect

[2,4,10,50]. The total neglect ratio is a measure of

relative responding to each body side and takes into

account total responsiveness. The data from the five

tests, which included a Pre-LD test (Test 1) and 2 weeks

of post-operative testing (Tests 2�/5), were analyzed. A

Group�/Tests ANOVA comparing the total neglectratios for the AGm [2], DCS, AGm/LSC, AGm/DCS,

and the AGm/LD groups revealed no significant main

effects (all P �/0.05), but did indicate a significant

Test�/Group interaction (F (16,104)�/2.138, P B/

0.012). In order to explore the significant interaction,

individual one-way ANOVAs were done to compare the

groups at each of the five tests. The results, as illustrated

in Fig. 2, indicated significant differences among thegroups for Tests 2�/5 (all P B/0.001). The lack of a

significant difference on Test 1 (Pretest) reflects the

screening for severe neglect found in all but the DCS

groups. Individual comparisons using LSD analyses

revealed that on Test 2, both the DCS and AGm/DCS

groups, despite the absence of Pre-LD neglect, demon-

strated significantly more neglect than both the AGm

and AGm/LD (all P B/0.01), but did not differ fromeach other or the AGm/LSC group (all P �/0.05). On

Tests 3�/5, DCS and AGm/DCS groups demonstrated

significant neglect when compared with the AGm/LD,


AGm, and the AGm/LSC operates (all P B/0.01), but

did not differ from one another. These results indicate

that LD had an immediate and lasting therapeutic effect

in the AGm and AGm/LD groups, which was observed

immediately following LD. In the AGm/LSC group, the

therapeutic effects of LD did not emerge until approxi-

mately 48 h after LD treatment. In contrast, LD did not

induce recovery for neglect produced by unilateral

lesions of the DCS or combined unilateral lesions of

the AGm/DCS. The fact that the AGm/LSC group

demonstrated LD-induced recovery further suggests

that damage to the DCS, and not striatal damage in

general, prevented LD-induced recovery in the DCS and

AGm/DCS groups.

The DCS subjects that received 72 h of LD did not

demonstrate any evidence of behavioral recovery from

severe neglect. The absence of LD-induced recovery in

the DCS and AGm/DCS groups was not due merely to

insufficient duration of exposure to LD because neither

48 h nor 72 h of LD was effective.

Fig. 1. Maximum (dark shading) and minimum (light shading) extents of the lesion for individual subjects in the AGm, DCS, AGm/DCS, AGm/

LSC, AGm/LD, and AGm/noLD groups.


Because LD-induced changes in neglect ratios give no

indication of whether an asymmetry in orientation is

due to an increase in contralesional (neglect side)

responding, a decrease in ipsilesional (non-neglect side)

responding, or both, separate analyses of ipsi- and

contralesional raw scores were conducted. Group�/

Test ANOVAs were done to evaluate possible group

differences in ipsi- and contralesional responsiveness

across tests. For ipsilesional responding, the results

indicated a significant group effect (F (4,30)�/2.862,

P B/0.04). Post hoc analysis indicated that, collapsed

across test, the AGm/DCS and AGm/LSC groups

demonstrated significantly greater ipsilesional respond-

ing than the other groups (all P B/0.03). For contrale-

sional responding, the results indicate a significant

group effect (F (4,30)�/16.665, P B/0.001) and

Group�/Test interaction (F (4,30)�/19.250, P B/

0.001). To further evaluate the Group�/Test interaction

for contralesional responding, one-way ANOVAs were

performed to compare contralesional responding among

groups at each of the five tests. The results, as illustrated

in Fig. 3, indicated significant differences among the

groups for Tests 1�/5 (all P B/0.004). Individual com-

parisons using LSD analyses revealed that for Test 1

(Pre-LD), the DCS group exhibited more contralesional

responding than all other groups (all P B/0.001). As

indicated earlier in Section 2, immediate post-operative

neglect was not exhibited in 50% of the DCS operates.

For Test 2, LSD analysis revealed the following: the

AGm/DCS and the DCS groups demonstrated signifi-

cantly less contralesional responding than the AGm and

AGm/LD groups (all P B/0.001), the AGm/DCS group

demonstrated significantly less contralesional respond-

ing than the DCS and AGm/LSC groups (all P B/0.05),

and the AGm/LSC group exhibited reliably less con-

tralesional responding than the AGm and AGm/LD

groups (all P B/0.02). Finally, on Tests 3�/5, both the

DCS and AGm/DCS groups demonstrated significantly

less contralesional responding than the AGm, AGm/

LSC, and AGm/LD operates (all P B/0.02). Taken

together, the results of the raw scores parallel the resultsof the neglect ratio and indicate that LD produced

dramatic and lasting recovery from severe neglect

induced by unilateral AGm lesions, although delayed

in the AGm/LSC group. LD did not have an effect on

neglect produced by unilateral lesions of the DCS or

combined unilateral lesions of the AGm/DCS. Further-

more, the raw score analyses indicated that recovery

produced by LD was primarily the product of anincrease in contralesional (previously neglected side)

responding, as found in prior studies [2,9]. These results

are also consistent with the findings of Vargo et al. [59],

which indicated that the symmetry of striatal functional

activity, rather than a specific change in the lesioned

hemisphere, was correlated with recovery from neglect.

3.3. Modalities

In order to evaluate the effects of LD on the

individual modalities, individual Group�/Test ANOVA

were done using neglect ratios for the visual, tactile, andauditory modalities. The results are presented graphi-

cally in Fig. 4.

3.3.1. Visual

The analyses of the visual neglect ratios revealed a

significant main effect for group (F (4,29)�/10.556, P B/

0.0001) and a significant Group�/Test interaction

Fig. 2. Mean total neglect ratios in the AGm, DCS, AGm/DCS, AGm/LSC, and AGm/LD groups as a function of test. A ratio of 1.0 represents

symmetrical responding. (') DCS and AGm/DCS groups were significantly different from both the AGm and AGm/LD groups (P B/0.05). (w)

DCS and AGm/DCS groups were significantly different from all other groups (P B/0.01). Error bars represent standard errors.


(F (16,29)�/2.721, P B/0.001). Subsequent one-way AN-

OVAs comparing groups at each level of test revealed

significant differences at Tests 2�/5 (all P B/0.02). Post

hoc LSD analyses comparing the groups revealed that,on Test 2, the AGm/DCS group demonstrated more

severe neglect than the DCS, AGm, and AGm/LD

groups (all P B/0.02), and that the DCS and AGm/

LSC groups demonstrated more severe neglect than the

AGm/LD group (all P B/0.03). For Test 3, the AGm/

DCS and DCS groups exhibited significantly greater

visual neglect than the AGm, AGm/LSC, and AGm/LD

groups (all P B/0.001). The AGm/DCS and the DCSgroups exhibited significantly greater visual neglect than

both the AGm and AGm/LSC groups on Test 4 (all

P B/0.001), but not the AGm/LD group (P �/0.05). On

Test 5, the DCS group exhibited significantly greater

visual neglect than all other groups (all P B/0.01) except

the AGm/DCS group (P �/0.05). In general, the results

of the visual orientation tests indicate that, relative to

AGm/DCS and the DCS groups, LD produced recoveryfrom visual neglect in the AGm, AGm/LSC, and AGm/

LD groups.

3.3.2. Tactile

The Group�/Test analysis of the ratios for tactile

neglect revealed a significant main effect for group

(F (4,17)�/17.371, P B/0.001) and a significant

Group�/Test interaction (F (16,29)�/3.649, P B/

0.0001). Individual one-way ANOVA comparisonsamong the groups at each level of test revealed

significant group differences at Tests 2�/5 (all P B/

0.001). Post hoc LSD analyses comparing the groups

at each test revealed that on Test 2, the AGm/DCS and

DCS groups exhibited significantly greater tactile ne-

glect than both the AGm and AGm/LD groups (all P B/

0.001), but did not differ from each other or the AGm/LSC group (P �/0.05). On Tests 3�/5, the AGm/DCS

and DCS groups exhibited significantly greater tactile

neglect than the AGm, AGm/LSC, and AGm/LD

groups (all P B/0.02), but did not differ from one

another. Overall, these results indicate that relative to

AGm/DCS and the DCS groups, LD produced recovery

from tactile neglect in the AGm, AGm/LSC, and AGm/

LD groups.

3.3.3. Auditory

The Group�/Test analysis for the auditory modality

revealed a significant effect for group (F (4,14)�/8.366,

P B/0.001) and a significant Group�/Test interaction

(F (16,29)�/2.565, P B/0.005). One-way ANOVA ana-

lyses were conducted to examine the differences among

the groups at each of the tests which indicated sig-

nificant group differences on Tests 2�/5 (all P B/0.03).Post hoc LSD analyses revealed that the AGm/DCS and

DCS groups exhibited significantly greater auditory

neglect than the AGm group (P B/0.03), but did not

differ from each other or the AGm/LD or AGm/LSC

groups (all P �/0.05) on Tests 2 and 3. On Test 4, the

AGm/DCS and DCS groups exhibited significantly

greater auditory neglect than the AGm and AGm/LD

groups (P B/0.01), but did not differ from each other orthe AGm/LSC group (P �/0.05). On Test 5, the AGm/

DCS and DCS groups exhibited significantly greater

auditory neglect than both the AGm and AGm/LSC

Fig. 3. Mean contralesional raw scores for the AGm, DCS, AGm/DCS, AGm/LSC, and AGm/LD groups as a function of test. A score of 18.0

represents complete responsiveness across all modalities. (') DCS and AGm/DCS groups were significantly different from both the AGm and AGm/

LD groups (P B/0.001). (w) DCS and AGm/DCS groups were significantly different from all other groups (P B/0.02). (#) DCS is significantly

different from the AGm, AGm/LD, and AGm/LSC groups (P B/0.001). Error bars represent standard errors.


groups (all P B/0.02), but did not differ from each other

or the AGm/LD group (all P �/0.05). Overall, LD was

effective in eliminating severe auditory neglect in the

AGm group, and to a lesser extent the AGm/LSC and

AGm/DCS groups.

In general, the results obtained in the individual

modalities corroborate the findings from the overall

neglect ratio analyses. They also support findings from

prior studies of neglect produced by unilateral AGm

destruction [10,26,56] and unilateral lesions of the DCS

[50,52]. In this study, 48 h of LD was particularly

effective in producing recovery from severe neglect in

the visual and tactile modalities. The failure to find

significant auditory neglect in the AGm/LSC and AGm/

LD groups is not uncommon. Unilateral AGm or DCS

operates may demonstrate some variability of neglect

symptoms within the individual modalities [9,50,52].

3.4. Extinction

3.4.1. Contacts

In order to examine the potential differences in

frequency of initial contact, a Group�/Test�/Response

(ipsi- and contralesional) ANOVA was done. The resultsrevealed a main effect for response (F (1,29)�/18.002,

P B/0.001) and an insignificant effect for group

(F (4,29)�/1.783, P �/0.05). Significant Group�/Re-

sponse (F (4,29)�/5.341, P B/0.002) and Test�/Re-

sponse (F (6,29)�/17.421, P B/0.001) interactions were

also obtained.

In order to examine the Group�/Response interac-

tion, individual analyses were done to examine groupdifferences for each side of response (ipsi- and contrale-

sional). For ipsilesional contacts, there was no signifi-

cant effect of group (F (4,29)�/2.585, P �/0.05). In

Fig. 4. Individual modality neglect ratios in the AGm, DCS, AGm/DCS, AGm/LSC, and AGm/LD groups as a function of test. A ratio of 0.0

represents symmetrical responding. (w) DCS and AGm/DCS groups were significantly different from all other groups (P B/0.02). (') DCS and

AGm/DCS groups were significantly different from both the AGm and AGm/LD groups (P B/0.01). Error bars represent standard errors. (#) DCS is

significantly different from the AGm, AGm/LD, and AGm/LSC groups (P B/0.05). (*) DCS and AGm/DCS groups were significantly different from

the AGm group (P B/0.05). (^) AGm/DCS group is significantly different from the DCS, AGm, and AGm/LD groups (P B/0.02), and that the

AGm/LD group is significantly different from the DCS and AGm/LSC groups (P B/0.03). (�/) DCS and AGm/DCS groups were significantly

different from the AGm and AGm/LSC groups (P B/0.02). Error bars represent standard errors.


contrast, a significant group effect was obtained for

contralesional contacts (F(4,29)�/7.162, P B/0.001).

Pairwise comparisons revealed that the frequency of

contacting the contralesional tab first was significantly

greater in the DCS operates when compared with all

other groups (all P B/0.007), reflecting the absence of an

extinction deficit. In addition, it was also found that the

AGm/LSC group exhibited significantly fewer contrale-

sional contacts than the AGm/noLD group (P B/0.04).

No other differences were detected among the AGm/

noLD, AGm/DCS, AGm/LSC, and AGm/LD groups

(all P �/0.05).

To evaluate the Test�/Response interaction, separate

comparisons were done for ipsi- and contralesional

contacts collapsed across group. The results indicated

that both ipsilesional (F (6,24)�/6.378, P B/0.017) and

contralesional (F (6,24)�/16.701, P B/0.0001) initial

contacts changed significantly over tests. Pairwise com-

parisons revealed the frequency of contacting the

contralesional tab was greater for Test 1 (Pretest) than

Tests 2�/7 (all P B/0.0001). For ipsilesional contacts, the

frequency on Test 1 (Pretest) was significantly smaller

than Tests 2�/7 (all P B/0.0001).

Analyses of the Test�/Response interaction indicated

that when groups are analyzed together, all operates

displayed a significant increase in ipsilesional contacts

and significant decrease in contralesional contacts after

surgery. However, the Group�/Response interaction

revealed that the DCS operates, unlike the other groups,

did not change their preoperative contralesional paw

preference and thus displayed significantly more con-

tacts to the contralesional side than the other groups.

Taken together, the results suggest that all groups,

except the DCS, exhibited a post-surgical change in

contact paw preference, indicative of an extinction

deficit.

Fig. 5. (A) Mean frequency of contralesional contacts in the AGm, DCS, AGm/DCS, AGm/LSC, AGm/LD, and AGm/noLD groups as a function

of test. The maximum number of potential contacts is 5.0. With the exception of the DCS group, all groups demonstrated a significant and lasting

reduction in the frequency of contralesional contacts. Error bars represent standard errors. (B) Mean frequency of contralesional removals in the

AGm, DCS, AGm/DCS, AGm/LSC, AGm/LD, and AGm/noLD groups as a function of test. The maximum number of potential removals is 5.0.

With the exception of the DCS and AGm/DCS groups, all groups demonstrated a significant and lasting reduction in the frequency of contralesional

removals. Error bars represent standard errors.


In order to determine whether individual groups

displayed a change in paw preference for contact, a

series of within-subject analyses were done which

separately examined contra- and ipsilesional frequencyof contact for each group across tests. With regard to

ipsilesional tab contacts, the AGm/noLD, AGm/LD,

AGm/DCS, and AGm/LSC groups demonstrated a

significant test effect (all P B/0.02). In these groups,

paired sample t-tests were done to compare Test 1

(Pretest) to subsequent Post-LD tests. For the AGm/

noLD group, the results indicated that Test 1 differed

significantly from Tests 2, 3, 4, and 6 (all P B/0.03); anindication that ipsilesional tab contact increased follow-

ing the AGm lesion. In a similar fashion, the AGm/DCS

group significantly increased ipsilesional contacts on

Tests 2 and 3, as did the AGm/LSC group on Test 3 (all

P B/0.01). For the DCS group, the analysis revealed no

significant change in ipsilesional contacts.

The analysis for the contralesional contacts revealed a

significant test effect for the AGm/noLD, AGm/LD,AGm/DCS, and AGm/LSC groups (all P B/0.008). As

seen in Fig. 5A, the analyses comparing Test 1 with the

subsequent tests showed that the AGm/noLD, AGm/

LD, AGm/DCS, and AGm/LSC lesions produced a

significant decrease in contacts to the contralesional

preoperatively preferred paw on Tests 2�/7 (all P B/

0.04). Taken together, the within-subject analyses in-

dicated that all groups except the DCS group demon-strated extinction post-surgically, as evidenced by a

significant increase in ipsilesional contacts and a sig-

nificant decrease in contralesional contacts. Further,

results from this study support recent findings from our

lab which demonstrate that DCS lesions alone do not

produce extinction [52].

3.4.2. Removals

A Group�/Test�/Response (ipsi- and contralesional)ANOVA was done to examine the pattern of tab

removals. The results indicated that there were no

significant main effects (all P �/0.23), but there was a

significant Test�/Response (F (6,150)�/8.372, P B/

0.0001) interaction. The Response�/Group interaction,

although not significant, was noteworthy (F (4,25)�/

2.686, P B/0.054).

In order to evaluate the Test�/Response (ipsi- andcontralesional) interaction, individual comparisons were

done for ipsi- and contralesional removals collapsed

across group. The results indicated that both ipsilesional

(F (6,24)�/10.344, P B/0.0001) and contralesional

(F (6,24)�/8.996, P B/0.0001) removals changed signifi-

cantly over the duration of testing. Follow-up compar-

isons revealed that when, collapsed across all groups,

Test 1 differed significantly from Tests 2�/7 for bothipsilesional (all P B/0.005) and contralesional (all P B/

0.008) removals. These results suggest that, when

collapsed across all groups, there was a significant

increase in ipsilesional removal and a significant de-

crease in contralesional removal after surgery.

In order to compare more directly ipsi- and contrale-

sional removals, additional within-subject analyses weredone to separately examine contra- and ipsilesional

responses for each group across the tests. With regard

to ipsilesional tab removals, only the AGm/DCS and

AGm/LD groups demonstrated a significant test effect

(all P B/0.049). Paired sample t-tests comparing Test 1

(Pretest) to subsequent post-surgical tests indicated that

the number of Pretest ipsilesional tab removals in both

the AGm/LD and AGm/DCS groups significantlyincreased on post-surgical Tests 2, 3, 4, 6, and 7 (all

P B/0.04).

With regard to the contralesional tab removals, the

AGm/noLD, AGm/LD, and AGm/DCS groups demon-

strated a significant test effect (P B/0.002). Paired

sample t -tests comparing Test 1 (Pretest) to subsequent

post-surgical tests indicated that the number of con-

tralesional tab removals in the AGm/noLD, AGm/LD,and AGm/DCS lesion groups decreased post-surgically

(all P B/0.04). Overall, the removal within-subject

analyses indicated that the AGm/DCS, AGm/LD, and

AGm/noLD groups exhibited significant extinction, as

evidenced by a significant change in paw preference

post-surgery. The AGm/DCS and AGm/LD groups

demonstrated a significant increase in ipsilesional re-

movals and a significant decrease in contralesionalremovals post-surgically. The AGm/noLD groups also

demonstrated a significant decrease in contralesional

responding post-surgery (see Fig. 5B). The results also

corroborate the findings from the contact analyses. The

failure of the AGm/LSC group to demonstrate any

significant change in ipsi- or contralesional removals is

likely due to a somewhat lower pretest removal

frequency in this group, as illustrated in Fig. 5B.

3.5. Allesthesia/allokinesia

Responses to the inappropriate side, away from the

side of stimulation (allesthetic/allokinetic responses),

were rated identically to appropriate orientations.

Because of the large number of zero scores, the total

number of allesthetic responses for the ipsi- and

contralesional sides were compared across the initialfive tests for each of the five groups using a Wilcoxon

Signed-Ranks test. There were no significant differences

between ipsi- and contralesional allesthesia/allokinesia

responding in any of the groups (all P �/0.05).

3.6. Circling

Wilcoxon Signed-Ranks tests were conducted tocompare the amount of ipsilesional vs. contralesional

circling in the five groups. The analyses of circling

behavior revealed no significant differences between


ipsi- and contralesional circling within any of the groups

(all P �/0.05). Thus, any neglect or extinction deficits

cannot be explained by a circling bias or postural

asymmetries [44].

4. Discussion

Crowne et al. [14,15] found that animals that experi-

enced eye closure or 48 h of LD did not demonstrate

neglect following unilateral AGm lesions. In both

studies, LD was effective in producing virtually com-

plete sparing from AGm-induced neglect. Further, theywere able to demonstrate that the sparing of function

was due to the therapeutic effects of LD and not the

result of auditory or activity changes in the colony [15].

Similarly, LD has also been found to produce sparing

and recovery of function from sensory motor deficits

produced by lesions of the lateral hypothalamus [21,42].

However, LD was not effective in producing sparing of

neglect induced by unilateral lesions of the superiorcolliculus [15]. Corwin and Vargo [9] extended the

findings of Crowne et al. on sparing of function

[14,15] by demonstrating that LD can produce dramatic

recovery from severe neglect if administered within 4 h.

Most recently, Vargo et al. [59] have suggested that the

crucial site for LD-induced recovery may be the

dorsolateral striatum, by demonstrating that recovery

was correlated with alterations in functional activity inthis region.

The results of this study extend these findings and

indicate that the striatal projection zone of the AGm,

the DCS, may be a crucial site within the dorsolateral

striatum for the mechanisms of LD-induced recovery

from neglect induced by unilateral AGm destruction.

Combined unilateral destruction of the AGm/DCS

prohibited recovery, whereas combined unilateralAGm/LSC lesions equivalent in size, but outside of the

projection zone of AGm did not prohibit the therapeutic

effects of LD on severe neglect. These findings support

prior studies which indicate that the DCS may play a

critical role in recovery from neglect induced by

unilateral AGm lesions. In studies examining sponta-

neous recovery, AGm-induced neglect and recovery

were correlated with changes in immediate gene expres-sion in the dorsolateral striatum [54]. In a subsequent

study, Vargo and Marshall [55] found that changes in

NMDA and kainate receptors in this same region were

correlated with spontaneous recovery from AGm-in-

duced neglect. Recent observations also support the role

of the DCS in acute drug-induced recovery from neglect.

Systemic administration of apomorphine has been

found to produce acute recovery from AGm lesion-induced neglect [10,26]. The likely site of action for the

therapeutic effects of apomorphine is the DCS [49].

Direct infusion of apomorphine into the DCS in rats

with severe neglect produced by AGm lesions produced

virtually the same therapeutic effects as systemic injec-

tions [49]. Infusion into the more lateral striatum did not

produce a therapeutic effect [49]. Further, it has beendemonstrated that apomorphine is ineffective in produ-

cing recovery from severe neglect in unilateral DCS

operates [50]. These findings on the role of the DCS in

spontaneous and drug-induced recovery, when taken

together with the present results, indicate that the

integrity of the DCS may be necessary for recovery

from AGm-induced neglect.

Recent anatomical findings in rats indicate that theDCS is a convergence zone for projections from cortical

association areas including the AGm, PPC, and the

ventrolateral orbital cortex [5,39]. Damage to any one of

these interconnected cortical regions produces neglect

and deficits in spatial processing [2,4,8,11,14,15,26�/29].

In addition, the DCS has been implicated as a multi-

modal convergence region of striatum [35]. Previous

work in primates has also suggested that interconnectedcortical areas, that have been implicated in spatial and

attention behavior, are likely to have converging corti-

costriatal projections [36,46]. The importance of corti-

costriatal relationships in rats has also been implicated

in attentional deficits following bilateral lesions of

striatum [41], or via disconnection studies [6].

A second major finding of this study is that the

therapeutic effects of LD do not extend to extinction. Inthe same subjects that demonstrated recovery from

neglect as a result of exposure to LD, there was no

evidence that the effects generalized to extinction. For

example, the AGm and AGm/LSC groups demonstrated

dramatic LD-induced multimodal recovery from severe

neglect by the second test after LD, but a severe

extinction deficit was unaffected. These findings

strongly suggest that deficits associated with the neglectsyndrome likely have distinct or dissociable anatomical

and pharmacological substrates [47,48,52], and that the

eventual treatment of these components of the neglect

syndrome will be quite complex [25]. Recent pilot data

from our laboratory supports this contention by de-

monstrating that apomorphine produces a therapeutic

effect on neglect but not extinction in rats with

unilateral AGm lesions (Pyter et al., unpublished).These findings provide support for the dissociation of

neglect symptoms as found in an earlier study, which

compared the effects of rostral and caudal AGm lesions.

Unilateral destruction of the rostral AGm produced

significant allesthesia/allokinesia without severe neglect,

whereas caudal AGm lesions produced severe neglect

without significant allesthesia [26]. Taken together, these

studies suggest that the rat model may be useful fordetermining the neural substrates, which underlie the

specific deficits that comprise the neglect syndrome.

The present findings have potential relevance for the

treatment of neglect. Behavioral treatments rarely gen-


eralize outside of the therapeutic context or across tasks

within the same therapeutic context [13,40]. Based on

findings from rodent models of neglect, drugs have been

administered to patients, but only those with chronicneglect and stable behavioral baselines because of the

concern that drug effects may interfere with ongoing

recovery [17,19,24]. Fleet et al. [17] and Hurford et al.

[24] examined the effects of bromocriptine, a D2

receptor agonist, in patients with chronic neglect.

Bromocriptine produced recovery across a range of

measures, and when treatment was terminated, neglect

worsened. Recently, Geminiani et al. [19] found thatapomorphine can also produce acute recovery from

neglect in humans. While some hope is raised by these

studies, the specific mechanism or site of action to

account for these effects was unknown.

The evidence discussed above strongly suggests that

the DCS plays a crucial role in neglect induced by

cortical lesions, and that the DCS may be the critical site

for the mechanisms leading to spontaneous recovery[50,54,55], the therapeutic effects of DA receptor

agonists [49], and LD-induced recovery [59] in rodents.

The results of these studies further our understanding of

the role of DCS as a crucial site in a cortical�/subcortical

network which mediates directed attention, and within

which the dynamic changes that lead to recovery from

neglect may occur. Further, these results may help to

provide a rational basis for the therapeutic administra-tion of drugs or environmental manipulations in neglect

patients. The finding that LD does not have a ther-

apeutic effect on extinction points to the need for a more

detailed understanding of the neural substrates, which

underlie extinction. This is particularly compelling

because many patients that recover from neglect still

exhibit extinction deficits [25].

Acknowledgements

The authors wish to express their appreciation to

Kevin Harris for help with the histological processing

and behavioral testing. This work was supported by the

NIMH grant MH60399.

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