Patterns of default mode network in temporal lobe epilepsy with and without hippocampal sclerosis.

The default mode network (DMN) consists of the deactivation of specific regions during the performance of cognitive tasks and activation during resting or mind wandering. Several pieces of evidence indicate the impairment of DMN in patients with mesial temporal lobe epilepsy (MTLE). However, most of these studies combined different underlying etiologies, failing to disentangle the influence of seizures and presence and side of hippocampal sclerosis (HS). We included 119 patients with MTLE divided into right-HS (n = 42), left-HS (n = 46), and magnetic resonance imaging (MRI)-negative MTLE (n = 31) and controls (n = 59). All underwent resting-state seed-based functional connectivity (FC), with a seed placed at the posterior cingulate cortex (PCC), an essential node for the DMN. To access group inferences, we used an SPM (Statistical Parametric Mapping) full-factorial model to compare patterns of activation using pairwise comparisons among all groups. Our results indicate a different pattern of DMN FC when controlling for side and presence of HS. The group with right-HS had increased FC in the left angular gyrus and the left middle occipital gyrus, when compared to controls, and increased FC of the left hippocampus when compared to the group with left-HS. The MRI-negative group had increased FC of the left hippocampus, left ventral diencephalon, and left fusiform gyrus as compared to left-HS, but did not show any areas of reduced FC compared to controls. By contrast, the group with left-HS did not show areas of increased FC compared to controls or the right-HS and had reduced FC in the left hippocampus compared to controls. Hence, the right-HS presented increased FC in areas related to the DMN in the left hemisphere; the MRI-negative group also showed increased FC in left-sided structures close to temporal lobe when compared to left-HS, probably indicating engagement in a compensatory system. In a subanalysis considering only the MRI-negative with left-sided EEG (electroencephalogram) subgroup, we found differences against controls, with left angular gyrus more connected in the first group, but no significant differences when compared to the group with left-HS. We conclude that the origin of seizures on the left hemisphere seems to engender a less prominent capacity of recruiting other neighbor areas related to DMN as compared to right-HS and controls. Considering recent studies that have revealed the importance of DMN for cognitive skills and memory, our findings may indicate that deficiencies exhibited by patients with left-HS temporal lobe epilepsy (TLE) in connecting to the DMN could be a surrogate marker of their known worse neuropsychological performance. Further studies with direct comparisons between cognitive tests and FC within the DMN are needed to validate these findings, especially for MRI-negative patients. This article is part of the Special Issue "NEWroscience 2018".

Hippocampal atrophy disrupts the language network but not hemispheric language lateralization.

OBJECTIVE: It is still unclear how temporal lobe epilepsy (TLE) with and without hippocampal atrophy (HA) affects cortical language distribution. We aimed to investigate the role of the hippocampus on language lateralization, activation pattern, and functional connectivity (FC) in patients with TLE. METHODS: We investigated 93 patients with TLE-divided into right HA (RHA), left HA (LHA), and negative magnetic resonance imaging (MRI) (non-HA)-and 101 controls using a semantic-language functional MRI (fMRI) task and the Boston Naming Test (BNT). RESULTS: Groups did not differ in the frequency of atypical language lateralization (LL), which correlated differently with handedness in each brain region and group. Blood-oxygen-level dependend (BOLD) activation patterns and region of interest (ROI)-to-ROI FC differed between LHA and controls, as well as between LHA and non-HA patients. In the task activation pattern analysis, there was a decrease in the activation of patients with LHA relative to controls, exactly in the left hippocampus. However, non-HA patients had increased FC relative to controls in the left superior temporal gyrus region. Seed-to-voxel FC demonstrated greater differences between patients and controls and smaller differences among patient groups. The non-HA group was similar to controls, except for increased BOLD activation and increase FC in the superior temporal gyri. RHA and LHA differed from controls in BNT. BNT correlated with fMRI activation in RHA and non-HA groups. SIGNIFICANCE: LHA affected naming performance, fMRI semantic task activation pattern, and FC more than RHA and non-HA. Contrary to our expectations, LHA did not increase the frequency of atypical LL. Regardless of the side, HA impacts negatively on the language network but not on hemispheric language lateralization.

Anxiety and depression symptoms disrupt resting state connectivity in patients with genetic generalized epilepsies.

OBJECTIVE: To analyze the lifetime trajectories in genetic generalized epilepsies (GGEs) and investigate the impact of symptoms of anxiety and depression on resting state functional connectivity (FC). METHODS: Seventy-four GGE patients were classified according to the pharmacological response as seizure-free (12 patients), pharmacoresistant (PhR; 14 patients), and fluctuating (FL; 48 patients). Fifty-four subjects completed both the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), and 38 also underwent 3-T resting state functional magnetic resonance imaging. These 38 patients were subdivided into a positive group (13 patients with concurrent symptoms of depression and anxiety) and a negative group (21 asymptomatic patients and four with mild anxiety or depression symptoms). For FC analysis of resting state networks, we matched 38 healthy asymptomatic volunteers and used the UF2C toolbox running on MATLAB2017/SPM12. RESULTS: The PhR group presented shorter duration of epilepsy (P = 0.016) and follow-up (P < 0.001) compared to the FL group. The PhR group showed higher levels (median = 20) on the BAI and BDI. Myoclonic seizures were the most difficult to control, as 50% of subjects persisted with them at last appointment, compared to generalized tonic-clonic seizures and absence seizures (<40%). Patients with concurrent anxiety and depression symptoms were 7.7 times more likely to exhibit pharmacoresistant seizures, although an increase of 1 year of epilepsy duration was associated with a decrease in the odds of presenting pharmacoresistance by a factor of 0.9. Overall, FC was altered between default mode network (DMN) and visuospatial/dorsal attention. However, only the positive group displayed abnormal FC between DMN and left executive control network, and between salience and visuospatial/dorsal attention. SIGNIFICANCE: Our findings may help clinicians to have a better understanding of GGE clinical course and increase attention to the potential relationship of psychopathologies and brain connectivity.

Enhancement of affective processing induced by bifrontal transcranial direct current stimulation in patients with major depression.

OBJECTIVE: Our aim was to evaluate whether one single section of transcranial direct current stimulation (tDCS), a neuromodulatory technique that noninvasively modifies cortical excitability, could induce acute changes in the negative attentional bias in patients with major depression. SUBJECTS AND METHODS: Randomized, double-blind, sham-controlled, parallel design enrolling 24 age-, gender-matched, drug-free, depressed subjects. Anode and cathode were placed over the left and right dorsolateral prefrontal cortex. We performed a word Emotional Stroop Task collecting the response times (RTs) for positive-, negative-, and neutral-related words. The emotional Stroop effect for negative vs. neutral and vs. positive words was used as the measure of attentional bias. RESULTS: At baseline, RTs were significantly slower for negative vs. positive words. We found that active but not sham tDCS significantly modified the negative attentional bias, abolishing slower RT for negative words. CONCLUSION: Active but not sham tDCS significantly modified the negative attentional bias. These findings add evidence that a single tDCS session transiently induces potent changes in affective processing, which might be one of the mechanisms of tDCS underlying mood changes.

The sertraline versus electrical current therapy for treating depression clinical study (select-TDCS): results of the crossover and follow-up phases.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising nonpharmacological therapy for major depression. In the Sertraline versus Electrical Current Therapy for Treating Depression Clinical Trial (SELECT-TDCS) trial, phase-I (Brunoni et al., JAMA Psychiatry, 2013) we found that tDCS is effective for the acute episode. Here, we describe tDCS effects during phases II (crossover) and III (follow-up) of this trial (NCTs: 01149889 and 01149213). METHODS: Phase II (n = 25) was the open-label, crossover phase in which phase-I nonresponders who had received sham-tDCS received a 10-day course of active-tDCS. In phase-III (n = 42), all active-tDCS responders (>50% Montgomery-Asberg Depression Rating Scale (MADRS) improvement or MADRS ≤ 12) were enrolled to a 24-week, follow-up phase in which a maximum of nine tDCS sessions were performed-every other week for 3 months and, thereafter, once a month for the subsequent 3 months-sessions would be interrupted earlier whether the subject relapsed. TDCS was applied at 2 mA/30 min, with the anode over the left and the cathode over the right dorsolateral prefrontal cortex. Relapse was the outcome measure. RESULTS: In phase-II, 52% of completers responded to tDCS. In phase-III, the mean response duration was 11.7 weeks. The survival rate per Kaplan-Meier analysis was 47%. Patients with treatment-resistant depression presented a much lower 24-week survival rate as compared to nonrefractory patients (10% vs. 77%, OR = 5.52; P < .01). Antidepressant use (sertraline 50 mg/day, eight patients) was not a predictor of relapse. TDCS was well tolerated and with few side effects. CONCLUSION: Continuation tDCS protocols should be optimized as to prevent relapse among tDCS responders, particularly for patients with baseline treatment-resistant depression.

White matter microstructure associated with anhedonia among individuals with bipolar disorders and high-risk for bipolar disorders.

BACKGROUND: Anhedonia - a key symptom of depression - is highly associated with poorer outcomes and suicidal behavior. Alterations in the circuitry of reward-related brain regions have been robustly associated with anhedonia in unipolar depression, but not bipolar disorder (BD). We investigated white matter microstructures associated with anhedonia in participants with BD types I and II and first-degree relatives of patients with BD (BD-siblings). METHODS: Eighty participants (BD types I and II: 56 [70%], and BD-siblings: 24 [30%]) underwent diffusion tensor imaging (DTI); Fractional anisotropy (FA) of different tracts were computed. Anhedonia was assessed using item 8, ("inability to feel'') of the MADRS scale. General linear models were used to compare the FA of different tracts in participants with and without anhedonia controlling for several clinical and demographic variables. RESULTS: The mean age of the sample was 37 (± 11) years old, and 68.8% were female. Participants with anhedonia (32.5%) presented lower mean FA in the left uncinate fasciculus (UF) (p = 0.005), right temporal endings of the superior longitudinal fasciculus (SLFT) (p = 0.04), and in the left and right parietal endings of the superior longitudinal fasciculus (SLFP) (p = 0.003, and p = 0.04, respectively). Similar comparisons between participants with or without current depressive episodes and between participants with or without inner tension according to the MADRS did not show significant differences, specificity of the findings for anhedonia. CONCLUSIONS: Lower FA in the left UF and SLF are potential neuroimaging markers of anhedonia in individuals with BD and high-risk for BD.

Major Depressive Disorder Associated With Reduced Cortical Thickness in Women With Temporal Lobe Epilepsy.

Background: Major Depressive Disorder (MDD) is highly prevalent in patients with mesial temporal lobe epilepsy (MTLE), especially in women, carrying significant morbidity. This study aimed to investigate the cortical thickness (CT) abnormalities associated with MDD in women with MTLE and hippocampal atrophy (HA). Also, we investigated the impact of MDD upon the volumes of the hippocampus and amygdala in these patients. Methods: We included 50 women with MTLE and HA (20 left, LMTLE; 30 right, RMTLE), 41 healthy women in the control group, and 15 women with MDD without epilepsy. MTLE patients were subdivided into three groups: MTLE-without-MDD (23 MTLE patients without MDD), MTLE-mild-MDD (nine MTLE patients with mild symptoms of MDD), and MTLE-severe-MDD (18 MTLE patients with moderate to severe symptoms of MDD). The five groups were balanced for age (p = 0.56). All participants had high-resolution 3D T1-weighted images in a 3T scanner. We used FreeSurfer 6.0 for volumetry and CT parcellation. All participants were submitted to a clinical psychological evaluation through the Structured Clinical Interview for DSM-IV (SCID-IV) and completed the Beck Depression Inventory (BDI-II). Results: We identified a smaller ipsilateral amygdala volume (p = 0.04) in the MTLE-severe-MDD group when compared to the control group. Our results presented a reduced ipsilateral lateral orbitofrontal cortex (p = 0.02) in the MTLE-severe-MDD in comparison to the MTLE-mild-MDD group. We also identified a thinner ipsilateral fusiform gyrus (p < 0.01) in the MTLE-severe-MDD compared to both MTLE-without-MDD and control groups. A reduced CT of the contralateral superior frontal gyrus (p = 0.02) was observed in the MTLE-severe-MDD in comparison to the MTLE-mild-MDD group. Conclusions: The identification of areas with reduced CT and atrophy of the ipsilateral amygdala in women with MTLE and MDD suggest that the cortical thinning in the network of the paralimbic system is related to the co-occurrence and intensity of depressive symptoms in this group.

Bifrontal tDCS prevents implicit learning acquisition in antidepressant-free patients with major depressive disorder.

The findings for implicit (procedural) learning impairment in major depression are mixed. We investigated this issue using transcranial direct current stimulation (tDCS), a method that non-invasively increases/decreases cortical activity. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS. We used a bifrontal setup - anode and cathode over the left and the right dorsolateral prefrontal cortex (DLPFC), respectively. The probabilistic classification-learning (PCL) task was administered before and during tDCS. The percentage of correct responses improved during sham; although not during active tDCS. Procedural or implicit learning acquisition between tasks also occurred only for sham. We discuss whether DLPFC activation decreased activity in subcortical structures due to the depressive state. The deactivation of the right DLPFC by cathodal tDCS can also account for our results. To conclude, active bifrontal tDCS prevented implicit learning in depressive patients. Further studies with different tDCS montages and in other samples are necessary.

Sertraline vs. ELectrical Current Therapy for Treating Depression Clinical Trial--SELECT TDCS: design, rationale and objectives.

BACKGROUND: Despite significant advancements in psychopharmacology, treating major depressive disorder (MDD) is still a challenge considering the efficacy, tolerability, safety, and economical costs of most antidepressant drugs. One approach that has been increasingly investigated is modulation of cortical activity with tools of non-invasive brain stimulation - such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS). Due to its profile, tDCS seems to be a safe and affordable approach. METHODS AND DESIGN: The SELECT TDCS trial aims to compare sertraline vs. tDCS in a double-blinded, randomized, factorial trial enrolling 120 participants to be allocated to four groups to receive sertraline+tDCS, sertraline, tDCS or placebo. Eligibility criteria are moderate-to-severe unipolar depression (Hamilton Depression Rating Scale >17) not currently on sertraline treatment. Treatment will last 6weeks and the primary outcome is depression change in the Montgomery-Asberg Depression Rating Score (MADRS). Potential biological markers that mediate response, such as BDNF serum levels, Val66Met BDNF polymorphism, and heart rate variability will also be examined. A neuropsychological battery with a focus on executive functioning will be administered. DISCUSSION: With this design we will be able to investigate whether tDCS is more effective than placebo in a sample of patients free of antidepressants and in addition, we will be able to secondarily compare the effect sizes of sertraline vs. tDCS and also the comparison between tDCS and combination of tDCS and sertraline.