Giovanna Zunta-Soares

Deep brain stimulation of the medial forebrain bundle: Distinctive responses in resistant depression

BACKGROUND Treatment resistant depression (TRD) is a serious, disabling disease. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB), as proposed by Schlaepfer et al. (2013), has led to rapid anti-depressant response but has not been replicated. METHODS In this interim analysis of an ongoing pilot study of ten subjects, we assessed the efficacy of MFB-DBS in a cohort of four TRD patients over a 52-week period using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary assessment tool. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients. RESULTS Intraoperatively, responder patients displayed immediate increased signs of energy and motivation upon stimulation at target. There was no significant mean change in mood during sham stimulation phase. Three of 4 patients had >50% decrease in MADRS scores at 7 days post-stimulation initiation relative to baseline. One patient withdrew from study participation. At 26 weeks, two of 3 remaining patients continue to have >80% decrease in MADRS scores. One patient failed to have response; evaluation of modulated fiber tracts revealed reduced frontal connectivity to the target region. LIMITATIONS This is an interim report, with limited conclusions. CONCLUSION This study of MFB-DBS shows similar rapid anti-depressant effects within the first week of stimulation as initially reported by Schlaepfer et al. (2013). Implementation of anhedonia measurements would greatly augment characterization of the striking motivational effects observed. We urge others to pursue this target to further prove efficacy. ClinicalTrials.gov (identifier: NCT02046330) https://clinicaltrials.gov/ct2/show/NCT02046330.

Hippocampal subfield volumes in mood disorders

Volume reduction and shape abnormality of the hippocampus have been associated with mood disorders. However, the hippocampus is not a uniform structure and consists of several subfields, such as the cornu ammonis (CA) subfields CA1–4, the dentate gyrus (DG) including a granule cell layer (GCL) and a molecular layer (ML) that continuously crosses adjacent subiculum (Sub) and CA fields. It is known that cellular and molecular mechanisms associated with mood disorders may be localized to specific hippocampal subfields. Thus, it is necessary to investigate the link between the in vivo hippocampal subfield volumes and specific mood disorders, such as bipolar disorder (BD) and major depressive disorder (MDD). In the present study, we used a state-of-the-art hippocampal segmentation approach, and we found that patients with BD had reduced volumes of hippocampal subfields, specifically in the left CA4, GCL, ML and both sides of the hippocampal tail, compared with healthy subjects and patients with MDD. The volume reduction was especially severe in patients with bipolar I disorder (BD-I). We also demonstrated that hippocampal subfield volume reduction was associated with the progression of the illness. For patients with BD-I, the volumes of the right CA1, ML and Sub decreased as the illness duration increased, and the volumes of both sides of the CA2/3, CA4 and hippocampal tail had negative correlations with the number of manic episodes. These results indicated that among the mood disorders the hippocampal subfields were more affected in BD-I compared with BD-II and MDD, and manic episodes had focused progressive effect on the CA2/3 and CA4 and hippocampal tail.

Lithium effect on renal glomerular functionin individuals with intellectual disability

Objective: The current study evaluated the effects of chronic administration of lithium on renal functioning in an intellectually disabled population. Methods: Fifty-seven lithium-treated individuals were compared with 24 behaviorally symptomatic controls using a retrospective chart review method. Serum creatinine levels and creatinine clearance activities were compared at baseline, at the time of peak creatinine levels, and at the end of the study in 2006. Results: The mean length of lithium administration was 8.76 years (range, 1-23 years). Chronic lithium administration yielded a significant increase in peak serum creatinine levels and a decrease in the corresponding creatinine clearance activity. Of the subjects, 22.8% had peak creatinine levels of 1.5 mg or higher per 100 mL (a common threshold for renal insufficiency). This contrasted with 0% (none) for the symptomatic control subjects (P = 0.008). In addition, 26.3% of the lithium-treated subjects had creatinine clearance activities less than 55 mL/min and 17.5% had less than 50 mL/min, both indicative of renal insufficiency, versus none of the symptomatic control subjects (P = 0.004 and P = 0.029, respectively). With lithium withdrawal, further deterioration of renal function did not occur in most cases, and many showed improvement, with decreases in serum creatinine levels and increases in creatinine clearance activity. Conclusions: Chronic administration of lithium led to clinically significant increases in serum creatinine levels and decreases in creatinine clearance in lithium-treated intellectually disabled individuals.

Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: A preliminary analysis

First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.

Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients

Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs). Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity. Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD.

Clinical outcomes associated with comorbid posttraumatic stress disorder among patients with bipolar disorder.

OBJECTIVE To assess clinical outcomes associated with the presence of a lifetime history of comorbid posttraumatic stress disorder in subjects with bipolar disorder. METHODS This cross-sectional study of 284 subjects with bipolar disorder (DSM-IV) assessed the association between lifetime comorbid posttraumatic stress disorder (DSM-IV) and clinical characteristics. Participants were included from January 2006 to June 2009. We assessed age at onset, number of mood episodes, presence of rapid cycling, first drug use, suicide attempts, hospitalizations, functional impairment, and quality of life. Diagnostic, clinical, and functional assessments were carried out using the Structured Clinical Interview for DSM-IV Axis I Disorders, patient edition (SCID-I/P), the Functioning Assessment Short Test, and the World Health Organization Quality of Life scale. The number of manic episodes as assessed by SCID-I/P was the primary outcome. RESULTS The prevalence of lifetime comorbid posttraumatic stress disorder was 19.7% (56 subjects). Subjects with bipolar disorder and posttraumatic stress disorder had an accelerated course of illness, with a lower age at onset of manic/hypomanic episodes (P = .009) and earlier initiation of illicit drug use (P = .008). In addition, they were more likely to be younger when they received the diagnosis of bipolar disorder (P = .036) and had a higher number of manic/hypomanic episodes (P = .01). Quality of life was worse in all domains among subjects who presented the comorbidity, and rates of functional impairment were higher. CONCLUSIONS Comorbid posttraumatic stress disorder was associated with increased morbidity and accelerated illness progression among subjects with bipolar disorder.

A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported to lead to rapid antidepressant effects. In this longitudinal study, we expand upon the initial results we reported at 26 weeks (Fenoy et al., 2016), showing sustained antidepressant effects of MFB DBS on six patients with treatment-resistant depression (TRD) over 1 year. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary assessment tool. Deterministic fiber tracking was used to individually map the target area; analysis was performed to compare modulated fiber tracts between patients. Intraoperatively, upon stimulation at target, responders reported immediate increases in energy and motivation. An insertional effect was seen during the 4-week sham stimulation phase from baseline (28% mean MADRS reduction, p = 0.02). However, after 1 week of initiating stimulation, three of six patients had a > 50% decrease in MADRS scores relative to baseline (43% mean MADRS reduction, p = 0.005). One patient withdrew from study participation. At 52 weeks, four of remaining five patients have > 70% decrease in MADRS scores relative to baseline (73% mean MADRS reduction, p = 0.007). Evaluation of modulated fiber tracts reveals significant common orbitofrontal connectivity to the target region in all responders. Neuropsychological testing and 18F-fluoro-deoxyglucose-positron emission tomography cerebral metabolism evaluations performed at baseline and at 52 weeks showed minimal changes and verified safety. This longitudinal evaluation of MFB DBS demonstrated rapid antidepressant effects, as initially reported by Schlaepfer et al. (2013), and supports the use of DBS for TRD.

Brain gyrification and neuroprogression in bipolar disorder

Bipolar disorder has a prevalence of about 1%–5% worldwide and is associated with premature death by multiple causes, including cardiovascular disease, diabetes, and suicide. Less appreciated, however, is the emerging evidence suggesting that bipolar disorder may present a progressive course with neuroanatomical changes (1). In this sense, the term neuroprogression was put forward as the pathological rewiring of the brain that takes place in parallel with the cognitive and clinical deterioration in the course of bipolar disorder (1). Brain gyrification is an important anatomical characteristic of the human cortex. The spatial folding due to gyrification makes it possible for our brain to host more cortical neurons within a limited cranial volume than a brain without cortical gyrification. Some studies reported that the gyrification in patients with bipolar disorder was altered (2). However, the relationship between the brain gyrification and neuroprogression in bipolar disorder was still unknown. Previous studies on neuroprogression categorize the progressive stages of bipolar disorder according to prior numbers of manic episodes and hospitalizations, and provided valuable insights of the relationship between the brain changes and the neuroprogression of bipolar disorder (3, 4). In the current study, we used the same method to classify subjects with bipolar disorder as ‘BD-Late’, if they had 10 or more manic episodes and one or more hospitalizations due to manic or depressive episodes and as ‘BD-Early’, if they had three or less manic episodes. The remaining subjects were classified as the ‘Intermediate-stage’ (BD-Intermediate). Sixty-nine patients with bipolar I disorder (16 BD-Early, 38 BD-Intermediate and 15 BD-Late) according to DSM-IV and 80 healthy controls were recruited. Patients with head trauma with residual effects, neurological disorder, and uncontrolled major medical conditions were excluded. Axis-I diagnoses and clinical characteristics were assessed with the Structured Clinical Interview for DSM-IV axis-I Disorders (SCID-I). Patients with comorbidities were not excluded. However, only nine (13%) patients had comorbidities with substance abuse and 14 (20%) with PTSD, and their distribution in the three stage groups were not significantly different under v tests (P > 0.05). Only seven percent of patients were in mania, 46% patients were in depression and 22% were euthymic at the time of the scan. The mood states were not significantly different across the three stage groups. Current dimensional mood symptoms were assessed with the Hamilton Depression Scale (HAM-D) and the Young Mania Rating Scale (YMRS). All the subjects signed written consent forms and the study was approved by local IRB committee. We acquired structural T1-weighted scans using a Philips 1.5 Tesla MRI scanner (Philips Medical System, Andover, MA, USA) with a three-dimensional axial fast field echo sequence. The parameters were as reported previously (3). The average cortical gyrification of all subjects was the average of local gyrification index (GI) at each cortical surface vertex estimated using the Freesurfer software suite version 5.3.0 (http://surfer.nmr.mgh.harvard.edu). The GI is the ratio of the cortical surface area to an envelope surface that smoothly contains the brain (5). We used the general linear model and Spearman’s correlation to estimate the effect of stages (HC, BD-Early, BD-Intermediate, BD-Late; severity from low to high) on the cortical GI and local GI on the cortical surface. We considered Pvalues <0.05 significant. We found a significant stage effect on the GI (F (3,143) = 3.792; P = 0.050). Further post hoc analysis showed that BD-Intermediate (P = 0.034) and BD-Late (P = 0.025) subjects had significantly lower GI than HC, while BD-Early had similar GI with HC (P > 0.05), but these results did not survive Bonferroni correction. Furthermore, the correlation between the GI and stages of bipolar disorder was significant (r = 0.181, P = 0.027, confidence interval with bootstrapping [ 0.286, 0.077]). It is worth mentioning that illness duration was not different among groups. Surface-based analysis based on Spearman’s correlation also found negative local GI changes from early to late stages at a false discovery rate (FDR) of 0.3 across the cortical surface. These results indicate progressive changes of brain gyrification in different stages of bipolar disorder, and provide evidence of the brain gyrification as a marker of bipolar disorder stages. These findings are consistent with previous findings about the pathophysiologic associations between number of episodes and hospitalization, brain alterations and cognitive impairment, and further support the neuroprogression theory (1).