On the Functional Neuroanatomy of Intrinsic and Phasic Alertness

Wal ter Sturm

1
and Kl aus Wi l l mes
Department of NeurologyNeuropsychology, Medical Faculty of theRWTH Aachen, D-52074 Aachen, Germany
Recei ved November 24, 2000
Intrinsic and phasic alertness are the most basic
aspects of attention intensity probably constituting
the basis for the more complex and capacity-demand-
ingaspects of attention selectivity. Intrinsic alertness
represents the cognitive control of wakefulness and
arousal and is typically assessed by simple reaction
time tasks without a preceding warning stimulus.
Phasic alertness, in contrast, is called for in reaction
time tasks in which a warning stimulus precedes the
target, and it represents the ability to increase re-
sponse readiness subsequent to external cueing. We
report PET andfMRI datafromboththeliteratureand
our ownexperimentstodelineatethecortical andsub-
cortical networks subserving alertness, sustained at-
tention (as another aspect of attention intensity), and
spatial orientingof attention. Irrespectiveof stimulus
modality, there seems to exist a mostly right-hemi-
spheric frontal, parietal, thalamic, andbrain-stemnet-
work which is coactivated by alerting and orienting
attentional demands. Thesendings corroborateboth
the hypothesis of a frontal modulation of brain-stem
activation probably via the reticular nucleus of the
thalamus and of a coactivation of the posterior atten-
tion systeminvolved in spatial orienting by the ante-
rior alerting network. Under conditions of phasic
alertnessthereareadditional activationsof left-hemi-
spherefrontal andparietal structureswhichareinter-
preted as basal aspects of attention selectivity rather
than additional features of alerting. 2001 Academic Press
Key Words: alertness; sustained attention; vigilance;
attention; PET; fMRI.
INTRODUCTION
I n accordance wi th attenti onal theori es by Posner
and Boi es (1971), Posner and Rafal (1987), and Van
Zomeren and Brouwer (1994), attenti on can be subdi -
vi ded i nto two broad domai ns, one representi ng i nten-
si ty aspects, i .e., al ertness and sustai ned attenti on, the
other sel ecti on aspects, i .e., focussed and di vi ded atten-
ti on. The i ntensi ty aspects probabl y are a prerequi si te
for the more compl ex and capaci ty-demandi ng di men-
si ons of attenti on sel ecti vi ty (Sturm et al., 1997).
Wi thi n the theoreti cal concepts menti oned above
al ertness compri ses on the one hand a state of general
wakeful ness (toni c arousal or toni c al ertness) wi th a
characteri sti c ci rcadi an vari ati on and on the other
hand the abi l i ty to i ncrease response readi ness for a
short peri od of ti me subsequent to external cues or
sti mul i (phasi c al ertness). Moreover, i n the absence of
an external cue, the l evel of al ertness can be modul ated
i n a topdown mode i n sel f-i ni ti ated preparati on for a
subsequent response to an expected sti mul us (Sturm et
al., 1999). Some authors have dened even such short
peri ods of endogenousl y mai ntai ni ng vi gi l ant respond-
i ng as sustai ned attenti on (cf. Robertson et al., 1997).
More often, sustai ned attenti on and vi gi l ance have
been dened as the abi l i ty to mai ntai n a certai n l evel of
arousal and al ertness whi ch requi res mental effort and
al so topdown control of attenti on. The di fference be-
tween sustai ned attenti on and vi gi l ance i s seen i n the
frequency wi th whi ch cri ti cal /target sti mul i are pre-
sented and have to be responded to. Under vi gi l ance
condi ti ons, cri ti cal sti mul i have a very l ow frequency of
occurrence, thus resul ti ng i n extremel y monotonous
si tuati ons whi ch pose hi gh demands on vol i ti onal (up)
regul ati on of a certai n attenti onal l evel . The term sus-
tai ned attenti on i s used i n a more general way, com-
pri si ng al l si tuati ons that cal l for a prol onged state of
sti cki ng to a task wi th consi derabl y more frequent
i mperati ve sti mul i than under vi gi l ance condi ti ons.
A typi cal task for the assessment of i ntri nsi c (and
toni c) al ertness i n the sense of a general l evel of re-
sponse readi ness compri ses si mpl e reacti on ti me (RT)
measurements to vi sual , audi tory, or somatosensory
sti mul i . I n thi s way, an opti mal l evel of arousal has to
be mai ntai ned for a rather short ti me i nterval of some
mi nutes. Phasi c al ertness i s requi red whenever a
warni ng sti mul us i n the same or a di fferent sensory
modal i ty precedes the target sti mul us. Sustai ned at-
tenti on i n contrast to al ertness tasks typi cal l y do not
focus on pure speed of response but rather on the
1
To whom correspondence and repri nt requests shoul d be ad-
dressed at Neurol ogi cal Cl i ni c, Uni versi ty Hospi tal RWTH Aachen,
Pauwel sstrasse 30, D-52074 Aachen, Germany. Fax: 49 241 8888
444. E-mai l : sturm@neuropsych.rwth-aachen.de.
NeuroI mage 14, S76S84 (2001)
doi :10.1006/ni mg.2001.0839, avai l abl e onl i ne at http://www.i deal i brary.com on
S76
1053-8119/01 $35.00
Copyri ght 2001 by Academi c Press
Al l ri ghts of reproducti on i n any form reserved.
number of hi ts, mi sses (and fal se al arms), and thei r
ti me course.
NEUROPSYCHOLOGY OF ALERTNESS
Lesi on studi es i n stroke pati ents have shown an
i mportant contri buti on of the ri ght hemi sphere i n sub-
servi ng al ertness. Howes and Bol l er (1975), Posner et
al. (1987), and Ladavas (1987) have found a dramati c
i ncrease i n si mpl e vi sual and audi tory RT subsequent
to ri ght-hemi sphere (RH) l esi ons. Neverthel ess, Posner
et al. (1987) as wel l as Tartagl i one et al. (1986) have
shown that RH pati ents do prot from a warni ng sti m-
ul us. Thi s i ndi cates that i t i s the i ntri nsi c and not the
phasi c aspect of al ertness whi ch i s i mpai red after RH
l esi ons.
Furthermore, studi es usi ng l ateral i zed sti mul us pre-
sentati on i n heal thy subjects (Di mond and Beaumont,
1973; Hei l man and Van den Abel l , 1979; Sturm et al.,
1989) and i n spl i t-brai n pati ents (Di mond, 1979) cor-
roborate the assumpti on that the ri ght hemi sphere
pl ays a cruci al rol e i n mai ntai ni ng and control l i ng i n-
tensi ty aspects of attenti on. From l esi on studi es i n rats
there i s evi dence for a RH bi as i n the noradrenergi c
(NA) system (Robi nson, 1979, 1985), ori gi nati ng i n the
l ocus coerul eus and projecti ng most strongl y to frontal
areas. These studi es support the hypothesi s that there
al so exi sts topdown regul ati on of thi s noradrenergi c
acti vati on by the ri ght frontal cortex si nce l esi ons i n
thi s area l ed to a si gni cant decrease of NA i n both
hemi spheres and i n the l ocus coerul eus (Robi nson and
Coyl e, 1980). I n a PETstudy on the effects of cl oni di ne,
an 2-adrenoceptor agoni st and noradrenal i ne antag-
oni st, on acti vati on duri ng a rapi d vi sual i nformati on
processi ng task, Coul l and co-workers (1997) found,
under cl oni di ne, a decrease of acti vati on i n the ri ght
thal amus and bi l ateral l y i n the superi or frontal and
i nferi or pari etal cortex but an i ncrease i n the ri ght
anteri or ci ngul ate. I t seems that under the i nuence of
cl oni di ne the subjects needed more effort to cope wi th
the demands of the cogni ti ve task, whi ch mi ght cal l for
a hi gher i nternal cogni ti ve control of arousal . Posner
and Petersen (1990) propose a RH NA al erti ng network
i nvol vi ng the l ocus coerul eus as the ori gi n of the NA
system (Aston-Jones et al., 1984) as wel l as the frontal
areas, but al so i nvol vi ng spreadi ng acti vati on to the
pari etal cortex. Accordi ng to Fernandez-Duque and
Posner (1997) the al erti ng network seems to coacti vate,
ei ther di rectl y or vi a the brai n stem, the posteri or
attenti on system i n the pari etal cortex i nvol ved i n spa-
ti al ori enti ng of attenti on (Posner and Petersen, 1990).
I nteracti ons between the anteri or and the posteri or
attenti on systems have al so been i mpl i ed by Robertson
et al. (1995), who found that sustai ned attenti on trai n-
i ng, whi ch woul d i nvol ve the anteri or attenti on system,
l eads to i mprovement on tests of uni l ateral negl ect. I n
both studi es i t i s suggested that the anteri or, sustai ned
attenti on system mi ght hel p pati ents i n compensati ng
for deci ts i n the posteri or ori enti ng system.
NEUROIMAGING STUDIES OF ALERTNESS
AND SUSTAINED ATTENTION
I n the rst i magi ng study whi ch expl i ci tl y addressed
the i ssue of al ertness, Ki nomura et al. (1996) exami ned
10 heal thy subjects i n a PETexperi ment. The RTtasks
requi red ri ght thumb presses of a response key to a
si mpl e vi sual and a somatosensory sti mul us. When
contrasti ng both acti vati on tasks wi th a rest condi ti on,
si gni cant rCBF i ncreases were found i n the mesence-
phal i c tegmentum, i ncl udi ng the mesencephal i c reti c-
ul ar formati on, and i n the l eft i nterl ami nar thal ami c
regi on. These acti vati ons were si mi l ar for both sti mu-
l us modal i ti es.
A corti cal and subcorti cal , mostl y ri ght-hemi sphere
network for i ntri nsi c al ertness was reveal ed i n a PET
study by Sturm and co-workers (1999). Under the
al ertness condi ti on, subjects had to make rapi d ri ght
thumb presses to a si mpl e, central l y presented whi te
dot on a computer moni tor. The sensori motor control
condi ti on compri sed passi ve watchi ng of a whi te dot
i ckeri ng rapi dl y just bel ow the i ndi vi dual s i cker
fusi on frequency and an automati c, regul ar pressi ng of
a response key wi th the ri ght thumb. The subtracti on
i mage of the two condi ti ons showed ri ght-hemi sphere
acti vati on i n the anteri or ci ngul ate gyrus, i n the dor-
sol ateral frontal cortex, i n the i nferi or pari etal l obul e,
i n the mi ddl e and superi or temporal gyrus, i n the ri ght
thal amus, and i n the dorsal pontomesencephal i c teg-
mentum.
For an i nterpretati on of the ndi ngs, we have pro-
posed a network i n whi ch the anteri or ci ngul ate gyrus
and the dorsol ateral frontal cortex i ntri nsi cal l y control
the brai n-stem NA acti vati on system vi a the reti cul ar
nucl eus of the thal amus. A comparabl e frontal control
system was suggested by Gui l l ery et al. (1998) as wel l
as by Stuss and Benson (1986) for the control of sel ec-
ti ve attenti on.
A very si mi l ar ri ght-hemi sphere corti cal and subcor-
ti cal network was acti vated i n a PET study (n 10
normal subjects) of i ntri nsi c al ertness wi th audi tory
sti mul ati on, usi ng a 1000-Hz tone si gnal as the target
sti mul us (Wei s et al., 2000). Otherwi se the experi men-
tal set-up was i denti cal to that of our study on vi sual
i ntri nsi c al erti ng. There was ri ght-hemi sphere acti va-
ti on i n the dorso- and ventrol ateral frontal cortex, i n
the anteri or ci ngul ate gyrus, i n the i nferi or temporal
gyrus, as wel l as i n the thal amus (cf. Fi g. 1). Wi th a
more l i beral voxel wi se si gni cance l evel of 5% there
was al so a smal l brai n-stem acti vati on i n the pon-
tomesencephal i c regi on. The si mi l ari ty of acti vati on
patterns under vi sual or audi tory sti mul ati on makes a
supramodal ri ght-hemi sphere network for the control
of i ntri nsi c al erti ng probabl e.
S77 I NTRI NSI C AND PHASI C ALERTNESS
S78 STURM AND WI LLMES
When the same task was gi ven to 5 of these 10
subjects under a phasi c al ertness condi ti on wi th a vi -
sual , central l y presented warni ng sti mul us, appeari ng
for 400 ms randoml y wi thi n 1001000 ms before the
audi tory target sti mul us, a more extended acti vati on
pattern compared to the i ntri nsi c al ertness condi ti on
was reveal ed (cf. Fi g. 2, l eft). There were addi ti onal
acti vati ons i n the thal amus as wel l as i n the superi or
and ventrol ateral frontal gyrus of the l eft hemi sphere.
I n a further experi ment on phasi c al erti ng conducted
wi th the remai ni ng ve subjects, both the target and
the warni ng sti mul us were gi ven audi tori l y. The warn-
i ng sti mul us was a 200-Hz tone si gnal l asti ng for 400
ms, agai n gi ven 1001000 ms before the target. Under
thi s condi ti on, the ri ght- and l eft-hemi sphere network
found under the vi sual warni ng condi ti on was obtai ned
agai n (cf. Fi g. 2, mi ddl e).
Addi ti onal l y, i n the ri ght-hand part of Fi g. 2, a con-
juncti on anal ysi s over the two phasi c al ertness condi -
ti ons (vi sual and audi tory warni ng) i s presented. The
same ri ght- and l eft-hemi sphere pattern of acti vati ons
seen i n the l eft and mi ddl e of Fi g. 2 shows up agai n,
l endi ng further support to the si mi l ari ty of acti vati on
areas under both warni ng condi ti ons.
We i nterpret the more extended ri ght-hemi sphere
network under the phasi c al erti ng condi ti ons to be a
consequence of the extri nsi c acti vati on by the warn-
i ng sti mul us. The addi ti onal l eft frontal acti vati on i s
consi dered to be an i ndi cati on of el ementary attenti on
sel ecti vi ty, si nce under the phasi c al ertness condi ti on
responses to the warni ng sti mul us have to be i nhi bi ted
i n an acti ve way. Thi s ndi ng i s congruent wi th the
observati on that, after l eft-hemi sphere l esi ons, pa-
ti ents present wi th choi ce reacti on deci ts (Dee and
van Al l en, 1973) and show sl owed down responses after
a warni ng i n a phasi c al ertness task (Tartagl i one et al.,
1986).
The di sti ncti on between i ntri nsi c (nonphasi c) al ert-
ness and sustai ned attenti on i s not cl ear-cut i n the
PET l i terature. Some authors, i n contrast to contem-
porary taxonomi es of attenti onal functi ons, have de-
ned even short peri ods of endogenousl y mai ntai ni ng
vi gi l ant respondi ng as sustai ned attenti on. I n these
tasks, subjects have to moni tor frequent occurrences of
certai n sti mul i . The total number of hi ts and mi sses for
these sti mul i i s taken as the pri mary dependent vari -
abl e. Usual l y, these tasks do not stress speed of re-
sponse as tasks of al erti ng typi cal l y do. PET (Cohen et
al., 1988; Pardo et al., 1991) and fMRI studi es (Lewi n et
al., 1996) usi ng thi s ki nd of sustai ned attenti on tasks
have reveal ed a frontopari etal network for the vi sual
and somatosensory modal i ty. Subjects had to moni tor
i rregul arl y appeari ng events such as the attenuati on of
a central l y presented l i ght source or the short-term
i nterrupti on of an otherwi se conti nuous tacti l e sti mu-
l us, and they had to count these events.
Paus and co-workers (1997) coul d demonstrate that
the same network as descri bed for al ertness tasks was
al so acti ve i n the mai ntenance of a certai n attenti onal
l evel i n a cl assi cal audi tory vi gi l ance task l asti ng for 60
mi n. Every 2 s, the subjects were presented a tone
si gnal l asti ng for 1 s. I n onl y 5% of these si gnal s there
was a drop i n the i ntensi ty of the tone at the end of the
si gnal to whi ch subjects had to respond as qui ckl y as
possi bl e vi a a response key wi th thei r ri ght i ndex n-
ger. Every 10 mi n rCBF was measured for 60 s and,
addi ti onal l y, the EEG was regi stered. The authors
found an i ncrease i n reacti on ti me and of acti vi ty i n
the EEG over ti me whi ch correl ated wi th the decrease
of the l evel of neural acti vi ty i n the thal amus, the ri ght
ventro- and dorsol ateral frontal cortex, and the pari -
etal and the temporal cortex. The l evel of acti vati on
decrease over ti me i n the thal amus covari ed wi th the
l evel of acti vi ty i n the ri ght pontomesencephal i c teg-
mentum, the anteri or ci ngul ate, and the substanti a
i nnomi nata. Coul l and co-workers (1996) i n another
PET study on sustai ned attenti on found si mi l ar acti -
vati ons for corti cal and thal ami c structures. Agai n, the
speci c rol e of the frontal and pari etal cortex i n sus-
tai ned attenti on was poi nted out. The fact that acti va-
ti on i n these two areas decreased over ti me onl y for a
nonsel ecti ve attenti on task and not for a sel ecti ve task
was i nterpreted as a functi onal modul ati on of sel ecti ve
by sustai ned attenti on.
I n practi cal l y al l al ertness and sustai ned attenti on
studi es there al so was an acti vati on of the ri ght i nfe-
ri or pari etal cortex i n addi ti on to the ri ght frontal and
subcorti cal acti vati ons al though the al ertness tasks
di d not requi re a spati al shi ft of attenti on. Thi s obser-
vati on of an i nferi or pari etal acti vati on can be i nter-
FIG. 1. Adjusted mean rCBF i n young mal e ri ght-handed subjects (n 10) for i ntri nsi c al ertness (audi tory sti mul ati on) mi nus combi ned
sensory and motor control task. Regi ons compri si ng at l east k 20 voxel s, each wi th P 0.01; projecti on on 3D templ ate i n SPM96. (Data
acqui si ti on: GE PC4096 Pl us scanner, [
15
O]butanol , 6 scans. Per scan: start of task 30 s before i njecti on, 40 s si ngl e ti me frame, reconstructed
i mage resol uti on 9 mm FWHM, 15 transverse sl i ces 6.5 mm apart. I mage processi ng: reconstructed PETdata converted to ANALYZE format
(Robb, 1991), al l scans normal i zed i nto the standard stereotaxi c anatomi cal space of the atl as by Tal ai rach and Tournoux (1988), i mages
smoothed wi th a Gaussi an l ter of 15 15 15 mm. Data anal ysi s: SPM96 (Fri ston et al., 1995a,b).)
FIG. 2. (Left) Resul ts of SPM96 anal ysi s i n young mal e ri ght-handed subjects (n 5) for phasi c al ertness (audi tory target, vi sual
warni ng) mi nus combi ned sensory and motor control task. Regi ons compri si ng at l east k 20 voxel s, each wi th P 0.01. (Mi ddl e) Resul ts
of SPM96 anal ysi s i n young mal e ri ght-handed subjects (n 5) for phasi c al ertness (audi tory target, audi tory warni ng) mi nus combi ned
sensory and motor control task. Regi ons compri si ng at l east k 20 voxel s, each wi th P 0.01. (Ri ght) Conjuncti on anal ysi s of both phasi c
al ertness tasks (vi sual or audi tory warni ng) for the contrasts depi cted i n Fi gs. 3 and 4.
S79 I NTRI NSI C AND PHASI C ALERTNESS
preted as a coacti vati on of the posteri or attenti on sys-
tem by the anteri or al erti ng network as suggested by
Fernandez-Duque and Posner (1997). Thi s i nterpreta-
ti on can al so be used to expl ai n why i n ri ght-hemi -
sphere-l esi oned pati ents i mpai rments of i ntensi ty as-
pects of attenti on and persi sti ng negl ect symptoms are
frequentl y associ ated cl osel y.
Thi s cl ose si mi l ari ty between ori enti ng and al erti ng
networks was demonstrated i n an fMRI -study by
Achten and co-workers (1999). I n 10 normal subjects a
covert vi sual -ori enti ng task (respondi ng to the onset of
vi sual targets presented randoml y at an unpredi ctabl e
l ocati on i n both vi sual el ds whi l e xati ng a central
square) and an al ertness task (respondi ng to the same
targets, but now presented central l y i nsi de the xati on
square) were gi ven. Contrasti ng the two tasks wi th a
rest condi ti onputti ng asi de motor and pri mary vi -
sual acti vati onsdemonstrated acti vati on cl usters i n
dorsol ateral prefrontal regi ons, i n the anteri or ci ngu-
l ate gyrus, i n the superi or and i nferi or pari etal cortex
as wel l as i n the superi or temporal gyrus, and i n the
thal amus (top l eft and mi ddl e of Fi g. 3). For both tasks,
these acti vati on foci were stronger i n the ri ght hemi -
sphere.
Compared to the al ertness condi ti on, the task of
covert ori enti ng of attenti on i nduced stronger bi l ateral
acti vati ons i n occi pi tal vi sual areas and i n regi ons of
the superi or pari etal cortex as wel l as some smal l ad-
di ti onal acti vati ons i n the ri ght mi ddl e frontal gyrus
(Fi g. 3, top ri ght). A conjuncti on anal ysi s for the spati al
attenti on and the al ertness task conrmed the i nvol ve-
ment of hi ghl y overl appi ng networks i n the control of
both attenti onal functi ons (Fi g. 3, bottom).
A 69-year-ol d femal e pati ent after a ri ght-hemi -
sphere stroke wi th l esi ons i n the ri ght caudate nucl eus,
the ri ght i nternal capsul e, the ri ght nucl eus l enti for-
mi s, and the ri ght pari etal and temporal opercul um
after more than 2 years sti l l presented wi th a severe
l eft-si ded negl ect. For some tasks (l etter cancel l ati on,
fast responses to sti mul i presented i n the ri ght and l eft
vi sual el d under exti ncti on condi ti ons) part of the
sti mul i i n the ri ght hal f of the di spl ay were negl ected,
too. We treated the pati ent wi th a computeri zed al ert-
ness trai ni ng for 14 1-h sessi ons (AI XTENT; Sturm et
al., 1993, 1997). On a computer screen, the pati ent i s
shown ei ther a car or a motorcycl e dri vi ng on a road.
The pati ent has to handl e two response keys: one for
speed and the other for braki ng. The objecti ve i s both to
dri ve the vehi cl e as qui ckl y as possi bl e and to stop i t
just i n ti me to avoi d crashi ng i nto obstacl es appeari ng
i n front of i t. The general goal of the trai ni ng i s the
i mprovement of the al ertness l evel i ndi cated by an
i mpai red response ti me l evel i n a standardi zed al ert-
ness test (452-ms medi an response ti me; i ntrai ndi -
vi dual vari abi l i ty PR 4) before the trai ni ng. No spati al
ori enti ng or other negl ect-ori ented trai ni ng procedures
were admi ni stered.
Twi ce before (basel i ne testi ng) and once after the
trai ni ng an al ertness test (vi sual response ti me) and
four negl ect tests were carri ed out (l i ne bi secti on, l i ne
cancel l ati on, l etter cancel l ati on, fast responses to sti m-
ul i presented i n the ri ght and l eft vi sual el d under
exti ncti on condi ti onssubtest Negl ect of the TAP by
Zi mmermann and Fi mm, 1995). Duri ng the basel i ne
phase there was no change of performance for any of
the tasks, al l i ndi cati ng severe al ertness deci ts (see
above) and negl ect symptoms. After the trai ni ng there
was a sl i ght i mprovement i n the response ti me of the
al ertness task (432 ms) and a si gni cant i mprovement
i n the i ntrai ndi vi dual response ti me vari abi l i ty (per-
centi l e rank 10). There was a consi derabl e i mprove-
ment for every si ngl e negl ect task (l i ne bi secti on, pre
17.1% mean shi ft to the ri ght, post 6.7%; l i ne cancel -
l ati on, pre 5 l eft omi ssi ons, post no l eft omi ssi ons,
prepost change P 0.023, one-tai l ed, Fi shers exact
test), wi th the strongest effects for the l etter cancel l a-
ti on and the Negl ect test of the TAP (l etter cancel l a-
ti on, pre 20 l eft, 11 ri ght omi ssi ons, post 14 resp. 0;
prepost change l eft P 0.010, ri ght P 0.0006,
one-tai l ed, Fi shers exact test; Negl ect test, pre 22 l eft,
14 ri ght omi ssi ons, post 17 resp. 5; prepost change l eft
P 0.024, ri ght P 0.007, one-tai l ed, Fi shers exact
test). Addi ti onal l y, before and after the trai ni ng, an
fMRI acti vati on study was carri ed out usi ng a negl ect
task si mi l ar to the hemi el d response test (Negl ect test
of the TAP) menti oned above. Before the trai ni ng, the
pati ent di d not respond to any l eft-si ded sti mul i and
even negl ected many sti mul i i n the ri ght hemi el d
duri ng the acti vati on phase. The SPM anal ysi s
(Negl ect test mi nus rest) reveal ed vi rtual l y no acti va-
ti on of the ri ght hemi sphere (except for some ti ny ri ght
frontal and i nferi or pari etal spots) but al so a very
reduced l eft-si ded acti vati on pattern (superi or pari etal
cortex, i nferi or temporal gyrus; Fi g. 4, l eft). After the
trai ni ng, there was a l arge ri ght and a much smal l er
l eft prefrontal acti vati on, as wel l as a much more pro-
nounced l eft-hemi sphere pari etal focus. Al so both ri ght
and l eft occi pi tal areas showed much more acti vi ty
than before the trai ni ng (Fi g. 4, ri ght). Furthermore,
there was an extended acti vati on of ri ght thal ami c
structures, showi ng no acti vi ty before the trai ni ng at
al l . I t seems that the al ertness trai ni ng i mproved the
functi on of at l east part of the ri ght frontal al erti ng
network, whi ch probabl y coacti vated pari etal and even
occi pi tal areas as hypothesi zed by Fernandez-Duque
and Posner (1997), thus l eadi ng to a substanti al i m-
provement of negl ect symptoms behavi oral l y.
CONCLUSIONS
Al l the resul ts from the functi onal i magi ng studi es
on al erti ng and sustai ned attenti on reveal that for both
i ntensi ty aspects of attenti on comparabl e ri ght-hemi -
sphere networks seem to be acti ve. I n these networks
S80 STURM AND WI LLMES
both the anteri or ci ngul ate gyrus, as a center for an-
ti ci pati on of acti ons and preparati on of attenti onal ac-
ti vi ty (Carter et al., 1999; LaBerge et al., 1990; Murtha
et al., 1996), and the dorsol ateral frontal cortex seem to
exert topdown control over the probabl y noradrener-
gi c acti vati on provi ded by brai n stem structures (Rob-
bi ns, 1984). Thi s topdown control probabl y i s medi -
ated by the reti cul ar nucl eus of the thal amus (Steri ade
FIG. 3. Covert ori enti ng of attenti on mi nus rest (top mi ddl e) and i ntri nsi c al ertness mi nus rest (top l eft) i n n 10 ri ght-handed subjects
(5 femal e, 5 mal e). Regi ons compri si ng at l east k 20 voxel s, each wi th P 0.01, superi mposed on the SPM96 3D templ ate. (Boxcar paradi gm
wi th three peri ods of al ternati ng rest (28 s) and sti mul ati on (60 s) condi ti ons. I magi ng: 1.5-T Phi l i ps NT Gyroscan wi th standard bi rdcage
head coi l . EPI T2*-w sequences: TR 4000 ms, TE 40 ms, FA 40. Matri x 64 64, FOV 250 mm, 15 conti guous 7-mm sl i ces paral l el
to the AC-PC l i ne, no gap. I mage processi ng: al l scans normal i zed i nto the standard stereotaxi c anatomi cal space of the atl as by Tal ai rach
and Tournoux (1988). Data anal ysi s: SPM99.) Top ri ght: Compl ex contrast between ori enti ng and i ntri nsi c al ertness for the si mpl e contrasts
depi cted i n the top l eft and mi ddl e. Bottom: Regi ons of si gni cant acti vati on based on SPM99 conjuncti on anal ysi s for the ori enti ng and the
al ertness task (n 10, P
corr.
0.05).
S81 I NTRI NSI C AND PHASI C ALERTNESS
et al., 1986; Yi ngl i ng et al., 1975), whi ch speci cal l y
opens thal ami c gates i n accordance wi th the frontal
executi ve systems. Vi a thi s way, brai n-stem acti vati on
can be di rected to corti cal areas whi ch need i t for
speci c i nformati on processi ng. The al ertness network
seems to operate supramodal l y, al though under the
audi tory sti mul ati on we found some addi ti onal acti va-
ti on of the ri ght ventrol ateral frontal cortex, both un-
der al ertness and under vi gi l ance condi ti ons. Thi s an-
teri or al erti ng system seems to coacti vate the
posteri or ori enti ng network i n the i nferi or pari etal
l obe automati cal l y, even i f the parti cul ar task does not
cal l for overt or even covert ori enti ng of attenti on (Pos-
ner and Petersen, 1990; Fernandez-Duque and Posner,
1997; Achten et al. 1999).
Si gni cant acti vati ons i n thal ami c and mesence-
phal i c structures, however, were detected onl y i n al ert-
ness and sustai ned attenti on tasks, i f very rapi d re-
spondi ng was requi red. Obvi ousl y, onl y under these
condi ti ons i s an opti mal l evel of al ertness evoked. I t
i s l i kel y that such a l evel of al ertness has not been
acti vated i n some PET and fMRI studi es on sustai ned
attenti on, i n whi ch onl y certai n events had to be mon-
i tored wi thout a need for fast responses. I n these stud-
i es throughout, there was onl y a dorsol ateral frontal
and i nferi or pari etal acti vati on i n the ri ght hemi -
sphere.
The strong associ ati on between al erti ng and ori ent-
i ng networks mi ght be hel pful for more gl obal attempts
to amel i orate negl ect symptoms after ri ght-hemi -
sphere damage, as shown i n a rst therapy study by
Robertson and co-workers (1995) usi ng sel f-i nstructi on
techni ques to enhance the l evel of sustai ned attenti on
i n negl ect pati ents and i n both the behavi oral and the
functi onal i magi ng resul ts of our attempt to i mprove
al ertness i n a pati ent presenti ng wi th severe negl ect
symptoms 2 years postonset.
Under phasi c al ertness condi ti ons, i .e., after the pre-
sentati on of a warni ng sti mul us shortl y before the tar-
get sti mul us, two changes i n acti vati on patterns occur
i n compari son to the i ntri nsi c al ertness tasks. Fi rst,
the ri ght-hemi sphere network, al though otherwi se
FIG. 4. Negl ect (covert ori enti ng task) mi nus rest before (l eft) and after (ri ght) al ertness trai ni ng i n a pati ent sufferi ng from severe
negl ect symptoms 2 years postonset. Regi ons compri si ng at l east k 5 voxel s, each wi th P 0.001, superi mposed on the SPM96 3D templ ate.
Further techni cal detai l s as i n top row of Fi g. 3.
S82 STURM AND WI LLMES
i denti cal , seems to be enl arged, whi ch may resul t from
an external l y i ni ti ated addi ti onal acti vati on by the
warni ng sti mul us. Second, there are l eft dorsol ateral
frontal and i nferi or pari etal acti vati ons whi ch, how-
ever, shoul d not be ascri bed to an addi ti onal al erti ng
effect. Rather they can be i nterpreted as a si gn of
el ementary attenti onal sel ecti vi ty probabl y caused by
the need to sel ect between warni ng and target sti mu-
l us. Thi s i nterpretati on i s corroborated by the observa-
ti on that pati ents after l eft-hemi sphere l esi ons often
suffer from probl ems wi th sel ecti ve attenti on. Whether
thi s sel ecti vi ty has to be attri buted to the operati on of
a worki ng memory system i n l eft-frontal cortex (hol d-
i ng i n mi nd the condi ti on not to respond to the warni ng
but onl y to the target sti mul us) or to an acti ve i nhi bi -
ti on process i tsel f sti l l has to be cl ari ed.
ACKNOWLEDGMENTS
Al l PET studi es were supported by Grant 01 KO 9705-8/11 from
the German Mi ni stry for Educati on and Sci ence (BMBF) and the
fMRI study was supported by a research grant from the Medi cal
Facul ty, RWTH Aachen, to the I nterdi sci pl i nary Cl i ni cal Research
Group ZNS (TP-13). We thank PD Dr. I ng. H. Herzog and L.
Kemna of the I nsti tute for Medi ci ne (I ME) at the Research Center
Jul i ch for access to and assi stance wi th the PET measurements,
Prof. Dr. A. Thron of the Department for Neuroradi ol ogy, Uni versi ty
Hospi tal , RWTH Aachen, for access to the fMRI i magi ng faci l i ti es as
wel l as S. Wei s and K. Specht for doi ng the SPM anal yses, F. Longoni
and Th. Di etri ch for assi stance wi th the experi mental exami nati ons,
and Dr. phi l . B. Fi mm for programmi ng the experi mental versi ons of
subtests of the computeri zed test battery for attenti on functi ons
(TAP; Zi mmermann and Fi mm, 1995) that were used i n the PET-
and fMRI -scanni ng sessi ons.
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