Resting-state fMRI study of treatment-naïve temporal lobe epilepsy patients with depressive symptoms
Highlights
► The patients with depressive symptoms showed regional alteration in limbic system. ► They also showed disrupted mood regulation network. ► They are treatment-naïve TLE patients.
Introduction
Up to 20 to 55% of patients with temporal lobe epilepsy (TLE) have psychological depressive symptoms (Kanner, 2008, Tellez-Zenteno et al., 2007). This prevalence is significantly higher than in patients with other chronic diseases, such as diabetes and asthma (Ettinger et al., 2004), and the symptoms lead to a decreased quality of life and a higher risk of suicide (Christensen et al., 2007). Furthermore, when major depression precedes the first epileptic attack, it is associated with a 1.7-fold increased risk of developing seizures (Hesdorffer et al., 2006). Contrary to traditional beliefs, which proposed that depressive symptoms result from a secondary reaction to the epileptic episodes, Kanner (2004)suggested that depressive symptoms may share common pathogenic pathways with epilepsy and that these common pathways may facilitate the development of one condition in the presence of the other. Moreover, depressive disorders may be a predictor of treatment-resistant epilepsy (Kanner, 2008).
To date, animal models and human neuroimaging studies have been used to study the bidirectional relationship between the two conditions (Gilliam et al., 2007, Hasler et al., 2007, Mazarati et al., 2007, Savic et al., 2004). A rat animal model demonstrated that depressive behavior developed due to neuronal plasticity that was associated with repeated electrical kindling (Mazarati et al., 2007). A positron emission tomography (PET) study found significantly decreased serotonin (5HT1A) binding potentials (BP) in the epileptogenic hippocampus and amygdala and a negative correlation between depressive symptoms and the BPs in the anterior cingulate (ACC) (Savic et al., 2004). Using 1H-MRS to detect the creatine/N-acetylaspartate (Cr/NAA) ratio, Gilliam et al. (2007) found abnormalities in the hippocampus that correlated with depressive symptoms in patients with TLE (Gilliam et al., 2007). These findings highlight the involvement of the prefrontal-limbic system and paralimbic structures in these conditions. However, previous neuroimaging experiments were conducted on patients receiving anti-epilepsy drugs (AEDs) and antidepressants; thus, the potential impact of AEDs and antidepressants on brain activity could not be ruled out. To the best of our knowledge, no experiments on treatment-naïve patients with epilepsy (PWEs) have been carried out, and these studies may be critical to elucidate the underlying mechanisms.
Resting state functional magnetic resonance imaging (fMRI) employs the amplitude of low-frequency (0.01–0.08 Hz) fluctuations (ALFF) of the blood-oxygen-level dependent (BOLD) signal to detect regional activity alterations and is widely used to study neuropsychological illnesses. Resting state fMRI can provide information not only on synchronous regional cerebral activity using the ALFF intensity (Goncalves et al., 2006, Shmuel and Leopold, 2008), but it also avoids performance confounds in task-design fMRI research (Callicott et al., 2003). Moreover, resting state fMRI allows the integrity of brain networks to be examined using connectivity analysis.
The present investigation is the first to use resting state fMRI to examine both regional ALFF intensity and brain network connectivity in treatment-naïve TLE patients with and without depressive symptoms compared with a cohort of normal controls. We hypothesized the following: 1. TLE patients with depressive symptoms show ALFF alterations in the prefrontal lobe-limbic systems; and 2. connectivity analysis in the patients with depression symptoms (PDSs) group reveal disruption of the mood regulation network compared with the two other groups, while the patients without depression symptoms (nPDSs) group would show epileptic network alteration.
Section snippets
Participants
A total of 23 treatment naïve (including AEDs and antidepressants) TLE patients (all right handed, male/female: 13/10, average age: 35.0 ± 8.8) and 17 healthy controls (all right handed, male/female: 10/7, average age: 34.9 ± 6.9) were recruited from the out-patient department in the West China Hospital of Sichuan University, China, from July, 2009, to August, 2010. This study was approved by the local ethics committee, and all participants signed informed consent forms. Patients had clinical
Results
We acquired resting fMRI data from 23 patients (male/female: 13/10, average age: 35.0 ± 8.8) and 17 normal controls (male/female: 10/7, average age: 34.9 ± 6.9) on a 3.0 T MR system (Siemens, Trio Tim, Erlangen). The 23 PWE were divided into two groups based on their SDS score. The patients who scored over 50 were included in the PDS group (male/female: 4/3, average age: 37.2 ± 11.1) and the remaining patients were placed into the nPDS group (male/female: 9/7, average age: 34.0 ± 7.8). The disease
Discussion
We are the first to demonstrate that treatment naïve patients show altered regional brain activity in the prefrontal-limbic system and a disruption in the mood regulation network. We found significantly increased ALFF values in the bilateral thalamus, insula and right ACC and decreased ALFF values in the left amygdala and left mPFC for the PDS group compared with the nPDS group. Using connectivity analysis, we found a decreased brain network between the limbic system, temporal lobe and inferior
Conclusion
Taken together, the current results demonstrate that treatment-naïve TLE patients show hyperactivity in the prefrontal-limbic and striatal brain areas and in the ACC with decreased functional connectivity within the prefrontal-limbic system in the PDS group. Longitudinal studies of these patients may illustrate whether the alteration in the PDS group predicts treatment outcomes, and these studies may help understand the lifetime disease course in PDS patients (Hermann et al., 2008).
Acknowledgments
This study was supported by the National Basic Research Program (973 Program No. 2007CB512305) and National Natural Science Foundation of China (Grant No. 81030027), and Dr. Qiyong Gong acknowledges the support from his CMB Distinguished Professorship Award administered by the Institute of International Education, USA.
References (35)
Spontaneous low-frequency blood oxygenation level-dependent fluctuations and functional connectivity analysis of the ‘resting’ brain
Magn. Reson. Imaging
(2008)- et al.
Epilepsy and risk of suicide: a population-based case–control study
Lancet Neurol.
(2007) - et al.
Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania
Psychiatry Res.
(2008) - et al.
Correlating the alpha rhythm to BOLD using simultaneous EEG/fMRI: inter-subject variability
Neuroimage
(2006) - et al.
5-HT1A receptor binding in temporal lobe epilepsy patients with and without major depression
Biol. Psychiatry
(2007) - et al.
The neurobehavioural comorbidities of epilepsy: can a natural history be developed?
Lancet Neurol.
(2008) Do epilepsy and psychiatric disorders share common pathogenic mechanisms? A look at depression and epilepsy
Clin. Neurosci. Res.
(2004)- et al.
An E3 ubiquitin ligase, really interesting new gene (RING) finger 41, is a candidate gene for anxiety-like behavior and beta-carboline-induced seizures
Biol. Psychiatry
(2009) - et al.
Kindling epileptogenesis in immature rats leads to persistent depressive behavior
Epilepsy Behav.
(2007) - et al.
Preoperative depressive symptoms predict postoperative seizure outcome in temporal and frontal lobe epilepsy
Epilepsy Behav.
(2009)
Functional MRI in chronic epilepsy: associations with cognitive impairment
Lancet Neurol.
Altered spontaneous neuronal activity of the default-mode network in mesial temporal lobe epilepsy
Brain Res.
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy
Epilepsia
Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy
Epilepsia
Cortical thickness analysis in temporal lobe epilepsy: reproducibility and relation to outcome
Neurology
Decreased basal fMRI functional connectivity in epileptogenic networks and contralateral compensatory mechanisms
Hum. Brain Mapp.
Interictal functional connectivity of human epileptic networks assessed by intracerebral EEG and BOLD signal fluctuations
PLoS One
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