Multimodal imaging measures in the prediction of clinical response to deep brain stimulation for refractory depression: A machine learning approach.

OBJECTIVES: This study compared machine learning models using unimodal imaging measures and combined multi-modal imaging measures for deep brain stimulation (DBS) outcome prediction in treatment resistant depression (TRD). METHODS: Regional brain glucose metabolism (CMRGlu), cerebral blood flow (CBF), and grey matter volume (GMV) were measured at baseline using 18F-fluorodeoxy glucose (18F-FDG) positron emission tomography (PET), arterial spin labelling (ASL) magnetic resonance imaging (MRI), and T1-weighted MRI, respectively, in 19 patients with TRD receiving subcallosal cingulate (SCC)-DBS. Responders (n = 9) were defined by a 50% reduction in HAMD-17 at 6 months from the baseline. Using an atlas-based approach, values of each measure were determined for pre-selected brain regions. OneR feature selection algorithm and the naïve Bayes model was used for classification. Leave-out-one cross validation was used for classifier evaluation. RESULTS: The performance accuracy of the CMRGlu classification model (84%) was greater than CBF (74%) or GMV (74%) models. The classification model using the three image modalities together led to a similar accuracy (84%0 compared to the CMRGlu classification model. CONCLUSIONS: CMRGlu imaging measures may be useful for the development of multivariate prediction models for SCC-DBS studies for TRD. The future of multivariate methods for multimodal imaging may rest on the selection of complementing features and the developing better models.Clinical Trial Registration: ClinicalTrials.gov (#NCT01983904).

Inequity of healthcare access for patients with diabetic foot disease: a retrospective study in south-east Queensland.

OBJECTIVES: Logan local government area (LGA) in Queensland has the highest diabetes prevalence (6.5%) within Metro South Health (MSH). The study aimed to determine the burden of, and equity of access to secondary healthcare, for diabetic foot disease (DFD) for Logan residents to better inform healthcare services planning. DESIGN: A retrospective analysis of hospital admissions data between January 2018 and December 2021. SETTING, PARTICIPANTS: All episodes of care for DFD provided by MSH hospitals to patients with a residential address in the three LGAs serving the region were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was number of episodes of care for DFD by LGA of residence and hospital of presentation. Secondary outcomes were DFD-related hospital occupied bed days and number of lower extremity amputations. RESULTS: Among residents in the MSH region, almost half of all episodes of care (47%) and bed days (48%) for DFD were for patients residing in Logan LGA. 40% of episodes of care, 57% of bed days and 73% of lower extremity amputations for DFD for these patients occurred outside of Logan LGA. These findings led to the planning of an integrated model of care for DFD at Logan hospital to improve and make care available locally. CONCLUSIONS: Our study suggests that Logan residents with DFD had poor access to care despite the highest burden. Analysing epidemiology of care for DFD with an equity lens and highlighting gaps in service delivery is paramount to addressing the inequity paradigm.

Functional brain network features specify DBS outcome for patients with treatment resistant depression.

Deep brain stimulation (DBS) has shown therapeutic benefits for treatment resistant depression (TRD). Stimulation of the subcallosal cingulate gyrus (SCG) aims to alter dysregulation between subcortical and cortex. However, the 50% response rates for SCG-DBS indicates that selection of appropriate patients is challenging. Since stimulation influences large-scale network function, we hypothesized that network features can be used as biomarkers to inform outcome. In this pilot project, we used resting-state EEG recorded longitudinally from 10 TRD patients with SCG-DBS (11 at baseline). EEGs were recorded before DBS-surgery, 1-3 months, and 6 months post surgery. We used graph theoretical analysis to calculate clustering coefficient, global efficiency, eigenvector centrality, energy, and entropy of source-localized EEG networks to determine their topological/dynamical features. Patients were classified as responders based on achieving a 50% or greater reduction in Hamilton Depression (HAM-D) scores from baseline to 12 months post surgery. In the delta band, false discovery rate analysis revealed that global brain network features (segregation, integration, synchronization, and complexity) were significantly lower and centrality of subgenual anterior cingulate cortex (ACC) was higher in responders than in non-responders. Accordingly, longitudinal analysis showed SCG-DBS increased global network features and decreased centrality of subgenual ACC. Similarly, a clustering method separated two groups by network features and significant correlations were identified longitudinally between network changes and depression symptoms. Despite recent speculation that certain subtypes of TRD are more likely to respond to DBS, in the SCG it seems that underlying brain network features are associated with ability to respond to DBS. SCG-DBS increased segregation, integration, and synchronizability of brain networks, suggesting that information processing became faster and more efficient, in those patients in whom it was lower at baseline. Centrality results suggest these changes may occur via altered connectivity in specific brain regions especially ACC. We highlight potential mechanisms of therapeutic effect for SCG-DBS.

Density-dependent changes in elk resource selection over successional time scales following forest disturbance.

There is an increasing need to understand how animals respond to modifications of their habitat following landscape-scale disturbances such as wildfire or timber harvest. Such disturbances can promote increased use by herbivores due to changes in plant community structure that improve forage conditions, but can also cause avoidance if other habitat functions provided by cover are substantially reduced or eliminated. Quantifying the total effects of these disturbances, however, is challenging because they may not fully be apparent unless observed at successional timescales. Further, the effects of disturbances that improve habitat quality may be density dependent, such that the benefits are (1) less valuable to high-density populations because the per-capita benefits are reduced when shared among more users or, alternatively, (2) more valuable to animals living in high densities because resources may be more depleted from the greater intraspecific competition. We used 30 years of telemetry data on elk occurring at two distinct population densities to quantify changes in space use at diel, monthly, and successional timescales following timber harvest. Elk selected logged areas at night only, with selection strongest during midsummer, and peak selection occurring 14 years post harvest, but persisting for 26-33 years. This pattern of increased selection at night following a reduction in overhead canopy cover is consistent with elk exploiting improved nutritional conditions for foraging. The magnitude of selection for logged areas was 73% higher for elk at low population density, consistent with predictions from the ideal free distribution. Yet elk avoided these same areas during daytime for up to 28 years post logging and instead selected untreated forest, suggesting a role for cover to meet other life history requirements. Our results demonstrate that while landscape-scale disturbances can lead to increased selection by large herbivores and suggest that the improvement in foraging conditions can persist over short-term successional timescales, the magnitude of the benefits may not be equal across population densities. Further, the enduring avoidance of logging treatments during the daytime indicates a need for structurally intact forests and suggests that a mosaic of forest patches of varying successional stages and structural completeness is likely to be the most beneficial to large herbivores.

Aperiodic subthalamic activity predicts motor severity and stimulation response in Parkinson disease.

INTRODUCTION: Rhythmic beta activity in the subthalamic nucleus (STN) local field potential (LFP) is associated with Parkinson disease (PD) severity, though not all studies have found this relationship. We investigated whether aperiodic 'noise' elements of LFP, specifically slope of the 1/f broadband, predict PD motor symptoms and outcomes of STN-DBS. METHODS: We studied micro-LFP from 19 PD patients undergoing STN-DBS, relating the aperiodic 1/f slope and the periodic beta oscillation components to motor severity using the UPDRS-III and improvement with DBS at 1 year. RESULTS: Beta power, not 1/f slope, independently predicted baseline UPDRS-III (r = 0.425, p = 0.020; r = -0.434, p = 0.032, respectively), but multiple regression using both predicted better (F (2, 16) = 6.621, p = 0.008, R2 = 0.453). Only multiple regression using both slope and beta power predicted improvement in UPDRS-III at 1 year post-operatively (F (2, 15) = 6.049, R2 = 0.446, p = 0.012). CONCLUSIONS: Both beta synchronization and slope of the 1/f broadband are informative of motor symptoms in PD and predict response to STN-DBS.

A Rare Case of a Fractured Exeter V40 Stem in Revision Hip Arthroplasty.

Introduction: The Exeter stem by Stryker is a polished, double wedge, tapered,and stainless steel cemented implant that is known to have high mechanical strength, and therefore can carry a significant load. Case Report: Due to the rare nature of fractures of this type of implant, its success and effectiveness within hip arthroplasty, the Exeter stem has become one of the most commonly used surgical treatment regimens for hip fractures. At present, there are only a handful of published papers detailing a fracture through an Exeter stem implant. Conclusion: The current case report documents a rare case of a fractured Exeter V40 stem and its subsequent treatment.

A seasonal pulse of ungulate neonates influences space use by carnivores in a multi-predator, multi-prey system.

The behavioral mechanisms by which predators encounter prey are poorly resolved. In particular, the extent to which predators engage in active search for prey versus incidentally encountering them has not been well studied in many systems and particularly not for neonate prey during the birth pulse. Parturition of many large herbivores occurs during a short and predictable temporal window in which young are highly vulnerable to predation. Our study aims to determine how a suite of carnivores responds to the seasonal pulse of newborn ungulates using contemporaneous global positioning system (GPS) locations of four species of predators and two species of prey. We used step-selection functions to assess whether coyotes, cougars, black bears, and bobcats encountered parturient adult female ungulates more often than expected by chance in a low-density population of mule deer and a high-density population of elk. We then assessed whether the carnivore species that encountered parturient prey more often than expected by chance did so by shifting their habitat use toward areas with a high probability of encountering neonates. None of the four carnivore species encountered GPS-collared parturient mule deer more often than expected by chance. By contrast, we determined that cougar and male bear movements positioned them in the proximity of GPS-collared parturient elk more often than expected by chance which may provide evidence of searching behavior. Although both male bears and cougars exhibited behavior consistent with active search for neonates, only male bears used elk parturition habitat in a way that dynamically tracked the phenology of the elk birth pulse suggesting that maximizing encounters with juvenile elk was a motivation when selecting resources. Our results suggest that there is high interspecific and intersexual variability in foraging strategies among large mammalian predators and their prey.

'Boom-and-busted' dynamics of phytoplankton-virus interactions explain the paradox of the plankton.

Rapid virus proliferation can exert a powerful control on phytoplankton host populations, playing a significant role in marine biogeochemistry and ecology. We explore how marine lytic viruses impact phytoplankton succession, affecting host and nonhost populations. Using an in silico food web we conducted simulation experiments under a range of different abiotic and biotic conditions, exploring virus-host-grazer interactions and manipulating competition, allometry, motility and cyst cycles. Virus-host and predator-prey interactions, and interactions with competitors, generate bloom dynamics with a pronounced 'boom-and-busted' dynamic (BBeD) which leads to the suppression of otherwise potentially successful phytoplankton species. The BBeD is less pronounced at low nutrient loading through distancing of phytoplankton hosts, while high sediment loading and high nonhost biomass decrease the abundance of viruses through adsorption. Larger hosts are inherently more distanced, but motility increases virus attack, while cyst cycles promote spatial and temporal distancing. Virus control of phytoplankton bloom development appears more important than virus-induced termination of those blooms. This affects plankton succession - not only the growth of species infected by the virus, but also those that compete for the same resources and are collectively subjected to common grazer control. The role of viruses in structuring plankton communities via BBeDs can thus provide an explanation for the paradox of the plankton.

Nitrous oxide and methane in a changing Arctic Ocean.

Human activities are changing the Arctic environment at an unprecedented rate resulting in rapid warming, freshening, sea ice retreat and ocean acidification of the Arctic Ocean. Trace gases such as nitrous oxide (N2O) and methane (CH4) play important roles in both the atmospheric reactivity and radiative budget of the Arctic and thus have a high potential to influence the region's climate. However, little is known about how these rapid physical and chemical changes will impact the emissions of major climate-relevant trace gases from the Arctic Ocean. The combined consequences of these stressors present a complex combination of environmental changes which might impact on trace gas production and their subsequent release to the Arctic atmosphere. Here we present our current understanding of nitrous oxide and methane cycling in the Arctic Ocean and its relevance for regional and global atmosphere and climate and offer our thoughts on how this might change over coming decades.

Personality changes with subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) is a promising investigational approach for treatment-resistant depression. However, reports suggesting changes in personality with DBS for movement disorders have raised clinical and ethical concerns. We prospectively examined changes in personality dimensions and antidepressant response to subcallosal cingulate (SCC)-DBS for treatment-resistant depression. METHODS: Twenty-two patients with treatment-resistant depression underwent SCC-DBS. We used the NEO Five-Factor Inventory for personality assessment at baseline and every 3 months until 15 months post-DBS. We assessed depression severity monthly using the Hamilton Depression Rating Scale. RESULTS: We found a significant decrease in neuroticism (p = 0.002) and an increase in extraversion (p = 0.001) over time, showing a change toward normative data. Improvement on the Hamilton Depression Rating Scale was correlated with decreases in neuroticism at 6 months (p = 0.001) and 12 months (p < 0.001), and with an increase in extraversion at 12 months (p = 0.01). Changes on the Hamilton Depression Rating Scale over time had a significant covariate effect on neuroticism (p < 0.001) and extraversion (p = 0.001). Baseline openness and agreeableness predicted response to DBS at 6 (p = 0.006) and 12 months (p = 0.004), respectively. LIMITATIONS: Limitations included a small sample size, a lack of sham control and the use of subjective personality evaluation. CONCLUSION: We observed positive personality changes following SCC-DBS, with reduced neuroticism and increased extraversion related to clinical improvement in depression, suggesting a state effect. As well, pretreatment levels of openness and agreeableness may have predicted subsequent response to DBS. The NEO Five-Factor Inventory assessment may have a role in clinical decision-making and prognostic evaluation in patients with treatment-resistant depression who undergo SCC-DBS.

Variable strategies to solve risk-reward tradeoffs in carnivore communities.

Mesopredator release theory suggests that dominant predators suppress subordinate carnivores and ultimately shape community dynamics, but the assumption that subordinate species are only negatively affected ignores the possibility of facilitation through scavenging. We examined the interplay within a carnivore community consisting of cougars, coyotes, black bears, and bobcats using contemporaneous Global Positioning System telemetry data from 51 individuals; diet analysis from 972 DNA-metabarcoded scats; and data from 128 physical investigations of cougar kill sites, 28 of which were monitored with remote cameras. Resource provisioning from competitively dominant cougars to coyotes through scavenging was so prolific as to be an overwhelming determinant of coyote behavior, space use, and resource acquisition. This was evident via the strong attraction of coyotes to cougar kill sites, frequent scavenging of cougar-killed prey, and coyote diets that nearly matched cougars in the magnitude of ungulate consumption. Yet coyotes were often killed by cougars and used space to minimize encounters, complicating the fitness benefits gained from scavenging. We estimated that 23% (95% CI: 8 to 55%) of the coyote population in our study area was killed by cougars annually, suggesting that coyote interactions with cougars are a complex behavioral game of risk and reward. In contrast, we found no indication that bobcat space use or diet was influenced by cougars. Black bears avoided cougars, but there was no evidence of attraction to cougar kill sites and much lower levels of ungulate consumption and carcass visitation than for coyotes. Interspecific interactions among carnivores are multifaceted, encompassing both suppression and facilitation.

Early post-treatment blood oxygenation level-dependent responses to emotion processing associated with clinical response to pharmacological treatment in major depressive disorder.

INTRODUCTION: Pre-treatment blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been used for the early identification of patients with major depressive disorder (MDD) who later respond or fail to respond to medication. However, BOLD responses early after treatment initiation may offer insight into early neural changes associated with later clinical response. The present study evaluated both pre-treatment and early post-treatment fMRI responses to an emotion processing task, to further our understanding of neural changes associated with a successful response to pharmacological intervention. METHODS: MDD patients who responded (n = 22) and failed to respond (n = 12) after 8 weeks of treatment with either citalopram or quetiapine extended release, and healthy controls (n = 18) underwent two fMRI scans, baseline (pre-treatment), and early post-treatment (one week after treatment commencement). Participants completed an emotional face matching task at both scans. RESULTS: Using threshold-free cluster enhancement (TFCE) and non-parametric permutation testing, fMRI activation maps showed that after one week of treatment, responders demonstrated increased activation in the left parietal lobule, precentral gyrus, and bilateral insula (all P < 0.05 threshold-free cluster enhancement (TFCE) family-wise error-corrected) to negative facial expressions. Non-responders showed some small increases in the precentral gyrus, while controls showed no differences between scans. Compared to non-responders, responders showed some increased activation in the superior parietal lobule and middle temporal gyrus at the post-treatment scan. There were no group differences between responders, non-responders, and controls at baseline. CONCLUSIONS: One week after treatment commencement, BOLD signal changes in the parietal lobules, insula, and middle temporal gyrus were related to clinical response to pharmacological treatment.

Evaluating and integrating spatial capture-recapture models with data of variable individual identifiability.

Spatial capture-recapture (SCR) models have become the preferred tool for estimating densities of carnivores. Within this family of models are variants requiring identification of all individuals in each encounter (SCR), a subset of individuals only (generalized spatial mark-resight, gSMR), or no individual identification (spatial count or spatial presence-absence). Although each technique has been shown through simulation to yield unbiased results, the consistency and relative precision of estimates across methods in real-world settings are seldom considered. We tested a suite of models ranging from those only requiring detections of unmarked individuals to others that integrate remote camera, physical capture, genetic, and global positioning system (GPS) data into a hybrid model, to estimate population densities of black bears, bobcats, cougars, and coyotes. For each species, we genotyped fecal DNA collected with detection dogs during a 20-d period. A subset of individuals from each species was affixed with GPS collars bearing unique markings and resighted by remote cameras over 140 d contemporaneous with scat collection. Camera-based gSMR models produced density estimates that differed by <10% from genetic SCR for bears, cougars, and coyotes once important sources of variation (sex or behavioral status) were controlled for. For bobcats, SCR estimates were 33% higher than gSMR. The cause of the discrepancies in estimates was likely attributable to challenges designing a study compatible for species with disparate home range sizes and the difficulty of collecting sufficient data in a timeframe in which demographic closure could be assumed. Unmarked models estimated densities that varied greatly from SCR, but estimates became more consistent in models wherein more individuals were identifiable. Hybrid models containing all data sources exhibited the most precise estimates for all species. For studies in which only sparse data can be obtained and the strictest model assumptions are unlikely to be met, we suggest researchers use caution making inference from models lacking individual identity. For best results, we further recommend the use of methods requiring at least a subset of the population is marked and that multiple data sets are incorporated when possible.

Metabolic activity in subcallosal cingulate predicts response to deep brain stimulation for depression.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression (TRD), but response rates in open-label studies were not replicated in a large multicenter trial. Identifying biomarkers of response could improve patient selection and outcomes. We examined SCC metabolic activity as both a predictor and marker of SCC DBS treatment response. Brain glucose metabolism (CMRGlu) was measured with [18F] FDG-PET at baseline and 6 months post DBS in 20 TRD patients in a double-blind randomized controlled trial where two stimulation types (long pulse width (LPW) n = 9 and short pulse width (SPW) n = 11) were used. Responders (n = 10) were defined by a ≥48% reduction in Hamilton Depression Rating Scale scores after 6 months. The response rates were similar with five responders in each stimulation group: LPW (55.6%) and SPW (44.5%). First, differences in SCC CMRGlu in responders and non-responders were compared at baseline. Then machine learning analysis was performed with a leave-one-out cross-validation using a Gaussian naive Bayes classifier to test whether baseline CMRGlu in SCC could categorize responders. Finally, we compared 6-month change in metabolic activity with change in depression severity. All analyses were controlled for age. Baseline SCC CMRGlu was significantly higher in responders than non-responders. The machine learning analysis predicted response with 80% accuracy. Furthermore, reduction in SCC CMRGlu 6 months post DBS correlated with symptom improvement (r(17) = 0.509; p = 0.031). This is the first evidence of an image-based treatment selection biomarker that predicts SCC DBS response. Future studies could utilize SCC metabolic activity for prospective patient selection.

Tract-based analysis of target engagement by subcallosal cingulate deep brain stimulation for treatment resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response. OBJECTIVE: Here we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response. METHODS: DTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue. RESULTS: Medial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006). CONCLUSIONS: A wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS.

Rostral anterior cingulate glutamate predicts response to subcallosal deep brain stimulation for resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) provided benefit for treatment-resistant depression (TRD) in open-label studies but failed in a recent randomized sham-controlled trial. Informed patient selection, based on reliable biomarkers, is needed to optimize outcome. We investigated if rostral anterior cingulate (rACC) glutamate/glutamine concentration could serve as a potential biomarker of response. METHODS: Sixteen adults with TRD (Major Depression; MDD = 14; Bipolar Depression; BD =2) underwent proton magnetic resonance spectroscopy using a short-echo proton spectroscopy with a voxel placed in the rACC, prior to DBS. Improvement in depression was assessed using the 17-item Hamilton Rating Scale for Depression (HDRS). Glutamate and glutamine concentrations at baseline in the rACC were examined in relation to clinical outcomes at six months. RESULTS: Lower baseline glutamate predicted significant reduction in HDRS scores in all TRD patients (p = 0.018), and predicted both HDRS reduction (p = 0.002) and 6-month response outcome in MDD-TRD patients (p = 0.013). Neither baseline glutamine nor glutamine/glutamate ratio significantly related to outcome or symptom improvement. LIMITATIONS: Our study was limited by sample size, though it is large for a DBS study. We measured from a single voxel in the brain, so we cannot be certain our findings are specific to the rACC. CONCLUSIONS: These preliminary results suggest that baseline rACC-glutamate concentration could serve as a response-predictive biomarker for SCC-DBS, particularly in patients with resistant major depression. If our findings are replicated and validated, rACC-glutamate may provide a basis to prospectively select TRD patients to improve likelihood of response to SCC-DBS.

Long versus short pulse width subcallosal cingulate stimulation for treatment-resistant depression: a randomised, double-blind, crossover trial.

BACKGROUND: Stimulation adjustment is required to optimise outcomes of deep brain stimulation (DBS) for treatment-resistant depression, but controlled data for ideal stimulation parameters are poor or insufficient. We aimed to establish the efficacy and safety of short pulse width (SPW) and long pulse width (LPW) subcallosal cingulate DBS in depression. METHODS: We did a double-blind, randomised, crossover trial in an academic hospital in Calgary, AB, Canada. Patients had DSM IV-defined major depressive disorder and bipolar depression (20-70 years old, both sexes) and did not respond to treatment for more than 1 year, with a score of 20 or more on the 17-item Hamilton Depression Rating Scale (HDRS) at recruitment. Patients underwent bilateral DBS implantation into the subcallosal cingulate white matter using diffusion tensor imaging tractography. Patients were randomly assigned 1:1 without stratification using a computerised list generator to receive either SPW (90 µs) or LPW (210-450 µs) stimulation for 6 months. Patients and the clinician assessing outcomes were masked to the stimulation group. Keeping frequency constant (130 Hz), either pulse width or voltage was increased monthly, based on response using the HDRS. Patients who did not respond to treatment (<50% reduction in HDRS from baseline) at 6 months crossed over to the opposite stimulation for another 6 months. All patients received individualised cognitive behavioural therapy (CBT) for 12 weeks. The primary outcome was change in HDRS at 6 months and 12 months using intention-to-treat analysis. This study is registered with ClinicalTrials.gov, NCT01983904. FINDINGS: Between Dec 5, 2013, and Sept 30, 2016, of 225 patients screened for eligibility, 23 patients were selected for DBS surgery. After one patient withdrew, 22 (mean age 46·4 years, SEM 3·1; 10 [45%] female, 12 [55%] male) were randomly assigned, ten (45%) to LPW stimulation and 12 (55%) to SPW stimulation. Patients were followed up at 6 months and 12 months. There was a significant reduction in HDRS scores (p<0·0001) with no difference between SPW and LPW groups (p=0·54) in the randomisation phase at 6 months. Crossover groups did not show a significant decrease in HDRS within groups (p=0·15) and between groups (p=0·21) from 6-12 months. Adverse events were equal between groups. Worsening anxiety and depression were the most common psychological adverse events. One patient in the SPW group died by suicide. INTERPRETATION: Both LPW and SPW stimulation of subcallosal cingulate white matter tracts carried similar risks and were equally effective in reducing depressive symptoms, suggesting a role for both pulse width and amplitude titration in optimising clinical outcomes in patients with treatment-resistant depression. FUNDING: Alberta Innovates Health Solutions.

Intrinsic thalamocortical connectivity varies in the age of onset subtypes in major depressive disorder.

BACKGROUND: Differences in the thalamocortical system have been shown in patients with major depressive disorder (MDD). Given prior evidence of phenotypic heterogeneity by the age of onset in MDD, we examined whether differences in thalamocortical connectivity could identify biological subtypes of MDD defined by the age of illness onset. METHODS: A total of 94 subjects including 20 early-onset (EO) MDD (onset, 18 years), 34 adult-onset (AO) MDD, and 40 healthy controls (HCs) underwent resting-state functional MRI. Blood-oxygen-level-dependent time courses were extracted from six cortical regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and precentral and postcentral gyri. Each ROI's time course was then correlated with each voxel in thalamus, while covarying out signal from every other ROI. RESULTS: The analysis of variance results showed significant main effects of group in frontal and temporal connectivity with thalamus. Group contrasts showed a right fronto-thalamic hypo-connectivity only in AO-MDD, but not in EO-MDD, when compared to HCs. However, direct comparison between EO-MDD and AO-MDD showed no differences. Furthermore, there was a right temporal-thalamic hyperconnectivity in both EO-MDD and AO-MDD patients relative to HCs. These results were not accounted for by sex, age, or illness burden. CONCLUSION: The age of illness onset may be a source of heterogeneity in fronto-thalamic intrinsic connectivity in MDD.

Fire history influences large-herbivore behavior at circadian, seasonal, and successional scales.

Recurrent environmental changes often prompt animals to alter their behavior leading to predictable patterns across a range of temporal scales. The nested nature of circadian and seasonal behavior complicates tests for effects of rarer disturbance events like fire. Fire can dramatically alter plant community structure, with important knock-on effects at higher trophic levels, but the strength and timing of fire's effects on herbivores remain unclear. We combined prescribed fire treatments with fine-scale location data to quantify herbivore responses to fire across three temporal scales. Between 2001 and 2003, 26 stands of fir (Abies spp.) and Douglas-fir (Pseudotsuga menziesii) were thinned and burned; 27 similar stands were left untreated as experimental controls. Analyzing female elk (Cervus canadensis) locations across 21 yr (1996-2016), we found crepuscular, seasonal, and successional shifts in behavioral responses to fire. Elk displayed "commuting" behavior, avoiding burns during the day, but selecting them at night. Elk selection for burns was strongest in early summer and the relative probability of elk using burns peaked quickly (5 yr post burn) before gradually returning to pre-treatment levels (15 yr post burn). Our results demonstrate that fire history has complex, persistent effects on herbivore behavior, and suggest that herbivores benefit from heterogeneous landscapes containing a range of successional stages.