Brain Advance Access originally published online on September 2, 2008
Brain 2008 131(10):2765-2782; doi:10.1093/brain/awn194
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Comorbidity between temporal lobe epilepsy and depression: a [18F]MPPF PET study
1CTRS-IDEE, Hospices Civils de Lyon, 2INSERM U821, University Claude Bernard Lyon 1 and Neuroscience Federative Institute of Lyon, Lyon, 3Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, 4INSERM U879, University Claude Bernard Lyon 1 and Neuroscience Federative Institute of Lyon, Lyon, France, 5Department of Clinical Neuroscience, Division of Neuroscience and Mental Health, Imperial College, London, UK, 6CERMEP-imagerie du vivant, 7EA4166 and CH le Vinatier, University Claude Bernard Lyon 1 and Neuroscience Federative Institute of Lyon, Lyon, France and 8Department of Neurology, Columbia University, New York, NY, USA
Correspondence to: P. Ryvlin, Unité 301, Hôpital Neurologique, 59 bd Pinel, 69003, Lyon, France E-mail: ryvlin{at}cermep.fr
 |
Summary |
|---|
 Top Summary IntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Brain and brainstem changes of serotoninergic 5-hydroxytryptophan (5-HT)1A receptor density have been reported in patients with major depressive disorder as well as in patients with temporal lobe epilepsy (TLE), using PET and the selective antagonist radiotracers [11C]WAY-100635 or [18F]FC-WAY. We used a distinct 5-HT1A antagonist, [18F]MPPF, whose binding potential depends on both receptor density and extracellular serotonin concentration, in 24 patients with drug-resistant TLE and MRI evidence of hippocampal sclerosis but without prior antidepressant exposure. Their Beck Depression Inventory (BDI-2) score ranged from 0 to 34, with nine patients having a score >11. We used a simplified reference tissue model, statistical parametric mapping and anatomical regions of interest (ROIs) to correlate parametric images of [18F]MPPF BP with the total BDI score and its four subclasses. The total BDI score, as well as symptoms of psychomotor anhedonia and negative cognition, correlated positively with [18F]MPPF BP in the raphe nuclei and in the insula contralateral to seizure onset, whereas somatic symptoms correlated positively with [18F]MPPF binding potential in the hippocampal/parahippocampal region ipsilateral to seizure onset, the left mid-cingulate gyrus and the inferior dorsolateral frontal cortex, bilaterally. We confirm an association of depressive symptoms in TLE patients with changes of the central serotoninergic pathways, in particular within the raphe nuclei, insula, cingulate gyrus and epileptogenic hippocampus. These changes are likely to reflect lower extracellular serotonin concentration in more depressed patients, with an upregulation of receptors a less likely alternative.
Key Words: depressive symptoms; TLE; [18F]MPPF
Abbreviations: 5-HT, 5-hydroxytryptophan; BDI, Beck Depression Inventory; BP, binding potential; MDD, major depressive disorder; TLE, temporal lobe epilepsy
Received September 11, 2007. Revised July 26, 2008. Accepted July 31, 2008.
|
Introduction |
|---|
|
TopSummaryIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Mood disorders are the most frequent psychiatric comorbidity in patients with epilepsy (Mendez et al., 1986
; Robertson, 1987), with a prevalence of depression estimated between 11% and 60% in patients with recurrent seizures (Kanner, 2003). Depression is reported most frequently in patients with temporal lobe epilepsy (TLE) (Jones et al., 2005a), particularly in those with left TLE (Robertson, 1987; Altshuler et al., 1990) and possibly hippocampal sclerosis (Quiske et al., 2000).
Serotonin (5-hydroxytryptophan, 5-HT) is known to be involved in the pathophysiology of major depressive disorder (MDD) (Dhaenen, 2001; Drevets, 2002), with numerous studies showing a reduction of serotonin plasma concentration in patients with MDD (Asberg et al., 1976; Meltzer, 1990) while pharmacological and post-mortem investigations suggest a reduction of serotoninergic neurotransmission in this condition (Lopez et al., 1998).
PET studies of 5-HT1A serotoninergic receptors in depressed patients, using the antagonist [11C]WAY-100635, have reported partly discordant results (Drevets et al., 1999, 2000, 2007; Sargent et al., 2000; Parsey et al., 2006). While the original investigations showed a reduction of binding potential (BP) in various limbic and neocortical brain regions, as well as in the raphe nuclei, of untreated and treated MDD patients (Drevets et al., 1999, 2000, 2007; Sargent et al., 2000; Bhagwagar et al., 2004), a recent study reported an increased BP in the same regions in MDD patients never exposed to antidepressants and no significant abnormality in those with previous exposure to these drugs (Parsey et al., 2006). Another [11C]WAY-100635 study using an intrasubject design to compare patients before and after antidepressant exposure showed no difference between the two conditions. However, at baseline, future non-responders demonstrated higher bilateral orbitofrontal BP than future responders (Moses-Kolko et al., 2007). These controversial findings might partly reflect a difference in the methods used to calculate BP (Innis et al., 2007), as well as in the selected patient samples.
Abnormalities of the 5-HT1A receptors in similar regions have also been reported in TLE using various antagonists, including [11C]WAY-100635, [18F]FCWAY and [18F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2-pirydynyl)-p-fluorobenzamido]-ethyl-piperazine). All showed a BP reduction that predominated over the epileptogenic temporo-limbic structures (Toczek et al., 2003; Merlet et al., 2004a, b; Savic et al., 2004; Giovacchini et al., 2005; Ito et al., 2007). Some of these studies also found a negative correlation between various depression scales and 5-HT1A BP, suggesting lower BP in more depressed patients (Savic et al., 2004; Giovacchini et al., 2005). This correlation was observed ipsilateral to the epileptogenic temporal lobe, either in the anterior cingulate gyrus (Savic et al., 2004) or in the hippocampus (Giovacchini et al., 2005; Theodore et al., 2007). Accordingly, it was recently reported that TLE patients with a current or past history of MDD showed lower [18F]FCWAY binding than did TLE patients with no such history in hippocampus, temporal neocortex, anterior insula, anterior cingulate and raphe nuclei (Hasler et al., 2007). All patients included in these studies were free from antidepressants but no information was provided regarding previous exposure to these drugs.
In the present study, we used another specific antagonist of 5-HT1A receptors, [18F]MPPF, in TLE patients with hippocampal sclerosis and no previous antidepressant exposure to investigate the correlation between 5-HT1A BP and various components of depressive symptoms, as measured with the Beck Depression Inventory (BDI-2) scale (Cathébras et al., 1994). [18F]MPPF has a lower affinity for 5-HT1A receptors than WAY-100635, close to that of 5-HT [Ki = 3.3 nM (Zhuang et al., 1994)], allowing its displacement by endogenous serotonin (Zimmer et al., 2002; Rbah et al., 2003). It thus offers the possibility to further investigate changes of the serotoninergic system that would not solely reflect 5-HT1A receptor density but also the extracellular concentration of endogenous 5-HT.
|
Material and Methods |
|---|
|
TopSummaryIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Patients
We prospectively included 24 consecutive patients who fulfilled the following criteria: (i) drug-resistant focal epilepsy, (ii) ongoing pre-surgical evaluation, (iii) temporal lobe origin of seizures highly suggested by all available electroclinical data (Wieser et al., 2004
), (iv) MRI signs of hippocampal sclerosis with or without loss of grey-white matter demarcation in the anterior temporal lobe and no other significant MRI finding and (v) no previous or current exposure to antidepressants. All the selected patients also gave their informed consent to participate in this study, which was approved by the local Ethics committee (CCPPRB, Centre Léon Bérard, Lyon) in accordance with the Declaration of Helsinki. This series was independent from our previously published studies of [18F]MPPF-PET in seven patients with mesial temporal epilepsy, none of whom had benefited from a BDI assessment (Merlet et al., 2004a, b).
All patients gave a detailed description of their past history and ictal symptoms and underwent long-term video-scalp-EEG monitoring that provided informative ictal electroclinical data. They all benefited from an optimal MRI, as well as an FDG-PET. In addition, four patients underwent an intracerebral EEG investigation, primarily prompted by the presence of ictal signs or symptoms, suggesting the possibility of ‘temporal plus’ epilepsy (Barba et al., 2007). In these patients, the invasive investigation eventually demonstrated a temporo-limbic epileptogenic zone.
Evaluation of depressive symptoms
At the time of referral to our epilepsy centre, none of the selected patients was diagnosed as suffering from any psychiatric disorder, including MDD, but this partly reflects the fact that patients with previous exposure to antidepressants were excluded from the study as well as the current state of underassessment of psychiatric comorbidity in patients with epilepsy in France.
On the day of the PET scanning, depressive symptoms were evaluated using the BDI-2 scale (Karzmark et al., 2001). The BDI-2 is a validated self-rating questionnaire that consists of a 21-item scale, with four severity ratings for each item. Factor analysis has suggested that BDI-2 reflected one underlying second-order dimension of self-reported depression composed of two first-order factors representing cognitive and non-cognitive (somatic-affective) symptoms (Steer et al., 1999). The cognitive dimension includes the following eight items: #2 (pessimism), #3 (past failure), #5 (guilty feelings), #6 (punishment feelings), #7 (self-dislike), #8 (self-criticalness), #9 (suicidal thoughts) and #14 (worthlessness), whereas the somatic-affective dimension is represented by all remaining 13 items. More recently, the dimensions of the BDI-2 were further divided into four symptom classes (Dunn et al., 2002). One of these four dimensions, called negative cognition, includes six of the eight cognitive symptoms previously identified by Steer et al. (1999) (#3, #5, #6, #7, #8 and #14; see above). The other three components represent subscales of the somatic-affective dimension, as detailed below:
- psychomotor anhedonia includes items #4 (anhedonia), #11 (irritation), #12 (social anhedonia), #13 (difficulty making decisions) and #15 (ability to work);
- vegetative symptoms includes items #16 (late insomnia) and #18 (loss of appetite) and
- somatic symptoms includes items #19 (loss of weight) and #20 (health worries).
).
The ability of the BDI-2 to identify major depression in patients with epilepsy has also been validated in a series of 174 subjects, using the Mini International Neuropsychiatric Interview and Mood Disorders module of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Axis I Disorders-Research Version (Jones et al., 2005b). ROC analysis showed that using a cutoff score of 11, the BDI-2 had a sensitivity of 0.962, a specificity of 0.8 and a negative predictive value above 0.99, indicating that any patients with a score 
11 are very unlikely to suffer from MDD (Jones et al., 2005b).
Our patients did not benefit from a standardized psychiatric interview technique as part of this study. The primary aim of our study was to correlate [18F]MPPF PET data with various symptoms of depression and not with the presence or absence of MDD. However, the mental health of our patients was systematically assessed during their pre-surgical evaluation through a multi-level and individualized procedure. The latter always included a clinical assessment performed by the senior epileptologist in charge of the pre-surgical evaluation, in order to determine whether or not the patient was psychologically amenable to surgery and the risk of postoperative psychiatric complications. A second level of assessment, performed in the majority of patients, consisted of a global cognitive and psychological evaluation by a clinical neuropsychologist. A third step was performed by a psychiatrist in patients selected through the two former evaluations and consisted of a standardized psychiatric interview. The majority of our patients who showed a BDI-2 score >11 (7 out of 9) underwent this third assessment. The delay between this psychiatric evaluation and the BDI-2 assessment varied from 1 week to 6 months. In contrast, the majority of those with a BDI-2 score <11 only benefited from the two first steps. As noted above, the chance that any of these latter patients suffered from MDD is <1%.
PET acquisition
The methodology of tracer production, scan acquisition and data pre-processing has been previously described (Merlet et al., 2004a; Costes et al., 2005). Briefly, [18F]MPPF PET studies were performed using a CTI-SIEMENS HR+ camera (Knoxville, TN, USA) in the afternoon. Prior to the emission acquisition, a 10 min transmission scan was performed. After intravenous injection of a bolus of 181.4 ± 32.1 MBq (mean ± SD) of [18F]MPPF into a radial vein of the left arm, the dynamic PET emission scan, consisting of 35 frames of increasing duration, was acquired to evaluate the local radioactivity concentration during 60 min post-injection. Patients were closely supervised throughout the whole PET acquisition and kept awake by talking to them when their level of vigilance dropped. Images were corrected for scatter and attenuation and reconstructed by 3D filtered back projection (Hanning filter) to provide a volume of 63 slices (2.42 mm thickness) with 128 x 128 voxels in plane (2.06 x 2.06 mm).
Pre-processing and visual analysis of PET data
A frame-to-frame realignment was systematically performed in Activis 2.8 (http://www.isc.cnrs.fr/the/activis.html). A previously validated simplified reference tissue model (Gunn et al., 1998) was then used to generate parametric images of BP values [BPND (non-displaceable) in consensus nomenclature (Innis et al., 2007)]. Cerebellar white matter, which is assumed to be devoid of 5-HT1A-specific binding, was used as a reference region (Costes et al., 2002).
Two of the investigators (A.D. and P.R.) independently reviewed the parametric images of BPND of all patients and reported all visually detectable asymmetries thought to be clinically significant.
Using Statistical Parametrical Mapping (SPM2, Wellcome Trust Centre for Neuroimaging, UCL, London, UK; http://www.fil.ion.ucl.ac.uk/spm/), parametric images of BPND were transformed into a standard stereotaxic space (MNI/ICBM152) using a ligand-specific template produced in-house and resliced to voxels of dimensions 2 x 2 x 2 mm. Normalized BPND images were then smoothed using an 8 x 8 x 8 mm FWHM isotropic Gaussian kernel to take into account interindividual anatomical variability and to improve the sensitivity of the statistical analysis (Friston et al., 1991).
Voxel-based analysis of PET data
All analyses were performed using SPM2 and an explicit mask that includes the entire brain and brainstem. In order to restrict our analysis to grey matter areas that contain a significant amount of 5-HT1A receptors, we further used an implicit mask that excluded all voxels in which BPND was <20% of the mean brain and brainstem activity. The resulting mask adequately delineated the cortex but failed to sample the raphe nuclei within the brainstem due to the important partial volume effect affecting this region. The latter was thus only evaluated using a region of interest [see Regions of interest analyses]. The threshold of 20% used for constructing the above mask adequately sampled the grey matter but might have excluded some voxels in epileptogenic brain regions showing a dramatic decrease in BPND. To ensure that this did not affect our main findings, we reprocessed our analyses using an explicit mask of the grey matter without any additional implicit mask. This explicit mask was constructed from a segmented normal MRI template that included all voxels having a probability of 40% or more to belong to grey matter (Fig. 1).
|
We first extracted the global average BPND values of each individual and looked for correlations between this value and the total BDI score as well as the scores for each of the four symptom classes (negative cognition, psychomotor-anhedonia, vegetative symptoms and somatic symptoms), using the bivariate correlation and Pearson coefficient function of SPSS (version 12.0 for Windows), with a bilateral level of significance at P < 0.05.
We then searched for correlations between BPND values and depressive symptoms using the analysis of covariance function of SPM, with a linear model at each and every voxel (Friston et al., 1995). This analysis was performed for the total BDI and the four symptom class scores. For each analysis, two contrasts were tested that looked for positive correlations (increasing BPND values with increasing BDI score) and negative correlations (decreasing BPND values with increasing BDI score). The global BPND was designated as a covariable of no interest. We processed all analyses using a visualization threshold of P < 0.01 at the voxel level but only retained clusters that were significant at the conventional P < 0.05 threshold at the cluster level after SPM standard correction for multiple comparisons. These results will be presented as Pcorrected values according to SPM nomenclature.
The above analyses were performed in a mixed population of patients with right and left TLE and thus searched for correlation between depressive symptoms and BPND values in brain regions regardless of their lateralization with respect to the epileptogenic temporal lobe. To further investigate this issue, we reprocessed the same analyses after flipping the PET volume of the eight patients with left TLE in order to get all epileptogenic temporal lobes lateralized to the right. Thus, left-sided correlations corresponded to brain regions contralateral to the epileptic temporal lobe and vice versa. Previous studies of [11C]flumazenil PET, [11C]diprenorphine PET and [18F]MPPF PET have used the same methodology in populations of patients with right- and left-sided epileptogenic zones (Hammers et al., 2002, 2003, 2007; Merlet et al., 2004a). We will further refer to this analysis as the ‘flipped PET data’ analysis to facilitate its presentation in the following sections, although only one-third of all PET volumes (corresponding to the eight patients with left TLE) were actually flipped.
Regions of interest analyses
The major role played by the raphe nuclei in the regulation of the central serotoninergic system and in the pathophysiology of MDD provided a strong rationale for specifically looking at this structure in our study. Since the raphe nuclei cannot be delineated on MRI but are the only detectable brainstem structure on [18F]MPPF PET images, we traced a region of interest (ROI) encompassing this structure on an average [18F]MPPF-PET image obtained from the 24 patients’ normalized datasets by thresholding the activity at 90% of the local maximum in the brainstem. This ROI extended on the 13 consecutive slices displaying the raphe, with a total volume of 400 mm3.
We also used anatomical ROIs extracted from a brain atlas (Kabani et al., 1998) to measure the BPND in cortical regions where voxel-based analysis disclosed significant correlations with BDI, in order to confirm this finding at the level of pre-defined anatomical regions. As for SPM analyses, we evaluated left- and right-sided ROI values, regardless of the lateralization of the epileptic temporal lobe, as well as ROI data contralateral and ipsilateral to the side of seizure onset.
We searched for correlations between BPND values and depressive symptoms using the partial correlation and Pearson coefficient function of SPSS (version 12.0 for Windows), with the global BPND as a control variable. For the raphe nuclei, we used a bilateral level of significance at P < 0.05, whereas we used a unilateral level of significance at P < 0.05 for the other ROIs, since these analyses aimed at confirming correlations previously shown by SPM analysis, the sign of which was thus specified. For the same reason, we did not further correct these analyses for multiple comparisons.
Post hoc ROI analyses
The conventional and flipped PET data analyses disclosed ambiguous results by showing very comparable lateralized findings pointing to the left hemisphere and that contralateral to seizure onset, respectively. In order to further investigate this issue, we performed additional ROI analyses in the subgroups of right and left TLE patients, separately, using the same methodology as above. Again, because these post hoc analyses aimed at exploring the most likely interpretation of our previous findings, and did not intend to disclose new correlations, we did not apply further corrections for multiple comparisons.
|
Results |
|---|
|
TopSummaryIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Clinical data
There were 12 males and 12 females with a mean age of 37.6 years (SD = 11.2 years; Table 1). Eight had left TLE and 16 had right TLE. The median duration of their epilepsy was 30.5 years (range, 10–55 years).
|
BDI scores ranged from 0 to 34 (median = 7), with nine patients reporting a score >11, eight of whom suffered from right TLE. Among these nine patients, seven had a psychiatric evaluation, including all six who were operated on. Among the seven evaluated patients, five fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria of MDD, whereas the two remaining patients were considered to suffer a milder form of depressive disorder. Among the two patients with BDI-2 score above 11 who were not evaluated by a psychiatrist, one was considered to suffer depression by the epileptologist in charge of the pre-surgical evaluation, but the patient declined to be referred to a psychiatrist for further evaluation, whereas the other was not diagnosed as being depressed during his pre-surgical evaluation. No other major psychiatric illness, including bipolar disease and schizophrenia, was noted in these 9 patients or in the 15 subjects with a BDI-2 score <11.
There was no difference in the proportion of patients with a BDI lower or greater than 11 receiving AEDs known to promote the release of serotonin. Indeed, 78% of patients with a BDI >11 were treated with carbamazepine, oxcarbazepine or lamotrigine at the time of the PET study, as compared with 73% of those with a BDI <11. Two patients in each group received a combination of carbamazepine and lamotrigine.
Visual analysis of PET data
The two investigators detected an asymmetry of regional BPND in all 24 patients. This abnormality always predominated over the mesial and polar aspects of the temporal lobes and pointed to lower BP on the side of the atrophic hippocampus and TLE.
Analysis of global BPND values
There was no correlation between the global BPND and either the total BDI score or that of the four symptom classes (Table 2).
|
Voxel-based analysis of PET-data
We found a positive correlation between the total BDI score and [18F]MPPF BPND within a single cluster that primarily included the left insula and extended towards the adjacent left parietal operculum and inferior post-central cortex (Pcorrected = 0.006; Fig. 2). There was no negative correlation between [18F]MPPF BPND and BDI score. Similarly, positive but no negative correlations were demonstrated between [18F]MPPF BPND and three of the four symptom classes of the BDI (Table 3). These correlations were observed within the same cluster as above for symptoms of negative cognition (Pcorrected < 0.001; Fig. 3) and psychomotor-anhedonia (Pcorrected < 0.001). In contrast, somatic symptoms correlated positively with [18F]MPPF BPND in three other clusters corresponding to the left mid-cingulate gyrus (Pcorrected = 0.001), and the right (Pcorrected < 0.001) and left (Pcorrected < 0.001) middle and inferior frontal gyri (Fig. 4). Vegetative symptoms did not correlate with [18F]MPPF BPND in any region.
|
|
|
|
These results were partly modified by flipping the PET volume of the 8 patients with a left TLE, resulting in the epileptogenic temporal lobe of all 24 patients being lateralized to the right (Table 3). Symptoms of negative cognition and psychomotor anhedonia still positively correlated with [18F]MPPF BPND in the insula and adjacent parietal operculum and post-central region contralateral to the epileptogenic temporal lobe (negative cognition: Pcorrected = 0.009; psychomotor-anhedonia: Pcorrected = 0.005; Fig. 5), but the total BDI score only showed a non-significant trend towards the same correlation with an uncorrected P-value of 0.007 at the cluster level. [18F]MPPF BPND also displayed positive correlation with somatic symptoms, comparable to those observed with non-flipped PET images, including the mid-cingulate gyrus contralateral to seizure onset (Pcorrected = 0.001) and the middle and inferior frontal gyri bilaterally (ipsilateral: Pcorrected < 0.001; contralateral: Pcorrected = 0.001; Fig. 4). In addition, somatic symptoms positively correlated with [18F]MPPF BPND in the mesial temporal region ipsilateral to seizure onset, within a cluster encompassing the parahippocampal gyrus and atrophic hippocampus (Pcorrected = 0.002). This was the only significant finding not previously disclosed in the SPM analyses of non-flipped PET volumes.
|
The above results were obtained using a 20% threshold implicit mask but were all confirmed when replacing the latter mask by an explicit mask of the grey matter.
ROI analyses
ROI analysis of the raphe nucleus showed a positive correlation between [18F]MPPF BPND and total BDI score (r = 0.55; P = 0.006), as well as with symptoms of psychomotor-anhedonia (r = 0.56; P = 0.006) and negative cognition (r = 0.44; P = 0.032) but not with somatic or vegetative symptoms (Table 3).
ROI analysis of the left insula confirmed the positive correlation between [18F]MPPF BPND and total BDI score (r = 0.49; P = 0.009), symptoms of psychomotor-anhedonia (r = 0.49; P = 0.009) and negative cognition (r = 0.48; P = 0.011), previously disclosed by SPM analyses. Similarly, we confirmed a positive correlation between [18F]MPPF BPND in the post-central region and negative symptoms (r = 0.36, P = 0.047) and a positive correlation between [18F]MPPF BPND in the left cingulate gyrus and somatic symptoms (r = 0.46; P = 0.013), whereas the frontal regions did not show the correlation observed with voxel-based analysis.
ROIs analysis of flipped PET data confirmed positive correlations between symptoms of negative cognition and psychomotor anhedonia and [18F]MPPF BPND in the insula contralateral to seizure onset (r = 0.46; P = 0.014 and r = 0.49; P = 0.009, respectively), as well as between somatic symptoms and [18F]MPPF BPND in the ipsilateral hippocampus (r = 0.44; P = 0.018), parahippocampal gyrus (r = 0.37; P = 0.042) and contralateral cingulate gyrus (r = 0.39; P = 0.033). In addition, [18F]MPPF BPND in the insula contralateral to seizure onset significantly correlated with the total BDI score (r = 0.51; P = 0.006). We confirmed positive correlations between [18F]MPPF BPND in the post-central region contralateral to seizure onset and total BDI score (r = 0.41, P = 0.027) and symptoms of negative cognition (r = 0.37, P = 0.043). Conversely, correlation between depressive symptoms and [18F]MPPF BPND delineated by SPM over the bilateral inferior and mid-frontal gyri failed to be confirmed by ROI analyses.
|
Discussion |
|---|
|
TopSummaryIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
The main finding of this study was the positive correlation between the total BDI score and [18F]MPPF BPND in the insula contralateral to seizure onset and the raphe nuclei in 24 TLE patients with hippocampal sclerosis and no previous exposure to antidepressants. The same correlations were observed between the insula and raphe [18F]MPPF BPND and BDI subscales, reflecting symptoms of negative cognition and psychomotor-anhedonia. Conversely somatic symptoms positively correlated with [18F]MPPF BPND in the hippocampus ipsilateral to seizure onset as well as in the left mid-cingulate gyrus. These results, which contrast with previously published data obtained with other radiotracers, suggest that depressive symptoms in TLE patients are associated with a complex alteration of the serotoninergic system that might combine changes in the extracellular concentration of 5-HT and 5-HT1A receptor density.
Direction of changes as compared with previous studies
The positive correlations observed in this study between [18F]MPPF BPND and depressive symptoms are at odds with the negative correlations previously reported by others in TLE patients using [11C]WAY-100635 and [18F]FCWAY (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007). There are several possible explanations for these discrepancies including differences in the brain regional distribution of PET changes, in the population studied and in the affinity of the PET ligands for 5-HT1A receptors. Each of these issues is discussed below.
Differences in the brain regional distribution of PET changes
One possible explanation of these discordant results could be that brain regions displaying positive correlations with depressive symptoms in this study differed from those showing negative correlations in previous series. Indeed, positive correlations primarily involved the raphe nuclei, insulo-parietal cortex, mid-cingulate gyrus and frontal dorsolateral cortex, whereas previously reported negative correlations were observed in the hippocampus and anterior cingulate gyrus ipsilaterally (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007). However, we also found a positive correlation between somatic symptoms of depression and [18F]MPPF BPND in the hippocampus ipsilateral to seizure onset, the same region where negative correlations were reported by others (Giovacchini et al., 2005), including after correction for partial volume effect in the atrophic hippocampus (Theodore et al., 2007). Furthermore, a recent [18F]FCWAY PET study showed that TLE patients with current or previous MDD had lower [18F]FCWAY binding than those without a history of MDD in many brain regions, including the anterior insula and the raphe (Hasler et al., 2007). Overall, the opposite direction of the correlations observed between depressive symptoms and [18F]MPPF BPND versus [11C]WAY-100635 or [18F]FCWAY BP is unlikely to primarily reflect regional differences in the distribution of positive versus negative correlations.
Differences in the population studied
Differences in the population studied could represent another explanation for the discordant findings observed with the various 5-HT1A PET ligands, though all of our patients demonstrated the typical pattern of 5-HT1A receptor abnormality reported by others using [11C]WAY-100635 or [18F]FCWAY that is a decreased [18F]MPPF BPND over their epileptogenic temporo-limbic regions (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007).
However, our patient group was more homogenous than those selected in previous studies, with all patients presenting MRI signs of hippocampal sclerosis, whereas the proportion of patients with hippocampal sclerosis varied from 57% to 73% in other series (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007). The pathophysiology of epilepsy-associated depression might differ between TLE patients with and without hippocampal sclerosis (Quiske et al., 2000; He
imovi et al., 2003) and could result in different observations in a population mixing these two types of patients as compared with a homogeneous group of TLE patients with hippocampal sclerosis. In addition, all our patients underwent a comprehensive pre-surgical evaluation that led to surgery in 71% of cases, 94% of whom were free of disabling seizure postoperatively (class I of Engel; Engel et al., 1998). In one previous study, 11 out of 14 patients entered a pre-surgical evaluation, only two of whom were operated upon and were seizure-free (Savic et al., 2004). In another series of 22 TLE patients, 14 were operated (64%), including 10 seizure-free postoperatively (71%) (Giovacchini et al., 2005).
Differences in antiepileptic drug plasma concentration might also be taken into consideration since the latter was found to influence the plasma-free fraction of [18F]FCWAY in patients with epilepsy (Theodore et al., 2006). However, this issue is unlikely to play a significant role in our study since our model for calculating parametric images of [18F]MPPF BPND does not depend on the plasma-free fraction of the PET tracer. Another important aspect of AED treatment is their potential to modify the intracerebral concentration of serotonin. The latter was found increased in rats treated with carbamazepine (Dailey et al., 1997; Ahmad et al., 2005), oxcarbazepine (Clinckers et al., 2005) and phenytoin (Ahmad et al., 2005). However, when used at the therapeutic level, neither phenytoin nor phenobarbital was found to be associated with change in cerebral 5-HT (Sudha et al., 1996; Okada et al., 1997). The impact of lamotrigine on brain serotonin appears more complex with an acute decreased release of 5-HT but lack of chronic changes (Ahmad et al., 2004; Ahmad et al., 2005). The other AEDs taken by our patients were not found to alter the intracerebral concentration of 5-HT (Takebayashi et al., 1995; Pugsley et al., 1998) or were not evaluated in this respect. Importantly, the same proportion of patients with and without a BDI >11 were treated with carbamazepine or oxcarbazepine (77 and 73%, respectively). Conversely, previous series that correlated depressive symptoms with 5-HT1A receptor density either ignored this issue (Giovacchini et al., 2005; Theodore et al., 2007) or reported differences in the proportion of patients with and without depressive symptoms receiving carbamazepine (Savic et al., 2004). Indeed, in this latter serie, 25% of patients with Montgomery Åsberg Depression Rating Scale (MADRS) score >20 were treated with carbamazepine as compared with 50% of those with a MADRS score <20.
More importantly, none of our patients has been ever exposed to antidepressant drugs. Previously published studies included TLE patients free of antidepressants at the time of PET scanning but did not specify whether their patients were previously exposed to such treatment (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007). A recent [11C]WAY-100635 study of patients with MDD suggests that a past history of antidepressant exposure has a major impact on the brain distribution of 5-HT1A receptors (Parsey et al., 2006). Indeed, MDD patients naïve of antidepressant exposure showed an increased [11C]WAY-100635 BP in most brain regions compared with controls, including the insula, the cingulate gyrus and the raphe nuclei, whereas MDD patients with previous antidepressant exposure failed to demonstrate such abnormalities (Parsey et al., 2006). It is noteworthy that the overexpression of 5-HT1A receptors observed in medication naïve MDD patients is consistent with the higher [18F]MPPF BPND found in the same brain regions in our TLE patients with higher BDI score and no previous exposure to antidepressants. Overall, differences in the population of TLE patients included in our study as compared with previous series might partly account for the discordant PET findings reported in prior publications (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007).
Differences in the affinity of the 5-HT1A PET ligands
A third explanation for these discrepancies could be the difference in affinity that distinguishes [18F]MPPF from [11C]WAY-100635 and [18F]FCWAY. Unlike the two latter PET tracers whose affinity is much higher than that of 5-HT, [18F]MPPF is characterized by a lower affinity, close enough to that of serotonin to be sensitive to the concentration of endogenous 5-HT (Zimmer et al., 2002; Rbah et al., 2003). Accordingly, a reduction of extracellular serotonin concentration could result in an increased [18F]MPPF BPND, whereas it would not directly influence [11C]WAY-100635 or [18F]FCWAY binding. Theoretically, this mechanism could even mask and override an underlying decreased density of 5-HT1A receptors. This hypothesis would be of particular interest for the positive correlation observed between somatic symptoms and [18F]MPPF BPND over the epileptogenic hippocampus since BPND was dramatically reduced in that region in most patients. Accordingly, a PET study using alpha-[11C]methyl-L-tryptophan, a precursor of 5-HT, has reported a reduction of this tracer uptake in the anterior cingulate gyrus and left mesial temporal cortex in depressed patients supporting the possibility of reduced extracellular serotonin concentration in depression (Rosa-Neto et al., 2004). However, it remains impossible to precisely predict the impact of such an abnormality on [18F]MPPF binding since we ignore the proportion of 5-HT1A receptors occupied by endogenous 5-HT in the living human brain and the magnitude of its reduction in depressive disorders.
Overall, our results of higher [18F]MPPF BPND in TLE patients with higher BDI score could either reflect greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT that could be associated with various changes in the number of 5-HT1A receptors. A combination of decreased extracellular concentration of 5-HT and number of 5-HT1A receptors in the most depressed patients would be consistent with previous [11C]WAY-100635 or [18F]FCWAY PET studies in TLE patients (Savic et al., 2004; Giovacchini et al., 2005; Theodore et al., 2007). Conversely, greater 5-HT1A receptor density in the more depressed patients, which might also well be associated with reduced extracellular concentration of 5-HT, would be more in agreement with the [11C]WAY-100635 PET findings reported in antidepressant naïve MDD patients (Parsey et al., 2006). In any event, both hypotheses provide new evidences regarding the pathophysiology of serotoninergic changes associated with depressive symptoms in TLE and point to the possibility of an underlying reduction of the extracellular concentration of 5-HT.
Interestingly, discordant [11C]WAY-100635 PET findings have also been reported in the field of depression. In contrast with the increased BP reported in antidepressant naïve MDD patients (Parsey et al., 2006), a majority of studies have demonstrated decreased BP in depressed patients as compared with controls in most brain regions, as well as in the raphe nuclei (Drevets et al., 1999, 2000, 2007; Sargent et al., 2000). In successfully treated MDD patients, the same direction of changes was observed, except in the raphe nuclei in which BP was found to be normal (Bhagwagar et al., 2004). Although the combination of the above findings might suggest that 5-HT1A receptor abnormalities in the raphe might resolve with antidepressant treatment, a recent paired scan study that directly looked at antidepressant-induced 5HT1A changes in MDD patients failed to confirm this hypothesis (Moses-Kolko et al., 2007).
Localization and lateralization of changes as a function of depressive symptoms
The primary aim of our study was to correlate cerebral [18F]MPPF BPND with the intensity of depressive symptoms, as measured by the BDI-2 scale, and not with the presence of MDD proper. This strategy allowed us to investigate for the first time the biological substratum of different dimensions of depressive symptoms in patients with epilepsy. Indeed, depression is a multidimensional disorder comprising cognitive, somatic, behavioural and social symptoms (Costello et al., 1992). Factor analysis has suggested that BDI-2 reflects two primary dimensions of depression, corresponding to cognitive and non-cognitive (somato-affective) symptoms (Steer et al., 1999). A more recent study has proposed a new cognitive dimension, referred to as negative cognition and restricted to a subset of six of the original eight cognitive symptoms (excluding pessimism and suicidal thoughts) and has further divided the 13 non-cognitive symptoms into three classes, defined as psychomotor anhedonia, vegetative and somatic (Dunn et al., 2002). We chose to use this latter and more detailed subdivision of depressive symptoms with the hope to more precisely delineate the underlying changes in 5-HT1A receptor BP. Nevertheless, the correlations found with negative cognition should similarly apply to the entire cognitive dimension defined by Steer et al. (1999) since these two scales highly correlated with each other in our population (r = 0.97). Furthermore, the distinction between psychomotor anhedonia and somatic symptoms proved relevant since these two symptom classes correlated with [18F]MPPF BPND in strikingly different brain regions as detailed below.
Correlations of the total BDI score and symptoms of negative cognition and psychomotor anhedonia with [18F]MPPF BPND in the raphe nuclei and the insula
Total BDI scores as well as symptoms of psychomotor-anhedonia and negative cognition correlated with [18F]MPPF BPND in the raphe nuclei. The raphe nuclei play a pivotal role in the serotoninergic system. 5-HT1A autoreceptors, located on the soma and dendrites of 5-HT neurons, exert a pre-synaptic negative feedback on serotoninergic neuron firing activity (Weissmann-Nanopoulos et al., 1985; Richer et al., 2002). However, the type and extent of dysfunction of the raphe nuclei in depression remain unclear. Post-mortem studies in suicide patients have reported both increased and decreased density of 5-HT neurons and 5-HT1A receptors (Stockmeier et al., 1998; Underwood et al., 1999; Arango et al., 2001) depending on their rostrocaudal localization within the raphe nuclei (Boldrini et al., 2007). Similarly, as previously discussed, [11C]WAY-100 635 PET studies have reported both increased and decreased BP in the raphe of MDD patients, although the latter did not correlate with the intensity of depressive or anxiety symptoms (Drevets et al., 1999, 2000; Sargent et al., 2000; Sullivan et al., 2005; Parsey et al., 2006). In addition, a PET study showed reduced [18F]FCWAY binding in the raphe in TLE patients with current or previous MDD compared with TLE patients without a history of MDD (Hasler et al., 2007). Finally, in unipolar MDD patients, FDG-PET demonstrated a positive correlation between symptoms of psychomotor-anhedonia and negative cognition and glucose metabolism in the dorsal raphe (Dunn et al., 2002), a result reminiscent of our [18F]MPPF findings in TLE patients. Overall, the strong correlation observed between depressive symptoms and [18F]MPPF BPND in the raphe nuclei support the view that an epilepsy-related dysfunction of these nuclei could represent part of the biological basis of comorbid depression in TLE.
Symptoms of negative cognition and psychomotor-anhedonia, as well as the total BDI score, also correlated with [18F]MPPF BPND in the insula of our patients. The insula is a site of multimodal integration that plays a pivotal role in limbic interactions (Shelley and Trimble, 2004; see Nagai et al., 2007 for review) and limbic-cortical pathways (Mayberg et al., 1997). Several FDG-PET and [11C]WAY-100635 studies have demonstrated insular abnormalities in MDD patients (Mayberg et al., 1999; Drevets, 2000; Drevets et al., 2000; Sargent et al., 2000; Kennedy et al., 2001; Kimbrell et al., 2002; Parsey et al., 2006; Fitzgerald et al., 2008), including negative correlation between insular cortex and the item ‘agitation’ of the Hamilton Depression Rating scale (Graff-Guerrero et al., 2004) and positive correlation between glucose metabolism and negative cognition symptoms of the BDI (Dunn et al., 2002). Acute intense sadness provoked by rehearsed autobiographical scripts was associated with an increased blood flow in the insula in normal subjects (Mayberg et al., 1999). It is also worth noting that the insula is one of the brain regions in which 5-HT1A BP is sensitive to previous antidepressant exposure (Sullivan et al., 2005). Finally, in patients with TLE, co-morbid depression was significantly associated with increased blood flow and reduced 5-HT1A receptor density in the insula (Ring et al., 1999; Hasler et al., 2007).
Correlations of somatic symptoms of depression with [18F]MPPF BPND in the hippocampus ipsilateral to seizure onset and in the frontal lobes
Somatic symptoms correlated positively with [18F]MPPF BPND in the mesial temporal region ipsilateral to seizure onset and more specifically over the hippocampus and parahippocampal gyrus. This finding is reminiscent of the correlation reported between the total BDI score and [18F]FCWAY BP over the epileptogenic hippocampus of TLE patients, although in the opposite direction for reasons already discussed (Giovacchini et al., 2005; Theodore et al., 2007). A bulk of evidence suggests that the hippocampus belongs to the limbic-frontal-subcortical network involved in the pathophysiology of MDD (Mayberg et al., 1997; Price, 1999; Sheline, 2003; Seminowicz et al., 2004). Indeed, decreased hippocampal volume, blood flow and glucose metabolism were reported in patients with MDD (Bremner et al., 2000; Kennedy et al., 2001; Saxena et al., 2001; Frodl et al., 2002; Videbech et al., 2002; Sheline et al., 2003b; Fitzgerald et al., 2008). Regarding hippocampal 5-HT1A receptors, decreased mRNA levels for receptor protein were observed in suicide victims as well as in rats exposed to acute stress, whereas [11C]WAY-100635 BP was found either decreased or increased in patients with MDD (Lopez et al., 1998, 1999; Drevets et al., 1999, 2000; Sargent et al., 2000; Lopez-Figueroa et al., 2004; Parsey et al., 2006). Like the insula, the hippocampus is one of the brain regions in which 5-HT1A receptor density appears to be sensitive to previous antidepressant exposure (Sullivan et al., 2004), a finding that might partly account for the above discordant results. Paradoxically, in patients with TLE, the role of hippocampal atrophy in the pathophysiology of comorbid depression remains elusive. Indeed, no association was found between depression and the presence or intensity of hippocampal atrophy (Lehrner et al., 1999; Baxendale et al., 2005; Briellmann et al., 2007; Richardson et al., 2007; Theodore et al., 2007), while a negative correlation was observed in the same region between depressive symptoms and creatine/N-acetylaspartate ratio, as measured by magnetic resonance spectroscopy (Gilliam et al., 2007). According to this complex framework, it appears that depressive symptoms in TLE patients are more closely related to the serotoninergic dysfunction than to the atrophy of the epileptic hippocampus. In this respect, it is worth noting that the epileptic hippocampus consistently shows a decreased BP of 5-HT1A receptor across studies and PET ligands, even in patients with no hippocampal atrophy or after correction for partial volume effect (Merlet et al., 2004a, b; Savic et al., 2004; Giovacchini et al., 2005; Ito et al., 2007). Most importantly, [18F]MPPF BPND was found decreased over the epileptic hippocampus of TLE patients with a magnitude comparable to that observed with [18F]FCWAY, despite the fact that these two PET ligands show a correlation with BDI scores of opposing directions (Merlet et al., 2004a, b; Giovacchini et al., 2005; Theodore et al., 2007). In other words, our positive correlation between somatic depressive symptoms and [18F]MPPF BPND in the epileptic hippocampus is built upon an epilepsy-related major decrease of 5-HT1A receptor availability in that region. In our view, these abnormalities are likely to represent one of the biological links between TLE and the more global pre- and post-synaptic serotoninergic dysfunction associated with comorbid depression.
Correlations between somatic symptoms of the BDI and [18F]MPPF BPND were also observed in the mid-cingulate gyrus, and to a lesser degree, over the frontal dorsolateral cortex. All these regions are thought to be involved in the pathophysiology of depression (Drevets, 2000; Drevets et al., 2000; Kennedy et al., 2001; Anderson et al., 2004). Indeed, various symptoms of MDD were found to correlate with cerebral blood flow, glucose metabolism and [11C]WAY-100635 BP in the cingulate gyrus and frontal cortex in previous studies (Bench et al., 1993; Dunn et al., 2002; Videbech et al., 2002; Graff-Guerrero et al., 2004; Milak et al., 2005). Furthermore, negative correlations were observed between [11C]WAY-100635 BP in the anterior cingulate gyrus and anxiety symptoms, including somatic anxiety (Sullivan et al., 2004) and the anxiety facet of neuroticism in control subjects (Tauscher et al., 2001).
Limitations of this study
We did not perform a systematic standardized psychiatric interview technique during this study, a limitation that prevents us from drawing firm conclusions regarding the pathophysiology of comorbid MDD in epilepsy. We nevertheless feel very confident regarding the reliability of the psychiatric status of the majority of our patients. First, the risk that any of our 15 TLE patients with a BDI-2 cutoff scores 11 suffered current MDD (i.e. within the past 2 weeks) is below 1%, according to previous work in the field (Jones et al., 2005b). Second, the mental health of all our patients was thoroughly evaluated by an experienced senior epileptologist during their pre-surgical evaluation. Third, seven out of nine patients with a BDI-2 cutoff scores >11 were further evaluated by a psychiatrist, leading to a diagnosis of MDD in five and mild depressive disorder in the remaining two. Finally, no other major psychiatric illness was noted in our population. The relevance of our approach is further supported by our results, showing that the different classes of depressive symptoms correlated with [18F]MPPF BPND in distinct brain regions.
Whether the correlation observed in our study primarily involved the left insula or that contralateral to seizure onset remains uncertain. Indeed, both the conventional and flipped PET data showed lateralized findings, pointing to the left hemisphere and that contralateral to seizure onset, respectively. This ambiguity partly reflected an imbalance between patients with right and left TLE (16 and 8, respectively, in our sample) that was even more marked among patients whose BDI score was >11 (8 right TLE versus 1 left TLE). Unfortunately, we could not control for this situation since our protocol required the inclusion of a specific number of consecutive patients fulfilling our inclusion criteria, regardless of the lateralization of their epileptic focus. This imbalance resulted in right TLE patients’ data having a major influence on the overall findings. Consequently, left hemispheric data largely corresponded to those contralateral to seizure onset and vice versa. The fact that SPM analysis of unflipped PET volumes disclosed a significant correlation with the total BDI score over the left insula, while the analysis of flipped PET data only showed a non-significant trend within the insula contralateral to seizure onset (although this correlation proved significant when re-evaluated with ROIs), could argue for the former hypothesis. In our view, the less significant results obtained with flipped PET data is more likely to reflect anatomical differences between the left and right insula not corrected by spatial normalization, resulting in a suboptimal anatomical matching between the right and flipped left insula within our [18F]MPPF BPND template and in a less sensitive statistical analysis of this brain structure. Indeed, ROI analyses that do not suffer this anatomical limitation showed similar Pearson coefficients for the left insula and that contralateral to seizure onset. Other minor and indirect arguments in favour of a left-sided lateralization of depression-associated [18F]MPPF PET changes derive from the observation of predominantly left hemispheric FDG-PET abnormalities in depressed patients (Kennedy et al., 2001; Drevets et al., 2002; Anderson et al., 2004) and higher rates of depression in patients with left frontal strokes or post-traumatic scars than in those with the same type of right frontal lesions (Lipsey et al., 1983; Robinson et al., 1984, 1988; Jorge et al., 1993). Some studies have also reported a higher incidence of depression in patients with left rather than right TLE (Robertson, 1987; Altshuler et al., 1990; Victoroff et al., 1994) but this issue remains debated (Kohler et al., 1999). For instance, in our population, only 13% of patients with left TLE had a BDI score >11, as compared with 50% of right TLE patients.
The post hoc ROI analyses of the subgroup of patients with left TLE provided a more compelling argument towards the alternative view of a primary involvement of the insula contralateral to seizure onset rather than of the left insula proper. In this population, the BDI correlated with [18F]MPPF BPND in the right (i.e. contralateral to seizure onset) but not in the left insula (Table 4). Although these findings could be partly influenced by the smaller number of patients with left rather than right TLE, they are strongly supported by the Pearson coefficients obtained in these two populations for left and right TLE, respectively. Overall, we believe that the correlations observed between depressive symptoms and [18F]MPPF BPND are more likely to involve the insula contralateral to the epileptogenic zone than the left insula. The question then arises of the pathophysiological significance of this finding. One possibility could be that the serotoninergic dysfunction associated with depressive symptoms would normally affect both insula but would be obscured on the side ipsilateral to the epileptic temporal lobe by 5-HT1A receptor changes related to the frequent propagation of epileptic discharges into that region (Isnard et al., 2000). Another possibility could be that the emergence of depressive symptoms in patients with unilateral TLE depends more on the bilateralization of serotoninergic dysfunction than on the intensity of ipsilateral abnormalities.
|
As for the previous correlations observed in the insula, we cannot firmly conclude as to whether those seen in the cingulate gyrus primarily involve the left side or that contralateral to seizure onset, although post hoc analyses in left TLE patients favoured the former possibility. Interestingly, glucose metabolism in the left cingulate gyrus was also found to correlate positively with depressive symptoms in MDD patients, although not specifically with somatic symptoms (Dunn et al., 2002
). A prior [11C]WAY-100635 PET study of TLE patients also reported correlation between depression and 5-HT1A receptors density in the cingulate gyrus (Savic et al., 2004). However, this correlation was negative rather than positive, ipsilateral to seizure onset rather than left-sided or contralateral and predominated in the anterior rather than the mid-portion of the cingulate gyrus. Overall, our data suggest that complex changes of the central serotoninergic system are associated with the type and intensity of depressive symptoms in TLE patients. These changes appear to predominate over the raphe nuclei and the insula, and to a lesser extent the left mid-cingulate gyrus, the left and right frontal dorsolateral cortex, and the hippocampal region ipsilateral to seizure onset, with some regional specificity for the different symptom classes. At present, it remains difficult to firmly conclude on the molecular substratum underlying higher [18F]MPPF-BPND in the more depressed TLE patients (i.e. decreased serotonin concentration versus higher number of 5-HT1A receptors) in as much as previously published [11C]WAY-100635 and [18F]FCWAY studies in TLE and MDD provide conflicting results. However, it is our view that our findings most likely reflect a decreased extracellular concentration of serotonin at the pre- and post-synaptic levels of the major central serotoninergic pathways.
|
Acknowledgements |
|---|
We thank Didier Le Bars for [18F]MPPF radiosynthesis and the CERMEP medical team for assistance and are greatly indebted to Drs F. Mauguière, G. Demarquay, J. Isnard, C. Fisher, D. Rosenberg, E. Hirsh and P. Kahane for referring some of the patients of this serie.
|
References |
|---|
|
TopSummaryIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Ahmad S, Fowler LJ, Whitton PS. Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat. Br J Pharmacol (2004) 142:136–42.[CrossRef][Web of Science][Medline]
Ahmad S, Fowler LJ, Whitton PS. Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids. Epilepsy Res (2005) 63:141–9.[CrossRef][Web of Science][Medline]
Altshuler LL, Devinsky O, Post RM, Theodore W. Depression, anxiety, and temporal lobe epilepsy. Laterality of focus and symptoms. Arch Neurol (1990) 47:284–8.
Anderson AD, Oquendo MA, Parsey RV, Milak MS, Campbell C, Mann JJ. Regional brain responses to serotonin in major depressive disorder. J Affect Disord (2004) 82:411–7.[Web of Science][Medline]
Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology (2001) 25:892–903.[CrossRef][Web of Science][Medline]
Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V. ‘Serotonin depression’–a biochemical subgroup within the affective disorders? Science (1976) 191:478–80.
Barba C, Barbati G, Minotti L, Hoffmann D, Kahane P. Ictal clinical and scalp-EEG findings differentiating temporal lobe epilepsies from temporal ‘plus’ epilepsies. Brain (2007) 130(Pt 7):1957–67.
Baxendale SA, Thompson PJ, Duncan JS. Epilepsy & depression: the effects of comorbidity on hippocampal volume–a pilot study. Seizure (2005) 14:435–8.[Web of Science][Medline]
Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ. Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med (1993) 23:579–90.[Web of Science][Medline]
Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry (2004) 9:386–92.[CrossRef][Web of Science][Medline]
Boldrini M, Underwood MD, Mann JJ, Arango V. Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res (2008) 42:433–42.[CrossRef][Web of Science][Medline]
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry (2000) 157:115–8.
Briellmann RS, Hopwood MJ, Jackson GD. Major depression in temporal lobe epilepsy with hippocampal sclerosis: clinical and imaging correlates. J Neurol Neurosurg Psychiatry (2007) 78:1226–30.
Cathébras P, Mosnier C, Lévy M, Bouchou K, Rousset H. Screening for depression in patients with medical hospitalization. Comparison of two self-evaluation scales and clinical assessment with a structured questionnaire. Encephale (1994) 20:311–7.[Web of Science][Medline]
Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y. Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine. Neurosci Lett (2005) 390:48–53.[CrossRef][Web of Science][Medline]
Costello CG. Research on symptoms versus research on syndromes: arguments in favour of allocating more research time to the study of symptoms. Br J Psychiatry (1992) 160:304–8.
Costes N, Merlet I, Zimmer L, Lavenne F, Cinotti L, Delforge J, et al. Modeling [18F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection. J Cereb Blood Flow Metab (2002) 22:753–65.[Web of Science][Medline]
Costes N, Merlet I, Ostrowsky K, Faillenot I, Lavenne F, Zimmer L, et al. A 18F-MPPF PET normative database of 5-HT1A receptor binding in men and women over aging. J Nucl Med (2005) 46:1980–9.
Dailey JW, Reith ME, Yan QS, Li MY, Jobe PC. Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+. Eur J Pharmacol (1997) 328:153–62.[CrossRef][Web of Science][Medline]
Dhaenen H. Imaging the serotonergic system in depression. Eur Arch Psychiatry Clin Neurosci (2001) 251(Suppl 2):II76–80.[Medline]
Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry (2000) 48:813–29.[CrossRef][Web of Science][Medline]
Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol (2002) 12:527–44.[CrossRef][Web of Science][Medline]
Drevets WC, Frank E, Price JC, Kupfer DJ, Greer PJ, Mathis C. Serotonin type-1A receptor imaging in depression. Nucl Med Biol (2000) 27:499–507.[CrossRef][Web of Science][Medline]
Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry (1999) 46:1375–87.[CrossRef][Web of Science][Medline]
Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, et al. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol (2007) 34:865–77.[CrossRef][Web of Science][Medline]
Dunn RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, et al. Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression. Biol Psychiatry (2002) 51:387–99.[CrossRef][Web of Science][Medline]
Engel J Jr. Classifications of the international league against epilepsy: time for reappraisal. Epilepsia (1998) 39:1014–7.[CrossRef][Web of Science][Medline]
Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp (2008) 29:683–95.[CrossRef][Web of Science][Medline]
Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ. Comparing functional (PET) images: the assessment of significant changes. J Cereb Blood Flow Metab (1991) 11:690–9.[Web of Science][Medline]
Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RJS. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp (1995) 3:189–210.
Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, et al. Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry (2002) 159:1112–8.
Gilliam FG, Maton BM, Martin RC, Sawrie SM, Faught RE, Hugg JW, et al. Hippocampal 1H-MRSI correlates with severity of depression symptoms in temporal lobe epilepsy. Neurology (2007) 68:364–8.
Giovacchini G, Toczek MT, Bonwetsch R, Bagic A, Lang L, Fraser C, et al. 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J Nucl Med (2005) 46:1128–35.
Graff-Guerrero A, Gonzalez-Olvera J, Mendoza-Espinosa Y, Vaugier V, Garcia-Reyna JC. Correlation between cerebral blood flow and items of the Hamilton Rating Scale for Depression in antidepressant-naive patients. J Affect Disord (2004) 80:55–63.[CrossRef][Web of Science][Medline]
Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, et al. Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY- 100635 for PET. Neuroimage (1998) 8:426–40.[CrossRef][Web of Science][Medline]
Hammers A, Asselin MC, Hinz R, Kitchen I, Brooks DJ, Duncan JS, et al. Upregulation of opioid receptor binding following spontaneous epileptic seizures. Brain (2007) 130:1009–16.
Hammers A, Koepp MJ, Hurlemann R, Thom M, Richardson MP, Brooks DJ, et al. Abnormalities of grey and white matter [11C]flumazenil binding in temporal lobe epilepsy with normal MRI. Brain (2002) 125:2257–71.
Hammers A, Koepp MJ, Richardson MP, Hurlemann R, Brooks DJ, Duncan JS. Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients. Brain (2003) 126(Pt 6):1300–18.
Hasler G, Bonwetsch R, Giovacchini G, Toczek MT, Bagic A, Luckenbaugh DA, et al. 5-HT(1A) receptor binding in temporal lobe epilepsy patients with and without major depression. Biol Psychiatry (2007) 62:1258–64.[CrossRef][Web of Science][Medline]
Heimovi H, Goldstein JD, Sheline YI, Gilliam FG. Mechanisms of depression in epilepsy from a clinical perspective. Epilepsy Behav (2003) 4(Suppl 3):S25–30.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab (2007) 27:1533–39.[CrossRef][Web of Science][Medline]
Isnard J, Guénot M, Ostrowsky K, Sindou M, Mauguière F. The role of the insular cortex in temporal lobe epilepsy. Ann Neurol (2000) 48:614–23.[CrossRef][Web of Science][Medline]
Ito S, Suhara T, Ito H, Yasuno F, Ichimiya T, Takano A, et al. Changes in central 5-HT(1A) receptor binding in mesial temporal epilepsy measured by positron emission tomography with [(11)C]WAY100635. Epilepsy Res (2007) 73:111–8.[CrossRef][Web of Science][Medline]
Jones JE, Hermann BP, Barry JJ, Gilliam F, Kanner AM, Meador KJ. Clinical assessment of axis I psychiatric morbidity in chronic epilepsy: a multicenter investigation. J Neuropsychiatry Clin Neurosci Spring (2005a) 17:172–9.
Jones JE, Hermann BP, Woodard JL, Barry JJ, Gilliam F, Kanner AM, et al. Screening for major depression in epilepsy with common self-report depression inventories. Epilepsia (2005b) 46:731–5.[CrossRef][Web of Science][Medline]
Jorge RE, Robinson RG, Arndt SV, Forrester AW, Geisler F, Starkstein SE. Comparison between acute- and delayed-onset depression following traumatic brain injury. J Neuropsychiatry Clin Neurosci (1993) 5:43–9.
Kabani M, MacDonald D, Holmes C, Evans A. 3D anatomical atlas of the human brain. In: In: Proceedings of Fourth International Conference on Functional Mapping of the Human Brain, Montreal, Canada—Arthur W, Toga RSJF, John CM, eds. (1998) NeuroImage: Organization for Human Brain Mapping.
Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry (2003) 54:388–98.[CrossRef][Web of Science][Medline]
Karzmark P, Zeifert P, Barry J. Measurement of depression in epilepsy. Epilepsy Behav (2001) 2:124–8.[CrossRef][Medline]
Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry (2001) 158:899–905.
Kimbrell TA, Ketter TA, George MS, Little JT, Benson BE, Willis MW, et al. Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry (2002) 51:237–52.[CrossRef][Web of Science][Medline]
Kohler C, Norstrand JA, Baltuch G, O'Connor MJ, Gur RE, French JA, et al. Depression in temporal lobe epilepsy before epilepsy surgery. Epilepsia (1999) 40:336–40.[CrossRef][Web of Science][Medline]
Lehrner J, Kalchmayr R, Serles W, Olbrich A, Pataraia E, Aull S, et al. Health-related quality of life (HRQOL), activity of daily living (ADL) and depressive mood disorder in temporal lobe epilepsy patients. Seizure (1999) 8:88–92.[CrossRef][Web of Science][Medline]
Lipsey JR, Robinson RG, Pearlson GD, Rao K, Price TR. Mood change following bilateral hemisphere brain injury. Br J Psychiatry (1983) 143:266–73.
Lopez JF, Chalmers DT, Little KY, Watson SJ. A.E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry (1998) 43:547–73.[CrossRef][Web of Science][Medline]
Lopez JF, Liberzon I, Vazquez DM, Young EA, Watson SJ. Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress. Biol Psychiatry (1999) 45:934–7.[CrossRef][Web of Science][Medline]
Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, et al. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry (2004) 55:225–33.[CrossRef][Web of Science][Medline]
Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci (1997) 9:471–81.
Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry (1999) 156:675–82.
Meltzer HY. Role of serotonin in depression. Ann N Y Acad Sci (1990) 600:486–99.[Web of Science][Medline]
Mendez MF, Cummings JL, Benson DF. Depression in epilepsy: significance and phenomenology. Arch Neurol (1986) 43:766–70.
Merlet I, Ryvlin P, Costes N, Dufournel D, Isnard J, Faillenot I, et al. Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG. Neuroimage (2004a) 22:886–96.[CrossRef][Web of Science][Medline]
Merlet I, Ostrowsky K, Costes N, Ryvlin P, Isnard J, Faillenot I, et al. 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study. Brain (2004b) 127(Pt 4):900–13.
Milak MS, Parsey RV, Keilp J, Oquendo MA, Malone KM, Mann JJ. Neuroanatomic correlates of psychopathologic components of major depressive disorder. Arch Gen Psychiatry (2005) 62:397–408.
Moses-Kolko EL, Price JC, Thase ME, Meltzer CC, Kupfer DJ, Mathis CA, et al. Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635. Synapse (2007) 61:523–30.[CrossRef][Web of Science][Medline]
Nagai M, Kishi K, Kato S. Insular cortex and neuropsychiatric disorders: a review of recent literature. Eur Psychiatry (2007) 22:387–94.[CrossRef][Web of Science][Medline]
Okada M, Kawata Y, Kiryu K, Mizuno K, Wada K, Inomata H, et al. Effects of non-toxic and toxic concentrations of phenytoin on monoamines levels in rat brain. Epilepsy Res (1997) 28:155–63.[CrossRef][Web of Science][Medline]
Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY, et al. Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry (2006) 59:106–13.[CrossRef][Web of Science][Medline]
Price JL. Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci. (1999) 877:383–96.[CrossRef][Web of Science][Medline]
Pugsley TA, Whetzel SZ, Dooley DJ. Reduction of 3,4-diaminopyridine-induced biogenic amine synthesis and release in rat brain by gabapentin. Psychopharmacology (1998) 137:74–80.[CrossRef][Medline]
Quiske A, Helmstaedter C, Lux S, Elger CE. Depression in patients with temporal lobe epilepsy is related to mesial temporal sclerosis. Epilepsy Res (2000) 39:121–5.[CrossRef][Web of Science][Medline]
Rbah L, Leviel V, Zimmer L. Displacement of the PET ligand 18F-MPPF by the electrically evoked serotonin release in the rat hippocampus. Synapse (2003) 49:239–45.[CrossRef][Web of Science][Medline]
Richardson EJ, Griffith HR, Martin RC, Paige AL, Stewart CC, Jones J, et al. Structural and functional neuroimaging correlates of depression in temporal lobe epilepsy. Epilepsy Behav (2007) 10:242–9.[CrossRef][Web of Science][Medline]
Richer M, Hen R, Blier P. Modification of serotonin neuron properties in mice lacking 5-HT1A receptors. Eur J Pharmacol (2002) 435:195–203.[CrossRef][Web of Science][Medline]
Ring HA, Acton PD, Scull D, Costa DC, Gacinovik S, Trimble MR. Patterns of brain activity in patients with epilepsy and depression. Seizure (1999) 8:390–7.[CrossRef][Web of Science][Medline]
Robertson MM, Trimble MR, Townsend HR. Phenomenology of depression in epilepsy. Epilepsia (1987) 28:364–72.[Web of Science][Medline]
Robinson RG, Boston JD, Starkstein SE, Price TR. Comparison of mania and depression after brain injury: causal factors. Am J Psychiatry (1988) 145:172–8.
Robinson RG, Kubos KL, Starr LB, Rao K, Price TR. Mood disorders in stroke patients. importance of location of lesion. Brain (1984) 107(Pt 1):81–93.
Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, et al. Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry (2004) 61:556–63.
Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, et al. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry (2000) 57:174–80.
Savic I, Lindstrom P, Gulyas B, Halldin C, Andree B, Farde L. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology (2004) 62:1343–51.
Saxena S, Brody AL, Ho ML, Alborzian S, Ho MK, Maidment KM, et al. Cerebral metabolism in major depression and obsessive-compulsive disorder occurring separately and concurrently. Biol Psychiatry (2001) 50:159–70.[CrossRef][Web of Science][Medline]
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage (2004) 22:409–18.[CrossRef][Web of Science][Medline]
Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry (2003) 54:338–52.[CrossRef][Web of Science][Medline]
Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry (2003) 160:1516–8.
Shelley BP, Trimble MR. The insular lobe of Reil–its anatamico-functional, behavioural and neuropsychiatric attributes in humans–a review. World J Biol Psychiatry (2004) 5:176–200.[CrossRef][Web of Science][Medline]
Steer RA, Ball R, Ranieri WF, Beck AT. Dimensions of the Beck Depression Inventory-II in clinically depressed outpatients. J Clin Psychol. (1999) 55:117–28.[CrossRef][Web of Science][Medline]
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci (1998) 18:7394–401.
Sudha S, Lakshmana MK, Pradhan N. Phenobarbital in the anticonvulsant dose range does not impair learning and memory or alter brain AChE activity or monoamine levels. Pharmacol Biochem Behav (1996) 54:633–8.[CrossRef][Web of Science][Medline]
Sullivan GM, Oquendo MA, Simpson N, Van Heertum RL, Mann JJ, Parsey RV. Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety. Biol Psychiatry (2005) 58:947–54.[CrossRef][Web of Science][Medline]
Takebayashi M, Motohashi N, Saito H, Kagaya A, Yamawaki S. Effect of acute treatment with sodium valproate on catecholamine and serotonin synthesis in mouse cerebral cortex. Neuropsychobiology (1995) 32:124–7.[CrossRef][Web of Science][Medline]
Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A, et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology (2001) 24:522–30.[CrossRef][Web of Science][Medline]
Theodore WH, Giovacchini G, Bonwetsch R, Bagic A, Reeves-Tyer P, Herscovitch P, et al. The effect of antiepileptic drugs on 5-HT-receptor binding measured by positron emission tomography. Epilepsia. (2006) 47:499–503.[CrossRef][Web of Science][Medline]
Theodore WH, Hasler G, Giovacchini G, Kelley K, Reeves-Tyer P, Herscovitch P, et al. Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia (2007) 48:1526–30.[CrossRef][Web of Science][Medline]
Toczek MT, Carson RE, Lang L, Ma Y, Spanaki MV, Der MG, et al. PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology (2003) 60:749–56.
Underwood MD, Khaibulina AA, Ellis SP, Moran A, Rice PM, Mann JJ, et al. Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry (1999) 46:473–83.[CrossRef][Web of Science][Medline]
Victoroff JI, Benson F, Grafton ST, Engel J Jr, Mazziotta JC. Depression in complex partial seizures. electroencephalography and cerebral metabolic correlates. Arch Neurol (1994) 51:155–63.
Videbech P, Ravnkilde B, Pedersen TH, Hartvig H, Egander A, Clemmensen K, et al. The Danish PET/depression project: clinical symptoms and cerebral blood flow. A regions-of-interest analysis. Acta Psychiatr Scand (2002) 106:35–44.[CrossRef][Web of Science][Medline]
Weissmann-Nanopoulos D, Mach E, Magre S, Demassay Y, Pujol JF. Evidence for the localization of 5HT1-A binding sites on serotonin containing neurons in the raphe dorsalis and raphe centralis nuclei of the rat brain. Neurochem Int (1985) 7:1061–72.[CrossRef][Web of Science]
Wieser HG. and ILAE Commission on Neurosurgery of Epilepsy. ILAE commission report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia (2004) 45:695–714.[CrossRef][Medline]
Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF. Effect of endogenous serotonin on the binding of the 5-hT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis. J Neurochem. (2002) 80:278–86.[CrossRef][Web of Science][Medline]
Zhuang ZP, Kung MP, Chumpradit S, Mu M, Kung HF. Derivatives of 4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl-p-iodobenzamido)ethyl]pipera zine (p-MPPI) as 5-HT1A ligands. J Med Chem (1994) 37:4572–5.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||