Yazhuo Kong

Widespread modulation of cerebral perfusion induced during and after transcranial direct current stimulation applied to the left dorsolateral prefrontal cortex.

Noninvasive neuromodulatory techniques such as transcranial direct current stimulation (tDCS) are attracting increasing interest as potential therapies for a wide range of neurological and psychiatric conditions. When targeted to the dorsolateral prefrontal cortex (DLPFC), anodal, facilitatory tDCS has been shown to improve symptoms in a range of domains including working memory, mood, and pain perception (Boggio et al., 2008a; Dockery et al., 2009; Kalu et al., 2012). However, the mechanisms underlying these promising behavioral effects are not well understood. Here, we investigated brain perfusion changes, as assessed using whole-brain arterial spin labeling (ASL), during tDCS applied to the left DLPFC in healthy humans. We demonstrated increased perfusion in regions closely anatomically connected to the DLPFC during anodal tDCS in conjunction with a decreased functional coupling between the left DLPFC and the thalami bilaterally. Despite highly similar effects on cortical excitability during and after stimulation (Nitsche and Paulus, 2000, 2001), cortical perfusion changes were markedly different during these two time periods, with widespread decreases in cortical perfusion being demonstrated after both anodal and cathodal tDCS compared to the period during stimulation. These findings may at least partially explain the different effects on behavior in these time periods described previously in the motor system (Stagg et al., 2011). In addition, the data presented here provide mechanistic explanations for the behavioral effects of anodal tDCS applied to the left DLPFC in terms of modulating functional connectivity between the DLPFC and thalami, as has been hypothesized previously (Lorenz et al., 2003).

A Model of the Dynamic Relationship Between Blood Flow and Volume Changes During Brain Activation

The temporal relationship between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is important in the biophysical modeling and interpretation of the hemodynamic response to activation, particularly in the context of magnetic resonance imaging and the blood oxygen level–dependent signal. Grubb et al. (1974) measured the steady state relationship between changes in CBV and CBF after hypercapnic challenge. The relationship CBVαCBFΦ has been used extensively in the literature. Two similar models, the Balloon (Buxton et al., 1998) and the Windkessel (Mandeville et al., 1999), have been proposed to describe the temporal dynamics of changes in CBV with respect to changes in CBF. In this study, a dynamic model extending the Windkessel model by incorporating delayed compliance is presented. The extended model is better able to capture the dynamics of CBV changes after changes in CBF, particularly in the return-to-baseline stages of the response.

Assessment of physiological noise modelling methods for functional imaging of the spinal cord

The spinal cord is the main pathway for information between the central and the peripheral nervous systems. Non-invasive functional MRI offers the possibility of studying spinal cord function and central sensitisation processes. However, imaging neural activity in the spinal cord is more difficult than in the brain. A significant challenge when dealing with such data is the influence of physiological noise (primarily cardiac and respiratory), and currently there is no standard approach to account for these effects. We have previously studied the various sources of physiological noise for spinal cord fMRI at 1.5T and proposed a physiological noise model (PNM) (Brooks et al., 2008). An alternative de-noising strategy, selective averaging filter (SAF), was proposed by Deckers et al. (2006). In this study we reviewed and implemented published physiological noise correction methods at higher field (3T) and aimed to find the optimal models for gradient-echo-based BOLD acquisitions. Two general techniques were compared: physiological noise model (PNM) and selective averaging filter (SAF), along with regressors designed to account for specific signal compartments and physiological processes: cerebrospinal fluid (CSF), motion correction (MC) parameters, heart rate (HR), respiration volume per time (RVT), and the associated cardiac and respiratory response functions. Functional responses were recorded from the cervical spinal cord of 18 healthy subjects in response to noxious thermal and non-noxious punctate stimulation. The various combinations of models and regressors were compared in three ways: the model fit residuals, regression model F-tests and the number of activated voxels. The PNM was found to outperform SAF in all three tests. Furthermore, inclusion of the CSF regressor was crucial as it explained a significant amount of signal variance in the cord and increased the number of active cord voxels. Whilst HR, RVT and MC explained additional signal (noise) variance, they were also found (in particular HR and RVT) to have a negative impact on the parameter estimates (of interest)--as they may be correlated with task conditions e.g. noxious thermal stimuli. Convolution with previously published cardiac and respiratory impulse response functions was not found to be beneficial. The other novel aspect of current study is the investigation of the influence of pre-whitening together with PNM regressors on spinal fMRI data. Pre-whitening was found to reduce non-white noise, which was not accounted for by physiological noise correction, and decrease false positive detection rates.

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects.

Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the μ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the μ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral–ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.

Intrinsically organized resting state networks in the human spinal cord

Significance The human brain displays an enormous amount of intrinsic activity in the absence of any task or external stimulation. Here we demonstrate that the human spinal cord, the brain’s principal interface with the body, also shows such resting-state activity. We observed biologically plausible and spatially distinct networks that reflect the functional organisation of the spinal cord: networks in the anterior part likely relating to motor function and distinct networks in the posterior part likely reflecting sensory function. These networks were grouped along the spinal cord, consistent with motor output to, and sensory input from, the body. Together with previous brain imaging studies, our data suggest that resting-state activity constitutes a major functional signature of the entire central nervous system. Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals of the brain have repeatedly been observed when no task or external stimulation is present. These fluctuations likely reflect baseline neuronal activity of the brain and correspond to functionally relevant resting-state networks (RSN). It is not known however, whether intrinsically organized and spatially circumscribed RSNs also exist in the spinal cord, the brain’s principal sensorimotor interface with the body. Here, we use recent advances in spinal fMRI methodology and independent component analysis to answer this question in healthy human volunteers. We identified spatially distinct RSNs in the human spinal cord that were clearly separated into dorsal and ventral components, mirroring the functional neuroanatomy of the spinal cord and likely reflecting sensory and motor processing. Interestingly, dorsal (sensory) RSNs were separated into right and left components, presumably related to ongoing hemibody processing of somatosensory information, whereas ventral (motor) RSNs were bilateral, possibly related to commissural interneuronal networks involved in central pattern generation. Importantly, all of these RSNs showed a restricted spatial extent along the spinal cord and likely conform to the spinal cord’s functionally relevant segmental organization. Although the spatial and temporal properties of the dorsal and ventral RSNs were found to be significantly different, these networks showed significant interactions with each other at the segmental level. Together, our data demonstrate that intrinsically highly organized resting-state fluctuations exist in the human spinal cord and are thus a hallmark of the entire central nervous system.

Stimulus Site and Modality Dependence of Functional Activity within the Human Spinal Cord

Chronic pain is thought to arise because of maladaptive changes occurring within the peripheral nervous system and CNS. The transition from acute to chronic pain is known to involve the spinal cord (Woolf and Salter, 2000). Therefore, to investigate altered human spinal cord function and translate results obtained from other species, a noninvasive neuroimaging technique is desirable. We have investigated the functional response in the cervical spinal cord of 18 healthy human subjects (aged 22–40 years) to noxious thermal and non-noxious tactile stimulation of the left and right forearms. Physiological noise, which is a significant source of signal variability in the spinal cord, was accounted for in the general linear model. Group analysis, performed using a mixed-effects model, revealed distinct regions of activity that were dependent on both the side and the type of stimulation. In particular, thermal stimulation on the medial aspect of the wrist produced activity within the C6/C5 segment ipsilateral to the side of stimulation. Similar to data recorded in animals (Fitzgerald, 1982), painful thermal stimuli produced increased ipsilateral and decreased contralateral blood flow, which may reflect, respectively, excitatory and inhibitory processes. Nonpainful punctate stimulation of the thenar eminence provoked more diffuse activity but was still ipsilateral to the side of stimulation. These results present the first noninvasive evidence for a lateralized response to noxious and non-noxious stimuli in the human spinal cord. The development of these techniques opens the path to understanding, at a subject-specific level, central sensitization processes that contribute to chronic pain states.

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.

Importance Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. Objective This multicentre study tested previously reported criteria of ‘(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawsons finger-type lesion’ in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. Design Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. Participants 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. Results MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. Conclusions This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.

Spatial vs. Temporal Features in ICA of Resting-State fMRI – A Quantitative and Qualitative Investigation in the Context of Response Inhibition

Independent component analysis (ICA) can identify covarying functional networks in the resting brain. Despite its relatively widespread use, the potential of the temporal information (unlike spatial information) obtained by ICA from resting state fMRI (RS-fMRI) data is not always fully utilized. In this study, we systematically investigated which features in ICA of resting-state fMRI relate to behaviour, with stop signal reaction time (SSRT) in a stop-signal task taken as a test case. We did this by correlating SSRT with the following three kinds of measure obtained from RS-fMRI data: (1) the amplitude of each resting state network (RSN) (evaluated by the standard deviation of the RSN timeseries), (2) the temporal correlation between every pair of RSN timeseries, and (3) the spatial map of each RSN. For multiple networks, we found significant correlations not only between SSRT and spatial maps, but also between SSRT and network activity amplitude. Most of these correlations are of functional interpretability. The temporal correlations between RSN pairs were of functional significance, but these correlations did not appear to be very sensitive to finding SSRT correlations. In addition, we also investigated the effects of the decomposition dimension, spatial smoothing and Z-transformation of the spatial maps, as well as the techniques for evaluating the temporal correlation between RSN timeseries. Overall, the temporal information acquired by ICA enabled us to investigate brain function from a complementary perspective to the information provided by spatial maps.

Investigating resting-state functional connectivity in the cervical spinal cord at 3T.

ABSTRACT The study of spontaneous fluctuations in the blood‐oxygen‐level‐dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra‐high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting‐state connectivity between the dorsal horns as well as between the ventral horns, and a study in non‐human primates has shown that these resting‐state signals are impacted by spinal cord injury. As these studies were carried out at ultra‐high field strengths using region‐of‐interest (ROI) based analyses, we investigated whether such resting‐state signals could also be observed at the clinically more prevalent field strength of 3 T. In a reanalysis of a sample of 20 healthy human participants who underwent a resting‐state fMRI acquisition of the cervical spinal cord, we were able to observe significant dorsal horn connectivity as well as ventral horn connectivity, but no consistent effects for connectivity between dorsal and ventral horns, thus replicating the human 7 T results. These effects were not only observable when averaging along the acquired length of the spinal cord, but also when we examined each of the acquired spinal segments separately, which showed similar patterns of connectivity. Finally, we investigated the robustness of these resting‐state signals against variations in the analysis pipeline by varying the type of ROI creation, temporal filtering, nuisance regression and connectivity metric. We observed that – apart from the effects of band‐pass filtering – ventral horn connectivity showed excellent robustness, whereas dorsal horn connectivity showed moderate robustness. Together, our results provide evidence that spinal cord resting‐state connectivity is a robust and spatially consistent phenomenon that could be a valuable tool for investigating the effects of pathology, disease progression, and treatment response in neurological conditions with a spinal component, such as spinal cord injury.

Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development.

Background:Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. Methods:The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Results:Only gabapentin suppressed the secondary mechanical hyperalgesia–evoked neural response in a region of the brainstem’s descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Conclusions:Functional imaging with central sensitization can be used as a sensitive mechanism–based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.