miRNAs: Important Targets for Oral Cancer Pain Research.

Pain is a symptom shared by an incredible number of diseases. It is also one of the primary conditions that prompt individuals to seek medical treatment. Head and neck squamous cell carcinoma (HNSCC) corresponds to a heterogeneous disease that may arise from many distinct structures of a large, highly complex, and intricate region. HNSCC affects a great number of patients worldwide and is directly associated with chronic pain, which is especially prominent during the advanced stages of oral squamous cell carcinoma (OSCC), an anatomical and clinical subtype that corresponds to the great majority oral cancers. Although the cellular and molecular bases of oral cancer pain have not been fully established yet, the results of recent studies suggest that different epigenetic mechanisms may contribute to this process. For instance, there is strong scientific evidence that microRNAs (miRNAs), small RNA molecules that do not encode proteins, might act by regulating the mechanisms underlying cancer-related pain. Among the miRNAs that could possibly interfere in pain-signaling pathways, miR-125b, miR-181, and miR-339 emerge as some of the most promising candidates. In fact, such molecules apparently contribute to inflammatory pain. Moreover, these molecules possibly influence the activity of endogenous pain control systems (e.g., opioidergic and serotonergic systems), which could ultimately result in peripheral and central sensitization, central nervous system (CNS) phenomena innately associated with chronic pain. This review paper focuses on the current scientific knowledge regarding the involvement of miRNAs in cancer pain, with special attention dedicated to OSCC-related pain.

Immediate effects of tDCS on the µ-opioid system of a chronic pain patient.

We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a µ-opioid receptor (µOR) selective radiotracer, [(11)C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured µOR non-displaceable binding potential (µOR BP(ND)) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient's clinical pain. Interestingly, the single active tDCS application considerably decreased µORBP(ND) levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the µ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous µ-opioid release during acute motor cortex neuromodulation with tDCS.

Thickening in the somatosensory cortex of patients with migraine.

OBJECTIVE: To examine morphologic changes in the somatosensory cortex (SSC) of patients with migraine. METHODS: Cortical thickness of the SSC of patients with migraine was measured in vivo and compared with age- and sex-matched healthy subjects. The cohort was composed of 24 patients with migraine, subdivided into 12 patients who had migraine with aura, 12 patients who had migraine without aura, and 12 controls. Group and individual analyses were performed in the SSC and shown as average maps of significant changes in cortical thickness. RESULTS: Migraineurs had on average thicker SSCs than the control group. The most significant thickness changes were noticed in the caudal SSC, where the trigeminal area, including head and face, is somatotopically represented. CONCLUSIONS: Our findings indicate the presence of interictal structural changes in the somatosensory cortex (SSC) of migraineurs. The SSC plays a crucial role in the noxious and nonnoxious somatosensory processing. Thickening in the SSC is in line with diffusional abnormalities observed in the subcortical trigeminal somatosensory pathway of the same migraine cohort in a previous study. Repetitive migraine attacks may lead to, or be the result of, neuroplastic changes in cortical and subcortical structures of the trigeminal somatosensory system.

Interictal alterations of the trigeminal somatosensory pathway and periaqueductal gray matter in migraine.

Migraine has been traditionally considered a nonprogressive, paroxysmal disorder with no brain abnormalities between attacks. We used diffusion tensor imaging to examine interictal diffusion properties of the brains of migraineurs with aura, migraineurs without aura and matched healthy controls. Areas of lower fractional anisotropy were present in migraineurs along the thalamocortical tract. In addition, migraineurs with aura had lower fractional anisotropy in the ventral trigeminothalamic tract, and migraineurs without aura had lower fractional anisotropy in the ventrolateral periaqueductal grey matter. Our results indicate the presence of permanent interictal changes in migraineurs, pointing to an effect of migraine on the trigeminal somatosensory and modulatory pain systems.

Cluster headache: a review of neuroimaging findings.

Classified as a trigeminal autonomic cephalalgia, cluster headache is characterized by recurrent short-lived excruciating pain attacks, which are concurrent with autonomic signs. These clinical features have led to the assumption that cluster headache's pathophysiology involves central nervous system structures, including the hypothalamus. In the past decade, neuroimaging studies have confirmed such clinically derived theory by uncovering in vivo neuronal changes located in the inferior posterior hypothalamus. Using a variety of neuro-imaging techniques (functional , biochemical , and structural ) in patients with cluster headache, we are making improvements in our understanding of the role of the brain in this disorder. This article summarizes neuroimaging findings in cluster headache patients, describing neuronal changes that occur during attacks and remission, as well as during hypothalamic stimulation.

Anatomical alterations of the visual motion processing network in migraine with and without aura.

BACKGROUND: Patients suffering from migraine with aura (MWA) and migraine without aura (MWoA) show abnormalities in visual motion perception during and between attacks. Whether this represents the consequences of structural changes in motion-processing networks in migraineurs is unknown. Moreover, the diagnosis of migraine relies on patient's history, and finding differences in the brain of migraineurs might help to contribute to basic research aimed at better understanding the pathophysiology of migraine. METHODS AND FINDINGS: To investigate a common potential anatomical basis for these disturbances, we used high-resolution cortical thickness measurement and diffusion tensor imaging (DTI) to examine the motion-processing network in 24 migraine patients (12 with MWA and 12 MWoA) and 15 age-matched healthy controls (HCs). We found increased cortical thickness of motion-processing visual areas MT+ and V3A in migraineurs compared to HCs. Cortical thickness increases were accompanied by abnormalities of the subjacent white matter. In addition, DTI revealed that migraineurs have alterations in superior colliculus and the lateral geniculate nucleus, which are also involved in visual processing. CONCLUSIONS: A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The finding in patients with both MWA and MWoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether a "silent" cortical spreading depression develops as well in MWoA. In addition, these experimental data may provide clinicians and researchers with a noninvasively acquirable migraine biomarker.

Specific and somatotopic functional magnetic resonance imaging activation in the trigeminal ganglion by brush and noxious heat.

We used functional magnetic resonance imaging (fMRI) to assess activation in the trigeminal ganglion during innocuous mechanical (brush) and noxious thermal (46 degrees C) stimulation of the face within the receptive fields of each of the three divisions of the trigeminal nerve in healthy volunteers. For both stimulus types, we observed signal changes only in the ipsilateral ganglion, and activation occurred somatotopically, as predicted by the known anatomical segregation of the neurons comprising the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions of the nerve. Signal decreased after brush stimuli and increased after the application of noxious heat. The abilities to detect somatotopic activation within the ganglion and to segregate non-noxious mechanical from noxious thermal stimuli suggest that fMRI will be valuable for measuring changes in the trigeminal ganglion in human models of neuropathic pain and in the clinical condition itself and may also be useful in the evaluation of pain therapies.

A primer on diffusion tensor imaging of anatomical substructures.

In this article, the authors review the application of diffusion tensor (DT) magnetic resonance (MR) imaging to demonstrate anatomical substructures that cannot be resolved by conventional structural imaging. They review the physical basis of DT imaging and provide illustrative anatomical examples. The DT imaging technique measures the self-diffusion, or random thermal motion, of the endogenous water in nerve tissue. Because of the preferred diffusion of water molecules along the nerve fiber direction, DT imaging can measure the orientation of the neural fiber structure within each voxel of the MR image. The fiber orientation information yielded by DT imaging provides a new contrast mechanism that can be used to resolve images of anatomical substructures that cannot otherwise be visualized using conventional structural imaging. The authors illustrate how DT imaging can resolve individual pathways in the brainstem as well as individual nuclei of the thalamus and conclude by describing potential applications in neurosurgery.