Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin nerve degeneration.

ABSTRACT: Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.

Effects of Positive and Negative Expectations on Human Pain Perception Engage Separate But Interrelated and Dependently Regulated Cerebral Mechanisms.

Expectations substantially influence pain perception, but the relationship between positive and negative expectations remains unclear. Recent evidence indicates that the integration between pain-related expectations and prediction errors is crucial for pain perception, which suggests that aversive prediction error-associated regions, such as the anterior insular cortex (aIC) and rostral anterior cingulate cortex (rACC), may play a pivotal role in expectation-induced pain modulation and help to delineate the relationship between positive and negative expectations. In a stimulus expectancy paradigm combining fMRI in healthy volunteers of both sexes, we found that, although positive and negative expectations respectively engaged the right aIC and right rACC to modulate pain, their associated activations and pain rating changes were significantly correlated. When positive and negative expectations modulated pain, the right aIC and rACC exhibited opposite coupling with periaqueductal gray (PAG) and the mismatch between actual and expected pain respectively modulated their coupling with PAG and thalamus across individuals. Participants' certainty about expectations predicted the extent of pain modulation, with positive expectations involving connectivity between aIC and hippocampus, a region regulating anxiety, and negative expectations engaging connectivity between rACC and lateral orbitofrontal cortex, a region reflecting outcome value and certainty. Interestingly, the strength of these certainty-related connectivities was also significantly associated between positive and negative expectations. These findings suggest that aversive prediction-error-related regions interact with pain-processing circuits to underlie stimulus expectancy effects on pain, with positive and negative expectations engaging dissociable but interrelated neural responses that are dependently regulated by individual certainty about expectations.SIGNIFICANCE STATEMENT Positive and negative expectations substantially influence pain perception, but their relationship remains unclear. Using fMRI in a stimulus expectancy paradigm, we found that, although positive and negative expectations engaged separate brain regions encoding the mismatch between actual and expected pain and involved opposite functional connectivities with the descending pain modulatory system, they produced significantly correlated pain rating changes and brain activation. Moreover, participants' certainty about expectations predicted the magnitude of both types of pain modulation, with the underlying functional connectivities significantly correlated between positive and negative expectations. These findings advance current understanding about cognitive modulation of pain, suggesting that both types of pain modulation engage different aversive prediction error signals but are dependently regulated by individual certainty about expectations.