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Dopaminergic modulation of cortical function in patients with Parkinson's disease.

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Dopaminergic Modulation of Cortical
Function in Patients with
Parkinson’s Disease
Venkata S. Mattay, MD,1 Alessandro Tessitore, MD,1 Joseph H. Callicott, MD,1 Alessandro Bertolino, MD,1
Terry E. Goldberg, PhD,1 Thomas N. Chase, MD,2 Thomas M. Hyde, MD,1 and Daniel R. Weinberger, MD1
Patients with idiopathic Parkinson’s disease suffer not only from classic motor symptoms, but from deficits in cognitive
function, primarily those subserved by the prefrontal cortex as well. The aim of the current study was to investigate the
modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function in
patients with Parkinson’s disease. Ten patients with stage I and II Parkinson’s disease were studied with functional
magnetic resonance imaging, during a relatively hypodopaminergic state (ie, 12 hours after a last dose of dopamimetic
treatment), and again during a dopamine-replete state. Functional magnetic resonance imaging was performed under
three conditions: a working memory task, a cued sensorimotor task and rest. Consistent with prior data, the cortical
motor regions activated during the motor task showed greater activation during the dopamine-replete state; however, the
cortical regions subserving working memory displayed greater activation during the hypodopaminergic state. Interestingly, the increase in cortical activation during the working memory task in the hypodopaminergic state positively
correlated with errors in task performance, and the increased activation in the cortical motor regions during the
dopamine-replete state was positively correlated with improvement in motor function. These results support evidence
from basic research that dopamine modulates cortical networks subserving working memory and motor function via two
distinct mechanisms: nigrostriatal projections facilitate motor function indirectly via thalamic projections to motor cortices, whereas the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal
cortex. The results are also consistent with evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physiological efficiency
of this region.
Ann Neurol 2002;51:156 –164
DOI 10.1002/ana.10078
Although patients with idiopathic Parkinson’s disease
(PD) usually do not present with cognitive symptoms,
there is growing evidence that the motor symptoms
characteristic of this disease are also accompanied by a
pattern of progressive neuropsychological impairment.1
These deficits are similar to those seen in patients with
frontal lobe damage and include problems with verbal
learning,2 problem solving,3 self-ordered pointing,4
temporal sequencing,5 delayed response,6 conditional
associative learning,2,7 implicit learning,7 and forward
planning.8 Because most patients with PD do not suffer from primary frontal lobe pathology, these cognitive deficits must be a direct or indirect consequence of
degeneration of ascending catecholaminergic projections from the brainstem.
It is generally believed that degeneration of the sub-
stantia nigra pars compacta (SNpc) with subsequent
depletion of dopamine in the putamen and resulting
disruption of basal ganglia–thalamocortical loops results in the classical motor signs and symptoms of PD.
Akinesia is thought to result from functional deafferentation of the supplementary motor area (SMA),9 –12
whereas bradykinesia and rigidity appear to result from
functional deafferentation of the motor cortex.13 By
contrast, the neurobiological basis of the frontal cognitive impairment has not been clearly established. Two
mechanisms have been proposed,14 including either an
alteration in outflow of the caudate nuclei to frontal
cortex via the thalamus15 or diminished dopamine activity in the frontal lobes themselves consequent to degeneration of the frontal projections of the VTA and
other nigral cell groups.16 –21 The aim of the present
From the 1Clinical Brain Disorders Branch, National Institute of
Mental Health, 2Experimental Therapeutics Branch, National Institute of Neurological Diseases and Stroke, National Institutes of
Health, Bethesda, MD.
Published online Jan 31, 2002
Received Aug 6, 2001, and in revised form Sep 24. Accepted for
publication Sep 26, 2001.
156
© 2002 Wiley-Liss, Inc.
Address correspondence to Dr Mattay, Clinical Brain Disorders
Branch, National Institute of Mental Health, Bldg 10, Center
Drive, Room 4S-235, National Institutes of Health, Bethesda, MD
20982-1379. E-mail: vsm@helix.nih.gov
study was to delineate these mechanisms using blood
oxygen level-dependent (BOLD) functional magnetic
resonance imaging (fMRI), a method sensitive to
changes in the oxygen content in the blood, while patients performed a prefrontal cortex (PFC)-dependent
task, the N-Back working memory task (WMT), in a
relatively dopamine-depleted (ie, “drug-off”) state and
relatively dopamine-replete (ie, “drug-on”) state. To
specifically contrast the effects of dopamine on WM
circuitry with those on the motor circuitry, we studied
patients while they performed both a WMT and a visually paced motor task.
If the prefrontal cognitive deficits are primarily attributable to compromised outflow from the caudate
nuclei to the frontal cortex via the thalamus,15 one
might see more PFC activation during the “drug-on”
state than during the relatively “drug-off” state—
similar to the activation pattern changes seen in the
cortical motor areas after dopaminergic therapy.10 –12
Theoretically, dopamine diminishes inhibitory basal
ganglia output to the thalamus and, by relative disinhibition, leads to increased activity of thalamocortical
projection neurons.22 In contrast, if the prefrontal cognitive deficits are secondary to a direct cortical dopamine deficiency caused by reduced input through the
mesocortical dopamine pathway,17–21, 23–24 the physiological response might be qualitatively different. In
this case, the hypodopaminergic state would be associated with decreased cortical physiological efficiency in
information processing; that is, a larger neuronal pool
may be required to carry out the task in the dopaminedepleted state than during the dopamine-replete state.
This latter supposition is consistent with evidence from
animal and neuroimaging studies that suggests that
monoamines including dopamine optimize the signalto-noise response of pyramidal neurons in both a taskspecific and region-specific manner to improve cortical
efficiency.25–29 Greater activation under these circumstances may reflect a breakdown in local circuit inhibition,30 –32 as well as the recruitment of additional cortical resources to meet cognitive demands and maintain
proficiency.
Patients and Methods
Subjects
Ten patients with idiopathic PD participated in the study.
Patients were recruited from the Parkinson’s clinic of the Experimental Therapeutics Branch of the National Institute of
Neurological Disorders and Stroke, and from the surrounding community. fMRI was conducted under a protocol approved by the Institutional Review Board of the National
Institute of Mental Health, Intramural Research Program.
All subjects gave written informed consent before participation in this protocol.
Participants in the study included 2 patients with Hoehn
and Yahr stage I and 8 patients with stage II (mean age
⫹SE ⫽ 55 ⫾ 2.6 years) under treatment with Sinemet
(L-Dopa ⫹ carbidopa), alone or in combination with dopamine agonists. Before being scanned, all patients underwent
a thorough neurological examination. To preclude effects of
order and of novelty in terms of the MRI environment and
the task paradigms, all patients underwent a structural MRI
scan and were made to practice the tasks until they reached
ceiling in their performance on a separate day before the
fMRI sessions.
Each patient was studied twice, once during the “drugoff” state (ie, 12 hours after their last dopaminergic drug
dose the night before) and for a second time during the
“drug-on” state (ie, 1 to 2 hours after the first dose of the
day). Dopaminergic drug doses were adjusted to provide an
optimal therapeutic response. A brief neurological examination was carried out before each session to rate the severity of
patients’ motor functions (Unified Parkinson’s Disease Rating Scale [UPDRS], motor rating items 19 to 31).33 Patients
were asked to refrain from nicotine and caffeine for at least 4
hours and from over-the-counter medications for 24 hours
before the MRI studies.
Data Acquisition
BOLD fMRI data were collected on a standard 1.5T Signa
scanner (General Electric, Milwaukee, WI), using gradientecho whole-brain fast spiral acquisition to acquire 36 interleaved slices (3.75mm isotropic, TE ⫽ 24ms, TR ⫽ 56ms,
flip angle ⫽ 85 degrees, FOV ⫽ 24cm, matrix ⫽ 64 ⫻
64).34
Working Memory and Motor Tasks
BOLD fMRI was conducted while subjects performed a variation of the n-back WMT as previously described.35,36
N-Back refers to the number of previous stimuli that the
subject had to recall. The stimuli consisted of numbers (1– 4)
shown in random order and displayed at the points of a
diamond-shaped box. During each treatment condition, two
task combinations were administered: (1) eight cycles of the
2-Back (WMT) alternating with the 0-Back (sensorimotor
task), and (2) eight cycles of the 0-Back (which is essentially
a visually paced motor task), alternating with a rest condition. Each task combination was obtained in 4 minutes and
16 seconds, 128 whole-brain images with 16 images in each
cycle (8 during the 2-Back and 8 during the 0-Back, or 8
during the 0-Back and 8 during rest). Owing to time constraints, only 8 of the 10 patients were able to complete the
“0-Back versus rest” paradigm. Further, performance data
from 1 of the remaining 8 patients demonstrated multiple
involuntary button presses (probably because of excessive
hand tremor) during the “drug-off” state. Therefore, the data
from this patient were not included in the final group analysis for the “0-Back versus rest” comparison.
Image Processing and Data Analysis
After reconstruction of the individual time volumes, each
three-dimensional brain volume was registered to the first in
the time series, using a tricubic-spline interpolation.37 Data
sets were then chosen for their high quality (scan stability),
as demonstrated by small motion correction (⬍2 voxels) and
matched voxel variance across the two sessions.35,38 The in-
Mattay et al: Dopaminergic Modulation of Cortical Function
157
Table 1. Clinical Ratings, Task Accuracy, and Reaction Time Measurements
Drug State
Drug-off
Drug-on
a
UPDRS
(Motor Subscale)
Mean ⫾ SEa
2-Back
(% Correct)
Mean ⫾ SE
10 Pt
2-Back
(RT ms)
Mean ⫾ SE
10 Pt
0-Back
(% correct)
Mean ⫾ SE
7 Pt
0-Back
(RT ms)
Mean ⫾ SE
7 Pt
8.8 ⫾ 2.6
5.0 ⫾ 1.8
80.2 ⫾ 4.6
86.8 ⫾ 4.2
710 ⫾ 73
747 ⫾ 93
91.5 ⫾ 5.9
93.9 ⫾ 1.5
846 ⫾ 158
783 ⫾ 116
p ⬍ 0.003.
UPDRS ⫽ Unified Parkinson’s Disease Rating Scale; SE ⫽ standard error; RT ⫽ reaction time.
dividual whole-brain data were then spatially normalized to a
common stereotactic space (Montreal Neurological Institute
[MNI] template) via Automated Image Registration
3.08.39,40 Voxel-wise signal intensities were ratio normalized
to the whole brain mean and detrended in a linear fashion
with the baseline at each voxel set to 100.35,38 The data were
then smoothed with a Gaussian filter (8 ⫻ 8 ⫻ 8mm) to
control further for inter-individual variance in sulcal and gyral anatomy. Image analysis software and general linear
model statistics (SPM 99) were used to create group maps
for the “2-Back versus 0-Back” comparison (WM challenge)
and for the “0-Back versus rest” comparison (motor function) during both the “drug-off” and “drug-on” states. The
height threshold value was set to p ⬍ 0.05 (corrected for
multiple comparisons) with an extent threshold of three voxels. We then performed a “drug ⫻ task” interaction analysis
to assess the effect of dopaminergic therapy on task-related
activation.
To determine the relationship between drug-related
changes in BOLD response and change in motor function or
WM performance, we performed voxel-wise correlation analyses. To accomplish these correlation analyses, we first carried out a “drug ⫻ task” analysis for each subject separately
for each task condition (“2-Back vs 0-Back” and “0-Back vs
rest”) and created contrast images. We then performed a
second-level correlation analysis on these contrast images, using the simple regression model in SPM99 with two measures of improvement in motor function (ie, percentage
change in reaction time (RT) and percentage change in
UPDRS scores relative to the “drug-off” state) as covariates
of interest for the motor function analysis, and percent difference in performance scores of the 2-Back task between the
two drug conditions as a covariate of interest for the WM
data analysis.
Behavioral Data Analysis
We performed a Student’s t-test on the clinical ratings
(UPDRS–motor subscale scores), task performance, and RT
measures to look for significant differences across drug conditions. Task performance was measured as the percentage of
correct responses.
Results
Clinical Ratings, Task Accuracy, and Reaction
Time Measurements
All patients showed a significant improvement in motor symptoms during the “drug-on” state when com-
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February 2002
pared with the “drug-off” state (Table 1). No significant difference was found in performance of the
0-Back task between the two drug states. Although the
mean accuracy score on the 2-Back task tended to be
lower during the “drug-off” state, the difference did
not reach statistical significance; 6 patients performed
worse during the “drug-off” state, 2 patients performed
equally well during both drug conditions, and 2 patients had a marginally lower score during the “drugon” state.
There were no statistically significant differences in
RT for both task paradigms across the two drug states;
however, the mean RT for the 0-Back task during the
“drug-on” state was lower than during the “drug-off”
state; 5 of the 7 subjects showed a decrease in RT on
the 0-Back task after dopaminergic therapy. During the
two-back state, the mean RT was marginally and nonsignificantly longer during the “drug-on” state relative
to the “drug-off” state, because of paradoxically longer
RTs in 4 subjects during the “drug-on” state. While
the basis of this is unclear, 2 of these 4 subjects also
had a lower accuracy score during the “drug-on” state,
and 1 subject had similar accuracy scores during both
states.
Functional Magnetic Resonance Imaging
A main task effect during both
“drug-off” and “drug-on” sessions mapped to very similar locales. Consistent with earlier studies,35,41 the spatial distribution of the task-related responses included
PFC (BA 9-10/44 – 46), pericingulate cortex (including
the medial frontal gyrus), anterior cingulate (BA 24,
32), and parietal cortex (BA 7, 39 – 40) bilaterally.
However, the spatial extent of activation in these cortical regions was much greater during the “drug-off”
state than during the “drug-on” state. This is further
corroborated by the off ⬎ on “drug ⫻ task” interaction analysis (see Fig 1 and Table 2, part a), which
shows the cortical areas that are significantly more active during the “drug-off” state relative to the “drugon” state. There were also significant correlations between the relatively greater degree of activation in these
cortical regions and the degree of decrement in perforWM CHALLENGE.
mapped to very similar cortical locales. The spatial distribution of the task effects included supplementary
motor area (SMA; BA 6), lateral premotor cortex
(LPM; BA 6; left ⬎ right), sensorimotor cortex (SMC;
BA 4, 3,2 and 1; left ⬎ right) , parietal cortex (PAR;
BA 39, 40) and cerebellum (CER; right ⬎ left) bilaterally. However, consistent with evidence from earlier
neuroimaging literature10 –12 and contrary to the effect
observed during the 2-Back task, the spatial extent of
activation in these cortical regions was much greater
during the “drug-on” state than during the “drug-off”
state. This is further corroborated by the on ⬎ off
“drug ⫻ task” interaction analysis (see Fig 2a and Table 3, part a), which shows the cortical areas that are
significantly more active during the “drug-on” state relative to the “drug-off” state. This increase in activation
after dopaminergic therapy correlated significantly with
improvement in RT (see Table 2, part a, and Fig 2b).
Moreover, the increase in activation after dopaminergic
therapy in the right primary motor cortex, right PAR,
SMA, and left LPM covaried with improvement in
motor function (as determined by a change in UPDRS
motor subscale scores) (see Table 3, part c). This is the
opposite direction of the relationship of activation and
behavior seen in PFC during the WMT. No areas exhibited a significant off ⬎ on “drug ⫻ task” interaction.
Fig 1. Brain regions with greater activation during working
memory in the hypodopaminergic state. (A) Representative
slices from a group activation map showing brain regions with
a significant off ⬎ on “drug ⫻ task” interaction during
working memory challenge. Slices are arranged in radiological
orientation (ie, right side of brain to viewer’s left and vice
versa). Patients in the “drug-off” state show more activation of
the network subserving working memory. See Table 2, part A,
for coordinates of voxels with significant interaction. (B)
Group map of cortical regions that show significant correlations between drug-related differences in BOLD response and
a measure of difficulty in performing the working memory task
during the “drug-off” state. See Table 2, part B, for coordinates of significant voxels and statistics.
mance during the “drug-off” state relative to the “drugon” state, ie, a decrease in accuracy correlated with an
increase in cortical activation (see Fig 1b, see Table 2,
part b). In other words, the hypodopaminergic state
was associated with decreased efficiency in cortical processing during WM. There were no areas showing a
significant on ⬎ off “drug ⫻ task” interaction. Image
analysis limited to the 4 atypical subjects with prolonged RT in the “drug-on” state also showed the same
pattern as the whole group.
MOTOR FUNCTION (“0-BACK VS REST”).
As with WM,
there was a main effect of task on both sessions that
Discussion
We found that during a WM challenge in patients
with uncomplicated PD, the extent of cortical activation (particularly in the PFC, PAR and cingulate regions) was greater in the “drug-off” state relative to the
“drug-on” state. Although there was no significant difference in task performance across the two drug conditions, correlation analysis revealed that the worse the
patients performed, the more cortical tissue they activated (see Fig 1b). This finding of increased activity in
the cortical areas subserving WM during the “drug-off”
state even in the context of slightly poorer cognitive
function, is in contrast to the changes we observed in
the activity of cortical areas subserving motor function.
Consistent with earlier reports,10 –12 we noted greater
activation in the supplementary motor, primary motor,
and parietal cortices in the “drug-on state” (see Fig 2a
and Table 3). This increase in activity in cortical motor
regions was associated with improvement in motor
symptoms as determined by the motor subscale of
UPDRS and a decrease in RT during the motor task
(see Fig 2b). These activation changes in the cortical
motor regions are in agreement with the view that the
motor signs and symptoms in patients with PD result
from functional deafferentation of excitatory thalamic
inputs to the cortical motor regions probably due to
disruption of neural processing through basal ganglia–
thalamocortical loops.22 By contrast, the changes we
Mattay et al: Dopaminergic Modulation of Cortical Function
159
Table 2. Effects on Regions During Working Memory Challenge
Talairach
Coordinates
(x,y,z)
Region (Brodmann’s Area)
a: Regions that showed a significant off ⬎ on drug ⫻ task interaction
Left dorsal PFC (BA 10)
(⫺34
51
5)
Left dorsal PFC (BA 45/46)
(⫺40
36
5)
Right dorsal PFC (BA 9)
(33
25 34)
Right PFC (BA 8)
(33
11 43)
Anterior cingulate (BA 32/8)
(0
29 40)
Anterior cingulate (BA 32/6)
(3
15 46)
Right insular cortex
(39 ⫺15 10)
Left insular cortex
(⫺39 ⫺8
6)
Right PFC (BA 8)
(19
25 46)
Left PFC (BA 8)
(⫺23
15 49)
Left parietal cortex (BA 40)
(⫺50 ⫺21 23)
Right parietal cortex (BA 40)
(23 ⫺41 27)
Right precuneus (BA 7)
(7 ⫺47 53)
Maximum z value
Cluster
Level
Corrected
p
3.09
2.88
4.24
3.13
2.92
2.56
3.00
2.19
2.56
2.15
2.85
2.43
2.38
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.04
0.008
0.001
0.000
0.000
0.003
b: Regions that showed a significant correlation between drug-induced increase in BOLD response and decrement in
performance
Right PFC (BA 10)
(23
47
5)
2.26
0.05
Right PFC (BA 46)
(23
44 11)
2.33
0.05
Left PFC (BA 10)
(⫺34
47
5)
2.29
0.03
Left parietal cortex (BA 39)
(⫺46 ⫺51 19)
4.29
0.000
Left parietal cortex (BA 39/40)
(⫺34 ⫺51 33)
2.6
0.000
Right precuneus (BA 19)
(26 ⫺80 18)
3.57
0.000
Left superior temporal gyrus (BA 22)
(⫺50 ⫺47 14)
3.92
0.000
PFC ⫽ prefrontal cortex; BA ⫽ Brodmann’s area.
observed in the cortical regions subserving WM,
namely the more focused activation in the PFC after
dopaminergic therapy, are more consistent with our alternate hypothesis, namely, that relatively under active
dopaminergic terminals in PFC would impact directly
on its information processing, in terms of decreased efficiency or automaticity of this processing (ie, greater
extent of cortical activation may be required for the
same or poorer performance). Although this interpretation is speculative, the qualitatively differential physiological response to dopaminergic therapy observed
during the WM and motor tasks raises the possibility
that a mechanism other than the nigrostriatal dopaminergic system may mediate the changes in the WM
network. We discuss this interpretation within the context of the mesocortical dopaminergic system and prefrontal function, as well as the degeneration of this system in PD.
Mesocortical Dopaminergic System and
Prefrontal Function
Anatomical studies indicate that the frontal cortex receives dopaminergic fibers42 from the mesencephalon
and that dopamine receptors, particularly D1, mediate
dopamine effects in PFC related to WM.43 Neurophysiological and neuropharmacological data confirm
the role of these receptors in PFC function, especially
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WM.44 – 46 Dopamine afferents to pyramidal neurons
synapse on soma, but also on dendritic spines in close
proximity to glutamate inputs from other cortical neurons. Dopamine inputs to the dendritic shafts of local
circuit neurons also appear to be in close proximity to
glutamate presynaptic terminals.47 On the basis of
these observations, it has been suggested that dopamine
gates the excitatory impact of associative cortical information mediated by intracortically projecting glutamate neurons and by locally recurrent collaterals of pyramidal neurons.48 Evidence from electrophysiological
studies indicates that stimulation of the ventral tegmental area in animals with an intact mesocortical system causes partial depolarization and diminished spontaneous firing of action potentials of prefrontal
pyramidal neurons, which appear to be primed for associative inputs.49,50 In animals, dopamine is released
in PFC during WM,51 and depleting PFC of dopamine or blocking D1 receptors diminishes performance
on these tasks.52,53 Recent studies of neuronal interactions in tissue slice preparations indicate that D1 receptors modulate glutamate-induced excitability of intrinsic PFC neurons.29 Consistent with this anatomical
and electrophysiological information, experiments in
behaving monkeys have demonstrated that dopamine
modulates the firing responses of pyramidal neurons
and improves the prefrontal physiological signal to
stages of the disease the brain compensates for these
physiological alterations by recruiting extraneous neuronal assemblies. Advancing disease may decrease the
efficacy of these compensatory mechanisms as patients
become cognitively symptomatic. Furthermore, the
patterns we observed may be different in patients with
more advanced disease, as they may have more extensive degeneration of dopaminergic neurons.
Fig 2. Brain regions with greater activation during the motor
task in the dopamine replete state. (A) Representative slices
from a group activation map showing brain regions with a
significant on ⬎ off “drug ⫻ task” interaction during the
motor task (“0-Back vs rest”). Consistent with evidence from
earlier neuroimaging data and contrary to our observations
during working memory challenge (Fig 1a), there was more
activation of the cortical motor regions during the “drug-on”
state relative to the “drug-off” state. See Table 3, part A, for
coordinates of voxels with significant interaction. (B) Group
map of cortical regions that show significant correlations between drug-induced change in BOLD response during the motor task with a measure of improvement in reaction time. See
Table 3, part B, for coordinates of significant voxels.
noise during executive cognition and WMT, respectively.45,54 This signal-to-noise-enhancing effect of
monoamines on cortical neuronal activity has also been
supported by neuroimaging studies in humans that
used monoaminergic drugs.27,36, 55–58
Our finding of more focal activation after dopaminergic therapy is therefore in conceptual agreement
with the evidence from the above studies and supports
the view that dopamine “focuses” prefrontal neuronal
assemblies to respond more precisely and efficiently to
specific stimuli. Consistent with this hypothesis, Cools
and colleagues recently demonstrated working memory
task-related rCBF decreases in the right DLPFC of patients with PD following dopaminergic therapy when
compared to the hypodopaminergic state.59 In the hypodopaminergic state of PD, this focusing function is
presumably altered and physiological STN ratio is diminished. Our data support this conclusion. It is plausible that to maintain cognitive proficiency in early
Degeneration of the Mesocortical Dopaminergic
System in PD
Whereas the hallmark of PD is dopaminergic neuronal
loss in SNpc leading to striatal denervation,60 there is
also evidence of considerable damage to the mesocorticolimbic dopaminergic system, which originates
largely in the VTA and medial SNpc.23,24,61,62 Consistent with evidence of mesocortical dopaminergic deafferentation from postmortem neurochemical studies,
investigators have used positron emission tomographic
imaging techniques to demonstrate neocortical monoamine terminal loss in the frontal cortex of patients
with PD17 and a reduction in presynaptic dopaminergic function, not only in the nigrostriatal system, but
also in the mesocortical system in patients with early
PD.19 –21 A positive correlation between F-18 fluorodopa binding in the frontal cortex and performance on
prefrontal tasks has also been reported.19 In another
study, based on the absence of a significant correlation
between C-11 Nomifensine (a radioligand of dopamine
and norepinephrine presynaptic reuptake sites) binding
in the caudate and WM performance, Marie and colleagues18 suggested that the prefrontal dopaminergic
system plays a more prominent role in WM, rather
than the striatal dopaminergic system. In essence, these
imaging data combined with the previously mentioned
evidence of cortical signal-to-noise-enhancing effects of
dopamine support our hypothesis that direct cortical
involvement of the mesocortical dopaminergic system
may be responsible for decreased efficiency of PFC
function in patients with early PD. Although cognitive
performance may benefit from dopaminergic therapies
aimed at improving motor symptoms, higher doses required in later stages of the disease have been reported
to exacerbate cognitive deficits in some patients, possibly owing to excessive dopamine receptor stimulation
in striatum or PFC30,31,46,63– 65 or to extension of the
degenerative process to additional neuronal populations.
To our knowledge, this is the first study in which
the physiological effects of dopaminergic modulation
on both PFC function and motor function in patients
with PD were assayed simultaneously. Although our results and conclusions are not based on direct in vivo
measurement of extrastriatal dopaminergic cortical activity, they are well supported by, and consistent with,
findings in experimental animal paradigms. These re-
Mattay et al: Dopaminergic Modulation of Cortical Function
161
Table 3. Effects on Regions during Motor Task
Talairach
Coordinates
(x,y,z)
Region (Brodmann’s Area)
a: Regions that showed a significant on ⬎ off drug ⫻ task interaction
Right primary motor cortex (BA 4)
(33 ⫺18 55)
Left primary motor cortex (BA 4)
(⫺43 ⫺18 38)
Right premotor area (BA 6)
(30 ⫺4 45)
Supplementary motor area (BA 6)
(⫺10 ⫺22 68)
Right parietal cortex (BA 7)
(19 ⫺62 56)
Left parietal cortex (BA 40)
(⫺13 ⫺70 52)
Left parietal cortex (BA 40)
(⫺46 ⫺37 27)
Maximum z value
Cluster
Level
Corrected
p
2.67
2.14
2.56
3.08
3.53
2.72
3.21
0.03
0.04
0.02
0.04
0.000
0.000
0.000
b: Regions that showed a significant correlation between drug-induced increase in BOLD response and improvement in reaction time
Left primary motor cortex (BA 4)
(⫺34 ⫺12 44)
2.31
0.03
Left premotor area (BA 6)
(⫺10 ⫺18 68)
2.78
0.01
Supplementary motor area (BA 6)
(⫺4 ⫺22 64)
1.90
0.01
Left parietal cortex (BA 7)
(⫺27 ⫺51 53)
2.51
0.000
Left parietal cortex (BA 40)
(⫺34 ⫺44 46)
1.94
0.000
c: Regions that showed a significant correlation between drug-induced increase in BOLD response during the motor task and
improvement in UPDRS scores
Right primary motor cortex (BA 4)
(26 ⫺14 58)
2.75
0.03
Left premotor area (BA 6)
(⫺17 ⫺12 61)
2.44
0.03
Supplementary motor area (BA 6)
(⫺10 ⫺8 65)
2.51
0.04
Right parietal cortex (BA 7)
(⫺33 ⫺44 50)
2.75
0.003
BA ⫽ Brodmann’s area.
sults support the notion that dopamine modulates cortical circuitry invoked by the WMT differently than it
does the cortical motor system. Consistent with the
model reported by Alexander and colleagues,22 it appears that dopamine modulates motor function
through the nigrostriatal–thalamocortical loop, whereas
its effect on WM function appears to be primarily
through the mesocortical dopaminergic system. Our results also show that even early in the disease, when
there are no gross deficits in cognition at the behavioral
level, the brain regions subserving WM function are
performing additional work to accomplish the task;
that is, they are inefficient.
The authors thank Dr Joseph A. Frank (Laboratory of Diagnostic
Radiology Research, NIH), and Dr Jeff Duyn (Laboratory of Functional and Molecular Imaging, NINDS, NIH), for providing fMRI
resources and expertise; Dr Richard Coppola (Clinical Brain Disorders Branch, NIMH, NIH), for task development; Dr Saumitra
Das, and Dr Sam Lee (Clinical Brain Disorders Branch, NIMH,
NIH), for research assistance; Dr Andreas Meyer-Lindenberg, Dr
Phillip Kohn, Dr Ahmad Hariri, and Dr Francesco Fera (Clinical
Brain Disorders Branch, NIMH, NIH), for advice on fMRI data
analysis; and Marge Gillespie, RN (Experimental Therapeutics
Branch, NINDS, NIH), for her help with patient recruitment.
162
Annals of Neurology
Vol 51
No 2
February 2002
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