Decreases in Frontal and Parietal Lobe Regional Cerebral Blood Flow Related to Habituation

Journal of Cerebral Blood Flow and Metabolism 12:546-553 © 1992 The International Society of Cerebral Blood Flow and Metabolism Published by Raven Press, Ltd" New York

Decreases in Frontal and Parietal Lobe Regional Cerebral

Blood Flow Related to Habituation

tSteven Warach, *tRuben C. Gur, *tRaquel E. Gur, HBrett E. Skolnick, §Walter D. Obrist, and *Martin Reivich

*Cerebrovascular Research Center, Department of Neurology, and tBrain Behavior Laboratory, Departments of

Neurology and Psychiatry, University of Pennsylvania; tDepartment of Neurology, Graduate Hospital, Philadelphia,

Pennsylvania; and §Division of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, U,S,A,

Summary: We previously reported decreased mean CBF between consecutive resting conditions, ascribed to ha­bituation. Here we address the regional specificity of ha­bituation over three consecutive flow studies. Regional CBF (rCBF) was measured in 55 adults (12 right-handed men, 12 right-handed women, 14 left-handed men, 17 left­handed women), with the 133Xe inhalation technique, dur­ing three conditions: resting, verbal tasks (analogies), and spatial tasks (line orientation). Changes in rCBF attribut­able to the cognitive tasks were eliminated by correcting these values to a resting equivalent. There was a progres­sive decrease in mean rCBF over time, reflecting habitu­ation. This effect differed by region, with specificity at frontal (prefrontal, inferior frontal, midfrontal, superior frontal) and inferior parietal regions. In the inferior pari­etal region, habituation was more marked in the left than

We previously reported a decrease in regional CBF (rCBF) between two consecutive resting mea­surements embedded within other conditions (Warach et al. , 1988). We interpreted this decrease as consistent with habituation to the experimental setting because the decrease was greater initially in a series of measurements than when they occurred later. Also supporting the notion that the effects were due to habituation, the effect was greater

Received May 28, 1991; final revision received February 14, 1992; accepted February 18, 1992.

Address correspondence and reprint requests to Dr. R. C. Gur at Brain Behavior Laboratory, Department of Psychiatry, Uni­versity of Pennsylvania, 10th Fl. Gates Bldg., Philadelphia, PA 19104, U.S.A.

Dr. S. Warach's present address is Department of Neurology, Beth Israel Hospital, Boston, MA, U.S.A.

Dr. W. D. Obrist's present address is Department of Neuro­surgery, University of Pittsburgh, Pittsburgh, PA, U.S.A.

Abbreviations used: MANOY A, multivariate analysis of vari­ance; rCBF, regional CBF.

546

the right hemisphere. Right-handers showed greater ha­bituation than did left-handers. There was no sex differ­ence in global habituation, but males showed greater left whereas females showed greater right hemispheric habit­uation. The results suggest that habituation to the exper­imental setting has measurable effects on rCBF, which are differently lateralized for men and women. These ef­fects are superimposed on task activation and are most pronounced in regions that have been implicated in atten­tional processes. Thus, regional decrement in brain activ­ity related to habituation seems to complement atten­tional effects, suggesting a neural network for habituation reciprocating that for attention. Key Words: Attention­Cerebral blood flow-Frontal cortex-Habituation­Handedness-Parietal cortex.

when two subjects familiar with the experimental setting (the laboratory technicians) were excluded from analysis. Females showed a greater habitua­tion than males, consistent with similar sex differ­ences in habituation reported with other psycho­physiological techniques.

Two questions were not addressed in the previ­ous report: Is an effect of habituation evident when task conditions are imposed? Is there a regional specificity to the habituation effect? In the present study, rCBF was consecutively determined during resting baseline and two different task conditions. Cognitive task introduces a novelty to each mea­surement and might be expected to reduce the mag­nitude of habituation. If a decrease in rCBF unre­lated to cognitive task is nonetheless present, it would suggest that an independent effect of habitu­ation is superimposed upon task-specific patterns of rCBF activation. The previous study found no evi­dence of regional specificity to the effect of habitu-

HABITUATION EFFECTS ON CBF 547

ation. One reason could have been the small sample size employed (15 subjects). The present report is based on 55 subjects.

Since habituation involves a decrease in orienting to novel stimuli, the literature on regional localiza­tion of attention is pertinent. Mesulam (1981, 1990)

has proposed a cortical network involved in di­rected attention. The four components of this net­work include the posterior parietal cortex, frontal cortex, limbic structures, and a reticular compo­nent. Lesions of parietal or frontal cortex can result in the syndrome of unilateral neglect (e.g., Heilman and Valenstein, 1972; Ogden, 1985). Evidence that the right hemisphere is dominant for attentional functions includes observations that (a) hemineglect follows right hemispheric lesions (e. g. , Ogden, 1985; see review in Mesulam, 1981); (b) the right hemisphere directs attention to both halves of ex­trapersonal space, whereas the left hemisphere di­rects primarily to contralateral extrapersonal space (Weintraub and Mesulam, 1987); and (c) rCBF (Ro­land, 1982) and cerebral metabolism (Reivich et al. , 1983) are preferentially increased in the right pari­etal lobe during tasks requiring sustained attention.

METHODS

Subjects The subjects were 55 normal, young volunteers (12

right-handed men, 12 right-handed women, 14 left-handed men, and 17 left-handed women). This is a subsample of the 62 subjects reported in Our et al. (1982). Seven of these were eliminated because they had inadequate data for more than two detectors (Our et al. examined hemi­spheric and not regional data) and five additional subjects were eliminated because they overlapped with the sample reported in Warach et al. (1988). Five new subjects stud­ied under identical conditions were added to the sample. SUbjects had no history of neurological or psychiatric dis­ease. Ages ranged from 18 to 25 years (mean ± SD 20.4 ± 2.1 years).

Procedures Measurements of rCBF were made using the l33Xe in­

halation technique as previously described (Obrist et aI., 1975; Obrist and Wilkinson, 1985, 1990) and applied in our laboratory (Our et aI., 1982, 1987, 1988). rCBF was measured by eight homotopic pairs of collimated N aI crystal detectors, held in place by a helmet and oriented at angles perpendicular to the skull. The approximate lo­cation of the tissue viewed by the detectors is illustrated in Fig. 1. A trace amount of l33Xe in room air was inhaled for 60 s, followed by 14 min of breathing of room air. End-tidal 133Xe concentration was determined by contin­uous recordings of the exhaled air, while brain clearance of the isotope was monitored by 16 collimated detectors. A least-squares fit of the clearance curves was performed by a two-compartment deconvolution, using end-tidal 133Xe as an input function (Obrist and Wilkinson, 1985, 1990).

There were three determinations of rCBF conducted within a single session. The integrity of rCBF measure-

FIG. 1. Detector location over brain. The detectors were ori­ented at angles perpendicular to the curvature of the skull, as indicated by the ellipses. Locations are over homotopic re­gions in each hemisphere.

ments was evaluated for absence of artifacts and ade­quate count rates, curve fits, and estimation of end-tidal carbon dioxide levels. Particular attention was paid to the possible influence of air passage artifact, including pre­cautions to eliminate artifactually contaminated detectors and the use of the method of Obrist et al. (1975, 1990) for start fit estimation. Continuous capnographic recordings provided an estimate of Pc02• Each study was separated by 15-20 min to ensure that background activity was at acceptable levels «10% of peak counts). Linear back­ground correction was performed for the first study and a monoexponential correction of residual activity was used for subsequent studies (Obrist et aI., 1967; Risberg, 1980). Careful evaluation of the integrity of the exponential fits was assessed. Background counts were recorded at 5-s intervals for 100 s prior to the administration of 133Xe. For detectors that yielded background parameters that were clearly aberrant (half-times < 10 min or >300 min), background subtraction was based upon the mean half­times of acceptable background values for that rCBF measurement.

The order of conditions was randomly counterbalanced across subjects (Latin-square design). The conditions were resting baseline, verbal tasks (analogies), and spatial tasks (line orientation). A detailed description of the rest­ing baseline condition and the tasks and their effects on rCBF is in Our et al. (1982). Briefly, in the resting con­dition, the subjects were not deprived of visual or audi­tory input. However, ambient illumination and noise were restricted to minimal levels necessary for the oper­ation of the laboratory. Subjects were instructed to relax but remain awake with their eyes open. For the cognitive tasks, subjects were instructed on how to perform using standard procedures, and a set of practice items verified their understanding. Since subjects were studied in a su­pine position, the stimuli were projected onto a screen on the ceiling, and subjects indicated their answers with a bimanually operated flashlight. Instructions as to the na­ture of each condition were presented during the 20-min period prior to the study. The laboratory technicians were both men.

Data analysis The rCBF index used in this report is Fl, the fast flow

compartment (Obrist and Wilkinson, 1985, 1990). This

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548 S. WARACH ET AL.

parameter was chosen over the initial slope (IS) since it provides a more direct estimation of gray matter reBF than the noncompartmental IS. Instability of F} in the presence of slippage (overlap between the fast- and slow­clearing compartments in patients with brain lesions) is not an issue in this sample of normal young adults. Values for deleted detectors were estimated by BMDPAM using a stepwise procedure and all values (Dixon et aI., 1985). The data were corrected for Pe02 by 3.5% per millimeter mercury difference from the average Pe02 of the three measurements for each subject. There were no sex or handedness differences in Pe02 (Table 1); however, the results were analyzed both with and without Pe02 correc­tion, yielding the same effects. In Results, the Pe02-corrected values for reBF will be reported.

The data were adjusted to remove effects specific for cognitive activation in the following manner. For each sex and handedness subgroup, a correction factor for each task was computed as the ratio of the mean of rest­ing to mean of the verbal or spatial condition in each region. The correction factors were multiplied by the reBF values for the cognitive task to produce a trans­formed data set in which task-specific effects have been eliminated and values made equivalent to resting condi­tion.

The results were analyzed in a multivariate analysis of variance (MANOV A) design, with sex and handedness as between-group factors and time (first, second, third reBF determination), hemisphere (left, right), and region (1-8) as within-group (repeated-measures) factors. An MANOVA model was utilized (BMDP4V; Dixon et aI., 1985) according to the recommendation of Vasey and Thayer (1987), since this avoids the likely violation of the sphericity assumption inherent in a repeated-measures ANOV A performed with a univariate model. Significant interactions were decomposed using the simple effects option on the BMDP4V MANOV A.

RESULTS

There was an overall effect of time: Mean rCBF decreased progressively with successive determina­tion (F[2,50] = 4.57, P = O.OIS) (Fig. 2; Table 2).

Although the magnitude of decrease was somewhat greater in men than women, the interaction of time x sex was not significant (F[2,SO] < 1). There was a significant time x handedness interaction (F[2,SO]

= 3.39, P = 0.042); right-handers showed a signif­icant decrease with time (F[2,SO] = 6.13, P = 0.004), but left-handers did not (Fig. 3).

There was no overall hemispheric difference

TABLE 1. Mean ± SD end-tidal PeG2 values (mm Hg)

Men Women

Time 1 40.72 ± 4.3 39.17 ± 3.3 2 40.84 ± 4.3 38.97 ± 2.8 3 40.81 ± 4.2 39.08 ± 2.6

Handedness Right Left Time 1 39.31 ± 3.9 40.36 ± 3.8

2 39.78 ± 3.7 39.91 ± 3.7 3 39.46 ± 3.9 40.24 ± 2.2

J Cereb Blood Flow Metab, Vol. 12, No.4, 1992

...-. c: E

---01 o o ..-

---

E

..-u..

Change in mean rCBF over time

78 ,-------------------------------�

76

74

72

70

F[2,50]=4.57, p=O.015

68�---.---------r--------_r--� Time 1 Time 2 Time 3

reBF DETERMINATION FIG. 2. Mean F1 (fast compartment flow) decreases progres­sively with each successive 14·min regional CBF (rCBF) de­termination separated by �15-20 min between studies.

(F[ 1 ,S1] < 1), nor an interaction of time x hemi­sphere (F[2,SO] = 1.9S, NS); i. e., summed across all groups, the hemispheres did not differ in the pat­tern of decrease. However, the three-way interac­tion of time x hemisphere x sex was significant (F[2,SO] = 3.47, P = 0.039). This reflects a greater decrease over time in the left hemisphere relative to the right in males and a greater decrease in the right relative to left in females (Fig. 4).

A significant time x region interaction was ob­served (F[14,38] = 2.S7, P = 0.011), indicating that regions (summed across hemispheres) differed in changes over time. Significant regional decreases over time were observed in regions 1, 2, 3, 4 (all four frontal regions), and 6 (an inferior parietal re­gion; Fig. S). The three-way time x hemisphere x region interaction, which could have indicated hemispheric differences in the decrease specific to

HABITUATION EFFECTS ON CBF 549

TABLE 2. Summary of statistical results

Effect df F P Time 2,50 4.57 0.015

x sex 2,50 <1 NS x handedness 2,50 3.39 0.042 x region 14,38 2.57 0.011 x hemisphere 2,50 1.95 NS x hemisphere at region 6 2,50 3.96 0.025 x hemisphere x sex 2,50 3.47 0.039

Mean ± SD (mil tOO g/min) Time 1 74.3 ± 11.68 Time 2 73.1 ± 18.11 Time 3 72.3 ± 11.17

Sex Men Women Time I 70.1 ± 10.45 78.2 ± 10.55 Time 2 68.4 ± 9.45 77.3 ± 11.32 Time 3 67.2 ± 8.15 76.9 ± 11.32

certain regions, was not significant (F[ 14,38] = 1.37, NS). However, since hemisphere differences are of particular interest, we examined time x hemisphere interaction for each region. There was a time x hemisphere interaction only at region 6

(F[2,50] = 3.96, p = 0.025), reflecting a change with time primarily in the left hemisphere in this inferior parietal region (Fig. 6).

DISCUSSION

Experimental paradigms to study habituation, the progressive decline in neuronal responsiveness re­sulting from the repetition of a stimulus (Thompson and Spencer, 1966), have usually examined repeti­tions of a single stimulus. However, the experimen-

tal setting of repeated rCBF measurements can it­self be considered a set of novel stimuli, and the rCBF may show effects of habituation to this set of stimuli that can be superimposed on experimental manipulations (Warach et aI. , 1988). This possibility receives further support in the present study. rCBF

progressively decreased with successive determina­tions, with most pronounced decreases in frontal and inferior parietal regions. The frontal regions sampled correspond to prefrontal, inferior frontal, midfrontal, and superior frontal cortex.

Thus, the results support the hypothesis that ha­bituation occurs during repeated rCBF measure­ments and that it has regional specificity. This rep­licates our earlier report on resting rCBF (Warach et aI. , 1988), extending generalizability of habitua­tion to rCBF obtained during cognitive task activa­tion. Risberg et ai. (1977) likewise reported de­creased frontal rCBF for habituation. Increased frontal rCBF seen on the first administration of Raven's progressive matrices was not present when an equivalent form of the test was administered on the following day, although increases in the parietal lobe persisted.

Since habituation can be considered the process complementary to attention, a comparison of the present findings with data on attentional processing is of relevance. There is evidence that the role of the frontal and parietal lobes in attention may differ. Hemineglect due to frontal lesions is more likely to result in spontaneous inattention, whereas hemine­glect due to parietal lesions is more likely to result

Time X Handedness

FIG. 3. Interaction of time x handedness, with right-handers, not left-handers, showing a sig­nificant decrease in mean F1• rCBF, regional CBF.

-c:

E --01

o o ,-:.::: E

,-u.

78 �------------------------------�

76

74

72

70

cr----D., , , ,

F[2,501=3.39, p=O.042

'0

68�----r----------r----------r---�

TIME 1 TIME2 TIME3

reBF DETERMINATION

____ Right-handers (n=24)

- 0 - Left-handers (n=31)

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550 S. WARACH ET AL.

Time X Hemisphere X Sex

80 ,-------,--------.----____ ,-______ �

� C 75

E �

01 0 0 � E

'-----' 70

LI'. � "-

"-"-

"-D-...

65L-------�------� ________ L-____ �

TIME TIME 2 TIME 3 o FEMALES o MALES

FIG. 4. Interaction of time x hemisphere x sex. Males had greater Fj decrease in the left hemisphere, whereas females had greater decrease in the right hemisphere. Solid lines represent the left hemisphere and dashed lines the right hemisphere.

in extinction (Mesulam, 1981). Patients with frontal lobe lesions show greater impairment in discrimi­nating novel from familiar stimuli than patients with posterior lesions (Rizzolatti et aI., 1987). In patients

with frontal lesions, event-related potentials to stimulus novelty were of decreased magnitude, compared with normal controls, when relevant au­ditory stimuli were presented contralateral to the lesion. They were increased in magnitude when ir­

relevant stimuli were presented contralaterally (Knight et aI., 1981). Increases in bilateral rCBF in prefrontal, midfrontal, superior mesial frontal, and

right inferior parietal cortex were noted by Roland (1982) to occur with directed attention, and further increases in superior mesial frontal regions oc­curred when discrimination between relevant and irrelevant stimuli was required. The orientation of the superior frontal detector in this study makes inclusion of data from superior mesial frontal cortex likely. Thus, the decrease we found in rCBF oc­curred in regions implicated in attentional func­tions.

J Cereb Blood Flow Metab, Vol. 12, No.4, 1992

Since the literature suggests right hemisphere in­volvement in attentional processes (e.g., Mesulam, 1981; Hugdahl et aI., 1982), hemispheric differences in response to habituation were investigated. The only region with an asymmetric effect for habitua­tion was the inferior parietal area, where the left hemisphere showed greater habituation. This can be considered as consistent with right parietal in­volvement in the vigilance aspects of attention. Hemineglect was relatively more common follow­ing anterior lesions in the left and posterior lesions in the right hemisphere (Ogden, 1985). Patients with parietal lesions appear to be particularly impaired on aspects of an attentional task requiring disen­gagement of attention in preparation for shifting at­tention to another target (Posner et aI., 1984). This effect is more pronounced when the target of the attention shift is contralateral to the lesion (Posner et aI., 1987). Thus, parietal regions may be more involved in vigilance than in functions involving dis­crimination between relevant and nonrelevant stim­uli. Indeed, increase in right inferior parietal glu­cose metabolism during a vigilance task was ob­served by Reivich et al. (1983), and lateralized task effects were shown in this region in conjunction with frontal effects (Gur et aI., 1983). Posner and colleagues found right lateralized effects of atten­tional tasks in the "posterior attentional system" (Posner and Peterson, 1990). This evidence is con­sistent with the association between attentional ne­glect and right parietal lesions. Our finding that the right homotopic region demonstrates no attentua­tion in rCBF over time, whereas the left homotopic region is involved in habituation, if sustained, sug­gests interhemispheric reciprocity in regulating the complementary processes of attention and habitua­tion.

Habituation effects in this study were superim­posed upon the effects of cognitive tasks, Since the data were corrected to a resting equivalent, the re­sults are not attributed to sensory, motor, or cog­nitive components induced by the tasks. Hence, they reflect effects of repeating the nonspecific as­pects of the experimental setting. Effects due to shifting focus of attention from the experimental en­vironment toward the tasks are likewise eliminated. Habituation to monitoring the environment may

have contributed to the rCBF results, but not atten­tion directed to task-related stimuli.

We did not replicate our earlier report of sex dif­ference in habituation to consecutive resting mea­surements, females showing greater decrement (Warach et aI., 1988). Two reasons may account for this discrepancy: (a) Two of the men in the small sample of the previous study were familiar with the

HABITUATION EFFECTS ON CBF 551

TIME X REGION

Region 1 Region 2 Region 3 Region 4

78

, 76

74 -C 72 .-

E 70 F[ ,50]=5.91, p=O. 05 F[ ,50]=5.45, p=O. 07 F[2,50]=7.24, -

0) F[ ,50]=3.51, p=O. 38 0 68 I I I I I I ..1.1 -..---,---.---'

0 ,... -

E - 78

,... U. 76

74

72

70

68

Region 5

� TIME 1 TIME 2 TIME 3

Region 6

F[2, 0]=3.61, p=O.O 4 I I I I I TIME 1 TIME 2 TIME 3

Region 7 Region 8

TIME 1 TIME 2 TIME 3 TIME 1 TIME TIME 3

reBF DETERMINATION FIG. 5. Interaction of time x region, illustrated as the simple effect of time at each homotopic pair of regions. Simple effects were significant for the regions indicated: 1,2,3,4, and 6. rCBF, regional CBF.

experimental setting and possibly attenuated effects of habituation. (b) The contexts of the resting con­ditions was different. The resting condition in this study always preceded or succeeded a cognitive task, whereas the resting conditions were sequen­tial in the previous study. Conceivably, sex differ­ences exist for repeated resting conditions, but they are moderated by cognitive activity.

Males showed a greater left than right hemisphere decrease in rCBF with time, while females showed no significant difference. This may indicate sex dif­

ferences in hemispheric specialization for habitua­tion, perhaps reflecting a greater lateralization of vigilant (i.e., non habituating) functions to the right hemisphere in males. Alternatively, it could be due to sex differences along psychological variables known to affect habituation [e .g., the perception of stimuli as noxious (Kopacz and Smith, 1971) or dif­fering gender combinations of experimenter and subject (Fisher and Kostes, 1974)].

Our results are perhaps the first report of a hand­edness difference in habituation, right-handers

showing a greater decrement in rCBF than left­handers. There is some evidence that left-handers (Lacroix and Comper, 1979) and right-handers with familial sinistrality (Ketterer and Smith, 1977) show lateralized patterns of skin conductance responses to verbal or spatial stimuli that differ from those in right-handers.

It is possible that decreases in subjects' level of anxiety contributed to the global effect observed here. Anxiety level has been shown to affect rCBF, with low anxiety positively related to rCBF and high anxiety inversely related (Gur et al., 1987,

1988). Anxiety was not assessed in the present sam­ple, but it is unlikely to explain the consistent de­cline in rCBF.

Habituation in the mammalian brain is considered to represent an active neural process rather than a

fatigue-like phenomenon (Sokolov, 1963; Mesulam,

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552 S. WARACH ET AL.

Time X Hemisphere for Region 6

7B ,-------------------------------------�

76

-t:

E 74 --01

0 0 T"" ::::: E 72

........

T"" LI-

70

6B �----_r----------�------------r_--� TIme 1 TIme 2 Time 3

reBF DETERMINATION

1985). Evidence of such a process in this study would have entailed a progressive increase in rCBF over time in some regions functionally connected in an inhibitory manner to regions reflecting the pro­gressive decreases. This was not observed, but the present study did not measure rCBF in cingulate cortex, basal forebrain, some frontal regions, thal­amus, or brainstem reticular formation. An assess­ment of rCBF or cerebral metabolism in these re­gions may reveal a more extensive regional speci­ficity to habituation and provide evidence of an

interplay of regions regulating habituation. This may also permit assessment of the relative contri­butions of habituation and attention. The different effects of habituation in the present report and that of Warach et al. (1988) indirectly support the notion that habituation is more than a passive decrement in neural activity. Factors such as variation in cogni­tive conditions, sex, and handedness modify the neural manifestation of habituation. Further study might assess the contribution of anxiety, age, stim­ulus features, personality factors, and other vari­ables that have been identified as modifiers of the habituation process (O'Gorman, 1977).

Acknowledgment: This work was supported by NIH grant NS 19039 and NIMH grant MH 30456. Dr. Warach was supported in part by the American Heart Association through Harvard Medical School. Wayne Amarnek and David Epstein served as CBF technicians. Dr. M.-Marsel

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___ Left Hemisphere

- 0 - Right Hemisphere

FIG. 6. Interaction of time x hemisphere for region 6 (F[2,50)

= 3.96, P = 0.025), showing a greater decrease in the left than right hemisphere. rCBF, re­gional CBF .

Mesulam provided thoughtful comments on the manu­script.

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