Medio-dorsal thalamic dysconnectivity in chronic knee pain: A possible mechanism for negative affect and pain comorbidity.

The reciprocal interaction between pain and negative affect is acknowledged but pain-related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed-based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect-related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain-free controls. In conclusion, we demonstrate mediodorsal thalamo-cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect.

Theta Burst Stimulation of the Human Motor Cortex Modulates Secondary Hyperalgesia to Punctate Mechanical Stimuli.

OBJECTIVES: Many chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols. MATERIALS AND METHODS: In a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states. Secondary hyperalgesia (a form of use-dependent central sensitization) was induced using a well-established injury-free pain model and assessed by standardized quantitative sensory testing involving light touch and pinprick pain thresholds in addition to stimulus-response functions. RESULTS: We found that continuous TBS of the human motor cortex has a facilitatory (pronociceptive) effect on the magnitude of perceived pain to secondary hyperalgesia, which may rely on induction and expression of neural plasticity through heterosynaptic long-term potentiation-like mechanisms. CONCLUSIONS: By defining the underlying mechanisms of TBS-driven synaptic plasticity in the nociceptive system, we offer new insight into disease mechanisms and provide targets for promoting functional recovery and repair in chronic pain. For clinical applications, this knowledge is critical for development of more efficacious and mechanisms-based neuromodulation protocols, which are urgently needed to address the chronic pain and opioid epidemics.

Brain perfusion patterns are altered in chronic knee pain: a spatial covariance analysis of arterial spin labelling MRI.

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.

Altered connectivity of the right anterior insula drives the pain connectome changes in chronic knee osteoarthritis.

Resting-state functional connectivity (FC) has proven a powerful approach to understand the neural underpinnings of chronic pain, reporting altered connectivity in 3 main networks: the default mode network (DMN), central executive network, and the salience network (SN). The interrelation and possible mechanisms of these changes are less well understood in chronic pain. Based on emerging evidence of its role to drive switches between network states, the right anterior insula (rAI, an SN hub) may play a dominant role in network connectivity changes underpinning chronic pain. To test this hypothesis, we used seed-based resting-state FC analysis including dynamic and effective connectivity metrics in 25 people with chronic osteoarthritis (OA) pain and 19 matched healthy volunteers. Compared with controls, participants with painful knee OA presented with increased anticorrelation between the rAI (SN) and DMN regions. Also, the left dorsal prefrontal cortex (central executive network hub) showed more negative FC with the right temporal gyrus. Granger causality analysis revealed increased negative influence of the rAI on the posterior cingulate (DMN) in patients with OA in line with the observed enhanced anticorrelation. Moreover, dynamic FC was lower in the DMN of patients and thus more similar to temporal dynamics of the SN. Together, these findings evidence a widespread network disruption in patients with persistent OA pain and point toward a driving role of the rAI.

Affective touch and attachment style modulate pain: a laser-evoked potentials study.

Affective touch and cutaneous pain are two sub-modalities of interoception with contrasting affective qualities (pleasantness/unpleasantness) and social meanings (care/harm), yet their direct relationship has not been investigated. In 50 women, taking into account individual attachment styles, we assessed the role of affective touch and particularly the contribution of the C tactile (CT) system in subjective and electrophysiological responses to noxious skin stimulation, namely N1 and N2-P2 laser-evoked potentials. When pleasant, slow (versus fast) velocity touch was administered to the (non-CT-containing) palm of the hand, higher attachment anxiety predicted increased subjective pain ratings, in the same direction as changes in N2 amplitude. By contrast, when pleasant touch was administered to CT-containing skin of the arm, higher attachment anxiety predicted attenuated N1 and N2 amplitudes. Higher attachment avoidance predicted opposite results. Thus, CT-based affective touch can modulate pain in early and late processing stages (N1 and N2 components), with the direction of effects depending on attachment style. Affective touch not involving the CT system seems to affect predominately the conscious perception of pain, possibly reflecting socio-cognitive factors further up the neurocognitive hierarchy. Affective touch may thus convey information about available social resources and gate pain responses depending on individual expectations of social support.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.