Chia-Shu Lin

Brain Signature of Chronic Orofacial Pain: A Systematic Review and Meta-Analysis on Neuroimaging Research of Trigeminal Neuropathic Pain and Temporomandibular Joint Disorders

Brain neuroimaging has been widely used to investigate the bran signature of chronic orofacial pain, including trigeminal neuropathic pain (TNP) and pain related to temporomandibular joint disorders (TMD). We here systematically reviewed the neuroimaging literature regarding the functional and structural changes in the brain of TNP and TMD pain patients, using a computerized search of journal articles via PubMed. Ten TNP studies and 14 TMD studies were reviewed. Study quality and risk of bias were assessed based on the criteria of patient selection, the history of medication, the use of standardized pain/psychological assessments, and the model and statistics of imaging analyses. Qualitative meta-analysis was performed by examining the brain regions which showed significant changes in either brain functions (including the blood-oxygen-level dependent signal, cerebral blood flow and the magnetic resonance spectroscopy signal) or brain structure (including gray matter and white matter anatomy). We hypothesized that the neuroimaging findings would display a common pattern as well as distinct patterns of brain signature in the disorders. This major hypothesis was supported by the following findings: (1) TNP and TMD patients showed consistent functional/structural changes in the thalamus and the primary somatosensory cortex, indicating the thalamocortical pathway as the major site of plasticity. (2) The TNP patients showed more alterations at the thalamocortical pathway, and the two disorders showed distinct patterns of thalamic and insular connectivity. Additionally, functional and structural changes were frequently reported in the prefrontal cortex and the basal ganglia, suggesting the role of cognitive modulation and reward processing in chronic orofacial pain. The findings highlight the potential for brain neuroimaging as an investigating tool for understanding chronic orofacial pain.

Neural Network of Body Representation Differs between Transsexuals and Cissexuals

Body image is the internal representation of an individual’s own physical appearance. Individuals with gender identity disorder (GID), commonly referred to as transsexuals (TXs), are unable to form a satisfactory body image due to the dissonance between their biological sex and gender identity. We reasoned that changes in the resting-state functional connectivity (rsFC) network would neurologically reflect such experiential incongruence in TXs. Using graph theory-based network analysis, we investigated the regional changes of the degree centrality of the rsFC network. The degree centrality is an index of the functional importance of a node in a neural network. We hypothesized that three key regions of the body representation network, i.e., the primary somatosensory cortex, the superior parietal lobule and the insula, would show a higher degree centrality in TXs. Twenty-three pre-treatment TXs (11 male-to-female and 12 female-to-male TXs) as one psychosocial group and 23 age-matched healthy cissexual control subjects (CISs, 11 males and 12 females) were recruited. Resting-state functional magnetic resonance imaging was performed, and binarized rsFC networks were constructed. The TXs demonstrated a significantly higher degree centrality in the bilateral superior parietal lobule and the primary somatosensory cortex. In addition, the connectivity between the right insula and the bilateral primary somatosensory cortices was negatively correlated with the selfness rating of their desired genders. These data indicate that the key components of body representation manifest in TXs as critical function hubs in the rsFC network. The negative association may imply a coping mechanism that dissociates bodily emotion from body image. The changes in the functional connectome may serve as representational markers for the dysphoric bodily self of TXs.

Functional dissociation within insular cortex: The effect of pre-stimulus anxiety on pain

Brain activity resulting from changes in pain intensity may not only reflect changes in stimulus intensity but also in emotional distress. The anterior and mid-posterior insula have been associated with anticipatory anxiety and sensory-discrimination, respectively. We hypothesized that the two sub-divisions would exhibit different post-stimulus responses to increased pain intensity after removing the confounding effect of anticipatory anxiety. Using functional magnetic resonance imaging, activity was found in the anterior and mid-posterior insula in response to both low- and high-intensity painful stimuli delivered at the same level of anticipatory anxiety. Anterior insula activity covaried with anxiety ratings. When the pain intensity increased and the level of anticipatory anxiety was matched, increased activity was found in the mid-posterior insula but not in the anterior insula. The increase in activity covaried with increased pain intensity. These findings support the notion that encoding in the anterior insula primarily depends on the pre-stimulus context, i.e., anticipatory anxiety rather than the perceived pain intensity, and encoding in the mid-posterior insula is related to pain intensity changes.

Pain Catastrophizing is Associated with Dental Pain in a Stressful Context

Pain is associated with anxiety in a dental setting. It has remained unclear how cognitive-affective factors modulate pain and anxiety in a stressful context, such as receiving dental procedures. We hypothesized that both the situational factor (unpredictability about painful stimuli) and the trait factor (pain catastrophizing, i.e., the tendency to interpret pain in negative orientation) account for dental pain. Fifteen healthy participants were recruited to perform an associative learning task. They were asked to learn the pairing between visual cues and the intensity of incoming painful stimuli delivered at the right upper central incisor. Brain activation associated with pain was recorded by functional magnetic resonance imaging (fMRI). The participants reported increased anxiety and pain in the stressful context, where stimuli intensity was not predicted by the preceding cue. The score of the Pain Catastrophizing Scale was positively correlated with the increased pain modulated by unpredictability. Brain activation at the right posterior hippocampus, a region critically related to associative learning of aversive stimuli and context, was correlated with the individual catastrophizing level. Our findings suggest that both the situational factor (unpredictability) and the trait factor (catastrophizing) influence dental pain, highlighting the role of cognitive-affective factors in pain control of dental patients.

Predictability-mediated pain modulation in context of multiple cues: An event-related fMRI study

When the pain intensity of an impending stimulus is highly unpredictable, the uncertain expectation of pain may exacerbate the perceived pain intensity of the stimulus, compared to the same stimulus delivered with certain expectation. Here, we address how the perception of physically identical stimuli delivered with different predictability of the pain intensity is influenced by learning. We hypothesized that the difference in perceived pain intensity following high and low predictable cues could be explained by: (1) uncertainty-driven hyperalgesia associated with hippocampal activity; (2) certainty-driven hypoalgesia associated with activity in the periaqueductal gray (PAG) and the rostral anterior cingulate cortex (rACC); and (3) a mixed model of both. To test this hypothesis, two sessions of a delayed conditioning paradigm was employed in conjunction with event-related functional magnetic resonance imaging and trial-by-trial rating of the pain intensity. Participants had to simultaneously learn the outcome association of two cues. One cue was always delivered at the same intensity while the other cue was delivered either at a matched or a substantially higher intensity. As expected, the uncertain condition resulted in higher perceived pain intensity than the certain condition. However, this effect occurred only in the second session and was driven by decreased perceived pain in the certain condition. Furthermore, this effect was associated with decreased activity in the PAG but not the rACC. The changing pain ratings and PAG activity across sessions reflect a dynamic learning process that may mirror decreased perceived threat of and/or decreased attention to pain in the certain condition.

Brain signature characterizing the body-brain-mind axis of transsexuals.

Individuals with gender identity disorder (GID), who are commonly referred to as transsexuals (TXs), are afflicted by negative psychosocial stressors. Central to the psychological complex of TXs is the conviction of belonging to the opposite sex. Neuroanatomical and functional brain imaging studies have demonstrated that the GID is associated with brain alterations. In this study, we found that TXs identify, when viewing male-female couples in erotic or non-erotic (“neutral”) interactions, with the couple member of the desired gender in both situations. By means of functional magnetic resonance imaging, we found that the TXs, as opposed to controls (CONs), displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs.

Meta-analysis on Brain Representation of Experimental Dental Pain

Functional magnetic resonance imaging (fMRI) has been widely used for investigating the brain representation associated with dental pain evoked by pulpal electrical stimulation. However, because of the heterogeneity of experimental designs and the small sample size of individual studies, the common brain representation regarding dental pain has remained elusive. We used imaging meta-analysis to investigate six dental pain-related fMRI studies (n = 87) and tested 3 hypotheses: (1) Dental pain is associated with the ‘core’ pain-related network; (2) pain-related brain activation is somatotopically organized in the somatosensory cortex; and (3) dental pain is associated with the cognitive-affective network related to pain. Qualitative and quantitative meta-analyses revealed: (1) common activation of the core pain-related network, including the somatosensory cortex, the insula, and the cingulate cortex; (2) inconsistency in somatotopically organized activation of the primary somatosensory cortex; and (3) common activation in the dorsolateral prefrontal cortex, suggesting a role of re-appraisal and coping in the experience of dental pain. In conclusion, fMRI combined with pulpal stimulation can effectively evoke activity in the pain-related network. The dental pain-related brain representation disclosed the mechanisms of how sensory and cognitive-affective factors shape dental pain, which will help in the development of more effective customized methods for central pain control.

Sculpting the Intrinsic Modular Organization of Spontaneous Brain Activity by Art.

Artistic training is a complex learning that requires the meticulous orchestration of sophisticated polysensory, motor, cognitive, and emotional elements of mental capacity to harvest an aesthetic creation. In this study, we investigated the architecture of the resting-state functional connectivity networks from professional painters, dancers and pianists. Using a graph-based network analysis, we focused on the art-related changes of modular organization and functional hubs in the resting-state functional connectivity network. We report that the brain architecture of artists consists of a hierarchical modular organization where art-unique and artistic form-specific brain states collectively mirror the mind states of virtuosos. We show that even in the resting state, this type of extraordinary and long-lasting training can macroscopically imprint a neural network system of spontaneous activity in which the related brain regions become functionally and topologically modularized in both domain-general and domain-specific manners. The attuned modularity reflects a resilient plasticity nurtured by long-term experience.

Functional and Structural Signatures of the Anterior Insula are associated with Risk-taking Tendency of Analgesic Decision-making.

In a medical context, decision-making is associated with complicated assessment of gains, losses and uncertainty of outcomes. We here provide novel evidence about the brain mechanisms underlying decision-making of analgesic treatment. Thirty-six healthy participants were recruited and completed the Analgesic Decision-making Task (ADT), which quantified individual tendency of risk-taking (RPI), as the frequency of choosing a riskier option to relieve pain. All the participants received resting-state (rs) functional magnetic resonance imaging (MRI) and structural MRI. On rs-functional connectome, degree centrality (DC) of the bilateral anterior insula (aINS) was positively correlated with the RPI. The functional connectivity between the aINS, the nucleus accumbens and multiple brain regions, predominantly the medial frontal cortex, was positively correlated with the RPI. On structural signatures, the RPI was positively correlated with grey matter volume at the right aINS, and such an association was mediated by DC of the left aINS. Regression analyses revealed that both DC of the left aINS and participants’ imagined pain relief, as the utility of pain reduction, could predict the individual RPI. The findings suggest that the functional and structural brain signature of the aINS is associated with the individual differences of risk-taking tendency in the context of analgesic decision-making.

Preferences for Analgesic Treatments Are Influenced by Probability of the Occurrence of Adverse Effects and the Time to Reach Maximal Therapeutic Effects.

Research on shared medical decision-making suggested that both the potency of a treatment and the probability of it being successful influence individual treatment preferences. Patients also need to consider the negative attributes of treatments, such as the occurrence of adverse effects or a slow start to the therapeutic effects. It remains unclear how these attributes influence individual treatment preferences. We investigated how the analgesic effect, the adverse effect, and the time-course effect influenced the preference of analgesic treatments. Forty-five healthy volunteers participated in three hypothetical analgesic decision-making tasks. They were instructed to imagine that they were experiencing pain and choose between two hypothetical analgesic treatments: the more potent radical treatment and the less potent conservative treatment. The potency of a treatment was countered by the following attributes: the probability of working successfully, the probability of inducing an adverse effect, and the time required for the treatment to reach its maximal effect. We found that (a) when the overall probability that a treatment would induce an adverse effect decreased, the participants changed their preference from a conservative treatment to a radical treatment; (b) when the time-course for a treatment to reach its maximal effect was shortened, the participants changed their preference from a conservative treatment to a radical treatment, and (c) individual differences in prior clinical pain and the degree of imagined pain relief were associated with preferences. The findings showed that the adverse effects and the time course of treatments guide the analgesic treatment preferences, highlighting the importance of sharing information about negative attributes of treatments in pain management. The findings imply that patients may over-emphasize the occurrence of adverse effect or a slow time-course of treatment effect. In terms of shared medical decision-making, clinicians should clarify these negative attributes related to treatment to patients.