Functional Neuroimaging of the Subjective

download report

Transcript Functional Neuroimaging of the Subjective

Functional Neuroimaging of the Subjective Effects of Intranasal d-Amphetamine
Kelly, T.H., Kluemper, C.T., Emurian, C.E., Corbly, C.R., Martin, C.A., Andersen, A.H., Joseph, J.E., and Lile, J.A.
University of Kentucky
Visual Analog Scale Ratings
Background
Results and Conclusions
1) d-Amphetamine engendered prototypical stimulant-like VAS ratings (Figure 1).
Intranasal drug delivery is a useful method for both clinical practice and research.
Drugs administered via the intranasal route have a faster onset of action and higher
bioavailability compared to oral dosing, without the risk of injury and personal
discomfort associated with routes requiring a needle stick, such as intravenous or
intramuscular administration. The fast onset and high bioavailability of intranasal drug
delivery, however, can also be associated with enhanced abuse potential. This study
characterized intranasal d-amphetamine by examining neural activation via BOLD
signals in brain regions during subjective reporting of drug effects. d-Amphetamine is
a useful tool in human laboratory models because it can be safely administered to
healthy subjects. Few controlled studies of the effects of intranasal d-amphetamine in
humans have been published, despite reports that diverted prescriptions are used via
this route. None have examined functional brain activation among healthy volunteers.
2) Differential brain activation patterns were observed bilaterally following placebo and active drug
administration in the paracentral gyrus, middle temporal gyrus, thalamus and globus pallidus (Figures 2-5).
Unilateral hemispheric activation was observed in other brain regions [e.g., motor (left precentral gyrus)
and visual (left superior and middle occipital gyrus) cortex (data not shown)].
3) d-Amphetamine enhanced brain activation in the paracentral gyrus and reduced activation in the thalamus
and globus pallidus (Figures 2, 4, 5). The middle temporal gyrus, a region associated with the default mode
network, exhibited deactivation during VAS item completion (Figure 3). Active but not placebo damphetamine altered this response.
4) Patterns of brain activation varied during individual VAS item ratrings. Differential patterns of brain
activation observed following placebo and active drug administration during ratings of ‘Feel Drug’ were
observed across all four brain regions (Figures 2-5). Bilateral activation was observed during ratings of
‘Take Again’ and ‘Feel Drug’ in the paracentral gyrus (Figure 2), while activation occurred only in the left
hemisphere of the thalamus (Figure 4). In contrast, no brain activation in any of these regions was
engendered by d-amphetamine during VAS ratings of ‘Anxious’ (data not shown).
Method
5) These results indicate that patterns of brain activation during drug ratings associated with the positive
subjective effects of drugs are sensitive to drug effects. Future studies will be needed to determine
whether these effects are predictive of individual differences in drug-taking behavior.
Take Again
Left Hemisphere
60
Right Hemisphere
35
30
25
20
0
0
-5
-60
15
30
-10
45
0
15
30
45
0
Placebo
32 mg/70 kg
40
30
25
25
20
-10
0
-20
-10
-30
-20
-40
30
45
0
15
45
10
40
50
30
40
20
x = 40
20
0
-10
0
-20
-10
-30
30
0
45
15
-5
0
-10
-5
-15
15
30
45
15
25
0
20
-5
-15
-20
-30
Globus Pallidus
Like Drug
Left Hemisphere
20
15
10
-20
5
0
-30
-10
-40
y = 48
0
-5
-35
-35
15
30
Time
45
Right Hemisphere
10
-25
Placebo
32 mg/70 kg
45
45
15
PE
-15
PE
-10
30
Like Drug
5
-10
30
Time
PE
-5
15
Figure 4: Dose- and time-response function of intranasal d-amphetamine on parameter estimates of BOLD response during ratings of Take Again, Feel Drug
and Like Drug in the left (left column) and Like Drug in the right (right column) thalamus (region indicated in the center panels). Significant dose and/or dose
x time interactions were observed on all scales. Simple-effects tests indicated that significant differences between active and placebo doses were limited to
sessions occurring post-dose administration.
Like Drug
Right Hemisphere
Left Hemisphere
0
45
Time
Middle Temporal Gyrus
0
Placebo
32 mg/70 kg
x = 40
0
Figure 2: Dose- and time-response function of intranasal d-amphetamine on parameter estimates of BOLD response during ratings of Take Again, Feel Drug
and Like Drug in the left (left column) and right (right column) paracentral gyrus (region indicated in the center panels). Significant dose and/or dose x time
interactions were observed on all scales. Simple-effects tests indicated that significant differences between active and placebo doses were limited to
sessions occurring post-dose administration.
Like Drug
30
40
35
30
25
20
15
10
5
0
-5
-10
-15
Time
Time
5
Like Drug
10
10
10
5
0
PE
30
PE
60
Right Hemisphere
0
Like Drug
Like Drug
15
30
y = 48
y = 48
15
PE
0
10
15
PE
PE
20
10
Like Drug
15
20
20
30
-25
45
30
y = 48
0
30
Feel Drug
50
0
15
Feel Drug
40
PE
15
5
-40
70
PE
20
10
-20
Feel Drug
50
Left Hemisphere
40
40
0
60
Thalamus
Take Again
Take Again
PE
80
70
60
50
40
30
20
10
0
-10
-20
-30
Paracentral Gyrus
PE
PE
Figure 1: Dose- and time-response function of intranasal d-amphetamine on ratings of Like Drug, Take Again, Feel Drug, Stimulated and
Anxious on a Visual Analog Scale. Significant dose and/or dose x time interactions were observed on all but the anxious scales.
PE
Subjects: Six healthy Caucasian females, ages 20 to 27, using oral birth control that
included a placebo phase, completed medical screening and gave written consent to
participate. No other substance use history was reported or identified via urinalysis
throughout the study.
Design: A double-blind, placebo-controlled, randomized design was used to compare
the effects of intranasal d-amphetamine (0, 32 mg).
Procedure: Subjects completed one practice sessions to become familiarized with the
magnetic resonance imaging facility and the neuroimaging process, behavioral and
cardiovascular measures and daily laboratory routine. During these sessions, the
subjects also practiced administration of an intranasal drug solution (saline), but no
active doses of d-amphetamine were administered. Subjects then completed two
experimental sessions that were scheduled during the placebo phase of the oral birth
control regimen when estradiol and progesterone levels were at their nadir.
Visual-Analog Rating Scales (VAS): Ratings of ‘Drug Effect,’‘Like Drug,’ ‘Willing to
Take Again,’ ‘Stimulated,’ and‘Anxious’ were obtained by placing marks on a 100-unit
line anchored with "Not at all" on the left and "Extremely" on the right.
Daily Schedule: After successfully completing intake evaluations, including urine
pregnancy and drug-use testing, subjects completed 15 minute assessments before
(i.e., baseline, time 0) and 15, 30 and 45 min after drug administration in the MRI facility
while brain activation (BOLD signal) was measured. During assessments, each VAS
item was presented on 6 occasions according to a randomized block design such that
each item was presented in a random order before any item was repeated. Each VAS
item presentation consisted of a 30 s trial. The trial was initiated by the presentation
of the item. Subject responses terminated the VAS item display and initiated a fixation
crosshair for the remainder of the 30 s trial.
Drug: Intranasal d-amphetamine was delivered using a syringe
capped with a mucosal atomization device (Wolfe Tory Medical,
Inc.). An active placebo consisted of 100 mg/mL magnesium
sulfate.
Cardiovascular Measures: Heart rate and blood pressure were
recorded immediately after completing computer tasks.
Brain Activation: A Siemens Trio 3.0 Tesla magnet is used to collect functional
brain images. A T2*-weighted gradient echo sequence was used with the following
parameters: 29ms echo time, 64x64 matrix, 224x224-mm field of view, 40
3.5-mm axial, slices acquired in interleaved order, 3s repetition time. A 3D shim was
performed before all EPI image acquisitions. High-resolution structural images (with
1mm cubic voxels) were acquired with a T1-weighted MPRAGE sequence (TE = 2.93
ms, TR = 2100 ms, 256x256 matrix, acquired in the sagittal direction). An 8-channel
head coil was used. Using the FSL package, images in each participant’s time series
was motion corrected with the MCFLIRT module. Images in the time series were
spatially smoothed with a 3D Gaussian kernel (FWHM = 7.5 mm) and temporally
smoothed using a high-pass filter. Subjects’ motion corrected and smoothed 4D EPI
image was registered to the ICBM152 T1 template using the registration matrix created
from the three step process which involved registering the average EPI volume to the
MPRAGE volume and the MPRAGE volume to the ICBM152 T1 template, using the
FLIRT (Linear Image Registration Tool) module of the FSL package. Customized
square waveforms were generated for each individual and were convolved with a
double gamma hemodynamic response function (HRF) We then used FILM (FMRIB
Improved Linear Model) to estimate the hemodynamic parameters for five explanatory
variables; one for each VAS question, and generate statistical contrasts maps of
interest. Contrast maps were warped into common MNI space before mixed-effect
group analysis was performed.
Data Analysis: Anatomical masks were then generated from the Automated
Anatomical Labeling Atlas and parameter estimates (PE) were extracted for each
subject. These PEs were then analyzed using repeated-measures ANOVA with dose (0
and 32 mg) and time as factors using SAS.
-45
0
15
30
45
Time
Figure 3: Dose- and time-response function of intranasal d-amphetamine on parameter estimates of BOLD response during ratings of Like Drug in the left
(left column) and right (right column) middle temporal gyrus (region indicated in the center panels). Significant dose and/or dose x time interactions were
observed on the scale. Simple-effects tests indicated that significant differences between active and placebo doses were limited to sessions occurring postdose administration.
5
0
-5
Placebo
32 mg/70 kg
-10
-15
-15
0
15
30
Time
45
z = 35
0
15
30
45
Time
Figure 5: Dose- and time-response function of intranasal d-amphetamine on parameter estimates of BOLD response during ratings of Like Drug in the left
(left column) and right (right column) globus pallidus (region indicated in the center panels). Significant dose and/or dose x time interactions were observed
on the scale. Simple-effects tests indicated that significant differences between active and placebo doses were limited to sessions occurring post-dose
administration.