Functional brainstem representations of the human trigeminal cervical complex.

BACKGROUND: The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is still not well understood. METHODS: After preregistration (clinicaltrials.gov: NCT03999060), we mapped the functional representations of this trigemino-cervical complex non-invasively in 87 humans using high-resolution protocols for functional magnetic resonance imaging during painful electrical stimulation in two separate experiments. The imaging protocol and analysis was optimized for the lower brainstem and upper spinal cord, to identify activation of the spinal trigeminal nuclei. The stimulation protocol involved four electrodes which were positioned on the left side according to the three branches of the trigeminal nerve and the greater occipital nerve. The stimulation site was randomized and each site was repeated 10 times per session. The participants partook in three sessions resulting in 30 trials per stimulation site. RESULTS: We show a large overlap of peripheral dermatomes on brainstem representations and a somatotopic arrangement of the three branches of the trigeminal nerve along the perioral-periauricular axis and for the greater occipital nerve in brainstem below pons, as well as in thalamus, insula and cerebellum. The co-localization of greater occipital nerve with V1 along the lower part of brainstem is of particular interest since some headache patients profit from an anesthetic block of the greater occipital nerve. CONCLUSION: Our data provide anatomical evidence for a functional inter-inhibitory network between the trigeminal branches and greater occipital nerve in healthy humans as postulated in animal work. We further show that functional trigeminal representations intermingle perioral and periauricular facial dermatomes with individual branches of the trigeminal nerve in an onion shaped manner and overlap in a typical within-body-part somatotopic arrangement.Trial registration: clinicaltrials.gov: NCT03999060.

Aura phenomena do not initiate migraine attacks-Findings from neuroimaging.

OBJECTIVES/BACKGROUND: As cortical spreading depolarization (CSD) has been suggested to be the cause of migraine aura and as CSD can activate trigeminal nociceptive neurons in animals, it has been suggested that CSD may be the cause of migraine attacks. This raises the question of how migraine pain is generated in migraine attacks without aura and has led to the hypothesis that CSD may also occur in subcortical regions in the form of "silent" CSDs, and accordingly "silent auras". METHODS: In this case study, we provide evidence for common neuronal alterations preceding headache attacks with and without aura in a male patient with migraine, who underwent daily event-correlated functional magnetic resonance imaging of trigeminal nociception for a period of 30 days. During these days the man experienced migraine attacks with and without aura. RESULTS: Comparing the preictal phases between both attack types revealed a common hyperactivation of the hypothalamus (p < 0.01), which was already present 2 days before the actual attack. CONCLUSION: The time frame of the central pathophysiological orchestration of migraine attacks, irrelevant of the presence of later aura, strongly suggests that the aura is an epiphenomenon that is unrelated and does not initiate headache attacks.

Indomethacin has no effect on trigeminally provoked parasympathetic output.

BACKGROUND: Unlike other non-steroidal anti-inflammatory drugs, indomethacin has been shown to be highly effective in two forms of trigeminal autonomic cephalalgias, hemicrania continua and paroxysmal hemicrania and in some forms of idiopathic stabbing headaches. This specificity is unique in the headache field. Previous findings suggest the involvement of the trigeminal autonomic reflex to play an important role in the pathophysiology of these diseases. METHODS: 22 healthy participants were enrolled in a double-blind, three-day within-subject design. The participants received indomethacin, ibuprofen or placebo in a randomized order. After an incubation period of 65 min the baseline lacrimation and the lacrimation during intranasal stimulation evoked by kinetic oscillation stimulation were assessed using Schirmer II lacrimation tests. The lacrimation difference in mm was calculated and compared in a repeated measures ANOVA. RESULTS: No significant differences were found between the three conditions. CONCLUSION: In our study, neither indomethacin nor ibuprofen had an inhibitory effect on the trigeminal autonomic reflex. We suggest that blocking this reflex may not be the treatment mechanism of indomethacin.

Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine.

OBJECTIVE: Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. METHODS: Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. RESULTS: Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. INTERPRETATION: Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.

Greater occipital nerve block modulates nociceptive signals within the trigeminocervical complex.

INTRODUCTION: The pharmacological block of the greater occipital nerve has been proven effective in numerous headache and facial pain syndromes. This clinical effect supports the hypothesis of a strong functional interaction between the occipital and trigeminal nerves which has been proposed in neurophysiological in vivo experiments in rodents. Although it is likely that the interaction has to occur in the central nervous system, the exact site and the mechanisms of the interaction remain largely unknown. METHODS: Focusing on these questions we investigated in a double-blind, placebo-controlled, randomised study the influence of an occipital nerve block with lidocaine 1% on neuronal activation in the trigeminocervical complex using high-resolution functional magnetic resonance on a 3T scanner. In order to investigate potential clinical effects on the trigeminal nerve, we further performed quantitative sensory testing and analysed a potential shift in thermal detection and pain thresholds. RESULTS: The pharmacological block of the greater occipital nerve induced an occipital anaesthesia ipsilateral to the block. Functional imaging revealed that the occipital injection of lidocaine but not placebo significantly reduced nociceptive trigeminal activation. CONCLUSIONS: These data suggest that the functional inhibition of the occipital nerve block on trigeminal nociceptive activity is likely to occur at the C2 level where the occipital nerve enters the trigeminocervical complex and converges on the same central nuclei before the signal crosses the midline at that level and is then transmitted to higher processing centres.

Hypothalamic activation discriminates painful and non-painful initiation of the trigeminal autonomic reflex - an fMRI study.

BACKGROUND: The role of the trigeminal autonomic reflex in headache syndromes, such as cluster headache, is undisputed but sparsely investigated. The aim of the present study was therefore, to identify neural correlates that play a role in the initiation of the trigeminal autonomic reflex. We further aimed to discriminate between components of the reflex that are involved in nociceptive compared to non-nociceptive processing. METHODS: Kinetic Oscillation Stimulation (KOS) in the left nostril was applied in order to provoke autonomic symptoms (e.g. lacrimation) via the trigeminal autonomic reflex in 26 healthy participants using functional magnetic resonance imaging. Unpleasantness and painfulness were assessed on a visual analog scale (VAS), in order to assess the quality of the stimulus (e.g. pain or no pain). RESULTS: During non-painful activation, specific regions involved in the trigeminal autonomic reflex became activated, including several brainstem nuclei but also cerebellar and bilateral insular regions. However, when the input leading to activation of the trigeminal autonomic reflex was perceived as painful, activation of the anterior hypothalamus, the locus coeruleus (LC), the ventral posteriomedial nucleus of the thalamus (VPM), as well as an activation of ipsilateral insular regions, was observed. CONCLUSION: Our results suggest the anterior hypothalamus, besides the thalamus and specific brain stem regions, play a significant role in networks that mediate autonomic output (e.g. lacrimation) following trigeminal input, but only if the trigeminal system is activated by a stimulus comprising a painful component.

Reshaping cortical activity with subthalamic stimulation in Parkinson's disease during finger tapping and gait mapped by near infrared spectroscopy.

Exploration of motor cortex activity is essential to understanding the pathophysiology in Parkinson's Disease (PD), but only simple motor tasks can be investigated using a fMRI or PET. We aim to investigate the cortical activity of PD patients during a complex motor task (gait) to verify the impact of deep brain stimulation in the subthalamic nucleus (DBS-STN) by using Near-Infrared-Spectroscopy (NIRS). NIRS is a neuroimaging method of brain cortical activity using low-energy optical radiation to detect local changes in (de)oxyhemoglobin concentration. We used a multichannel portable NIRS during finger tapping (FT) and gait. To determine the signal activity, our methodology consisted of a pre-processing phase for the raw signal, followed by statistical analysis based on a general linear model. Processed recordings from 9 patients were statistically compared between the on and off states of DBS-STN. DBS-STN led to an increased activity in the contralateral motor cortex areas during FT. During gait, we observed a concentration of activity towards the cortex central area in the "stimulation-on" state. Our study shows how NIRS can be used to detect functional changes in the cortex of patients with PD with DBS-STN and indicates its future use for applications unsuited for PET and a fMRI.

Satiety-induced enhanced neuronal activity in the frontal operculum relates to the desire for food in the obese female brain.

In the present pilot study, we questioned how eating to satiety affects cognitive influences on the desire for food and corresponding neuronal activity in the obese female brain. During EEG recording, lean (n = 10) and obese women (n = 10) self-rated the ability to reappraise visually presented food. All women were measured twice, when hungry and after eating to satiety. After eating to satiety, reappraisal of food was easier than when being hungry. Comparing the EEG data of the sated to the hungry state, we found that only in obese women the frontal operculum was involved not only in the reappraisal of food but also in admitting the desire for the same food. The right frontal operculum in the obese female brain, assumed to primarily host gustatory processes, may be involved in opposing cognitive influences on the desire for food. These findings may help to find potential brain targets for non-invasive brain stimulation or neurofeedback studies that aim at modulating the desire for food.

Altered muscle activity during rest and during mental or physical activity is not a trait symptom of migraine - a neck muscle EMG study.

BACKGROUND: Migraineurs have a high prevalence of neck pain prior to or during headache attacks. Whether neck pain is a symptom of migraine or an indicator for a constant neck muscle dysfunction potentially triggering migraine attacks is a topic of scientific debate. The presence of myofascial trigger points in neck muscles including the trapezius muscle, points towards muscle alterations associated with migraine. We measured electromyography (EMG) of the neck muscles in a large cohort to identify whether neck pain and neckmuscle tension reported by migraine patients can be attributed to increased neck muscle activation during rest, mental stress or physical activity. METHODS: Surface EMG responses of the trapezius muscle were recorded during a paradigm including rest periods, mental stress and physical activity of 102 participants (31 chronic migraine, 43 episodic migraine, 28 healthy participants). RESULTS: All groups showed increased trapezius activity during mental stress and physical activity compared to rest. There was no statistically significant difference between migraine patients and healthy controls for any of the 3 conditions except for the initial mental stress situation (F (2,56.022) = 8.302, p = 0.001), where controls increased tension by only 4.75%, episodic migraineurs by 17.39% and chronic migraineurs by 28.61%. Both migraine groups returned to resting EMG levels within the same timeframe as healthy controls. CONCLUSIONS: Neck pain associated with migraine can therefore not be attributed to increased trapezius activity during rest, mental stress and physical activity or prolonged muscle activity and should not be seen as a constantly underlying trigger but rather as an accompanying symptom of migraine.

Activity and connectivity of the cerebellum in trigeminal nociception.

The role of the cerebellum in pathologies of the trigeminal nervous system is still unknown although recently gathered evidence point to a modulatory rather than a passive role. Here we provide evidence for the activation of specific cerebellar areas during nociceptive trigeminal input in the left nostril in a large number of volunteers (54 subjects) and an additional independent group (18 subjects) as measured by functional magnetic resonance imaging (fMRI). Peak voxel activity ipsilateral to the stimulated side can be seen in cerebellar lobules VI, VIIIa and Crus I, and vermal lobule VIIIa, although some activations are also seen in the contralateral side. The individuals' intensity and unpleasantness ratings are mostly processed in the hemispheric lobules VI stretching to V, representing the face areas of the cerebellar's fractured homunculus. We found a robust functional connectivity during nociception between the cerebellum and the rostral part of the pons as well as the periaqueductal grey and the thalamus, involving the descending antinociceptive network as well as areas known to form close loops with the cerebellum in the motor domain. Cerebellar connectivity with higher cortical areas include most of the known hubs in pain processing which are the insular cortex, operculum and putamen, and the face areas in the precentral gyrus. The current data provide a solid basis for further research of the cerebellar's activity and connectivity in primary headache and facial pain syndromes.

Rapid and specific gray matter changes in M1 induced by balance training.

Training-induced changes in cortical structure can be observed non-invasively with magnetic resonance imaging (MRI). While macroscopic changes were found mainly after weeks to several months of training in humans, imaging of motor cortical networks in animals revealed rapid microstructural alterations after a few hours of training. We used MRI to test the hypothesis of immediate and specific training-induced alterations in motor cortical gray matter in humans. We found localized increases in motor cortical thickness after 1h of practice in a complex balancing task. These changes were specific to motor cortical effector representations primarily responsible for balance control in our task (lower limb and trunk) and these effects could be confirmed in a replication study. Cortical thickness changes (i) linearly increased across the training session, (ii) occurred independent of alterations in resting cerebral blood flow and (iii) were not triggered by repetitive use of the lower limbs. Our findings show that motor learning triggers rapid and specific gray matter changes in M1.

Neural control of vascular reactions: impact of emotion and attention.

This study investigated the neural regions involved in blood pressure reactions to negative stimuli and their possible modulation by attention. Twenty-four healthy human subjects (11 females; age = 24.75 ± 2.49 years) participated in an affective perceptual load task that manipulated attention to negative/neutral distractor pictures. fMRI data were collected simultaneously with continuous recording of peripheral arterial blood pressure. A parametric modulation analysis examined the impact of attention and emotion on the relation between neural activation and blood pressure reactivity during the task. When attention was available for processing the distractor pictures, negative pictures resulted in behavioral interference, neural activation in brain regions previously related to emotion, a transient decrease of blood pressure, and a positive correlation between blood pressure response and activation in a network including prefrontal and parietal regions, the amygdala, caudate, and mid-brain. These effects were modulated by attention; behavioral and neural responses to highly negative distractor pictures (compared with neutral pictures) were smaller or diminished, as was the negative blood pressure response when the central task involved high perceptual load. Furthermore, comparing high and low load revealed enhanced activation in frontoparietal regions implicated in attention control. Our results fit theories emphasizing the role of attention in the control of behavioral and neural reactions to irrelevant emotional distracting information. Our findings furthermore extend the function of attention to the control of autonomous reactions associated with negative emotions by showing altered blood pressure reactions to emotional stimuli, the latter being of potential clinical relevance.

Monochromatic ultra-slow (~0.1 Hz) oscillations in the human electroencephalogram and their relation to hemodynamics.

Previous studies demonstrated the presence of Monochromatic Ultra-Slow Oscillations (MUSO) in human EEG. In the present study we explored the biological origin of MUSO by simultaneous recordings of EEG, Near-Infrared Spectroscopy (NIRS), arterial blood pressure, respiration and Laser Doppler flowmetry. We used a head-up tilt test in order to check whether MUSO might relate to Mayer waves in arterial blood pressure, known to be enhanced by the tilting procedure. MUSO were detected in 8 out of 10 subjects during rest and showed a striking monochromatic spectrum (0.07-0.14 Hz). The spatial topography of MUSO was complex, showing multiple foci variable across subjects. While the head-up tilt test increased the relative power of Mayer waves, it had no effect on MUSO. On the other hand, the relative spectral power of 0.1 Hz oscillations in EEG, NIRS and blood pressure signals were positively correlated across subjects in the tilted condition. Eight subjects showed a coherence between MUSO and NIRS/arterial blood pressure. Moreover, MUSO at different electrode sites demonstrated coherence not reducible to volume conduction, thus indicating that MUSO are unlikely to be generated by one source. We related our experimental findings to known biological phenomena being generated at about 0.1 Hz, i.e.: arterial blood pressure, cerebral and skin vasomotion, respiration and neuronal activity. While no definite conclusion can yet be drawn as to an exact physiological mechanism of MUSO, we suggest that these oscillations might be of a rather extraneuronal origin reflecting cerebral vasomotion.

A wearable multi-channel fNIRS system for brain imaging in freely moving subjects.

Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subject's head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related ΔHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans.

Cerebellar somatotopy of the trigemino-cervical complex during nociception.

INTRODUCTION: The somatotopic organization of the human cerebellum processes somato-motoric input. Its role during pain perception for nociceptive input remains ambiguous. A standardized experimental trigeminal nociceptive input in functional imaging might clarify the role of the cerebellum in trigeminal nociception. Also of interest is the greater occipital nerve, which innervates the back of the head, and can influence the trigeminal perception due to functional coupling within the brainstem, forming the so-called trigemino-cervical complex. METHODS: In our preregistered study (clinicaltrials.gov: NTC03999060), we stimulated the greater occipital as well as the three main branches of the trigeminal nerve during functional magnetic resonance imaging in two independent cohorts of young healthy volunteers without psychiatric, neurological or pain-related disorders to disentangle overlapping somatotopic cerebellar organization of the nerves innervating the human head. RESULTS: We found a dominant effect of the first trigeminal branch in the cerebellum, underpinning its particular role for headache diseases, and somatotopic representations in bilateral cerebellar lobules I-IV, V, VIIb, VIIIa and Crus I as well as in the brainstem. SIGNIFICANCE: The study expands the current knowledge on facial and head pain processing by the cerebellum and provides an initial somatotopic map of the trigemino-cervical complex in the human cerebellum with a predominant representation of the first trigeminal branch.

Functional representation of trigeminal nociceptive input in the human periaqueductal gray.

The periaqueductal gray (PAG) is located in the mesencephalon in the upper brainstem and, as part of the descending pain modulation, is considered a crucial structure for pain control. Its modulatory effect on painful sensation is often seen as a systemic function affecting the whole body similarly. However, recent animal data suggest some kind of somatotopy in the PAG. This would make the PAG capable of dermatome-specific analgesic function. We electrically stimulated the three peripheral dermatomes of the trigemino-cervical complex and the greater occipital nerve in 61 humans during optimized brainstem functional magnetic resonance imaging. We provide evidence for a fine-grained and highly specific somatotopic representation of nociceptive input in the PAG in humans and a functional connectivity between the individual representations of the peripheral nerves in the PAG and the brainstem nuclei of these nerves. Our data suggest that the downstream antinociceptive properties of the PAG may be rather specific down to the level of individual dermatomes.

Enhanced performance by a hybrid NIRS-EEG brain computer interface.

Noninvasive Brain Computer Interfaces (BCI) have been promoted to be used for neuroprosthetics. However, reports on applications with electroencephalography (EEG) show a demand for a better accuracy and stability. Here we investigate whether near-infrared spectroscopy (NIRS) can be used to enhance the EEG approach. In our study both methods were applied simultaneously in a real-time Sensory Motor Rhythm (SMR)-based BCI paradigm, involving executed movements as well as motor imagery. We tested how the classification of NIRS data can complement ongoing real-time EEG classification. Our results show that simultaneous measurements of NIRS and EEG can significantly improve the classification accuracy of motor imagery in over 90% of considered subjects and increases performance by 5% on average (p<0:01). However, the long time delay of the hemodynamic response may hinder an overall increase of bit-rates. Furthermore we find that EEG and NIRS complement each other in terms of information content and are thus a viable multimodal imaging technique, suitable for BCI.

Somatosensory activation of two fingers can be discriminated with ultrahigh-density diffuse optical tomography.

Topographic non-invasive near infrared spectroscopy (NIRS) has become a well-established tool for functional brain imaging. Applying up to 100 optodes over the head of a subject, allows achieving a spatial resolution in the centimeter range. This resolution is poor compared to other functional imaging tools. However, recently it was shown that diffuse optical tomography (DOT) as an extension of NIRS based on high-density (HD) probe arrays and supplemented by an advanced image reconstruction procedure allows describing activation patterns with a spatial resolution in the millimeter range. Building on these findings, we hypothesize that HD-DOT may render very focal activations accessible which would be missed by the traditionally used sparse arrays. We examined activation patterns in the primary somatosensory cortex, since its somatotopic organization is very fine-grained. We performed a vibrotactile stimulation study of the first and fifth finger in eight human subjects, using a 900-channel continuous-wave DOT imaging system for achieving a higher resolution than conventional topographic NIRS. To compare the results to a well-established high-resolution imaging technique, the same paradigm was investigated in the same subjects by means of functional magnetic resonance imaging (fMRI). In this work, we tested the advantage of ultrahigh-density probe arrays and show that highly focal activations would be missed by classical next-nearest neighbor NIRS approach, but also by DOT, when using a sparse probe array. Distinct activation patterns for both fingers correlated well with the expected neuroanatomy in five of eight subjects. Additionally we show that activation for different fingers is projected to different tissue depths in the DOT image. Comparison to the fMRI data yielded similar activation foci in seven out of ten finger representations in these five subjects when comparing the lateral localization of DOT and fMRI results.

High-Density Electroencephalography-Informed Multiband Functional Magnetic Resonance Imaging Reveals Rhythm-Specific Activations Within the Trigeminal Nociceptive Network.

The interest in exploring trigeminal pain processing has grown in recent years, mainly due to various pathologies (such as migraine) related to this system. However, research efforts have mainly focused on understanding molecular mechanisms or studying pathological states. On the contrary, non-invasive imaging studies are limited by either spatial or temporal resolution depending on the modality used. This can be overcome by using multimodal imaging techniques such as simultaneous functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Although this technique has already been applied to neuroscientific research areas and consequently gained insights into diverse sensory systems and pathologies, only a few studies have applied EEG-fMRI in the field of pain processing and none in the trigeminal system. Focusing on trigeminal nociception, we used a trigeminal pain paradigm, which has been well-studied in either modality. For validation, we first acquired stand-alone measures with each imaging modality before fusing them in a simultaneous session. Furthermore, we introduced a new, yet simple, non-parametric correlation technique, which exploits trial-to-trial variance of both measurement techniques with Spearman's correlations, to consolidate the results gained by the two modalities. This new technique does not presume a linear relationship and needs a few repetitions per subject. We also showed cross-validation by analyzing visual stimulations. Using these techniques, we showed that EEG power changes in the theta-band induced by trigeminal pain correlate with fMRI activation within the brainstem, whereas those of gamma-band oscillations correlate with BOLD signals in higher cortical areas.