Functional brain imaging: what has it brought to our understanding of neuropathic pain? A special focus on allodynic pain mechanisms.

Brain responses to nociception are well identified. The same is not true for allodynic pain, a strong painful sensation in response to touch or innocuous cold stimuli that may be experienced by patients with neuropathic pain. Brain (or spinal cord) reorganization that may explain this paradoxical perception still remains largely unknown. Allodynic pain is associated with abnormally increased activity in SII and in the anterior insular cortex, contralateral and/or ipsilateral to allodynia. Because a bilateral increase in activity has been repeatedly reported in these areas in nociceptive conditions, the observed activation during allodynia can explain that a physiologically nonpainful stimulus could be perceived by the damaged nervous system as a painful one. Both secondary somatosensory and insular cortices receive input from the thalamus, which is a major relay of sensory and spinothalamic pathways, the involvement of which is known to be crucial for the development of neuropathic pain. Both thalamic function and structure have been reported to be abnormal or impaired in neuropathic pain conditions including in the basal state, possibly explaining the spontaneous component of neuropathic pain. A further indication as to how the brain can create neuropathic pain response in SII and insular cortices stems from examples of diseases, including single-case reports in whom a focal brain lesion leads to central pain disappearance. Additional studies are required to certify the contribution of these areas to the disease processes, to disentangle abnormalities respectively related to pain and to deafferentation, and, in the future, to guide targeting of stimulation studies.

Basal Ganglia Perfusion in Fibromyalgia is Related to Pain Disability and Disease Impact: An Arterial Spin Labeling Study.

OBJECTIVES: Pain disability is a major impediment to fibromyalgia (FM) patients' quality of life. Neuroimaging studies have demonstrated abnormal pain processing in FM. However, it is not known whether there are brain abnormalities linked to pain disability. Understanding neural correlates of pain disability in FM, independent from pain intensity, could provide a framework to guide future more efficient therapy strategies to improve patients' functional ability. METHODS: We used arterial spin labeling to image cerebral blood flow (CBF) in 23 FM patients and 16 controls. Functional connectivity was also estimated using blood oxygenation level-dependent imaging to further investigate the possible underpinnings of the observed CBF changes. RESULTS: Among patients, CBF in the basal ganglia correlated negatively with pain disability index and positively with the overall impact of FM (Fibromyalgia Impact Questionnaire) but did not correlate with pain intensity. Whole-brain analysis revealed no CBF differences between the 2 groups; however, post hoc analysis in the basal ganglia showed CBF reductions mainly in the right putamen and right lateral globus pallidus in patients, likely reflecting the negative correlation with the pain disability index. However, the connectivity of the corresponding corticobasal ganglia-thalamus loop, that is, motor network (the connection between supplementary motor area, putamen, and thalamus) remained intact. DISCUSSION: Basal ganglia perfusion reflects long-term symptoms, including somatic and psychological components of FM rather than pain intensity. These CBF findings may reflect differences in behavioral and psychological responses between patients.

Imperceptible somatosensory stimulation alters sensorimotor background rhythm and connectivity.

Most sensory input to our body is not consciously perceived. Nevertheless, it may reach the cortex and influence our behavior. In this study, we investigated noninvasive neural signatures of unconscious cortical stimulus processing to understand mechanisms, which (1) prevent low-intensity somatosensory stimuli from getting access to conscious experience and which (2) can explain the associated impediment of conscious perception for additional stimuli. Stimulation of digit 2 in humans far below the detection threshold elicited a cortical evoked potential (P1) at 60 ms, but no further somatosensory evoked potential components. No event-related desynchronization was detected; rather, there was a transient synchronization in the alpha frequency range. Using the same stimulation during fMRI, a reduced centrality of contralateral primary somatosensory cortex (SI) was found, which appeared to be mainly driven by reduced functional connectivity to frontoparietal areas. We conclude that after subthreshold stimulation the (excitatory) feedforward sweep of bottom-up processing terminates in SI preventing access to conscious experience. We speculate that this interruption is due to a predominance of inhibitory processing in SI. The increase in alpha activity and the disconnection of SI from frontoparietal areas are likely correlates of an elevated perception threshold and may thus serve as a gating mechanism for the access to conscious experience.

Widespread vestibular activation of the rodent cortex.

Much of our understanding of the neuronal mechanisms of spatial navigation is derived from chronic recordings in rodents in which head-direction, place, and grid cells have all been described. However, despite the proposed importance of self-reference information to these internal representations of space, their congruence with vestibular signaling remains unclear. Here we have undertaken brain-wide functional mapping using both fMRI and electrophysiological methods to directly determine the spatial extent, strength, and time course of vestibular signaling across the rat forebrain. We find distributed activity throughout thalamic, limbic, and particularly primary sensory cortical areas in addition to known head-direction pathways. We also observe activation of frontal regions, including infralimbic and cingulate cortices, indicating integration of vestibular information throughout functionally diverse cortical regions. These whole-brain activity maps therefore suggest a widespread contribution of vestibular signaling to a self-centered framework for multimodal sensorimotor integration in support of movement planning, execution, spatial navigation, and autonomic responses to gravito-inertial changes.

New whole-body sensory-motor gradients revealed using phase-locked analysis and verified using multivoxel pattern analysis and functional connectivity.

Topographic organization is one of the main principles of organization in the human brain. Specifically, whole-brain topographic mapping using spectral analysis is responsible for one of the greatest advances in vision research. Thus, it is intriguing that although topography is a key feature also in the motor system, whole-body somatosensory-motor mapping using spectral analysis has not been conducted in humans outside M1/SMA. Here, using this method, we were able to map a homunculus in the globus pallidus, a key target area for deep brain stimulation, which has not been mapped noninvasively or in healthy subjects. The analysis clarifies contradictory and partial results regarding somatotopy in the caudal-cingulate zone and rostral-cingulate zone in the medial wall and in the putamen. Most of the results were confirmed at the single-subject level and were found to be compatible with results from animal studies. Using multivoxel pattern analysis, we could predict movements of individual body parts in these homunculi, thus confirming that they contain somatotopic information. Using functional connectivity, we demonstrate interhemispheric functional somatotopic connectivity of these homunculi, such that the somatotopy in one hemisphere could have been found given the connectivity pattern of the corresponding regions of interest in the other hemisphere. When inspecting the somatotopic and nonsomatotopic connectivity patterns, a similarity index indicated that the pattern of connected and nonconnected regions of interest across different homunculi is similar for different body parts and hemispheres. The results show that topographical gradients are even more widespread than previously assumed in the somatosensory-motor system. Spectral analysis can thus potentially serve as a gold standard for defining somatosensory-motor system areas for basic research and clinical applications.

What Makes the Muscle Twitch: Motor System Connectivity and TMS-Induced Activity.

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evokes several volleys of corticospinal activity. While the earliest wave (D-wave) originates from axonal activation of cortico-spinal neurons (CSN), later waves (I-waves) result from activation of mono- and polysynaptic inputs to CSNs. Different coil orientations preferentially stimulate cortical elements evoking different outputs: latero-medial-induced current (LM) elicits D-waves and short-latency electromyographic responses (MEPs); posterior-anterior current (PA) evokes early I-waves. Anterior-posterior current (AP) is more variable and tends to recruit later I-waves, featuring longer onset latencies compared with PA-TMS. We tested whether the variability in response to AP-TMS was related to functional connectivity of the stimulated M1 in 20 right-handed healthy subjects who underwent functional magnetic resonance imaging while performing an isometric contraction task. The MEP-latency after AP-TMS (relative to LM-TMS) was strongly correlated with functional connectivity between the stimulated M1 and a network involving cortical premotor areas. This indicates that stronger premotor-M1 connectivity increases the probability that AP-TMS recruits shorter latency input to CSNs. In conclusion, our data strongly support the hypothesis that TMS of M1 activates distinct neuronal pathways depending on the orientation of the stimulation coil. Particularly, AP currents seem to recruit short latency cortico-cortical projections from premotor areas.

DISC1 Ser704Cys impacts thalamic-prefrontal connectivity.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been thought as a putative susceptibility gene for various psychiatric disorders, and DISC1 Ser704Cys is associated with variations of brain morphology and function. Moreover, our recent diffusion magnetic resonance imaging (dMRI) study reported that DISC1 Ser704Cys was associated with information transfer efficiency in the brain anatomical network. However, the effects of the DISC1 gene on functional brain connectivity and networks, especially for thalamic-prefrontal circuit, which are disrupted in various psychiatric disorders, are largely unknown. Using a functional connectivity density (FCD) mapping method based on functional magnetic resonance imaging data in a large sample of healthy Han Chinese subjects, we first investigated the association between DISC1 Ser704Cys and short- and long-range FCD hubs. Compared with Ser homozygotes, Cys-allele individuals had increased long-range FCD hubs in the bilateral thalami. The functional and anatomical connectivity of the thalamus to the prefrontal cortex was further analyzed. Significantly increased thalamic-prefrontal functional connectivity and decreased thalamic-prefrontal anatomical connectivity were found in DISC1 Cys-allele carriers. Our findings provide consistent evidence that the DISC1 Ser704Cys polymorphism influences the thalamic-prefrontal circuits in humans and may provide new insights into the neural mechanisms that link DISC1 and the risk for psychiatric disorders.

Enhancement of resting-state fcMRI networks by prior sensory stimulation.

It is important to consider the effect of a previous experimental condition when analyzing resting-state functional connectivity magnetic resonance imaging (fcMRI) data. In this work, a simple sensory stimulation functional MRI (fMRI) experiment was conducted between two resting-state fcMRI acquisitions in anesthetized rats using a high-field small-animal MR scanner. Previous human studies have reported fcMRI network alteration by prior task/stimulus utilizing similar experimental paradigms. An anesthetized rat preparation was used to test whether brain regions with higher level functions are involved in post-task/stimulus fcMRI network alteration. We demonstrate significant fcMRI enhancement poststimulation in the sensory cortical, limbic, and insular brain regions in rats. These brain regions have been previously implicated in vigilance and anesthetic arousal networks. We tested their experimental paradigm in several inbred strains of rats with known phenotypic differences in anesthetic susceptibility and cerebral vascular function. Brown Norway (BN), Dahl Salt-Sensitive (SS), and consomic SSBN13 strains were tested. We have previously shown significant differences in blood oxygen level-dependent fMRI activity and fcMRI networks across these strains. Here we report statistically significant interstrain differences in regional fcMRI poststimulation enhancement. In the SS strain, poststimulation enhancement occurred in posterior sensory and limbic cortical brain regions. In the BN strain, poststimulation enhancement appeared in anterior cingulate and subcortical limbic brain regions. These results imply that a prior condition has a significant impact on fcMRI networks that depend on intersubject difference in genetics and physiology.

Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information.

Boosted activation of right inferior frontoparietal network: a basis for illusory movement awareness.

The feeling of illusory movement is considered important in the study of human behavior because it is deeply related to motor consciousness. However, the neural basis underlying the illusion of movement remains to be understood. Following optimal vibratory stimulation of muscle tendon, certain subjects experience illusory movements while others do not. In the present fMRI study, we sought to uncover the neural basis of illusory movement awareness by contrasting a posteriori these two types of subjects. Examining fMRI data using leave-one-subject-out general linear models and region of interest analyses, we found that a non-limb-specific associative network, including the opercular part of the right inferior frontal gyrus and the right inferior parietal lobule, was more active in subjects with illusions. On the other hand, levels of activation in other brain areas involved in kinaesthetic processing were rather similar between the two subsamples of subjects. These results suggest that activation of the right inferior frontoparietal areas, once passed a certain threshold, forms the basis of illusory movements. This is consistent with the global neuronal workspace hypothesis that associates conscious processing with surges of frontoparietal activity.

Event-related fMRI at 7T reveals overlapping cortical representations for adjacent fingertips in S1 of individual subjects.

Recent fMRI studies of the human primary somatosensory cortex have been able to differentiate the cortical representations of different fingertips at a single-subject level. These studies did not, however, investigate the expected overlap in cortical activation due to the stimulation of different fingers. Here, we used an event-related design in six subjects at 7 Tesla to explore the overlap in cortical responses elicited in S1 by vibrotactile stimulation of the five fingertips. We found that all parts of S1 show some degree of spatial overlap between the cortical representations of adjacent or even nonadjacent fingertips. In S1, the posterior bank of the central sulcus showed less overlap than regions in the post-central gyrus, which responded to up to five fingertips. The functional properties of these two areas are consistent with the known layout of cytoarchitectonically defined subareas, and we speculate that they correspond to subarea 3b (S1 proper) and subarea 1, respectively. In contrast with previous fMRI studies, however, we did not observe discrete activation clusters that could unequivocally be attributed to different subareas of S1. Venous maps based on T2*-weighted structural images suggest that the observed overlap is not driven by extra-vascular contributions from large veins.

Temporal sequencing of brain activations during naturally occurring thermoregulatory events.

Thermoregulatory events are associated with activity in the constituents of the spinothalamic tract. Whereas studies have assessed activity within constituents of this pathway, in vivo functional magnetic resonance imaging (fMRI) studies have not determined if neuronal activity in the constituents of the tract is temporally ordered. Ordered activity would be expected in naturally occurring thermal events, such as menopausal hot flashes (HFs), which occur in physiological sequence. The origins of HFs may lie in brainstem structures where neuronal activity may occur earlier than in interoceptive centers, such as the insula and the prefrontal cortex. To study such time ordering, we conducted blood oxygen level-dependent-based fMRI in a group of postmenopausal women to measure neuronal activity in the brainstem, insula, and prefrontal cortex around the onset of an HF (detected using synchronously acquired skin conductance responses). Rise in brainstem activity occurred before the detectable onset of an HF. Activity in the insular and prefrontal trailed that in the brainstem, appearing following the onset of the HF. Additional activations associated with HF's were observed in the anterior cingulate cortex and the basal ganglia. Pre-HF brainstem responses may reflect the functional origins of internal thermoregulatory events. By comparison insular, prefrontal and striatal activity may be associated with the phenomenological correlates of HFs.

Category-specific integration of homeostatic signals in caudal but not rostral human insula.

Prevailing theories hold that the insula is functionally organized along its caudal-to-rostral axis, with posterior regions coding lower-level sensory information and anterior regions coding higher-level stimulus significance relative to the body's homeostatic needs. Contrary to predictions of this model, the response of the taste-sensitive region of the caudal, but not rostral, insula to food images was directly related to the body's homeostatic state as indexed by levels of peripheral glucose.

Multimodal convergence within the intraparietal sulcus of the macaque monkey.

The parietal cortex is highly multimodal and plays a key role in the processing of objects and actions in space, both in human and nonhuman primates. Despite the accumulated knowledge in both species, we lack the following: (1) a general description of the multisensory convergence in this cortical region to situate sparser lesion and electrophysiological recording studies; and (2) a way to compare and extrapolate monkey data to human results. Here, we use functional magnetic resonance imaging (fMRI) in the monkey to provide a bridge between human and monkey studies. We focus on the intraparietal sulcus (IPS) and specifically probe its involvement in the processing of visual, tactile, and auditory moving stimuli around and toward the face. We describe three major findings: (1) the visual and tactile modalities are strongly represented and activate mostly nonoverlapping sectors within the IPS. The visual domain occupies its posterior two-thirds and the tactile modality its anterior one-third. The auditory modality is much less represented, mostly on the medial IPS bank. (2) Processing of the movement component of sensory stimuli is specific to the fundus of the IPS and coincides with the anatomical definition of monkey ventral intraparietal area (VIP). (3) A cortical sector within VIP processes movement around and toward the face independently of the sensory modality. This amodal representation of movement may be a key component in the construction of peripersonal space. Overall, our observations highlight strong homologies between macaque and human VIP organization.

Pain and plasticity: is chronic pain always associated with somatosensory cortex activity and reorganization?

The somatosensory cortex remodels in response to sensory deprivation, with regions deprived of input invaded by neighboring representations. The degree of cortical reorganization is correlated with ongoing pain intensity, which has led to the assumption that chronic pain conditions are invariably associated with somatosensory cortex reorganization. Because the presentation and etiology of chronic pain vary, we determined whether cortical changes in human subjects are similar for differing pain types. Using functional and anatomical magnetic resonance imaging, we found that, while human patients with neuropathic pain displayed cortical reorganization and changes in somatosensory cortex activity, patients with non-neuropathic chronic pain did not. Furthermore, cortical reorganization in neuropathic pain patients was associated with changes in regional anatomy. These data, by showing that pain per se is not associated with cortical plasticity, suggest that treatments aimed at reversing cortical reorganization should only be considered for use in patients with certain types of chronic pain.

Working memory of somatosensory stimuli: an fMRI study.

In a previous study, we have shown that passive recognition of tactile geometrical shapes (i.e. no exploratory movement) engages prefrontal and premotor areas in addition to somatosensory regions (Savini et al., 2010). In the present study we tested the hypothesis that these regions are involved not only in the perception but also during working memory of such somatic information. We performed functional magnetic resonance imaging (fMRI) during the execution of N-BACK tasks, with 2D geometrical shapes blindly pressed on the subjects' right hand palm. Three conditions with increasing memory load (0-BACK, 1-BACK, 2-BACK) were used. Results showed that primary somatosensory area (SI), secondary somatosensory area (SII) and bilateral Insula were active in all conditions, confirming their importance in coding somatosensory stimuli. Activation of fronto-parietal circuit in supplementary motor area (SMA), right superior parietal lobe (rSPL), bilateral middle frontal gyrus, left inferior frontal gyrus, and right superior frontal sulcus was significantly larger during 1-BACK and 2-BACK than 0-BACK. Left superior parietal lobe and right frontal eye field showed a higher activation during the 2-BACK than 0-BACK. Finally, SMA and rSPL were characterized by a statistically significant higher activation during 2-BACK than 1-BACK, revealing their sensitivity to the memory load. These results suggest that working memory of tactile geometrical shapes (no exploratory movement) involves a complex circuit of modal and supramodal fronto-parietal areas.

Unreliable evoked responses in autism.

Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and controls. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary nonsocial sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing properties such as reliability, plasticity, and adaptation/habituation are altered in autism.

Parallel processing of nociceptive and non-nociceptive somatosensory information in the human primary and secondary somatosensory cortices: evidence from dynamic causal modeling of functional magnetic resonance imaging data.

Several studies have suggested that, in higher primates, nociceptive somatosensory information is processed in parallel in the primary (S1) and secondary (S2) somatosensory cortices, whereas non-nociceptive somatosensory input is processed serially from S1 to S2. However, evidence suggesting that both nociceptive and non-nociceptive somatosensory inputs are processed in parallel in S1 and S2 also exists. Here, we aimed to clarify whether or not the hierarchical organization of nociceptive and non-nociceptive somatosensory processing in S1 and S2 differs in humans. To address this question, we applied dynamic causal modeling and Bayesian model selection to functional magnetic resonance imaging (fMRI) data collected during the selective stimulation of nociceptive and non-nociceptive somatosensory afferents in humans. This novel approach allowed us to explore how nociceptive and non-nociceptive somatosensory information flows within the somatosensory system. We found that the neural activities elicited by both nociceptive and non-nociceptive somatosensory stimuli are best explained by models in which the fMRI responses in both S1 and S2 depend on direct thalamocortical projections. These observations indicate that, in humans, both nociceptive and non-nociceptive information are processed in parallel in S1 and S2.

Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study.

Although the effects of cannabis on perception are well documented, little is known about their neural basis or how these may contribute to the formation of psychotic symptoms. We used functional magnetic resonance imaging (fMRI) to assess the effects of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during visual and auditory processing in healthy volunteers. In total, 14 healthy volunteers were scanned on three occasions. Identical 10 mg THC, 600 mg CBD, and placebo capsules were allocated in a balanced double-blinded pseudo-randomized crossover design. Plasma levels of each substance, physiological parameters, and measures of psychopathology were taken at baseline and at regular intervals following ingestion of substances. Volunteers listened passively to words read and viewed a radial visual checkerboard in alternating blocks during fMRI scanning. Administration of THC was associated with increases in anxiety, intoxication, and positive psychotic symptoms, whereas CBD had no significant symptomatic effects. THC decreased activation relative to placebo in bilateral temporal cortices during auditory processing, and increased and decreased activation in different visual areas during visual processing. CBD was associated with activation in right temporal cortex during auditory processing, and when contrasted, THC and CBD had opposite effects in the right posterior superior temporal gyrus, the right-sided homolog to Wernicke's area. Moreover, the attenuation of activation in this area (maximum 61, -15, -2) by THC during auditory processing was correlated with its acute effect on psychotic symptoms. Single doses of THC and CBD differently modulate brain function in areas that process auditory and visual stimuli and relate to induced psychotic symptoms.

Inferior olive response to passive tactile and visual stimulation with variable interstimulus intervals.

The unique anatomical and electrophysiological features of the inferior olive and its importance to cerebellar function have been recognized for decades. However, understanding the exact function of the inferior olive has been limited by the general lack of correlation between its neural activity and specific behavioral states. Electrophysiological studies in animals showed that the inferior olive response to sensory stimuli is generally invariant to stimulus properties but is enhanced by unexpected stimuli. Using functional magnetic resonance imaging in humans, we have shown that the inferior olive is activated when subjects performed a task requiring perception of visual stimuli with unpredictable timing (Xu et al. J Neurosci 26(22):5990-5995, 2006, Liu et al. J Neurophysiol 100(3):1557-1561, 2008). In the current study, subjects were scanned while passively perceiving visual and tactile stimuli that were rendered unpredictable by continuously varying interstimulus intervals (ISIs). Sequences of visual stimuli and tactile stimuli to the right hand were presented separately within the same scanning session. In addition to the activation of multiple areas in the cerebellar cortex consistent with previous imaging studies, the results show that both tactile and visual stimulation with variable ISIs were effective in activating the inferior olive. Together with our previous findings, the current results are consistent with the electrophysiological studies in animals and further support the view that the inferior olive and the climbing fiber system primarily convey the temporal information of sensory input regardless of the modality.