Age-Related Repetitive Transcranial Magnetic Stimulation Effects on Executive Function in Depression: A Systematic Review.

OBJECTIVE: The aims of the current review were to: 1) examine whether the rTMS effects on executive function increase as age advances; 2) to examine the potential of rTMS to remediate executive function in older depressed patients; and 3) to assess the relationship between the executive function and mood benefits from rTMS in depression. METHODS: Randomized or matched-groups, blind, sham-controlled studies (12 studies, 347 participants) on excitatory rTMS applied to left DLPFC in depression were reviewed. RESULTS: A series of meta-regressions found no evidence of greater rTMS effects on executive functions as age advances. Similarly, meta-analyses showed no significant rTMS effects on executive functions in older depressed individuals. However, meta-regression analyses showed that the size of the executive function benefits from rTMS in depression are positively related to the effect size of mood symptom reduction. Despite its correlational nature, this finding is consistent with the idea that improvement in executive function may play a critical role in depression recovery. CONCLUSIONS: The authors consider these findings preliminary because of the modest number of available studies. Based on a qualitative review, the authors describe methodologic modifications that may increase rTMS efficacy for both executive functions and mood in late-life depression.

Does Transcranial Direct Current Stimulation Improve Healthy Working Memory?: A Meta-analytic Review.

Transcranial direct current stimulation (tDCS) has been reported to improve working memory (WM) performance in healthy individuals, suggesting its value as a means of cognitive enhancement. However, recent meta-analyses concluded that tDCS has little or no effect on WM in healthy participants. In this article, we review reasons why these meta-analyses may have underestimated the effect of tDCS on WM and report a more comprehensive and arguably more sensitive meta-analysis. Consistent with our interest in enhancement, we focused on anodal stimulation. Thirty-one articles matched inclusion criteria and were included in four primary meta-analyses assessing the WM effects of anodal stimulation over the left and right dorsolateral pFC (DLPFC) and right parietal lobe as well as left DLPFC stimulation coupled with WM training. These analyses revealed a small but significant effect of left DLPFC stimulation coupled with WM training. Left DLPFC stimulation alone also enhanced WM performance, but the effect was reduced to nonsignificance after correction for publication bias. No other effects were significant, including a variety of tested moderators. Additional meta-analyses were undertaken with study selection criteria based on previous meta-analyses, to reassess the findings from these studies using the analytic methods of this study. These analyses revealed a mix of significant and nonsignificant small effects. We conclude that the primary WM enhancement potential of tDCS probably lies in its use during training.

Executive Dysfunction Predicts Treatment Response to Neuroplasticity-Based Computerized Cognitive Remediation (nCCR-GD) in Elderly Patients with Major Depression.

OBJECTIVES: Executive dysfunction (ED) is a predictor of poor treatment response of late-life depression to pharmacotherapy. In response to the consistency of these findings, we designed neuroplasticity-based computerized cognitive remediation (nCCR-GD) intervention to target and improve ED in patients who failed to remit with antidepressant treatment. This study tests the hypothesis that ED at baseline will predict favorable treatment response to nCCR-GD. METHODS: 11 elderly patients with treatment-resistant major depression were treated with a 30-hour, 4-week, unblinded, nCCR-GD treatment trial. Neuropsychological performance was assessed at baseline and after treatment ceased. RESULTS: ED at baseline was associated with greater reduction in Montgomery-Asberg Depression Rating Scale score over the 4-week treatment ß = -0.74, F(2,8) = 10.85, p = 0.009, R(2) = 0.55. CONCLUSIONS: ED predicts favorable treatment response to nCCR-GD in older adults suffering from major depression resistant to antidepressants. This finding is opposed to studies testing pharmacotherapy where ED predicts poorer treatment response.

Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis.

The use of prescription stimulants to enhance healthy cognition has significant social, ethical, and public health implications. The large number of enhancement users across various ages and occupations emphasizes the importance of examining these drugs' efficacy in a nonclinical sample. The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition.

Comparison of Functional and Structural Neural Network Features in Older Adults With Depression With vs Without Apathy and Association With Response to Escitalopram: Secondary Analysis of a Nonrandomized Clinical Trial.

Importance: Apathy is prevalent among individuals with late-life depression and is associated with poor response to pharmacotherapy, including chronicity and disability. Elucidating brain networks associated with apathy and poor treatment outcomes can inform intervention development. Objectives: To assess the brain network features of apathy among individuals with late-life depression and identify brain network abnormalities associated with poor antidepressant response. Design, Setting, and Participants: This secondary analysis of a single-group, open-label nonrandomized clinical trial of escitalopram conducted at an outpatient geriatric psychiatry clinic enrolled 40 adults aged 59 to 85 years with major depressive disorder from July 1, 2012, to July 31, 2019. Interventions: After a 2-week washout period, participants received escitalopram titrated to a target of 20 mg/d for 12 weeks. Main Outcomes and Measures: Baseline and posttreatment magnetic resonance imaging (MRI), clinical, and cognitive assessments were conducted. Functional MRI was used to map group differences in resting state functional connectivity (rsFC) of the salience network, and diffusion MRI connectometry was performed to evaluate pathway-level disruptions in structural connectivity. The Apathy Evaluation Scale was used to quantify apathy, and the Hamilton Depression Rating Scale (HAM-D) was used to quantify the primary outcome of depression severity. Results: Forty participants (26 women [65%]; mean [SD] age, 70.0 [6.6] years [range, 59-85 years]) with depression were included; 20 participants (50%) also had apathy. Relative to nonapathetic participants with depression, those with depression and apathy had lower rsFC of salience network seeds with the dorsolateral prefrontal cortex (DLPFC), premotor cortex, midcingulate cortex, and paracentral lobule and greater rsFC with the lateral temporal cortex and temporal pole (z score >2.7; Bonferroni-corrected threshold of P < .0125). Compared with participants without apathy, those with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus (t score >2.5; false discovery rate-corrected P = .02). Twenty-seven participants completed escitalopram treatment; 16 (59%) achieved remission (HAM-D score <10). Lower insula-DLPFC/midcingulate cortex rsFC was associated with less symptomatic improvement (HAM-D % change) (ß [df] = 0.588 [26]; P = .001) and a higher likelihood of nonremission (odds ratio, 1.041 [95% CI, 1.003-1.081]; P = .04) after treatment and, in regression models, was a mediator of the association between baseline apathy and persistence of depression. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was associated with residual cognitive difficulties on measures of attention (ß [df] = 0.445 [26]; P = .04) and executive function (ß [df] = 0.384 [26]; P = .04). Conclusions and Relevance: This study suggests that disturbances in connectivity between the salience network and other large-scale networks that support goal-directed behavior may give rise to apathy and may be associated with poor response of late-life depression to antidepressant pharmacotherapy. These network disturbances may serve as targets for novel interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT01728194.

Attention, Motivation, and Study Habits in Users of Unprescribed ADHD Medication.

OBJECTIVE: Despite the limited effectiveness of ADHD medications on healthy cognition, prescription stimulants' cognitive enhancement use is increasing. This article examines enhancement users' attention, motivation, and study habits. METHOD: A total of 61 users of unprescribed stimulants and 67 controls (no history of prescription stimulant use) completed tests of objectively measured and subjectively reported attention. Self-reports on study habits, as well as motivation during laboratory attention testing, were also administered. RESULTS: Our data replicated previous findings of relatively lower self-reported attention functioning in users. Extending past research, we showed that user-control differences in attention were still present but less pronounced on objective measures than on self-report. In addition, we obtained evidence of lower motivation during cognitive testing and less optimal study habits among users, as compared with their non-using peers. CONCLUSION: Unprescribed stimulant use is more strongly related to compromised study habits, low motivation, and a subjective perception of attention problems than to objective attention performance.

White matter abnormalities predict residual negative self-referential thinking following treatment of late-life depression with escitalopram: A preliminary study.

BACKGROUND: Negative self-referential thinking is a common symptom of depression associated with poor treatment response. In late-life depression, white matter abnormalities may contribute to negative self-referential thoughts following antidepressant treatment. We investigated the association of fractional anisotropy (FA) in select regions of the negative valence system (NVS) with residual negative self-referential thoughts following treatment with escitalopram for late-life depression. METHODS: The participants were older adults with major depression and psychiatrically normal controls. Depressed participants received 12 weeks of treatment with escitalopram. To assess self-referential thinking, participants completed a Trait Adjective Task at baseline and at week 12. Baseline MRI scans included a diffusion imaging sequence for FA analyses. RESULTS: Participants with late-life depression differed from controls on all performance measures of the Trait Adjective Task at baseline and at 12 weeks. Depressed participants endorsed fewer negative personality traits and more positive personality traits at week 12 compared to baseline. Lower FA in the dorsal anterior cingulate and in the uncinate fasciculus in depressed participants was correlated with residual negative self-referential thinking (e.g., more endorsed negative adjectives, fewer rejected negative adjectives) at treatment end. LIMITATIONS: The sample size is modest so the findings are preliminary. FA analyses were restricted to predetermined regions. CONCLUSIONS: Negative self-referential thinking improved in depressed older adults following 12 weeks of treatment with escitalopram. Baseline FA in select white matter regions of the NVS was associated with residual negative self-referential thinking. These findings may help identify treatment targets for residual negative self-referential thoughts.

A double-blind pilot dosing study of low field magnetic stimulation (LFMS) for treatment-resistant depression (TRD).

BACKGROUND: Low field magnetic stimulation is a potentially rapid-acting treatment for depression with mood-enhancing effects in as little as one 20-min session. The most convincing data for LFMS has come from treating bipolar depression. We examined whether LFMS also has rapid mood-enhancing effects in treatment-resistant major depressive disorder, and whether these effects are dose-dependent. OBJECTIVE/HYPOTHESIS: We hypothesized that a single 20-min session of LFMS would reduce depressive symptom severity and that the magnitude of this change would be greater after three 20-min sessions than after a single 20-min session. METHODS: In a double-blind randomized controlled trial, 30 participants (age 21-65) with treatment-resistant depression were randomized to three 20-min active or sham LFMS treatments with 48 h between treatments. Response was assessed immediately following LFMS treatment using the 6-item Hamilton Depression Rating Scale (HAMD-6), the Positive and Negative Affect Scale (PANAS) and the Visual Analog Scale. RESULTS: Following the 3rd session of LFMS, the effect of LFMS on VAS and HAMD-6 was superior to sham (F (1, 24) = 7.45, p = 0.03, Bonferroni-Holm corrected; F (1, 22) = 6.92, p = 0.03, Bonferroni-Holm corrected, respectively). There were no differences between sham and LFMS following the initial or second session with the effect not becoming significant until after the third session. CONCLUSIONS: Three 20-min LFMS sessions were required for active LFMS to have a mood-enhancing effect for individuals with treatment-resistant depression. As this effect may be transient, future work should address dosing schedules of longer treatment courses as well as biomarker-based targeting of LFMS to optimize patient selection and treatment outcomes.

Perception of Social Support and Cognitive Performance in Older Adults With Depression.

This cross-sectional study assesses the association between perceived social support and cognitive performance in older adults with depression.

Functional connectivity of the left DLPFC to striatum predicts treatment response of depression to TMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is a non-invasive, safe, and efficacious treatment for depression. TMS has been shown to normalize abnormal functional connectivity of cortico-cortical circuits in depression and baseline functional connectivity of these circuits predicts treatment response. Less is known about the relationship between functional connectivity of frontostriatal circuits and treatment response. OBJECTIVE/HYPOTHESIS: We investigated whether baseline functional connectivity of distinct frontostriatal circuits predicted response to TMS. METHODS: Resting-state fMRI (rsfMRI) was acquired in 27 currently depressed subjects with treatment resistant depression and 27 healthy controls. Depressed subjects were treated with 5 weeks of daily TMS over the left dorsolateral prefrontal cortex (DLPFC). The functional connectivity between limbic, executive, rostral motor, and caudal motor regions of frontal cortex and their corresponding striatal targets were determined at baseline using an existing atlas based on diffusion tensor imaging. TMS treatment response was measured by percent reduction in the 24-item Hamilton Depression Rating Scale (HAMD24). In an exploratory analysis, correlations were determined between baseline functional connectivity and TMS treatment response. RESULTS: Seven cortical clusters belonging to the executive and rostral motor frontostriatal projections had reduced functional connectivity in depression compared to healthy controls. No frontostriatal projections showed increased functional connectivity in depression (voxel-wise p < 0.01, family-wise α < 0.01). Only baseline functional connectivity between the left DLPFC and the striatum predicted TMS response. Higher baseline functional connectivity correlated with greater reductions in HAMD24 (Pearson's R = 0.58, p = 0.002). CONCLUSION(S): In an exploratory analysis, higher functional connectivity between the left DLPFC and striatum predicted better treatment response. Our findings suggest that the antidepressant mechanism of action of TMS may require connectivity from cortex proximal to the stimulation site to the striatum.

Network-Guided Transcranial Magnetic Stimulation for Depression.

PURPOSE OF REVIEW: First, we will identify candidate predictive biomarkers of antidepressant response of TMS based on the neuroimaging literature. Next, we will review the effects of TMS on networks involved in depression. Finally, we will discuss ways in which our current understanding of network engagement by TMS may be used to optimize its antidepressant effect. RECENT FINDINGS: The past few years has seen significant interest in the antidepressant mechanisms of TMS. Studies using functional neuroimaging and neurochemical imaging have demonstrated engagement of networks known to be important in depression. Current evidence supports a model whereby TMS normalizes network function gradually over the course of several treatments. This may, in turn, mediate its antidepressant effect. SUMMARY: One strategy to optimize the antidepressant effect of TMS is to more precisely target networks relevant in depression. We propose methods to achieve this using functional and neurochemical imaging.

Cognitive enhancement.

Cognitive enhancement refers to the improvement of cognitive ability in normal healthy individuals. In this article, we focus on the use of pharmaceutical agents and brain stimulation for cognitive enhancement, reviewing the most common methods of pharmacologic and electronic cognitive enhancement, and the mechanisms by which they are believed to work, the effectiveness of these methods and their prevalence. We note the many gaps in our knowledge of these matters, including open questions about the size, reliability and nature of the enhancing effects, and we conclude with recommendations for further research. WIREs Cogn Sci 2014, 5:95-103. doi: 10.1002/wcs.1250 CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.

Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people.

Psychostimulants such as mixed amphetamine salts (MAS, brand name Adderall) are widely used for cognitive enhancement by healthy young people, yet laboratory research on effectiveness has yielded variable results. The present study assessed the effects of MAS in healthy young adults with an adequately powered double-blind cross-over placebo-controlled trial. We examined effects in 13 measures of cognitive ability including episodic memory, working memory, inhibitory control, convergent creativity, intelligence and scholastic achievement, with the goals of determining (1) whether the drug is at least moderately enhancing (Cohen's d >= .5) to some or all cognitive abilities tested, (2) whether its effects on cognition are moderated by baseline ability or COMT genotype, and (3) whether it induces an illusory perception of cognitive enhancement. The results did not reveal enhancement of any cognitive abilities by MAS for participants in general. There was a suggestion of moderation of enhancement by baseline ability and COMT genotype in a minority of tasks, with MAS enhancing lower ability participants on word recall, embedded figures and Raven's Progressive Matrices. Despite the lack of enhancement observed for most measures and most participants, participants nevertheless believed their performance was more enhanced by the active capsule than by placebo. We conclude that MAS has no more than small effects on cognition in healthy young adults, although users may perceive the drug as enhancing their cognition. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Enhancement stimulants: perceived motivational and cognitive advantages.

Psychostimulants like Adderall and Ritalin are widely used for cognitive enhancement by people without ADHD, although the empirical literature has shown little conclusive evidence for effectiveness in this population. This paper explores one potential explanation of this discrepancy: the possibility that the benefit from enhancement stimulants is at least in part motivational, rather than purely cognitive. We review relevant laboratory, survey, and interview research and present the results of a new survey of enhancement users with the goal of comparing perceived cognitive and motivational effects. These users perceived stimulant effects on motivationally-related factors, especially "energy" and "motivation," and reported motivational effects to be at least as pronounced as cognitive effects, including the effects on "attention."