Li Min Chen

YNICL Journal 2025 Journal Article

Correspondence between thalamic injury-induced changes in resting-state fMRI of monkeys and their sensorimotor behaviors and neural activities

• Anirban Sengupta
• Pai-Feng Yang
• Jamie L. Reed
• Arabinda Mishra
• Feng Wang
• Isaac V Manzanera Esteve
• Zhangyan Yang
• Li Min Chen

Resting state functional MRI (rsfMRI) exploits variations in blood-oxygenation-level-dependent (BOLD) signals to infer resting state functional connectivity (FC) within and between brain networks. However, there have been few reports quantifying and validating the results of rsfMRI analyses with other metrics of brain circuits. We measured longitudinal changes in FC both within and between brain networks in three squirrel monkeys after focal lesions of the thalamic ventroposterior lateral nucleus (VPL) that were intended to disrupt the input to somatosensory cortex and impair manual dexterity. Local field potential signals were recorded to assess electrophysiological changes during each animal's recovery, and behavioral performances were measured longitudinally using a sugar-pellet grasping task. Finally, end-point histological evaluations were performed on brain tissue slices to quantify the VPL damage. The rsfMRI data analysis showed significant decrease in FC measures both within and between networks immediately post-injury, which started to recover at different time-points for each animal. The trajectories of FC recovery for each animal mirrored their individual behavioral recovery time-courses. Electrophysiological measurements of inter-electrode coherences and end-point histological measures also aligned well with the graded injury effects measured using rsfMRI-based FC. A simple algorithm employing FC measures from the somatosensory network could accurately predict each monkeys' behavioral recovery timeframe after four weeks post-injury. Whole brain between-network FC measures further revealed that the injury effects were not limited to thalamocortical connections but were rather more widespread. Overall, this study provides evidence of the validity of rsfMRI based FC measures as indicators of the functional integrity and behavioral relevance following an injury to a specific brain circuit.

YNICL Journal 2025 Journal Article

Corrigendum to “Correspondence between thalamic injury-induced changes in resting-state fMRI of monkeys and their sensorimotor behaviors and neural activities”. [NeuroImage Clin. 45 (2025) 103753]

• Anirban Sengupta
• Pai-Feng Yang
• Jamie L. Reed
• Arabinda Mishra
• Feng Wang
• Isaac V. Manzanera Esteve
• Zhangyan Yang
• Li Min Chen

YNIMG Journal 2024 Journal Article

fMRI, LFP, and anatomical evidence for hierarchical nociceptive routing pathway between somatosensory and insular cortices

• Hongyan Zhu
• Yan Tao
• Siqi Wang
• Xutao Zhu
• Kunzhang Lin
• Ning Zheng
• Li Min Chen
• Fuqiang Xu

The directional organization of multiple nociceptive regions, particularly within obscure operculoinsular areas, underlying multidimensional pain processing remains elusive. This study aims to establish the fundamental organization between somatosensory and insular cortices in routing nociceptive information. By employing an integrated multimodal approach of high-field fMRI, intracranial electrophysiology, and transsynaptic viral tracing in rats, we observed a hierarchically organized connection of S1/S2 → posterior insula → anterior insula in routing nociceptive information. The directional nociceptive pathway determined by early fMRI responses was consistent with that examined by early evoked LFP, intrinsic effective connectivity, and anatomical projection, suggesting fMRI could provide a valuable facility to discern directional neural circuits in animals and humans non-invasively. Moreover, our knowledge of the nociceptive hierarchical organization of somatosensory and insular cortices and the interface role of the posterior insula may have implications for the development of targeted pain therapies.

YNIMG Journal 2022 Journal Article

Graph theory analysis identified two hubs that connect sensorimotor and cognitive and cortical and subcortical nociceptive networks in the non-human primate

• Ruiqi Wu
• Feng Wang
• Pai-Feng Yang
• John C Gore
• Li Min Chen

Pain perception involves multiple brain regions and networks. Understanding how these brain networks work together is fundamental for appreciating network-wise changes reported in patients with chronic pain disorders. Parcellating pain related networks and understanding their causal relationships is the first step to understand how painful information is processed, integrated, and modulated, and it requires direct manipulation of specific brain regions. Nonhuman primates (NHP) offer an ideal model system to achieve these goals because cortical and subcortical regions in the NHP brain are established based on a variety of different types of data collected in a way that is not feasible or, at least, extremely difficult in humans (i.e., histology data, tract-tracing, intracerebral recordings). In addition, different methodological techniques can also help characterize and further understand these brain cortical and subcortical regions over the course of development. Here we used a heat nociceptive stimulation that is proven to elicit activity of nociceptive neurons in the cortex to refine and parcellate the whole brain nociceptive functional networks, to identify key network hubs, and to characterize network-wise temporal dynamic signatures using high-resolution fMRI. We first functionally localized 24 cortical and subcortical regions that responded to heat nociceptive stimuli (somatosensory area 1/2, area 3a/3b, S2, posterior insula (pIns), anterior insula, area 7b, posterior parietal cortex, anterior cingulate cortex (ACC), prefrontal cortex, caudate, and mediodorsal (MD) and ventral posterior lateral (VPL) thalamic nuclei) and used them as seeds in resting state fMRI (rsfMRI) data analysis. We applied both hierarchical clustering and graph-theory analyses of the pairwise rsfMRI correlation metrics and identified five cortical and one subcortical sub-networks: strong resting state functional connectivity (rsFC) between ACC and prefrontal regions, parietal cortex and area 7b, S2 and posterior insula, areas 3a/3b and 1/2 within the S1 cortex, and thalamic MD and caudate nuclei. The rsFC strengths between cortical areas within each subnetwork were significantly stronger than those between subcortical regions. Regions within each sub-network also exhibited highly correlated temporal dynamics at rest, but the overall dynamic patterns varied drastically across sub-networks. Graph-theory analysis identified the MD nucleus as a hub that connects subcortical and cortical nociceptive sub-networks. The S2-pIns connection joins the sensory and affective/cognitive sub-networks.

YNIMG Journal 2021 Journal Article

Functional networks in non-human primate spinal cord and the effects of injury

• Anirban Sengupta
• Arabinda Mishra
• Feng Wang
• Muwei Li
• Pai-Feng Yang
• Li Min Chen
• John C. Gore

Spontaneous fluctuations of Blood Oxygenation-Level Dependent (BOLD) MRI signal in a resting state have previously been detected and analyzed to describe intrinsic functional networks in the spinal cord of rodents, non-human primates and human subjects. In this study we combined high resolution imaging at high field with data-driven Independent Component Analysis (ICA) to i) delineate fine-scale functional networks within and between segments of the cervical spinal cord of monkeys, and also to ii) characterize the longitudinal effects of a unilateral dorsal column injury on these networks. Seven distinct functional hubs were revealed within each spinal segment, with new hubs detected at bilateral intermediate and gray commissure regions in addition to the bilateral dorsal and ventral horns previously reported. Pair-wise correlations revealed significantly stronger connections between hubs on the dominant hand side. Unilateral dorsal-column injuries disrupted predominantly inter-segmental rather than intra-segmental functional connectivities as revealed by correlation strengths and graph-theory based community structures. The effects of injury on inter-segmental connectivity were evident along the length of the cord both below and above the lesion region. Connectivity strengths recovered over time and there was revival of inter-segmental communities as animals recovered function. BOLD signals of frequency 0.01-0.033 Hz were found to be most affected by injury. The results in this study provide new insights into the intrinsic functional architecture of spinal cord and underscore the potential of functional connectivity measures to characterize changes in networks after an injury and during recovery.

YNIMG Journal 2021 Journal Article

Longitudinal fMRI measures of cortical reactivation and hand use with and without training after sensory loss in primates

• Hui-Xin Qi
• Jamie L. Reed
• Feng Wang
• Christopher L. Gross
• Xin Liu
• Li Min Chen
• Jon H. Kaas

In a series of previous studies, we demonstrated that damage to the dorsal column in the cervical spinal cord deactivates the contralateral somatosensory hand cortex and impairs hand use in a reach-to-grasp task in squirrel monkeys. Nevertheless, considerable cortical reactivation and behavioral recovery occurs over the following weeks to months after lesion. This timeframe may also be a window for targeted therapies to promote cortical reactivation and functional reorganization, aiding in the recovery process. Here we asked if and how task specific training of an impaired hand would improve behavioral recovery and cortical reorganization in predictable ways, and if recovery related cortical changes would be detectable using noninvasive functional magnetic resonance imaging (fMRI). We further asked if invasive neurophysiological mapping reflected fMRI results. A reach-to-grasp task was used to test impairment and recovery of hand use before and after dorsal column lesions (DC-lesion). The activation and organization of the affected primary somatosensory cortex (area 3b) was evaluated with two types of fMRI - either blood oxygenation level dependent (BOLD) or cerebral blood volume (CBV) with a contrast agent of monocrystalline iron oxide nanocolloid (MION) - before and after DC-lesion. At the end of the behavioral and fMRI studies, microelectrode recordings in the somatosensory areas 3a, 3b and 1 were used to characterize neuronal responses and verify the somatotopy of cortical reactivations. Our results indicate that even after nearly complete DC lesions, monkeys had both considerable post-lesion behavioral recovery, as well as cortical reactivation assessed with fMRI followed by extracellular recordings. Generalized linear regression analyses indicate that lesion extent is correlated with the behavioral outcome, as well as with the difference in the percent signal change from pre-lesion peak activation in fMRI. Monkeys showed behavioral recovery and nearly complete cortical reactivation by 9-12 weeks post-lesion (particularly when the DC-lesion was incomplete). Importantly, the specific training group revealed trends for earlier behavioral recovery and had higher magnitude of fMRI responses to digit stimulation by 5-8 weeks post-lesion. Specific kinematic measures of hand movements in the selected retrieval task predicted recovery time and related to lesion characteristics better than overall task performance success. For measures of cortical reactivation, we found that CBV scans provided stronger signals to vibrotactile digit stimulation as compared to BOLD scans, and thereby may be the preferred non-invasive way to study the cortical reactivation process after sensory deprivations from digits. When the reactivation of cortex for each of the digits was considered, the reactivation by digit 2 stimulation as measured with microelectrode maps and fMRI maps was best correlated with overall behavioral recovery.

YNICL Journal 2021 Journal Article

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys

• Feng Wang
• Zhongliang Zu
• Tung-Lin Wu
• Xinqiang Yan
• Ming Lu
• Pai-Feng Yang
• Nellie E. Byun
• Jamie L. Reed

PURPOSE: , semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions. METHODS: ) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites. RESULTS: of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, -1.6 and -3.5 ppm RF offsets. CONCLUSION: correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

YNIMG Journal 2019 Journal Article

Resting-state white matter-cortical connectivity in non-human primate brain

• Tung-Lin Wu
• Feng Wang
• Muwei Li
• Kurt G. Schilling
• Yurui Gao
• Adam W. Anderson
• Li Min Chen
• Zhaohua Ding

Numerous studies have used functional magnetic resonance imaging (fMRI) to characterize functional connectivity between cortical regions by analyzing correlations in blood oxygenation level dependent (BOLD) signals in a resting state. However, to date, there have been only a handful of studies reporting resting state BOLD signals in white matter. Nonetheless, a growing number of reports has emerged in recent years suggesting white matter BOLD signals can be reliably detected, though their biophysical origins remain unclear. Moreover, recent studies have identified robust correlations in a resting state between signals from cortex and specific white matter tracts. In order to further validate and interpret these findings, we studied a non-human primate model to investigate resting-state connectivity patterns between parcellated cortical volumes and specific white matter bundles. Our results show that resting-state connectivity patterns between white and gray matter structures are not randomly distributed but share notable similarities with diffusion- and histology-derived anatomic connectivities. This suggests that resting-state BOLD correlations between white matter fiber tracts and the gray matter regions to which they connect are directly related to the anatomic arrangement and density of WM fibers. We also measured how different levels of baseline neural activity, induced by varying levels of anesthesia, modulate these patterns. As anesthesia levels were raised, we observed weakened correlation coefficients between specific white matter tracts and gray matter regions while key features of the connectivity pattern remained similar. Overall, results from this study provide further evidence that neural activity is detectable by BOLD fMRI in both gray and white matter throughout the resting brain. The combined use of gray and white matter functional connectivity could also offer refined full-scale functional parcellation of the entire brain to characterize its functional architecture.

YNICL Journal 2019 Journal Article

Spatiotemporal trajectories of quantitative magnetization transfer measurements in injured spinal cord using simplified acquisitions

• Feng Wang
• Tung-Lin Wu
• Ke Li
• Li Min Chen
• John C. Gore

PURPOSE: This study aims to systematically evaluate the accuracy and precision of pool size ratio (PSR) measurements from quantitative magnetization transfer (qMT) acquisitions using simplified models in the context of assessing injury-associated spatiotemporal changes in spinal cords of non-human primates. This study also aims to characterize changes in the spinal tissue pathology in individual subjects, both regionally and longitudinally, in order to demonstrate the relationship between regional tissue compositional changes and sensorimotor behavioral recovery after cervical spinal cord injury (SCI). METHODS: MRI scans were recorded on anesthetized monkeys at 9.4 T, before and serially after a unilateral section of the dorsal column tract. Images were acquired following saturating RF pulses at different offset frequencies. Models incorporating two pools of protons but with differing numbers of variable parameters were used to fit the data to derive qMT parameters. The results using different amounts of measured data and assuming different numbers of variable model parameters were compared. Behavioral impairments and recovery were assessed by a food grasping-retrieving task. Histological sections were obtained post mortem for validation of the injury. RESULTS: QMT fitting provided maps of pool size ratio (PSR), the relative amounts of immobilized protons exchanging magnetization compared to the "free" water. All the selected modeling approaches detected a lesion/cyst at the site of injury as significant reductions in PSR values. The regional contrasts in the PSR maps obtained using the different fittings varied, but the 2-parameter fitting results showed strong positive correlations with results from 5-parameter modeling. 2-parameter fitting results with modest (>3) RF offsets showed comparable sensitivity for detecting demyelination in white matter and loss of macromolecules in gray matter around lesion sites compared to 5-parameter fitting with fully-sampled data acquisitions. Histology confirmed that decreases of PSR corresponded to regional demyelination around lesion sites, especially when demyelination occurred along the dorsal column on the injury side. Longitudinally, PSR values of injured dorsal column tract and gray matter horns exhibited remarkable recovery that associated with behavioral improvement. CONCLUSION: Simplified qMT modeling approaches provide efficient and sensitive means to detect and characterize injury-associated demyelination in white matter tracts and loss of macromolecules in gray matter and to monitor its recovery over time.

YNIMG Journal 2017 Journal Article

High-resolution functional MRI identified distinct global intrinsic functional networks of nociceptive posterior insula and S2 regions in squirrel monkey brain

• Ruiqi Wu
• Feng Wang
• Pai-Feng Yang
• Li Min Chen

Numerous functional imaging and electrophysiological studies in humans and animals indicate that the two contiguous areas of secondary somatosensory cortex (S2) and posterior insula (pIns) are core regions in nociceptive processing and pain perception. In this study, we tested the hypothesis that the S2-pIns connection serves as a hub for connecting distinct sensory and affective nociceptive processing networks in the squirrel monkey brain. At 9. 4T, we first mapped the brain regions that respond to nociceptive heat stimuli with high-resolution fMRI, and then used seed-based resting-state fMRI (rsfMRI) analysis to delineate and refine the global intrinsic functional connectivity circuits of the proximal S2 and pIns regions. In each subject, nociceptive (47. 5°C) heat-evoked fMRI activations were detected in many brain regions, including primary somatosensory (S1), S2, pIns, area 7b, anterior cingulate cortex (ACC), primary motor cortex, prefrontal cortex, supplementary motor area, thalamus, and caudate. Using the heat-evoked fMRI activation foci in S2 and pIns as the seeds, voxel-wise whole-brain resting-state functional connectivity (rsFC) analysis revealed strong functional connections between contralateral S2 and pIns, as well as their corresponding regions in the ipsilateral hemisphere. Spatial similarity and overlap analysis identified each region as part of two distinct intrinsic functional networks with 7% overlap: sensory S2-S1-area 7b and affective pIns-ACC-PCC networks. Moreover, a high degree of overlap was observed between the combined rsFC maps of nociceptive S2 and pIns regions and the nociceptive heat-evoked activation map. In summary, our study provides evidence for the existence of two distinct intrinsic functional networks for S2 and pIns nociceptive regions, and these two networks are joined via the S2-pIns connection. Brain regions that are involved in processing nociceptive inputs are also highly interconnected at rest. The presence of robust and distinct S1-S2-area 7b and pIns-ACC-PCC rsFC networks under anesthesia underscores their fundamental roles in processing nociceptive information.

YNIMG Journal 2011 Journal Article

Differentiation of somatosensory cortices by high-resolution fMRI at 7 T

• Elizabeth Ann Stringer
• Li Min Chen
• Robert M. Friedman
• Christopher Gatenby
• John C. Gore

This study aimed to evaluate the ability of BOLD signals at high MRI field (7T) to map fine-scale single-digit activations in subdivisions (areas 3b and 1) of the human primary somatosensory cortex (SI) in individual subjects. We acquired BOLD fMRI data from cortical areas around the central suclus in six healthy human subjects while stimulating individual finger pads with 2-Hz air puffs. Discrete, single-digit responses were identified in an area along the posterior bank of the central sulcus corresponding to area 3b and in an area along the crest of the postcentral gyrus corresponding to area 1. In single subjects, activations of digits 1 to 4 in both areas 3b and 1 were organized in a somatotopic manner. The separation of digit representations was measured for adjacent digits and was approximately 1. 6 times greater in area 3b than in area 1. Within individual subjects, the cortical responses to single-digit stimulations and the magnitude of the BOLD signals were reproducible across imaging runs and were comparable across subjects. Our findings demonstrate that BOLD fMRI at 7T is capable of revealing the somatotopic organization of single-digit activations with good within-subject reliability and reproducibility, and activation maps can be acquired within a reasonably short time window, which are essential characteristics for several neurological applications within patient populations.