Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated ...efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes.
To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD.
In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials.
Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS.
The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed.
A total of 87 participants (mean SD age, 67.1 6.7 years; 47 54.0% female) were randomized to standard bilateral rTMS and 85 (mean SD age, 66.3 5.3 years; 45 52.9% female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI -0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 2.3%; TBS: 6 of 85 7.1%; P = .14; χ2 = 2.2).
In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD.
ClinicalTrials.gov Identifier: NCT02998580.
•We analyzed data of depressed patients receiving transcranial magnetic stimulation.•Nearly half of these patients had depression with a seasonal pattern.•Patients with seasonal pattern improved ...similar to those without seasonal pattern.
Individuals with major depressive disorder (MDD) may exhibit a seasonal pattern. The impact of a seasonal pattern in depressive symptoms on rTMS outcomes is unexplored. A retrospective analysis was performed on patients with MDD receiving open-label high frequency rTMS to the left dorsolateral prefrontal cortex. Having a seasonal pattern was defined as scoring ≥ 12 on the Personal Inventory for Depression and Seasonal Affective Disorder (PIDS). Primary outcomes included improvement in the Hamilton Depression Rating Scale (HAMD) and remission. Secondary analyses included the use of the self-rated Quick Inventory of Depressive Symptomatology (QIDS) to assess for changes in atypical neurovegetative symptoms. Multiple linear regression, multiple logistic regression, and linear mixed effects analyses were performed. 46 % (58/127) of the sample had a seasonal pattern. Seasonal pattern did not significantly influence improvement in HAMD (PIDS < 12, 7.8, SD 5.9; PIDS ≥ 12, 10.4, SD 4.9 or remission (PIDS < 12, 30 %; PIDS ≥ 12, 34 %). There were equivalent degrees of improvement in atypical neurovegetative symptoms over time as assessed using the QIDS. Depression with seasonal pattern was found to respond to rTMS treatment similarly to depression without seasonal pattern, suggesting that this may be a viable treatment for this group.
History of adverse childhood experiences (ACEs) is associated with poorer treatment outcomes in depression. How ACEs affect outcomes from repetitive transcranial magnetic stimulation (rTMS) is not ...well-defined. The primary aim was to investigate whether ACEs affect depression outcomes in patients receiving high frequency rTMS, either deep TMS (dTMS) or intermittent theta burst stimulation (iTBS), to the left dorsolateral prefrontal cortex.
The Hamilton Depression Rating Scale (HAMD-17) was collected at baseline and every 2 weeks for 4–6 weeks. Outcomes included improvement in HAMD-17 and remission. The ACE-10 questionnaire was used to quantify categories of ACEs. Data from 99 patients with MDD receiving an acute rTMS course were analyzed.
Patients had a mean of 2.4 ACEs (SD 2.5). No significant differences in outcomes were found between dTMS or iTBS so these data were pooled. Using a continuous ACE variable showed no significant impact on outcomes. Using a categorical ACE variable (0, 1, 2, 3, 4 or more) did not reveal significant effects of ACEs on outcomes. Higher ACE was associated with steeper decrease in HAMD-17 only from baseline to week 2 but not at other times.
This was an open-label study. The well-validated ACE questionnaire does not measure severity or frequency of adversities.
Patients with depression receiving rTMS reported on average 2.4 ACEs. ACE scores may lead to a steeper early decline in HAMD-17 but did not otherwise impact depression outcomes. Presence of high levels of ACEs should not preclude consideration of rTMS for depression.
•Adverse childhood experiences are prevalent among depressed patients receiving rTMS.•Childhood adversity is known to predict poor outcomes from depression treatments.•Childhood adversity does not predict poorer outcomes from rTMS for depression.
Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease ...progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T1-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an ε4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.
To determine if
ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).
A total of 289 ...patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and
ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and
ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in
ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in
ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.
A significant interaction was observed between WMH and
ε4 for language, but not for memory or executive functions. Separate analyses in
ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in
ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in
ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in
ε4 carriers only.
ε4 may influence the association between WMH and cognitive performance in AD and DLB.
Response to repetitive transcranial magnetic stimulation (rTMS) among individuals with major depressive disorder (MDD) varies widely. The neural mechanisms underlying rTMS are thought to involve ...changes in large-scale networks. Whether structural network integrity and plasticity are associated with response to rTMS therapy is unclear. Structural MRIs were acquired from a series of 70 adult healthy controls and 268 persons with MDD who participated in two arms of a large randomized, non-inferiority trial, THREE-D, comparing intermittent theta-burst stimulation to high-frequency rTMS of the left dorsolateral prefrontal cortex (DLPFC). Patients were grouped according to percentage improvement on the 17-item Hamilton Depression Rating Score at treatment completion. For the entire sample and then for each treatment arm, multivariate analyses were used to characterize structural covariance networks (SCN) from cortical gray matter thickness, volume, and surface area maps from T1-weighted MRI. The association between SCNs and clinical improvement was assessed. For both study arms, cortical thickness and volume SCNs distinguished healthy controls from MDD (p = 0.005); however, post-hoc analyses did not reveal a significant association between pre-treatment SCN expression and clinical improvement. We also isolated an anticorrelated SCN between the left DLPFC rTMS target site and the subgenual anterior cingulate cortex across cortical measures (p = 0.0004). Post-treatment change in cortical thickness SCN architecture was associated with clinical improvement in treatment responders (p = 0.001), but not in non-responders. Structural network changes may underpin clinical response to rTMS, and SCNs are useful for understanding the pathophysiology of depression and neural mechanisms of plasticity and response to circuit-based treatments.
Alcohol use disorder (AUD) is a highly prevalent, often refractory, medical illness. The symptoms of AUD are driven by dysfunction in several neurocircuits centered on the nucleus accumbens (NAc). ...Case reports and animal studies suggest NAc-DBS may be an effective harm-reduction treatment in severe AUD. Six patients with severe, refractory AUD underwent NAc-DBS. Safety metrics and clinical outcomes were recorded. Positron emission tomography (FDG-PET) was used to measure glucose metabolism in the NAc at baseline and 6 months. Functional magnetic resonance imaging (fMRI) was used to characterize postoperative changes in NAc functional connectivity to the rest of the brain, as well as NAc and dorsal striatal reactivity to alcoholic visual cues. This study was registered with ClinicalTrials.gov, NCT03660124. All patients experienced a reduction in craving. There was a significant reduction in alcohol consumption, alcohol-related compulsivity, and anxiety at 12 months. There was no significant change in depression. FDG-PET analysis demonstrated reduced NAc metabolism by 6 months, which correlated with improvements in compulsive drinking behaviors. Clinical improvement correlated with reduced functional connectivity between the NAc and the visual association cortex. Active DBS was associated with reduced activation of the dorsal striatum during passive viewing of alcohol-containing pictures. NAc-DBS is feasible and safe in patients with severe, otherwise refractory AUD. It is associated with a reduction in cravings and addictive behavior. A potential mechanism underlying this process is a down-regulation of the NAc, a disruption of its functional connectivity to the visual association cortex, and interference of cue-elicited dorsal striatum reactivity. Trial Registration NCT03660124 ( www.clinicaltrials.gov ).
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