Giovacchini G, Toczek MT, Bonwetsch R, et al. 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction

PET Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1408, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 08/2005; 46(7):1128-35.
Source: PubMed


Preclinical studies suggest that serotonin 1A receptors (5-HT 1A) play a role in temporal lobe epilepsy (TLE). Previous PET studies reported decreased 5-HT 1A binding ipsilateral to epileptic foci but did not correct for the partial-volume effect (PVE) due to structural atrophy.
We used PET with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY), a 5-HT 1A receptor antagonist, to study 22 patients with TLE and 10 control subjects. In patients, 18F-FDG scans also were performed. An automated MR-based partial-volume correction (PVC) algorithm was applied. Psychiatric symptoms were assessed with the Beck Depression Inventory Scale.
Before PVC, significant (uncorrected P < 0.05) reductions of 18F-FCWAY binding potential (BP) were detected in both mesial and lateral temporal structures, mainly ipsilateral to the seizure focus, in the insula, and in the raphe. Group differences were maximal in ipsilateral mesial temporal regions (corrected P < 0.05). After PVC, differences in mesial, but not lateral, temporal structures and in the insula remained highly significant (corrected P < 0.05). Significant (uncorrected P < 0.05) BP reductions were also detected in TLE patients with normal MR images (n = 6), in mesial temporal structures. After PVC, asymmetries in BP remained significantly greater than for glucose metabolism in hippocampus and parahippocampus. There was a significant inverse relation between the Beck Depression score and the ipsilateral hippocampal BP, both before and after PVC.
Our study shows that in TLE patients, reductions of 5-HT 1A receptor binding in mesial temporal structures and insula are still significant after PVC. In contrast, partial-volume effects may be an important contributor to 5-HT 1A receptor-binding reductions in lateral temporal lobe. Reduction of 5-HT 1A receptors in the ipsilateral hippocampus may contribute to depressive symptoms in TLE patients.

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    • "Since the GABA A receptor is predominantly located in gray matter, rather than white (Heiss and Herholz, 2006), in order to focus on the BP ND in gray matter we used a mask with this high gray matter proportion. Secondly, GABA A receptor BP ND maps were then corrected for partial volume effects on a voxelwise basis by dividing by the gray matter proportion within each voxel following spatial smoothing using a 2.5 mm at FWHM kernel (corresponding to the PET scanner resolution) (Giovacchini et al., 2005; la Fougere et al., 2011). All BP ND values for subsequent analyses were taken from within the masked gray matter region. "
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    ABSTRACT: Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [(18)F]Flumazenil PET to measure GABA(A) receptor binding potentials. It was demonstrated that the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABA(A) receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity.
    Frontiers in Human Neuroscience 12/2012; 6:337. DOI:10.3389/fnhum.2012.00337 · 2.99 Impact Factor
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    • "In addition, when analyses were restricted to cases with an unprovoked ''localized onset'' seizure, depression was 17 times more common among affected cases than among nonseizure controls (Forsgren & Nystrçm, 1990; Hesdorffer et al., 2000); the strong links between temporal or frontal lobe epilepsy and depression are particularly well recognized (Grabowska-Grzyb et al., 2006; García-Morales et al., 2008). Perhaps the more acute neurochemical/structural changes in the brain associated with a partial epileptic focus contribute to depression onset by disrupting neural circuits involved in emotional processing (Giovacchini et al., 2005; Chayasirisobhon, 2009). Epilepsy is treated with a number of antiepileptic drugs (AEDs) according to etiology, age, and pattern of onset, some of which may themselves alter psychobiologic processes (Andersohn et al., 2010; Arana et al., 2010). "
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    ABSTRACT: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self-assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (β = -0.451, p < 0.001) and BDI-II scores (β = -0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (β = -0.060, p = 0.008), lack of a driving license (β = -0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (β = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic-clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score <10), but even in this subgroup the BDI-II score was retained as a significant predictor. In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures.
    Epilepsia 12/2011; 52(12):2181-91. DOI:10.1111/j.1528-1167.2011.03325.x · 4.57 Impact Factor
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    • "Estimation of distribution volume (V) was performed with data fitted to a 2 compartment 3 parameter model using metabolite-corrected input arterial function. To correct for structural atrophy, we used an MRI-based partial volume correction (PVC) algorithm (Giovacchini et al 2005). To correct for potential antiepileptic drug (AED) effects on ligand protein binding, we used free fraction corrected V (V/f1) as our binding measure. "
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    ABSTRACT: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study. We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.
    Epilepsia 11/2011; 53(1):129-33. DOI:10.1111/j.1528-1167.2011.03309.x · 4.57 Impact Factor
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