Journal of Cerehral Blood Flow alld Metabolism 18:724-734 © 1998 The International Society of Cerebral Blood Flow and Metabolism Published by Lippincott-Raven Publishers, Philadelphia

Cocaine Decreases Cortical Cerebral Blood Flow But Does Not

Obscure Regional Activation in Functional Magnetic Resonance

Imaging in Human Subjects

*Randy L. Gollub, *tHans C. Breiter, t:J:Howard Kantor, §David Kennedy, *David Gastfriend,

*R. Thomas Mathew, §Nikos Makris, t Alex Guimaraes, *Jonn Riorden, tTerry Campbell,

tMary Foley, *Steve E. Hyman, tBruce Rosen, and tRobert Weisskoff

*Department of Psychiatry, tNuclear Magnetic Resonance Center, Department (�f Radiology, tDepartment of Cardiology,

Massachusetts General Hospital and Harvard Medical School, and §the Center for Morphometric Analysis, Massachusetts

General Hospital, Boston, Massachusetts, U.S.A.

Summary: The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (IV) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan se­quences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg IV over 30 seconds) in­creased heart rate and mean blood pressure and decreased end tidal carbon dioxide (C02), All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged

Cocaine addiction is a serious social problem with few

effective treatment strategies. There is limited knowl­

edge of the neurobiology of cocaine addiction, and such

knowledge might help develop more specific treatments.

We wished to apply the newly developed technology of

functional magnetic resonance imaging (fMRI) to study

the mediating neuroanatomy of the cognitive and re-

Received July 28,1 997; final revision received November 1 7,1 997; accepted November 1 7 , 1 997.

Supported by National Institute of Drug Abuse grants DA09467-02, DA0027S-0 1 and DA0026S-0 1 , and National Institutes of Health grant MOl RROJ066 to the Mallinckrodt General Clinical Research Center at Massachusettes General Hospital.

Address correspondence and reprint requests to Dr. Randy L. Gollub, Psychiatric Neuroimaging. Massachusetts General Hospital, CNY 9 1 09, 1 49 1 3th Street, Charlestown, MA 02 1 29, U.S.A.

Abbreviations used: BOLD, blood oxygen level-dependent; CBF, ce­rebral blood flow; ETC02, end-expiratory carbon dioxide; FAIR, flow­sensitive alternating inversion recovery; fMRI, functional magnetic reso­nance imaging; HR, heart rate; MBP, mean blood pressure; ROI, region of interest; SPECT, single photon emission computed tomography.

724

after saline infusion (-2.4 ± 6.5%) but decreased (- 14. 1 ±

8.5%) after cocaine infusion (n = 8, P < 0.0 1). No decreases were detected in white matter, nor were changes found com­paring BOLD signal intensity in cortical gray matter immedi­ately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small ( 14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reli­ably. Key Words: Cerebral blood flow (CBF)-Functional magnetic resonance imaging (fMRI)-Neuroimaging­Psychostimulants.

warding aspects of cocaine abuse in cocaine-dependent

subjects. However, we were concerned that the effects of

cocaine on systemic and cerebral hemodynamics might

interfere with the acquisition of meaningful local neuro­

nal activation maps because fMRI signals depend on

intact coupling between metabolic demand and cerebral

blood flow (CBF).

The most widely used tMRI method, blood oxygen­

ation level-dependent (BOLD) scanning, uses changes in

venous oxygenation of brain tissue as an indirect marker

of detecting neuronal acti vation (Kwong et aI., 1992;

Bandettini et aI., 1992; Blamire et aI., 1992; Ogawa et

aI., 1992; Ogawa et aI., 1990; Turner et aI., 1991). Pos­

itron emission tomography studies have demonstrated

that regional neuronal activation due to sensory stimula­

tion results in an increase in CBF that exceeds the in­

crease in oxygen metabolic demand of that region of

brain tissue (Fox and Raichle, 1986; Fox et aI., 1988).

Enhanced CBF leads to a decrease in local venous de-

COCAINE EFFECTS IN HUMAN fMRI 725

oxyhemoglobin concentration. Because deoxygenated

hemoglobin is a paramagnetic endogenous contrast agent

that decreases local signal intensity (Ogawa et aI., 1992),

enhanced CBF leads to increased BOLD signal.

Cocaine has several direct and indirect effects on the

cerebral vascular bed that may influence the neuronal­

vascular coupling. Most importantly, acute cocaine ad­

ministration increases heart rate and may alter systemic

vascular resistance which, despite central nervous system

autoregulatory mechanisms, may influence CBF. Co­

caine-induced hyperventilation (Richard et aI., 1993)

may reduce the partial pressure of carbon dioxide

(Paco2) in the systemic circulation, which would result

in vasoconstriction of central nervous system vascular

beds (Edvinsson et aI., 1993; Vi Hringer and Dirnagl,

1995). Finally, each of the monoamines, dopamine, nor­

epinephrine, and serotonin, are known to have potent

vasomotor actions on the perivascular nerve fibers inner­

vating central nervous system blood vessels (Edvinsson

et aI., 1993). Cocaine, by virtue of its blockade of mono­

amine reuptake, enhances the actions of these endog­

enously released neurotransmitters. Because dopamine,

norepinephrine, and serotonin receptors (and transmitter

release) are distributed differentially in the brain, it is

difficult to predict the exact consequences of this effect

on regional CBF.

Recent human neuroimaging studies investigating the

effects of acute cocaine infusion suggest that this drug

may cause fairly widespread changes in glucose metabo­

lism and CBF. A 14% decrease in global glucose use

after acute cocaine infusion has been demonstrated using

fluorodeoxyglucose positron emission tomography (Lon­

don et aI., 1990). In this study, 26 of 29 brain regions

(including all neocortical areas, basal ganglia, portions of

the hippocampal formation, thalamus, and midbrain) that

were investigated showed a significant decrement in re­

gional cerebral metabolic rate for glucose. Decreased

relative CBF in multiple brain regions, including the

basal ganglia, inferior cingulate, and inferior frontal cor­

tex, using single photon emission computed tomography

(SPECT) imaging also has been reported (Pearlson et aI.,

1993). More recently, an approximate 30% global de­

crease in absolute CBF has been reported using SPECT

and a microsphere model in a small cohort of cocaine­

dependent subjects (Wallace et aI., 1996). However, a

conflicting recent study reports increased global CBF

when assessed using the xenon 133 inhalation technique

with SPECT imaging after acute cocaine infusion

(Mathew et aI., 1996).

These observations suggest the possibility that cocaine

effects on CBF may decrease the sensitivity of fMRI

signals associated with BOLD imaging during and im­

mediately after acute cocaine infusion. We used a re­

cently developed fMRI pulse sequence, flow-sensitive

alternating inversion recovery (FAIR) (Kwong et aI.,

1993; Kwong et aI., 1994; Kwong et aI., 1995; Kim,

1995), to measure global effects of cocaine on CBF. The

FAIR technique uses endogenous water protons as a

tracer to detect relative CBF changes. Pairs of inversion

recovery images are acquired by interleaving slice­

selective inversion and nonselective inversion. The sig­

nal enhancement (FAIR image) measured by the differ­

ence between the paired images is directly proportional

to blood flow. Relative changes in images collected dur­

ing two different conditions estimate CBF changes

(Kwong et aI., 1995; Kim, 1995). This method has been

used previously to map functional activation on the basis

of changes in CBF after visual stimulation (Kwong et aI.,

1993) and finger movements (Kim, 1995).

In addition to directly assessing the effect of cocaine

on CBF using FAIR imaging, we also were interested in

determining the stability of the BOLD signal in the set­

ting of the many nonspecific effects of the drug on the

cerebral vascular system. We used a high-contrast, mov­

ing visual stimulus that reliably produces near maximal

fMRI activation in primary sensory occipital cortex

(Kwong et aI., 1992, Tootell et aI, 1995) to determine the

effect of cocaine on BOLD activation.

The goals of this study were 1) to record the detailed

physiologic response to a cocaine infusion in the fMRI

environment; 2) to determine the effect of the cocaine­

induced physiologic changes on global CBF as determined

by the FAIR technique and compare this finding with the

effects of cocaine on the global BOLD signal; and 3) to

quantify the effects of cocaine on functional activation in

occipital cortex using a BOLD scan sequence in a robust,

well-characterized visual stimulation paradigm. The re­

sults of this study support the specificity of the findings

we have reported on the regional brain activation due to

acute cocaine administration (Breiter, et aI., 1997).

MATERIALS AND METHODS

Subject characterization Seventeen actively abusing cocaine-dependent subjects be­

tween the ages of 27 and 46 years (34.5 ± 4.6 years, mean ±

standard deviation [SD]; J 3 men, 4 women; 10 white, 7 black) were recruited by advertising. Substance abuse and other psy­chiatric symptoms were evaluated using standard instruments (Addiction Severity Index [McLellan et aI., 1980], Mini­Structured Clinical Interview for DSM-IIIIR [American Psy­chiatric Association, 19871, Hamilton Anxiety Scale and the Hamilton Depression Scale [Hamilton, 1959; 1960]). Evidence or history of physical disease, history of head trauma with loss of consciousness, family history of sudden cardiac death or cardiac disease, or fulfillment of criteria for any axis I psychi­atric diagnosis other than nicotine and/or cocaine dependence, alcohol or marijuana abuse, or abnormal response to a test dose (0.2 mg/kg intravenously over 30 seconds) of cocaine were exclusionary criteria. Subjects reported heavy, long-term co­caine use (median 7.8 ± 6.0 years; range, 2-25 years) with current use being 16 ± 8.2 days/month (range, 6-30 days). Smoking was the current primary route of self-administration for most subjects; many had abused cocaine intravenously in

J Cereb Blood Flow Metab. Vol. 18, No. 7, 1998

726 R. L. GOLLUB ET AL.

the past. None were receiving or seeking treatment for sub­stance abuse. All subjects had a urinalysis confirming recent cocaine use but were abstinent from cocaine and alcohol for at least 19 to 28 hours before each imaging session. All were right handed, as assessed by self-report. Subjects gave informed con­sent and the experimental protocol was approved by the Sub­committee on Human Studies at the Massachusetts General Hospital (MGH).

Experimental design Each subject was admitted to the MGH General Clinical

Research Center (GCRC) for the screening procedures; those meeting all criteria were boarded overnight on the unit in preparation for imaging the following day. In the morning, each subject had bilateral intravenous catheters placed (right forearm for cocaine infusion, left forearm for serial venous blood sam­pling for quantitative cocaine levels). Scanning was performed between II AM and 3 PM, during which the subject was in the scanner for two epochs of time each lasting from 45 to 90 minutes. During each scanning epoch, one infusion was given, either cocaine (0.6 mg/kg, maximum dose 40 mg) or saline (both in a volume of 10 mL administered over 30 seconds intravenously) in a randomized, double-blind order. Five dif­ferent scans were performed during each epoch (Fig. I). The infusion itself was made 5 minutes into an 18-minute BOLD scan (the cocaine-specific regional activations revealed in this part of the study are reported in a separate manuscript, Breiter et a!., 1997). The infusion scan was bracketed by FAIR and visual stimulation BOLD scans. The time interval between functional scans within an epoch was kept to a minimum. The entire sequence of five functional scans was completed within 45 to 60 minutes. The subject was removed from the scanner for a 15- to 30-minute rest and then was returned to magnet, where the entire sequence was repeated for the second infusion.

Sequential 3-mL venous blood samples were collected im­mediately before and at I, 3, 5, 10, 15, 30, 60, 90, and 120 minutes after each infusion. The 120-minute sample for the first infusion also was the preinfusion sample for the second infu­sion. Cocaine quantitative assays were performed by the MGH Clinical Chemistry Laboratory (Puopolo et aI., 1992).

Physiologic monitoring Physiologic monitoring was conducted using an InVivo Omni­

Trak 3100 patient monitoring system (Invi vo Research, Orlando, FL, U.S.A.) modified to permit on-line computer acquisition of physiologic measurements. Electrocardiogram, heart rate (HR), end-expiratory carbon dioxide (ETC02), and noninvasive sys­temic mean blood pressure (MBP) were measured continuously. The temporal resolution of the system for sampling blood pres­sure was once every 2 minutes. Values for each of the other

Infusion #1

t

parameters were sampled once per second, except for the elec­trocardiogram trace, which was digitized at a rate of 100 Hz.

The measured physiologic parameters were ported to a Mac­intosh Power PC 7 100 (Cupertino, CA, U.S.A.) running a cus­tom National Instruments LabView data acquisition program (National Instruments, Austin, TX, U.S.A.). This program al­lowed simultaneous acquisition of 1) digitized analog electro­cardiogram trace, 2) the scanner trigger pulse, which indicated when the gradient coils of the magnet were firing, and 3) physi­ologic measures from the In Vivo system.

Precautions taken to ensure safe conduct of the study in­cluded use of advanced cardiac life support (ACLS) trained personnel, frequent running of mock codes, and the presence of a cardiologist at the time of all infusions, whose sole respon­sibility was to monitor subject safety. Because of magnetohy­drodynamic effects on the electrocardiogram tracing, a baseline rhythm strip was obtained before each drug infusion, to which all subsequent tracings were compared.

Imaging parameters Images were collected on a GE 1.5T Signa imager, retrofit­

ted for echo planar imaging by Advanced NMR, Inc. (Wil­mington, MA, U.S.A.), using a quadrature head volume coil for signal reception. A dental impression bite bar was used to help stabilize head position and minimize movement between scans. A sagittal localizer scan was performed for placement of the experimental slices, followed by an automated shim procedure to improve Bo magnetic field homogeneity (Reese et aI., 1995). An echo planar imaging multislice T I-weighted spin echo high-resolution scan for anatomic referencing of functional data was performed.

Functional scans were obtained to examine task-related dif­ferences in cerebral activity during visual stimulation using a T 2 *-weighted asymmetric spin echo sequence (the BOLD scans) (� T [offset time) = -25 ms, TR [repetition time) =

3000 ms, TE [echo time] = 70 ms, Flip = 90°, in plane resolution = 3. 1 x 3. 1 mm, through-plane resolution = 8 mm). Fifteen contiguous axial slices were chosen to extend from the superior surface of the cortex through the temporal lobes for the BOLD scans. Sixty images per slice were collected for a total scan duration of 3 minutes.

Flow-sensitive alternating inversion recovery scans were collected for a single slice, using the center slice of the 15 slices used for the BOLD scans so that all imaging could be per­formed without movement of the subject within the bore of the magnet. This slice plane sampled frontal, parietal, and cingulate cortical regions. The FAIR imaging consisted of an inversion recovery sequence (TR time = 3500 ms, TE = 40 ms, TI [inversion time) = 1300 ms, in plane resolution = 3. 1 x 3. 1 mm, through-plane resolution = 8 mm). One hundred twenty-

Infusion #2

t 0:-: •.•.•.•.•.•.• :-., ..•.•.•.•.•.•.•.•.•.• f_h!lr�ru.t BOLD .:»':.'I�.!f_l�: ::::::::::::::::::::: �:.:.:!::::::::;::::

j j /1 ,I-' ----""'"1 ----...-.pool o 1 Hour 2 Hours 3 Hours 4 Hours

FIG. 1. Schematic diagram of experimental paradigm. BOLD, blood oxygen level-dependent; FAIR, flow-sensitive alternating inversion recovery.

J Cereb Blood Flow Metab, Vol. 18, No. 7, 1998

COCAINE EFFECTS IN HUMAN fMRI 727

eight images (64 pairs) of the single 8-mm slice were collected during each 7:38 minute scan.

The BOLD imaging parameters during the infusion scan were identical to those reported previously for the visual stimu­lation BOLD scans, with the exception of a longer TR (8000 ms) and longer scanning duration (136 images per slice, total scan time 18:24 minutes) (Breiter et aI., 1997).

Visual stimulation paradigm Subjects lay supine in the magnet looking up into a mirror

aimed at a rear-projection screen situated at chin level. Images were projected from outside the scanner room, through a col­limating lens, onto the rear-projection screen. S-VHS video signals were generated from a Macintosh computer equipped with a Radius VideoVision interface.

The visual stimulus used was a circular black-and-white checkerboard pattern counterphase t1ickering at 4 Hz. This stimulus optimally evokes fMRI measurable cortical gray mat­ter activity in both primary and secondary visual areas, includ­ing the motion sensitive area mediotemporal (Tootell et aI., 1995; Sereno et a!., 1995). The experimental paradigm con­sisted of alternating 45-second blocks of rest (darkness) and visual stimulation. The subject was instructed to remain still with eyes open and fixed on the center of the screen throughout the 3-minute scan.

DATA ANALYSIS

Physiology

Continuously collected physiologic measures were

matched to concurrently collected scanner trigger pulses

to determine values at relevant time points in the study.

Data were analyzed first by an analysis of variance

(ANOV A) with time as the factor. When significant F

values were obtained for one of the physiologic mea­

sures, the individual time points were compared by post

hoc Student's t tests to determine at what times the

change from baseline, defined as the value just before the

infusion, was significant. The Bonferroni correction for

multiple comparisons was used; the criteria for signifi­

cance at the 0.05 level was P < 0.007.

Motion correction

All data sets were motion-corrected using a software

registration algorithm based on the work of Woods and

colleagues (Jiang et aI., 1995; Woods et aI., 1992). As

discussed previously (Breiter et aI., 1996), the motion

correction process often causes artifact in the first and

last slices in a stack of slices. In the case of a single slice

(as in the FAIR data sets), the algorithm minimizes

within plane motion only and does not corrupt the slice

data. Because of the complexity of MRI signal depen­

dence on bulk movement, this motion correction algo­

rithm remains an approximation. As a result, any data set

evidencing excessive motion (movement > 1.5 mm for

the FAIR scans, and> 3.5 mm for the BOLD scans) was

excluded from further analysis.

Flow-sensitive alternating inversion recovery data

Flow-weighted images were obtained by subtracting

the flow-insensitive images from the flow-sensitive im-

ages. The resulting subtraction images were used as an

index of steady-state flow values (Kim, 1995; Kwong et

aI., 1995). The percent change at each pixel between

steady state flow measured during the preinfusion scan

and the postinfusion scan was used to estimate the per­

cent CBF change due to the infusion (Kwong et aI.,

1995; Kim, 1995). Regions of interest (ROIs) (whole

slice, cortical gray matter and white matter) were drawn

on the first FAIR image collected for each subject. The

average signal intensity value for the averaged pixels

within a given ROJ was calculated for each of the four

scans from each subject. To determine the effect of co­

caine on CBF, we calculated the percent change between

the pre infusion and postinfusion FAIR scans in the av­

erage signal intensity for each of these ROIs. The CBF

measurements made by this FAIR technique are relative

values; however, the percent change in this measurement

after cocaine infusion provides a reasonable estimate of

the absolute change in CBF.

The same ROIs generated for the FAIR data analysis

were used to determine the average signal intensity of the

first 38 images (5 minutes of preinfusion resting state)

and the last 38 images (last 5 minutes of BOLD scan).

The percent difference between these values for each

subject was used as the measure of global BOLD signal

change due to the infusion. Statistical significance was

determined using Student's t tests to compare the change

in CBF after saline (pre minus post) and cocaine (pre

minus post) infusion with degrees of freedom (n - 1)

determined by the number of subjects (n) in the com­

parison.

Of the 17 subjects studied, 8 subjects had interpretable

FAIR data sets for both the saline and cocaine infusions

(2 did not have saline infusions, 6 were excluded because

of excessive movement, and I was excluded because of

technical problems with the scanner). One of the studies

included in the final analysis was collected during a rep­

licate imaging session; data from the original imaging

session had to be discarded; thus, the subject is repre­

sented only once in the final cohort.

Visual stimulation data

Motion-corrected images were transformed into statis­

tical maps using parametric unpaired Student's t tests to

compare, at each pixel, the mean of the time points in the

stimulated versus rest conditions. The image data were

smoothed, using a two-dimensional, center-weighted

kernel analogous to a Hanning filter, so that each pixel

was correlated with its neighboring pixels. This process

decreased the effective spatial resolution to 6 x 6 x 8

mm3. The statistical map was transformed to a P value

map and displayed in pseudocolor (as a useful surrogate

for a map of neural activity) and superimposed on a

gray-scale high resolution Tl-weighted echo planar im­

age. The resultant maps were examined to identify re-

J Cereb Blood Flow Metab, Vol. 18, No. 7, 1998

728 R. L. GOLLUB ET AL.

gions that showed significant visual stimulation-related

signal change (activation) (Breiter et aI., 1996; Breiter et

aI., 1997).

The values used to make quantitative pre- versus post­

saline and cocaine infusion comparisons of fMRJ signal

change were obtained using an ROI that represented

equally weighted activation in each of the four scans.

Thus, for each subject, the four visual stimulation BOLD

scans were averaged together, and the averaged data

were used to generate an averaged Student's t test sta­

tistical map. This averaged t map was adjusted to display

all voxels with a threshold above to the conservative P < 10-6 level, which would represent the Bonferroni correc­

tion for every voxel we acquired in the brain (Breiter, et

aI., 1997), and was used to draw an RaJ for each slice

containing significantly activated pixels in the primary

visual cortical region. These ROls then were used to

calculate the percent signal change in each of the four

visual stimulation scans. A weighted average percent sig­

nal change (% D) from the ROls was calculated for each

of the four visual stimulation BOLD scans. Two-way

ANOV A was used to determine significant change due

to drug and condition.

Eight of the 17 subjects had interpretable visual stimu­

lation BOLD scans for both the saline and cocaine infu­

sions (2 did not have saline infusions, 3 were excluded

because of technical problems with the scanner, and 4

� 100 � 1ii -0=: 8 � � 80

60

i _ 120 � 0:: '" � i 100 .. -;; 80 �

···S" Saline Infusion ........ Cocaine Infusio

, ,

were excluded because of flawed timing of the visual

stimulus presentation). One of the studies included in the

final analysis was collected during a replicate imaging

session because their data from the original imaging ses­

sion had to be discarded.

RESULTS

Cocaine levels

Plasma samples taken before the first infusion dem­

onstrated absence of residual cocaine in all of the sub­

jects studied. Peak plasma cocaine leve (Cmax) after the

cocaine infusion ranged from 197 to 893 /-Lg/L with a

mean of 389 ± 233 (n = 7 subjects). The time to peak

varied from 3 to 15 minutes in the group.

Physiology

Physiologic monitoring during the fMRI study showed

the expected effects of cocaine on the cardiorespiratory

system (Figs. 2 and 3). In all subjects, the HR began to

increase within the first minute after cocaine infusion;

MBP increased more slowly and less dramatically, and

the ETC02 dropped slightly after a delay. The changes in

HR, MBP, and Ll ETC02 after cocaine infusion were

statistically significant according to the ANa V A criteria

(P < 0.0001, P < 0.002 and P < 0.0001, respectively).

Figure 2 shows the averaged physiologic data from all

subjects at selected time points most relevant to the in­

terpretation of the fMRI data. Figure 3 shows the con-

N o u :�l + + � ... ? -6 ______________________________________________ �_ *_* _** ____ �---

Visual FAIR pre-infusion 2 min post 5 min post 10 min post FAIR Visual Stimulation Stimulation

FIG. 2. Averaged physiologic responses at specific time points relative to the cocaine (_) and saline (0) infusions are shown; heart rate (HR) in the top portion, mean blood pressure (MBP) in the center, and change in end-expiratory carbon dioxide (ETC02) at the bottom. The measures shown are at discrete time points; the connecting lines do not represent continuous data but rather serve to facilitate comparisons between data points. Each graph includes measurements taken during the preinfusion visual stimulation blood oxygen level-dependent (BOLD) scan, during the preinfusion flow-sensitive alternating inversion recovery (FAIR) scan, during the infusion BOLD scan (preinfusion and at 2, 5, and 10 minutes postinfusion), and during the postinfusion FAIR and visual stimulation scans. Note how stable the physiologic measures are throughout the saline infusion and during the preinfusion interval before cocaine. Data were analyzed first by analysis of variance, with time of measurement as the factor. When significant Fvalues were obtained for one of the physiologic measures, individual time pOints were compared by post hoc Student's t tests to determine at what times the change from baseline was significant. The Bonferroni correction for multiple comparisons was used; the criteria for significance at the 0.05 level was P < 0.007. The mean ± standard deviation is presented for each measure for the entire group (n = 17 for cocaine, n = 14 for saline) studied. There were no significant differences between the values shown here and those of the subgroups used for the final quantitative visual stimulation BOLD or FAIR studies. * P < 0.05; **P < 0.01; ***P < 0.001; ****P < 10-7.

J Cereh Blood Flow Metab. Vol. 18. No. 7. 1998

COCAINE EFFECTS IN HUMAN fMRI 729

tinuous physiologic data (HR, MBP, and 11 ETC02) re­

corded from a representative subject during each of the

two scanning epochs (saline and cocaine infusions). In

both the averaged and the individual data, note the sta­

bility of the measurements over the duration of the saline

infusion scanning epoch as well as during the preinfusion

phase of the cocaine infusion scanning epoch.

Cocaine (n = 17) caused the HR to rapidly increase

from a preinfusion value of 60 ± 7 bpm to 79 ± 16 bpm

at 2 minutes postinfusion (P < 0.000 I), to 82 ± 12 bpm

at 5 minutes postinfusion (P < 10-6), to 93 ± 14 bpm at

10 minutes postinfusion (P < 10-8). By the time the

postcocaine infusion FAIR scan was collected, the HR

(8 1 ± 1 1 bpm) had begun to return to baseline; however,

it still was elevated significantly over the HR (59 ± 6

bpm) at the time of the preinfusion FAIR scan (P < 0.0001). Similarly, the HR continued to return toward

baseline as the postcocaine infusion visual stimulation

BOLD scan was collected; however, the HR still was

elevated significantly over the preinfusion visual stimu­

lation time point (62 ± 4 bpm compared with 75 ± 10

bpm, P < 0.01). Normal sinus rhythm was observed in all

subjects throughout the study.

Mean blood pressure increased slightly from 96 ± 12

torr before the cocaine infusion to 10 1 ± 12 torr at 2

minutes postinfusion (P < 0. 1 1, not significant [NS]),

then up to III ± 15 torr at 5 minutes (P < 0.002) before

starting to slowly decrease. The MBP still was slightly

but not significantly elevated by the time the postcocaine

infusion FAIR and postcocaine visual stimulation scans

were collected.

ETC02 measures do not reflect absolute measures of

PaC02; however, ETC02 provides a reliable estimate of

true changes in PaC02. Because of this, we chose to

analyze and display the data in the figures in terms of the

change in ETC02 (11 ETC02) from the baseline measure

for each individual. The absolute values of ETC02 de­

creased slowly from a preinfusion value of 39 ± 4 mm

Hg to 36 ± 4 mm Hg by 10 minutes and remained at this

level during the time the postinfusion FAIR scan was

collected. The 11 ETC02 was significantly different be­

tween the pre- and postcocaine infusion FAIR (P < 0.00 1) and visual stimulation BOLD (P < 0.05) scans.

There was no change in any of the measured physi­

ologic parameters during the scanning epoch in which

saline was infused. Note the greater variability in the

group data points after the cocaine infusion in all three

measures. This indicates the interindividual variability

not only in magnitude of change but also in the duration

of the response. In all subjects, all measures had returned

to baseline by 2 hours after the cocaine infusion. Statis­

tical analysis of these physiologic measures for the sub­

groups used for the FAIR data analysis and the visual

stimulation BOLD data analysis did not differ from the

whole group.

Flow-sensitive alternating inversion recovery

imaging data

Eight subjects had interpretable data from matched

pre- and postcocaine and pre- and postsaline FAIR scans.

The three ROls generated for each subject to analyze the

FAIR data included whole slice (43 1 1 ± 363 mm2), cor­

tical gray matter (2022 ± 32 1 mm2) and white matter

(354 mm2). These are shown for a typical subject in Fig.

4. The slice plane included regions of frontal, cingulate,

and parietal cortex.

By FAIR imaging, both whole-slice and cortical gray

matter CBF were unchanged (-3.7 ± 5.3% and -2.4 ± 6.5%, respectively) after saline infusion, but decreased

(- 13.3 ± 6.8% and - 14. 1 ± 8.5%, respectively) after

cocaine infusion (whole slice P < 0.0 1, cortical gray

matter P < 0.0 1; Table I). This effect was not seen when

the ROI included only areas of white matter (Table 1).

Increasing the cohort to include subjects with usable data

from only one of the two infusions did not alter the

results; for n = 9 saline infusions and n = 14 cocaine

infusions, there was a significant decrease in FAIR mea­

sured CBF after cocaine but not saline in the whole slice

(- 12.7 ± 7. 1 %, P < 0.00 1) and in cortical gray matter

(- 14.0 ± 8. 1 %, P < 0.0006). This decrease was not de­

tected in white matter (-5.8 ± 17.6%).

In contrast, the BOLD signal intensity did not change

significantly in these same ROIs when the average of 5

minutes of preinfusion images were compared with the

average of 5 minutes of postinfusion images after co­

caine or saline infusions (n = 8, Table 2). The percent

signal change was less than 0.5%.

Visual stimulation data

All subjects showed specific fMRI signal increases in

the primary visual cortical area that temporally corre­

lated with the stimulus presentations. Quantitative analy­

sis showed no significant difference in the visual stimu­

lation-induced fMRI signal increase in primary visual

cortex after cocaine or saline infusion (Table 3, Fig.

5).The marked stability of this activation across multiple

scans for each subject is apparent in the group data pre­

sented in Table 3. The range of activation that was ob­

served (0.77-2.97%), including all four scans from each

of the eight subjects analyzed, was well within that re­

ported by others (Kwong et aI., 1992, Tootell et aI.,

1995) using this type of paradigm. Figure 5 presents the

TABLE 1. FAIR percent change preinfusion versus postinfusion

Saline Cocaine

Whole

-3.7 ± 5.3 - 1 3.3 ± 6.8*

Cortical gray White

-2.4 ± 6.5 -3.2 ± 1 1 . 1 - 1 4. 1 ± 8.5t -3.3 ± 1 6.4

Mean ± SD, n = 8 paired infusions. FAIR, flow-sensitive alternating inversion recovery.

* p < 0.007; tP < 0.0 1 .

J Cereb Blood Flow Metab, Vol. 18, No. 7, 1998

730

... ....

�

Of

o U E-< � <1

o

FIG. 4. The regions of interest (ROls) used in the quantitative flow-sensitive alternating in­version recovery (FAIR) data analysis for one representative subject are shown in yellow superimposed on first FAIR image. In this subject, the ROI for the whole slice was 4311 ± 363 mm2, cortical gray matter was 2022 ± 321 mm2, and white matter was 354 mm2. The ROls were used to calcu­late the percent change pre­versus postinfusion for both the FAIR and blood oxygen leve l-d e p e n d e n t (BOLD) scans.

J Cereb Blood Flow Metab, Vol. 18, No. 7, 1998

R. L. GOLLUB ET AL.

Time (seconds)

FIG. 3. Continuously recorded physiologic measures from a representative subject col­lected during the saline infu­sion epoch (dotted lines) and cocaine infusion epoch (solid lines). Heart rate (HR) is shown in the top portion, mean blood pressure (MBP) in the center, and change in end­expiratory carbon dioxide (ETC02) at the bottom. The 30-second infusion is indicated by the thin gray bar. The HR begins to increase rapidly within the first minute after the cocaine infusion; the increase in MBP is slower and less dra­matic, as is the delayed de­crease in ETC02. Note the greater variability of the mea­sures in the interval immedi­ately following the cocaine in­fusion.

FIG. 5. Demonstration that vi­sual stimulation produces equivalent functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) activation in primary visual cortex in the presence or absence of cocaine. Quan­titative and qualitative assess­ment of a single subject is dis­played in these Student's ttest maps from each of the four vi­sual stimulation scans (before and after the saline and co­caine infusions), thresholded to the conservative P < 10-6 level and displayed superim­posed on the first image of the BOLD scan from that slice, which includes a portion of the primary visual cortex. The per­cent signal change is indicated adjacent to each map.

COCAINE EFFECTS IN HUMANfMRI 731

TABLE 2. BOLD percent change preinjilsion versus postinjusion

Saline Cocaine

Whole

-0.4 ± 0.5 0.2 ± 0.7

Cortical gray

-0.5 ± 0.5 0.2 ± 0.8

White

-0.3 ± 0.7 0.3 ± 0.5

Mean ± SO, n = 8 paired infusions. BOLD, blood oxygen level­dependent.

data from a representative subject; the Student's t test

statistical maps of a single slice, which include a portion

of the primary visual cortex from each of the four visual

stimulation scans, thresholded to the conservative P < 10-6 level, are shown superimposed on the high­

resolution T I-weighted scan. The variance in the fMRI

signal itself did not change after cocaine infusion for

either the baseline (dark) or activation (flashing lights)

condition (n = 7).

DISCUSSION

The physiologic responses to the 0.6-mg/kg intrave­

nous cocaine infusion reported in the present study are in

close accord with previously published studies in expe­

rienced cocaine abusers (Fischman and Schuster, 1982;

Fischman et aI., 1985; Foltin and Fischman, 1991;

Mathew et aI., 1996). All subjects responded to the drug

with a rapid increase in HR that slowly returned to rest­

ing rate by 45 to 90 minutes, a moderately fast but more

modest rise in MBP that also returned to baseline levels

by 45 to 90 minutes, and a slow-onset, small decrease in

ETC02. Cocaine has been shown to increase systolic BP

with less effect on diastolic BP (Foltin et aI., 1995).

Because our noninvasive pressure transducer only mea­

sures MBP, the apparent cocaine effect on BP may ap­

pear smaller than reported in other studies (Mathew et

aI., 1996). Although we did not measure respiratory rate

systematically, we did note a rise in respiratory rate in

several of the subjects similar to that reported in a recent

study (Mathew et aI., 1996).

Cocaine (0.6 mg/kg) reduced the relative CBF in cor­

tical gray matter by 14%, as assessed by FAIR imaging.

The cocaine effect was specific because the decrease was

found in cortical gray matter but could not be detected in

white matter and was not present after saline infusions.

Global BOLD fMRI signal intensity in cerebral gray

matter was unchanged at a comparable time point. At a

time point very close to the FAIR-measured decrease in

CBF, stimulus-induced BOLD activation in primary vi­

sual cortex was unchanged quantitatively by cocaine in­

fusion. Thus, despite a measurable global cortical gray

matter decrease in CBF after cocaine infusion, neuro­

nally mediated specific regional increases in BOLD im­

aging still could be measured reliably.

The observation that acute cocaine infusion decreased

global cortical gray matter CBF but did not change visual

TABLE 3. Percent change in BOLD signal intensity in primary visual cortex during visual stimulation

Saline Cocaine

Mean ± SO. n dependent.

Preinfusion

1 .5 1 ± 0.52 1 .64 ± 0.68

Postinfusion

1 .72 ± 0.80 1 .47 ± 0.55

8 paired infusions. BOLD, blood oxygen level-

stimulation-induced increases in CBF, as measured by

the BOLD imaging, is noteworthy. This result suggests

that fMRI imaging with BOLD contrast is a viable

method for future neuroimaging studies that use pharma­

cologic challenges with drugs that have effects on the

cardiac and/or respiratory system.

A limitation of this study is that the quantitative as­

sessment of cocaine effects on the visual stimulation

BOLD activation was not performed at the time of maxi­

mal drug effect. Although not maximal, acute cocaine

effects still were evident during the postinfusion visual

stimulation BOLD scan, as evidenced by subjective rat­

ings (data not shown), persistently elevated HR and

MBP, and persistently decreased ETC02.

Our results, a 14% decrease in CBF in frontal, parietal,

and cingulate cortical areas 15 to 30 minutes after co­

caine infusion, are consistent with several prior neuro­

imaging studies demonstrating widespread psychostimu­

lant-induced decrease in CBF. Acute cocaine infusion

decreased relative CBF, as assessed by SPECT imaging

using the tracer technetium Tc 99m hexamethyl­

propyleneamine-oxime (HM-PAO; Pearlson et aI.,

1993). Although these investigators measured CBF 1 and

5 minutes after drug infusion, the relative decrease in

CBF was evident in multiple cortical regions. More re­

cently, Wallace and colleagues (1996) reported a 30%

decrease in absolute CBF at the time of peak cocaine

subjective effects (within the first few minutes after in­

travenous infusion), using technetium Tc 99m HM-PAO

SPECT with a modified microsphere model, in all brain

regions assessed (including right and left sides of the

caudate, putamen, globus pallidus, thalamus, anterior

cingulate, prefrontal, precentral, and occipital cortex, as

well as cerebellum). This seems consistent with our 14%

decrease measured 15 to 30 minutes after infusion of a

comparable dose of cocaine. Acute methylphenidate in­

fusion decreased CBF globally, as assessed by positron

emission tomography 150-water studies (Wang et aI.,

1994). The CBF decrease was present by 5 to 10 minutes

after methylphenidate infusion, persisted at 30 minutes

postinfusion, and was seen in all cortical regions inves­

tigated. Our results conflict with those presented by

Mathew and colleagues (1996), who used the xenon 133

inhalation technique with SPECT imaging to measure an

increase in CBF after acute 0.3-mg/kg cocaine infusion.

This increase still was evident at the 30-minute postin-

J Cereb Blood Flow Metab. Vol. 18, No. 7. 1998

732 R. L. GOLLUB ET AL.

fusion time point, which corresponds to the time at which

our FAIR data were collected. A possible explanation for

the difference between studies is dose dependence be­

cause Mathew et al. (1996) studied a dose roughly half

the amount that was used in the present study. Also, they

did not determine cocaine use by toxicology screens be­

fore or by quantitative levels at the time of the study, so

prior exposure or current intoxication are possible con­

founding factors.

The cocaine-induced decrease in CBF in cortical gray

matter documented by the FAIR scans could have re­

sulted, at least in part, from an increase in respiratory

rate, which drove down the partial pressure of CO2

(PaC02), signaling vasoconstriction in brain tissue (Guy­

ton and Hall, 1996; Edvinsson et a!., 1993). Coupling of

CBF and neuronal oxygen metabolism is maintained in

nonpathologic and normocapnic humans. However, this

coupling is perturbed by changes in PaC02 over the

range of 20 to 80 mm Hg; across this range, CBF in­

creases fourfold without a change in the cerebral meta­

bolic rate of oxygen (CMR02). Current literature sug­

gests that in the human brain, a l-mm Hg change in

partial pressure of CO2 in the blood signals a 3% to 5%

change in CBF (Maximilian et aI., 1980; Kety and

Schmidt, 1948). The 2-mm Hg decrease in mean ETC02,

measured at the time the postcocaine infusion FAIR scan

was acquired, would predict approximately a 6% to 10%

CBF decrease; such a decrease is consistent with our

results. However, for each individual, the correlation be­

tween change in ETC02 and percent change in FAIR

after cocaine infusion did not reach statistical signifi­

cance (r = 0.15 , df 12, P < 0.6, NS). When the data

from both saline and cocaine infusions were included in

the analysis, the trend was concordant with the predicted

relationship between PaC02 and CBF, yet the correlation

between the measures still did not reach statistical sig­

nificance (r = 0.36, df 23, P < 0.09, NS) (Fig. 6). The

calculated regression slope for the correlation between

change in ETC02 and percent change in FAIR is a 2.1 %

change per mm Hg (Fig. 6). We conclude that although

it is possible that a respiratory-driven decrease in PaC02

may explain partially the drop in CBF after cocaine in­

fusion, this explanation still is questionable.

The absence of a concomitant BOLD decrease at a

time point close to the occurrence of a FAIR decrease has

several potential interpretations. The first is that the de­

crease in CBF was so small that it is detectable with

fMRI only when using a flow-sensitive technique such as

FAIR. Cerebral blood flow changes contribute less to

changes in BOLD signal intensity than do changes in

oxygenation level. However, we do not think that the

absence of BOLD signal change is due to inadequate

sensitivity. Monte Carlo simulations predict that each 1%

change in T 2 *-weighted fMRI signal intensity corre­

sponds to a CBF change of approximately 13% (Boxer­

man et aI., 1995). A change of this magnitude in the T 2 *

fMRI signal intensity measured 13 to 18 minutes after

cocaine infusion should have been large enough to detect

in our cohort, given the low noise in the data. We believe

that a concomitant decrease in glucose metabolism after

acute cocaine infusion (London et aI., 1990) offset the

decrease in BOLD signal intensity caused by decreased

CBF, with the result that matching changes in blood flow

and oxygen consumption left the hemoglobin oxygen

saturation nearly unchanged. A similar decrease in glu­

cose metabolism also has been demonstrated using tluo­

rodeoxyglucose positron emission tomography studies of

healthy human subjects after acute administration of an­

other psychostimulant, D-amphetamine (Wolkin et aI.,

1987).

A possible alternative explanation is that the decrease

in FAIR is an artifact caused by cocaine-induced vaso­

spasm. Flow-sensitive alternating inversion recovery

measurements of CBF can be affected by the transit time

of blood through large vessels (Buxton et aI., 1996).

Cocaine is a known stimulant of the sympathetic nervous

5,-------------------------------------------------------,

<>

� ;o.! -< -5 • � • =

....

� <> =sJ = • � .= ·15 U

l � •

slope: 2.1 % change FAIR! mm Hg •

-25 ·5 ·4 -3 -2 ·1 o

Change in ETC02 (mm Hg)

J Cereb Blood Flow Metab. Vol. II!. No. 7. 1998

• <>

2

FIG. 6. Correlation between change in end-expiratory car­bon dioxide (ETC02) and per­cent change in flow-sensitive alternating inversion recovery (FAIR) after cocaine (.) and saline ( 0 ) infusions. Data from 14 individuals are presented, eight sets of which are repre­sented twice, once for each in­fusion. Calculated slope of the regression line is 2.1 % change in FAIR per millimeters of mer­cury change in ETC02.

COCAINE EFFECTS IN HUMAN fMRI 733

system and thus would activate the superior cervical gan­

glion that innervates cerebral vasculature. Stimulation of

this pathway signals vasoconstriction; if autoregulatory

mechanisms maintain constant CBF. the increased ve­

locity of flow through the large vessels may create errors

in the quantitation of perfusion. Although the FAIR tech­

nique is less sensitive to these artifacts than other inver­

sion-preparation schemes, we cannot rule out this poten­

tial artifact.

CONCLUSION

These infusion experiments demonstrate that the ef­

fects of intravenous cocaine infusion do not obscure neu­

ronally mediated regional changes in fMRI BOLD sig­

nal. Although a global CBF decrease was measured, vi­

sual stimulation produced regionally specific changes in

primary visual cortex by tMRI BOLD imaging that were

indistinguishable from baseline. We conclude that in the

presence of cocaine, the fundamental coupling of neuro­

nal activity to CBF remains intact. Our results strongly

suggest that despite the cardiovascular and respiratory

effects of cocaine in humans, fMRI scanning using the

BOLD technique will allow visualization of neuronally

mediated changes in BOLD signal corresponding to the

subjective experience of the cocaine.

Acknowledgments: The authors thank Ken Kwong for con­sultation on the FAIR studies, John Baker for assistance in development of the physiologic data acquisition system, and the staff of the Mallinckrodt GCRC at Massachusetts General Hospital for excellent care of the research subjects.

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