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Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS

Authors:
  • Centre for Integrative Neurosciences A.C. (HM-CINAC)
  • Institute of Neurology and Neurosurgery Havana Cuba
  • NeuroHelvetia Project

Abstract and Figures

Introduction: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported. Methods: A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism. Results: A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem. Conclusion: It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state.
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ISSN: 0269-9052 (print), 1362-301X (electronic)
Brain Inj, Early Online: 1–10
!
2013 Informa UK Ltd. DOI: 10.3109/02699052.2013.794961
CASE STUDY
Zolpidem induces paradoxical metabolic and vascular changes in a
patient with PVS
Rafael Rodriguez-Rojas
1,2
, Calixto Machado
3
, La
´
zaro A
´
lvarez
1
, Maylen Carballo
1
, Mario Estevez
3
, Jesus Perez-Nellar
4
,
Nancy Pavon
1
, Mauricio Chinchilla
4
, Frederick R. Carrick
5
, & Philip DeFina
6
1
International Center of Neurological Restoration, Havana, Cuba,
2
International Center for Theoretical Physics, Trieste, Italy,
3
Institute of Neurology
and Neurosurgery, Havana, Cuba,
4
Hermanos Ameijeras Hospital, Havana, Cuba,
5
Carrick Institute for Graduate Studies, Tampa, FL, USA, and
6
International Brain Research Foundation, NJ, USA
Abstract
Introduction: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which
has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing
effect of zolpidem in patients with severe brain damage has been repeatedly reported.
Methods: A placebo-controlled magnetic resonance study was conducted to evaluate its effect
on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-
matched healthy volunteer. A multi-modal analysis was used to assess aspects in the
pharmacologically-induced changes in the resting-state brain metabolism.
Results: A significantly increased BOLD signal was transiently localized in the left frontal cortices,
bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The
healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD
signal changes were found to significantly correlate with concentrations of extravascular
metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified
GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the
significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after
zolpidem.
Conclusion: It was concluded that proton-MRS and BOLD signal assessment could be used to
study zolpidem-induced metabolic modulation in a resting state.
Keywords
Functional magnetic resonance imaging,
magnetic resonance spectroscopy,
persistent vegetative state, Zolpidem
History
Received 18 November 2011
Revised 7 February 2013
Accepted 6 April 2013
Published online 5 August 2013
Introduction
Patients in a persistent vegetative state (PVS) are awake but
apparently unaware of themselves or their environment. These
patients have a poor prognosis and treatments for providing
recovery are very limited. In recent years several reports
have been published about a paradoxical ‘arousing’ effect
of zolpidem (Ambien
®
) in patients with severe brain damage
[1–5]. These anecdotal benefits have provided hope that
damage to cognitive function may be reversible and motivated
expectation of promoting further recovery. Zolpidem is a non-
benzodiazepine drug belonging to the imidazopiridine class
used in insomnia therapy, which has selectivity to stimulate
the effect of gamma aminobutyric acid (GABA) [6]. Clauss
et al. [7] first reported in 2000 the use of zolpidem in brain
injury after an accidental prescription in a PVS case caused
the patient to wake up and speak to relatives within 15
minutes of receiving zolpidem. The effect lasted for 3 hours.
Despite an increasing number of similar reports, the
Correspondence: Rafael Rodriguez-Rojas, BSc, MSc, International
Center of Neurological Restoration, Ciudad de La Habana 11300, Cuba.
E-mail: rafael.rguez@infomed.sld.cu
neurophysiological processes underlying the unexpected
effect of zolpidem in patients with disorders of consciousness
remains unexplained.
Functional neuroimaging has provided new insights for the
assessment of cerebral function in the PVS and MCS under
pharmacological interventions. Improved perfusion and elec-
trophysiological activity in hypoactive brain areas have been
reported after zolpidem use [2, 8–11]. Other case reports
assessing the efficacy for zolpidem in neurological diseases
have been recently published (for review see Hoque and
Chesson [12]). Changes in brain PET and SPECT after
zolpidem are often accompanied by clinical improvements in
severely brain-damaged patients, such as awakening, release
from brain injury symptoms and in sleep anomalies [2, 8, 11].
In summary, there is some evidence about the potential
zolpidem effect to repeal metabolic, haemodynamic and
electric abnormal activity after severe brain injury.
Advanced magnetic resonance methods, such as functional
magnetic resonance imaging (fMRI) and proton magnetic
resonance spectroscopy (
1
H-MRS), have been shown to be
powerful tools to assess residual brain activity and outcome
prediction in severely brain-damaged patients [13]. fMRI
based on blood oxygen level-dependent (BOLD) signal is
3
2 R. Rodriguez-Rojas et al. Brain Inj, Early Online: 1–10
related to a variety of physiological parameters as well as
CBF. The magnitude of BOLD changes due to elevated
neuronal activity is determined by decreased susceptibility
effects resulting from the local increase of oxygenated
haemoglobin [14]. However, the application of classical
fMRI (i.e. based on task-related design) to study pharmaco-
logically-induced BOLD signal changes in PVS is limited.
Major concerns are related to inter-subject variability, the
necessity of prior hypotheses about the site of drug effect and
the requirement of patient’s collaboration.
Recent evidence supports that ‘resting-state’ brain activity,
characterized by slow signal fluctuations, provides a means of
examining the topological organization of functional brain
networks [15]. Hence, resting state fMRI (RS-fMRI) has
become a novel method to measure structured activity
patterns reflecting a ‘default mode’ of brain function [15,
16]. RS-fMRI is particularly attractive in patients with PVS
because no explicit performance or action is required by the
subject [17]. Additionally, RS-fMRI is able to identify
specific and detectable changes in the functional topography
induced by drug deliveries in the central nervous system
(CNS) [18, 19].
A limitation of the BOLD signal as a biomarker for CNS
pharmacological intervention stems from the fact that the
fMRI signal is driven by blood flow and volume changes that
are secondary to metabolism caused by neural activity. In this
framework, fMRI and
1
H-MRS provide complementary
information for investigating the human brain metabolism.
Localized
1
H-MRS has been used to monitor metabolic
changes associated with several brain pathologies [20]. In
PVS and MCS cases,
1
H-MRS has evidenced both local and
diffuse biochemical impairment by quantifying several
neurometabolites [21]. The potential of
1
H-MRS to provide
specific brain metabolic information endorses its use for
explaining the relative contribution of extravascular compart-
ments to BOLD signal dynamics [20].
The authors have recently described the paradoxical
arousing effect of zolpidem in one case in PVS, where
clinical, autonomic and electrophysiological changes were
reported [10]. A combined RS-fMRI and
1
H-MRS placebo-
controlled study was conducted in the same patient and an
age- and sex-matched normal volunteer. This multi-modal
analysis was used in order to assess aspects of the
pharmacologically-induced changes in resting-state brain
metabolism. This approach can improve understanding of
the physiological processes underlying the zolpidem effect
and could be useful for the monitoring of new therapeutic
alternatives in patients with PVS.
Methods
Patient and control
A placebo-controlled study was conducted to examine
metabolic and vascular processes induced by zolpidem in a
21 year old female patient (YOR), who suffered a stroke
causing a top of the basilar artery syndrome and who had
been in PVS for 5 years. Previous MRI showed destruction
of the rostral part of the pons, the mesencephalon and
both thalami. YOR showed a circadian wakefulness, although
she remained with her eyes closed for long periods of time.
With informed written consent of her parents, two imaging
studies were conducted, separated by an interval of 48 hours.
During the acquisition the patient received 10 mg of zolpidem
or placebo, respectively, through a percutaneous endoscopic
gastrostomy. Throughout both sessions, clinical and physio-
logical parameters were controlled. A control healthy subject
(DMC) matched for age and gender, without any history of
autonomic or other nervous system disorder, non-smoker and
who was not under any medication, was also studied. An
acute dose of zolpidem (10 mg dissolved in 30 ml saline
solution) was administered orally to DMC. Pharmacologic
intervention was approved by the Institute of Neurology and
Neurosurgery Ethics Committee, Havana, Cuba.
Clinical and neurophysiological assessment
Clinical assessment during MRI scanning is challenging,
since geometrical characteristics of the scanner, a noisy
environment and severe movement restrictions impair the
application of standard evaluation scales. Considering these
inherent difficulties, a detailed clinical evaluation of the
therapeutic effect of zolpidem was conducted in the week
before the MRI scan, following the same study timeline. YOR
was evaluated using the JFK Coma Recovery Scale-Revised
(CRS-R) [22] in conjunction with electroencephalographic
and autonomic recordings. Methodological details have been
reported elsewhere [10]. During the MRI session, continuous
bedside monitoring was carried out to appreciate behavioural
changes in both patient and control.
Data collection
Magnetic resonance data were collected on a Magnetom
Symphony 1.5 Tesla MR system (Siemens, Earlangen,
Germany), using a standard head coil for radio frequency
transmission and signal reception. Subjects remained in the
same spatial location inside the scanner during the whole MRI
study. The head was padded with foam to minimize head
movement. For co-registration with functional images, a 3D
whole-head MPRAGE image was collected. Furthermore,
T2-weighted images in axial and coronal orientations were
acquired to aid co-registration of the MRS voxel.
The functional image acquisition protocol involved con-
secutive blocks of MRS and fMRI, with a total duration of 10
minutes per block. The first image block acquisition started
15 minutes before zolpidem administration; after medication,
consecutive blocks were acquired during 95 minutes (for
clarification of the study timeline, see Figure 1(a)). BOLD
sensitive functional images were acquired using an inter-
leaved ascending EPI sequence, consisting of 36 axial slices
with no inter-slice gap. Each run comprised 60 T2*-weighted
volumes (TR/TE ¼ 3000/50 ms; flip angle ¼ 90
o
, matrix size
¼
64
x
64
x
36, voxel size
¼
3
x
3
x
4 mm ).
Proton MRS
In vivo
1
H-MRS spectra were acquired after manual shim
adjustment by using a spin-echo single-voxel sequence
(SVS_SE, TR/TE ¼ 5000/30 ms, voxel size ¼ 10
x
20
x
10
mm
3
), combined with water suppression technique.
Localization of the volume of interest (VOI) to the left
DOI: 10.3109/02699052.2013.794961 Zolpidem induces metabolic and BOLD changes in PVS 3
Figure 1. (a) Scanning session time line.
After a T1-weighted high resolution and a
baseline acquisition block, patient received
an acute dose of zolpidem (10 mg). During
the next 80 minutes, consecutive blocks of
1H-MRS and fMRI were acquired. (b) EEG
power spectra density showing pharmacolo-
gical modulation of neural activity in frontal
region. Details in Machado et al. [9] (c) 3D
rendering of patient’s MRI. Black arrow
points to the EEG-based selected region for
MRS acquisition.
frontal cortex was decided based on a previous EEG
study of patient YOR, showing brain activation in that
region after zolpidem administration, in temporal concord-
ance with autonomic and behavioural changes (Figures 1b
and c) [10].
The intensities of
1
H-MRS metabolites were estimated
using the automated spectral fitting routine available in
commercial software Syngo MR A30 (Siemens, Erlangen,
Germany) that included baseline correction. Spectral data
were smoothed with Hamming filtering (half width
¼
300 ms)
to improve signal-to-noise ratio. Metabolite concentrations
were calculated for N-acetyl-aspartate (NAA), Glutamate/
Glutamine (Glx), choline-containing compounds (Cho), cre-
atine/phosphocreatine (Cr), myo-inositol (Ins) and lactate/
lipid (Lac
þ
Lip). Metabolite concentration ratios were
calculated for inter-subject comparison, using the sum of Cr
integrals as denominators.
Resting state fMRI
Data processing and analysis
EPI images were spatially interpolated online for a first level
motion correction, using a 3D-K-space procedure available in
the Syngo MR A30 workstation. These movement parameters
were used to correct MRS voxel location when necessary.
Offline pre-processing and analysis was followed using the
SPM5 package (Wellcome Department of Cognitive
Neurology, London, UK) running in Matlab 7.4 (Mathworks
Inc., Sherborne, MA). All functional EPI images were
spatially re-aligned to the first image of the first series
using a least squares approach and a 6-parameter (rigid body)
spatial transformation. Further pre-processing included spatial
re-sampling at an isotropic voxel size (1 mm
3
), slice-timing
and spatial smoothing with an isotropic 8-mm full-width-at-
half-maximum Gaussian kernel.
The pre-medication fMRI run was considered as baseline
and the term activation was used to represent the transient
signal increase after zolpidem administration. Students t-tests
were conducted at each voxel to detect the zolpidem-induced
changes in the BOLD time courses on each time point vs the
baseline. Condition-specific effects were estimated using
conventional General Lineal Model (GLM) analysis running
in SPM5. Re-alignment parameters (translation and rotation
in x, y, z dimension) were included as covariates of no interest
to correct for possible head movements. The resulting maps
were checked subsequently for plausibility. All areas reaching
significance on the cluster level, with thresholds at a family-
wise error (FWE) corrected probability of 0.05, were
reported. To further eliminate random noise, cluster filtering
(cluster size410 contiguous pixels) was applied to produce
final statistical parametric maps of t deviates SPM{T},
subsequently normalized to SPM{Z}. The same scheme was
applied to compare zolpidem vs placebo.
Haemodynamic modelling
The fMRI time series data were calculated by averaging the
time courses of all voxels from a cubic VOI in the left frontal
cortex, centred on maxima in the SPM{T} on the activation
cluster closest to MRS voxel’s mid-point. A unique time
course per subject was obtained by combining all the fMRI
runs. A SPM5 toolbox was used to estimate the pharmaco-
logical activation/deactivation parameters and the zolpidem-
induced within-subject variability, considering the haemo-
dynamic model detailed in Friston et al. [23]. The underlying
hypothesis considers that the pharmacological effect on CBF
is constant over each BOLD acquisition. Taking into consid-
eration that the acquisition time per run is 3 minutes, this was
considered a plausible approach. Allowing for measuring the
‘resting state’ signal instead of the classical fMRI evoked
signal, this study was more interested in the relative efficacy
of the pharmacological intervention to eliciting a CBF
modulation. With this aim, the efficacy " with which neuronal
activity causes a change in the flow inducing signal was
calculated. Estimation was performed using the Bayesian
inference available in SPM5 [24]. To quantitatively determine
the relationship between the electrophysiological activities
and haemodynamic responses, a Pearson test was carried out
to explore the linear correlation between the percentage of
4 R. Rodriguez-Rojas et al. Brain Inj, Early Online: 1–10
Figure 2. MRS study in patient (top) and normal volunteer (down). Left: 1H-MRS spectrum acquired before zolpidem administration. The inset depicts
the three dimensionally localized MRS voxel (gray voxel, 10
x
20
x
10 mm
3
) in frontal cortex. Note spatial correspondence with fMRI maps (black
spots). Right: Time courses of metabolites during the observation period following administration of zolpidem (straight line) and placebo
(discontinuous line).
change of the metabolite concentrations and the neuronal
efficacies.
Results
Clinical and physiological behaviour
The zolpidem-induced alteration of awareness in the patient,
confirmed by transient modulation of clinical, neurophysio-
logical and autonomic conditions, is briefly summarized
below. A detailed description of those changes has been
recently reported [10] and is beyond the scope of this paper.
In addition, a clinical trial on patients with PVS, including
YOR, was recently carried out to explore changes on several
clinical and physiological parameters in response to zolpidem
administration [25].
During the imaging session, both patient and healthy
control presented with behavioural signs consistent with their
previous clinical and physiological assessment [10]. After
administration of zolpidem, patient YOR changed from her
usual sleep-like state (longer periods of time with her eyes
closed) and started to open and close her eyes, remaining
open from minute 20–65, together with non-stereotyped limb
movements and startle reactions. During the first study
several spontaneous yawns appeared with triggered modula-
tion of the EEG spectrogram [10], while during MRI
acquisition only one spontaneous yawn appeared at minute
45. Those changes were accompanied by autonomic effects:
modulation of heart rate variability and slow tachycardia
waves [10]. No other arousal events were observed. Normal
subject DMC reported periods of decreased arousal and a
clear tendency to sleep to the end of the acquisition with no
other symptoms during study. Placebo administration did not
induce any significant change in the patients cognitive
performance.
Proton MRS
Figure 2 (left panel) shows the baseline spectra for patient and
control, acquired before zolpidem administration. In com-
parison with the normal values, the patient showed a
significant increase (over 100%) in Creatine-normalized
lactate
þ
lipid levels ([Lac
þ
Lip]/Cr). A slight decrease in
Ins (10.2%) and an increase in Glx (7.8%) were also found.
Differences in other metabolites were under 5% and con-
sidered non-significant. The last acquisition block in patient
YOR after zolpidem was dismissed due to excessive move-
ment. All other spectra were of good quality and highly
reproducible throughout the whole study for both subjects.
Coincidence in the spatial location of the MRS voxel and the
frontal activated cluster of the left frontal cortex is shown as
an inset in Figure 2.
Time-dependent behaviour of metabolite concentrations in
the patient showed progressively augmented concentrations of
NAA, Glx and [Lac
þ
Lip] after medication, from 25–55
minutes, whereafter concentrations of these metabolites began
to gradually decrease (Figure 2, top right panel). Percentage
of change (PC) in those metabolites reached a maximum of
38, 42 and 30%, respectively. Ins also showed a tendency to
increase in the same period, but with an irregular temporal
behaviour. Cr showed a consistent but not significant (55%)
0.001 4.74
(
-
9,
-
11, 8)
supe
r
ior
frontal
L Thalamus
0.002 4.22
(
-
40, 41, 24)
L middle frontal
0.012 4.69
(
-
6, 43, 68)
Precuneus
0.008 4.97
(
-
25,
-
23, 60)
L senso
r
y-moto
area
0.000 6.32
(40,
-
53,
-
27)
R cerebellum
0.000 6.04
(57,
-
30,
-
8)
R middle temporal
0.001 5.81
(14,
-
38,
-
46)
R cerebellum
0.000 5.66
(
-
52,
-
35,
-
22)
L infe
r
io
r
temporal
0.007 5.16
(
-
18,
-
50,
-
42)
L cerebellum
0.009 5.10
(
-
35,
-
28,
-
8)
L hippocampus
0.012 5.05
(42,
-
36, 6)
R supe
r
io
r
temporal
0.014 5.02
(34,
-
10,
-
20)
R hippocampus
0.018 4.95
(
-
64,
-
36,
-
12)
L middle temporal
0.021 4.53
(4, 35,
-
4)
Ante
r
io
r
cingulate
0.026 4.46
(14,
-
10, 2)
R thalamus
0.032 4.17
(
-
22,
-
48, 74)
L supe
r
io
r
p
arietal
0.038 4.04
(31,
-
39, 74)
R supe
r
io
r
p
a
r
ietal
0.012 5.95
(8,
-
54, 76)
Precuneus
DOI: 10.3109/02699052.2013.794961 Zolpidem induces metabolic and BOLD changes in PVS 5
trend to decrease during acquisitions, with a tendency to
recovery at the end of the study. In contrast, metabolite
profiles in normal DMC showed a progressive decrease in
NAA concentrations, reaching a maximum PC of 27%
(Figure 2, lower right panel). Glx profile showed slight but
sustained decrease, while Cr presented a trend to slightly
increase during the first hour and a switch to a decreasing
tendency after that period. No evidence for consistent changes
in [Lac
þ
Lip] and Ins were found.
Resting state fMRI
Following zolpidem administration, RS-fMRI analysis
revealed multiple areas of zolpidem-induced modulations of
brain activity, displaying divergent trends in the patient and
the frontal spontaneous BOLD signal tended to wane after 90
minutes in the patient. In contrast, no significant differences
were found in the magnitude of the BOLD time-course when
the placebo was compared with the baseline. Mild transient
changes in the middle frontal and temporal regions did not
survive multiple comparisons correction.
A robust decrease in spontaneous activity in the healthy
control was observed in orbito-frontal and anterior cingulate
areas, superior parietal and precuneus and the cerebellum.
Table 1. Regions with significant zolpidem-induced BOLD signal
modulation, as compared with baseline.
Cluster level Voxel level
control. Activations were first tested for each condition
relative to baseline. Brain regions with statistically significant
modulation of spontaneous activity are detailed in Table I and
P
FWE
K
E
P
FWE
Patient
Z
value
MNI
Coordinates
Brain region
(AAL Atlas)
in the online supplementary table. Figure 3 displays the
representative thresholded SPM{T} maps in the patient and
the control, overlaid on respective rendering of 3D-T1
weighted volumes. Zolpidem therapy induced a clearly
divergent flow signal between subjects in the left frontal
lobe, especially in the medial and orbitofrontal cortices and in
the cingulate areas, with a sustained increase in the patient
and a decrease in the normal volunteer.
50.001 881 0.001 7.11 (
-
3, 44, 8)
L anterior
cingulate area
0.001 4.99 (
-
9,
-
56, 5)
L medial
0.023 54
0.011 63
0.011 37
Control
50.001 30287
The patient showed a significantly increased BOLD signal
at p50.01, FWE corrected for multiple comparisons,
localized in the inferio
r
and middle frontal cor
t
ex, comprising
p
ortions of
b
ilateral anterior cingulated and orbitofrontal
cortices, left thalamus and the right head of the caudate
nucleus. All these findings were consistently reproducible
throughou
t
all conditions. A transien
t
activation at
p
50.05,
FWE corrected, was observed in the middle frontal cortex and

p
recuneus. Additionall
y
, significant
p
harmacological activa-
0.002 45
tion in the sensory-motor cortex was observed 1 hour after
zolpidem intake (online supplementary table). Differences in
P
FWE
: P-value corrected by family-wise error; K
E
:cluster extent in
voxels; R: right; L: left
Figure 3. Statistically thresholded zolpidem-induced BOLD changes in four time points, rendered on the patient (upper) and normal (down) T1
volumes. Results are thresholded for display at whole brain family wise error corrected (p50.05). Colour scale represents t-values.
6 R. Rodriguez-Rojas et al. Brain Inj, Early Online: 1–10
Figure 4. Zolpidem-induced hemodynamic changes in patient (top) and normal (down). The left column shows the 3D rendered maximum intensity
projections of statistical parametric mapping. Arrow points to selected VOI in medial frontal region. The column on the center shows measured (dashed
line) and estimated (solid line) BOLD time series. The column on the right shows the temporal dynamic of neuronal efficacy ".
After the second and third acquisition, a statistically signifi-
cant decrease in the amplitude of the BOLD signal extended
to the neighbouring inferior frontal regions, and temporal and
inferior parietal areas (see online supplementary table). A
wide inhibition was found in both thalami after 45 minutes of
zolpidem ingestion. The most significant change from
baseline was at the end of the study, rv92 minutes after
zolpidem administration, which, in consideration of the
pharmacodynamic properties of this drug in healthy subjects,
was the expected peak [26, 27].
Haemodynamics
Estimation of a biophysical model for the haemodynamic
time series allows for an evaluation of metabolic interactions
at the neuronal level. The left panel of Figure 4 shows the
maximum intensities of SPM{T} maps in the patient and
control, projected onto the respective brain surfaces. White
arrows point to frontal clusters where the haemodynamic
parameters were estimated. In the BOLD signal dynamics
profiles, shown in the central panel, it becomes clear that
there is a divergent response to the pharmacological inter-
vention in the patient and control. BOLD signal intensity in
the middle frontal cortex of the patient is rising after zolpidem
intake, showing a weak drop after 1 hour. In contrast, there are
BOLD signal decreases in the healthy control and this
behaviour remains to the end of the study. This results in
changes in the neuronal efficacy ", as shown in the right panel
of Figure 5. Finally, the linear correlation analysis between
the percentage of change of the metabolite concentrations and
the neuronal efficacies show a statistically significant rela-
tionship between the BOLD signal changes and NAA/Cr
(R
2
¼ 0.885, p50.05) and Glx/Cr (R
2
¼ 0.744, p50.05)
concentrations (Figure 5).
Discussion
The aim of this placebo-controlled study was to examine
metabolic and vascular processes induced by zolpidem in
brain networks in a patient with severe brain injury. Results
were compared with a closely matched normal volunteer in
order to address the paradoxical clinical effect of zolpidem in
a neurophysiological framework. To the authors’ knowledge,
the present study is the first scrutiny of pharmacological
modulation of spontaneous metabolic activity, induced by
zolpidem, in a patient with PVS.
Clinical and physiological behaviour
Vascular and metabolic modulation is associated with clin-
ically and neuro-physiologically detectable alteration of the
awareness state [10]. A detailed discussion of the latter is
beyond the scope of this paper and will be the topic of further
research [25]. However, despite difficulties inherent to the
behavioural assessment during imaging, it is interesting to
note the consistency of changes with those reported during the
previous physiological study [10]. Increasing attention was
confirmed by eye and limb movements, yawning and arousal
periods. More interesting, those signs were matched in time
with the modulation of electroencephalographic and cardio-
vascular activity. One should note that, although yawning is
not uncommon in patients with PVS, it was rare in YOR.
In fact, yawning related to the paradoxical effect of Zolpidem
administration was first reported in this patient [10]. This is a
complex neural response that has been associated with
DOI: 10.3109/02699052.2013.794961 Zolpidem induces metabolic and BOLD changes in PVS 7
Figure 5. Percent of changes of the normalized metabolites concentrations against neuronal efficacy ". Only N-acetyl-aspartate (NAA) and Glutamate/
Glutamine (Glx) concentrations showed significant linear correlation with temporal dynamics of BOLD signal (significance at p50.05).
transient increases in arousal state and is mediated by a
cortico-subcortical circuit [28–30]. Her parents and medical
staff confirmed that such alterations from the sleep-like basal
state were very unusual in YOR. These findings support the
results, as discussed below.
Proton spectroscopy
1
H-MRS is a well-established approach to studying the brain
energy metabolism. The data showed a detectable and
consistent increase of NAA levels in the patient within
1 hour after pharmacological intervention. In contrast, the
tendency to signal decline remained in the normal control
during the whole study. The exact role of this metabolite is
under discussion, but it is considered a metabolic marker for
neuronal density and function [31]. According to recent
findings, the NAA synthesis reaction proceeds, among other
situations, when energy production via the Krebs cycle is
required [31].
Clark et al. [32] recently hypothesized that the abundant
NAA in neuronal tissue can also serve as a large pool for
replenishing Glx in periods of speedy or dynamic signalling
demands and stress, helping to provide adequate levels of this
metabolite. This hypothesis is consistent with a sustained
increase of Glx in this patient during data acquisition. At
present, a convergent set of data points out that glutamate
signalling in astrocytes provides a mechanism to strongly
connect synaptic activity and glucose consumption [33]. This
metabolic pathway, often referred to as the astrocyte-neuron-
lactate shuttle, is a clear example of co-operation between
astrocytes and neurons. The basic mechanism in neurometa-
bolic coupling is the glutamate stimulated aerobic glycolysis
in astrocytes, which results in the release of lactate from
astrocytes [32–35]. The same metabolic pathway can explain
a transient increase in Lac concentrations.
As it has been previously argued that Glx stimulates
aerobic glycolysis in astrocytes, this process results in a
transient Lac over-production, released from astrocytes to the
extracellular space, followed by a recoupling phase during
which Lac would be oxidized by neurons to serve as an
energy fuel [33–35]. It is interesting to note that, although the
MRS voxel that was located in the frontal tissue appeared
normal on conventional MRI sequences, an abnormally high
Lac concentration was found, suggesting that neuronal
populations are exposed to ongoing metabolic stress.
Resting state fMRI
As a whole, the results in the patient with PVS point to a
zolpidem-induced increased metabolism related to a dor-
mancy switch-off in the frontal cortex, posterior cingulated
areas, precuneus and thalamus. In contrast, results in the
healthy control suggest an inhibitory effect over those areas,
aside from the cerebellum. These findings are in agreement
with recent studies showing that the condition of the resting
state fMRI-identified networks could be related to the level of
conscious processing in patients with disorder of conscious-
ness (DOC) [17, 36, 37]. These results also complement the
previous findings in healthy volunteers showing a zolpidem-
induced decrease in BOLD signal affecting a distributed
network during visual stimulation [38].
Sedative-hypnotic effects of zolpidem are due to its
selective action on GABA receptors [27]. Up to now, the
reason for its paradoxical effect in PVS remains unknown.
However, based on these results and on previous studies
showing an inverse relationship between GABA-mediated
neuronal inhibition and the magnitude of the BOLD signal
[38], a hypothesis can be advanced. After brain injury, an
increment of excitatory and inhibitory neurotransmitters
occurs, mostly glutamate and GABA [6, 11]. GABAs
inhibitory effect predominates, suppressing cellular metabol-
ism, which protects cells from an unfavourable environment,
leading to loss of consciousness. A slower secondary
protective response converts GABA receptors to a hypersen-
sitive state, so that decreased levels of this neurotransmitter
can preserve their suppressive effect and uphold a trend
of synchronized slow-wave activity in the brain, termed
the neurodormant state [6]. When zolpidem attaches to the
modified GABA receptors of the neurodormant cells, the
receptor structure is deformed and abnormal cell metabolism
ceases and, hence, dormancy is switched off. If dormancy
involves large or important functional areas, clinical changes
related to brain activation after zolpidem can be dramatic.
CBF and metabolic increments have been documented using
99mTc-HMPAO SPECT or 18F-FDG PET, indicating that
those non-functioning areas start to function again after
8 R. Rodriguez-Rojas et al. Brain Inj, Early Online: 1–10
zolpidem [2, 8, 11]. Future studies should be carried out to
clarify the possible pharmacological contribution on neuro-
vascular tone.
It is agreed that the changes on BOLD signal are not
necessarily or exclusively related to the modulation of the
resting-state vascular dynamics, considering that during this
study YOR showed signs of arousal after zolpidem. RS-fMRI
studies are not sufficient to predict potential recovery to
awareness from PVS and elucidate the differential contribu-
tion of attentional circuitry to BOLD signal modulation. More
complex fMRI designs involving higher levels of processing
are necessary to assess the potential of zolpidem to induce
conversion of residual cognitive functions into high-level
processing, indicative of awareness. Methodological handi-
caps of this approach are discussed below.
Haemodynamic
From a physiological perspective, calculation of haemo-
dynamic parameters is more interesting and rigorous because
it allows one to explore neural mechanisms that underpin the
transient modulation of CBF, induced by zolpidem. A time-
course plot of adjusted and fitted BOLD data exhibited a
divergent behaviour in the patient and normal subject,
showing tendencies to increase and decrease the resting
metabolism, respectively. Consequently, the estimation of
neural efficacy confirmed that behaviour, whereas placebo
did not cause observable modulation of the haemodynamic
response. As explained in Friston et al. [23, p. 470], that
parameter ‘represents the efficacy with which neuronal
activity causes an increase in (flow inducing) signal’. In the
framework of haemodynamic modelling, the multiplying of
the stimulation function (i.e. pharmacological intervention)
and neuronal efficacy is equivalent to the vascular input from
the neural activity inducing modulation of RS-fMRI signal.
According to these results, the temporal dynamics of this
parameter in a patient with PVS strongly suggest that
zolpidem invokes an increase in CBF, which reaches its
maximum rv45 minutes to 1 hour after administration. A
decreasing tendency in the healthy subject is interpreted as a
reduced efficacy of the ensuing synaptic activity to induce a
vascular signal, which is coherent with an inhibitory activity
over the frontal cortices.
The high relationship of NAA and Glx concentrations with
the haemodynamic changes stresses the contribution of
extravascular compartments of the brain tissue to the BOLD
signal. The role of Lac during brain activation and its
functional involvement in metabolic activity has been
assessed by several studies. A transitory Lac peak has been
demonstrated using
1
H-MRS during visual [39, 40], motor
[41] and cognitive [42] stimulations. No significant correl-
ation was found with the BOLD signal. This apparent
inconsistency is probably due to the essential differences of
RS-fMRI and the activation studies. The significance of Lac
in slow oscillations in neural activity, characterizing the
default network, has not been clarified. In healthy tissues, Lac
concentration is close to the detection limits at 1.5 tesla and
subtle changes cannot be considered in a reliable analysis.
Despite those facts, a clear enlargement of the Lac signal was
obtained in this patient after zolpidem, which was not
replicated after placebo. Seen together with the behaviour
of NAA and Glx, those changes suggest a zolpidem-induced
modulation of neurometabolism, underlying detectable
changes in CBF.
Methodological considerations
These results provide new evidence about the physiological
processes triggering the pharmacological action of zolpidem,
but do not address the possible predictive markers of its
efficacy. The main limitation to this study is that the findings
are limited to a single patient. However, large scale trials from
patients with severe brain damage present challenging
complexities related with acquisition, analysis and interpret-
ation of neuroimaging data, inhomogeneities in lesion
topology, functional response to pharmacological intervention
and neurochemical profile, which are unique for each patient.
Previous neuroimaging studies, using zolpidem in patients
with reduced cognitive behaviour, have demonstrated that
single-patient placebo-controlled trials are a plausible
approach to identifying functional responses to drug admin-
istration [9, 12]. These results are consistent with those
reports and with the proposed GABA-mediated thalamo-
cortical modulatory mechanism suggested earlier in this
discussion. Additionally, comparison with age- and sex-
matched healthy subjects allows one to partially overcome
this limitation and to advance conclusions about a specific
drug-effect in cases with PVS.
The use of creatine/phosphocreatine to calculate metabol-
ite ratios, although it is a common practice, may lead to
confounding results. Cr plays a crucial role in ATP synthesis
and is, therefore, roughly considered a marker of energy
metabolism of both neurons and astrocytes, decreasing during
hypermetabolic processes [43]. While not significant, Cr
tended to slightly decrease in the patient during the experi-
ment, probably in relation to the homeostasis of cellular
bioenergetics. However, normalization corrects for the partial
volume effect and MRI inhomogeneities, thus preventing the
intra- and inter-subject variance, and is critical in quantifying
low-abundance metabolites such as Lac.
Because no explicit task is being performed during the
resting-state BOLD experiment, this approach is very attract-
ive compared with the standard on/off paradigms in non-
communicative patients such as those with DOC. Despite
these advantages, several concerns have been associated with
the resting baseline phMRI [18]. First, long resting BOLD
sequences often rely on an average measure over a block of
time, making the steady state difficult to reach during
acquisition. In this GLM design each acquisition block
comprised 3 minutes. Considering the pharmacokinetics
through the gastrointestinal system, one can assume each
acquisition as a single condition (input function) related to
zolpidem or placebo concentration in the steady state.
Second, the knowledge of the pharmacological effect on the
‘resting’ BOLD signal and its relation with cognitive state is
still limited. However, in recent years several studies have
shown that a spontaneous fMRI signal is related to the
underlying structured patterns of neural activity [15].
Increasing attention has been paid to the significance of this
‘default network’ for cognitive behaviour and significant
DOI: 10.3109/02699052.2013.794961 Zolpidem induces metabolic and BOLD changes in PVS 9
correlation between functional neuroimages and the level of
consciousness in DOC patients has been recently reported
[17, 36]. These results are then consistent with the hypothesis
that zolpidem caused modulation in the thalamus-cortical
functional network, inducing detectable variations in the
BOLD signal driven by blood flow and volume changes. The
proposal that those variations are secondary to pharmacolo-
gically-induced metabolic changes, caused by neural activity,
is supported by consistent changes in extravascular metabolite
concentrations and previous EEG measurements [10]. Future
experiments using triggered EEG and fMRI acquisition,
absolute MRS quantification and fMRI-based connectivity
analysis can make notable contributions to the understanding
of drug-induced changes in neurovascular coupling of DOC
patients.
Conclusions
The findings suggest that zolpidem increases the spontaneous
BOLD signal fluctuations in a widely distributed cortico-
subcortical network. This phenomenon supports that zolpi-
dem can abnormally promote awareness in the resting human
brain. Based on concurrent changes in the concentration of
extravascular brain metabolites and previous studies regarding
zolpidem’s mechanism of action on GABA-A receptors,
a pharmacological modulation of metabolic efficiency is
proposed in the thalamo-fronto-parietal network, suggested
as the ‘default network’, subserving basic functions related to
consciousness. It is concluded that a combined
1
H-MRS and
BOLD signal assessment might contribute to improve the
comprehension of the pharmacological modulation of neuro-
vascular coupling in PVS. Further studies in larger patient
cohorts are needed to confirm those mechanisms by using
simultaneous multi-modal techniques.
Acknowledgements
The authors are grateful to Professor Ralf Clauss for his useful
discussions, constructive suggestions and English language
assistance. The authors are grateful to the anonymous referees
for their significant and constructive comments, which greatly
improved the paper. The authors express appreciation to
Lic.Marta Cristofol for manuscript revision and Dr Juan A.
Piedra for helping during image acquisitions.
Declaration of interest
This work was supported by the International Center for
Neurological Restoration and the Institute of Neurology and
Neurosurgery, in Havana. RRR was partially supported by the
Associate Researcher Program of the International Center for
Theoretical Physics, in Trieste. The authors report no
conflicts of interest.
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... One doubleblind, placebo-controlled crossover study in 84 patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) or a minimally conscious state (MCS) identified 5% of patients as "definite responders" [70], whereas another prospective open-label trial in 60 patients with DoC showed behavioral improvements in 20% of patients, without a change in level of consciousness [71]. Zolpidem responses have been associated with regional increased metabolism on fluorodeoxyglucose positron emission tomography [72], an increased blood-oxygen level-dependent signal on functional MRI (fMRI) [73], reduced burst suppression on electroencephalography (EEG) [74], and restoration of thalamocortical signaling on dynamic EEG analyses [68,69,75]. ...
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