Background

Free water (FW) in neuroimaging is non-flowing extracellular water in the cranium and brain tissue, and includes both cerebral spinal fluid (CSF) and fluid in intercellular space or edema. For a region such as a voxel (spatial unit of measurement in neuroimaging), the FW fraction is defined as the volume fraction of FW within that volume. Quantifying the FW fraction allows estimating contamination by fluid of neuroimaging or magnetic resonance spectroscopy measurements within a voxel.

New method

An upper limit to the fraction of FW within a voxel, based on any diffusion tensor imaging (DTI) sequence including a standard single shell at one b-value, can be derived from the standard diffusion tensor by scaling the third eigenvalue of the diffusion tensor. Assuming a two-compartment model, the diffusivity of a voxel is a combination of tissue and FW diffusivity. FW fraction is FW volume divided by voxel volume. Assuming FW diffuses equally in all directions, the diffusivity component is representable by a single, non-tensor diffusivity value. Since the diffusivity of water is known for a given temperature, and brain temperature is relatively constant, the FW diffusivity value can be assumed constant. The third eigenvector of the voxel diffusion tensor is the direction of least diffusivity and since the FW component of diffusivity is equal in all directions, we show that FW diffusivity cannot be lower than the third eigenvalue. Assuming FW contributes proportionally to voxel diffusivity, we show that the third eigenvalue divided by water diffusivity (as a constant based on known water diffusivity at 36.7 °C) forms an upper limit on the FW-fraction (f_UL ).

Results

We calculated f_UL for 384 subjects from the IXI dataset. Values mostly ranged from 0.1 to 0.6, and were closely related to radial diffusivity.Comparison with Existing Methods:f_UL is easily calculated from any DTI data, but is not a true estimate of FW-fraction.

Conclusions

The f_UL measure offers a starting point in calculating the true FW-fraction of a voxel, or an easy-to-calculate voxel characteristic.

Study objectives

Obstructive sleep apnea (OSA) is defined by pauses in breathing during sleep, but daytime breathing dysregulation may also be present. Sleep may unmask breathing instability in OSA that is usually masked by behavioral influences during wakefulness. A breath-hold (BH) challenge has been used to demonstrate breathing instability. One measure of breathing stability is breathing rate variability (BRV). We aimed to assess BRV during rest and in response to BH in OSA.

Methods

We studied 62 participants (31 with untreated OSA: respiratory event index [mean ± SD] 20 ± 15 events/h, 12 females, age 51 ± 14 years, body mass index [BMI] 32 ± 8 kg/m²; 31 controls: 17 females, age 47 ± 13 years; BMI 26 ± 4 kg/m²). Breathing movements were collected using a chest belt for 5 minutes of rest and during a BH protocol (60 seconds baseline, 30 seconds BH, 90 seconds recovery, 3 repeats). From the breathing movements, we calculated median breathing rate (BR) and interquartile BRV at rest. We calculated change in BRV during BH recovery from baseline. Group comparisons of OSA vs control were conducted using analysis of covariance with age, sex, and BMI as covariates.

Results

We found 10% higher BRV in OSA vs controls (P < .05) during rest. In response to BH, BRV increased 7% in OSA vs 1% in controls (P < .001). Resting BR was not significantly different in OSA and controls, and sex and age did not have any significant interaction effects. BMI was associated with BR at rest (P < .05) and change in BRV with BH (P < .001), but no significant BMI-by-group interaction effect was observed.

Conclusions

The findings suggest breathing instability as reflected by BRV is high in OSA during wakefulness, both at rest and in response to a stimulus. Breathing instability together with high blood pressure variability in OSA may reflect a compromised cardiorespiratory consequence in OSA during wakefulness.

Citation

Pal A, Martinez F, Akey MA, et al. Breathing rate variability in obstructive sleep apnea during wakefulness. J Clin Sleep Med. 2022;18(3):825-833.

The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = -0.58, p = 0.003; migraineurs r = -0.25, p = 0.17 and V1 controls r = -0.52, p = 0.002; migraineurs r = -0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

Background

The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli.

Methods

Functional magnetic resonance imaging was performed in 29 healthy controls and 25 migraineurs during the interictal and immediately (within 24-h) prior to migraine phases. We assessed activation of higher cortical areas during noxious orofacial heat stimulation using a thermode device and assessed whole scan and pain-related changes in connectivity.

Results

Despite similar overall pain intensity ratings between all three groups, migraineurs in the group immediately prior to migraine displayed greater activation of the ipsilateral nucleus accumbens, the contralateral ventrolateral prefrontal cortex and two clusters in the dorsolateral prefrontal cortex (dlPFC). Reduced whole scan dlPFC [Z + 44] connectivity with cortical/subcortical and brainstem regions involved in pain modulation such as the putamen and primary motor cortex was demonstrated in migraineurs. Pain-related changes in connectivity of the dlPFC and the hypothalamus immediately prior to migraine was also found to be reduced with brainstem pain modulatory areas such as the rostral ventromedial medulla and dorsolateral pons.

Conclusions

These data reveal that the modulation of brainstem pain modulatory areas by higher cortical regions may be aberrant during pain and these alterations in this descending pain modulatory pathway manifests exclusively prior to the development of a migraine attack.

BACKGROUND:There is histological evidence of microstructural changes in the zygomaticotemporal branch of the trigeminal nerve in migraineurs. This raises the possibility that altered trigeminal nerve properties contribute to migraine pathophysiology. Whilst it is not possible to explore the anatomy of small trigeminal nerve branches it is possible to explore the anatomy of the trigeminal root entry zone using magnetic resonance imaging in humans. The aim of this investigation is to assess the microstructure of the trigeminal nerve in vivo to determine if nerve alterations occur in individuals with episodic migraine. METHODS:In 39 migraineurs and 39 matched controls, T1-weighted anatomical images were used to calculate the volume (mm3) and maximal cross-sectional area of the trigeminal nerve root entry zone; diffusion tensor images were used to calculate fractional anisotropy, mean diffusion, axial diffusion and radial diffusion. RESULTS:There were significant differences between the left and right nerve of controls and migraineurs with respect to volume and not cross-sectional area. Migraineurs displayed reduced axial diffusion in the right nerve compared to the left nerve, and reduced fractional anisotropy in the left nerve compared to left controls. Furthermore, although there were no differences in mean diffusion or radial diffusion, regional analysis of the nerve revealed significantly greater radial diffusion in the middle and rostral portion of the left trigeminal nerve in migraineurs compared with controls. CONCLUSIONS:Migraine pathophysiology is associated with microstructural abnormalities within the trigeminal nerve that are consistent with histological evidence of altered myelin and/or organization. These peripheral nerve changes may provide further insight into migraine pathophysiology and enable a greater understanding for targeted treatments of pain alleviation.

Background The exact mechanisms responsible for migraine remain unknown, although it has been proposed that changes in brainstem anatomy and function, even between attacks, may contribute to the initiation and maintenance of headache during migraine attacks. The aim of this investigation is to use brainstem-specific analyses of anatomical and diffusion weighted images to determine if the trigeminal system displays altered structure in individuals with migraine. Methods Voxel-based morphometry of T1-weighted anatomical images (57 controls, 24 migraineurs) and diffusion tensor images (22 controls, 24 migraineurs) were used to assess brainstem anatomy in individuals with migraine compared with controls. Results We found grey matter volume decreases in migraineurs in the spinal trigeminal nucleus and dorsomedial pons. In addition, reduced grey matter volume and increased free water diffusivity occurred in areas of the descending pain modulatory system, including midbrain periaqueductal gray matter, dorsolateral pons, and medullary raphe. These changes were not correlated to migraine frequency, duration, intensity or time to next migraine. Conclusion Brainstem anatomy changes may underlie changes in activity that result in activation of the ascending trigeminal pathway and the perception of head pain during a migraine attack.

Although the mechanisms responsible for migraine initiation remain unknown, recent evidence shows that brain function is different immediately preceding a migraine. This is consistent with the idea that altered brain function, particularly in brainstem sites, may either trigger a migraine or facilitate a peripheral trigger that activates the brain, resulting in pain. The aim of this longitudinal study is therefore to expand on the above findings, and to determine if brainstem function oscillates over a migraine cycle in individual subjects. We performed resting state functional magnetic resonance imaging in three migraineurs and five controls each weekday for four weeks. We found that although resting activity variability was similar in controls and interictal migraineurs, brainstem variability increased dramatically during the 24-hour period preceding a migraine. This increase occurred in brainstem areas in which orofacial afferents terminate: the spinal trigeminal nucleus and dorsal pons. These increases were characterized by increased power at infra-slow frequencies, principally between 0.03 and 0.06 Hz. Furthermore, these power increases were associated with increased regional homogeneity, a measure of local signal coherence. The results show within-individual alterations in brain activity immediately preceding migraine onset and support the hypothesis that altered regional brainstem function before a migraine attack is involved in underlying migraine neurobiology.

The neural mechanism responsible for migraine remains unclear. While the role of an external trigger in migraine initiation remains vigorously debated, it is generally assumed that migraineurs display altered brain function between attacks. This idea stems from relatively few brain imaging studies with even fewer studies exploring changes in the 24 h period immediately prior to a migraine attack. Using functional magnetic resonance imaging, we measured infra-slow oscillatory activity, regional homogeneity, and connectivity strengths of resting activity in migraineurs directly before (n = 8), after (n = 11), and between migraine attacks (n = 26) and in healthy control subjects (n = 78). Comparisons between controls and each migraine group and between migraine groups were made for each of these measures. Directly prior to a migraine, increased infra-slow oscillatory activity occurred in brainstem and hypothalamic regions that also display altered activity during a migraine itself, that is, the spinal trigeminal nucleus, dorsal pons, and hypothalamus. Furthermore, these midbrain and hypothalamic sites displayed increased connectivity strengths and regional homogeneity directly prior to a migraine. Remarkably, these resting oscillatory and connectivity changes did not occur directly after or between migraine attacks and were significantly different to control subjects. These data provide evidence of altered brainstem and hypothalamic function in the period immediately before a migraine and raise the prospect that such changes contribute to the expression of a migraine attack.

The neural mechanisms responsible for the initiation and expression of migraines remain unknown. Although there is growing evidence of changes in brainstem anatomy and function between attacks, very little is known about brainstem function and structure in the period immediately prior to a migraine. The aim of this investigation is to use brainstem-specific analyses of diffusion weighted images to determine whether the brainstem pain processing regions display altered structure in individuals with migraine across the migraine cycle, and in particular immediately prior to a migraine. Diffusion tensor images (29 controls, 36 migraineurs) were used to assess brainstem anatomy in migraineurs compared with controls. We found that during the interictal phase, migraineurs displayed greater mean diffusivity (MD) in the region of the spinal trigeminal nucleus (SpV), dorsomedial pons (dmPons)/dorsolateral pons (dlPons), and midbrain periaqueductal gray matter (PAG)/cuneiform nucleus (CNF). Remarkably, the MD returned to controls levels during the 24-h period immediately prior to a migraine, only to increase again within the three following days. Additionally, fractional anisotropy (FA) was significantly elevated in the region of the medial lemniscus/ventral trigeminal thalamic tract in migraineurs compared with controls over the entire migraine cycle. These data show that regional brainstem anatomy changes over the migraine cycle, with specific anatomical changes occurring in the 24-h period prior to onset. These changes may contribute to the activation of the ascending trigeminal pathway by either an increase in basal traffic or by sensitizing the trigeminal nuclei to external triggers, with activation ultimately resulting in perception of head pain during a migraine attack.