Commentary on “Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain”

In patients, as well as in animal models, hypersensitivity to external stimuli (hyperalgesia and allodynia) or spontaneous pain is often the first, and the most disabling, symptom of neuropathy (Davis et al., 2020). The increased activity of sensitive neurons drives pain development, making ion channel modulation a fundamental target for current pharmacotherapy as well as one of the most investigated by the R&D departments of pharmaceutical companies (Bennett et al., 2019).

An orchestrated process promotes peripheral and central sensitization. Altered ion channel functionality, neurotransmitters, and soluble factors release as well as epigenetic regulations lead to maladaptive changes in neurons, glia, immune cells, and their network (Finnerup et al., 2021). Also when the initial damage is located in the peripheral nervous system (PNS), the hyperexcitability of sensory neurons evolves in the sensitization of the central nervous system (CNS) leading to chronicization (Latremoliere and Woolf, 2009). The mechanisms by which the different regions of the somatosensory nervous system may communicate and organize a coordinate signaling that sustains pain persistence remains largely unclear.

Studying the pain-related low-frequency cortical oscillations, Chen et al. (2023) recorded (by electrocorticography) a marked increase in the power of theta band in the somato-sensory cortex (S1) of mice after spared nerve injury (SNI). This phenomenon correlated with mechanical hypersensitivity. Temporally, the increase in S1 oscillation was significant within 3 days, but not in the first 24 hours after SNI; a timing also followed by the enhancement of Ca²⁺ activity and synchrony of S1 pyramidal neurons (in vivo two-photon Ca²⁺ imaging). Since the peripheral origin of the damage, the authors hypothesized that dorsal root ganglia (DRG) neurons may contribute to cortical synchrony. By using a recently developed imaging technique (Chen et al., 2019), they performed Ca²⁺ imaging of lumbar DRG sensory neurons in awake mice. The DRG-integrated Ca²⁺ activity was higher within 3 hours after SNI, increasing over 3 days; synchrony was enhanced on days 1 and 3 and persisted over 3 weeks. So the increase in the level and synchrony of DRG neuronal activity preceded 1–2 days that of S1 cortical oscillation. The injured peripheral afferents were involved in DRG stimulation through local P2X3-mediated purinergic signaling. In naive mice, the enhancement of synchrony, not the level, of DRG neuronal activity was pivotal to increase the synchrony of S1 pyramidal activity and cortical oscillations as well as to induce S1 synaptic plasticity and pain-like behavior. Summarizing, the damage to a peripheral nerve evokes synchronized activity of DRG neurons, the DRG synchrony is critical for the following increase in activity synchrony of pyramidal neurons, S1 low-frequency cortical oscillations, synaptic plasticity, and finally, neuropathic pain.

An enhancement of low-frequency cortical oscillations is reported in human subjects affected by neuropathic pain (Sarnthein et al., 2006); similarly, the increase of neuronal synchronization is widespread in animals in neuropathic conditions (Zheng et al., 2021). Okada et al. (2021) demonstrated that artificially increasing neuronal activity and synchrony reduced pain threshold.

Recently, Ding et al. (2023) reported that spontaneous pain induced a synchronized neural dynamic in the primary somatosensory cortex (S1) dampened by effective pain therapies. Vice versa, the restoration of a “normal” range of neural dynamics through attenuation of pain-induced S1 synchronization (chemogenetically inhibiting pain-related c-Fos expressing neurons or selectively activating GABAergic interneurons) alleviated pain-like behavior, confirming the direct relationship between cortical hypersynchrony and pain.

The synchrony of neuronal activity is important for the development of sensory circuits as in developing retinal ganglion neurons and cochlea. So neural connections are modulated by the intrinsically generated activity of neurons to shape synapses into a useful network even before the senses have become operational (Leighton and Lohman, 2016). In adulthood, in the visual cortex, neural synchronization allows to establish relations in different parts of the visual field (Gray et al., 1989); in the olfactory system, synchrony is linked to combinatorial representations of time and space during an odor response (Wehr and Laurent, 1996). Due to the distributed organization of sensory systems, the representation of sensory objects requires the integration of responses across different cortical regions. Transient synchronization of neuronal discharges has been proposed as one possible mechanism (Singer, 1999). Furthermore, studies in human subjects have revealed that neural synchrony is associated with cognitive functions that require large-scale integration of distributed neural activity (Roux et al., 2022). On the other hand, the relevance of neural synchrony was studied also in pathological brain states (Uhlhaas and Singer, 2006). Schizophrenia was related to impaired neural synchrony, and hypersynchronous states were reported for Alzheimer’s disease, Parkinson’s disease, and epileptic seizures (Babiloni et al., 2016, 2020; Shuman et al., 2020).

In the mechanisms of pain sensitization, synchrony may be considered a maladaptive response to the pathological modification of sensory neurons’ functionality. The work of Chen et al. (2023) suggests that neuronal synchrony is able to coordinate and integrate activity from the periphery to the CNS leveling up sensitivity. Neuropathic pain results from the pathological, but organized, cooperation of several nervous areas leading to secondary hyperalgesia (extension also outside of the area of tissue injury), pain spontaneity and persistence, even after the healing of the original damage; synchrony emerges as a novel player in this network.

Interestingly, the reversal of the synchronization alleviates pain, confirming the role in hypersensitivity but also offering a new, intriguing possibility of treatment. How this approach may be realized, in particular by reducing peripheral activity synchronization remains to be explored. Similarly, the study of gender-dependent differences in the role of synchrony in pain is currently a fascinating hypothesis as well. Finally, DRG and cortical synchrony may represent potential biomarkers of neuropathy useful to an early diagnosis but also to be used in the assessment of the validity of new candidate drugs.

Taken together, Chen et al. (2023), through advanced in vivo imaging techniques, provided new insights into the role of neuronal synchrony across the nervous system during neuropathic pain development.