PET Mapping for Brain-Computer-Interface-Based Stimulation ...jnm.snmjournals.org/content/early/2016/02/24/... · 1 ABSTRACT Brain-computer interface (BCI) based technology has great

Brief Communications

PET Mapping for Brain-Computer-Interface-Based Stimulation in a Rat Model with Intracranial

Electrode Implantation in the Ventro-posterior Medial Thalamus

Yunqi Zhu1-5✝, Kedi Xu6✝, Caiyun Xu1-5✝, Jiacheng Zhang6, Jianfeng Ji1-5, Xiaoxiang Zheng6*, Hong

Zhang1-5 and Mei Tian1-5*

1Department of Nuclear Medicine, The Second Hospital of Zhejiang University School of Medicine,

Hangzhou, China; 2Zhejiang University Medical PET Center, Hangzhou, China; 3Key Laboratory of

Medical Molecular Imaging of Zhejiang Province, Hangzhou, China; 4Institute of Nuclear Medicine and

Molecular Imaging, Zhejiang University, Hangzhou, China; 5Collaborative Innovation Center for Brain

Science, Fudan University, Shanghai, China, and 6Qiushi Academy for Advanced Studies (QAAS),

Zhejiang University, Hangzhou, China

✝These authors contribute equal to this paper.

Running title: PET mapping of brain-computer interface

Word count: 3093

*Correspondence: Prof. Mei Tian, Department of Nuclear Medicine, The Second Affiliated Hospital of

Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China, Email:

[email protected]

Prof. Xiaoxiang Zheng, Qiushi Academy for Advanced Studies (QAAS), Zhejiang University, Hangzhou,

China, Email: [email protected]

Journal of Nuclear Medicine, published on February 25, 2016 as doi:10.2967/jnumed.115.171868by on July 30, 2020. For personal use only. jnm.snmjournals.org Downloaded from

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ABSTRACT

Brain-computer interface (BCI) based technology has great potential in improving the quality of life for

neurological patients. This study aims to use positron emission tomography (PET) mapping for

BCI-based stimulation in a rat model with intracranial electrode implantation in the ventro-posterior

medial thalamus (VPM). Methods: PET imaging studies were conducted before and after the VPM

stimulation. Results: Intracranial stimulation to the right VPM induced significant orienting performance.

18F-FDG accumulations were found significantly increased in the paraventricular thalamic nucleus (PVT),

septohippocampal nucleus, bilateral lateral septum (LS), bilateral amygdala, bilateral piriform cortex,

bilateral endopiriform nucleaus, bilateral insular cortex, olfactory bulb, and the left Crus Ⅱ of the

ansiform lobule of cerebellum (Crus Ⅱ) after the VPM stimulation; but decreased in the bilateral

somatosensory cortex (S1), right secondary visual cortex and the right simple lobule of cerebellum.

Conclusion: This study demonstrated that PET mapping could identify specific brain regions associated

with orienting performance by the VPM stimulation in rats. PET molecular imaging could be an important

approach for BCI-based research and its clinical applications.

Keywords: Positron emission tomography (PET), brain-computer interface (BCI), electrical stimulation,

ventro-posterior medial nucleus (VPM)

by on July 30, 2020. For personal use only. jnm.snmjournals.org Downloaded from


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INTRODUCTION

Brain computer interface (BCI) systems have gained great visibility in the past years as it merges the

fields of bio-robotics and neuroscience. Clinically, it is a promising new therapeutic strategy for the

restoration of sensory and motor functions in patients with neurological disorders (1, 2). Owing to the

technical advancement of implantable microelectrodes and processing electronics, remote control of the

animal’s orienting performance has been succeeded by appropriate repeated trainings after artificially

introduced electrical commands into the somatosensory cortical (S1) and medial forebrain bundle (MFB)

(3). During the training, the rats learned to interpret remote brain stimulation as instructions for directing

their trajectory of locomotion. Recently, our group demonstrated a novel control method by direct

stimulation of the ventro-posterior medial thalamus (VPM) which could initiate orienting performance in

freely roaming rats without repeated training sessions (See Supplementary Video-1) (4). VPM is known

as a somatosensory relay station that relays inputs sensory information from individual whiskers and

projects to the primary somatosensory cortex (S1) (5), however, it is unclear which brain regions are

involved in the orienting performance induced by the VPM stimulation. Thus, we hypothesized that by

using positron emission tomography (PET) molecular imaging mapping approach, we could explore the

intracranial VPM stimulation related orienting function and identify the specific cerebral activation pattern.

In this present study, we conducted PET imaging in a freely moving rat model before and after VPM

stimulation. To our knowledge, this is the first PET imaging study on the BCI-based stimulation in a rat

model with intracranial electrode implantation in the VPM.

MATERIALS AND METHODS

Animals and Intracranial Stimulation Electrode Implantation

Twelve Sprague Dawley rats (male, 250-280 g) were used for this study. Bipolar electrical

stimulation electrodes were constructed with insulated Nichrome wires (A-M System, bar diameter 50

μm, 0.4 mm between electrodes tips) (4). The animal was secured on a stereotaxic frame (RWD Life



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Science Co.) under pentobarbital sodium anesthesia (50 mg/kg, i.p.), then the electrode was implanted

to the right VPM thalamus according to the Rat Brain Atlas (6) and fixed on the skull by dental cement.

The animal was given one week to recover from the above procedure. All the animal experiments were

approved by the Institutional Animal Care and Use Committee at Zhejiang University.

Electrical Stimulation and Orienting Performance

To deliver electrical stimulation directly into the VPM, an isolated stimulator (A-M System) was

connected to the implanted electrode with a flexible extension cable, allowing the animal to move freely.

The stimulus paradigm was a 30-minute-block-design with 180 cycles consisting of 1 sec of stimulation

ON followed by 9 sec of rest. The intracranial VPM stimulation induced orienting performance was

captured by a video camera, and the “turning angle” was calculated as shown in Figure 1A. The turning

angle ranges from 30° to 60° was regarded as a successful stimulus. The animals with turning angle of

less than 30° or larger than 60° were excluded from this study.

PET Imaging Protocol and Data Analysis

All animals were food deprived overnight before PET imaging studies. Baseline and

post-stimulation microPET studies were performed in a microPET R4 scanner (Siemens Medical

Solutions) at 7 and 10 day after the stereotaxic surgery, respectively. In the post-stimulation microPET

studies, each rat was subjected to VPM stimulation for 30 min immediately after 18F-FDG injection (18.5

MBq) via tail vein. PET images were acquired at 40 min after 18F-FDG injection and analyzed using an

improved toolbox for voxelwise analysis of rat brain images on statistical parametric mapping (SPM) 8

(7). Groups were compared using a paired t-test with a significance threshold of P < 0.001.

RESULTS



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Upon completion of the last PET imaging, brain sections were stained with hematoxylin and eosin

(H.E.). The pathological confirmation verified the appropriate sites of intracranial electrode implantation.

A representative image of H.E staining was presented in Figure 1B.

The intracranial electrical stimulation of the right VPM induced ipsilateral orienting performance

towards the right side. A representative orienting performance was presented in the Supplemental

Video-2. Among the 12 tested rats, 8 showed appropriate turning angle ranged from 30° - 60° during the

stimulation period, while the other 4 with turning angles less than 30° were excluded from this study.

After VPM stimulation, significantly increased 18F-FDG accumulations were found in the

paraventricular thalamic nucleus (PVT), septohippocampal nucleus, bilateral lateral septum (LS),

bilateral amygdala, bilateral piriform cortex, bilateral endopiriform nucleaus, bilateral insular cortex,

olfactory bulb, and the left Crus II of the ansiform lobule of cerebellum (Crus II ) (Table 1, Fig. 2A and 3),

while significantly decreased 18F-FDG accumulations were observed in the bilateral somatosensory

cortex (S1), right secondary visual cortex and the right simple lobule of cerebellum (Table 1, Fig. 2B and

4).

DISSCUSSION

Born as highly multidisciplinary field, basic research on BCI has moved at a stunning pace since

the first experiment demonstrated that electrical activity generated by ensembles of cortical neurons

could directly control a robotic manipulator (8). Noninvasive neuroimaging modalities are gaining

momentum in the research arena for BCI systems. Although functional magnetic resonance imaging

(fMRI) is surfaced as the major tool used for noninvasive characterization of brain function with superior

spatial resolution (9), PET has advantage of tracing the bio-chemical changes in cognitive or behavioral

brain function during real-time tasks without the interference of ambient noise generated by the MRI

scanner, and is suitable for the brain implanted with metal-based electrodes.

In the current study, by using 18F-FDG PET imaging, we found that VPM stimulation induced



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increased glucose metabolism in the PVT, septohippocampal nucleus, bilateral LS, bilateral amygdala,

bilateral piriform cortex, bilateral endopiriform nucleaus, bilateral insular cortex, olfactory bulb, and the

left Crus Ⅱ after the VPM stimulation, but significantly decreased 18F-FDG accumulations were

observed in the bilateral S1, right secondary visual cortex and the right simple lobule of cerebellum. To

the best of our knowledge, this is the first study using PET as a neuroimaging tool to investigate the

BCI-based electrical stimulation induced orienting performance in the rat model with electrode implanted

in the VMP.

One of the significant findings in our study was the increased glucose metabolism in the PVT,

amygdala, hippocampus and LS after VMP stimulation. The PVT is a major source of projections to the

nucleus accumbens (NAc), the bed nucleus of the stria terminalis and the central nucleus of the

amygdala as well as the cortical areas associated with these subcortical regions. The PVT participates

in the functional integration of limbic cortical and striatal circuitry, and is notable for providing a very

dense projection to the nucleus accumbens, a part of the striatum strongly associated with the regulation

of locomotion (10). Also, within the NAc, PVT profiles were found occasionally made synapses onto

spines and distal dendrites (11). Consequently, the PVT with its direct and indirect projections to the

nucleus accumbens forms an impressive neural network that could exert control over locomotor activity

(12). The amygdala is a critical component of the neural circuitry underlying fear associations and

emotional learning (13). Previous work indicates an essential role of the basolateral amygdala in

stimulus-reward learning and the dorsal hippocampus in spatial learning and memory (14). Interestingly,

increased glucose metabolism were observed in not only amygdala and PVT, but also in the

septohippocampal nucleus and bilateral LS in this current study, which is consistent with the very recent

literature on hippocampus to lateral septum pathway (15). The optogenetic stimulation of projections

from LS to lateral hypothalamus decreased locomotion, suggesting that LS is crucial for control of

locomotion and arousal.

The insular cortex is part of the neocortex located in the lateral temporal lobe and is highly

interconnected with multiple brain networks. (16). Electrical stimulation of insula elicited body



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movements in nonhuman primates, and indicated a role in sensorimotor processing (17). The

mid-posterior insula has also been implicated in the processing of awareness with relation to the position,

movement and sensation of the body, and thus may be necessary for coordinating movements

effectively (18). The cerebellum has been implicated in the control of action and acquisition of motor

skills (19), particularly, the posterolateral regions (Crus I and II) involved in adaptation to force field and

visuomotor perturbation (20). Taking the above literatures and our findings together, we suggest that the

insula and cerebellum may involve in movement coordination and controlling turning angle.

We found that the VPM electrical stimulation resulted in decreased glucose metabolism in S1,

which was supported by other studies. Electrical stimulation has been shown to evoke strong and

long-lasting cortical inhibition that suppressed neurons from firing (21). A recent study investigated

visually evoked responses in visual cortex (22). The results showed that visual stimuli evoked fewer

spikes during waking than during anesthesia and spikes evoked during wakefulness were quickly

followed by a significant and long-lasting hyperpolarization, and suggests that cortical responses to

sensory stimulation are dominated by synaptic inhibition in the awake cortex (22). Thus, we speculate

that electrical stimulation of the VPM might lead to initial activation of cortical pyramidal neurons;

subsequently, thalamocortical input recruits strong postsynaptic inhibition shunts the initial excitatory

input within the course of the hyperpolarization, resulting in a long-lasting decrease in baseline activity of

the S1. In the future, PET imaging study combined with electrophysiological recording and EEGs in the

same subject would provide more insights into the BCI-based stimulation related brain function.

In summary, the present report presents several important findings concerning the role of specific

brain regions involved in the VPM stimulation. Future study of inter-regional neural connectivity by using

multi-modality imaging approaches would provide more insights into the BCI-based stimulation.

CONCLUSION

This study demonstrated that PET mapping could identify specific brain regions associated with

orienting performance by the VPM stimulation in rats. PET molecular imaging could be an important



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approach for BCI-based research and its clinical applications.

DISCLOSURE

This research was supported by Grants from the National Key Basic Research Program of China

(2013CB329506), Zhejiang Provincial Natural Science Foundation of China under Grant

(LR13H180001), the National Natural Science Foundation of China (81425015, 81271601, 61305145),

and the Specialized Research Fund for the Doctoral Program of Higher Education (20130101110015,

20130101120166).

ACKNOWLEDGEMENT

We thank Chaonan Yu for providing technical support on the animal surgery.



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15. Bender F, Gorbati M, Cadavieco MC, et al. Theta oscillations regulate the speed of locomotion via a hippocampus to

lateral septum pathway. Nat Commun. 2015;6:8521.

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FIGURE 1. (A) Schematic illustration for the calculation of “turning angle”. The turning angle is

calculated from the different position directions between pre- and post-stimulation. (B) H.E. staining of

the site of stimulation electrode placement. Arrow indicates the track of the intracranial electrode.



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FIGURE 2. In vivo PET images of the rat brain. Serial coronal (A) and transverse (B) sections

demonstrated significant changes of glucose metabolism after VPM electrical stimulation (P<0.001).

Differences for brain regions have been color coded and are superimposed on MRI template.



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FIGURE 3. Representative sagittal, transverse, and coronal images demonstrated increased glucose

metabolism in the left (A) and right amygdala (B), and left Crus II (C) induced by VPM stimulation

(P<0.001).



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FIGURE 4. Representative sagittal, transverse, and coronal images demonstrated decreased glucose

metabolism in the left (A) and right (B) S1 induced by VPM stimulation (P<0.001).



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TABLE 1

Significant Metabolic Changes after the VPM Stimulation (Baseline vs. Stimulation)

Region

Coordinate (mm) Cluster level

x y z t value z score Puncorrected

Increased

Paraventricular thalamic nucleus 0 5 -2 30.02 5.70 < 0.001

Septohipppocampal nucleus 0 4 0 30.02 5.70 < 0.001

Right lateral septum 1 5 0 30.02 5.70 < 0.001

Left lateral septum -1 5 0 30.02 5.70 < 0.001

Right amygdala 5 8 -3 11.16 4.41 < 0.001

Right piriform cortex 6 9 -3 11.16 4.41 < 0.001

Right endopiriform nucleus 6 8 -2 5.75 3.39 < 0.001

Right insular cortex 6 8 -2 5.75 3.39 < 0.001

Left amygdala -5 8 -3 6.86 3.67 < 0.001

Left piriform cortex -6 9 -3 5.41 3.29 < 0.001

Left endopiriform nucleus -6 8 -2 6.86 3.67 < 0.001

Left insular cortex -6 8 -2 6.86 3.67 < 0.001

Olfactory bulb 0 3 6 7.42 3.80 < 0.001

Left Crus Ⅱ of the ansiform lobule

of cerebellum

-4 5 -13 6.76 3.65 < 0.001

Decreased

Right primary somatosensory cortex 5 2 0 9.17 4.12 < 0.001

Left primary somatosensory cortex -5 1 3 8.13 3.94 < 0.001

Right secondary visual cortex 5 3 -9 6.30 3.54 < 0.001

Right simple lobule of cerebellum 3 1 -10 5.13 3.20 < 0.001



Doi: 10.2967/jnumed.115.171868Published online: February 25, 2016.J Nucl Med. Yunqi Zhu, Kedi Xu, Caiyun Xu, Jiacheng Zhang, Jianfeng Ji, Xiaoxiang Zheng, Hong Zhang and Mei Tian Intracranial Electrode Implantation in the Ventro-posterior Medial ThalamusPET Mapping for Brain-Computer-Interface-Based Stimulation in a Rat Model with

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PET Mapping for Brain-Computer-Interface-Based Stimulation ...jnm.snmjournals.org/content/early/2016/02/24/... · 1 ABSTRACT Brain-computer interface (BCI) based technology has great