Abstract Introduction Previous work suggests that ruminative thoughts, even when not sleep-related, are associated with more severe insomnia symptoms. However, few studies have examined whether interventions that target insomnia may also improve rumination over time. It remains untested whether improvements in insomnia severity resulting from CBTI are driving improvements in rumination. Likewise, it is unknown whether the link between higher rumination and insomnia is present at all assessed timepoints. Here we conducted a secondary analysis of a previous single-arm mechanistic CBTI trial (NCT04424407) to test the hypotheses that (1) CBTI would be associated with improvements in rumination, (2) improvements in rumination would be associated with improvements in insomnia, and (3) that these associations would persist after treatment. Methods Fifty individuals (age mean+/-SD = 40.36+/-10.95 years; 64% female; 48 completers), with co-occurring insomnia and depressive symptoms completed the insomnia severity index (ISI) and Ruminative Responses Scale-Short (RRS) before and after receiving 6-sessions of CBTI. Linear mixed effects models tested the impact of CBTI on rumination, longitudinal associations between ISI and RRS, and whether treatment moderated these associations. Linear regression tested associations between symptoms changes. Age and sex were included as covariates in all models. Results CBTI was associated with an improvement in rumination (b=-2.65, p=0.002) following treatment. Improvements in insomnia symptoms were not associated with changes in rumination (b=-0.04, p=0.85). Rumination and insomnia were not associated with each other overtime (b=0.05, p=0.74). Moderation analyses revealed that the associations were not different across timepoints (b=0.03, p=0.90): ISI and RRS were not associated at baseline nor post-treatment (|b’s|< 0.07, p’s>0.70). Conclusion CBTI was associated with improvement in rumination at post-treatment. However, counter to our hypotheses, insomnia and rumination symptoms were not associated. Limited variability in insomnia and rumination scores in our sample may be occluding our expected effects (i.e. all participants had insomnia/depression at study entry). These findings indicate that improvements in rumination following CBTI may not be due to changes in insomnia itself. Future studies should examine whether subcomponents of rumination, mood variability, or broader sleep health shape these relationships. Support (if any) R61MH120245 and R33MH120245

This secondary analysis of a randomized clinical trial explored (1) changes in memory performance and slow-wave activity (SWA) in older adults with insomnia disorder following cognitive behavioral therapy for insomnia (CBT-I) and its component therapies, (2) associations between changes in SWA and changes in memory performance, and (3) whether individual CBT-I component therapies (behavioral therapy (BT) and cognitive therapy (CT)) differ in their associations with these outcomes. A secondary analysis was conducted using data from 104 older adults with insomnia disorder who underwent polysomnography and RBANS memory testing to assess immediate (list learning and story memory) and delayed memory (list recall, story recall, figure recall, and list recognition) at baseline and again at 6-months following randomization to six sessions of CBT-I, BT, or CT. Linear-mixed effects models examined changes in memory and SWA from baseline and at 6-month follow-up. Regression analyses examined relationships between changes in SWA and memory. At 6-month follow-up, participants showed improvements in immediate memory (list learning and story memory) and delayed memory (list recall, story recall, and figure recall) compared to baseline. SWA did not change significantly following treatment. However, within-person increases in SWA were positively associated with improvements in list learning performance. Outcomes did not differ among treatments (CBT-I, BT, CT). Although a definitive randomized controlled trial is necessary to test causality, these findings add to a growing body of literature on sleep and memory and suggest a potential role for SWA in memory processes in older adults with insomnia. This study was a secondary analysis conducted using data from a clinical trial registered on ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT02117388 . Treatments for Insomnia: Mediators, Moderators and Quality of Life. ClinicalTrials.gov, NCT02117388. This secondary analysis leverages previously collected data from a clinical trial to explore changes in memory performance and SWA, and their potential associations, in older adults with insomnia disorder who received cognitive behavioral therapy for insomnia (CBT-I) or its individual component therapies cognitive therapy (CT) and behavioral therapy (BT). Memory performance improved from baseline to 6-month follow-up and within-person increases in SWA were positively associated with memory performance. While this secondary analysis cannot establish causality, these findings add to a growing body of literature on sleep and memory and suggest a potential role for SWA in memory processes in older adults with insomnia. These associations provide support for further investigation in confirmatory trials designed to test causal mechanisms.

Treating insomnia with Cognitive-Behavioral Therapy for Insomnia (CBT-I) improves depression symptoms, but the underlying mechanisms remain unknown. This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) examined fronto-limbic and sleep mechanisms of CBT-I's antidepressant response in 48 participants (64% female; age 25-60) with insomnia and depression symptoms. Participants completed functional magnetic resonance imaging (fMRI), polysomnography (PSG), and symptom assessments before and after 6 CBT-I sessions. CBT-I resulted in reduced amygdala reactivity to fearful faces (d=0.55, p=0.008). Depression and sleep (objective and self-reported insomnia symptoms also improved. However, fMRI-assessed fronto-limbic changes were not associated with reduction of depressive symptom severity. Instead, reduced depressive symptoms correlated with reduced self-reported insomnia symptoms (p=0.001, 𝜂2𝑝=0.19) and increased objective sleep efficiency (p=0.04, 𝜂2𝑝=0.10). Notably, pre-treatment PSG-assessed sleep efficiency, but not fronto-limbic function nor insomnia symptoms, predicted reduced depressive symptoms (p=0.007, 𝜂2𝑝=0.16), suggesting that lower objective sleep efficiency prior to treatment may be associated with greater antidepressant benefit from CBT-I.

Depression and insomnia are bidirectionally related. It is hypothesized that fronto-limbic brain function, specifically the amygdala and medial prefrontal cortex (mPFC), links sleep and mood disturbances and represents targets of insomnia-related emotional dysfunction. A primary aim of this first-phase of a two-phase mechanistic clinical trial was to test whether insomnia treatment engages these affective circuits. Secondarily, we examined treatment-related changes in emotion and sleep outcomes and their associations with changes in fronto-limbic brain function. 47 adults (64% female; age 25-60) with depression and insomnia completed six sessions of therapist-delivered cognitive-behavioral therapy for insomnia (CBT-I). FMRI of emotional faces and regulation tasks and at-home polysomnography were acquired before and after treatment. Primary outcomes were treatment-associated changes in amygdala reactivity and amygdala-mPFC task-modulated connectivity, analyzed using linear mixed-effect modeling and FDR-correction across task-contrasts and mPFC regions-of-interest (q=0.05). Secondary outcomes included depression, anxiety, and insomnia symptoms, emotion regulation habits, N3 duration, and sleep efficiency. Secondary analyses examining associations between fronto-limbic brain function and secondary outcomes used linear regression. All models controlled for age and sex. Following treatment, participants experienced reduced amygdala reactivity to fearful faces (b=-0.17 [CI:-0.25-0.08], puncorrected=0.003, padjusted=0.008) and a trend towards increased amygdala connectivity with the subgenual anterior cingulate cortex that did not survive FDR correction (b=0.16 [CI:0.008-0.31], puncorrected=0.045, padjusted=0.23). No significant changes were observed in regions-of-interest during active emotion regulation (b< 0.05 [CI:-1.26-0.23], puncorrected>0.64). Treatment was associated with improvements in depression, anxiety, and habitual cognitive reappraisal (p’s< 0.002), as well as reduced insomnia symptoms and increased N3 sleep and sleep efficiency (p’s< 0.001). Despite parallel improvements in brain, mood, and sleep, amygdala reactivity changes were only associated with improvements in cognitive reappraisal (b=5.4 [CI: 0.94-9.91], p=0.019). There were no other relationships between changes in amygdala reactivity or connectivity with emotion or sleep improvements (all p’s>0.293). This is the first study to establish that CBT-I is associated with improved fronto-limbic brain function, mood, emotion regulation, and objective sleep quality in individuals with co-occurring insomnia and depression symptoms. However, the improvements in emotion and sleep largely do not appear to be driven by the changes in brain function. R61 MH120245-01

Background and Objectives:Investigation into different allelic variants may yield new associative genes to predict late-onset Alzheimer disease (LOAD). Variable number tandem repeats (VNTRs) are important polymorphic components of the genome; however, they have been previously overlooked because of their complex genotyping. New software can now determine differing lengths of VNTRs; however, this has not been tested in a large case-control population. Methods:We used VNTRseek to genotype over 200,000 tandem repeats in 9,501 cases and controls from the Alzheimer's Disease Sequencing Project. We first identified limiting factors of this analysis and then examined the association of VNTRs with AD diagnosis in a subset of non-Hispanic White participants. Results:We found that VNTRs were highly associated with areas of the genome with a high number of previously identified variants. From our case-control analysis, we identified 9 VNTRs with a repeat allele length associated with LOAD including VNTRs on DSC3, NR2E3, CCNY, PKP4, GRAP, and MAP6. Discussion:We were able to show the feasibility of this new type of analysis in large-scale whole-genome sequencing data and identify promising VNTRs that are associated with LOAD.

To determine the relative effectiveness and predictors of cognitive therapy (CT), behavioral therapy (BT), and cognitive behavioral therapy (CBT) for insomnia in older adults. In a registered clinical trial (NCT02117388), 128 older adults with insomnia disorder were randomly assigned to receive CBT, BT, or CT. Insomnia Severity Index (ISI) score was the primary outcome. Sleep diaries, fatigue, beliefs about sleep, cognitive arousal, and stress were secondary outcomes. Split-plot linear mixed models assessed within- and between-subject changes in outcomes among the treatments. As a secondary analysis, we used linear regression to test predictors of insomnia symptoms improvement, including sleep diary measures, cognitive arousal, stress, beliefs about sleep, baseline ISI score, and age. Benjamini-Hochberg correction was applied. All groups exhibited insomnia symptom reduction at posttreatment (CT: d = −2.53, P < .001; BT: d = −2.39, P < .001; CBT: d = −2.90, P < .001) and at the 6-month follow-up (CT: d = −2.68, P < .001; BT: d = −2.85, P < .001; CBT: d = −3.14, P < .001). There were no group differences in the magnitude of ISI improvement (Padj = .63), response (Padj > .63), or remission (ISI < 8; Padj > .27). All groups exhibited significant improvements in secondary outcomes at posttreatment (Padj < .05) and at the 6-month follow-up (Padj < .05). At posttreatment, the CT and CBT groups showed greater reductions in beliefs about sleep than the BT group (FInteraction(2,185) = 5.99, Padj = .03), and the CBT group showed a greater time in bed reduction than the CT group (FInteraction(2,185) = 7.05, Padj = .01). Baseline ISI was the only treatment predictor (b = 1.95, Padj < .001). CBT for insomnia and its components each independently result in significant improvements in self-reported insomnia symptoms, beliefs about sleep, worry, and fatigue in older adults. Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Treatments for Insomnia: Mediators, Moderators and Quality of Life; URL: https://clinicaltrials.gov/study/NCT02117388 ; Identifier: NCT02117388. O’Hora KP, Morehouse AB, Freidman L, et al. Comparative effectiveness and predictors of cognitive behavioral therapy for insomnia and its components in older adults: main outcomes of a randomized dismantling trial. J Clin Sleep Med. 2025;21(10):1679–1695.

BACKGROUND:Transcranial magnetic stimulation (TMS) is a promising non-pharmacological intervention for treatment of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Yet, we know little about precisely where stimulation would be ideal to improve cognitive function. OBJECTIVE:To examine the network functional connectivity (fc) characteristics of prefrontal and parietal stimulation sites, given that these sites have led to improved cognitive function in TMS studies involving MCI-AD and unimpaired participants. METHODS:Resting-state functional MRI data were acquired from 32 MCI participants at the baseline visit of an ongoing TMS trial and used to compute connectivity with prefrontal and parietal stimulation locations, selected on the basis of previous TMS studies. The TMS seed maps were examined for extent of spatial overlap with eight canonical networks. After identifying the network most likely to be targeted by TMS, we applied strategies that may provide purer targeting. Finally, we examined network connectivity in relation to participants' behavioral characteristics because of the potential for TMS treatment to be personalized. RESULTS:The prefrontal TMS seed map overlapped primarily with the salience network. The prefrontal site is also notable for its anti-correlated connectivity with the AD-vulnerable posterior cingulate cortex (PCC). The parietal TMS seed map showed the expected strong positive connectivity with the PCC and other default network regions. Nonetheless, this particular parietal site may simultaneously modulate the fronto-parietal network. Strategies to improve network targeting and to personalize TMS are reported as secondary findings. CONCLUSION:These results can be applied to network-targeted brain stimulation for MCI and early AD treatment. Greater precision and personalization of TMS offer the promise of achieving better outcomes for individuals with MCI or mild AD dementia.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

Clinical transcranial magnetic stimulation (TMS) is a well-established therapeutic intervention for treatment resistant depression and related comorbidities, yet standard TMS treatment often requires 30 daily treatments. Thus, treatment dropout could be a significant challenge for implementation. To better understand who is at risk of dropout and potentially guide future novel applications of TMS, this study examined predictors of dropout from the Veterans Affairs’ nationwide TMS program for veterans with treatment resistant depression (TRD). The sample comprised n=1,588 veterans undergoing clinical TMS treatment. We used receiver operating characteristic (ROC) analysis, which calculates the sensitivity and specificity of predictor variables at each cut-off point, to identify optimal cut-off points for the variables that significantly predicted treatment dropout. Key predictors included age and depression severity, measured by the Patient Health Questionnaire-9 (PHQ-9). Results indicated that veterans in early adulthood, specifically younger than 42 years old, were more likely to drop out, with a 22.7% dropout rate compared to 16.3% for those 42 and older (χ2=9.34, p<0.001). For veterans 42 years and older, those with severe depressive symptoms (i.e., PHQ-9 score of 24 or higher) had an increased dropout rate of 22.4% (χ2=4.96, p<0.05) compared to 15.3% among those with less severe depressive symptoms. Furthermore, we found that comorbidities did not significantly impact dropout rates. Post-hoc analyses revealed personal reasons as the most common cause for dropout, particularly among younger veterans. These findings underscore the importance of considering age and symptom severity in managing TMS treatment to improve adherence and outcomes. Future research should explore specific barriers and facilitators to treatment adherence, especially among high-risk populations.

Recent meta-analyses show that 30-70% of individuals with a history of traumatic brain injury (TBI) suffer from persistent sleep disturbances. Further, more than 80% of all TBI cases are mild (mTBI) and report more insomnia than those with moderate-to-severe TBI. Given the positive track record of Cognitive Behavioral Therapy for Insomnia (CBT-I) in other conditions, CBT-I could also be an effective treatment for insomnia in those with mTBI, despite common comorbidities. In this RCT (NCT03261674) veterans (n=110, 29.1 % female, 51.2±11.5 years old) were randomized to either CBT-I or an active control involving pseudo desensitization. During the treatment, participants had access to a therapist for six 60-minute sessions, once per week, for six consecutive weeks. Treatment was remotely delivered nationwide via telehealth. Independently living veterans with chronic (>3 months since injury) mTBI and insomnia were included in the trial. Comorbid post-traumatic stress disorder (PTSD) was permitted. Central nervous system-active medications were allowed as long as the dose, timing, and formulation were stable (≥ 3 weeks pre-treatment). All sleep measures were based on self-report. The primary outcome measure was the Insomnia Severity Index (ISI) and treatment effects were tested using intent-to-treat analyses based on linear mixed effects models with data derived from multiple imputations. CBT-I was associated with significantly greater improvement in ISI (p <.001, Beta=0.59) compared to controls. At post treatment, CBT-I had > 8-point reduction of ISI from 16.4±3.6 to 7.4±5.3; controls only improved moderately from 15.6±4.6 to 10.2±6.2. Pre-post improvements in CBT-I were accompanied with improved (p’s <.001) sleep efficiency (+12.1±12.0 %), mental health (SF-36 mental component score, -4.8±12.3), depression (PHQ-8, -4.2±5.2), and reduced time in bed (-1.0±1.3 h), wake after sleep onset (-32.6±33.6 min), sleep onset latency (-30.4±42.1 min), early morning awakenings (-28.2±42.2 min) while total sleep time remained virtually unchanged (+0.1±1.3 h). Despite high rates of co-morbid PTSD and cognitive difficulties associated with mTBI, CBT-I remains a robust treatment for insomnia in this group. Future efforts should focus on increasing accessibility of CBT-I for individuals who have recently sustained a mTBI. VA REHABILITATION RESEARCH & DEVELOPMENT

We previously identified a cognitive biotype of depression characterized by treatment resistance, impaired cognitive control behavioral performance and dysfunction in the cognitive control circuit, comprising the dorsolateral prefrontal cortex (dLPFC) and dorsal anterior cingulate cortex (dACC). Therapeutic transcranial magnetic stimulation (TMS) to the left dLPFC is a promising option for individuals whose depression does not respond to pharmacotherapy. Here, 43 veterans with treatment-resistant depression were assessed before TMS, after early TMS and post-TMS using functional magnetic resonance imaging during a Go-NoGo paradigm, behavioral cognitive control tests and symptom questionnaires. Stratifying veterans at baseline based on task-evoked dLPFC-dACC connectivity, we demonstrate that TMS-related improvement in cognitive control circuit connectivity and behavioral performance is specific to individuals with reduced connectivity at baseline (cognitive biotype +), whereas individuals with intact connectivity at baseline (cognitive biotype -) did not demonstrate significant changes. Our findings show that dLPFC-dACC connectivity during cognitive control is both a promising diagnostic biomarker for a cognitive biotype of depression and a response biomarker for cognitive improvement after TMS applied to the dLPFC.

Background:We previously identified a cognitive biotype of depression characterized by dysfunction of the brain's cognitive control circuit, comprising the dorsolateral prefrontal cortex (dLPFC) and dorsal anterior cingulate cortex (dACC), derived from functional magnetic resonance imaging (fMRI). We evaluate these circuit metrics as personalized predictors of antidepressant remission. Methods:We undertook a secondary analysis of data from the international Study to Predict Optimized Treatment in Depression (iSPOT-D) for 159 patients who completed fMRI during a GoNoGo task, 8 weeks treatment with one of three study antidepressants and who were assessed for remission status (Hamilton Depression Rating Scale score of ≤ 7). Circuit predictors of remission were dLPFC and dACC activity and connectivity quantified in standard deviations. Using established software implementing receiver operating analysis (ROC) we calculated the sensitivity and specificity of these predictors at every cut-point for every circuit measure. We calculated number needed to treat (NNT) metrics for the ROC model identifying optimal cut-point values. Results:ROC models identified maximum separation of remitters (62.5%) from non-remitters (21.2%) at an initial cut-point of -0.75 standard deviations for dLPFC activity and averaged circuit metrics at secondary cutpoints. The NNT was 3.72, implying that if 4 patients (rounding of 3.72) were randomly selected, one would be likely to remit, but if circuit metrics informed treatment, two would be likely to remit. Conclusions:Our findings contribute to identifying clinically actionable circuit measures for clinical trials and clinical practice. Future studies are needed to replicate these findings and expand the assessment of longer-term outcomes.

OBJECTIVE:To investigate the preliminary efficacy of a combined physical exercise + cognitive training intervention for older adults with amnestic mild cognitive impairment (aMCI). DESIGN:Randomized clinical trial. SETTING:Veteran Affairs Hospital, Palo Alto, CA. PARTICIPANTS:Sample included 72 community-dwelling volunteers (mean age 72.4 ± 9.5) diagnosed with aMCI. INTERVENTION:Participants were randomized to either a combined aerobic and resistance exercise + cognitive training (CARE+CT) or stretching exercise + CT (SE+CT). MEASUREMENTS:Primary outcomes included intervention specific assessments of word list and name-face recall. Secondary cognitive outcomes included standardized composite scores that reflect cognitive domains (e.g., learning and memory, executive function, processing speed, visuospatial ability, language). Secondary physiological outcomes included VO2 max and functional capacity (e.g., distance walked 6-minute walk test). APOE and BDNF were determined from whole blood samples. RESULTS:Controlling for age and employment status, linear mixed effects models revealed that all participants experienced significant improvement in the delayed recall of word list, learning and memory and executive function. Only the CARE+CT condition had significant improvement in processing speed and functional capacity. APOE4 status impacted cognitive benefits of those in the SE+CT condition. CONCLUSIONS:Results provide preliminary support for combined exercise and cognitive training interventions for older adults with aMCI. Further research is needed to understand the mechanisms involved as well as the impact of these interventions in diverse samples. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01962038.

Objective: While typical aging is associated with decreased cortical volume, major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) likely exacerbates this process. Cerebral atrophy leads to increased coil-to-cortex distance and when using transcranial magnetic stimulation (TMS), potentially reducing effectiveness in older adults. Methods: Data from a large-scale quality improvement project was used. Included veterans eligible for TMS and completed TMS treatment. Age was assessed as a predictive factor of depression outcomes after TMS treatment among veterans. Secondary analyses examined the impact of age on 1) MDD response and remission and 2) MDD change within MDD-only verses comorbid MDD and PTSD groups. Results: The entire sample included 471 veterans. Primary analysis revealed age as a negative predictor of depression outcomes (p = 0.019). Secondary analyses found age to be a significant predictor of remission (p = 0.004), but not clinical response. Age was not a predictive factor in depression outcomes between those with MDD-only compared to MDD+PTSD. Conclusions: Increased age predicts greater MDD symptom reduction after TMS. Although age did not predict response rates, it did predict increased rates of remission in veterans. Age did not differentially predict depression outcomes between those with or without PTSD. The sample size was sufficient to discern a difference in efficaciousness, and limitations were those inherent to registry studies in veterans. This data indicates that TMS can be an important treatment option for older individuals. (Am J Geriatr Psychiatry 2024; 32:315-325)

OBJECTIVE:The Benton Visual Form Discrimination Test (VFDT) is a commonly used measure of visual discrimination and visual recognition memory and has shown promise in distinguishing between different levels of cognitive impairment. We assess the predictive diagnostic utility of the VFDT in a sample of older Veterans with cognitive concerns.METHOD:Subjects included a total of 172 mostly male Veterans over the age of 64 (mean = 76.0; SD = 7.6) recruited from a VA clinic specializing in neuropsychological assessment of older Veterans. The clinical sample included 56 subjects diagnosed with Major Neurocognitive Disorder, 74 diagnosed with Mild Neurocognitive Disorder, and 42 with No Neurocognitive Impairment. Impairment categories were modeled in separate multinomial logistic regressions with two versions of the VFDT as predictors: the Visual Form Discrimination Test-Recognition Subtest (VFDT-Rec) test (visual recognition memory) and the Visual Form Discrimination Test-Matching Subtest VFDT-Mat test (visual form discrimination). Years of education were included as a covariate.RESULTS:After adjusting for education, higher VFDT-Rec total scores were associated with lower odds of being categorized with a greater degree of cognitive/functional impairment (OR 0.66-0.83, p < .001). VFDT-Mat scores showed a similar pattern, but only reached statistical significance for the Major versus No Neurocognitive Impairment (OR = 0.77, p = .0010) and Major versus Mild comparisons (OR = 0.89, p = .0233).CONCLUSIONS:The VFDT may enhance the confidence of differential diagnosis of dementia in older adult Veterans. Formal education-adjusted norms need to be established for clinical use.