Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception.

The study by Tan et al. represents a major step forward in understanding the role of neuronal oscillations in the cerebral processing of pain. The study builds upon studies in humans, which have provided accumulating evidence that pain is associated with rhythmic neuronal activity at frequencies between 40 and 100 Hz, i.e., neuronal gamma oscillations. However, these human studies have important limitations. First, electroencephalography and magnetoencephalography recordings are highly sensitive to artifacts. Hence, reports of gamma oscillations have rightly raised concerns regarding artifact contamination, particularly from muscles. Second, the evidence is mostly correlative so far. Hence, the causal relationship between gamma oscillations and pain has remained unclear. Third, the effects of pain-related gamma oscillations on other brain areas are largely unknown. Thus, remote effects of gamma oscillations remain to be demonstrated, particularly when considering that pain is essentially a brain network phenomenon.

The current study in awake, behaving mice overcomes some of these limitations. The study elegantly combines different pain models, intracortical recordings, optical stimulation, behavioral tests, and immunohistochemistry to particularly investigate the role of gamma oscillations in the primary somatosensory cortex (S1). Three findings are most remarkable.

First, the results confirm that brief as well as longer-lasting painful stimulation induces gamma oscillations in S1, and that these gamma oscillations are closely related to pain behavior and hypersensitivity. This finding provides convincing evidence for the existence and functional significance of pain-related gamma oscillations devoid of concerns related to artifacts in human EEG and MEG recordings.

Second, the study reveals that the optogenetic entrainment of gamma oscillations in S1 induces hypersensitivity and indicators of pain aversion and negative affect. These observations add a crucial causal link to the correlative observations of human studies.

Third, the findings reveal a highly interesting and in part surprising pattern of remote effects. The entrainment of gamma oscillations in S1 yields a complex and diverse pattern of effects in the prefrontal cortex with increases in the rostral anterior cingulate cortex, decreases in the prelimbic cortex and no effect in the mid-cingulate cortex. Moreover, increases of brain activity were found in brainstem centers of the descending pain modulatory system. Further evidence shows that these remote effects are involved in the serotonergic facilitation of pain behavior. These network effects elucidate the functional significance of pain-related gamma oscillations beyond their local effects and unravel a formerly unknown mechanism of descending pain modulation.

The study represents an outstanding example of how animal studies complement and extend human studies to further the understanding of the brain mechanisms of pain. It particularly shows how the optogenetic manipulation of oscillations in animals adds crucial causal information to correlative findings in humans. Moreover, the study significantly extends the understanding of the network effects of gamma oscillations. Specifically, the diverse effects in the prefrontal cortex should inspire further investigations. Disentangling these effects and finding their correspondence in humans is a major challenge, since prefrontal brain areas likely play a key role in chronic pain states. Finally, the descending modulatory effects of gamma oscillations in S1 are highly interesting, as the understanding of pain modulatory effects in the brain helps us further optimize pain treatments. Thus, the current study represents an ideal example of how translating forth and back between animal and human studies advances the knowledge of the brain mechanisms of pain. I am therefore looking forward to seeing the current approach extended to other oscillatory phenomena and brain areas, and to complementary studies in humans.

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