Keywords: Migraine Disorders - Medication Overuse Headache - Orbitofrontal Cortex - Diffusion
Tensor Imaging
Palavras-chave: Transtornos de Enxaqueca - Cefaleia por Uso Excessivo de Medicamentos - Córtex Pré-Frontal
- Imagem por Tensor de Difusão
INTRODUCTION
Migraine is the most common primary headache impacting the population of patients
who are at a younger and more productive age[1 ]. Comorbid conditions that occur with severe debilitating headaches lead to serious
social and economic burdens. Neuropsychiatric symptoms such as anxiety (particularly
panic and phobia), depression, bipolar disorder, obsessive-compulsive disorder and
nicotine dependence, along with psychiatric disorders such as substance abuse[2 ],[3 ], frequently accompany migraine[3 ].
Medication overuse headache (MOH) occurs mostly among patients who have chronic migraines.
It has been observed that MOH develops in 8.2% of the migraine patients living in
Brazil[4 ]. MOH recurs in nearly 30% of the patients within one year following discontinuation
of pain medication and adjustment of the treatment[5 ]. Given this knowledge and studies that have assessed the association between migraine
and substance abuse, it is considered that there is a predisposition link between
migraine and substance abuse[3 ].
The basic features of substance abuse, such as compulsive drug use and drug-induced
recurrence, have been found to be partially caused by changes in the functioning of
the orbitofrontal cortex (OFC)[6 ],[7 ]. Through hypofunctioning of the OFC, the inhibition mechanism is impaired[8 ], and this induces an increase in impulsivity and deterioration in reward and decision-making
mechanisms[6 ],[9 ]. This is observed among substance abusers and contributes to development of MOH
in migraine patients. In a PET study, glucose metabolism was measured before and after
drug withdrawal in chronic migraine and MOH cases, and several regions of the brain
that are associated with pain were found to be hypometabolic. However, they were rapidly
reactivated upon withdrawal of analgesics. On the contrary, it has been observed that
hypometabolism in the OFC remained despite drug withdrawal, and it has been put forward
that this might be associated with relapses among MOH patients[10 ]. Given this information, we established the hypothesis of our research on the premise
that MOH could develop as a result of behavioral pathologies induced by structural
impairments in the OFC of migraine patients.
Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that
is used to map and characterize the three-dimensional diffusion of water as a function
of spatial location. Several DTI parameters are used to assess diffusion and, indirectly,
fiber tract microstructure. DTI shows where neuronal/axonal loss occurs as a result
of neurodegeneration and inflammation. Fractional anisotropy (FA) measures the anisotropic
diffusion of water molecules and the average diffusion coefficient (ADC) describes
the magnitude of the average molecular displacement through diffusion[11 ]. In the literature, only a limited number of neuroimaging studies have been conducted
among migraine patients who developed MOH, and there[10 ],[12 ],[13 ] is no study that has assessed the OFC through DTI.
In our research, we aimed to compare the OFC of patients with and without MOH, through
the method of region of interest (ROI) based on DTI.
METHODS
Study procedure
Our research was designed as a prospective, observational cross-sectional study. The
study was performed in accordance with the ethical guidelines that were stated in
the “Helsinki Declaration” and was approved by the Gaziosmanpasa Training and Research
Hospital Ethics Committee. Written informed consent was obtained from the participants
after they had been given precise explanations about the scope of the procedures.
Participants
Eighty-two patients who had been admitted to the neurology outpatient clinic and diagnosed
with migraine were included in the study. The inclusion criteria were that the participants
needed to be between the ages of 18‒65 and to be diagnosed with migraine based on
the International Classification of Headache Disorders (ICHD-III-B). This classification
states that migraine is a unilateral throbbing severe headache that lasts for 4 to
72 hours; it is described as a primary headache that arises due to physical activity
and co-occurs with nausea, vomiting, phonophobia and photophobia[14 ]. Our exclusion criteria comprised presence of the following: additional headaches
(apart from migraine and MOH), neurodegenerative diseases, history of neurosurgery
procedure, head trauma, history of stroke, previously known psychiatric disorders,
withdrawal from the study, use of a prosthesis that was incompatible with MRI, use
of metal appendages (metal kneecaps and pacemakers), claustrophobia and cerebral lesions
that hindered examination of cranial MR imaging of the patient (including lacunar
infarctions and leukoaraiosis, detection of vascular lesions in cranial MRI or poor
quality of MRI). As a result, 24 patients excluded. Thirteen patients with migraine
declined to participate or did not go to their MRI appointment. After the MRI, 11
additional patients were excluded due to leukoencephalopathy. Fifty-eight patients
completed the study protocol and these formed our sample for analysis.
The sociodemographic characteristics of the patients, family history, duration of
illness, presence of aura, frequency of monthly episodes and the names and quantities
of analgesics that were being administered to the patients every month were recorded.
To measure the severity of pain, a user-friendly visual analogue scale (VAS)[15 ] was used, in which the “0” point represented the absence of any pain, while the
“10” point represented the most severe pain in the patient's life.
The patients were subdivided into two groups: those who had MOH and those who did
not. In accordance with the International Classification of Headache Diseases (ICHD-III-B),
MOH was defined as a situation in which a patient who has had primary headache on
more than 15 days/month for more than three months has drug intake on more than 10
days a month over a period of at least 3 months in the case of ergotamine, triptans,
opioids and combinations of analgesics in particular; while for simple analgesics
this situation was considered to consist of regular intake of drugs on more than 15
days a month over a period of at least 3 months[14 ]. All of our participants were using simple analgesics at the time of the interview.
Magnetic resonance imaging protocol
MRI was performed using 1.5 T-MRI units (GE Signa Explorer; GE, Milwaukee, WI, USA).
3D T1W volumetric sequences (TR/TE/TI, 8.7/3.2/450 ms) without contrast were applied
using fast gradient brain volume imaging (BRAVO) with an isotropic voxel resolution
of 1 mm. Generalized parallel imaging was applied by using auto-calibrating reconstruction
for cartesian (ARC) with an acceleration factor of two for phase-encoding direction.
The DTI included a single-shot, spin-echo, echo-planar sequence with TR: 4950 ms TE:
102 ms; matrix: 128 × 128 field of view: 230 mm and slice thickness 5.5 mm; and 24
diffusion-encoding directions were used with the values of b=0 s/mm[2 ] and b=1000 s/mm[2 ]. Parallel imaging was performed through ARC with an acceleration factor of two.
The Advantage Workstation (AW) scanner console (software version 4.6; GE Healthcare)
was used for fractional anisotropy (FA) apparent diffusion coefficient (ADC) map reconstruction.
The 3D T1W images were used as anatomical references for placement and tracing of
ROIs. These images were coupled with the corresponding region of FA-ADC maps at the
same section level. All the ROIs were drawn manually in circular shapes with constant
size. The adaptation of the sizes and placement of the ROIs in the OFC ([Figure 1 ]) were achieved through simultaneous assessment by experienced radiologists (SND).
The radiologist was blinded to neurological symptoms during the imaging analysis.
Figure 1 Placement of the regions of interest in the orbitofrontal region.
Statistical analysis
The IBM SPSS statistics software, version 20.0, was used for the statistical analysis
of the data. Categorical measurements were evaluated as numbers and percentages, while
numerical measurements were evaluated as the mean and standard deviation (or median
and minimum-maximum), and descriptive statistical methods were used. The distribution
of the data was evaluated based on the Shapiro-Wilk test. In cross-group comparisons,
the independent-sample t test was used for data with normal distribution, whereas
the Mann-Whitney U test was used for data that did not have normal distribution. The
patients were subdivided into two groups (with and without MOH). The OFC DTI metrics
of the two groups were compared. To assess the association between OFC and MOH (dependent
variable: DTI value of OFC; independent variables: age, gender, duration of illness,
frequency of the episodes, pain severity and presence of MOH), multivariate regression
analysis was used. Statistical significance was considered as p<0.05 in all tests.
RESULTS
The mean age of all the patients was 35.98±7.92 years (range: 18-65), and 84.5% (n=49)
of them were female, while 15.5% (n=9) of them were male. Among all the patients,
67.24% (n=39) had a family history of migraine; and 39.7% (n=23) had migraine with
aura, while 60.3% (n=35) had migraine without aura. The mean duration of the disease
was 7.36±7.26 years, while the incidence of migraines per month was 8.13±4.90, and
the mean VAS value was 8.87±1.20. It was determined that the mean OFC FA values of
all patients were 0.29±0.05 × 10-3 mm[2 ]/s on the right side and 0.30±0.05 × 10-3 mm[2 ]/s on the left side; while the mean values of OFC ADC was 8.27±0.61 × 10-3 mm[2 ]/s on the right side and 8.14±0.54 × 10-3 mm[2 ]/s on the left side. The amount of analgesic, which was administered in all patients,
was 11.50±10.27 per month and 43.1% (n=25) of the patients had MOH ([Table 1 ]).
Table 1
Sociodemographic, clinical and diffusion tensor imaging data of all the patients.
Age (mean±SD)
35.98±7.92 years
(min-max values)
(18‒51)
Gender % (n)
Female
84.5% (n=49)
Male
15.5% (n=9)
Family history % (n)
Yes
67.24% (n=39)
No
42.86% (n=19)
Aura % (n)
Yes
39.7% (n=23)
No
60.3% (n=35)
Duration of diagnosis of migraine (mean±SD)
7.36±7.26 years
Monthly incidence of migraine (mean±SD)
8.13±4.90
VAS score (mean±SD)
8.87±1.20
OFC FA (mean±SD)
Right
0.29±0.05 × 10-3 mm[2 ]/s
Left
0.30±0.05 × 10-3 mm[2 ]/s
OFC ADC (mean±SD)
Right
8.27±0.61 × 10-3 mm[2 ]/s
Left
8.14±0.54 × 10[3 ] mm[2 ]/s
Medication overuse headache % (n)
Yes
43.1% (n=25)
No
56.9% (n=33)
SD: standard deviation; VAS: visual analog scale; OFC: orbitofrontal cortex; FA: fractional
anisotropy; ADC: apparent diffusion coefficient.
The patients were divided into two groups: those with MOH (group I) and those without
MOH (group II). The two groups were similar in terms of age, gender, family history,
migraine with aura/without aura and duration of diagnosis of migraine (p>0.05). It
was found that there was a significant difference in FA values of the left-side OFC
between the two groups (0.32±0.01 versus 0.29±0.01; p=0.04) ([Table 2 ]).
Table 2
Comparison of sociodemographic, clinical and diffusion tensor imaging data of the
groups.
MOH (+) (n=25)
MOH (-) (n=33)
p-value
Age (mean±SD)
36.80±1.60
35.36±1.37
0.50*
(min-max)
(18‒51)
(18‒49)
Gender % (n)
Female
88.00% (n=22)
81.82% (n=27)
Male
12.00% (n=3)
18.18% (n=6)
0.71**
Family history % (n)
Yes
68.00% (n=17)
66.67% (n=22)
No
32.00% (n=8)
33.33% (n=11)
0.97**
Aura % (n)
Yes
40.00% (n=10)
39.39% (n=13)
No
60.00% (n=15)
60.61% (n=20)
0.74**
Duration of diagnosis of migraine (mean±SD)
6.68±1.07
7.87±1.47
0.51*
Monthly incidence of migraine (mean±SD)
11.48±0.88
5.60±0.62
<0.001*
Amount of painkiller administered per month (pcs/month)
19.60±2.14
5.36±0.61
<0.001*
VAS score (mean±SD)
9.20±0.17
8.63±0.24
0.06*
OFC FA (mean±SD) x 10-3 mm[2 ]/s
Right
0.30±0.01
0.29±0.01
0.71*
Left
0.32±0.01
0.29±0.01
0.04*
OFC ADC (mean±SD) x 10-3 mm[2 ]/s
Right
8.30±0.61
8.23±0.60
0.69*
Left
8.20±0.55
8.05±0.52
0.29*
MOH: medication overuse headache; SD: standard deviation;
* independent-sample t test;
** Pearson's chi-square; OFC: orbitofrontal cortex; FA: fractional anisotropy; ADC: apparent
diffusion coefficient.
The multivariate regression analysis, which was performed to assess the relationship
between the presence of MOH and left OFC FA value, independent of age, gender, duration
of illness, incidence of the attack and severity of pain, detected that there was
a significant correlation between the MOH and the FA value of the left OFC (ß=0.43;
p=0.01).
DISCUSSION
In our study, we found a significant relationship between occurrence of MOH and changes
to the OFC in patients who had been diagnosed with migraine, which was also compatible
with our hypothesis. Our findings suggest that medication overuse behavior might be
a consequence of a susceptibility to substance abuse due to OFC impairment. However,
it should be kept in mind that medication overuse may also cause OFC impairment. This
is a bidirectional relationship. The OFC plays a vital role in generating and using
outcome predictions.
In a study evaluating chronic migraine patients (n=42) with medication overuse, using
neuropsychiatric tests, these patients manifested significant deterioration in orbitofrontal
task performance, compared with patients with episodic migraine (n=42) and a control
group without headache (n=41)[16 ]. In another study evaluating medication overuse among migraine patients through
neuropsychological tests, Iowa gambling task scores for OFC function were assessed.
It was found that there was a significant deterioration in decision-making tests and
Iowa gambling task scores among migraine patients with addictive-like behavior, whose
decision-making and outcome perception was impaired despite the adverse impacts of
medication overuse[17 ]. Taking into consideration these findings, we aimed to evaluate the microstructure
of the OFC by means of the DTI MRI technique, among migraine patients who developed
MOH. Consequently, microstructural impairment, which we detected in the OFC, accounts
for the finding that our migraine patients in whom MOH developed displayed behavior
of continuing to take medication even though they were aware of the potential detrimental
impacts of medication overuse.
It has been revealed in studies evaluating MOH patients through the voxel-based morphometry
MRI technique that the OFC volume was smaller in non-responding MOH patients[18 ],[19 ]. In a study by Riederer et al., the gray matter volumes of patients with MOH were
measured by using voxel-based morphometry MRI. Whereas increases in the volumes of
the thalamus bilaterally and the ventral striatum were observed, there were decreases
in the volumes of the OFC, anterior cingulate cortex, insula and precuneus[20 ]. In a study on MOH through functional MRI, it was revealed that the functioning
of the primary somatosensory cortex, inferior parietal lobule, supramarginal gyrus
and regions of the lateral pathway of the pain matrix returned to normal six months
after discontinuation of the painkillers that the patients had been receiving. Based
on this finding, it was suggested that MOH did not cause irreversible damage[21 ]. However, the regions that were examined through MRI in that study were merely the
regions that play a role in the pain mechanism. It was also reported in another study,
in which positron emission tomography was used, that recovery from hypometabolism
occurred in these regions following discontinuation of the medication. Nonetheless,
the hypometabolism that had been detected in the OFCs remained after cessation of
the medication and MOH relapse was linked to the OFC damage[10 ]. This finding is also compatible with those of previous studies, in which it was
suggested that changes to the OFC were associated with impaired decision-making ability
and behavior of drug and substance abuse[22 ],[23 ]. Similarly, in our study, the microstructural changes to the OFC in migraine patients
were found to be compatible with MOH. However, in our study, the microstructure of
the OFC was assessed through DTI MRI, and this was done using a novel design, compared
with the previous functional MRI and PET studies.
Our research and other studies in the literature relating to the OFC demonstrated
that impairment of the patients’ management of behaviors occurs. These outcomes can
be foreseen, as conclusions drawn from the functional, structural and volume changes
in the OFC. It could be considered that migraine patients’ pathological drug use behavior
develops in MOH as a result of an impairment in the OFCs of these patients. Indeed,
the fact that changes to the OFC were found to be significantly associated with FA
values based on the DTI findings from patients with MOH verifies this argument.
Limitations
Only the OFC was assessed in our study, and the linkages of the OFC, limbic and paralimbic
regions were not assessed. Following cessation of these patients’ medications, their
MRIs were not repeated. Moreover, no psychiatric interviews or neuropsychological
tests on OFC function (objection alternation and object reversal learning tasks, gambling
tasks, go/no-go tasks, olfactory recognition, theory of mind and social processing
measures, and self-rating or family-rating scales on the patient's behavior)[24 ] were conducted on our patients to determine their behavioral pathologies.
In conclusion, the OFC is a cortical structure that enables individuals to adjust
and control their behaviors and to benefit from the consequences, through conclusions
that they have drawn from the events that they experienced previously, for the new
circumstances that they encounter.
Our research gives rise to the notion that frequent medication overuse among migraine
patients could be associated with dysfunction of this region. This result is crucial
since it indicates that the OFC could be a marker for response to treatment or could
be a manifestation of adverse outcomes. Furthermore, from our review of the literature,
we determined that there were no studies analogous to ours, in terms of study design.
We believe that, thanks to this finding, we have made a remarkable contribution to
identification of the pathophysiology of MOH. However, in future studies, it might
be pertinent to identify whether the process is reversible, through repeating patients’
MRIs and investigating whether there would be a continuation of impact on the OFC,
after regulation of these patients’ prophylactic treatments and cessation of their
analgesics.
