Higher BDNF plasma levels are associated with a normalization of memory dysfunctions during an antidepressant treatment.

One important symptom of patients with major depressive disorder (MDD) is memory dysfunction. However, little is known about the relationship between memory performance and depression severity, about the course of memory performance during antidepressant treatment as well as about the relationship between memory performance and brain-derived neurotrophic factor (BDNF). Memory function [learning and delayed recall) was assessed in 173 MDD patients (mean age 39.7 ± 11.3 years] treated by a pre-defined treatment algorithm within the early medication change (EMC) study at baseline, days 28 and 56. Depression severity was assessed in weekly intervals, BDNF plasma levels were measured at baseline, days 14 and 56, BDNF exon IV and p11 methylation status at baseline. Linear mixed regression models revealed that the course of depression severity was not associated with the course of learning or delayed recall in the total group. 63 (36%) of the investigated patients showed memory deficits (percent range ≤ 16) at baseline. Of those, 26(41%) patients experienced a normalization of their memory deficits during treatment. Patients with a normalization of their delayed recall performance had significantly higher plasma BDNF levels (p = 0.040) from baseline to day 56 than patients with persistent deficits. Baseline BDNF exon IV promoter and p11 gene methylation status were not associated with memory performance. Our results corroborate a concomitant amelioration of learning and delayed recall dysfunctions with successful antidepressant therapy in a subgroup of patients and support a role of BDNF in the neural mechanisms underlying the normalization of memory dysfunctions in MDD. ClinicalTrials.gov number: NCT00974155; EudraCT: 2008-008280-96.

Hippocampal resection length and memory outcome in selective epilepsy surgery.

OBJECTIVE: In temporal lobe epilepsy surgery, there is a trend towards becoming more selective in order to achieve seizure control with an optimal neuropsychological outcome. The present study evaluated whether mesial resection length matters for memory outcome after selective amygdalo-hippocampectomy (SAH). Therefore, a sub-analysis of the larger SFB/TR3/A1 multicentre randomised trial on seizure outcome and mesial resection length in temporal lobe surgery was performed. METHODS: A homogeneous group of 67 selectively operated patients with hippocampal sclerosis as the sole pathology were allocated to a short (2.5 cm, n=34) or a long (3.5 cm, n=33) mesial resection. Repeated memory assessment and three-dimensional MRI data sets served as dependent within group variables, and intraoperatively determined resection lengths (short/long), resected hippocampal volumes (small/large) and side of surgery were independent between group variables. RESULTS: Resection length did not have a significant effect on seizure or on memory outcome. The resected hippocampal volume also did not affect seizure outcome but it did make a difference with regard to memory outcome. Outcome in verbal learning and memory was poorer after resection of larger left hippocampal volumes. Figural memory outcome was poorer with larger resected volumes on either side. INTERPRETATION: The data indicate that in SAH, mesial resection length and resected volumes have no differential effect on seizure outcome. The findings on memory outcome are best explained by suggesting that hippocampal volumes take the degree of preoperative pathology into account whereas resection length does not. This suggests resection of non-pathological functional tissues as the basis for memory outcome after SAH.

Neurodevelopmental disruption in early-onset temporal lobe epilepsy: evidence from a voxel-based morphometry study.

Childhood onset of epilepsy has long been associated with an adverse impact on brain development and cognition. In this study it is proposed that earlier (vs later) onset of temporal lobe epilepsy (TLE) has a negative developmental impact on distant brain structures. One hundred ten patients with TLE were assigned to early (≤14 years, N=58) and late (>15 years, N=52) age at onset of epilepsy groups. Voxel-based morphometry revealed onset-dependent abnormalities (in terms of a gray matter excess in the early-onset group), which were found mainly in frontal regions. An excess of gray matter is not a usual finding in TLE. However, within a neurodevelopmental framework, retained gray matter is discussed as reflecting neurodevelopmental disruption. The findings indicate the importance of quantitative MRI for the detection of subtle secondary abnormalities in focal TLE and once more underline the importance of early seizure management in children with intractable TLE.

Widespread affections of large fiber tracts in postoperative temporal lobe epilepsy.

Temporal lobe epilepsy with hippocampus sclerosis (HS) is the most frequent focal epilepsy and often refractory to anticonvulsant therapy. Secondary structural damage has been reported in several studies of temporal lobe epilepsy and unilateral hippocampal sclerosis. Applying diffusion tensor imaging (DTI) we investigated alterations in white matter following temporal lobe surgery in patients with medial temporal lobe epilepsy. We examined 40 patients who underwent surgery at our hospital for HS between 1996 and 2006 with diffusion tensor imaging (DTI). Images were obtained at a 3 T MRI scanner employing 60 gradient directions. Tract-based spatial statistics (TBSS), a novel voxel-based approach, was applied to analyze the data. Both patients with left- as well as right-sided surgery exhibited widespread degradation of fractional anisotropy (FA) in main fiber tracts not limited to the respective temporal lobe such as the uncinate fasciculus, the fronto-occipital fasciculus, the superior longitudinal fasciculus, the corpus callosum and the corticospinal tract on the respective hemisphere. Patients with left-hemispheric surgery showed more widespread affections ipsilaterally and also FA decrease in the contralateral inferior longitudinal fasciculus. DTI demonstrates widespread clusters of abnormal diffusivity and anisotropy in prominent white matter tracts linking mesial temporal lobe structures with other brain areas. Alterations in the ipsilateral mesial temporal lobe can be attributed to be a result of surgery, whereas extratemporal FA decrease is more likely the result of the underlying seizure disorder.

Age at onset of epilepsy as a determinant of intellectual impairment in temporal lobe epilepsy.

Intellectual impairment in addition to memory problems in temporal lobe epilepsy (TLE) has been postulated to be a result of a mental decline caused by chronic epilepsy. Longer duration, however, is often confounded with earlier age at onset of epilepsy (AOE). IQ and memory were evaluated in 188 patients (age>16) with TLE with an AOE before age 14 (N=91) or after age 15 (N=97). Earlier AOE did not differentially affect memory aspects more associated with temporomesial structures, but it negatively affected IQ and aspects of memory that are more related to temporolateral and extratemporal lobe structures. As earlier AOE was also associated with lower educational levels and because one may not assume that these are lost with chronicity of epilepsy, the results can be interpreted as reflecting developmental hindrance of extratemporal lobe functions in early-onset TLE rather than cognitive decline due to a longer duration of epilepsy.

Shrinkage of the hippocampal remnant after surgery for temporal lobe epilepsy: impact on seizure and neuropsychological outcomes.

The aim of this study was to investigate the influence of the postoperative hippocampal remnant on postoperative seizure and neuropsychological outcome in temporal lobe epilepsy (TLE). Postoperative volumetric MRI measurements of 53 patients surgically treated for TLE revealed a postoperative volume loss of the hippocampal remnant compared with the respective preoperative segment in all patients. Extent of preoperative hippocampal pathology, remnant shrinkage, resection volume, and postoperative volume of the hippocampal remnant did not correlate with seizure outcome 1 year after surgery. With respect to neuropsychological outcome, performance on tasks assessing verbal memory and language-related functions was impaired in patients with left-sided pathology after surgery. Performance of patients with right-sided pathology (n=26) demonstrated no significant correlation with hippocampal measures or with neuropsychological data. Degree of hippocampal remnant shrinkage seems to be associated with decreased verbal memory performance in patients with left-sided TLE.

Early improvement of executive test performance during antidepressant treatment predicts treatment outcome in patients with Major Depressive Disorder.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 -patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96.

Positive correlation between the density of neuropeptide y positive neurons in the amygdala and parameters of self-reported anxiety and depression in mesiotemporal lobe epilepsy patients.

BACKGROUND: Neuropeptide Y (NPY) has been implicated in depression, anxiety, and memory. Expression of human NPY and the number of NPY-positive neurons in the rodent amygdala correlate with anxiety and stress-related behavior. Increased NPY expression in the epileptic brain is supposed to represent an adaptive mechanism counteracting epilepsy-related hyperexcitability. We attempted to investigate whether NPY-positive neurons in the human amygdala are involved in these processes. METHODS: In 34 adult epileptic patients undergoing temporal lobe surgery for seizure control, the density of NPY-positive neurons was assessed in the basal, lateral, and accessory-basal amygdala nuclei. Cell counts were related to self-reported depression, anxiety, quality of life, clinical parameters (onset and duration of epilepsy, seizure frequency), antiepileptic medication, and amygdala and hippocampal magnetic resonance imaging volumetric measures. RESULTS: Densities of NPY-positive basolateral amygdala neurons showed significant positive correlations with depression and anxiety scores, and they were negatively correlated with lamotrigine dosage. In contrast, NPY cell counts showed no relation to clinical factors or amygdalar and hippocampal volumes. CONCLUSIONS: The results point to a role of amygdalar NPY in negative emotion and might reflect state processes at least in patients with temporal lobe epilepsy. Correlations with common clinical parameters of epilepsy were not found. The question of a disease-related reduction of the density of NPY-positive amygdalar neurons in temporal lobe epilepsy requires further investigation.

Volume determination of amygdala and hippocampus at 1.5 and 3.0T MRI in temporal lobe epilepsy.

Since magnetic resonance imaging (MRI) technique is constantly evolving with higher field strength scanners, the question arises whether images from different field strength scanners can be used interchangeably for scientific and clinical purposes. We address this issue in a study group of patients with temporal lobe epilepsy (TLE). Two different quantification methods for analysing structural (MRI) were used. Conventional volumetry was performed by manually tracing amygdala and hippocampus volumes on both 1.5 and 3T scans of 10 TLE patients. Additionally a voxel-based morphometry (VBM)-based extraction of those structures was conducted. As an answer to the main question, it was determined that the volumetrically derived volumes of amygdala and hippocampus from 1.5 and 3.0T images did not differ. Our findings concerning the volumetry are consistent with findings in healthy controls, thus offering the possibility to use volumetry of the different scanners interchangeably. The results of the VBM-analyses show satisfying inter-scanner volume quantification but not consistent enough to be deemed interchangeable. Further investigations analysing the outcomes of conventional VBM of different field strength scanners are necessary.