*EEG as a predictor for acute postoperative pain and the development of chronic postsurgical pain after breast cancer surgery*

A worldwide clinical observation is that a certain number of patients who have
undergone surgery suffer from acute postoperative pain. Despite interventions
such as implementation of acute pain services and specific pain management
procedures, a significant number of patients experience acute postoperative
pain and develop chronic postsurgical pain (CPSP). CPSP is characterized as
continuous or recurrent pain, persisting beyond normal healing time. The term
*chronic* refers to a period exceeding three months. Several studies reported
negative consequences of postoperative pain and CPSP, ranging from immediate
internal physiological problems (cardiac, pulmonal and gastrointestinal),
prolonged recovery time, psychological complaints such as depression, anxiety
and a decreased quality of life, as well as socio-economic problems (resumption
of work and extra use of the health care system).
There is consensus that chronic pain states are multidimensional in nature. A
large body of literature exists, illustrating the effects of somatic,
psychological and socio-cultural factors in both the development and
maintenance of chronic pain. How these multidimensional factors are
interrelated is still the topic of much debate and research.
Especially patients undergoing breast surgery are at risk of developing CPSP.
Estimates of the prevalence of chronic pain after breast surgery have been
presented in a recent study in Denmark. Of 1543 patients 13% perceived severe
pain and 39% reported moderate pain. In another study of 196 patients, 20% had
severe pain in the first month after a partial or complete mastectomy. Besides
the damage of the operation and therefore the level of acute pain, at least
three (psychological) factors may play a role in the chronification process:
First, being aware of the probability of having a life-threatening disease is
emotionally severely distressing. Second, as was shown recently, response
expectancies, coping strategies, optimism (catastrophizing thoughts about
post-surgical complaints and outcome) are likely to contribute to patients*
experiences of complaints after breast surgery. Third, the physical integrity
of the feminine body, by lumpectomy or mastectomy, is damaged, having several
possible consequences at the psychological level (depression, disturbed body
image, sexual / relational problems, etc).
In attempts to predict CPSP, at least four categories of variables have been
investigated: patient characteristics, preoperative psychological variables,
operation-related variables and genetic factors (see figure 1), with
suggestions of increased risk related to factors from all categories.
In order to measure psychological variables, studies almost without exception
rely on self-report questionnaires. It is known, however, that data derived
from such questionnaires are subject to several forms of bias. As a result, a
trend in recent studies is to validate questionnaire-based data with objective
psychophysiological measures. An example is the work by Vossen et al. who tried
to demonstrate how subjectively reported pain is associated with specific EEG
parameters, namely the N2 and P3 components of the pain event-related potential
(ERP). The authors concluded that ERP was associated with self-reported pain in
daily life up to two weeks later. Furthermore, it was demonstrated that
depressed patients with chronic back pain showed less habituation to
experimental pain stimuli. Another study by Nir et al utilized continuous EEG
to investigate the properties of peak alpha frequency (PAF) as an objective
cortical measure associated with subjective perception of tonic pain.
Additionally, a study investigated the mechanism of attentional effect of pain.
Pain was closely associated with changes in neuronal gamma oscillations in the
human brain. The authors stated that in the hypervigilant state of chronic
pain, maladaptive changes in the attentional effects of pain may be associated
with abnormal changes in neuronal gamma oscillations. This may represent a
possible mechanism in the pathophysiology of chronic pain.
In sum, it is known that several pre- and perioperative factors play a
predictive role in the severity of acute postoperative pain and the development
of CPSP. Additionally, EEG measurements associated with pain are emerging, but
prediction of clinical pain with EEG has not been studied yet. Furthermore, in
the field of chronic pain, the onset of psychophysiological mechanisms remains
to be elucidated. Thus EEG measures may be informative in this regard, and may
give us a more objective measure of pain.


This study focuses on predictability of acute postoperative pain as well as
CPSP based on the results of five so called psychophysiological *vulnerability*
experiments.
1. Experiments investigating attentional bias towards pain. In a recent review,
the significance of attentional bias towards pain as a risk factor in the
chronification process of pain was demonstrated. Therefore, the hypothesis that
in a population of breast cancer patients attentional bias towards pain-related
words is associated with cortical activity, as measured with EEG / ERP,
requires further examination.
2. A large body of literature exists, showing an association between abnormal
stress reactivity (measured as muscle-reactivity and heart rate) and the
development of chronic pain. Rehabilitation centre *t Roessingh in Enschede in
the Netherlands has substantial experience in performing such experiments, and
many articles supervised by Prof. Hermens have been published.
3. As already mentioned above, a dissertation project carried out at Maastricht
University demonstrated the importance of abnormal habituation as a possible
mechanism in the chronification process of pain.
4. Mood reactivity can be experimentally manipulated by so called *mood
inductions*. Examples are: looking at pictures or movies with different
emotional content. Especially in research concerning depression, the degree of
reactivity seems to be a significant *vulnerability* parameter. Because of the
strong relationship between chronic pain and depression, abnormal mood
reactivity might also be an important factor in the chronification of
postoperative pain.
5. Recently, a brief task was developed assessing variation in detecting
affectively meaningful speech (speech illusion) in neutral random signals
(white noise) and the
degree to which this was associated with psychological instability, which is
also predicted to contribute to development of pain as an underlying marker of
affective dysregulation, a phenomenon which is likely to occur in varying
degrees after breast surgery.

Apart from a preoperative baseline-EEG and the five vulnerability experiments,
a second follow-up EEG is required in order to yield insight into cortical
responsiveness to the five vulnerability experiments changes over time, and how
this is associated with changes in pain perception. Stated in another way: a
follow-up EEG enables us to investigate changes in the EEG between patients
with or without CPSP, and changes therein.
More insight into the five psychophysiological vulnerability mechanisms may
help in the process of identifying patients *at risk* (based on a preoperative
assessment EEG-protocol), for developing acute postoperative pain and CPSP.
Secondly, the protocol may be used as a tool to evaluate the effect of future
(preventive) interventions. Finally, the results may lead to the development of
new *tailor-made* treatments.
The choice of patients undergoing breast cancer surgery is deliberate: First,
the vast majority of these patients do not experience pain in the region of the
breast preoperatively. This is in contrast to most other populations undergoing
an operation. Second, it is known that crucial psychological factors such as
depression and anxiety (which influence the development of chronic pain) are
prominent. The occurrence of depression and anxiety in breast cancer patients
lies between 25-35%. Third, the observed prevalence of CPSP in this group is
relatively high, at 20-52%.

Primary Objective:
1. A search for (objective) EEG predictors (independent variables) for both
acute and chronic postoperative pain (dependent variables) after breast cancer
surgery. The EEG variables are derived from the above mentioned five
vulnerability experiments.

Secondary Objectives:
1. To determine if, in response to the five vulnerability experiments, there
are changes in cortical processing in relation to the chronification process of
postoperative pain.
2. To compare the EEG/ERP t0 and t6 months results in the breast surgery
population with a general (non-surgical, female) population with respect to the
development of chronic pain.
3. Determination of the prevalence of CPSP after mamma surgery in MUMC.
4. To compare the influence of psychosocial factors, measured with
questionnaires between breast cancer patients and patients undergoing a
hysterectomy with no underlying cancer (see the Peeters, Theunissen, Marcus et
al study currently being performed in the MUMC).

A prospective cohort study with five moments of assessment:

a. preoperative
b. perioperative up to day 4 postoperatively
c. follow-up 1 (at 3 months)
d. follow-up 2 (at 6 months)
e. follow-up 3 (at 12 months)

Preoperatively and at 6 months, the assessments consist of an
psychophysiological (EEG, ECG, EMG) registration while performing the five
vulnerability tasks, as well as several health-related and psychological
questionnaires.
Perioperative data concerning type of surgery, amount of analgesia, and
subjective pain ratings are collected. In the first four days after surgery
patients are asked to complete a pain diary. At follow-up 1 and 3 a
questionnaire measuring the presence of CPSP and health status is mailed.

There is no benefit for patients participating in the study. No financial (or
other) reward will be given. Travel expenses will be compensated. There are no
risks involved. We estimate the burden for the patient to be moderate because
of the following two factors:
1. A twofold EEG measurement (of two and a half hours each), which takes place
at the university, outside the hospital.
2. The completion of several pain- and health related questionnaires, which is
approximately 1 hour before the operation and 30 minutes at three months, six
months and at one year follow-up