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University of Kentucky Master's Theses
Graduate School
2004
CEREBRAL ACTIVATION DURING
THERMAL STIMULATION OF BURNING
MOUTH DISORDER PATIENTS: AN f MRI
STUDY
Romulo J.C. Albuquerque
University of Kentucky, [email protected]
Recommended Citation
Albuquerque, Romulo J.C., "CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH
DISORDER PATIENTS: AN fMRI STUDY" (2004). University of Kentucky Master's Theses. Paper 238.
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ABSTRACT OF THESIS
CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH
DISORDER PATIENTS: AN fMRI STUDY
Functional magnetic resonance imaging (fMRI) has been widely used to study
cortical and subcortical mechanisms related to pain. The pathophysiology of burning
mouth disorder (BMD) is not clearly understood. Central neuropathic mechanisms are
thought to be main players in BMD. This study aimed to compare the location and
extension of brain activation following thermal stimulation of the trigeminal nerve with
fMRI blood oxygenation level dependent (BOLD) signal. This study included 8 female
patients with BMD and 8 matched pain-free volunteers. Qualitative and quantitative
differences in brain activation patterns between the two study groups were
demonstrated. There were differences in the activation maps regarding the location of
activation, with patients displaying greater BOLD signal changes in the right anterior
cingulate cortex (ACC BA 32/24) and bilateral precuneus (p<0.005). The control group
showed larger BOLD signal changes in the bilateral thalamus, right middle frontal gyrus,
right pre-central gyrus, left lingual gyrus and cerebellum (p<0.005). It was also
demonstrated that patients had far less volumetric activation throughout the entire brain
compared to the control group. These data are discussed in light of recent findings
suggesting brain hypofunction as a key player in chronic neuropathic pain conditions.
KEYWORDS: Burning Mouth Disorder, Functional Magnetic Resonance Imaging, Brain
Activation, Trigeminal Thermal Stimulation, Thalamic Hypofunction
Romulo J.C. Albuquerque, DDS
July 27, 2004
CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH
DISORDER PATIENTS: AN fMRI STUDY
By
Romulo Jose Cunha Albuquerque
Reny de Leeuw, DDS, PhD
Director of Thesis
Karen Novak, DDS, MS, PhD
Director of Graduate Studies
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THESIS
Romulo Jose Cunha Albuquerque
The Graduate School
University of Kentucky
2004
CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH
DISORDER PATIENTS: AN fMRI STUDY
______________________________________
THESIS
______________________________________
A thesis submitted in partial fulfillment of the
requirements for the degree of Masters of Science
at the University of Kentucky
By
Romulo Jose Cunha Albuquerque
Lexington, Kentucky
Director: Dr. Reny de Leeuw, Professor of Dentistry
Lexington, Kentucky
2004
Copyright © 2004, Romulo J.C. Albuquerque
ACKNOWLEDGMENTS
The following thesis, while an individual work, benefited from the insights and
direction of several people. First, my Thesis Committee, Dr. Reny de Leeuw (Thesis
Chair), Dr. Jeffrey Okeson and Dr. Charles Carlson, exemplifies the high quality
scholarship to which I aspire. In addition, Anders Andersen and Craig Miller provided
timely and instructive comments and evaluation for the development of this work. My
fellow residents, staff from the Orofacial Pain Center and staff from the Magnetic
Resonance Imaging and Spectroscopy Center (Agnes Bognar, Nancy Bailey and David
Powell) were indispensable part for the accomplishment of this research. I would like to
thank the Orofacial Pain Center and the Magnetic Resonance Imaging and
Spectroscopy Center for having funded this study. In particular, I would like to
acknowledge my patients and volunteers for their willingness to take part in this study.
Their role is indisputably vital to the advances that science has undergone throughout
its history.
For my part, I would like to thank Dr. Jeffrey Okeson for having given me the
opportunity to embark this intellectual journey at the Orofacial Pain Center. I would also
like to thank my family, who back in Brazil has supported me by all means through this
academic process. Above all, this work would not have been possible if it was not for
my wife Lisandra Garcia. She was my harbor when storms came through. She was my
friend, my family, my “everything”. I dedicate this thesis to her.
iii
TABLE OF CONTENTS
Acknowledgments……………………………………………………………………..………..iii
Table of Contents……………………………………………………………………………….iv
List of Tables……………………………………………………………………………..……..vi
List of Figures………………………………………………………………………..…………vii
List of Files……………………………………………………………………………………..viii
1. Introduction……………………………………………………………………….…………..1
2. Purpose of the Study……………………………………………………………….………..3
3. Review of the Literature……………………………………………………………………..4
3.1. Technical Foundation of Functional Neuroimaging Methods: an Emphasis
on fMRI……………………………………………………………………………...……4
3.2. PET vs. fMRI…………………………………………………………………..……5
3.3. Functional Neuroanatomy of Pain…………………………………………..……5
3.4. Common Supraspinal Sites Depicted by Neuroimaging Pain Studies…….....7
3.5. Functional Neuroimaging in Chronic Pain………………………………….….15
3.6. Functional Brain Imaging in Orofacial Pain………………………………...….17
3.7. Burning Mouth Disorder………………………………………………………….22
3.8. Hypothesis……………………………………………………………………...…27
4. Materials and Methods…………………………………………………………………..…29
4.1. Study Design…………………………………………………………………...…29
4.2. Study Population…………………………………………………………….……29
4.3. Subject Recruitment Method………………………………………………..…..30
4.4. Research Procedures……………………………………………………………31
4.5. Statistical Analysis……………………………………………………………….34
iv
5. Results………………………………………………………………………………….……37
5.1. Demographics and Psychophysical Tests………………………………..……37
5.2. Functional MRI Data Analysis……………………………………………..……40
6. Discussion………………………………………………………………………………...…46
6.1. Qualitative Differences in Brain Activation Between Patients and
Controls……………………………………………………………………………...….47
6.2. Quantitative Differences in Brain Activation Between Patients and
Controls……………………………………………………………………………...….50
6.3. Future Research Directions…………………………………………………..…54
6.4. Study Limitations………………………………………………………………....55
7. Summary………………………………………………………………………………….…57
References…………………………………………………………………………….…….…58
Vita………………………………………………………………………………………………71
v
LIST OF TABLES
Table 1. Detailed description of the patient population ………………………………...…38
Table 2. Comparison between patients with BMD (n=8) and controls (n=8) regarding the
psychophysical data…………………………………………………………………………...39
Table 3. Comparison between patients with BMD (n=8) and controls (n=8) regarding the
SCL-90 subscales…………………………………………………………………………..…39
Table 4. Comparison between patients with BMD (n=8) and controls (n=8) regarding the
BDI and STAI scores………………………………………………………………………….40
Table 5. Areas of differential activation between BMD patients (n=8) and pain-free
volunteers (n=8)…………………………………………………………………………….….44
Table 6. Location and size of the detected clusters of activity in the patient group…….44
Table 7. Location and size of the detected clusters of activity in the control group…….45
vi
LIST OF FIGURES
Figure 1. Magnetic resonance image of the left anterior cingulate cortex located by the
Talairach coordinates (x,y,z)=(5[L],27[A],23[S])…............................................................8
Figure 2. Schematic representation of the anterior cingulate cortex and its subdivisions.
………………………………………………………………………………………………...…..9
Figure 3. Magnetic resonance image of the left insular cortex located by the Talairach
coordinates (x,y,z)=(34[L],0[A],4[S])…………………………………………………………11
Figure 4. Magnetic resonance image of the left thalamus located by the Talairach
coordinates (x,y,z)=(9[L],15[P],9[S])…………………………………………………………13
Figure 5. Magnetic resonance image of the left dorsolateral prefrontal cortex located by
the Talairach coordinates (x,y,z)=(42[L],8[A],29[S])……………………………………….14
Figure 6. Thermal stimulation paradigm (in degrees Celsius)……..……………………..33
Figure 7. Activation map of the BMD group (n=8)………………………………………….41
Figure 8. Activation map of the control group (n=8)………………………………….…….41
Figure 9. Activation map of the comparison between BMD group (n=8) and control
group (n=8)……………………………………………………………………………………..42
vii
LIST OF FIGURES
File 1. ………………………………………………………………………….. fMRI_BMD.pdf
viii
1. Introduction
Extensive attention has been given to the understanding of the
mechanisms involved in nociception, pain modulation and perception by researchers
and clinicians around the world. At the present time, however, the implications of the
central nervous system (CNS), especially supra-spinal mechanisms, in chronic pain
conditions, pain perception and modulation processes are poorly understood. Most of
our knowledge is derived from either extrapolations from animal model studies [1, 2] or
case reports from patients who had different types of injuries, neuropathies, or surgical
procedures involving the CNS [3, 4] [5, 6]. The use of positron emission tomography
(PET) and the recent development of functional magnetic resonance imaging (fMRI)
have added objective knowledge of pain processing and have clarified some of the
features and implications of the CNS in the complex pain modulation networks.
The neural circuits of pain are far beyond a simple nociceptive input barrage
arising from the periphery to the CNS. Rather, pain processing networks are under the
influence of several modulating factors that will be elaborated below. Further, the neural
circuits of pain have different dimensions and aspects as proposed by Melzack [7] in the
pain “neuromatrix”. These circuits comprise a widely distributed neural network that
includes parallel somatosensory, limbic and thalamocortical components that enable the
sensory-discriminative, affective-motivational and evaluative-cognitive dimensions of
pain experience.
Functional MRI studies have been performed since Belliveau and colleagues
published the first paper in 1991. [8] A series of different central processing
mechanisms have been explored with functional MRI techniques, such as attention and
1
cognition, [9],[10] language, [11] memory, learning, vision processing, auditory
perception, [12] cerebellum neurophysiology, [13] and sensory and motor functions.
Functional MRI has also been used in neurosurgical planning and for implantation of
electrodes within different brain structures for the treatment of neuropathic pain
conditions. [14]
A variety of functional neuroimaging studies have been conducted to clarify the
role of neural structures and cortical regions implicated in the pain “neuromatrix”.
Creative, elegant and well-planned research has been designed to explore the
“neuromatrix” associated with acute pain models (chemical, thermal and mechanical
stimuli) and clinical pain conditions, such as migraines, [15] cluster headaches [16-19],
neuropathic pain [20-22] and phantom limb pain. [23] These studies have greatly
improved our understanding about the role of many CNS structures in the underlying
mechanisms of the above mentioned clinical pain entities. Other orofacial pain
disorders, have not yet been the focus of extensive neuroimaging studies. Orofacial
pain disorders comprise a variety of acute and chronic pain conditions that include, but
are not limited to temporomandibular joint disorders, masticatory myofascial pain,
trigeminal neuralgia and continuous neuropathic pains, including burning mouth
disorder (BMD). Some of these disorders do not respond to peripheral interventions
and it is likely that CNS mechanisms are primarily involved in their etiologies. [24]
Brain-imaging studies are a powerful tool for exploring and understanding more of the
features of the complex central network of pain in the orofacial region as well as
exploring the likely pathophysiology of chronic orofacial pain conditions, such as BMD.
Copyright © 2004, Romulo J.C. Albuquerque
2
2. Purpose of the Study
Functional MRI studies investigating stimulation of the trigeminal nerve are
scarce. To date, chronic orofacial pain conditions have not been investigated under the
spectrum of fMRI. This study intends to investigate differences in location and extent of
activation of brain regions involved in the sensory-discriminative and emotional-affective
components of trigeminal pain processing between patients with BMD and age-matched
pain-free volunteers.
Copyright © 2004, Romulo J.C. Albuquerque
3
3. Review of the Literature
3.1. Technical Foundation of Functional Neuroimaging Methods: an Emphasis on
fMRI
Brain-imaging studies rely on the ability of techniques, such as positron emission
tomography (PET) and functional magnetic resonance imaging (fMRI), to detect
“activity” within the central nervous system. This activity is presumably related to
glucose metabolism (PET) and blood perfusion changes (fMRI) most likely associated
with neuronal firing [25] [8]. The respective imaging techniques do not directly measure
neuronal activity, but translate changes in regional blood flow and blood oxygenation
levels associated with such activity into detectable signals. The most common way of
detecting brain activity with fMRI is by measuring relative changes in oxyhemoglobin
and deoxyhemoglobin levels. Thus, blood oxygenation level dependent (BOLD) signals
are measured in and around the microvasculature of active centers in the CNS. More
specifically, oxygenated hemoglobin circulates through the brain capillary network and
has magnetic susceptibility similar to the surrounding tissues. When activated, neurons
extract oxygen from the capillaries, distending the venous vessels and causing
oxygenated blood perfusion and relative dilution and reduction of deoxyhemoglobin
concentration.[25] Oxygenated hemoglobin and deoxyhemoglobin have diamagnetic
and paramagnetic properties, respectively. They serve as a type of endogenous image
contrast. When the relative concentration of oxyhemoglobin and deoxyhemoglobin
change, the signal of the T2* weighted MRI changes as well. The local physiological
changes result in increased magnetic signal and create a brighter image in the area of
activation. [26] Maps of brain activation are developed by extensive processing and
4
statistical analysis of the acquired images. Statistical correlations between the BOLD
signal and the desired study stimuli are then calculated for each voxel of the brain
image throughout the experiment time. In summary, neural activity has been linked to
physiological changes in the local microvasculature that are detectable with imaging
techniques such as fMRI [8, 27].
3.2. PET vs. fMRI
When compared to PET imaging, functional MRI renders a series of advantages,
as described by Peyron et al. (2000) [28] For instance, functional MRI has superior
temporal and spatial resolution; there is no need for radioactive image contrast as is
needed for PET, and no injection is required. Further, in fMRI, individual subject data
may be analyzed, in contrast to PET studies, where images require pooling in order to
achieve interpretable results.
Functional MRI also has some disadvantages when
compared to PET. Pulsating artifacts impede a detailed visualization of brainstem and
thalamic activation. In addition, fMRI is limited to comparisons of cerebral neuronal
activation with resting states (baseline activity); and it is therefore unable to portray
possible certain neuronal events related to, for example, chronic pain states.[28]
Notwithstanding the differences presented between the two techniques, results from
both imaging techniques are generally comparable [29].
3.3. Functional Neuroanatomy of Pain
In order to comprehend the most common findings of fMRI studies, it is important
to review some of the functional neuroanatomy of the pain-processing network. The
5
conduction of information to the CNS (afferent conduction) is performed by different
types of neurons: the first-order neurons that conduct the input from the periphery into
the spinal cord; the second-order neurons, which travel along the spinothalamic
pathway ascending to the higher centers (thalamus, cortex) of the CNS; and the third/fourth-order (interneurons) neurons, which carry impulses through a multi-synaptic path
to the thalamus, reticular formation, other parts of the brainstem and other brain
structures, such as the cerebellum, superior colliculus, pontine parabrachial nucleus
and periaqueductal gray matter. [30] Nociceptive input is just one of the many different
types of afferent signaling barrages (sensory pathways) ascending to the CNS and it will
be the main focus of our discussion in this section.
The nociceptive conduction process involves two main pathways: the lateral and
the medial pain system. The lateral pain system, also called the neospinothalamic tract
mainly relays information to the ventral posterior lateral nucleus, ventral posterior medial
nucleus and ventral posterior inferior nucleus of the thalamus. The lateral thalamic
nuclei project to the primary (SI) and secondary (SII) somatosensory cortices and are
thought to be implicated in mediating the sensory-discriminative aspect of the pain
experience. When the stimulus travels through the lateral pain system, contralateral
activation of the brain is expected [31, 32].
The medial pain system, or paleospinothalamic tract, mainly involves medial
thalamic structures, such as the ventral part of the ventral medial nucleus, the
ventrocaudal part of the medial dorsal nucleus, the parafascicular nucleus and the
contralateral nucleus. The medial thalamic nuclei send information to the insula and
anterior cingulate cortex (ACC) and comprise primarily the affective-motivational portion
6
of the pain experience. The medial pain system possesses spinothalamic and
spinoreticular projections to various brainstem nuclei and the limbic structures. [33]
From the limbic system the nociceptive stimulus is conducted to both right and left
cerebral cortices, expressing most likely, a bilateral activation. A word of caution is in
place here because there are several additional cortico-cortical connections that may
also be important in pain pathways.[31] Thus dichotomizing the pain pathways into a
lateral and medial system is much too simplistic. .
3.4. Common Supraspinal Sites Depicted by Neuroimaging Pain Studies
Different brain regions have shown activation during acute painful stimulation, in
terms of functional neural imaging. The meaning of such activation is the center of
extensive debate. In this section, the most commonly activated brain structures are
described and the functional relevance of these findings is discussed.
3.4.A. Anterior Cingulate Cortex (ACC)
The ACC is one of the most commonly investigated brain structures. It is located
above the corpus callosum (Figure 1), and is one of the many components of the brain
hemispheres’ medial wall. In recent studies, the ACC has been divided into two main
components, based on the cytoarchitecture, organization and function. The two
components are the anterior or rostral portion (aACC), also called the perigenual
cingulate, and the posterior or caudal portion (pACC). The pACC is subdivided into a
dorsal portion and a ventral portion, which is also called the midcingulate region (Figure
2).[34] [35]
7
Fig 1. Magnetic resonance image of the left anterior cingulate cortex located by the Talairach coordinates
(x,y,z)=(5[L],27[A],23[S]).
The ACC has been directly and indirectly related to the neural circuitry of pain.
There have been reports of ACC involvement in pain, anticipation of pain, [9] anxiety,
[36] attention and motor responses. [37] It has been suggested that the rostral portion of
the ACC (perigenual cortex) subserves the affective reaction to pain. In other words,
activity in the rostral ACC is directly related to the unpleasantness of the stimuli, [38],[6,
31, 39]. Apparently this region of the cingulate cortex also plays an important role in
processing anxiety [36] [40].
Based on experimental studies in healthy subjects, activity within the ventral
portion of the pACC (midcingulate cortex) has been linked to thermal painful stimuli.
Recent evidence supports the hypothesis that the midcingulate cortex possesses pain
intensity encoding properties. [41] [42] They demonstrated that the midcingulate cortex
was activated by painful stimuli only and that the amount of activation was proportional
to the intensity of the painful stimulation. Pain-related motor responses have been
related to activity in the dorsal subdivision of the pACC. [34]
8
Fig. 2 Schematic representation of the anterior cingulate cortex and its subdivisions. In blue = anterior
portion of the ACC (perigenual cingulate), in red and green = posterior portion of the ACC (red =
midcingulate cortex)
The ACC appears to exert a significant role in the pain modulatory system.[10]
Functional MRI data have shown that the anticipation of a painful stimulus resulted not
only in activation of the ACC, but also in higher pain ratings that were similar to actual
painful stimuli. [9] Another study showed that distraction from a painful stimulus also
activated ACC neurons, and this correlated with a decrease in the reported pain
intensity. [34] These results suggest that the ACC modulatory influence can be either
inhibitory or excitatory in nature.
The current literature suggests that the ACC is a major CNS player in chronic
neuropathic pain conditions. Increased activation of the midcingulate cortex has been
observed in some neuropathic conditions, [21], or after capsaicin application [43] Due to
conflicting data in the reports on neuropathic pain conditions, Peyron [28] suggested
9
that the level at which the deafferentation occurs (peripheral or central) may influence
the activity in the midcingulate cortex. This was based on the fact that decreased
activity in the midcingulate cortex has been shown to occur when an allodynic region is
stimulated in patients who suffered medullary infarcts. On the other hand, increased
activity within the midcingulate was demonstrated following stimulation of an allodynic
area secondary to peripheral nerve lesion. [44]
Taken together, the functional meaning of ACC activity upon experimental
stimulation can be very puzzling, since it is very likely that this structure possesses a
variety of functions within the CNS.[45] More detailed investigations are warranted to
further elucidate what the true functional roles of this cortical zone are.
3.4.B. Primary (SI) and Secondary (SII) Somatosensory Cortex
The primary somatosensory cortex (SI) is located in the postcentral gyrus and
receives somatosensory input from the ventral posterolateral and ventral posteromedial
nuclei of the thalamus. The secondary somatosensory cortex (SII) is positioned
immediately posterior to the SI and constitutes one of the functional components of the
parietal lobe of the brain. Both SI and SII are limited inferiorly by the Sylvian fissure
which separates the temporal from the parietal lobe in this specific region. [46] Despite
the fact that activation within the SI and SII has been correlated to painful stimulation,
[47], [48] the functional significance of activation of either region remains to be
elucidated. It has been suggested that both regions (SI and SII) are related to encoding
spatial, temporal and intensity aspects of noxious input, [49] [ Bornhovd, 2002 #384],[50]
[Peyron, 2000 #60] however, neither one of the somatosensory cortices are solely
10
involved in the interpretation of noxious input because they are activated by innocuous
sensory stimulation as well. [51]
3.4.C. Insula
The insular cortex lies deep beneath the lateral cerebral fissure (Figure 3) and it
is divided into two different components: anterior and posterior. [46]
The posterior
portion of the insula is localized in close proximity to the SII, which is why many PET
studies could not differentiate between activation in the SII and posterior portion of the
insular cortex. [52]
The insula has been implicated in both affective and sensory-
discriminative aspects of the pain experience. [6], [31], [48] Careful investigation of the
insular cortex using fMRI indicates that the posterior portion appears to be involved in
the sensory-discriminative dimension of the pain experience. [37] In addition, it has
been described as the thermosensory cortex because of its ability to encode thermal
stimulus intensity. [53] The anterior portion of the insula seems to be a component of
the affective-motivational aspect of the pain neuromatrix. Activity within this region may
be affected by attention towards the painful stimuli. [37]
Fig. 3. Magnetic resonance image of the left insular cortex located by the Talairach coordinates
(x,y,z)=(34[L],0[A],4[S])
11
3.4.D. Thalamus
The thalamus is a component of the diencephalon (Figure 4). Previously, it has
been described as a relay station located between the spinal cord and the cortex [33,
54]. The thalamus is an important relay station for both the medial and lateral pain
system. With respect to the pain experience, the roles of three thalamic regions have
been described. The posterior nuclei are involved in conduction and processing of
painful stimuli, the ventral posterior nuclei are thought to participate in the localization
process of the pain stimulation and the medial nuclei are implicated in the affectiveaversive nature of the painful stimuli. [55] Recent advances in spatial resolution with
fMRI have made it possible to evaluate the function of the thalamus in a more detailed
manner. [56] For instance, thalamic activation has been demonstrated during acute
phasic heat stimulation. [48, 57]
The thalamus possesses a great number of
interconnections and inhibitory synaptic networks. Therefore, bilateral activation of the
thalamus may not only reflect a sensory response, but could be related to the arousal
reaction induced by the painful stimuli as well. [28]
Thalamus hypoactivity has been linked to chronic pain conditions [20, 58]. The
facts that thalamic stimulation can produce analgesia and that thalamic stimulating
devices have been shown to reduce pain in some neuropathic pain states [59] reinforce
the premise that decreased thalamic activity may be one of the pathophysiological
markers for chronic pain. [60] Taken together, these data suggest the thalamus is a
dynamic CNS structure that relates to the sensory-discriminative and affectivemotivational dimensions of the pain experience. It is also very likely that activity in the
thalamus is compromised in chronic neuropathic pain conditions.
12
Fig. 4. Magnetic resonance image of the left thalamus located by the Talairach coordinates
(x,y,z)=(9[L],15[P],9[S])
3.4.E. Prefrontal Cortex
The prefrontal cortex is the most anterior portion of the frontal lobe (Figure 5) and
comprises Brodmann areas 9 and 10. The prefrontal cortex has several connections to
other brain structures, such as the dorsomedial nucleus of the thalamus, other cerebral
lobes and the hypothalamus [61]. The prefrontal cortex presumably plays a crucial role
in memory retrieval [62] and attention processing in normal individuals, when they
experience an experimentally induced noxious stimulus [41, 49]. Apparently, the
prefrontal cortex is activated by painful heat application, but the amount of activation
does not increase with increased stimulus intensity (on- and off-response). [41, 49]
Clearly, pain intensity encoding is not a task of the prefrontal cortex.
13
Fig 5 Magnetic resonance image of the left dorsolateral prefrontal cortex located by the Talairach
coordinates (x,y,z)=(42[L],8[A],29[S])
Prefrontal cortex functioning has been investigated in chronic pain patients.
Apkarian et al [22] reported that in the sympathetically maintained pain state, subjects
display prefrontal hyperactivity in response to painful stimuli that could be reversed after
pain blockade. Hsieh et al. [21] also found increased activity in parietal and prefrontal
cortices in chronic neuropathic pain patients. Hence, the prefrontal cortex may play an
important role in the pathophysiology of some chronic pain conditions.
3.4.F. Other Brain Regions
Several studies demonstrated activation of other brain structures such as the
inferior parietal cortex, cerebellum and amygdala during painful stimuli. These brain
areas were not always consistently activated and the functional significance of their
activation within the pain neuromatrix is even less understood than the previously
discussed brain structures. [31, 43] [41, 63]
14
3.5. Functional Neuroimaging in Chronic Pain
As previously mentioned, there are few neuroimaging studies of chronic pain
conditions. In this section, these studies are discussed in a more detailed manner, since
they are important to the development of the present study’s hypothesis.
Iadorola et al. [20] studied 5 patients with chronic neuropathic pain with oxygen15 water bolus PET. Four of these patients had pain confined to one lower limb and one
patient had ophthalmic post-herpetic neuralgia. The authors found that, in patients,
thalamic activity on the side receiving input from the symptomatic limb was decreased
compared to activity on the side receiving input from the asymptomatic limb and
compared to activity generated in control subjects. The decrease in thalamic activity
was most robust in anterior dorsal and posterior ventral regions. Earlier, Di Piero [58]
who studied 5 cancer pain patients with PET found contralateral decrease in thalamic
activity as well, and also found this in posterior and anterior nuclei. Di Piero [58] and
Iadorola [20] suggested that decreased thalamic activity may be a clinical feature
common to a wide variety of chronic pain disorders. It has been postulated that these
changes in thalamic activity may lead to a loss of central inhibition.
Using fMRI, Apkarian et al. (2001) studied 7 subjects with unilateral
sympathetically maintained pain limited to one hand before and after the SMP was
suppressed by sympathetic blockade. [22] In the clinical pain state, the subjects showed
increased prefrontal activity, and decreased parietal cortical and contralateral thalamic
activity in response to an additional painful stimulus. These activation patterns were
reversed after pain was eliminated by a sympathetic block (bupivacaine 0.2%).The
authors concluded that the altered activation patterns within the prefrontal and parietal
15
cortex and the thalamus may play a crucial role in the pathophysiology of
sympathetically maintained pains.
A similar study was previously done by Hsieh et al. [21] who studied 8 chronic
neuropathic pain patients before and after regional nerve block with PET. During the
clinical pain status, they found increased activity in bilateral insula, parietal and
prefrontal cortices and posterior cingulate and right anterior cingulate (BA24) regions.
They also noted decreased activity in the contralateral posterior thalamus. No
differences were found in the activity of SI and SII regions as it related to the pain status
before and after regional nerve block. These findings suggest that abnormal brain
responses may underlie sympathetically maintained pain and that prefrontal/limbic
networks may be extensively involved.
Gracely et al. [64] conducted an fMRI study whereby 16 fibromyalgia patients
were compared to 16 gender and age matched healthy controls. They reported their
results in terms of number of activated clusters for each group. For the same subjective
experience of pressure induced pain they found 19 regions of increased regional
cerebral blood flow in healthy controls and 12 regions of increased regional cerebral
blood flow in fibromyalgia patients. There were 7 regions common to both groups.
Statistical comparison between the two groups revealed 13 regions with higher
activation in the patient group. Their results strengthen the hypothesis that fibromyalgia
is a cortical or subcortical pain augmentation disorder. A similar study [65] also found
that chronic low back pain and fibromyalgia patients display more extensive common
patterns of activation when compared to normal volunteers. Together, these studies
also corroborate with the augmented central pain processing theory.[64, 65]
16
In summary, the available neuroimaging studies seem to suggest that alterations
in brain activation patterns are consistent findings in chronic pain patients. These
alterations have been observed not only when comparing patients to controls, but also
when comparing patients during the painful state and a pain-free situation. The ACC,
thalamus and prefrontal cortex seem to be areas where these alterations primarily
occur. Nonetheless, one has to take into account that the reported studies involve
different methods and heterogeneous clinical pain conditions.
3.6. Functional Brain Imaging in Orofacial Pain
Craniofacial pain conditions, such as masticatory muscle pain, TMJ pain, dental
pain, trigeminal neuralgia, burning mouth disorder and migraines are mediated by the
trigeminal nerve (CNV).
The CNV possesses unique brainstem mechanisms and
nociceptive transmission characteristics. The CNV has a unique somatotopical
organization, as it relates to a group of nuclei at the brainstem level: the trigeminal
spinal tract nucleus, the main sensory nucleus and the trigeminal motor nucleus.[30]
The trigeminal nerve also has distinctive macroscopic anatomical characteristics, such
as the intracranial location of the trigeminal nerve ganglion and its relationship to
adjacent structures. These peculiar features of the CNV may account for significant
differences in the central neural network of trigeminal pain versus pain in the rest of the
body.
Brain imaging studies have been used to explore the pain “neuromatrix”.
However, few studies focused on the central pain network related to activation of the
trigeminal nerve. With regard to the CNV, most of the functional brain imaging studies
17
were primarily intended to gain insight in the pathophysiology of headache disorders,
such as cluster headache, [16] SUNCT (short lasting neuralgiform headache with
conjunctival injection and tearing) [66] and migraine. [67, 68] Thus, so far, the available
studies have focused mainly on midbrain, pons and hypothalamic grey activation
evoked by input from the ophthalmic nerve branch (CNV1) of the CNV and the possible
role of these areas as neurovascular pain generators.
Derbyshire et al. (1994) investigated patients with “atypical facial pain” with PET.
However, the actual painful and non-painful thermal stimuli were applied on the back of
the right hand. They reported an increased regional cerebral blood flow (rCBF) in the
ACC and decreased blood flow in the prefrontal cortex and hypothesized that this
pattern of activation may compromise central inhibitory influences towards the
nociceptive input therefore contributing to the maintenance of the pain condition. [69]
Kupers et al. (2000)[59] presented a PET study whereby a single patient
suffering from atypical facial pain was successfully treated with a thalamic stimulator.
They were able to perform functional imaging of the patient during three different states:
before thalamic stimulation (pain state), during and after thalamic stimulation (pain-free
states). By comparing the pre- and post-thalamic stimulation status they found that
there were significant rCBF increases in the prefrontal and anterior insular cortices,
hypothalamus and periaqueductal gray that were related to the presence of pain.
Interestingly, there were no significant rCBF changes observed in thalamus, SI, SII and
ACC. Significant rCBF decreases were observed in the substantia nigra/red nucleus
and in the anterior pulvinar nucleus. The authors discussed their data emphasizing
possible differences in the cerebral processing of acute and chronic pain, however their
18
results need to be analyzed with caution since it reflects measurements of a single
individual. Thayer and Friedman (2002) commented on the role of such central
networks in light of maladaptive behaviors or brain states, which they contributed to
dysfunctional inhibitory processes. They argued that dysfunction in CNS regions could
lead to “disinhibition”, which would prohibit adaptability to normally innocuous stimuli
[70].
More recently, Kupers et al. (2004)[71] have carried out a PET study that
investigated the cerebral activation network related to experimental masseter muscle
pain and skin hyperesthesia overlying the painful muscle. They reported that painful
stimulation of the masseter was related to increased rCBF in the dorsal-posterior insula,
ACC, prefrontal cortex, right posterior parietal cortex, brainstem, cavernous sinus and
cerebellum. They also found that there were no rCBF changes in the SI and SII,
however, mechanical stimulation of the skin overlying the masseter muscle was
associated with increased rCBF of the SI face representation. Hyperesthesia was also
associated with rCBF increases in the subgenual cingulate and ventroposteromedial
and dorsomedial thalamus. Based on their findings they stated that deep muscle pain
and superficial cutaneous stimulation may possess a different CNS representation.
Differentiation of deep visceral and cutaneous pain in human brains has also
been demonstrated by Strigo et al. (2003)[72]. The authors implied that different
patterns of activation within insular, SI, motor, and prefrontal cortices may account for
the ability to discriminate visceral and cutaneous pain. They also stated that the
different emotional, autonomic and motor responses associated with these different
sensations may account for the observed different pattern of activation.
19
Functional MRI data of brain activation produced by stimulation of different
branches from the CNV, other than V1, are scarce. It is largely unknown whether the
CNS network of connections related to trigeminal input is similar to the areas activated
by stimulation in other areas of the body, such as the extremities. De Leeuw et al.
studied fMRI BOLD changes in different brain regions following acute phasic heat
stimulation of the V3 branch in normal subjects, and found that heat stimulation of the
trigeminal system resulted in activation of brain regions similar to those reported in
studies of peripheral body parts. [73] DaSilva et al. [74] have also explored activation of
CNS regions created by thermal stimulation of the trigeminal system in healthy subjects.
They focused their analysis on the somatotopic arrangement of the three trigeminal
branches in the trigeminal spinal tract nucleus, thalamus and somatosensory cortex.
Contralateral activation of ventroposteromedial thalamic nucleus was observed after
CNV stimulation, as opposed to contralateral ventroposterolateral nucleus activity
displayed when the thumb was stimulated. They also reported that SI activation pattern
was similar to the trigeminal spinal tract nucleus laminar organization (V2 rostral, V1
caudal and V3 medial) and that this activity pattern in SI was not the same as the one
created by the stimulation of the ipsilateral thumb.
Iannetti et al. [75] investigated the representation of the different divisions of the
trigeminal nerve within SI and SII in humans using non-painful mechanical tactile
stimulation. They mechanically stimulated the ophthalmic and mandibular trigeminal
branches of 14 healthy individuals and encountered contralateral activation of SI and SII
that largely overlapped. They also found that while V3 stimulation activated the
contralateral somatosensory cortices alone, V1 stimulation provoked activation in the
20
ipsilateral and contralateral sides of SI and SII. This study illustrated some of the distinct
cortical representations inherent to the trigeminal nerve. It is important to notice that
these authors were only investigating tactile cortical representation of the trigeminal
nerve and not pain.
Functional MRI has also been used to locate and identify brainstem and cervical
spinal cord nuclei that are related to cranial nerves sensory and motor pathways. In an
fMRI study, Komisaruk et al. [76] used cross-correlation analysis of regional blood
oxygen level-dependent (BOLD) signal intensity during specific motor and sensory
procedures such as brushing the face, left- and right eye movement, smiling and lip
puckering, pushing the tongue against the hard palate, swallowing, tasting a sweetsour-salty-bitter mixture, finger tapping and tongue movement and trapezius muscle
activation. They were able to locate the brainstem trigeminal main sensory nucleus
among other cranial nerves nuclei. Painful stimulation was not investigated in this study.
In summary, data from the above mentioned studies suggest that in orofacial
chronic pain states (atypical facial pain) it seems like the finding of a dysfunctional brain
network is also observed. The thalamus, prefrontal cortex and ACC appear to be the
major players in such dysfunction. During thermal acute pain stimulation it is possible
that the trigeminal nerve possesses unique thalamic transmission pathways with
activation of the ventroposteriormedial nucleus instead of the ventroposteriorlateral
nucleus.
21
3.7. Burning Mouth Disorder
Burning mouth disorder (BMD) is defined as an idiopathic, constant, most
commonly bilateral, burning sensation involving intra-oral soft tissues (tongue, lips and
oral mucosa).[77, 78] According to epidemiological studies its prevalence in the general
adult population is estimated to be between 1 and 3% [79, 80]. In the United States
more than 1 million people suffer from BMD. [81] Clinical studies indicate that postmenopausal females are more frequently affected by BMD [82]. For a complete review
of BMD epidemiology and clinical characteristics refer to Fraikin et al. [83], Grushka et
al. [78], Scala et al. [84] and Rhodus et al. [85]
It has been proposed that a distinction should be made between BMD and oral
burning. Whereas the term burning mouth disorder refers to an idiopathic burning of the
intra-oral tissues, the term oral burning has been suggested to imply that the burning
sensation is secondary to certain pathological states. These pathological states include
diabetes mellitus [79, 86], xerostomic drugs, nutritional deficiencies, salivary gland
pathology, mucosal pathology (candidiasis, lichen planus, geographic tongue), gastric
esophageal reflux and parafunctional habits. Rhodus et al. [85, 87] suggest that the
treatment of oral burning complaints should aim at identification and management of
possible contributing/precipitating factors as the ones listed above. After ruling out any
contributing factors, or in the absence of a positive response of the burning complaint to
management of these contributing factors, one should consider the possibility of an
idiopathic condition and therefore name it, more appropriately, BMD. Other authors
have proposed the classification of burning mouth syndrome as being either primary or
22
secondary in light of its relationship to the same etiological issues mentioned above.
[84]
The lack of consensus with regard to a clear definition of what is generally called
BMD makes it extremely difficult to review and interpret the results of studies about this
condition. A good illustration of such difficulties is the fact that some authors [88, 89]
believe that dysgeusia and xerostomia are concomitant findings and symptoms of what
they call burning mouth syndrome. Alternatively, other researchers believe that these
factors may have a causal relationship with the complaint of burning in the oral cavity.
This relationship, however, is not well understood and can only be established by longterm studies that evaluate for instance, whether pain reduction or elimination has any
impact on the dysgeusia and xerostomia or vice-versa.
The view that BMD is primarily a psychogenic disorder has lost support as a
result of recent studies.[90] It is a common observation that depression and anxiety
disorder are very frequently reported by patients with chronic pain conditions.[91, 92] Eli
et al. [93] have demonstrated that despite of their elevated psychological profile, BMD
symptoms may not be correlated with stressful life events. In fact, Carlson et al. did not
observe any significant clinical elevations on any of the SCL-90R subscales, including
depression, anxiety, and somatization in a sample of 33 BMD patients. Great
controversies still exist about the psychogenic factors and how they relate to BMD.
Interestingly, several studies indicate that the psychological profile abnormalities may
relate to the patients’s poor coping skills regarding their pain condition. [94, 95]
The pathophysiology of BMD is largely unexplained. Yet several reports in the
literature suggest that BMD is likely a neuropathic pain condition. The first line of
23
evidence supporting this hypothesis comes from the clinical trials that demonstrate
therapeutic effects of anti-epileptic agents, such as clonazepam [96-98] for BMD.
Secondly, sensory abnormalities have been shown to exist in patients suffering from
BMD. Svensson et al.[99] stimulated the intra- and peri-oral tissues with an argon laser
and showed that thermal sensory thresholds were higher in BMD patients. They also
reported that stimulation at sensory threshold levels frequently created a faint pinprick
sensation in patients while normal subjects only described a perception of warmth. Ito et
al. [100] have also found higher thermal pain thresholds in patients with BMD. Grushka
et al. [101] did not observe differences in thermal pain thresholds but they reported that
patients with BMD had decreased pain tolerance to thermal stimulation. Gao et al. [102]
showed abnormal sensory function in patients with BMD following electrical stimulation
of the tongue. All of these studies share the opinion that BMD is very likely a
neuropathic pain condition as it may represent abnormal transduction and/or processing
of input arising from the trigeminal afferent fibers to the CNS.
Nevertheless, to date there is still a great deal of controversy regarding the
likelihood that BMD is a neuropathic disorder. Moreover, some authors appear to
implicate peripheral neuropathic pathophysiological mechanisms [88, 89, 102-107],
while others believe that central neuropathic mechanisms are main players in
BMD.[108-112] The upcoming section will discuss the studies implicating peripheral and
central mechanisms in more details.
Proponents of a peripheral pathophysiology
Grushka et al. [88] suggested that BMD may be related to selective damage to
the chorda tympani and glossopharyngeal nerves (sensation of taste). They
24
hypothesized that this deafferentation may result in a loss of inhibition to pain that
ultimately leads to BMD. Nagler and Hershkovich [89] performed a taste and salivary
analysis in BMD patients and normal controls. They observed sialometrical and
sialochemical discrepancies between the control and the patient groups. In light of their
findings, they proposed that an oral neuropathy or neurologic transduction interruption
secondary to salivary compositional changes might be an etiological factor in BMD. Gao
et al. [102] demonstrated increased trigeminal nerve sensitivity and alterations in neural
transmission within the peripheral nervous system. Lauritano et al. [103] demonstrated
the existence of subclinical polyneuropathy in 50% of patients with BMD. In particular,
they detected a loss of function in small diameter nervous fibers. Histological
examination of tongue mucosa revealed a moderate atrophy in 70% patients. Heckman
et al. [104] also demonstrated disturbances in oral mucosal blood flow in patients with
BMD that would support the peripheral pathophysiology hypothesis. Additional support
for this hypothesis comes from clinical trials supporting the use of alpha-lipolic acid for
burning mouth disorder. Alpha-lipolic acid is a potent antioxidant mitochondrial
coenzyme that has shown to posses neuroprotective function. The use of alpha lipolic
acid is though to increase the levels of intracellular glutathione and eliminate free
radicals possibly produced by the altered peripheral nerve fibers. [105, 106, 113]
Proponents of a central pathophysiology
Central nervous system mechanisms involved in the pathophysiology of BMD
have been carefully investigated by a group of researchers from Finland. These authors
provided preliminary data implicating the CNS in the pathophysiology of BMD.
Jaaskelainen et al. [108] showed that BMD patients displayed blink reflex abnormalities.
25
They hypothesized that the abnormal reflexes could be due to a decreased
dopaminergic inhibition mediated by the basal ganglia and their connection to the facial
motor nuclei. To further test their hypothesis, they performed a fluorodopa-PET study in
10 BMD patients and 14 normal volunteers. [109] They demonstrated that BMD patients
had a dysfunction of the nigrostriatal dopaminergic system which confirmed their
neurophysiologic observations. These investigators also compared 10 BMD patients
with 11 healthy volunteers to explore differences in the striatal dopamine D1 and D2
receptors with PET. This study revealed a bilateral decrease in the D1/D2 ratio in the
putamen. According to the authors, this possibly reflects a decline in endogenous
dopamine levels in BMD patients.[111] Similar results were observed by the same
researchers in patients with atypical facial pain. [110] Hence, the authors discussed the
contention that disruption of the nigrostriatal dopaminergic system may primarily affect
the regulation of nociception of the trigeminal system and cause a loss of sensory
inhibition. These findings are in agreement with experimental data suggesting a role for
the basal ganglia in the various dimensions of the pain experience.[114] Based on their
preliminary results, the above mentioned group of authors developed a more robust
investigation with 52 BMD patients. For this larger trial, they used quantitative sensory
tests (QST) and blink reflex recordings to investigate the neural mechanisms of BMD
related pain. Abnormal findings, such as, increased excitability of the blink reflex and
abnormal sensory thresholds (warm allodynia or hypoesthesia) were recorded in the
great majority of patients. The authors felt that their data strengthened the hypothesis
that BMD disorder is a neuropathic condition and very likely a combination involving a
26
peripheral neurogenic mechanism(s) and an increased excitability of higher centers
within the CNS.[112]
In summary, the available literature suggests that BMD is a neuropathic entity
with peripheral and central neural pathophysiology. It is important to recognize that
these mechanisms need further elucidation. The only available neuroimaging data to
date comes from one PET study implicating basal ganglia nuclei in the pathophysiology
of BMD.[109] It is not known whether other CNS sites are also implicated in
pathophysiology of BMD. Functional MRI studies of BMD are an unexplored field of
investigation. In general, fMRI studies have provided a significant improvement in the
understanding of pain-related CNS functioning and appear to be a promising modality
for the investigation of disorders in which CNS mechanisms are potentially involved.
3.8. Hypothesis
Since we believe that BMD is in fact a painful neuropathy with substantial
involvement of the CNS in its pathophysiology, we hypothesize to demonstrate
increased BOLD signal intensity as well as larger clusters of activity within the ACC, and
decreased BOLD signal intensity and smaller clusters of activity involving the thalamus
in BMD as compared to the normal volunteers.
In other words, we expect to
demonstrate that BMD patients have similar brain activation patterns to those observed
in previous neuroimaging studies pertaining patients with chronic neuropathic pain
conditions. These studies demonstrated somewhat consistent altered patterns of brain
27
activation that are likely related to the chronic neuropathic pain condition.[115], [116],
[21], [20], . [58] [59].
Copyright © 2004, Romulo J.C. Albuquerque
28
4. Materials and Methods
4.1. Study Design:
The study is a block design fMRI study, consisting of eight female patients with
burning mouth disorder (BMD) and a control group of eight normal subjects.
4.2. Study Population:
Participants were eight right-handed female patients, who were diagnosed with
burning mouth disorder and eight right-handed control subjects matched by gender, age
and menstrual status. The age matching procedure consisted of recruiting subjects
within a maximum of five years age difference. The criteria for diagnosis of BMD were
an at least 3 months old history of an idiopathic burning sensation of the intraoral soft
tissues. All patients were previously screened for a variety of disorders that may
account for burning of the intra-oral soft tissues. Exclusion criteria included patients with
candidiasis, nutritional deficiencies, salivary flow disturbances, lichen planus or
geographic tongue. Patients who were taking xerostomic medications and angiotensin
converting enzyme (ACE) inhibitors were excluded, if a positive relationship was
clinically established between the use of the drug and the intra-oral burning. [87] [87]
We chose 8 subjects in each group because, as a general rule, results in fMRI
studies do not seem to improve beyond 10 to 12 subjects. With 10 subjects, the
variance and heterogeneity of subjects (the noise) increases faster than the additional
signal. Activation maps from a previous study [73] with nine subjects showed regions
that were activated with t values ranging from t= 3.7 to t=6.62 at sites of peak activation.
These values correspond approximately to p values < .0001 and the activations were in
regions where an effect was predicted (thalamus, insula, PFC, ACC, SI). Becerra and
29
co-workers [48] studied two groups of eight subjects who underwent identical
stimulation protocol to evaluate reliability and consistency. They found no significant
differences in activation between the two groups. Furthermore, the power of fMRI
studies not only depends on the number of subjects, but also on the number of
measurements during each scan. Each scanning session includes 128 consecutive MRI
signal measurements in which the signal intensity is recorded for each volumetric
(3.5mmX3.5mmX3mm) space of the brain over time.
Female patients were chosen as the study population to decrease the amount of
variability in fMRI signaling within the subjects. It is not well known how gender might
affect fMRI signal. It is also noteworthy that BMD is significantly more prevalent in
females with a male/female ratio of 6:1[79] [80] [78].
We chose to include only right-handed persons to reduce further potential
heterogeneity of the sample. In general, left-handed people seem to have a less
pronounced cerebral functional and anatomical asymmetry than right-handed people.
[117, 118],[119]
4.3. Subject Recruitment Method:
The patients were recruited from the Orofacial Pain Center of the University of
Kentucky. Participants had to be native speakers of American English, have pain for
more than 3 months and have burning pain levels above or equal to 3/10 where “0”
represents no burning pain and “10” represents the most extreme burning pain.
Patients with present neurological, psychological and chronic pain conditions, other than
the burning mouth disorder were excluded. The patients were asked to discontinue any
medications that could potentially affect brain function, such as anti-depressants,
30
anticonvulsants, antipsychotics and analgesics for at least 4 half-lives prior to the
scanning session. All patients were instructed to withdraw from caffeine on the day of
the scanning session. Patients who felt that they could not discontinue their medications
or caffeine were excluded from the study. The normal volunteers (control group) were
recruited by flyers that were posted throughout public areas of the University of
Kentucky campus. All participants were paid US$ 50.00 for their participation. This
study was approved by the Office of Research Integrity from the University of Kentucky.
4.4. Research Procedures:
4.4.A. Pre-fMRI Assessments
4.4.A.1. Psychometrics.
Patients
and
normal
volunteers
completed
a
battery
of
psychometric
questionnaires, consisting of the Symptom Check List-90 (SCL-90R), Beck Depression
Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). The SCL-90R is a 90-item
self report questionnaire that yields nine symptom dimensions and 3 global indices of
functioning. It is a measure of current symptom status. It has reliability coefficients
ranging from r's=0.77-0.90 for the symptom dimensions. Measures of psychological
status included the somatization, obsessive-compulsive, interpersonal sensitivity,
depression, anxiety, hostility, phobic anxiety and paranoid ideation subscales of the
SCL-90R. Average scores for each subscale were obtained according to instructions
outlined in the scoring manual. [120] The BDI [121] is a 21-item self report questionnaire
that measures cognitive, affective, somatic and vegetative symptoms of depression.
The BDI has shown strong internal consistency (α between .81 and 88) and is widely
used in clinical and non-clinical samples [122, 123] The STAI [124] is a 40-item self
31
report questionnaire that measures state and trait anxiety using a 4-point scale ranging
from “almost always” to “almost never”. This instrument also has shown good internal
consistency (α between .90 and .93).
4.4.A.2. Thermal Thresholds and Stimulus Protocol
Subjects were pre-exposed to the thermal stimuli sequence used in the fMRI
session. First, pain thresholds were determined with the method of limits. [125]
Threshold measurements were taken with a Peltier thermode (30 x 30 mm), which was
positioned on the skin overlying the right masseter. When necessary, the stimulus
temperature for heat pain was adjusted, so that the participant rated the painful stimulus
at least “3 out of 10”, but not higher than “8 out of 10” where “0” meant no pain and “10”
represented the worst imaginable pain. This was done to assure that the test protocol
elicited pain, but not to an extent that would incur movement of the participant. The
baseline adaptation temperature was set at 32°C in accordance with several previous
publications. The thermal test sequence, as used in the scanner, started with a 35second period of a 32°C baseline temperature, followed by a 35-second period of warm
(39.5°C) non-painful stimulation. After these non-painful temperatures, pulses of painful
heat (47-49°C) were delivered during a 35-second period. After a sequence of painful
stimuli, the thermode was brought back to adaptation temperature (32°C) for 35
seconds (Figure 6). Four of these sequences of baseline, warm and painful stimulation
formed a complete thermal cycle. The stimulus temperatures were well below the limits
of potentially tissue damaging temperature ranges. The patients were also instructed to
grade on a scale from 0 to 10 how much burning they were experiencing (present
burning index - PBI) right before engaging in the MRI scanning session.
32
Figure 6 Thermal stimulation paradigm (in degrees Celsius)
4.4.B. Functional MRI Session Protocol
After the participants had completed the pre-fMRI test sequence described
above, they were guided to the MRI scanner (1.5 Tesla vision system, Siemens,
Munich, Germany). The fMRI session allowed for the collection of three-dimensional
MPRAGE structural images for co-registration of fMRI data with anatomy, that enabled
the transformation to standardized stereotaxic coordinates [61]. Functional MRI data
were collected from 44 contiguous 3 (mm) thick axial slices beginning at the level of the
inferior portion of the cerebellum and yielding whole-brain coverage. A gradient echo
EPI sequence with TE= 45 (ms), TR= 4.0 (s), and FA=90o was used for functional
imaging. The in-plane resolution was 3.5 (mm) x 3.5 (mm) with an image size of 64 x 64
pixels for a field of view of 228 (mm). Magnetic field homogeneity, particularly at the
base of the brain, was carefully optimized using the field mapping and correction
facilities of the VISION system (MAPSHIM). Following the anatomy scan, the fMRI
session for each participant involved two complete thermal cycles in which stimulation
33
was delivered to the left side of the face in a blocked design with alternating epochs of
baseline, warm, and noxious heat.
Immediately after the fMRI session, patients were asked to grade the pain levels
elicited by the thermal painful stimulation on their face on a scale from “0” (no pain) to
“10” (most extreme pain). Our goal was to produce a similar subjective experience of
pain in both groups.
4.5. Statistical Analysis
4.5.A. Psychometric and Demographic Data Analysis
In order to detect possible significant differences between the patients and
individuals from the control group regarding the psychometric tests and demographic
information we performed an independent sample t-tests. It is important to note that the
primary objective of this study was to investigate differences in brain activation patterns
with fMRI and not to investigate psychometric or demographic differences. However, if
present, observed discrepancies would need to be taken into account in the
interpretation of our results
4.5.B. Functional MRI Data Analysis
The statistical analysis was carried out with the Analysis of Functional
Neuroimaging Software (AFNI). The functional images were corrected for motion
artifacts with automated motion correction software (MATLAB and SPM99). [126]. The
three-dimensional MPRAGE structural images were transformed into Talairach
coordinates on an individual basis using AFNI Software. The anterior commissure (AC),
posterior commissure (PC) as well as two midsagittal points were used to align the
individual brains at the AC-PC plane. Other landmarks, such as most anterior, posterior,
34
superior, inferior and lateral points of the brain were also used in the Talairach
transformation process.
The EPI sequences consisted of 128 full brain images that were acquired in a
timely manner. This means that every four seconds a full brain functional image was
obtained. The 128 time points of the EPI sequences were then correlated with a time
course box car reference function (.1D files). The reference profiles were designed
appropriately so as to set up contrasts for the separate comparison of baseline
temperature vs. warm temperature, baseline temperature vs. pain temperature and
warm temperature vs. pain temperature. Thus, activation maps were calculated on a
voxel-by-voxel basis for each of the three pairings of stimulus conditions in a particular
run.
Statistical parametric maps based on the mean fractional signal change and
sample variance within each run were transformed and resampled by cubic spline
interpolation as isotropic 2 mm voxels in the standard stereotaxic space of Talairach
and Tournoux [61] using the AFNI software package [127] and spatially smoothed in
MATLAB 5 (The MathWorks, Natick, MA) using an isotropic Gaussian spatial filter with
sigma equal to 3 millimeters. Functional data were then merged across runs and across
participants using the 3dmerge AFNI auxiliary software to generate average group
activation maps for each pairing of stimulus conditions. Activation maps were created
for each study group (patients and control subjects). Comparisons between the warm
(39.5 oC) versus painful heat (47-49 oC) status were used for the construction of the
statistical maps in each group. This is because the aim of the study is to compare
supra-spinal mechanisms as it relates to painful stimulation in BMD patients versus
normal individuals. We believe that by comparing warm to painful heat we construct
35
brain activation maps that relate to painful stimulation alone and not to the processing of
a warm stimulus or a temperature change. It is also important mentioning that this
research method is a block design fMRI study. As such, painful heat stimulation was
always preceded by warm stimulation.
Maps of the difference in activation between
patient and control groups were created using an AFNI auxiliary program 3dttest, which
allows for the execution of independent samples t-tests on a voxel-by-voxel basis for the
two sets of fMRI three-dimensional data sets.
A cluster analysis for each of the two groups was performed with the use of
3Dcluster and 3dclust AFNI auxiliary software. The cluster analysis allowed us to
measure the total volume of activation throughout the entire brain. Clusters of activity of
at least 1000 µl of volume and connectivity radius of 2mm were shown in the maps.
The Talairach coordinates for the center of mass and the location of each cluster were
recorded and used for comparison between the two groups. For didactic purposes the
differences regarding the magnitude of fractional signal changes throughout different
areas of the brain (3dttest) were reported as qualitative differences and the difference in
the amount of total brain activation (cluster analysis) were regarded as quantitative
differences.
Copyright © 2004, Romulo J.C. Albuquerque
36
5. Results
5.1. Demographics and Psychophysical Tests
This study included eight BMD female patients (mean age 49.1 ± 10.1) and eight
pain-free female volunteers (mean age 50.3 ± 12.3) matched with regard to age, and
menstrual or menopausal status. Six out of the eight patients were post-menopausal
and two patients still had a regular menstrual cycle. The two patients and two controls
with a regular menstrual cycle underwent MRI scanning during the low estrogen phase,
two days following the onset of menses. There were no significant differences between
the two groups regarding age (p=.845). The BMD patients reported a mean present
burning index of 4.3 ± 2.1 on a scale from “0” (no burning) to “10” (most extreme
burning). The mean duration of the BMD was 60.5 ± 38.4 months.
A detailed
description of the patient population is shown in Table 1.
There were no significant differences between the two groups related to thermal
pain thresholds, the pre-fMRI pain rating, the test temperature applied during the fMRI
session, and the post fMRI pain rating. The pain ratings were measured on a scale from
“0” (no pain) to “10” (most extreme pain)(Table 2).
The psychometric tests revealed significant differences between the two groups
regarding the SCL-90 subscales for somatization, interpersonal sensitivity and anxiety.
The other SCL-90 subscales did not differ between groups (Table 3). There were no
differences in the BDI and STAI (Table 4).
37
Table 1. Detailed description of the patient population
Pain
Location
Age
PBI
Duration
Patient #
of Pain
[yrs.]
[months]
Tongue
41
60
7
1
and Palate
Gingival
and
4
71
120
2
Buccal
Mucosa
Gingiva
and
3
47
60
3
Buccal
Mucosa
Tongue
49
36
8
4
and Palate
Gingiva
and
3
42
36
5
Buccal
Mucosa
Tongue
and
3
55
118
6
Buccal
Mucosa
Tongue
and
3
40
24
7
Buccal
Mucosa
Tongue
48
30
3
8
and Palate
49.1
Mean
48
4.3
(10.1)
(SD)
Menstrual
Status
HRT
PM
No
PM
No
PM
No
PM
No
PM
Yes
PM
No
Regular
No
Regular
No
-
-
PBI = present burning index on a scale (0-10); HRT = hormone replacement therapy; SD = standard
deviation; PM = post-menopausal
38
Table 2. Comparison between patients with Burning Mouth Disorder (n=8) and controls
(n=8) regarding the psychophysical data.
Controls
Psychophysical
Patients Mean
Mean tt-value
p-value
Measures
t-scores ± SD
Scores ± SD
Thermal Pain
45.4 ± 4.8
47.4 ± 2.6
-1.04
.322
Threshold (oC)
Test
Temperature
47.6 ± .9
48.1 ± .8
-1.14
.273
Applied During
the fMRI Session
(oC)
Pre-fMRI Pain
5.6 ± 1.9
5.3 ± 1.7
.43
.677
Rating (0-10)
Post fMRI Pain
7.1 ± 1.4
5.8 ± 1.8
1.75
.101
Rating (0-10)
SD = standard deviation
Table 3. Comparison between patients with Burning Mouth Disorder (n=8) and controls
(n=8) regarding the SCL-90 subscales
SCL-90R
Patients Mean Controls Mean
t-value
p-value
Subscales
t-scores ± SD t-scores ± SD
61.6 ± 13.2
47.1 ± 13.1
2.21
Somatization
.044
Obsessive
64.3 ± 10.5
53.3 ± 12.1
1.86
.083
Compulsive
Interpersonal
60.0 ± 10.6
49.9 ± 7.7
2.19
.046
Sensitivity
58.3 ± 10.1
52.6 ± 10.5
1.05
.313
Depression
59.9 ± 8.7
48.0 ± 10.7
2.41
Anxiety
.030
52.5 ± 9.6
52.0 ± 14.0
0.08
.935
Hostility
51.9 ± 9.8
46.9 ± 8.1
1.11
.285
Phobic Anxiety
Paranoid
55.3 ± 10.8
46.3 ± 8.1
1.89
.080
Ideations
56.4 ± 11.8
53.5 ± 10.4
.517
.613
Pscychoticism
SD = standard deviation
39
Table 4. Comparison between patients with Burning Mouth Disorder (n=8) and controls
(n=8) regarding the BDI and STAI scores
Controls
Patients
Test-Scores
Mean Scores Mean Scores
t-value
p-value
± SD
± SD
12.5 ± 13.1
7.4 ± 7.1
.98
.346
BDI
40.6 ± 13.7
29.8 ± 10.6
1.78
.097
State Anxiety
43.0 ± 13.3
37.3 ± 12.8
.88
.392
Trait Anxiety
BDI = Beck Depression Inventory; STAI = State Trait Anxiety Inventory; SD = standard deviation
5.2. Functional MRI Data Analysis
5.2.A. Individual Group Analysis
Statistical maps were constructed and analyzed for the BMD group and the
control group individually. Voxels in which significant differences in the fractional signal
change were observed (Z=3.0; p< 0.005) are shown in figure 7 for the BMD and figure 8
for the control subjects. The maps display activation in areas that include the ACC
(BA32/24), the right and left pre-central gyrus, the right post-central gyrus, the right and
left thalamus, the right insula, the right medial frontal gyrus, the right middle frontal
gyrus, the right and the left inferior parietal lobule, right and left precuneus and
cerebellum. The left lingual gyrus and the left posterior cingulate gyrus were activated in
volunteers but not in patients.
40
Figure 7. Activation map of the BMD group (n=8)
BMD Group (Warm vs. Pain)
Cerebellum
Thalamus
Precuneus
Post-central Gyrus
Insula
ACC (BA24/32)
Pre-central gyrus
Figure 8. Activation map of the control group (n=8)
Control Group (Warm vs. Pain)
Cerebellum
Lingual Gyrus
Thalamus
Post-central Gyrus
Insula
ACC (BA24/32)
Pre-central gyrus
41
5.2.B. Between Group Analyses
5.2.B.1. Qualitative Differences
Statistical comparison (t-test) between the BMD and control group’s activation
maps revealed significant differences in the ACC (BA32/24) and bilateral thalamus. In
addition, we detected differences in the following areas: left lingual gyrus, left
precuneus, right precuneus, right middle frontal gyrus, right pre-central gyrus and right
inferior semilunar lobule of the cerebellum. The activation maps corresponding to the
above mentioned differences are presented in figure 9. The ACC (BA32/24) and the
right and left precuneus showed greater fractional signal change in patients than normal
volunteers. In the remaining areas where a significant difference was detected there
was less pronounced fractional signal change in patients than in controls (Table 5).
Figure 9. Activation map of the comparison between BMD group (n=8) and control
group (n=8)
BMD Group vs. Control Group
BMD > Control
Control > BMD
Cerebellum
Lingual Gyrus
Thalamus
Precuneus
ACC (BA24/32)
Middle Frontal Gyrus
Pre-central gyrus
42
5.2.B.2. Quantitative Differences
As a general measurement of brain activation, we calculated the total volume of
activation for each group of subjects (BMD and controls) using a cluster size threshold
of 1000 µl (approximately 27 voxels) and voxel connectivity radius of 2mm. This
analysis revealed that the BMD group (24432 µl) displayed less volumetric brain activity
when compared to the control group (92528 µl). To better categorize this discrepancy in
the amount of activation between the two groups we also compared the two groups
taking into account the total number of separate clusters above the 1000 µl threshold in
each group. The BMD group cluster analysis revealed 4 large clusters of activity while
the control group had 10 clusters. Tables 6 and 7 display the Talairach coordinate for
the center of mass as well as the size of each of the detected clusters in the BMD group
and control group respectively. It is important to notice that the total volume of activation
displayed in Tables 6 and 7 will be slightly smaller than the total volume of activation
reported above. This is because during inspection of the statistical maps we detected a
large cluster of activity embracing three distinct brain regions in the statistical maps of
the control group. This large cluster in reality represented three separate clusters
connected by a small number of voxels. We decided to erode the data in order to
separate these three clusters. For a fair comparison the activation maps of both groups
were eroded. This was done by eliminating the voxels of activity that were marginal to
the main large initial cluster. By comparing the location of the center of mass from the
patient group versus the control group we observed that the location of 3 clusters were
common to both patients and controls. The common activation areas were: right insula,
right medial frontal gyrus and right inferior parietal lobule. A large cluster involving the
43
cingulate gyrus/BA32 was found exclusively in the patient group. Clusters located at
the right cerebellum, right anterior cingulate gyrus/BA 10, left cerebellar tonsil, right and
left thalamus, right inferior frontal gyrus and right middle frontal gyrus were unique to the
control group.
Table 5. Areas of differential activation between BMD patients (n=8) and pain-free
volunteers (n=8).
Mean Fractional
Talairach Coordinate
Signal Change
Anatomical Location
z-score
(mm)
(%)
x
y
z
BMD
Control
R ACC BA32/24
2.5
23.5
31.5
.23†
.04
-3.029
L Thalamic Medial Dorsal
-13.5 -20.5
11.5
.10
.31†
3.024
Nucleus
R Thalamic Medial Dorsal
8.5
-17.5
11.5
.18
.33*
2.044
Nucleus
R Middle Frontal Gyrus
37.5
23.5
31.5
-.02
.17*
2.527
R Pre-central Gyrus
36.5
3.5
36.5
.02
.16 *
2.143
L Lingual Gyrus
-18.5 -64.5
0.5
-.05
.32*
2.267
L Precuneus
-20.5 -65.5
19.5
.37*
.02
-2.022
R Precuneus
9.5
-68.5
19.5
.15‡
-.26
-4.479
R Cerebellar Inferior
5.5
-67.5 -34.5
-.06
.44†
3.283
Semilunar Lobule
BMD = burning mouth disorder; R = right side ; L = left side ; BA = Brodmann area ; * p<0.05 ; †
p<0.005; ‡ p<0.001
Table 6. Location and size of the detected clusters of activity in the patient group
Cluster
Talairach
Cluster #
Anatomical Location
volume
coordinates
(µl)
x
y
z
1
4.1
24.3
30.7 R Cingulate Gyrus / BA 32
2344
2
43.2
8.2
4.6
R Insula*
2232
3
1.2
-3.9
53.2 R Medial Frontal Gyrus*
1744
4
37.4 -39.6
44.9 R Inferior Parietal Lobule*
1264
R = right side; L = left side; BA = Brodmann area; * = areas activated in both patients and controls
44
Table 7. Location and size of the detected clusters of activity in the control group
Talairach
Cluster
coordinates
Cluster #
Anatomical Location
volume (µl)
x
y
z
1
14.4 -58.1 -26.8 R Cerebellum
10344
R Anterior Cingulate Gyrus /
2
4.8
53.1
-0.4
5024
BA 10
3
-26.2 -50.1 -32.1 L Cerebellar Tonsil
3512
4
-12.9 -17.5
13.6 L Thalamus
2344
5
28.3
3.4
12.4 R Insula *
2080
6
0.2
37.7
30.2 R Medial Frontal Gyrus*
1928
7
9.7
-13.5
12.4 R Thalamus
1912
8
40
3.1
32
R Inferior Frontal Gyrus
1800
9
33.1
30.7
29.8 R Middle Frontal Gyrus
1096
10
50.2 -41.9
31.5 R Inferior Parietal Lobule*
1000
R = right side; L = left side; BA = Brodmann area; * = areas activated in both patients and controls
Copyright © 2004, Romulo J.C. Albuquerque
45
6. Discussion
To the best of our knowledge, the present report is the only fMRI study with BMD
patients. This study demonstrated significant brain activation (p<0.005) in both BMD
patients and normal controls in pain related areas following thermal noxious stimulation.
The activation pattern was similar to that found in earlier fMRI studies involving painful
thermal stimulation of non-trigeminal [37, 39, 48, 63] and trigeminal sites [73]. The same
activation pattern has also been observed with painful heat stimulation of the nondominant arm in PET studies [52, 128]. The activated brain regions have been
implicated in the processing of different dimensions of the pain experience. Both groups
displayed significant changes in BOLD signal (p<0.005) at the SI and thalamus. These
two structures are likely related to the sensory-discriminative aspect of the pain
experience. We also observed significant (p<0.005) activation in the cingulate gyrus.
This structure is thought to be mediating the affective-motivational portion of pain.
Activation was further observed in the cerebellum, inferior parietal lobule, frontal gyrus
and pre-central gyrus. These regions are associated with the motor response to painful
stimulation. Finally, there was activation in the insula and frontal gyrus, both of which
are implicated in the processing of pain related memories.[28, 48, 129] The activation
of these brain regions in our study population indicates that our thermal stimulus
protocol is a reliable technique of thermal stimulation for the trigeminal nerve during
fMRI acquisition as demonstrated by de Leeuw (2001).[73] In both groups the activation
of the post-central gyrus (SI) occurred in the vicinity of the area that represents the
face.[74]
46
The primary objective of this study was to demonstrate differences in the location
and extension of activation between BMD patients and normal volunteers. We
demonstrated that BMD patients process thermal painful stimulation quantitatively and
qualitatively different than normal pain-free age and gender matched control subjects. It
is worth mentioning that there were no differences in the subjective experience of pain,
or in the temperatures used to create such experience. For this reason, brain activation
discrepancies found in this study cannot be explained in terms of the subjective
experience of pain but may reflect true functional disparities between the two groups.
On the other hand, our small group size may have precluded us to find true differences
with regard to these variables. In order to characterize these differences, we chose to
analyze the data in terms of the magnitude of fractional BOLD signal change on a voxelto-voxel basis, as well as in terms of the total volume of brain activation at a threshold of
1000µl.
6.1. Qualitative Differences in Brain Activation Between Patient and Controls
In terms of the locations of significant brain activation, we were able to show that
the BMD patients had greater BOLD signal change in the right ACC (BA24/32) and
bilateral precuneus than did normal controls. ACC hyperactivity has been demonstrated
in other neuroimaging studies involving chronic neuropathic pain conditions [16, 19, 21,
22, 69]. It is important to note that there are fundamental differences between this and
the above mentioned studies. Firstly, most of these previous studies used PET as their
imaging technique. Secondly, the findings of such studies reflect changes in activation
from a painful status to a pain-free state in the same group of patients. Our study
47
involves two distinct groups of subjects and explores differences in the processing of
transient painful stimuli delivered to the division of the trigeminal nerve that is
supposedly mediating the chronic pain condition. Therefore, our data merely suggest
that BMD patients have a dysfunctional ACC (BA32/24) while the other studies, in light
of their methods, more directly imply that the ACC (BA32/24) plays a role in the
pathophysiology of the chronic pain condition. Since the ACC has also been implicated
in the processing of anxiety, [34] it may be argued that the difference of activation at the
ACC reflects greater anxiety levels in the patient group as shown by the differences on
the SCL-90 anxiety subscale between the BMD and normal controls. The effects of
psychological variables such as anxiety, somatization and interpersonal sensitivity,
which have been shown to be elevated in our patient population, must always be taken
into account in brain imaging studies.
The precuneus was another area where patients displayed a greater magnitude
of activation when compared to the control subjects. Precuneus activation has been
linked to a variety of CNS processes. It appears that this region of the brain is a
multimodal association area [130] and possesses motor and sensory functions. For
example, precuneus activation has been shown during volitional swallowing [131, 132],
locomotor-related imagery [133] and painful somatosensory hallucinations. [134] Most
importantly, precuneus has been activated during mechanical muscle hyperesthesia in
the orofacial region [71]. It is possible that precuneus hyperexcitability is implicated in
the pathophysiology of BMD, however due to its dynamic functional characteristics it is
very difficult to determine its exact role with the presently available data.
48
The thalamus was found to be differently activated in patients as compared to
controls. Generally, thalamic responses to painful stimuli reflect discriminative and
attentional networks of pain processing mechanisms.[28] This study revealed that
control subjects had significantly greater bilateral BOLD signal changes in the thalamus
than BMD patients This implies that the thalamus in BMD patients may be hypoactive.
The area of activity within the thalamus appeared to involve the dorsal medial nucleus
as well as the ventral lateral nucleus of the thalamus. However spatial smoothing of
fMRI data makes it extremely difficult to draw accurate conclusions about the activation
of such small regions of the brain. The finding of thalamic hypoactivity is in agreement
with other neuroimaging studies that demonstrated thalamic hypofunction in patients
suffering from chronic pain conditions.[20-22, 64] Thalamic hypoactivity is unlikely
related to acute pain states, because thalamic hyperactivity has been demonstrated
during acute pain conditions such as angina pectoris [135], cluster headache[17] and
dental pain.[115]. Neuroimaging studies have shown significant increases in thalamic
activity following procedures that led to cessation of chronic pain. These procedures
include cordotomy for cancer pain [58], anesthetic blocks [21] and motor cortex
stimulation for neuropathic pain [136]. Therefore, in chronic pain conditions, it is
hypothesized that thalamic hypofunction is very likely a result of persistent,
spontaneous chronic pain input. The idea that a hypofunctional thalamus may be
directly related to the pathophysiology of neuropathic pain is supported by studies in
which thalamic stimulation provides pain relief [59, 60, 137]. Kupers et al. reported a
case of a patient with chronic orofacial neuropathic pain that was successfully treated
by thalamic stimulation. They showed with PET that following thalamic stimulation and
49
subsequent pain relief, there was an increase in rCBF in areas of the brainstem that are
often linked with descending inhibition of pain, such as the periaqueductal gray matter.
Consequently, it is thought that the hypofunctional thalamus does not allow for
adequate descending inhibition during chronic pain states. The present findings indicate
this may be the case for BMD as well.
This research showed that the control group also had significantly greater BOLD
signal increases in the right middle frontal gyrus, right pre-central gyrus, right cerebellar
inferior semilunar lobule and left lingual gyrus as compared to the BMD group. The right
middle frontal gyrus is the supplementary motor area (SMA) and it has shown to be
activated in other functional neuroimaging studies of pain [49, 138, 139]. Presumably,
the SMA is involved in the planning and readiness for a withdrawal response secondary
to pain.[128] The pre-central gyrus is the primary motor cortex and it has also displayed
rCBF changes during painful stimulation. The activation of this area is primarily related
to volunteer motor activities; however, in neuroimaging pain studies it is postulated that
its activation may also reflects withdrawal reaction or movement refrain [28]. Activation
of the cerebellum has been described in neurofunctional studies of pain.[17, 37, 43, 65,
71, 72, 138, 140] It is hypothesized that the cerebellum is involved in motor planning, as
well as in the cognitive, affective and nociceptive processing of pain. Recent evidence
reinforces the premise that the cerebellum is in fact involved in pain intensity encoding.
[141] Despite the similar subjective experience between the two groups the control
group displayed greater activation in areas responsible for the processing of motor
response, for instance cerebellum, SMA and pre-central gyrus. Interestingly, stimulation
of motor cortex has been shown to relieve neuropathic pain.[136] Given the diminished
50
response in BMD patients compared to controls, it could be postulated that these
cortical areas, primarily involved in motor function, also play a significant role in
descending inhibitory processes.
The lingual gyrus is part of the visual cortex; it is located within the occipital lobe.
Its function has been linked to the visual perception of motion [142, 143]; it has been
implicated in semantic language processing [144] and it has also been reported as a
site of processing aversive visual stimuli [145, 146]. In the present study, activation of
the lingual gyrus in the absence of a specific visual task is interesting. The relationship
between the lingual gyrus and pain processing is not understood.
In summary, this study showed significant qualitative differences in brain
activation patterns between BMD and normal controls. These differences are likely
related to a dysfunctional brain network present in BMD patients. These findings will be
the foundation for the development of a working hypothesis regarding BMD
pathophysiology.
6.2. Quantitative Differences in Brain Activation Between Patient and Controls
In terms of extent of brain activation, the present study showed that normal
volunteers had greater total volume of brain activation in response to the painful
stimulation than BMD patients. Additionally, our cluster analysis (size threshold of
1000µl) revealed that volunteers were able to activate more brain regions than did BMD
patients. Whereas only four clusters of activation were detected in patients, 10 were
detected in the normal volunteers. While a similar analysis methodology was used in a
51
neuroimaging study with fibromyalgia patients, contrasting results were found. [64] The
study reported that fibromyalgia patients showed a greater number of activated brain
areas than controls. The authors discussed their data in terms of cortical and subcortical
augmentation of pain processing in fibromyalgia patients. The increased number of
activated brain regions found by Gracely et al. may be related to several factors. Firstly,
they used the same stimulus intensity for all participants. Since fibromyalgia patients
have lower pressure pain threshold they produced different subjective pain ratings
between patients and volunteers. In our study we were able to create the same
subjective pain experience with equal stimulus intensities. Secondly, our study used
thermal stimulation of the trigeminal nerve, while they used mechanical stimulation
(pressure) to the left thumb nail. Thirdly, the difference between our study and Gracely
et al.’s may be secondary to the fact that fibromyalgia is a widespread pain and not a
focal and localized condition such as BMD. Our findings of diminished number of
clusters and total volumetric activity coupled with the previously mentioned qualitative
discrepancies in BMD patients as compared to normal controls may be interpreted as
representing impaired brain network connectivity dynamics essential for inhibitory
control. Thayer and Friedmann (2002) [70] reported that the behavior of living systems
may be defined as a self-organizing dynamic system. Moreover, they suggested that
inhibitory processes allow these systems to efficiently function in the face of changing
environmental demands. They also mention that the process of sensitization does not
always imply overall hyperactivity but it may be defined as a loss of inhibitory neural
processes leading to maladaptive activation of fewer brain pathways. Our findings imply
that BMD patients process acute thermal stimulation less dynamically than do normals.
52
Our theory is that patients with BMD have a diminished inhibitory control of sensory
experiences and as a consequence of such they may be more likely to experience intraoral proprioceptive information as burning pain. This theory of overall brain hypofunction
in BMD is supported by other studies where hypoactivity of the nigrostriatal
dopaminergic system was documented in BMD patients.[109, 111] It is possible that,
because of the multiple connections that exist between thalamus and the basal ganglia,
the thalamic hypofunction shown in BMD patients is primarily responsible for the
hypoactivity of the nigrostriatal dopaminergic system. It is also possible that the
hypofunctional thalamus is playing a crucial role in diminishing brain connectivity
dynamics. Hypofunction of the thalamus has been described in other chronic
neuropathic pain conditions and it may not be an exclusive feature of BMD.[21, 58] In
summary, these findings suggest quantitative differences in brain function between
patients with BMD and normal volunteers. These results support the development of a
working hypothesis that BMD may be a consequence of diminished brain dynamics that
lead to the perception of burning in the intra-oral tissues. In fact, the hypothesis of
overall brain hypofunction is an alternative explanation for why systematic literature
reviews describe cognitive behavioral therapy among the most efficacious treatment
modalities for BMD.[147, 148] Based on our findings, we might postulate that cognitive
behavioral therapy promotes brain dynamics leading to relief of the burning sensation. It
has been shown with PET and fMRI that cognitive behavioral therapy and relaxation
techniques are capable of changing brain activation patterns as well as sympathetic
activity [149, 150] The cognitive engagement that comes as a consequence of cognitive
behavioral therapy and relaxation may stimulate critical regions of the brain, such as the
53
cerebellum [150] just enough to re-establish inhibitory processes that have not been
functioning adequately.
It is very difficult to draw conclusions regarding differences in specific areas of
the brain and how they may relate to the pathophysiology of BMD. Despite the fact that
we found areas that were differentially activated, trying to assign a specific function to a
defined area of the human brain is very difficult as the brain involves multiple interacting
structures. The processing of sensory information by the CNS is very dynamic; and it is
possibly very different from individual to individual. It is important to note that our data
support our hypothesis that BMD patients would display brain activation patterns that
are similar to those reported in patients with chronic neuropathic pain (hypofunctional
thalamus, hyperfunctional ACC (BA24/32)). We also postulate that brain areas primarily
involved in motor tasks may be important for the descending inhibitory system and may
be playing a key role in the pathophysiology of BMD.
So, the question becomes how
can one behaviorally “activate” the thalamus and other CNS sites so it can do their
behavioral inhibitory work? This should be the focus of future investigations in this
newly emerging field.
6.3 Future Research Directions
Future studies should investigate if the same fMRI paradigm reveals similar
patterns of brain activation in other focal chronic neuropathic pain conditions in the
orofacial region, for example, continuous neuropathic pain.
Similar studies with
musculo-skeletal chronic pain conditions, for instance masticatory muscle pain
disorders, would also be warranted. These studies may help determine if the activation
54
patterns described above are unique features of BMD, other focal neuropathic pain
conditions, or just any chronic orofacial pain state.
Future studies should also investigate the effects that cognitive behavioral
therapy, diaphragmatic breathing and other behavioral strategies have in brain
activation patterns. Special attention should be given to how these behavioral
techniques modulate thalamic activity. Our working hypothesis of a hypofunctional brain
in BMD patients and the current evidence that cognitive behavioral therapy is an
effective treatment for this condition[147, 148] lead us to believe that these behavioral
approaches could potentially correct the maladaptive changes in brain function.
In light of its invasiveness, thalamic and other CNS stimulators may not be the
primary focus of investigation for BMD. However, studies involving such devices would
certainly help clarifying the implications of brain hypofunction in BMD. Thalamic
stimulators have been used in the treatment of neuropathic pain conditions [59, 151]
Stimulation of thalamus and other CNS sites (motor cortex, spinal cord) [14, 136, 152]
increased activity in the different brain regions and significantly decreased persistent
neuropathic pain conditions. Finally, studies on the role of primarily motor function
related brain areas in the descending inhibition processes are also warranted.
6.4. Study Limitations
The small sample size and consequent diminished statistical power put in
question the reliability of our psychophysical data (potential for type II error). In terms of
fMRI statistical analysis our sample size appears to be adequate. It would have been
better if we had recruited a larger number of patients with BMD from which
55
psychophysical data could be collected. After collection of psychophysical data, a
smaller sample of these patients could be randomly assigned to undergo fMRI
scanning. This alternative design would provide us more power regarding our
psychophysical conclusions. It is important mentioning that our psychophysical data
analysis was in agreement with other larger studies with BMD patients.[101, 153]
Another point that needs to be taken into account, as a limitation of this study, is
that there was potential bias in the selection of patients. Patients who were taking
medications that interfered with brain functioning, such as, antidepressants or
benzodiazepines; and who were unable to discontinue such medication were excluded
from this study. It is possible that only patients with milder cases of BMD were included
in our patient sample.
The large age range of our patient population and normal volunteer group could
have serious implications in our fMRI data analysis. It is well known that the brain
atrophies with age.[154] This could account for a large variability in brain anatomical
features and may have influenced our data in a negative way during the normalization
process and construction of three dimensional statistical maps. The tight matching
criteria of our study should have made this issue less problematic.
Copyright © 2004, Romulo J.C. Albuquerque
56
7. Summary
To the best of our knowledge, the present study is the only fMRI study
concerning BMD. This research’s results showed that BMD patients possess different
patterns of brain activation compared to normal volunteers, as it relates to an acute
thermal stimulation of the trigeminal nerve. These differences were qualitative and
quantitative It was demonstrated that BMD patients have brain activation patterns
similar to those reported in other neuropathic pain conditions.. When compared to
volunteers, patients with BMD showed greater BOLD signal changes in the ACC
BA32/24 and bilateral precuneus; and diminished BOLD signal changes in the bilateral
thalamus, right middle frontal gyrus, right pre-central gyrus, left lingual gyrus and
cerebellum.
It was also demonstrated that patients with BMD displayed far less
volumetric activation throughout the entire brain compared to the control group. This
study’s findings strengthen the theory of a central neuropathic mechanism for BMD and
have led to the development of a theory regarding the pathophysiology of BMD as it
relates to an overall hypofunctional and less dynamic brain.
Copyright © 2004, Romulo J.C. Albuquerque
57
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Vita
Bibliographical information
Name: Romulo Jose Cunha Albuquerque
Date of birth: February 08, 1976
Place of birth: Recife, PE, Brazil
Education
Fellowship in Orofacial Pain, from July 1, 2000 to June 30, 2001. University of
Kentucky College of Dentistry, Lexington, KY, USA.
DDS, from February 1996 to October 2000. University of Pernambuco College of
Dentistry, Recife, PE,Brazil.
Professional positions held
Resident (Full-Time) at the Orofacial Pain Center, from July, 2001 to June, 2002.
University of Kentucky College of Dentistry, Lexington, KY, USA.
Private Practice, from October 2000 to at Recife, PE, Brazil.
Fellow Dentist at the Orofacial Pain Center from the University of Pernambuco, from
August 1998 to December 2000. College of Dentistry, Recife, PE, Brazil.
Volunteer Dentist at the Pediatric Dentistry Department, from June 2000 to January
2001. Santo Amaro Dental Care Unit, Recife, PE, Brazil.
Professional affiliations
Member of the Kentucky Pain Society
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