Person:

Napadow, Vitaly

Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α2-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness. DOI: http://dx.doi.org/10.7554/eLife.04499.001

Previous work has shown that acupuncture stimulation evokes deactivation of a limbic-paralimbic-neocortical network (LPNN) as well as activation of somatosensory brain regions. This study explores the activity and functional connectivity of these regions during acupuncture vs. tactile stimulation and vs. acupuncture associated with inadvertent sharp pain. Acupuncture during 201 scans and tactile stimulation during 74 scans for comparison at acupoints LI4, ST36 and LV3 was monitored with fMRI and psychophysical response in 48 healthy subjects. Clusters of deactivated regions in the medial prefrontal, medial parietal and medial temporal lobes as well as activated regions in the sensorimotor and a few paralimbic structures can be identified during acupuncture by general linear model analysis and seed-based cross correlation analysis. Importantly, these clusters showed virtual identity with the default mode network and the anti-correlated task-positive network in response to stimulation. In addition, the amygdala and hypothalamus, structures not routinely reported in the default mode literature, were frequently involved in acupuncture. When acupuncture induced sharp pain, the deactivation was attenuated or became activated instead. Tactile stimulation induced greater activation of the somatosensory regions but less extensive deactivation of the LPNN. These results indicate that the deactivation of the LPNN during acupuncture cannot be completely explained by the demand of attention that is commonly proposed in the default mode literature. Our results suggest that acupuncture mobilizes the anti-correlated functional networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response.

Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional MRI, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region’s functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least five different, regionally-specific activity profiles in the brain. Linearly increasing (e.g., primary somatosensory/motor cortex, insulae) and intensity-independent (e.g., secondary somatosensory cortex) activation was noted in traditional pain processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (e.g., posterior cingulate cortex), linearly decreasing (e.g., contralateral inferior parietal lobule), and quadratic (U-shaped; e.g., medial prefrontal cortex). The latter observation suggests that: 1) different DMN subregions exhibit functional heterogeneity and 2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities in order to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

OBJECTIVE

A major impediment toward the development of novel treatment strategies for fibromyalgia (FM) is the lack of an objective marker which tracks with spontaneous clinical pain report. Resting state intrinsic brain connectivity in FM has demonstrated increased insular connectivity to the default mode network (DMN), a network whose activity is increased during rest. Moreover increased insular connectivity to the DMN was associated with increased spontaneous pain levels. However as these analyses were cross-sectional in nature, they provided no insight to dynamic changes in connectivity and their relationship with variation in clinical pain report.

METHODS

17 FM patients underwent resting state fMRI at baseline and following 4 weeks of a non-pharmacological intervention to diminish pain. Intrinsic DMN connectivity was evaluated using probabilistic independent component analysis. A paired analysis evaluated longitudinal changes in intrinsic DMN connectivity and a multiple linear regression investigated correlations between longitudinal changes in clinical pain and changes in intrinsic DMN connectivity. Changes in clinical pain were assessed with the Short Form of the McGill Pain Questionnaire (SF-MPQ).

RESULTS

Clinical pain was reduced following therapy (SF-MPQ sensory scale: p<0.02). Intrinsic DMN connectivity to the insula was reduced, and this reduction was correlated with reductions in pain (corrected p<0.05).

CONCLUSIONS

Our findings suggest that intrinsic brain connectivity can be used as a candidate objective marker that tracks intra-subject with changes in spontaneous chronic pain in FM. We propose that intrinsic connectivity measures could potentially be used either in research or clinical settings as a complementary, more objective outcome.