Table Of ContentCHRONIC PAIN AND BRAIN
ABNORMALITIES
CHRONIC PAIN
AND BRAIN
ABNORMALITIES
Editor
CARL Y. SAAB
Brown University, Providence, RI, USA
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Dedication
To Rafa, Sofia and Adam who promised to read this book, one day
Preface
This book is largely the brainchild of conversations ad-hoc to the
Society for Neuroscience annual convention in Washington D.C.,
November 2011. I had the honor and privilege at that event to chair a
Symposium entitled “Chronic Pain and Brain Abnormalities” by lead-
ing experts in the field of pain physiology. The speakers, including
several of the authors of this book, discussed clinical data showing
electrophysiological evidence for aberrant neural activity in the brains
of patients with chronic pain, in parallel with basic science evidence
from animal models of pain, which was corroborated by imaging data
suggestive of disrupted brain networks. Soon after the symposium, it
became clear that the subject matter and the topics presented merited
follow-up discussions in a book format. Such a book, we hoped, would
offer the reader better appreciation of the fundamentals of pain-related
abnormalities in the brain, as well as present and futuristic overviews
of emerging neurotechnological and theoretical tools available to study
these changes.
When John Lorber was presented with a young student of an above
average IQ, a first-class honors degree in mathematics, and normal social
skills, yet had virtually ‘no brain’ due to severe hydrocephalus, he asked
rhetorically “is a brain really necessary?”.1 Dr. Lorber further contended
“there must be a tremendous amount of redundancy or spare capacity in
the brain, just as there is with kidney and liver.” Indeed, a skeptic may
question whether a brain is at all necessary for pain, and if so, which
parts of it? Our response is that great strides have been made recently
that have helped us better tackle such dramatic claims by showing that
not only is a brain obviously necessary for the pain experience, but that
a brain needs to function properly within a very narrow range of activity
patterns to allow for normal feelings and thought processes. Disrupting
the exact timing of action potential discharges of single neurons within
a millisecond range, or shifting network oscillations between neuronal
networks by a few Hz may lead to devastating effects at the sensory and
cognitive levels.
We believe this book provides broad scholarly references for pain
practitioners, clinicians, scientists, therapists and biomedical engineers
inspiring to design the next generation neurotechnologies for probing
brain circuitry and modulating brain function. We share the vision that
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PREFACE
research into the mechanisms of pain in the brain, whether considered
simply correlative to, or causative of the pain experience, is a win–win
strategy that will potentially bring chronic pain patients closer to objec-
tive diagnostics and more effective therapies.
Carl Y. Saab, Editor
Reference
1. Lewin R. Is your brain really necessary? Science. 1980;210(4475):1232–1234.
List of Contributors
Daniel M. Aghion Department of Neurosurgery, Rhode Island Hospital and
Hasbro Children’s Hospital and Brown University, Alpert School of Medicine,
Providence, RI, USA
Radi Al-Masri Department of Endodontics, Prosthodontics and Operative
Dentistry, Baltimore College of Dental Surgery, University of Maryland
Baltimore, Baltimore, MD, USA
Lino Becerra P.A.I.N. Group, Boston Children’s Hospital, Harvard Medical
School, Waltham, MA, USA
David Borsook P.A.I.N. Group, Boston Children’s Hospital, Harvard Medical
School, Waltham, MA, USA
Garth Rees Cosgrove Department of Neurosurgery Rhode Island Hospital
and Hasbro Children’s Hospital and Brown University, Alpert School of
Medicine, Providence, RI, USA
Asaf Keller Department of Anatomy and Neurobiology, University of Mary-
land School of Medicine, Baltimore, MD, USA
J.H. Kim Department of Neurosurgery, Ansan Hospital, Korea University,
Seoul, Korea
K. Kobayashi Department of Neurological Surgery, Division of Applied
Systems Neuroscience, and Department of Advanced Medical Science, Nihon
University, Tokyo, Japan
Frederick A. Lenz Department of Neurosurgery, Johns Hopkins University,
Baltimore, MD, USA
C.C. Liu Department of Neurosurgery, Johns Hopkins University, Baltimore,
MD, USA
Rodolfo R. Llinás Department of Physiology & Neuroscience, NYU School of
Medicine, New York, NY, USA
T.M. Markman Department of Neurosurgery, Johns Hopkins University,
Baltimore, MD, USA
Eric Moulton P.A.I.N. Group, Boston Children’s Hospital, Harvard Medical
School, Waltham, MA, USA
Eric Newman P.A.I.N. Group, Boston Children’s Hospital, Harvard Medical
School, Waltham, MA, USA
Carl Y. Saab Brown University, Providence, RI, USA
Kerry Walton Department of Physiology & Neuroscience, NYU School of
Medicine, New York, NY, USA
J.C. Zhang Department of Neurosurgery, Johns Hopkins University, Baltimore,
MD, USA
xiii
List of Figures
Figure 2.1 Potential Basis Morphological Changes. A number of 21
physiological mechanisms have been proposed to explain the
gray and white matter changes visible in neuroimaging studies.
Decreased GM volume could be explained by
A a decrease in the number of neurons due to neuronal death,
B decreased vasculature, C and/or changes in dendritic spine
morphology such as decreased spine length and decreased
branching. Alterations in WM integrity could be explained by
D demyelination of axons, E axonal pruning, and/or F decreased
fiber density. These WM physiology alterations are thought to be
measured by FA G. FA decreases as number of axons decreases,
axons become less tightly packed, axonal diameter decreases,
and myelination decreases.
Figure 2.2 Gray Matter Changes in Chronic Pain. Cortical GM Differences 23
Between Three Chronic Pain Conditions (CBP, CRPS, OA).
C shows a comparison of areas of decreased GM density
between CBP patients (red), CRPS patients (yellow), and OA
patients (blue).
Figure 2.3 Default Mode Networks (DMN) in Chronic Pain. Activation 28
differences between CBP patients and healthy controls.
Compared to healthy controls, CBP patients exhibit deactivation
in the medial prefrontal cortex, amygdala, and posterior
cingulate/precuneus during an attention task.
Figure 2.4 White Matter Changes in Chronic Pain. Comparison of white 29
matter integrity (FA and tractography) between CRPS patients
and healthy controls. A shows decreased FA in CRPS patients
in a cluster within the left callosal fiber tract, adjacent to the
anterior cingulate cortex. B shows probabilistic tractography
using the region of decreased FA white matter as the seed. CRPS
patients exhibited decreased probability of connections between
the seed and the posterior cingulate as well as decreased
connectivity between the seed and the left hemisphere.
Figure 2.5 Comparison of Cortical Thickness Between CLBP Patients and 31
Healthy Controls following Treatment. A shows areas of thinner
cortex in CLBP patients as shown by positive t-values (red/
yellow). B shows random-field theory-based cluster-corrected
maps of cortical thinning in CLBP patients compared to healthy
controls. D shows uncorrected and corrected statistical maps
for patients who responded to treatment. Arrows point to the
cortical thickening that took place in the left DLPFC.
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LIST OF FIGURES
Figure 2.6 Effects of Chronic Opioids on Brain Structure/Function. 34
Inter-dependent amygdalar structural and functional changes
observed in prescription opioid-dependent subjects. A shows
the inter-dependent relationship between amygdalar volume
and functional connectivity. B shows the inter-dependent
relationship between amygdalar WM FA and functional
connectivity.
Figure 3.1 A shows spike trains for three different categories of firing 47
patterns. B shows rasters and C shows n versus n + 1 plots for
these categories as labeled.
Figure 3.2 Maps of Receptive Fields (Rfs) and Projected Fields for 51
Trajectories in the Region of the Principal Sensory Nucleus of
the Thalamus (Vc) in a Patient with Spinal Cord Transection at
Thoracic Level 8. A: Trajectory in the 15 mm lateral parasagittal
plane (Lat 15 mm) through the region of Vc that represents
the arm. B: trajectory 2 mm lateral to the 1 st (Lat 17 mm).
Top panels in A and B: position of the trajectory relative to
nuclear boundaries as predicted radiologically. The anterior
commissure (AC)-posterior commissure (PC) line is indicated
by the horizontal line in the panel, whereas the trajectories are
shown by the oblique lines. Ticks at right of trajectory: locations
of cells. Long ticks: cells with RFs. Short ticks: cells without RFs.
Stimulation sites are shown at left of the trajectory. Long ticks:
Somatosensory response to stimulation. Short ticks: No response
to stimulation. The “region of Vc” (Fig 4) includes sites 7–23 in
A and sites 9–23 in B. Scales are as indicated. The position
of nuclei is inferred from the AC–PC line and so is only an
approximation of nuclear location. Abbreviations: Vcpor,
ventralis caudalis portae; Vcpc, ventralis caudalis parvocellularis;
Lim, limitans; MG, medial geniculate; WM, white matter below
the ventral nuclear group; Vim, nucleus ventralis intermedius.
Bottom panels in A and B: paired figures for sites as numbered
in the middle panel. Figurine at right: RF. NR: cell without RF.
Figurine at left: PF for threshold microstimulation (TMS) at that
site. Number below figure: threshold (microamperes). At all
sites along both trajectories where sensations were evoked, that
sensation was described as tingling.
Figure 4.1 Comparisons of Mean Spectra Energy (power ratio 7–9 Hz: 63
9–11 Hz) in Three Groups of Patients and Control Group.
Patients in which the SCS did not bring relief (boxes) and those
with deafferentation pain (diagonal lines) has significantly more
low-frequency activity than the control group (vertical lines)
and patients with successful SCS (horizontal lines) The last two
groups were not significantly different. (*p < 0.05) Subject group
comparisons using a Mann-Whitney (unadjusted, one-sided
comparison) test found that the control group MSE ratio was
significantly different (p = 0.048) from the deafferentation group.
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LIST OF FIGURES
Figure 4.2 Example of Localization of Theta Activity in a Patient with 64
Brachial Plexus Avulsion Pain. Activity is localized to the
contralateral somatosensory cortex and bilaterally to the mesial
orbitofrontal ortices. Scale nA/mm2.
Figure 4.3 Example of Localization of Theta and Gamma Activity in a 68
Patient with Trigeminal Neuralgia Pain. Localization of a source
theta band A (4–8 Hz) and gamma band B activity (35–55 Hz)
in orbital frontal region on patient’s MRI. Such co-localization
is consistent with high frequency activity adjacent to low
frequency activity according to the edge effect in thalamocortical
dysrhythmia.
Figure 5.1 Coronal T1 weighted MRI of bilateral DBS electrodes in the 80
ventral striatum of a patient with intractable atypical facial pain.
Figure 5.2 Sagittal T1 weighted MRI of anterior cingulotomy lesion <48 90
hours after surgery with dramatic pain relief in a 47 year old
woman with diffuse osseous metastases.
Figure 6.1 Schematic of the main neuronal circuit components discussed in 108
this chapter. Green arrows represent excitatory connections, and
red arrows are inhibitory. Line thickness represents the strength
of the connection.
