headache paper 04-12-2011 lr revision to larry...

Neurodynamics Research Institute Leith

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Title:

Abnormal baseline neuronal activity in chronic migraine

Authors:

Cameron C. Leith, Ph.D.

Neurodynamics Research Institute, Chicago, IL, USA

Lawrence D. Robbins, M.D.

Robbins Headache Clinic, Northbrook, IL, USA

Correspondence and proofs:

Dr. Cameron Leith

Neurodynamics Research Institute, 1601 Robin Hood Place, Highland Pl., IL 60035

Telephone: 847-607-9523; Fax: 847-607-9523;

Email: [email protected]

Disclosure:

This investigator initiated study was supported by a research grant from Pfizer.


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Abstract

Objective: There may be subclinical changes in baseline neuronal activity in the brains

of chronic migraine patients. Current functional brain imaging techniques, incapable of

detecting these changes, only indirectly estimate brain activation via hemodynamic

events in limited gray matter areas. We attempted to evaluate these changes in the

axonal fiber tracts using an adapted diffusion tensor MRI method (aDTI) that is

independent of regional blood supply. Methods: Twenty chronic migraine patients and

20 healthy controls were evaluated via aDTI. All 20 patients had transformed from

episodic migraine without aura to chronic migraine. Diffusion anisotropy (FA) was

derived from the diffusion tensor matrix. The statistical parametric mapping method

was employed to perform a group analysis on FA, so as to capture minute changes in

FA in patients compared to controls. These small changes were the direct result of

elevated neural impulse traffic along the axonal fiber tract.

Results: In the patient group, loci of reduced FA of statistical significance were found

in the pontine fibers, midbrain fiber tracts, and internal capsule. Reduced FA was also

identified in the white matter components of the central pain matrix, including the

anterior cingulate cortex, insula, and temporal lobe. In addition, reduced FA loci were

found in the corpus callosum splenium, uncinate fasciculus, cerebellar peduncle, and

cerebellar white matter. aDTI of the control patients, as a group, did not reveal any

white matter abnormalities. Conclusion: Multiple subclinical abnormal white matter

loci, representing neuronal hyperactivity, were identified in the brains of chronic

migraineurs, using the aDTI method. No abnormal loci were detected in our control

subjects.


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Introduction

The prevalence of migraine in the United States is 18.2% for women and 6.5% among

men, according to the American Migraine Study II. 1 Migraine is often a progressive

disease, with sporadic migraine in the teens and 20’s, increasing in frequency over

time, resulting in chronic migraine (CM) in approximately 20% of episodic

migraineurs. 2 Once the disease progresses to the CM stage (headache at least 15 days

per month or over 180 days per year), the condition may be exceedingly difficult to

treat. This study focuses on these patients with long-standing chronic migraine.

The theory of sensitization of the central nervous system in migraineurs 3,4 has been

widely accepted. The kindling hypothesis has been put forth in epilepsy, depression,

and headache. 5 However, conventional neuroimaging methods have been unable to

detect progressive changes in the brain caused by repeated subthreshold stimulation or

self-activation. One population-based study, using conventional MRI, concluded that

migraine was a risk factor for subclinical brain lesions, including white matter (WM)

lesions. That study’s results have come under scrutiny. 6 Additional studies appear to

support “migraine as a risk factor hypothesis” from the hemodynamic, perfusion, and

vascular perspectives. 7,8 An important question to answer is: “What happens in the

axonal fiber tracts before lesions become conspicuous on conventional MR images?” If

studies demonstrated a progressive change by pharmacological intervention in the

brains of those with long-standing migraine or CM, it would bolster the argument that

early intervention may prevent irreversible brain damage. 9


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Since the observation of brainstem activation in migraine, the dorsal midbrain and

dorsolateral pons have been a primary focus in neuroimaging studies (using the PET or

BOLD fMRI techniques). Weiller et al. 10 first demonstrated brainstem activation

persistence post-sumatriptan administration. Similar brainstem activation has been

found in both episodic migraine and CM. 11 Migraine pathophysiology has only been

partially elucidated. Central sensitization may affect the pain neuromatrix, including the

cingulate cortex, insula, thalamus, and temporal lobe, as revealed by functional brain

imaging. Dysfunctional, inhibitory descending pathways in the brainstem, particularly

the periaqueductal gray, may play a major role in CM pathogenesis. Nevertheless,

previous functional brain imaging findings are mostly localized in the brain gray matter

12, as both fMRI and PET are hemodynamic-based imaging modalities.

8 In contrast, we

have examined baseline neuronal activity in brain white matter axonal fiber tracts,

utilizing an advanced MR imaging technology. The method that we used was an

adapted form of diffusion tensor imaging (aDTI). Conventional DTI measures the

restricted diffusion of water, giving information about the trajectory of WM tracts, as

well as about WM inflammation, demyelination, and ischemia. Our adapted diffusion

tensor MRI method is a promising tool for assessing physiologic hyperactivity in the

WM. Changes in the cell membrane architecture result in differences in water

diffusion. aDTI may detect very tiny differences. aDTI may be particularly useful in

detecting disease progression, as well as response to therapy. This study uses aDTI to

detect abnormal baseline neural impulse traffic in the WM axonal fiber tracts of chronic

migraineurs.


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Methods

Participants. Twenty chronic migraine patients (see Table 1), 18 women and 2 men,

ages 19 to 47 years (average = 36), and 20 healthy controls, 18 women and 2 men, ages

28 to 51 (average = 44), were evaluated via our aDTI method. The age of headache

onset for the migraine patients ranged from 1 to 36 years (average = 13). The years of

chronic migraine ranged from 5 to 26 (average = 11). The headache patients had the

classification of chronic migraine according to the International Classification of

Headache Disorders (ICHD-2). 13 All 20 patients had transformed from migraine

without aura to chronic migraine. They were not medication overuse patients. They had

utilized preventive and analgesic medications, plus triptans. After complete description

of the study, written informed consent was obtained from each participant. The study

was approved by the independent Western Institutional Review Board (Olympia, WA)

Biophysical model of aDTI. Following the convention in diffusion tensor imaging, 14

we used orthogonal quantities λ1, λ2 and λ3 to represent directional water diffusion at

any point along an axonal fiber tract, with λ1 parallel and λ2, λ3 perpendicular to the

tract. Because water molecules moved more easily along the axonal tract than in radial

directions perpendicular to the tract, it was always true that λ1 was much greater than λ2

and λ3. More importantly to aDTI, there was slightly elevated λ2 and λ3 (reduced

diffusion anisotropy FA) when neurons fired and sent neural impulses through the fiber

tract. aDTI detected this minute FA reduction as a direct result of elevated neural

impulse traffic along the fiber tract.


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Imaging. All images were acquired using a 1.5 Tesla MRI system (GE Healthcare,

Waukesha, WI). We used a standard birdcage head coil with foam padding to minimize

involuntary subject head movement. All MR sequences employed were within the

guidelines for the radiofrequency absorption rate and the magnetic field change rate.

MRI compatible ear plugs were worn by all subjects to reduce acoustic noise. The aDTI

acquisition used a single-shot diffusion-weighted (Stejskal-Tanner) spin-echo

echoplanar imaging technique. The sequence acquired a T2-weighted image (b = 0

seconds/mm2) and a few diffusion tensor images (diffusion-weighted, b = 1,000

seconds/mm2) in 6 diffusion gradient directions that were isotropically arranged in

space. These images were necessary to calculate a diffusion tensor volume. Eight

volumes of images were acquired from every subject to form a time series in analogy to

fMRI data acquisition. Thirty-five contiguous axial slices were prescribed to cover the

whole brain with TR = 8000 msec, TE = 123 msec, acquisition matrix = 128 x 128,

slice thickness = 5 mm, and FOV = 220 mm. A high-resolution, T1-weighted, 3D

Spoiled Gradient Echo (3D SPGR) image volume was acquired from every subject for

the purpose of mapping our functional data.

Analysis. The diffusion tensor, eigenvalues, and fractional diffusion anisotropy (FA)

were calculated using the FuncTool program (GE Healthcare, Waukesha, WI) for each

imaging voxel. Further image processing and statistical analysis were performed using

the Statistical Parametric Mapping (SPM) software originally developed by Friston et

al., 15 with the SPM2 version actually utilized in this study. For each subject, all T2

volumes in the aDTI time series were realigned to the first volume to correct for the

subject head motion. All FA volumes were aligned using the T2 volume alignment


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parameters. To facilitate a group analysis, realigned T2 volumes were spatially

normalized to the Montreal Neurological Institute (MNI) T2-Weighted brain template

using affine and nonlinear transformations. All volumes were resampled to 1 x 1 x 1

mm voxels using the sinc interpolation method during normalization. FA volumes were

normalized using the T2 normalization parameters. The subject-reported, worse

headache side was flipped to the right. This step was omitted if the subject was not able

to report a side at the time of MR scans. Finally, all FA volumes were spatially

smoothed using a 4-mm full-width-at-half-maximum isotropic Gaussian kernel, to

improve signal-to-noise ratio and to account for residual intersubject differences.

Statistical analysis was performed on a voxel-by-voxel basis using the general linear

model approach. 15 A within-subject, fixed-effect analysis was performed first with an

identical model used across subjects. A “two-sample t-test” against a single and

averaged FA volume was conducted for each subject. The averaged FA volume was

calculated from individual FA volumes of 36 age-matched controls previously collected

in our database 16. Subsequently, the contrast image volumes generated in the first step

were supplied to a random-effects analysis procedure 17. A “compare-population”

inference of FA reduction in CM patients compared to controls was conducted in the

random effect analysis. All MNI coordinates were converted to Talairach and Tournoux

18 coordinates through queries to the Talairach Daemon Databases

(http://ric.uthscsa.edu/resources). An uncorrected threshold of P < 0.001 was selected

for our tabular and brain map reporting.


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Results

The results were reported following the convention in statistical parametric mapping

that was widely used in fMRI. As we borrowed this analysis tool to analyze our aDTI

data, aDTI specifics were noted when necessary. Loci of reduced FA of statistical

significance in the white matter were identified by peak coordinates in the standard

Talairach and Tournoux space. A peak was defined as the voxel with the highest Z

score in a cluster 15. Thus, each peak identified a cluster of activated voxels in fMRI

language. We used “cluster(s)” and “locus (loci)” interchangeable in this report. Each

locus could contain many “foci”. All loci and representative foci identified in this study

were listed in Table 2.

Mesencepalon

Pontine fibers. There were a few prominent foci in the left pontine locus or cluster

localized at (−13, −37, −32) in Talairach and Tournoux coordinates (see Table 2). Two

foci at (−3, −29, −28) and (-9, -32, -32) in the left pons extended and connected to the

one in the medulla at (-5, -30, -36) (Fig. 1A). The one in the right pons was weaker, and

localized at (14, −25, −28).

Midbrain fiber tracts. There was strong, bilateral midbrain hyperactivity at levels from

z = -16 up to z = -8 (Table 2, Fig. 1D). These midbrain foci connected to the pontine

foci on each side of the brainstem midline.

Diencephalon


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Internal capsule. The posterior limb or the sensory limb of the internal capsule was

more extensively involved in FA reduction on the left side with representative foci at

(−16, −12, 5) and (-19, -19, 10) while the focus in the right internal capsule was more

anterior and lateral (Table 2, Fig. 1F). The foci on the left were closer to the left

thalamus. Those on the right were localized in the fiber tracts close to, or passing by,

the lentiform nuclei.

Telencephalon

Cingulate white matter. There were two anterior cingulate clusters in our findings, one

at (-12, 27, 35) in the left hemisphere, the other at (24, -18, 47) in the right half brain in

Talairach and Tournoux coordinates (Table 2, Fig. 1G). These clusters were actually in

the superior frontal white matter but each was in continuation with a cingulate white

matter focus at (-13, 12, 41) on the left and at (19, -8, 37) on the right.

Insular fibers and extreme capsule. The focus was localized at (33, -10, 5) in the

posterior insula white matter/extreme capsule on the right side (Table 2, Fig. 1E).

Uncinate fasciculus. White matter foci were localized in the temporal pole bilaterally.

The right-side focus was localized at (35, 4, -17) (Table 2), a location that the uncinate

fasciculus passes through. The left-side focus at (-31, -5, -29) was more posterior and

inferior in location compared to the focus in the right temporal lobe (Fig. 1C). It could

be localized in the adjacent, anterior commissural fibers.


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Corpus callosum splenium. The cluster was spatially extensive (Table 2, Fig. 1B) with

the peak localized at (-3, -36, 25). It contained many foci distributed along the fiber

crossings to the other cerebral hemisphere. Two were in the posterior cingulate white

matter at (-4, -29, 29) and (-17, -44, 34). Some others reached a focus at (-23, -57, 17)

in the temporal lobe and at (-18, -46, 39) in the parietal lobe. This reaching behavior

was lateralized to the left, with the general laterality in the telencephalon.

Temporal lobe white matter. The largest cluster was in the temporal lobe white matter

with the cluster peak localized at (-36, -40, -6) (Table 2, Fig. 1D). Some foci were

distributed along the course of the hippocampal formation, (-23, -32, 2), (-23, -25, -7),

(-31, -12, -15), and to the vicinity of the amygdala, (-21, -10, -8) (Fig. 1H).

Rombencephalon.

Reduced FA Loci were found in the cerebellar peduncle and cerebellar white matter

bilaterally (Table 2, Fig. 1C).

These specific, subclinical loci were characterized by very small FA reductions. There

was no voxel survived in the statistical testing of FA reduction in the control group.

The T1-weighted 3D SPGR and T2-weighted MRI scans of all subjects were

unremarkable.


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Discussion

We found multiple, migraine-specific, subclinical loci in the brain white matter axonal

fiber tracts of chronic migraineurs. These loci are characterized by very small FA

reductions. This is in contrast to those large reductions associated with structural

damage, demonstrated by previous DTI studies. The use of the conventional DTI

method has been unable to find any FA difference in between migraine patients and

healthy subjects. 19 Nevertheless, It has been established that elevated neuronal activity

increases water diffusion fluxes. 16,20

They are in the directions perpendicular to the

conducting axonal fiber trunk, which reduces diffusion anisotropy. The detection of this

minute FA reduction demands an adapted approach similar to the time series scheme in

fMRI. There is no significant morphometric change in the migraine brain, 21,22

which

contributes to the applicability of aDTI in migraine studies. It is not clear how those

VBM (Voxel Bases Morphometry) findings relate to chronic pain 22 as the brain

parenchyma is normally pulsating and slightly changing its size in response to certain

medicines.

The vast majority of published functional brain mapping work has focused on the gray

matter (GM). The cortex has been partitioned cytoarchitectonically, based upon the

neuron type and layer arrangement at each cortical location. Brodmann areas (BAs)

serve as common references in reporting cortical activation. The coordinate reference

frame by Talairach and Tournoux 18 has the focus on the cortex and basal brain. These

tools utilized in functional GM mapping have been applied to functional WM mapping


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with varying degrees of difficulty. We used these tools as references with caution in

this study as new tools in functional WM analysis and mapping were being developed.

Mesencepalon

Migraine pathophysiology is only partially understood. As the brainstem is implicated

in migraine pathogenesis, precise foci localization in the pons is critical for revealing

the neural substrates. However, potine localization has proven difficult to achieve in

previous functional brain imaging studies. The pons and brainstem have not been

cytoarchitechtonically mapped and labeled in a standard atlas. WM fiber tracts and GM

nuclei are tightly packed in the small space of the brainstem. Imaging of the brainstem

is susceptible to motion artifact caused by cardiac pulsations and respiratory

maneuvers. There has been a paucity of brainstem functional brain mapping studies.

The studies have previously been focused on the cerebral cortex. Most diffusion tensor

imaging studies assess the structural integrity of the cerebral white matter. Our current

study reveals a few WM loci in the brainstem. A close examination of these loci may

provide new insights into the “migraine generator”. 10

Pontine fibers. The WM foci identified are anterior to the aqueduct and posterior to the

corticospinal tract. In previous GM studies, foci were distributed in a caudorostral

range from z = -32 to z = -16 including those reported by Afridi and Giffin et al. 23 at

(−2, −28, −22) in the left dorsal pons, and (8, −12, −22) in the right anterior pons. A

deactivated pontine focus at (16, -28, -19) was reported by the same authors. A pontine

focus was localized at (4, -32, -32), a slightly different location, in a different study by


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the same group. 24 Weiller et al.

10described their pontine activation as slightly

lateralized to the left with the focus of maximum significance located at (4, -26, -16).

Bahra et al. reported a left dorsal rostral pontine focus at (-2, -28, -22) in one patient. 25

Similar brainstem activation was detected by fMRI in short-lasting unilateral

neuralgiform headache with conjunctival injection and tearing (SUNCT). 26 A PET

imaging study of eight chronic migraine patients with suboccipital stimulators by

Matharu et al. 11 found dorsal rostral pons foci at (0, -26, -24) and (2, -26, -24) and

indicated that activation localization and persistence were consistent with those found

in episodic migraine imaging studies.

It has been hypothesized that these pontine GM activation loci are in the dorsal raphe

nuclei, periaqueductal gray matter, and local ceruleus. 27 In our WM study of chronic

migraine patients, most of our foci are close to, but slightly ventral and lateral to, these

GM foci locations. This reflects the spatial relationship between the WM fiber tracts

and GM nuclei in the pons. Indeed, both the ascending and descending trigeminal

pathways in the pons are lateral and ventral to the periaqueductal GM. Our stronger

pontine locus is on the left, contralateral to the headache side. However, an ipsilateral

laterality finding in GM has previously been reported. 24

To explain our laterality finding in WM, there is a need to review the trigeminal

pathways in the brainstem. The fiber processes most relevant to migraine research are

those small diameter fibers carrying pain and temperature signals. After entering the

CNS at the midpons, they turn and descend in the spinal tract of V, through the pons


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and medulla, until reaching the spinal nucleus of V. This is the caudal medulla, where

they finally synapse and cross. The spinal nucleus of V is divided into three regions: (1)

the subnucleus oralis, (2) the subnucleus interpolaris, and (3) the subnucleus caudalis.

The pain fibers actually synapse in the subnucleus caudalis. The secondary afferents

from subnucleus caudalis cross to the opposite side, and join the spinothalamic tract

ascending to the thalamus. Our right pontine focus detected at (14, −25, −28) may well

be involved in the spinal tract of V. After synapsing and decussating, the secondary

afferents from the subnucleus caudalis exhibit hyperactivity at the left medullary focus

at (-5, -30, -36), and then, additionally in the left pons (as previously described in this

section).

The stronger, left-sided, pontine focus that we found may be interpreted as a

compromised descending antinociceptive control in the baseline operation of the

trigeminal neural network. Although these second order neurons were found to be

hyperactive unilaterally, the antinoceceptive function might be compromised

bilaterally. There is evidence for these in the midbrain foci that we found. However,

most other hyperactivity loci in our study are lateralized to the left.

Midbrain fiber tracts. Midbrain activation in migraine has scarcely been detected with

either fMRI or PET. Unilateral pontine GM activation extends rostrally to the level z =

-11 in the midbrain, as reported by Weiller et al. 10 In our study, there is strong,

bilateral midbrain hyperactivity found at levels from z = -16 up to z = -8. These

midbrain foci connect to the pontine foci on each side of the brainstem midline. The


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hyperactivity in the midbrain may not be completely attributable to the hyperactivity in

the afferents from the second order neurons. Red nucleus and substantia nigra

activation, in spontaneous migraine attacks, has been described in a previous report. 27

A complex, nonlinear interaction of the nociceptive and antinociceptive functions in the

brainstem is speculated. In our study, the left-sided laterality regains its strength as the

afferents course away from the midbrain.

Diencephalon

Sensory information from the face enters the ventroposterior medial (VPM) nucleus.

The thalamocortical afferents take signals from both ventroposterior lateral (VPL) and

VPM nuclei to the primary somatosensory cortex, where they are distributed in a

somatotopic fashion. The VPM relays affective pain signals, which are subject to

modulation, sensitization, and influence from the limbic system.

Internal capsule. Thalamic activation has been reported in GM activation studies.

Depending upon the study designs, hemodynamic-based activation foci fall in the left

thalamus,,,, 23,25

left pulvinar (in chronic migraine patients),,,, 11 bilateral thalami,,,,

26 and

right thalamus (in cluster headache patients). 28 The activation foci are confined to a

small space as defined laterally -16 to 6 mm; anterioposteriorlly -21 to -4 mm, and

vertically 3 to 14 mm in the Talairach and Tournoux coordinate frame. Matharu et al.

11described pulvinar activation at (-16, -32, 10). In our WM study, the posterior limb or

the sensory limb of the internal capsule is extensively involved on the left side, with

foci at (−16, −12, 5) and (-19, -19, 10). The focus in the right internal capsule is more


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anterior and lateral. A closer examination of our brain maps reveals that our WM foci

on the left are closer to the left thalamus, and those on the right are in the fiber tracts

passing by, or close to the lentiform nuclei. Although the foci on the right might be

relevant to the inhibitory motor control (another aspect in chronic pain processing),

further studies are needed to clarify the issue. Techniques in WM fiber tractography

may provide further migraine-relevant information on the fiber routes leading into, or

exiting from, these nuclei. Not only do the ventroposterior nuclei of the thalamus relay

the signals from the trigeminal sensory system to the cerebral cortex, but they may also

modulate the nociceptive signal in migraine. Migraine is a disease associated with a

complex and widespread array of sensory disturbances. 21 A further understanding of

these WM foci in the diencephalon is important for understanding cortical brain activity

in migraine.

Telencephalon

The feeling of pain, especially chronic pain, is a cognitive perception that integrates

sensory, affective, attentional, and motivational aspects, as well as personal memory

and experience. The main complaint from a migraine sufferer is usually the head pain.

Despite the trigeminal sensory nature of migraine, a migraine imaging study is

incomplete without analyzing activity in the cortical network or in the central pain

matrix. The WM fibers tracts interconnect cortical regions to form a distributed

network. Our study focus is on the signals traveling through these fiber tracts, while

referring to cortical regions only for localization.


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Cingulate white matter. There are two anterior cingulate (ACC) WM clusters in our

findings, one at (-12, 27, 35) in the left hemisphere, the other at (24, -18, 47) in the

right half brain in Talairach and Tournoux coordinates. One may notice from these

Talairach coordinates the relatively high locations of these foci. These clusters are

actually localized in the superior frontal WM but each is in continuity with a cingulate

WM focus at (-13, 12, 41) on the left and at (19, -8, 37) on the right. Initially, we

localized the right cingulate cluster in the centrum semiovale/corona radiata due to its

posterior position. We now relocalize it in the posterior midcingulate (pMCC) WM

based on a cytological investigation by Vogt et al. 29 The posterior end of the anterior

cingulate is at the border between BA23 and BA24, which previously was taken to be

halfway between the genu and splenium of the corpus callosum. New data have pushed

the border to a more posterior position, 22 mm behind the anterior commissure, in

Talairach and Tournoux coordinates. 29 It should be noted that cortical localization has

been exclusively addressed in previous functional brain imaging research, but it is still

a subject of debate. Localization in the WM is a major challenge. As the WM fibers

course away from the neurons, they may abruptly turn and join with other fiber tracts.

This renders localization in the white matter a difficult task. Our planned diffusion

tensor imaging fiber tracking investigation may be useful for future research. Each of

the WM loci may serve as a “seed”, or starting point, from which fiber tracking may

lead to identifying relevant brain areas.

Previous studies of nociception revealed that brain activation clusters may contain foci

in both the midcingulate and the prefrontal gyrus. 30 MCC activity may correlate with


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motor planning activity in the frontal cortex while head pain in chronic migraine may

activate the prefrontal cortex. 11 However, we chose not to use the GM activation

analogy to explain our WM findings before we had advanced WM localization. Instead,

we focused on the cingulate WM foci in this report. The posterior ACC may be

involved in the sensory consequences of pain while the midcingulate cortex may

function in pain intensity coding. 30,31

The anterior 1/3 of the MCC responds to pain

that is coupled to fear. The posterior 2/3 area the MCC does minimal processing of

affective information. 30,32

Most of these observations and conclusions have been made

in experimental studies with acute pain. These may or may not apply to our chronic

migraine pain situation. Our anterior MCC WM focus may be a subclinical indication

of a sensitized center for affective information processing, associated with elevated

negative affect and fear in CM. Our posterior MCC WM focus may imply a

subclinically altered neural substrate that abnormally codes stimulus intensity. It has

been reported, however, that activity at (-2, 24, 18) in the left anterior ACC correlates

positively with pain scores in chronic migraine patients. 11 The laterality issue will need

to be resolved in future studies.

Insular fibers and extreme capsule. The posterior insula is involved in the affective

aspects of pain perception. 33 One of our foci is at (33, -10, 5). It is localized in the right

posterior insula WM and extreme capsule. Bilateral anterior insula involvement has

been reported in cluster headache at (32, 10, 2) on the right side and at (-40, 12, -8) on

the left. 34 An ipsilateral anterior insular activation was reported at (36, 15, 3) in the

SUNCT syndrome. 26 A conversion of their coordinates to the standard Talairach


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coordinates was confirmatory. Bilateral involvement of the insula is frequently seen in

episodic migraine studies. However, its localization varies, such as bilateral posterior at

(28, -26, 0) and (-34, -30, 0); 25 bilateral anterior at (32, 20, 10) and (-60, 4, 8);

24

bilateral but anterior at (44, 12, 0) on the right and posterior at (-36, -14, 1) on the left.

23 The last two studies were in fact from the same group. In one PET study of chronic

migraine, 11 the authors reported that insular rCBF changes did not covariate with pain

scores, but rather with paraesthesia scores at (38, 4, -10) in the right anterior insula and

at (-36, -16, 16) in the left posterior insula. Most of these were experimental acute pain

studies. Our study focused on the baseline state of CM brains.

Uncinate fasciculus. We found bilateral, temporal pole foci, a unique finding. The

right focus is localized at (35, 4, -17), a location through which the uncinate fasciculus

passes. The uncinate fasciculus has large fiber bundles connecting the frontal and

temporal lobes. It is asymmetric in healthy controls, but relatively symmetric in

schizophrenia. 35 The significance of the uncinate fasciculus in migraine is unknown,

but it is known that psychiatric disorders and symptoms are often seen in CM. 36 The

left temporal pole focus at (-31, -5, -29) is more posterior and inferior in location

compared to the focus in the right temporal lobe. It may have been localized in the

adjacent anterior commissural fibers if the brain was as perfectly symmetric as depicted

by published brain atlases. In reality, it may still be localized in the uncinate fasciculus

because of the normal asymmetry of the fasciculus and the temporal lobe.


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Corpus callosum splenium. The corpus callusum splenium has not been addressed by

previously published functional imaging studies of migraine. We identified a cluster in

the corpus callosum spelenium, the first report of its kind. The locus is extensive, with

the peak localized at (-3, -36, 25). It contains many foci. The relevance of splenial

lesions to migraine is as follows: visual disturbances and photophobia are frequent

complaints from migraine sufferers. Our patients reported no visual aura but all had

photophobia. Transient lesions are actually often found in the splenium. 37 They have

been attributable to an antiepileptic drug, 38 or diet pills containing sympathomimetic

agents. 39 A transient, splenial lesion correlated with a kaleidoscopic visual disturbance

in one report. 39 The patient, with a familial migraine history, was diagnosed as

acephalgic migraine. The lesion and the visual symptoms disappeared after she stopped

using diet pills. It is unusual to attribute a transient splenium lesion to diet pills. The

heterogeneous condition of migraine is associated with symptoms that vary between

individuals, and within individuals from attack to attack. 36 Although the genetic basis

of migraine has been well addressed, 40,41

migraine markers that can be demonstrated

noninvasively are unknown. Our study may aid in that direction by identifying

subclinical foci commonly seen in chronic migraineurs. Some foci may be seen in

episodic migraineurs as well. If the transient lesions correlate with hyperactivity in the

splenial transfer, it will serve to support our central hypothesis.

Many foci in the splenium cluster are distributed along the fiber crossings to the other

cerebral hemisphere. Some are in the posterior cingulate WM, such as the ones at (-4, -

29, 29) and (-17, -44, 34). Others reach the temporal lobe at (-23, -57, 17) and parietal


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lobe at (-18, -46, 39). This reaching behavior is clearly left lateralized, in consistency

with the general laterality in the telencephalon.

Temporal lobe white matter. The largest cluster is in the temporal lobe WM, with the

cluster peak localized at (-36, -40, -6). The temporal lobe cluster alone may tilt the

overall laterality to the left, contralateral to the headache side in our study. While the

function of the temporal lobe in pain is unclear, 33 its activation has been reported in

migraine attacks 10,23

and in cluster headache attacks. 34 In the chronic migraine PET

study by Matharu et al., 11 rCBF changes in BA22 of the right temporal cortex

covariate with both the pain scores and the paraesthesia scores. The rCBF changes in

BA21, 41 in the left temporal lobe and BA 20/37 on the right covariate with only the

paraesthesia scores. Nevertheless, our findings in the left temporal lobe WM may not

have a direct connection to the acute pain. Our finding may be indicative of central

sensitization, involving emotional or affective processing circuitry. 42,43

This results

from a long history of transformation into chronic migraine. The foci distributed in the

hippocampal formation WM may correlate with psychopathology (such as anxiety)

commonly seen in migraine patients. Hippocampal volume reductions have been linked

to post-traumatic stress disorder (PTSD), as well as a complex array of psychiatric

comorbidities. 44,45

Functional brain imaging techniques are providing insight 42into the

altered temporal lobe function and abnormal activation in the left parahippocampal

gyrus and tail of the left hippocampus in PTSD patients. 46


22

22

In our white matter study, some foci in the left temporal lobe are distributed along the

course of the hippocampal formation, (-23, -32, 2), (-23, -25, -7), (-31, -12, -15), and to

the vicinity of the amygdala, (-21, -10, -8). Our findings were made at the CM baseline

when no experimental acute migraine attacks were present. Our data support the

argument that CM may be related to a dysfunctional brain neural network.

Rombencephalon.

The cerebellum may play a role in nociception. However, there is a paucity of studies

demonstrating cerebellar influences on the sensory experience. 47 Including the PET

study of episodic migraine by Weiller et al., 10 bilateral cerebellar activation has been

reported by most functional brain imaging investigations of episodic migraine attacks.

23-25 Sprenger et al. reported an ipsilateral, cerebellar activation on the right in self-

triggered SUNCT attacks. In the chronic migraine PET study by Matharu et al., 11 rCBF

changes in bilateral cerebellar areas covariate with both pain and paraesthesia scores.

These findings were noted in the cerebellar GM. We identified cerebellar WM loci.

Their connection to CM is yet to be understood.

Conclusion

Previous WM studies in migraine have generally reported “nonspecific damage”. 48,49

Our aDTI study presented a population group analysis. Scans of the subject groups did

not reveal any structural abnormality. Using aDTI, we found evidence for neural

hyperactivity in multiple WM areas specific to CM symptoms. The WM loci may well


23

23

be reversible. Future studies utilizing aDTI may be able to assess the progression of

chronic migraine, as well as the effects of therapy.

Acknowledgement: This investigator initiated study was supported by a research

grant from Pfizer.

headache paper 04-12-2011 lr revision to larry...

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