Journal of Cerebral Blood Flow and Metabolism 12:554-561 © 1992 The International Society of Cerebral Blood Flow and Metabolism Published by Raven Press, Ltd., New York
Vibration-Induced Regional Cerebral Blood Flow Responses in Normal Aging *:j:Lee W. Tempel and *t:J:Joel S. Perlmutter *Department of Neurology and Neurological Surgery (Neurology), tMallinckrodt Institute of Radiology (Radiation Sciences), and :f:The McDonnell Center for Studies of Higher Brain Function, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Summary: Task-induced changes in regional CBF (rCBF) can be measured with positron emission tomography (PET) and provide a powerful tool to map brain function. Many studies using these techniques have investigated responses in healthy young subjects. Since many patho logical conditions occur more commonly in older sub jects, it is necessary to compare blood flow responses in these patients with appropriately age-matched controls. Furthermore, the effects of normal aging on such blood flow responses remain unknown. For both reasons, we designed this study to determine whether vibration induced CBF responses change with advancing age in normals. CBF was measured with PET and bolus administered Hi50 in 26 subjects from 20 to 72 years old (mean = 39; SD = 19). Regional responses were identi-
fied by subtraction-image analysis. Left and right hand vibration produced consistent responses in contralateral primary sensorimotor area (PSA) and supplementary mo tor area (SMA). Response magnitudes were compared to age by linear regression. There were no substantial rela tionships between age and responses to vibration for PSA or SMA (PSA r = 0.28, p = 0.054; SMA r = 0.33, p = 0.13). Power analysis demonstrates a high degree of confidence (99.7% for PSA and 87% for SMA) for detect ing at least a moderate correlation (r = 0.6) between re sponse magnitude and age. We conclude that the rCBF responses to vibrotactile hand stimulation do not change with normal aging. Key Words: Normal aging-Blood flow-Activation-Human-Positron emission tomogra phy-Vibration.
Task-induced changes in regional CBF (rCBF) can be measured with positron emission tomogra phy (PET) and provide a powerful tool to map brain function. This approach has been used to map nor mal function (Fox et aI., 1984, 1986, 1987; Raichle, 1986; Petersen et aI., 1988) as well as to identify changes in brain responses in pathological condi tions (Tempel and Perlmutter, 1990; Reiman et aI., 1989). In both types of studies, the investigator as sumes that vascular reactivity is a faithful indicator of neuronal activity and alterations in blood flow responses imply alterations in neuronal activity
(Raichle, 1986). This critical assumption mandates caution when applying this method to patients that may have abnormal cerebral blood vessels, such as patients with cerebrovascular disease (Powers et aI., 1988). Since many pathological conditions oc cur more commonly in older subjects, it is neces sary to determine whether vascular reactivity, in this case as indicated by task-induced rCBF re sponses, changes with normal aging. Knowledge of these rCBF responses in older individuals is impor tant not only for comparisons with pathological conditions in older subjects but also for improving our understanding of how normal brain function may change with age. Previous studies have inves tigated potential alterations in "resting" brain func tion with age. None have evaluated the effects of aging on focal brain activation, although Gur et ai. (1987) found no age-related change in rCBF activa tion with a more global cognitive stimulation using the xenon-133 inhalation technique. For these rea sons, we designed this study to determine whether
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Received October 28, 1991; final revision received January 27, 1992; accepted January 29, 1992. Address correspondence and reprint requests to Dr. Lee W. Tempel at Washington University School of Medicine, Division of Radiation Sciences, 510 S. Kingshighway, St. Louis, MO 63110, U.S.A. Abbreviations used: ANOYA, analysis of variance; PET, pos itron emission tomography; PSA, primary sensorimotor area; rCBF, regional CBF; SMA, supplementary motor area.
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REGIONAL CBF RESPONSES IN NORMAL AGING focal rCBF activation produced by vibrotactile stimulation of a hand changes with normal aging. METHODS We studied 26 subjects including 14 men and 12 women ranging in age from 20 to 72 years (mean = 39, SD = 19). Twenty-three were right-handed, two left-handed, and one ambidextrous. None had evidence of neurological disease. None had a concomitant systemic condition pre senting a risk for, or indicative of, cardiovascular disease except one 60-year-old woman with a history of asymp tomatic hypertension treated with hydrochlorothiazide and propranolol. Furthermore, none had psychiatric dis ease, depression, or dementia by a standard psychiatric screening test (SCID-Hamilton Schedule for Psychiatric Interviews; Williams, 1988), Hamilton Depression Scale (Hamilton, 1960), and Mini Mental Status Exam (Folstein et aI., 1975). Nine subjects took medication but refrained from those that had any effect on blood flow or vascular reactivity: pseudoephedrine (none for at least 12 h prior to study) and propantheline bromide (none for 48 h prior to study). PET studies were performed with the PETT VI system in the low resolution mode (Ter-Pogossian et aI., 1982; Yamamoto et aI., 1982). Data were recorded simulta neously for seven slices with a center-to-center separa tion of 14.4 mm. In-plane (i.e., transverse) reconstructed resolution was about 18 mm (full width at half maximum) in the center of the field of view and axial resolution was about 14 mm at the center. Subject preparation included the percutaneous inser tion of a radial arterial catheter under local anesthesia, to permit frequent sampling of arterial blood, and insertion of an intravenous catheter for isotope injection in the op posite arm. The head was positioned with a special head holder that used an individually molded plastic face mask to prevent movement during the study. A laser perma nently attached to the wall projected a line onto the mask that corresponded to the position of the lowest PET slice. A lateral skull radiograph with this line marked by a ra dio-opaque wire provided a record of the subject's exact position in relation to the PET slices (Fox et aI., 1985). The overlapping position of radio-opaque markers placed in the external auditory canals confirmed that the head was not rotated about the anteroposterior or vertical axes. After the head was in place, a transmission scan used for individual attenuation correction was performed with a ring source of activity containing 68Ge/68Ga. Dur ing each PET scan, the room was darkened and the sub ject's eyes were closed. The ears were not occluded. Am bient room noise during the scans was almost entirely from cooling fans for the electronic equipment. Cerebral blood flow was measured using a 40-s emis sion scan following the i.v. bolus injection of about 10 ml of saline containing 55-80 mCi of 150-labeled water (Her scovitch et aI., 1983; Raichle et aI., 1983; Videen et aI., 1987). The short half-life (122 s) of 150 permitted up to eight repeated measurements in a single study session for each subject. All subjects had measurements of CBF in the resting state and then repeat measurements during vibrotactile stimulation with a vibrator (130 Hz, 2 mm amplitude) held to all five finger pads of one hand (Fox et aI., 1987). Each hand was stimulated during sequential scans with inter-
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posed resting-state scans. Stimulation was initiated at the time of bolus injection of the radiotracer and continued throughout the scan. Each subject was specifically in structed to relax with eyes closed, not to concentrate on the task or stimulus, and not to grasp the vibrator (passive vibration). These studies were approved by the Human Studies Committee and the Radioactive Drug Research Commit tee (United States Food and Drug Administration) of the Washington University School of Medicine. Written in formed consent was obtained before each PET study.
Data analysis Global CBF values were calculated for each scan using a "whole slice" method (Perlmutter et aI., 1985). A tem plate for each slice was made using the appropriate rest state scan by removing all pixels at the edges of the slice with values � ;:; a(/) Ii '0
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(8)
(A)
Left Hemisphere
Right Hemisphere
10 mm
10 mm
FIG. 3. Response locations to hand vibration. Mean coordinates for the primary sensorimotor area and supplementary motor area responses to vibration of the opposite hand in the 26 normal subjects (Y younger subjects 20-27 yrs, 0 older subjects 40-72 yrs) are shown on these pairs of midsagittal and lateral surface brain projections for left (A) and right (8) hemispheres (modified from Talairach et aI., 1967). Error bars correspond to 1 SO. The horizontal lines extending from the brain projections indicate a line through the anterior (AC) and posterior commissures ( PC). The vertical lines represent a line perpendicular to the AC-PC line and intersecting it at one half the distance from anterior to posterior commissure. =
icant differences in the anterior-posterior or verti cal coordinates in PSA or for the three coordinates of the responses in SMA. DISCUSSION We found that rCBF responses to vibrotactile stim ulation of a hand do not significantly decrease with advancing age. This demonstrates preservation of task-induced vascular reactivity and suggests that neu ronal activation does not decline with normal aging. Several technical factors may influence interpre tation of our findings. Response magnitude may be biased by the limited axial field of view of PETT VI. Several of the subjects were not positioned suffi ciently high in the scanner to include SMA. Simi larly, slice separation of 14.4 mm may be inade quate to detect a response between slices. Never theless, we found SMA responses with equal frequency in younger and older subjects. Although we found the magnitude of the center of the re sponse to be unchanged with age, it is possible that the response may be more diffuse in one group. We did not address this issue. Cortical atrophy could lower the measured magnitude of response in older subjects (Mazziotta et aI., 1981; Vide en et aI., 1988). Ignoring correction for atrophy would en hance the probability of finding a decreased re sponse with advancing age. We did not correct for atrophy and yet still did not identify such a de-
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=
crease. Consistent global CBF shifts between rest ing state and vibration could alter the response mag nitude found because of global normalization. If such shifts occurred preferentially within the older or younger subjects, this could bias our findings. We found no such shift from the resting to activated states in our present study. Subject selection and alterations in sensory per ception are biological factors that could affect re sponse magnitudes. We selected subjects without a history of cerebrovascular, cardiovascular, psychi atric, or neurologic disorders and tried to minimize medication effects. This is important because some studies have found decrements at rest of CBF, CMR02, or CMRglc with age (Scheinberg et aI., 1953; Fazekas et aI., 1955; Kety, 1956; Lassen et aI., 1960; Gottstein and Held, 1979; Frackowiak et aI., 1980; Frackowiak and Gibbs, 1983), whereas other investigators who have not, suggest that this may have been due, in part, to less stringent selec tion criteria for normals (Dastur et aI., 1963; Duara et aI., 1983, 1984; Perlmutter et aI., 1985). Regional CBF responses are assumed to indicate cortical responses but also could reflect functional loss peripherally at the sensory organ or centrally via altered conduction to cortex. Clinically, our subjects had normal sensory exams, but a subclin ical loss of sensory function could alter the rCBF response. Several investigators have measured vi-
REGIONAL CBF RESPONSES IN NORMAL AGING brotactile thresholds in normals and found an in crease in perception threshold with increasing age. However, a 100-Hz vibration with 100-fLm ampli tude exceeded the perception threshold for the old est subjects (Gerr et aI., 1990; Rowland et aI., 1989; Era et aI., 1986; Halonen, 1986). The vibrator used in the present study is far above this threshold, making it unlikely that a subclinical change in end organ function affected our results. Finally, changes in central conduction could affect rCBF responses. Electrophysiologists argue whether pe ripheral or central conduction times are prolonged with increasing age (Mervaala et aI., 1988; Verroust et aI., 1989, 1990; Allison et aI., 1983; Chu, 1986; Small and Matthews, 1978; Dorfman and Bosley, 1979; Hume et aI., 1982; Kakigi, 1987), but differ ences in conduction times are on the order of mil liseconds and unlikely to affect PET measurements of rCBF that integrate activity over 40 s. Finally, it is important to know how sensitive this study is for the detection of a significant decrease in response magnitude with age. A power analysis of our data demonstrates a high degree of confidence (99.7% for PSA and 87% for SMA) for detecting at least a moderate correlation (r = 0.6) between re sponse magnitude and age. Therefore, we are con fident that there is no significant relationship be tween magnitude of response and increasing age. In addition to response magnitudes, we found that response locations were the same in older and younger subjects with the one exception of a more medial PSA response in the right hemisphere in the younger group. This difference is of small magni tude (4 to 7 mm) compared to the standard devia tions (3.6 to 5.0 mm) of the PSA response locations. We did not find this in an earlier study (Tempel and Perlmutter, 1990), which may reflect sampling bias due to the small number of subjects. Structural or functional variability may increase the variance of response locations but the variance that we found is similar to that found by others (Fox et aI., 1987). Methodologically, this difference cannot be ac counted for by a systematic movement artifact be tween rest and activation scans in the younger sub jects. Artifact due to movement between scans was specifically assessed by percent difference images before accepting each subtraction pair for analysis. Also, such an artifactual difference would not be one-sided but would be reflected in a more lateral location in the opposite hemisphere. Response lo calization using our laboratory's automated search routine is an objective technique that is highly ac curate across subjects despite limitations of resolu tion with positron emission tomography in general
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and PETT VI in particular (Fox et aI., 1986) and would not be a source of location bias for one axis in one region's response. Additionally, if age related atrophy were playing an important role, we would expect a more medial response in the older subjects, just the opposite of what we found. While much has been reported on resting CBF in aging, little has been reported regarding the aging brain's capability to react to a stimulus. A stimulus, or task-induced rCBF response, is used as an index of neuronal activity. This index depends upon local vascular reactivity. If vascular reactivity changes with normal aging, it could affect our PET measured responses in blood flow independent of alterations in neuronal activity. Although there have been numerous investigations of vascular re sponses to alterations in CO2 or sudden hypoten sion, these data have not been entirely consistent. Most have found decreased reactivity with age (Amano et aI., 1983; Meyer, 1980; Yamamoto et aI., 1980; Yamaguchi et aI., 1979; Reich and Rusineck, 1989; Rogers et aI., 1985), but at least one large study (Davis et aI., 1983) did not and others found only nonsignificant trends (Schieve and Wilson, 1953). Since we did not find a decrease in vibration induced rCBF responses with age, this implies that neuronally driven vascular reactivity does not di minish with normal aging. Neuronally driven vascular reactivity, as mea sured by PET and H � 50, can be an important tool to assess physiological function in patients that may otherwise have normal "resting state" flow or me tabolism. For example, patients with focal dystonia have an abnormally low magnitude of response in the sensorimotor cortex to hand vibration, whereas, these same patients had no identifiable abnormality in the resting state (Tempel and Perlmutter, 1990). This approach, analogous to "stress tests" used in other disciplines, can be applied to patients with other neurological conditions, although several im portant caveats must be appreciated. Interpretation of an altered rCBF response to a particular task must consider task performance. For example, im paired sensory end organ function may impair a brain blood flow response to a sensory activation paradigm and not reflect any change in brain func tion, per se. Other activation paradigms may mea sure the brain response during performance of spe cific motor tasks. An investigator must carefully monitor subjects for differing task performance that, may not be due to changed brain function. For ex ample, in finger tapping, one group may systemat ically perform at a slower rate due to less interest, arthritis, or many other potential variables. Finally,
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any condition that impairs local vascular reactivity could invalidate regional CBF changes as an index of neuronal activity. Acknowledgment: We thank Lennis Lich, John Hood, Jr., and Lori McGee-Minnich for expert technical assis tance. We also appreciate the help of all the members of the Division of Radiation Sciences (Mallinckrodt Institute of Radiology). This work was supported by the McDon nell Center for the Study of Higher Brain Function; the Greater St. Louis Chapter of the American Parkinson Disease Association; NIH grants HL13851, NS06833, and AG08377; and National Research Service Award NS08688 (L.W.T.).
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Vibration-Induced Regional Cerebral Blood Flow Responses in Normal Aging *:j:Lee W. Tempel and *t:J:Joel S. Perlmutter *Department of Neurology and Neurological Surgery (Neurology), tMallinckrodt Institute of Radiology (Radiation Sciences), and :f:The McDonnell Center for Studies of Higher Brain Function, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
Summary: Task-induced changes in regional CBF (rCBF) can be measured with positron emission tomography (PET) and provide a powerful tool to map brain function. Many studies using these techniques have investigated responses in healthy young subjects. Since many patho logical conditions occur more commonly in older sub jects, it is necessary to compare blood flow responses in these patients with appropriately age-matched controls. Furthermore, the effects of normal aging on such blood flow responses remain unknown. For both reasons, we designed this study to determine whether vibration induced CBF responses change with advancing age in normals. CBF was measured with PET and bolus administered Hi50 in 26 subjects from 20 to 72 years old (mean = 39; SD = 19). Regional responses were identi-
fied by subtraction-image analysis. Left and right hand vibration produced consistent responses in contralateral primary sensorimotor area (PSA) and supplementary mo tor area (SMA). Response magnitudes were compared to age by linear regression. There were no substantial rela tionships between age and responses to vibration for PSA or SMA (PSA r = 0.28, p = 0.054; SMA r = 0.33, p = 0.13). Power analysis demonstrates a high degree of confidence (99.7% for PSA and 87% for SMA) for detect ing at least a moderate correlation (r = 0.6) between re sponse magnitude and age. We conclude that the rCBF responses to vibrotactile hand stimulation do not change with normal aging. Key Words: Normal aging-Blood flow-Activation-Human-Positron emission tomogra phy-Vibration.
Task-induced changes in regional CBF (rCBF) can be measured with positron emission tomogra phy (PET) and provide a powerful tool to map brain function. This approach has been used to map nor mal function (Fox et aI., 1984, 1986, 1987; Raichle, 1986; Petersen et aI., 1988) as well as to identify changes in brain responses in pathological condi tions (Tempel and Perlmutter, 1990; Reiman et aI., 1989). In both types of studies, the investigator as sumes that vascular reactivity is a faithful indicator of neuronal activity and alterations in blood flow responses imply alterations in neuronal activity
(Raichle, 1986). This critical assumption mandates caution when applying this method to patients that may have abnormal cerebral blood vessels, such as patients with cerebrovascular disease (Powers et aI., 1988). Since many pathological conditions oc cur more commonly in older subjects, it is neces sary to determine whether vascular reactivity, in this case as indicated by task-induced rCBF re sponses, changes with normal aging. Knowledge of these rCBF responses in older individuals is impor tant not only for comparisons with pathological conditions in older subjects but also for improving our understanding of how normal brain function may change with age. Previous studies have inves tigated potential alterations in "resting" brain func tion with age. None have evaluated the effects of aging on focal brain activation, although Gur et ai. (1987) found no age-related change in rCBF activa tion with a more global cognitive stimulation using the xenon-133 inhalation technique. For these rea sons, we designed this study to determine whether
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Received October 28, 1991; final revision received January 27, 1992; accepted January 29, 1992. Address correspondence and reprint requests to Dr. Lee W. Tempel at Washington University School of Medicine, Division of Radiation Sciences, 510 S. Kingshighway, St. Louis, MO 63110, U.S.A. Abbreviations used: ANOYA, analysis of variance; PET, pos itron emission tomography; PSA, primary sensorimotor area; rCBF, regional CBF; SMA, supplementary motor area.
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REGIONAL CBF RESPONSES IN NORMAL AGING focal rCBF activation produced by vibrotactile stimulation of a hand changes with normal aging. METHODS We studied 26 subjects including 14 men and 12 women ranging in age from 20 to 72 years (mean = 39, SD = 19). Twenty-three were right-handed, two left-handed, and one ambidextrous. None had evidence of neurological disease. None had a concomitant systemic condition pre senting a risk for, or indicative of, cardiovascular disease except one 60-year-old woman with a history of asymp tomatic hypertension treated with hydrochlorothiazide and propranolol. Furthermore, none had psychiatric dis ease, depression, or dementia by a standard psychiatric screening test (SCID-Hamilton Schedule for Psychiatric Interviews; Williams, 1988), Hamilton Depression Scale (Hamilton, 1960), and Mini Mental Status Exam (Folstein et aI., 1975). Nine subjects took medication but refrained from those that had any effect on blood flow or vascular reactivity: pseudoephedrine (none for at least 12 h prior to study) and propantheline bromide (none for 48 h prior to study). PET studies were performed with the PETT VI system in the low resolution mode (Ter-Pogossian et aI., 1982; Yamamoto et aI., 1982). Data were recorded simulta neously for seven slices with a center-to-center separa tion of 14.4 mm. In-plane (i.e., transverse) reconstructed resolution was about 18 mm (full width at half maximum) in the center of the field of view and axial resolution was about 14 mm at the center. Subject preparation included the percutaneous inser tion of a radial arterial catheter under local anesthesia, to permit frequent sampling of arterial blood, and insertion of an intravenous catheter for isotope injection in the op posite arm. The head was positioned with a special head holder that used an individually molded plastic face mask to prevent movement during the study. A laser perma nently attached to the wall projected a line onto the mask that corresponded to the position of the lowest PET slice. A lateral skull radiograph with this line marked by a ra dio-opaque wire provided a record of the subject's exact position in relation to the PET slices (Fox et aI., 1985). The overlapping position of radio-opaque markers placed in the external auditory canals confirmed that the head was not rotated about the anteroposterior or vertical axes. After the head was in place, a transmission scan used for individual attenuation correction was performed with a ring source of activity containing 68Ge/68Ga. Dur ing each PET scan, the room was darkened and the sub ject's eyes were closed. The ears were not occluded. Am bient room noise during the scans was almost entirely from cooling fans for the electronic equipment. Cerebral blood flow was measured using a 40-s emis sion scan following the i.v. bolus injection of about 10 ml of saline containing 55-80 mCi of 150-labeled water (Her scovitch et aI., 1983; Raichle et aI., 1983; Videen et aI., 1987). The short half-life (122 s) of 150 permitted up to eight repeated measurements in a single study session for each subject. All subjects had measurements of CBF in the resting state and then repeat measurements during vibrotactile stimulation with a vibrator (130 Hz, 2 mm amplitude) held to all five finger pads of one hand (Fox et aI., 1987). Each hand was stimulated during sequential scans with inter-
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posed resting-state scans. Stimulation was initiated at the time of bolus injection of the radiotracer and continued throughout the scan. Each subject was specifically in structed to relax with eyes closed, not to concentrate on the task or stimulus, and not to grasp the vibrator (passive vibration). These studies were approved by the Human Studies Committee and the Radioactive Drug Research Commit tee (United States Food and Drug Administration) of the Washington University School of Medicine. Written in formed consent was obtained before each PET study.
Data analysis Global CBF values were calculated for each scan using a "whole slice" method (Perlmutter et aI., 1985). A tem plate for each slice was made using the appropriate rest state scan by removing all pixels at the edges of the slice with values � ;:; a(/) Ii '0
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(8)
(A)
Left Hemisphere
Right Hemisphere
10 mm
10 mm
FIG. 3. Response locations to hand vibration. Mean coordinates for the primary sensorimotor area and supplementary motor area responses to vibration of the opposite hand in the 26 normal subjects (Y younger subjects 20-27 yrs, 0 older subjects 40-72 yrs) are shown on these pairs of midsagittal and lateral surface brain projections for left (A) and right (8) hemispheres (modified from Talairach et aI., 1967). Error bars correspond to 1 SO. The horizontal lines extending from the brain projections indicate a line through the anterior (AC) and posterior commissures ( PC). The vertical lines represent a line perpendicular to the AC-PC line and intersecting it at one half the distance from anterior to posterior commissure. =
icant differences in the anterior-posterior or verti cal coordinates in PSA or for the three coordinates of the responses in SMA. DISCUSSION We found that rCBF responses to vibrotactile stim ulation of a hand do not significantly decrease with advancing age. This demonstrates preservation of task-induced vascular reactivity and suggests that neu ronal activation does not decline with normal aging. Several technical factors may influence interpre tation of our findings. Response magnitude may be biased by the limited axial field of view of PETT VI. Several of the subjects were not positioned suffi ciently high in the scanner to include SMA. Simi larly, slice separation of 14.4 mm may be inade quate to detect a response between slices. Never theless, we found SMA responses with equal frequency in younger and older subjects. Although we found the magnitude of the center of the re sponse to be unchanged with age, it is possible that the response may be more diffuse in one group. We did not address this issue. Cortical atrophy could lower the measured magnitude of response in older subjects (Mazziotta et aI., 1981; Vide en et aI., 1988). Ignoring correction for atrophy would en hance the probability of finding a decreased re sponse with advancing age. We did not correct for atrophy and yet still did not identify such a de-
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=
crease. Consistent global CBF shifts between rest ing state and vibration could alter the response mag nitude found because of global normalization. If such shifts occurred preferentially within the older or younger subjects, this could bias our findings. We found no such shift from the resting to activated states in our present study. Subject selection and alterations in sensory per ception are biological factors that could affect re sponse magnitudes. We selected subjects without a history of cerebrovascular, cardiovascular, psychi atric, or neurologic disorders and tried to minimize medication effects. This is important because some studies have found decrements at rest of CBF, CMR02, or CMRglc with age (Scheinberg et aI., 1953; Fazekas et aI., 1955; Kety, 1956; Lassen et aI., 1960; Gottstein and Held, 1979; Frackowiak et aI., 1980; Frackowiak and Gibbs, 1983), whereas other investigators who have not, suggest that this may have been due, in part, to less stringent selec tion criteria for normals (Dastur et aI., 1963; Duara et aI., 1983, 1984; Perlmutter et aI., 1985). Regional CBF responses are assumed to indicate cortical responses but also could reflect functional loss peripherally at the sensory organ or centrally via altered conduction to cortex. Clinically, our subjects had normal sensory exams, but a subclin ical loss of sensory function could alter the rCBF response. Several investigators have measured vi-
REGIONAL CBF RESPONSES IN NORMAL AGING brotactile thresholds in normals and found an in crease in perception threshold with increasing age. However, a 100-Hz vibration with 100-fLm ampli tude exceeded the perception threshold for the old est subjects (Gerr et aI., 1990; Rowland et aI., 1989; Era et aI., 1986; Halonen, 1986). The vibrator used in the present study is far above this threshold, making it unlikely that a subclinical change in end organ function affected our results. Finally, changes in central conduction could affect rCBF responses. Electrophysiologists argue whether pe ripheral or central conduction times are prolonged with increasing age (Mervaala et aI., 1988; Verroust et aI., 1989, 1990; Allison et aI., 1983; Chu, 1986; Small and Matthews, 1978; Dorfman and Bosley, 1979; Hume et aI., 1982; Kakigi, 1987), but differ ences in conduction times are on the order of mil liseconds and unlikely to affect PET measurements of rCBF that integrate activity over 40 s. Finally, it is important to know how sensitive this study is for the detection of a significant decrease in response magnitude with age. A power analysis of our data demonstrates a high degree of confidence (99.7% for PSA and 87% for SMA) for detecting at least a moderate correlation (r = 0.6) between re sponse magnitude and age. Therefore, we are con fident that there is no significant relationship be tween magnitude of response and increasing age. In addition to response magnitudes, we found that response locations were the same in older and younger subjects with the one exception of a more medial PSA response in the right hemisphere in the younger group. This difference is of small magni tude (4 to 7 mm) compared to the standard devia tions (3.6 to 5.0 mm) of the PSA response locations. We did not find this in an earlier study (Tempel and Perlmutter, 1990), which may reflect sampling bias due to the small number of subjects. Structural or functional variability may increase the variance of response locations but the variance that we found is similar to that found by others (Fox et aI., 1987). Methodologically, this difference cannot be ac counted for by a systematic movement artifact be tween rest and activation scans in the younger sub jects. Artifact due to movement between scans was specifically assessed by percent difference images before accepting each subtraction pair for analysis. Also, such an artifactual difference would not be one-sided but would be reflected in a more lateral location in the opposite hemisphere. Response lo calization using our laboratory's automated search routine is an objective technique that is highly ac curate across subjects despite limitations of resolu tion with positron emission tomography in general
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and PETT VI in particular (Fox et aI., 1986) and would not be a source of location bias for one axis in one region's response. Additionally, if age related atrophy were playing an important role, we would expect a more medial response in the older subjects, just the opposite of what we found. While much has been reported on resting CBF in aging, little has been reported regarding the aging brain's capability to react to a stimulus. A stimulus, or task-induced rCBF response, is used as an index of neuronal activity. This index depends upon local vascular reactivity. If vascular reactivity changes with normal aging, it could affect our PET measured responses in blood flow independent of alterations in neuronal activity. Although there have been numerous investigations of vascular re sponses to alterations in CO2 or sudden hypoten sion, these data have not been entirely consistent. Most have found decreased reactivity with age (Amano et aI., 1983; Meyer, 1980; Yamamoto et aI., 1980; Yamaguchi et aI., 1979; Reich and Rusineck, 1989; Rogers et aI., 1985), but at least one large study (Davis et aI., 1983) did not and others found only nonsignificant trends (Schieve and Wilson, 1953). Since we did not find a decrease in vibration induced rCBF responses with age, this implies that neuronally driven vascular reactivity does not di minish with normal aging. Neuronally driven vascular reactivity, as mea sured by PET and H � 50, can be an important tool to assess physiological function in patients that may otherwise have normal "resting state" flow or me tabolism. For example, patients with focal dystonia have an abnormally low magnitude of response in the sensorimotor cortex to hand vibration, whereas, these same patients had no identifiable abnormality in the resting state (Tempel and Perlmutter, 1990). This approach, analogous to "stress tests" used in other disciplines, can be applied to patients with other neurological conditions, although several im portant caveats must be appreciated. Interpretation of an altered rCBF response to a particular task must consider task performance. For example, im paired sensory end organ function may impair a brain blood flow response to a sensory activation paradigm and not reflect any change in brain func tion, per se. Other activation paradigms may mea sure the brain response during performance of spe cific motor tasks. An investigator must carefully monitor subjects for differing task performance that, may not be due to changed brain function. For ex ample, in finger tapping, one group may systemat ically perform at a slower rate due to less interest, arthritis, or many other potential variables. Finally,
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any condition that impairs local vascular reactivity could invalidate regional CBF changes as an index of neuronal activity. Acknowledgment: We thank Lennis Lich, John Hood, Jr., and Lori McGee-Minnich for expert technical assis tance. We also appreciate the help of all the members of the Division of Radiation Sciences (Mallinckrodt Institute of Radiology). This work was supported by the McDon nell Center for the Study of Higher Brain Function; the Greater St. Louis Chapter of the American Parkinson Disease Association; NIH grants HL13851, NS06833, and AG08377; and National Research Service Award NS08688 (L.W.T.).
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