Functional Neural Connectivity Underlying Pain Experienced in Migraine, Dysmenorrhea

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Alterations within and between resting state functional neural networks are involved in pain processing.
Alterations within and between resting state functional neural networks are involved in pain processing.

The experience of pain is a complex phenomenon that broadly engages cognitive, emotional, and/or sensory systems. Its neural substrates and mechanisms remain to be elucidated, as very little data is available.1,2

Recent technological and methodological developments have generated techniques that allow to explore the dynamic relationship between functionally related but anatomically disparate brain regions.

Connections between neural networks are either anatomical or functional (eg, synchronous neuronal oscillations).2 The latter remote, neurophysiological interactions, demonstrating temporal dependency, are referred to as functional connectivity. 2-4 For example, the default mode network is predominantly activated and engaged during periods of spontaneous, stimulus-independent thought and remains quiescent during attention-demanding, goal-directed tasks. Likewise, the salience network, represents an intrinsic brain network associated with the modulation of attention between internal and external stimuli. These networks which extending to distinct brain regions have been associated with self-relevant emotional and mental processes, as well as information integration.5,6


Pain Processing

Current neurofunctional research aims to refine our understanding of how the dynamic dialogue between and within brain networks and/or systems contributes to the experience of pain and related behaviors. This is achieved using functional magnetic resonance imaging (fMRI) to examine networks while the brain is “at rest” (ie, while a subject is not performing a task and/or directed to think of anything in particular) with various approaches such as seed-based, independent component analysis-based and/or cluster based methods. 1, 7 One application has been the identification of pain modulatory circuits and the alterations observed in these networks in pain processing. 1,2

Relevance in Migraine

Accumulating evidence suggests that migraineurs exhibit altered functional connectivity in regions associated with mediating cognitive, affective, and sensory networks/systems. A recent study used machine-learning techniques to identify biomarkers capable of discriminating between individuals with migraine (n=58) and healthy controls (n=50) using resting-state fMRI.8

Thirty three pain-related regions were examined for functional connections and used in the classification algorithm to evaluate the accuracy of discrimination between migraineurs and healthy controls.

Results from this study suggested that the functional connectivity of the right middle temporal, middle cingulate, posterior insula, left ventromedial prefrontal and bilateral amygdala regions best discriminated migraineurs from healthy controls; moreover, migraineurs with longer illness duration (> 14 years; 96.7% accuracy) were more accurately classified, when compared to those with shorter illness duration (≤ 14 years; 82.1% accuracy).8

A separate study reported focal functional alterations that were significantly related to longer duration of interictal migraine without aura 9. Interestingly, baseline functional connectivity among migraineurs (not currently experiencing pain) are altered in regions classically associated with nociceptive processing (ie, periaqueductal gray matter).10

Funtional connectivity in dysmenorrhea

Dynamic changes in functional connectivity may affect pain perception, as indicated in aforementioned migraine and pain studies.2,11

In primary dysmenorrhea, functional connectivity between and within regions involved in self-referential processing (including the medial prefrontal cortex, posterior cingulate cortex and insula), in the control of the cognitive affect (eg, executive control and salience networks), and in pain modulation (eg, sensorimotor network), are altered. 7

In a study recently published in Scientific Reports, researchers sought to determine whether alterations in the functional interactions between networks involved in dysmenorrhea underlie pain experience.7Results indicated hypo-connectivity between the default-mode and salience networks, and hyper-connectivity between the default-mode and executive control networks in women with primary dysmenorrheal (n=46) compared with healthy age-matched controls (n=49). The authors interpreted these changes in connectivity as an adaptive transition from affective to cognitive processing of pain salience. This would suggest that women with chronic primary dysmenorrhea exhibit adaptive neuroplasticity and functional reorganization, in order to effectively modulate their subjective experience of pain during menstruation. 7

Conclusions

Taken together, results from studies evaluating various pain modalities indicate alterations within and between resting state functional networks. These observations add to current knowledge of activation of nociceptive pathways. In addition, individuals may be categorized in separate subgroups, each with a distinct resting state signature, thus providing basis for personalized pain management treatments and improved outcomes.

References

 1.  Bastuji H, Frot M, Mazza S, Perchet C, Magnin M, Garcia-Larrea L. Thalamic Responses to Nociceptive-Specific Input in Humans: Functional Dichotomies and Thalamo-Cortical Connectivity. Cereb Cortex 2016;26(6):2663-2676.

 2.  Colombo B, Rocca MA, Messina R, Guerrieri S, Filippi M. Resting-state fMRI functional connectivity: a new perspective to evaluate pain modulation in migraine? Neurol Sci 2015;36 Suppl 1:41-45.

 3.  Maleki N, Linnman C, Brawn J, Burstein R, Becerra L, Borsook D. Her versus his migraine: multiple sex differences in brain function and structure. Brain 2012;135(Pt 8):2546-2559. 

 4.  Burstein R, Jakubowski M, Garcia-Nicas E et al. Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol 2010;68(1):81-91.

 5.  Cha DS, De MF, Soczynska JK et al. The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2014;13(10):1750-1758.

 6.  Green SA, Hernandez L, Bookheimer SY, Dapretto M. Salience Network Connectivity in Autism Is Related to Brain and Behavioral Markers of Sensory Overresponsivity. J Am Acad Child Adolesc Psychiatry 2016;55(7):618-626.

 7.  Wu TH, Tu CH, Chao HT et al. Dynamic Changes of Functional Pain Connectome in Women with Primary Dysmenorrhea. Sci Rep 2016;6:24543.

 8.  Chong CD, Gaw N, Fu Y, Li J, Wu T, Schwedt TJ. Migraine classification using magnetic resonance imaging resting-state functional connectivity data. Cephalalgia 2016.

 9.  Yu D, Yuan K, Zhao L et al. Regional homogeneity abnormalities in patients with interictal migraine without aura: a resting-state study. NMR Biomed 2012;25(5):806-812.

10.Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol 2011;70(5):838-845.

11.Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 2008;28(6):1398-1403.

 

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