Randall Espinoza

Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression

BACKGROUND Electroconvulsive therapy (ECT) elicits a rapid and robust clinical response in patients with refractory depression. Neuroimaging measurements of structural plasticity relating to and predictive of ECT response may point to the mechanisms underlying rapid antidepressant effects and establish biomarkers to inform other treatments. Here, we determine the effects of diagnosis and of ECT on global and local variations of hippocampal and amygdala structures in major depression and predictors of ECT-related clinical response. METHODS Longitudinal changes in hippocampal and amygdala structures were examined in patients with major depression (N = 43, scanned three times: prior to ECT, after the second ECT session, and within 1 week of completing the ECT treatment series), referred for ECT as part of their standard clinical care. Cross-sectional comparisons with demographically similar controls (N = 32, scanned twice) established effects of diagnosis. RESULTS Patients showed smaller hippocampal volumes than controls at baseline (p < .04). Both the hippocampal and the amygdala volumes increased with ECT (p < .001) and in relation to symptom improvement (p < .01). Hippocampal volume at baseline predicted subsequent clinical response (p < .05). Shape analysis revealed pronounced morphometric changes in the anterior hippocampus and basolateral and centromedial amygdala. All structural measurements remained stable across time in controls. CONCLUSIONS ECT-induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and is pronounced in regions with prominent connections to ventromedial prefrontal cortex and other limbic structures. Smaller hippocampal volumes at baseline predict a more robust clinical response. Neurotrophic processes including neurogenesis shown in preclinical studies may underlie these structural changes.

Potential surgical targets for deep brain stimulation in treatment-resistant depression.

OBJECT The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application. METHODS A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites. RESULTS The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases. CONCLUSIONS Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.

Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm3 voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING Abbott (previously St Jude Medical).

Glutamate normalization with ECT treatment response in major depression.

Though psychotherapy, medications and brain stimulation are used to treat major depressive disorder (MDD), treatment response depends on several individualized clinical factors and frequently requires multiple treatment trials. To guide more effective personalized interventions, there is thus a need to identify biological markers to elucidate the mechanisms of response to predict treatment outcomes in MDD. Prior evidence suggests neurochemical disturbances in mood regulating networks, including the anterior cingulate cortex (ACC) and connected prefrontal and subcortical centers, contribute to MDD and play a role in treatment response1–4. To identify treatment-related changes in neurochemical markers implicated in MDD2, 4, 5, we applied single-voxel Proton Magnetic Resonance Spectroscopy (1HMRS) for cross sectional and longitudinal analysis of ACC glutamate (Glu), choline (Cho) and N-acetyl aspartate (NAA) in 10 patients with DSM-IVR diagnoses of MDD (mean age: 44.0 years, 7.93 SD; 6 females) followed prospectively during Index treatment and 10 demographically similar controls (mean age: 39.03 years, 9.55 SD; 6 females). Electroconvulsive therapy (ECT) was used as the therapeutic modality since it is a highly effective procedure for treating severe MDD that elicits rapid response in eligible individuals6. Patients were assessed at three time points: baseline, and after the 2nd and 6th ECT sessions, corresponding to ~48 hrs and 2 weeks post treatment initiation (see Supplementary Information (SI) for clinical details). The Hamilton (HAMD) and Montgomery-Asberg (MADRS) Depression Rating Scales recorded therapeutic response. Controls were assessed twice, ~2-weeks apart, to determine disease effects, normative values and to estimate the variance of serial scanning. All subjects, without neurological disorders, alcohol/substance abuse or dementia, provided UCLA Institutional Review Board-approved informed consent. High-resolution T1-weighted MPRAGE structural (FOV: 256; voxel size: 1 mm3; TR/TE: 2200/5.16 ms; flip angle: 12°) and single-voxel Point Resolved Spectroscopy (PRESS) acquisitions (TR/TE: 2000/30 ms; spectral width 2000 Hz; 1024 points) with (128 averages) and without water suppression (8 averages) were collected on a Siemens 3T Allegra system. Automatic and manual 3D shimming was applied to reduce B0 inhomogeneity for voxels (20×18×12 mm3) placed in midline anterior ACC gray matter [Fig 1A; see SI]. LCModel computed the levels of Glu, Cho and NAA relative to the unsuppressed water signal. Derived metabolites levels were corrected for voxel CSF content using corresponding tissue classified T1-weighted images7. Figure 1 A) Voxel placement and 1HMRS spectra in a single subject, B) Mean CSF-adjusted glutamate (left), NAA (middle) and choline (right) levels at each time point in patients and controls indicating significant disease effects (purple), group by time interactions ... Metabolites (with variances 0.50). For baseline comparisons, including age and gender as covariates, main effects of diagnosis were observed for Glu only, F(1,19)=8.61, p<.01 (lower in patients). General Linear Mixed Models (GLMMs) including metabolites from each time point and a subject variable to control for within-subject correlations, also showed a significant diagnosis by time interaction for Glu, F(1, 21.98)=4.94, p<.037. Glu levels increased significantly over time in patients approximating normal levels, F(2, 16.56)=4.05, p<.037, but remained stable in controls (p=.47). In patients, subsequent pairwise comparisons showed significant Glu elevations between baseline and the 6th ECT, p<.018. In the absence of overall effects of time, pairwise comparisons in patients also showed significant decreases in NAA, p<.048, and increases in Cho, p<.047 between baseline and the 6th ECT [Fig 1B]. HAMD and MADRS scores improved significantly with treatment, F(2, 16.67)=29.48 and F(2, 13.12)=19.79, both p<.0001. Variations in Glu correlated with MADRS scores across time, F(1, 15.78)=4.49, p<.05. Baseline Cho levels correlated significantly with overall change in HAMD ratings, r=.85, p<.0001; baseline Glu levels also showed a trend for predicting HAMD change, r=.59, p<.08 [Fig 1C]. MDD-related reductions in ACC glutamate normalize with ECT treatment and associate with clinically determined therapeutic response. Results are in line with prior reports indicating glutamate deficits in MDD2, 4 and extend earlier observations of increased glutamate/glutamine (Glx) in the left ACC in patients treated with ECT8, shown here to also mirror clinical response. NAA and Choline, though not discriminating diagnostic groups at baseline, also showed treatment effects in patients. Together, these neurochemical changes suggest treatment-induced neuroplasticity in the structure, density and integrity of mature neurons9 and/or may reflect changes relating to adult neurogenesis in connected hippocampal and subventricular regions10. Results also support that neurochemical signatures in the ACC may predict future therapeutic response through mechanisms potentially overlapping with other forms of treatment. Studies including additional treatment modalities, larger samples, and longer follow-ups with relapse rates may confirm these observations.

Neuromodulation for Depression. Invasive and Noninvasive (Deep Brain Stimulation, Transcranial Magnetic Stimulation, Trigeminal Nerve Stimulation).

Major depressive disorder is among the most disabling illnesses and, despite best practices with medication and psychotherapy, many patients remain ill even after several treatment trials. For many of these patients with treatment-resistant or pharmacoresistant depression, treatment with neuromodulation offers an alternative. Options range from systems that are implanted to others that are entirely noninvasive. This review surveys recent literature to update readers on 3 particular interventions: deep brain stimulation, transcranial magnetic stimulation, and trigeminal nerve stimulation. Additional comparative research is needed to delineate the relative advantages of these treatments, and how best to match individual patients to neuromodulation intervention.

The Use, Benefits, and Costs of Cholinesterase Inhibitors for Alzheimer's Dementia in Long-Term Care: Are the Data Relevant and Available?

Alzheimer’s disease (AD) is a progressive dementia that affects memory and other cognitive domains, and that is often associated with behavioral and functional problems. The most common dementing disorder, AD affects an estimated 4 million people in the United States. Approximately 6% to 8% of all persons older than 65 years have AD, and the prevalence of the disease nearly doubles every 5 years after the age of 60 such that over 40% of all persons older than 85 years could have AD. As the population ages, epidemiologists predict there will be 14 million persons with AD by the year 2040. The economic costs associated with AD are high, and nursing home expenses account for a significant portion of AD costs. Estimates of the cost to society of AD indicate that annual direct and indirect costs could be as high as

Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder

100 billion, making AD third after cancer and coronary heart disease in terms of total costs to society. Dementia is one of the most common diagnoses in nursing homes because it could occur in over 50% of these patients. Institutionalized patients with AD tend to have more comorbidities, more functional deficits, and more behavioral problems than community-dwelling patients with AD. In the first part of this article, we provide an overview of the evidence for the clinical benefits of cholinesterase inhibitor therapy in the general population of patients with AD across cognitive, behavioral, and functional domains. In the second part, we provide an overview of economic studies, with an emphasis on the relevance and applicability to longterm care. We examine the efficacy of the three main currently used cholinesterase inhibitors: donepezil, galantamine, and rivastigmine.

Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression

Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (P<0.05). Increases in left putamen volume (P<0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.

Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex

Background Electroconvulsive therapy (ECT) is a highly effective brain stimulation treatment for severe depression. Identifying neurochemical changes linked with ECT may point to biomarkers and predictors of successful treatment response. Methods We used proton magnetic resonance spectroscopy (1H-MRS) to measure longitudinal changes in glutamate/glutamine (Glx), creatine (Cre), choline (Cho) and N-acetylaspartate (NAA) in the dorsal (dACC) and subgenual anterior cingulate cortex (sgACC) and bilateral hippocampus in patients receiving ECT scanned at baseline, after the second ECT session and after the ECT treatment series. Patients were compared with demographically similar controls at baseline. Controls were assessed twice to establish normative values and variance. Results We included 50 patients (mean age 43.78 ± 14 yr) and 33 controls (mean age 39.33 ± 12 yr) in our study. Patients underwent a mean of 9 ± 4.1 sessions of ECT. At baseline, patients showed reduced Glx in the sgACC, reduced NAA in the left hippocampus and increased Glx in the left hippocampus relative to controls. ECT was associated with significant increases in Cre in the dACC and sgACC and decreases in NAA in the dACC and right hippocampus. Lower NAA levels in the dACC at baseline predicted reductions in depressive symptoms. Both ECT and symptom improvement were associated with decreased Glx in the left hippocampus and increased Glx in the sgACC. Limitations Attrition and clinical heterogeneity may have masked more subtle findings. Conclusion ECT elicits robust effects on brain chemistry, impacting Cre, NAA and Glx, which suggests restorative and neurotrophic processes. Differential effects of Glx in the sgACC and hippocampus, which approach control values with treatment, may reflect previously implicated underactive cortical and overactive subcortical limbic circuitry in patients with major depression. NAA levels at baseline are predictive of therapeutic outcome and could inform future treatment strategies.