Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study.

Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.08 ± 5.41) and 23 never-depressed comparison participants (ND, 12 women, age 70 ± 8.02), matched on age and cognitive status. We employed a semi-automated procedure to segment the LC into three bilateral sections along its rostro-caudal extent, and calculated relative contrast as a proxy of integrity. Then, we examined associations between integrity and LLD diagnosis, age, and cognition, as measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Delis-Kaplan Executive Function System (D-KEFS). We did not identify an effect of LLD diagnosis nor age on LC integrity, but exploratory canonical correlation analysis across the combined participant sample revealed a strong (Rc = 0.853) and significant multivariate relationship between integrity and cognition (Wilks' λ = 0.03, F(84, 162.44) = 1.66, p = <.01). The first and only significant variate explained 72.83% model variance, and linked better attention and delayed memory performance, faster processing speed, and lower verbal fluency performance with higher integrity in the right rostral but lower integrity in the left caudal LC. Our results complement prior evidence of LC involvement in cognition in healthy older adults, and extend this association to individuals with LLD.

D-cycloserine normalizes long-term motor plasticity after transcranial magnetic intermittent theta-burst stimulation in major depressive disorder.

OBJECTIVES: Major Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD. METHODS: We conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day. RESULTS: Acute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC. CONCLUSION: MDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism. SIGNIFICANCE: Agonism of NMDA receptors rescues iTBS motor plasticity in MDD.

Extending the Stabilized Supralinear Network model for binocular image processing.

The visual cortex is both extensive and intricate. Computational models are needed to clarify the relationships between its local mechanisms and high-level functions. The Stabilized Supralinear Network (SSN) model was recently shown to account for many receptive field phenomena in V1, and also to predict subtle receptive field properties that were subsequently confirmed in vivo. In this study, we performed a preliminary exploration of whether the SSN is suitable for incorporation into large, functional models of the visual cortex, considering both its extensibility and computational tractability. First, whereas the SSN receives abstract orientation signals as input, we extended it to receive images (through a linear-nonlinear stage), and found that the extended version behaved similarly. Secondly, whereas the SSN had previously been studied in a monocular context, we found that it could also reproduce data on interocular transfer of surround suppression. Finally, we reformulated the SSN as a convolutional neural network, and found that it scaled well on parallel hardware. These results provide additional support for the plausibility of the SSN as a model of lateral interactions in V1, and suggest that the SSN is well suited as a component of complex vision models. Future work will use the SSN to explore relationships between local network interactions and sophisticated vision processes in large networks.

Modeling the shape hierarchy for visually guided grasping.

The monkey anterior intraparietal area (AIP) encodes visual information about three-dimensional object shape that is used to shape the hand for grasping. We modeled shape tuning in visual AIP neurons and its relationship with curvature and gradient information from the caudal intraparietal area (CIP). The main goal was to gain insight into the kinds of shape parameterizations that can account for AIP tuning and that are consistent with both the inputs to AIP and the role of AIP in grasping. We first experimented with superquadric shape parameters. We considered superquadrics because they occupy a role in robotics that is similar to AIP, in that superquadric fits are derived from visual input and used for grasp planning. We also experimented with an alternative shape parameterization that was based on an Isomap dimension reduction of spatial derivatives of depth (i.e., distance from the observer to the object surface). We considered an Isomap-based model because its parameters lacked discontinuities between similar shapes. When we matched the dimension of the Isomap to the number of superquadric parameters, the superquadric model fit the AIP data somewhat more closely. However, higher-dimensional Isomaps provided excellent fits. Also, we found that the Isomap parameters could be approximated much more accurately than superquadric parameters by feedforward neural networks with CIP-like inputs. We conclude that Isomaps, or perhaps alternative dimension reductions of visual inputs to AIP, provide a promising model of AIP electrophysiology data. Further work is needed to test whether such shape parameterizations actually provide an effective basis for grasp control.