Jian Kong

YNIMG Journal 2023 Journal Article

Modulation effects of repeated transcranial direct current stimulation on the dorsal attention and frontal parietal networks and its association with placebo and nocebo effects

• Valeria Sacca
• Ya Wen
• Sierra Hodges
• Jian Kong

Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here, we investigated how repeated transcranial direct current stimulation (tDCS) applied at the dorsolateral prefrontal cortex (DLPFC) for three consecutive days can modulate the brain functional connectivity (FC) of two networks involved in cognitive control: the frontoparietal network (FPN) and dorsal attention network (DAN), and its association with placebo and nocebo effects. 81 healthy subjects were randomized to three groups: anodal, cathodal, and sham tDCS. Resting state fMRI scans were acquired pre- and post- tDCS on the first and third day of tDCS. An Independent Component Analysis (ICA) was performed to identify the FPN and DAN. ANCOVA was applied for group analysis. Compared to sham tDCS, 1) both cathodal and anodal tDCS increased the FC between the DAN and right parietal operculum; cathodal tDCS also increased the FC between the DAN and right postcentral gyrus; 2) anodal tDCS led to an increased FC between the FPN and right parietal operculum, while cathodal tDCS was associated with increased FC between the FPN and left superior parietal lobule/precuneus; 3) the FC increase between the DAN and right parietal operculum was significantly correlated to the placebo analgesia effect in the cathodal group. Our findings suggest that both repeated cathodal and anodal tDCS could modulate the FC of two important cognitive brain networks (DAN and FPN), which may modulate placebo / nocebo effects.

YNIMG Journal 2021 Journal Article

How expectations of pain elicited by consciously and unconsciously perceived cues unfold over time

• Yiheng Tu
• Dimitrios Pantazis
• Georgia Wilson
• Sheraz Khan
• Seppo Ahlfors
• Jian Kong

Expectation can shape the perception of pain within a fraction of time, but little is known about how perceived expectation unfolds over time and modulates pain perception. Here, we combine magnetoencephalography (MEG) and machine learning approaches to track the neural dynamics of expectations of pain in healthy participants with both sexes. We found that the expectation of pain, as conditioned by facial cues, can be decoded from MEG as early as 150 ms and up to 1100 ms after cue onset, but decoding expectation elicited by unconsciously perceived cues requires more time and decays faster compared to consciously perceived ones. Also, results from temporal generalization suggest that neural dynamics of decoding cue-based expectation were predominately sustained during cue presentation but transient after cue presentation. Finally, although decoding expectation elicited by consciously perceived cues were based on a series of time-restricted brain regions during cue presentation, decoding relied on the medial prefrontal cortex and anterior cingulate cortex after cue presentation for both consciously and unconsciously perceived cues. These findings reveal the conscious and unconscious processing of expectation during pain anticipation and may shed light on enhancing clinical care by demonstrating the impact of expectation cues.

YNIMG Journal 2021 Journal Article

Perturbing fMRI brain dynamics using transcranial direct current stimulation

• Yiheng Tu
• Jin Cao
• Seyhmus Guler
• Thalia Chai-Zhang
• Joan A. Camprodon
• Mark Vangel
• Randy L. Gollub
• Darin D. Dougherty

The dynamic nature of resting-state functional magnetic resonance imaging (fMRI) brain activity and connectivity has drawn great interest in the past decade. Specific temporal properties of fMRI brain dynamics, including metrics such as occurrence rate and transitions, have been associated with cognition and behaviors, indicating the existence of mechanism distruption in neuropsychiatric disorders. The development of new methods to manipulate fMRI brain dynamics will advance our understanding of these pathophysiological mechanisms from native observation to experimental mechanistic manipulation. In the present study, we applied repeated transcranial direct current stimulation (tDCS) to the right dorsolateral prefrontal cortex (rDLPFC) and the left orbitofrontal cortex (lOFC), during multiple simultaneous tDCS-fMRI sessions from 81 healthy participants to assess the modulatory effects of stimulating target brain regions on fMRI brain dynamics. Using the rDLPFC and the lOFC as seeds, respectively, we first identified two reoccurring co-activation patterns (CAPs) and calculated their temporal properties (e.g., occurrence rate and transitions) before administering tDCS. The spatial maps of CAPs were associated with different cognitive and disease domains using meta-analytical decoding analysis. We then investigated how active tDCS compared to sham tDCS in the modulation of the occurrence rates of these different CAPs and perturbations of transitions between CAPs. We found that by enhancing neuronal excitability of the rDLPFC and the lOFC, the occurrence rate of one CAP was significantly decreased while that of another CAP was significantly increased during the first 6 min of stimulation. Furthermore, these tDCS-associated changes persisted over subsequent testing sessions (both during and before/after tDCS) across three consecutive days. Active tDCS could perturb transitions between CAPs and a non-CAP state (when the rDLPFC and the lOFC were not activated), but not the transitions within CAPs. These results demonstrate the feasibility of modulating fMRI brain dynamics, and open new possibilities for discovering stimulation targets and dynamic connectivity patterns that can ensure the propagation of tDCS-induced neuronal excitability, which may facilitate the development of new treatments for disorders with altered dynamics.

YNICL Journal 2021 Journal Article

Uncinate fasciculus and its cortical terminals in aphasia after subcortical stroke: A multi-modal MRI study

• Binlong Zhang
• Jingling Chang
• Joel Park
• Zhongjian Tan
• Lu Tang
• Tianli Lyu
• Yi Han
• Ruiwen Fan

Aphasia, one of the most common cognitive impairments after stroke, is commonly considered to be a cortical deficit. However, many studies have reported cases of post subcortical stroke aphasia (PSSA). The pathology and recovery mechanism of PSSA remain unclear. This study aimed to investigate PSSA mechanism through a multimodal magnetic resonance imaging (MRI) approach and a two-session study design (baseline and one month after treatment). Thirty-six PSSA patients and twenty-four matched healthy controls (HC) were included. All patients had subcortical infarctions involving left subcortical white matter for 1 to 6 months. The patients underwent MRI scan and Western Aphasia Battery (WAB) examination before and after one month's comprehensive treatment. Region-wise lesion-symptom mapping (RLSM), tractography, fractional anisotropy (FA), and amplitude of low-frequency fluctuations (ALFF) analysis were conducted. After MRI preprocessing and exclusion, FA analysis included 35 patients pre-treatment and 16 patients post-treatment. ALFF analysis included 30 patients pre-treatment and 14 patients post-treatment. We found: 1) the amount of damage in the left uncinate fasciculus (UF) was associated with WAB aphasia quotient (AQ); 2) the left UF FA and left temporal pole (TP) ALFF were decreased and positively correlated with WAB-AQ, spontaneous speech, and naming in PSSA patients; and 3) PSSA patients showed increased left TP ALFF when their language ability recovered after treatment. The left TP ALFF change was positively correlated with AQ change. Our results demonstrate the importance of left UF and left TP (one of the cortical terminals of the left UF) in PSSA pathology and recovery. These results may further provide support for the disconnection theory in the mechanism of PSSA.

YNIMG Journal 2020 Journal Article

Characterizing the analgesic effects of real and imagined acupuncture using functional and structure MRI

• Jin Cao
• Yiheng Tu
• Georgia Wilson
• Scott P. Orr
• Jian Kong

Acupuncture and imagery interventions for pain management have a long history. The present study comparatively investigated whether acupuncture and video-guided acupuncture imagery treatment (VGAIT, watching a video of acupuncture on the participant's own body while imagining it being applied) could modulate brain regional connectivity to produce analgesic effects. The study also examined whether pre-intervention brain functional and structural features could be used to predict the magnitude of analgesic effects. Twenty-four healthy participants were recruited and received four different interventions (real acupuncture, sham acupuncture, VGAIT, and VGAIT control) in random order using a cross-over design. Pain thresholds and magnetic resonance imaging (MRI) data were collected before and after each intervention. We first compared the modulatory effects of real acupuncture and VGAIT on intra- and inter-regional intrinsic brain connectivity and found that real acupuncture decreased regional homogeneity (ReHo) and functional connectivity (FC) in sensorimotor areas, whereas VGAIT increased ReHo in basal ganglia (BG) (i.e., putamen) and FC between the BG subcortical network and default mode network. The altered ReHo and FC were associated with changes in pain threshold after real acupuncture and VGAIT, respectively. A multimodality fusion approach with pre-intervention ReHo and gray matter volume (GMV) as features was used to explore the brain profiles underlying individual variability of pain threshold changes by real acupuncture and VGAIT. Variability in acupuncture responses was associated with ReHo and GMV in BG, whereas VGAIT responses were associated with ReHo and GMV in the anterior insula. These results suggest that, through different pathways, both real acupuncture and VGAIT can modulate brain systems to produce analgesic effects.

YNICL Journal 2020 Journal Article

Corrigendum to “Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain” [Neuroimage Clinical 23 (2019) 101885]

• Yiheng Tu
• Ana Ortiz
• Randy L. Gollub
• Jin Cao
• Jessica Gerber
• Courtney Lang
• Joel Park
• Georgia Wilson

The authors regret to find several errors that do not influence the main findings or conclusions.Specifically, we have found that the values of pre-and post-treatment clinical sub-scores for 'physical function' and 'sleep' in Fig. 4 contain errors.The corrected Fig. 4 is shown below: As a result, the Results section 3.3 (Page 6, right column): "Real and sham acupuncture significantly reduced PROMIS sub-scores in

YNIMG Journal 2020 Journal Article

Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain

• Siyi Yu
• Wen Li
• Wei Shen
• Robert R. Edwards
• Randy L. Gollub
• Georgia Wilson
• Joel Park
• Ana Ortiz

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.

YNIMG Journal 2020 Journal Article

Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy

• Hyungjun Kim
• Ishtiaq Mawla
• Jeungchan Lee
• Jessica Gerber
• Kathryn Walker
• Jieun Kim
• Ana Ortiz
• Suk-Tak Chan

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i. e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e. g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N ​= ​50) and a large sample of cLBP patients (N ​= ​102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P ​= ​0. 01) over the low back, but not finger (P ​= ​0. 29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P ​< ​0. 05). GMV in cLBP correlated with greater 2PDT-back scores (ρ ​= ​0. 27, P ​= ​0. 02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ ​= ​0. 52, P ​= ​0. 03) and increased S1-back adjacent white matter FA (ρ ​= ​−0. 56, P ​= ​0. 01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.

YNIMG Journal 2019 Journal Article

A neural mechanism of direct and observational conditioning for placebo and nocebo responses

• Yiheng Tu
• Joel Park
• Seppo P. Ahlfors
• Sheraz Khan
• Natalia Egorova
• Courtney Lang
• Jin Cao
• Jian Kong

Classical theories suggest placebo analgesia and nocebo hyperalgesia are based on expectation and conditioned experience. Whereas the neural mechanism of how expectation modulates placebo and nocebo effects during pain anticipation have been extensively studied, little is known about how experience may change brain networks to produce placebo and nocebo responses. We investigated the neural pathways of direct and observational conditioning for conscious and nonconscious conditioned placebo/nocebo effects using magnetoencephalography and a face visual cue conditioning model. We found that both direct and observational conditioning produced conscious conditioned placebo and nocebo effects and a nonconscious conditioned nocebo effect. Alpha band brain connectivity changes before and after conditioning could predict the magnitude of conditioned placebo and nocebo effects. Particularly, the connectivity between the rostral anterior cingulate cortex and middle temporal gyrus was an important indicator for the manipulation of placebo and nocebo effects. Our study suggests that conditioning can mediate our pain experience by encoding experience and modulating brain networks.

YNICL Journal 2019 Journal Article

Corrigendum to ‘Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain’ Neuroimage Clinical, 23, 2019, 101885

• Yiheng Tu
• Ana Ortiz
• Randy L. Gollub
• Jin Cao
• Jessica Gerber
• Courtney Lang
• Joel Park
• Georgia Wilson

The authors regret to find several errors that do not influence the main findings or conclusions.Specifically, we have found that the values of pre-and post-treatment clinical sub-scores for 'physical function' and 'sleep' in Fig. 4 contain errors.The corrected Fig. 4 is shown below: As a result, the Results section 3.3 (Page 6, right column): "Real and sham acupuncture significantly reduced PROMIS sub-scores in

YNIMG Journal 2019 Journal Article

Decreased structural connectivity and resting-state brain activity in the lateral occipital cortex is associated with social communication deficits in boys with autism spectrum disorder

• Minyoung Jung
• Yiheng Tu
• Courtney Amanda Lang
• Ana Ortiz
• Joel Park
• Kristen Jorgenson
• Xue-Jun Kong
• Jian Kong

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical social communication and repetitive behaviors. In this study, we applied a multimodal approach to investigate brain structural connectivity, resting state activity, and surface area, as well as their associations with the core symptoms of ASD. Data from forty boys with ASD (mean age, 11. 5 years; age range, 5. 5–19. 5) and forty boys with typical development (TD) (mean age, 12. 3; age range, 5. 8–19. 7) were extracted from the Autism Brain Imaging Data Exchange II (ABIDE II) for data analysis. We found significantly decreased structural connectivity, resting state brain activity, and surface area at the occipital cortex in boys with ASD compared to boys with TD. In addition, we found that resting state brain activity and surface area in the lateral occipital cortex was negatively correlated with communication scores in boys with ASD. Our results suggest that decreased structural connectivity and resting-state brain activity in the occipital cortex may impair the integration of verbal and non-verbal communication cues in boys with ASD, thereby impacting their social development.

YNIMG Journal 2019 Journal Article

Identifying inter-individual differences in pain threshold using brain connectome: a test-retest reproducible study

• Yiheng Tu
• Binlong Zhang
• Jin Cao
• Georgia Wilson
• Zhiguo Zhang
• Jian Kong

Individuals are unique in terms of brain and behavior. Some are very sensitive to pain, while others have a high tolerance. However, how inter-individual intrinsic differences in the brain are related to pain is unknown. Here, we performed longitudinal test-retest analyses to investigate pain threshold variability among individuals using a resting-state fMRI brain connectome. Twenty-four healthy subjects who received four MRI sessions separated by at least 7 days were included in the data analysis. Subjects’ pain thresholds were measured using two modalities of experimental pain (heat and pressure) on two different locations (heat pain: leg and arm; pressure pain: leg and thumbnail). Behavioral results showed strong inter-individual variability and strong within-individual stability in pain threshold. Resting state fMRI data analyses showed that functional connectivity profiles can accurately identify subjects across four sessions, indicating that an individual’s connectivity profile may be intrinsic and unique. By using multivariate pattern analyses, we found that connectivity profiles could be used to predict an individual’s pain threshold at both within-session and between-session levels, with the most predictive contribution from medial-frontal and frontal-parietal networks. These results demonstrate the potential of using a resting-state fMRI brain connectome to build a ‘neural trait’ for characterizing an individual’s pain-related behavior, and such a ‘neural trait’ may eventually be used to personalize clinical assessments.

YNICL Journal 2019 Journal Article

Mind-body exercise improves cognitive function and modulates the function and structure of the hippocampus and anterior cingulate cortex in patients with mild cognitive impairment

• Jing Tao
• Jiao Liu
• Xiangli Chen
• Rui Xia
• Moyi Li
• Maomao Huang
• Shuzhen Li
• Joel Park

Mild cognitive impairment (MCI) is a common neurological disorder. This study aims to investigate the modulation effect of Baduanjin (a popular mind-body exercise) on MCI. 69 patients were randomized to Baduanjin, brisk walking, or an education control group for 24 weeks. The Montreal Cognitive Assessment (MoCA) and Magnetic Resonance Imaging scans were applied at baseline and at the end of the experiment. Compared to the brisk walking and control groups, the Baduanjin group experienced significantly increased MoCA scores. Amplitude of low-frequency fluctuations (ALFF) analysis showed significantly decreased ALFF values in the right hippocampus (classic low-freqency band, 0.01-0.08 Hz) in the Baduanjin group compared to the brisk walking group and increased ALFF values in the bilateral anterior cingulate cortex (ACC, slow-5 band, 0.01-0.027 Hz) in the Baduanjin group compared to the control group. Further, ALFF value changes in the right hippocampus and bilateral ACC were significantly associated with corresponding MoCA score changes across all groups. We also found increased gray matter volume in the Baduanjin group in the right hippocampus compared to the brisk walking group and in the bilateral ACC compared to the control group. In addition, there was an increased resting state functional connectivity between the hippocampus and right angular gyrus in the Baduanjin group compared to the control group. Our results demonstrate the potential of Baduanjin for the treatment of MCI.

YNICL Journal 2019 Journal Article

Multivariate resting-state functional connectivity predicts responses to real and sham acupuncture treatment in chronic low back pain

• Yiheng Tu
• Ana Ortiz
• Randy L. Gollub
• Jin Cao
• Jessica Gerber
• Courtney Lang
• Joel Park
• Georgia Wilson

Despite the high prevalence and socioeconomic impact of chronic low back pain (cLBP), treatments for cLBP are often unsatisfactory, and effectiveness varies widely across patients. Recent neuroimaging studies have demonstrated abnormal resting-state functional connectivity (rsFC) of the default mode, salience, central executive, and sensorimotor networks in chronic pain patients, but their role as predictors of treatment responsiveness has not yet been explored. In this study, we used machine learning approaches to test if pre-treatment rsFC can predict responses to both real and sham acupuncture treatments in cLBP patients. Fifty cLBP patients participated in 4 weeks of either real (N = 24, age = 39.0 ± 12.6, 16 females) or sham acupuncture (N = 26, age = 40.0 ± 13.7, 15 females) treatment in a single-blinded trial, and a resting-state fMRI scan prior to treatment was used in data analysis. Both real and sham acupuncture can produce significant pain reduction, with those receiving real treatment experiencing greater pain relief than those receiving sham treatment. We found that pre-treatment rsFC could predict symptom changes with up to 34% and 29% variances for real and sham treatment, respectively, and the rsFC characteristics that were significantly predictive for real and sham treatment differed. These results suggest a potential way to predict treatment responses and may facilitate the development of treatment plans that optimize time, cost, and available resources.

YNICL Journal 2019 Journal Article

Non-pharmacological and pharmacological interventions relieve insomnia symptoms by modulating a shared network: A controlled longitudinal study

• Fen Feng
• Siyi Yu
• Zhengyan Wang
• Jialin Wang
• Joel Park
• Georgia Wilson
• Mou Deng
• Youping Hu

BACKGROUND: Primary insomnia (PI) is one of the most common complaints among the general population. Both non-pharmacological and pharmacological therapies have proven effective in treating primary insomnia. However, the underlying mechanism of treatment remains unclear, and no studies have compared the underlying mechanisms of different treatments. METHODS: In this study, we investigated gray matter volume (GMV) and resting-state functional connectivity (rsFC) changes following both pharmacological and non-pharmacological treatments in patients with PI. A total of 67 PI patients were randomized into benzodiazepine treatment, cupping treatment, or a wait-list control group for 4 weeks. The Pittsburgh Sleep Quality Index (PSQI), gray matter volume (GMV), and resting-state functional connectivity (rsFC) of the hippocampus were measured at the beginning and end of the experiment. RESULTS: We found 1) significantly decreased PSQI scores in the cupping and benzodiazepine treatment groups compared to the control group with no significant differences between the two treatment groups; 2) significant GMV increases in the cupping group compared to the control group at the right hippocampus after 4 weeks of treatment; 3) significantly increased rsFC between the right hippocampus and left rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) in the two treatment groups, which was significantly associated with PSQI score decreases. DISCUSSION: Our findings suggest that benzodiazepine and cupping may share a common mechanism to relieve the symptoms of patients with PI.

YNICL Journal 2019 Journal Article

Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: An fMRI study

• Yue Zhang
• Jiao Liu
• Hui Li
• Zhaoxian Yan
• Xian Liu
• Jin Cao
• Joel Park
• Georgia Wilson

BACKGROUND: Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine. METHODS: Twenty-nine patients with migraine were recruited from outpatient neurology clinics. Each patient attended two magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) scan sessions separated by one week. Each session included a pre-stimulation resting state fMRI scan, fMRI scans during real or sham 1 Hz taVNS (with block design), and a post-stimulation resting state fMRI scan. RESULTS: Twenty-six patients were included in the final analyses. Real taVNS evoked fMRI signal decreases in brain areas belonging to the default mode network (DMN) and brain stem areas including the locus coeruleus (LC), raphe nuclei, parabrachial nucleus, and solitary nucleus. Sham taVNS evoked fMRI signal decreases in brain areas belonging to the DMN. Compared to sham taVNS, real taVNS produced greater deactivation at the bilateral LC. Resting state functional connectivity (rsFC) analysis showed that after taVNS, LC rsFC with the right temporoparietal junction and left secondary somatosensory cortex (S2) significantly increased compared to sham taVNS. The increased rsFC of the left LC-left S2 was significantly negatively associated with the frequency of migraine attacks during the preceding month. CONCLUSION: Our results suggest that taVNS at 1 Hz can significantly modulate activity/connectivity of brain regions associated with the vagus nerve central pathway and pain modulation system, which may shed light on the neural mechanisms underlying taVNS treatment of migraine.

YNICL Journal 2019 Journal Article

Visual network alterations in brain functional connectivity in chronic low back pain: A resting state functional connectivity and machine learning study

• Wei Shen
• Yiheng Tu
• Randy L. Gollub
• Ana Ortiz
• Vitaly Napadow
• Siyi Yu
• Georgia Wilson
• Joel Park

Chronic low back pain (cLBP) is associated with widespread functional and structural changes in the brain. This study aims to investigate the resting state functional connectivity (rsFC) changes of visual networks in cLBP patients and the feasibility of distinguishing cLBP patients from healthy controls using machine learning methods. cLBP (n = 90) and control individuals (n = 74) were enrolled and underwent resting-state BOLD fMRI scans. Primary, dorsal, and ventral visual networks derived from independent component analysis were used as regions of interest to compare resting state functional connectivity changes between the cLBP patients and healthy controls. We then applied a support vector machine classifier to distinguish the cLBP patients and control individuals. These results were further verified in a new cohort of subjects. We found that the functional connectivity between the primary visual network and the somatosensory/motor areas were significantly enhanced in cLBP patients. The rsFC between the primary visual network and S1 was negatively associated with duration of cLBP. In addition, we found that the rsFC of the visual network could achieve a classification accuracy of 79.3% in distinguishing cLBP patients from HCs, and these results were further validated in an independent cohort of subjects (accuracy = 66.7%). Our results demonstrate significant changes in the rsFC of the visual networks in cLBP patients. We speculate these alterations may represent an adaptation/self-adjustment mechanism and cross-model interaction between the visual, somatosensory, motor, attention, and salient networks in response to cLBP. Elucidating the role of the visual networks in cLBP may shed light on the pathophysiology and development of the disorder.

YNICL Journal 2018 Journal Article

Basal ganglia involvement in ARX patients: The reason for ARX patients very specific grasping?

• Aurore Curie
• Gaëlle Friocourt
• Vincent des Portes
• Alice Roy
• Tatjana Nazir
• Amandine Brun
• Anne Cheylus
• Pascale Marcorelles

The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c. 429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c. 429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA.

YNICL Journal 2018 Journal Article

Enhancing treatment of osteoarthritis knee pain by boosting expectancy: A functional neuroimaging study

• Jian Kong
• Zengjian Wang
• Jaclyn Leiser
• Domenic Minicucci
• Robert Edwards
• Irving Kirsch
• Ajay D. Wasan
• Courtney Lang

Objectives: Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism. Methods: Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipulation to enhance expectation), standard acupuncture, or treatment as usual (TAU). Each patient underwent six treatments before being debriefed, and four additional treatments after being debriefed. The fMRI scans were applied during the first and sixth treatment sessions. Results: We found significantly decreased knee pain in the boosted acupuncture group compared to the standard acupuncture or TAU groups after both six and ten treatments. Resting state functional connectivity (rsFC) analyses using the nucleus accumbens (NAc) as the seed showed rsFC increases between the NAc and the medial prefrontal cortex (MPFC)/rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex in the boosted group as compared to the standard acupuncture group after multiple treatments. Expectancy scores after the first treatment were significantly associated with increased NAc-rACC/MPFC rsFC and decreased knee pain following treatment. Conclusions: Our study provides a novel method and mechanism for boosting the treatment of pain in patients with KOA. Our findings may shed light on enhancing outcomes of pharmacological and integrative medicines in clinical settings.

YNIMG Journal 2018 Journal Article

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band

• Sheraz Khan
• Javeria A. Hashmi
• Fahimeh Mamashli
• Konstantinos Michmizos
• Manfred G. Kitzbichler
• Hari Bharadwaj
• Yousra Bekhti
• Santosh Ganesan

The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13–30 Hz) and gamma (31–80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.

YNICL Journal 2017 Journal Article

Acupuncture modulates the abnormal brainstem activity in migraine without aura patients

• Zhengjie Li
• Fang Zeng
• Tao Yin
• Lei Lan
• Nikos Makris
• Kristen Jorgenson
• Taipin Guo
• Feng Wu

Migraine is a common neurological disease with a high prevalence and unsatisfactory treatment options. The specific pathophysiological mechanisms of migraine remain unclear, which restricts the development of effective treatments for this prevalent disorder. The aims of this study were to 1) compare the spontaneous brain activity differences between Migraine without Aura (MwoA) patients and healthy controls (HCs), using amplitude of low-frequency fluctuations (ALFF) calculation method, and 2) explore how an effective treatment (verum acupuncture) could modulate the ALFF of MwoA patients. One hundred MwoA patients and forty-six matched HCs were recruited. Patients were randomized to four weeks' verum acupuncture, sham acupuncture, and waiting list groups. Patients had resting state BOLD-fMRI scan before and after treatment, while HCs only had resting state BOLD-fMRI scan at baseline. Headache intensity, headache frequency, self-rating anxiety and self-rating depression were used for clinical efficacy evaluation. Compared with HCs, MwoA patients showed increased ALFF in posterior insula and putamen/caudate, and reduced ALFF in rostral ventromedial medulla (RVM)/trigeminocervical complex (TCC). After longitudinal verum acupuncture treatment, the decreased ALFF of the RVM/TCC was normalized in migraine patients. Verum acupuncture and sham acupuncture have different modulation effects on ALFF of RVM/TCC in migraine patients. Our results suggest that impairment of the homeostasis of the trigeminovascular nociceptive pathway is involved in the neural pathophysiology of migraines. Effective treatments, such as verum acupuncture, could help to restore this imbalance.

YNICL Journal 2017 Journal Article

Anatomical brain difference of subthreshold depression in young and middle-aged individuals

• Jing Li
• Zengjian Wang
• JiWon Hwang
• Bingcong Zhao
• Xinjing Yang
• Suicheng Xin
• Yu Wang
• Huili Jiang

BACKGROUND: Subthreshold depression (StD) is associated with substantial functional impairments due to depressive symptoms that do not fully meet the diagnosis of major depressive disorder (MDD). Its high incidence in the general population and debilitating symptoms has recently put it at the forefront of mood disorder research. AIM: In this study we investigated common volumetric brain changes in both young and middle-aged StD patients. METHODS: = 76) underwent voxel-based morphometry (VBM). RESULTS: VBM analysis found that: 1) compared with healthy controls, StD patients showed decreased gray matter volume (GMV) in the bilateral globus pallidus and precentral gyrus, as well as increased GMV in the left thalamus and right rostral anterior cingulate cortex/medial prefrontal cortex; 2) there is a significant association between Center for Epidemiological Studies Depression Scale scores and the bilateral globus pallidus (negative) and left thalamus (positive); 3) there is no interaction between age (young vs. middle-age) and group (StD vs. controls). CONCLUSIONS: Our findings indicate significant VBM brain changes in both young and middle-aged individuals with StD. Individuals with StD, regardless of age, may share common neural characteristics.

YNICL Journal 2017 Journal Article

Disrupted functional connectivity of striatal sub-regions in Bell's palsy patients

• Wenwen Song
• Zhijian Cao
• Courtney Lang
• Minhui Dai
• Lihua Xuan
• Kun Lv
• Fangyuan Cui
• Kristen Jorgenson

The striatum plays an important role in controlling motor function in humans, and its degeneration has the ability to cause severe motor disorders. More specifically, previous studies have demonstrated a disruption in the connectivity of the cortico-striatal loop in patients suffering from motor disorders caused by dopamine dysregulation, such as Parkinson's disease. However, little is known about striatal functional connectivity in patients with motor dysfunction not caused by dopamine dysregulation. In this study, we used early-state Bell's palsy (BP) patients (within 14 days of onset) to investigate how functional connectivity between the striatum and motor cortex is affected by peripheral nerve injury in which the dopamine system remains fully functional. We found a significant increase in the connectivity between the contralateral putamen, and the ipsilateral primary sensory (S1) and motor cortex (M1) in BP patients compared to healthy controls. We also found increased connectivity between the ventral striatum and supplementary motor area (SMA), and the dorsal caudate and medial prefrontal lobe in BP patients compared to healthy controls. Our results demonstrate that the entirety of the striatum is affected following acute peripheral nerve injury, and suggests that this disrupted striatal functional connectivity may reflect a compensatory mechanism for the sensory-motor mismatch caused by BP.

YNICL Journal 2017 Journal Article

Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression

• Jiliang Fang
• Natalia Egorova
• Peijing Rong
• Jun Liu
• Yang Hong
• Yangyang Fan
• Xiaoling Wang
• Honghong Wang

Transcutaneous vagus nerve stimulation (tVNS), a non-invasive method of brain stimulation through the auricular branch of the vagus nerve, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism by which the effect on depression might be achieved has not been fully investigated, with only a few neuroimaging studies demonstrating tVNS-induced changes in the brains of healthy volunteers. Identifying specific neural pathways, which are influenced by tVNS compared with sham in depressed individuals, as well as determining neurobiomarkers of tVNS treatment success are needed to advance the application of tVNS for MDD. In order to address these questions, we measured fMRI brain activity of thirty-eight depressed patients assigned to undergo tVNS (n =17) or sham (n =21) treatment for 4weeks, during the first stimulation session. The results showed significant fMRI signal increases in the left anterior insula, revealed by a direct comparison of tVNS and sham stimulation. Importantly, the insula activation level during the first stimulation session in the tVNS group was significantly associated with the clinical improvement at the end of the four-week treatment, as indicated by the Hamilton Depression Rating Scale (HAM-D) score. Our findings suggest that anterior insula fMRI activity could serve as a potential cortical biomarker and an early predictor of tVNS longitudinal treatment success.

YNICL Journal 2017 Journal Article

Neurochemical changes in patients with chronic low back pain detected by proton magnetic resonance spectroscopy: A systematic review

• Xianjing Zhao
• Maosheng Xu
• Kristen Jorgenson
• Jian Kong

BACKGROUND: Low back pain is a highly prevalent health problem around the world, affecting 50% to 85% of people at some point in life. The purpose of this systematic review is to summarize the previous proton magnetic resonance spectroscopy studies on brain chemical changes in patients with chronic low back pain (CLBP). METHODS: We identified relevant studies from a literature search of PubMed and EMBASE from 1980 to March 2016. Data extraction was performed on the subjects' characteristics, MRS methods, spectral analyses, cerebral metabolites and perceptual measurements. RESULTS: -acetyl-aspartate (NAA) in the dorsolateral prefrontal cortex (DLPFC), right primary motor cortex, left somatosensory cortex (SSC), left anterior insula and anterior cingulate cortex (ACC); 2) glutamate in the ACC; 3) myo-inositol in the ACC and thalamus; 4) choline in the right SSC; and 5) glucose in the DLPFC. CONCLUSION: This review provides evidence for alterations in the biochemical profile of the brain in patients with CLBP, which suggests that biochemical changes may play a significant role in the development and pathophysiology of CLBP and shed light on the development of new treatments for CLBP.

YNICL Journal 2016 Journal Article

Repeated acupuncture treatments modulate amygdala resting state functional connectivity of depressive patients

• Xiaoyun Wang
• Zengjian Wang
• Jian Liu
• Jun Chen
• Xian Liu
• Guangning Nie
• Joon-Seok Byun
• Yilin Liang

As a widely-applied alternative therapy, acupuncture is gaining popularity in Western society. One challenge that remains, however, is incorporating it into mainstream medicine. One solution is to combine acupuncture with other conventional, mainstream treatments. In this study, we investigated the combination effect of acupuncture and the antidepressant fluoxetine, as well as its underlying mechanism using resting state functional connectivity (rsFC) in patients with major depressive disorders. Forty-six female depressed patients were randomized into a verum acupuncture plus fluoxetine or a sham acupuncture plus fluoxetine group for eight weeks. Resting-state fMRI data was collected before the first and last treatments. Results showed that compared with those in the sham acupuncture treatment, verum acupuncture treatment patients showed 1) greater clinical improvement as indicated by Montgomery-Åsberg Depression Rating Scale (MADRS) and Self-Rating Depression Scale (SDS) scores; 2) increased rsFC between the left amygdala and subgenual anterior cingulate cortex (sgACC)/preguenual anterior cingulate cortex (pgACC); 3) increased rsFC between the right amygdala and left parahippocampus (Para)/putamen (Pu). The strength of the amygdala-sgACC/pgACC rsFC was positively associated with corresponding clinical improvement (as indicated by a negative correlation with MADRS and SDS scores). Our findings demonstrate the additive effect of acupuncture to antidepressant treatment and suggest that this effect may be achieved through the limbic system, especially the amygdala and the ACC.

YNIMG Journal 2015 Journal Article

Distinct neural representations of placebo and nocebo effects

• Sonya Freeman
• Rongjun Yu
• Natalia Egorova
• Xiaoyan Chen
• Irving Kirsch
• Brian Claggett
• Ted J. Kaptchuk
• Randy L. Gollub

Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can change pain experiences in the same cohort of subjects. We first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled “Lidocaine” (positive expectancy), one labeled “Capsaicin” (negative expectancy) and one labeled “Neutral” by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed that expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancies were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both “Capsaicin” and “Lidocaine” conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancies. Our findings suggest that positive and negative expectancies engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

YNICL Journal 2015 Journal Article

Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

• Natalia Egorova
• Randy L. Gollub
• Jian Kong

Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG), medial frontal cortex (MFC) and bilateral hippocampus (Hpc). We demonstrate that the PAG-MFC and PAG-Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture-induced improvement in pain scores (compared to sham) is related to the modulation of PAG-MFC and PAG-Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory.

YNICL Journal 2014 Journal Article

Disrupted functional connectivity of the periaqueductal gray in chronic low back pain

• Rongjun Yu
• Randy L. Gollub
• Rosa Spaeth
• Vitaly Napadow
• Ajay Wasan
• Jian Kong

Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG-vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG-insula and PAG-amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.

YNIMG Journal 2014 Journal Article

Simultaneous fMRI–PET of the opioidergic pain system in human brain

• Hsiao-Ying Wey
• Ciprian Catana
• Jacob M. Hooker
• Darin D. Dougherty
• Gitte M. Knudsen
• Danny J.J. Wang
• Daniel B. Chonde
• Bruce R. Rosen

MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI–PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI–PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [11C]diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI–PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI–PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo.

YNIMG Journal 2009 Journal Article

An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment

• Jian Kong
• Ted J. Kaptchuk
• Ginger Polich
• Irving Kirsch
• Mark Vangel
• Carolyn Zyloney
• Bruce Rosen
• Randy L. Gollub

It is well established that expectation can significantly modulate pain perception. In this study, we combined an expectancy manipulation model and fMRI to investigate how expectation can modulate acupuncture treatment. Forty-eight subjects completed the study. The analysis on two verum acupuncture groups with different expectancy levels indicates that expectancy can significantly influence acupuncture analgesia for experimental pain. Conditioning positive expectation can amplify acupuncture analgesia as detected by subjective pain sensory rating changes and objective fMRI signal changes in response to calibrated noxious stimuli. Diminished positive expectation appeared to inhibit acupuncture analgesia. This modulation effect is spatially specific, inducing analgesia exclusively in regions of the body where expectation is focused. Thus, expectation should be used as an important covariate in future studies evaluating acupuncture efficacy. In addition, we also observed dissociation between subjective reported analgesia and objective fMRI signal changes to calibrated pain in the analysis across all four groups. We hypothesize that as a peripheral-central modulation, acupuncture needle stimulation may inhibit incoming noxious stimuli; while as a top-down modulation, expectancy (placebo) may work through the emotional circuit.

YNIMG Journal 2009 Journal Article

Expectancy and treatment interactions: A dissociation between acupuncture analgesia and expectancy evoked placebo analgesia

• Jian Kong
• Ted J. Kaptchuk
• Ginger Polich
• Irving Kirsch
• Mark Vangel
• Carolyn Zyloney
• Bruce Rosen
• Randy Gollub

YNIMG Journal 2007 Journal Article

Test–retest study of fMRI signal change evoked by electroacupuncture stimulation

• Jian Kong
• Randy L. Gollub
• J. Megan Webb
• Jiang-Ti Kong
• Mark G. Vangel
• Kenneth Kwong

YNIMG Journal 2001 Journal Article

Reliable intensity and laterality encoding of noxious pressure and heat pain in cortex within single subjects using 1.5T fMRI

• Randy Gollub
• Patrick Aquino
• Jian Kong
• Rick Gracely
• Todd Kramer
• Mark Dershwitz