Chun-Xia Li1 and Xiaodong Zhang1,2
1Yerkes Imaging Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States, 2Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate, Atlanta, GA, United States
Synopsis
Long-duration anesthesia administration
could cause neurocognitive decline in animals and humans. However, the
potential mechanism still remains unclear. In the present study, the functional
connectivity of adult rhesus monkeys under maintenance dosage of isoflurane (~1
%) for four hours was examined. The
results demonstrate that long-duration isoflurane exposure resulted in decreased functional connectivity in
posterior cingulate cortex (PCC)
dominant default-mode network (DMN).
The MRI findings suggest that the detrimental effects of isoflurane on brain
connectivity may be associated with the neurocognitive decline observed in subjects after
long-duration administration of isoflurane.Introduction
Long duration administration of isoflurane is
usually used in medical procedures and in vivo neuroimaging researches. It has
been reported that long-duration isoflurane administration would interfere with
memory function in adult rats [1] and may cause brain cell death, and neurocognitive
decline in immature rats [2]. In particular, anesthesia is a main cause of postoperative
cognitive dysfunction in patients. As the alteration of default mode network
(DMN) is closely associated with cognitive decline [3], we hypothesized DMN
could be influenced by the long duration administration of isoflurane. In the
present study, we examined the long-duration effect of isoflurane to DMN
network of adult rhesus monkeys by using resting-state functional MRI (rsfMRI) techniques
[4].
Methods
Adult female rhesus monkeys (n=5, 7-11 years old)
were anesthetized with ~1% isoflurane (~0.8 MAC maintenance dosage) mixed with oxygen
for about 4 hours. O2 saturation, blood pressure, heart rate,
respiration rate, body temperature and PaCO2, etc, were monitored continuously.
All the physiological parameters were recorded and maintained in normal ranges.
Isoflurane dosage was measured continuously with an anesthesia machine (GE
Datex-ohmeda Cardiocap/5). MRI data were acquired using a gradient echo Echo
Planar Imaging (EPI) sequence (TR/TE=2190 ms/25ms) and started ~15 minutes later after animals were
moved into the scanner (Siemens 3T Trio with a Tx/Rx volume coil). The MRI parameters
were: 150 volumes per scan, FOV = 96 mm × 96 mm, spatial resolution=
1.5×1.5×1.5mm3, 34 contiguous slices. Corresponding 3D T1 weighted images and
field map images were also acquired. rsfMRI data were preprocessed
firstly by applying field map for image distortion correction with FSL (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FUGUE).
Slice timing correction, rigid body registration, regressing out signal in white matter and cerebrospinal fluid (CSF)
time series with a general linear model, temporal filtering with 0.009 Hz
~0.0237 Hz band-pass, spatial smooth by a Gaussian blur with 2.5-mm full width
at half maximum was performed using a script from AFNI (http://afni.nimh.nih.gov) [5].
Anatomical regions of interest (ROI) corresponding to the whole posterior cingulate cortex (PCC),
anterior cingulated cortex
(ACC), and dorsal/media prefrontal cortex (DMPFC) were selected using
AFNI and the monkey brain atlas [6] with T1-weighted images as reference. The averaged time courses of rsfMRI signal in PCC were
used to perform seed-based correlation analysis. Z transformation was
applied to the individual correlation maps to show normalized correlation maps.
The averaged z values of
connectivity between PCC and ACC or DMPFC were examined for statistical
differences. All statistical
analyses were performed in SPSS 21.0. P-values less than 0.05 were considered
statistically significant.
Results
The correlation degree (z
score) of PCC with either DMPFC or ACC was obviously decreased after 3 hours
isoflurane administration (Fig. 1), but only the PCC-DMPFC connectivity
decreased significantly (see Table 1). Mean arterial pressure (MAP) and heart
rates were not showing significant changes during the 4-hour anesthesia although decreasing trends were
seen during the 4-hour isoflurane administration (Fig. 2).
Discussion and
conclusion
Vincent and colleagues [7] have demonstrated that DMN in human also exists
in macaques by examining the macaque brain under isoflurane (0.8%-1.5%), and
PCC has shown as a dominant region. Previous studies have
demonstrated the deactivation of DMN is related with cognitive decline [3]. Our
results indicate that PCC-ACC and PCC-DMPFC associations
decreased significantly after 3 hour
isoflurane exposure (Table 1). Probably it is because anesthetic results in breakdown of large-scale
synchronization between brain regions [8, 9]; Also, it may be due to the fact that anesthetic causes a global loss
of functional segregation/specialization, resulting in a decreased specificity.
Therefore regions become more homogeneously connected to each other [9]. In addition,
the decreased DMN
activity is at least partly due to dysfunction of neuron and glia cell caused
by long term isoflurane toxicity. Similar
finding was also reported in another study [10]. Our finding of decrease in DMN of PCC is consistent with prior studies
[11].
In
conclusion, long-duration administration of isoflurane could cause decreased DMN activity, which may be
associated with the cognitive decline seen in post anesthesia patients.
Acknowledgements
No acknowledgement found.References
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