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Background: Potentiating current antidepressant treatment is much needed. Based on animal studies, caffeine may augment the effects of currently available antidepressants., Objective: Here, we tested whether habitual caffeine consumption moderates the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) using intermittent theta-burst stimulation (iTBS)., Methods: Forty patients with current depressive episodes were randomized to active iTBS ( n  = 19) or sham treatment ( n  = 21; shielded side of the coil and weak transcutaneous electrical stimulation) delivered two times per day for 10-15 weekdays. Neuronavigated stimulation was applied to the dorsomedial prefrontal cortex. Symptom improvement was measured using change in self-reported Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Pretreatment habitual caffeine consumption was quantified using self-reports of number of cups of coffee and energy drinks consumed the 2 days before the treatment starts., Results: Habitual caffeine consumption was associated with symptom improvement following active iTBS ( r  = 0.51, 95% confidence interval (CI): 0.08-0.78, p  = 0.025) but not following sham treatment ( r  = -0.02, 95% CI: -0.45 to 0.42, p  = 0.938). A multiple regression analysis corroborated the findings by showing a significant caffeine consumption × treatment group interaction (β = 0.62, p  = 0.043), but no main effects of treatment group (β = 0.22, p  = 0.140) or caffeine consumption (β = -0.01, p  = 0.948). No group differences in pretreatment symptom scores or caffeine consumption were detected ( p values > 0.86)., Conclusion: Habitual caffeine consumption moderated the antidepressant effect of dorsomedial iTBS, consistent with caffeine improving antidepressant pharmacological treatments in animals. Caffeine is an antagonist of adenosine receptors and may enhance antidepressant effects through downstream dopaminergic targets.

Goal-irrelevant information may interfere with ongoing task activities if not controlled properly. Evidence suggests that the ability to control interference is connected mainly to the prefrontal cortex (pFC). However, it remains unclear whether gray matter (GM) volume in prefrontal regions influences individual differences in interference control (IC) and if these relationships are affected by aging. Using cross-sectional and longitudinal estimates over a 4- to 5-year period, we examined the relationship between relative IC scores, obtained from a 2-back working memory task, GM volumes, and performance in different cognitive domains. By identifying individuals with either no or high levels of interference, we demonstrated that participants with superior IC had larger volume of the ventrolateral pFC, regardless of participant demographics. The same pattern was observed both at baseline and follow-up. Cross-sectional estimates further showed that interference increased as a function of age, but interference did not change between baseline and follow-up. Similarly, across-sample associations between IC and pFC volume were found in the cross-sectional data, along with no longitudinal change-change relationships. Moreover, relative IC scores could be linked to composite scores of fluid intelligence, indicating that control of interference may relate to performance in expected cognitive domains. These results provide new evidence that a relative IC score can be related to volume of specific and relevant regions within pFC and that this relationship is not modulated by age. This supports a view that the GM volume in these regions plays a role in resisting interference during a working memory task.

Cross-sectional neuroimaging studies suggest that hippocampal and prefrontal cortex functions underlie individual differences in memory ability in older individuals, but it is unclear how individual differences in cognitive ability in youth contribute to cognitive and neuroimaging measures in older age. Here, we investigated the relative influences of midlife memory ability and age-related memory change on memory-related BOLD-signal variability at one time point, using a sample from a longitudinal population-based aging study (N = 203, aged 55-80 years). Hierarchical regression analyses showed that midlife memory ability, assessed 15-20 years earlier, explained at least as much variance as memory change in clusters in the left inferior prefrontal cortex and the bilateral hippocampus, during memory encoding. Furthermore, memory change estimates demonstrated higher sensitivity than current memory levels in identifying distinct frontal regions where activity was selectively related to age-related memory change, as opposed to midlife memory. These findings highlight challenges in interpreting individual differences in neurocognitive measures as age-related changes in the absence of longitudinal data and also demonstrate the improved sensitivity of longitudinal measures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Work in functional neuroimaging has mapped interference resolution processing onto left inferior frontal regions for both verbal working memory and a variety of semantic processing tasks. The proximity of the identified regions from these different tasks suggests the existence of a common, domain-general interference resolution mechanism. The current research specifically tests this idea in a within-subject design using fMRI to assess the activation associated with variable selection requirements in a semantic retrieval task (verb generation) and a verbal working memory task with a trial-specific proactive interference manipulation (recent-probes). High interference trials on both tasks were associated with activity in the midventrolateral region of the left inferior frontal gyrus, and the regions activated in each task strongly overlapped. The results indicate that an elemental component of executive control associated with interference resolution during retrieval from working memory and from semantic memory can be mapped to a common portion of the left inferior frontal gyrus.

Age-related differences in cognitive performance are well documented. These differences are most pronounced during tasks with high demands on cognitive control, and it has been proposed that selective alteration of prefrontal activity is associated with cognitive changes in old age. Here, differences in the neural systems underlying selection requirements for older and younger adults were investigated using functional magnetic resonance imaging (fMRI). A verb generation task was used, and selection requirements were varied with regard to whether each noun could be associated with either few (scissors-cut) or many (ball-bounce, kick, throw...) competing alternatives. The two age groups showed statistically equivalent behavioral performance across the task conditions but marked differences in activation. Across both age groups, high selection demands activated several regions including bilateral frontal, left anterior frontal, left inferior temporal regions, and the dorsal anterior cingulate cortex (ACC). Between-group comparisons using region-of-interest analyses revealed less activation for senior adults in left inferior frontal gyrus (IFG), left inferior temporal gyrus, and the anterior cingulate and higher activation in right inferior frontal gyrus compared to young adults. These findings indicate age-related changes in multiple regions contributing to aspects of selection requirements during verb generation.

Regions of the prefrontal cortex (PFC) are typically activated in many different cognitive functions. In most studies, the focus has been on the role of specific PFC regions in specific cognitive domains, but more recently similarities in PFC activations across cognitive domains have been stressed. Such similarities may suggest that a region mediates a common function across a variety of cognitive tasks. In this study, we compared the activation patterns associated with tests of working memory, semantic memory and episodic memory. The results converged on a general involvement of four regions across memory tests. These were located in left frontopolar cortex, left mid-ventrolateral PFC, left mid-dorsolateral PFC and dorsal anterior cingulate cortex. These findings provide evidence that some PFC regions are engaged during many different memory tests. The findings are discussed in relation to theories about the functional contribution of the PFC regions and the architecture of memory.

Proactive interference (PI) appears when familiar information interferes with newly acquired information and is a major cause of forgetting in working memory. It has been proposed that encoding of item–context associations might help mitigate familiarity-based PI. Here, we investigate whether encoding-related brain activation could predict subsequent level of PI at retrieval using trial-specific parametric modulation. Participants were scanned with event-related fMRI while performing a 2-back working memory task with embedded 3-back lures designed to induce PI. We found that the ability to control interference in working memory was modulated by level of activation in the left inferior frontal gyrus, left hippocampus, and bilateral caudate nucleus during encoding. These results provide insight to the processes underlying control of PI in working memory and suggest that encoding of temporal context details support subsequent interference control. [ABSTRACT FROM AUTHOR]

Semantic judgements involve the use of general knowledge about the world in specific situations. Such judgements are typically associated with activity in a number of brain regions that include the left inferior frontal gyrus (IFG). However, previous studies showed activity in brain regions associated with mentalizing, including the right temporoparietal junction (TPJ), in semantic judgements that involved social knowledge. The aim of the present study was to investigate if social and non‐social semantic judgements are dissociated using a combination of fMRI and repetitive TMS. To study this, we asked participants to estimate the percentage of exemplars in a given category that shared a specified attribute. Categories could be either social (i.e., stereotypes) or non‐social (i.e., object categories). As expected, fMRI results (n = 26) showed enhanced activity in the left IFG that was specific to non‐social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation (n = 19) to this brain region specifically disrupted non‐social semantic judgements. Also as expected, the right TPJ showed enhanced activity to social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation to this brain region specifically disrupted social semantic judgements. It is possible that the causal networks involved in social and non‐social semantic judgements may be more complex than expected. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner. Computational modelling combined with a probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil. We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony. Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine. Author summary: There are multiple therapeutic protocols with a limited remission rate, for treatment-resistant depression, using repetitive transcranial magnetic stimulation (rTMS). It is still unclear how we match different rTMS protocols to patients to optimize the therapy. Currently, the process of determining the best rTMS protocol for each individual involves trial and error. Whole-brain computational modelling alongside multimodal neuroimaging paves the way to find the optimal therapeutic protocol for each patient, by integrating multi-modal neuroimaging through theoretical models of brain dynamics. In this work, whole-brain modelling helped us identify two covert clinically relevant subtypes in our depression cohort, exhibiting different responses to the same rTMS therapy applied over the dorsomedial prefrontal cortex. Patients assigned to the subtype with blunted resting-state frequency dynamics improved more in specific affective and negative symptoms. Moreover, we further indicated that the summative scores of phenotypic behaviors for depression are not well-suited for dissociating the depression subtypes and measuring the treatment outcome. In conclusion, our results suggest that studying whole-brain dynamics could have profound implications for identifying reliable biomarkers and neurostimulation targets for the treatment of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate whether treatment of a depressive episode with intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) had any effects on heart rate variability (HRV). We also investigated if changes in HRV covaried with symptom change after iTBS and if HRV could predict symptom change. Methods: We included 49 patients with a current depressive episode. All were randomized to receive a double-blind treatment course with active or sham iTBS over the DMPFC. HRV data were obtained from 1 h of night data before and after the iTBS. The standard deviation of the RR interval (SDNN) was chosen as primary outcome measure. Depressive, negative, and anxiety symptoms as well as self-rated health were assessed by clinicians or by self-report. Results: The groupxtime linear mixed model revealed no effect of iTBS on SDNN (estimate = -1.8, 95% confidence interval [CI]: -19.9 to 16.2). There were neither correlations between HRV and depressive, negative, or anxiety symptom change after iTBS nor with self-assessed health. No predictive value of HRV was found. Conclusions: Treatment for depression with dorsomedial iTBS had neither negative nor positive effects on the cardiac autonomic nervous system. [ABSTRACT FROM AUTHOR]

To better understand the neural mechanisms behind the effect of intermittent theta-burst stimulation (iTBS), we investigated how the prefrontal blood oxygenation response measured by changes in oxygenated haemoglobin (oxy-Hb) was modulated during a sham-controlled iTBS treatment course, and whether this was related to depressive symptom change. In this randomised, double-blind study, patients with ongoing treatment-resistant depression received either active (n = 18) or sham (n = 21) iTBS over the dorsomedial prefrontal cortex for ten to fifteen days with two sessions daily. Event-related functional near-infrared spectroscopy (fNIRS) was measured during each iTBS train, and resting-state oxy-Hb was compared before and after each iTBS session at the first, fifth, and last treatment day. Patients receiving active iTBS had an increase of the event-related oxy-Hb response compared to the sham group on the fifth (bilateral prefrontal cortices p <.001) and last (left prefrontal p =.007, right prefrontal p =.025) treatment day. Resting-state analysis showed suppressed oxy-Hb change in active iTBS compared to sham iTBS on the last treatment day (p =.024). Oxy-Hb change was unrelated to depressive symptom change (p =.474). This study describes a modulation of the blood oxygenation response over the prefrontal cortex that was built up during the course of active iTBS treatment in depression. [ABSTRACT FROM AUTHOR]

Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral correlates in humans are scarce. Post mortem findings suggest genotype specific expressions of DARPP-32 in the dorsal frontal lobes. Therefore, we investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (♀54%). The major homozygote G, T, or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352, the two latter in complete linkage disequilibrium), at the DARPP-32 regulating PPP1R1B gene, influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had an overall larger prefrontal volume in addition to greater EM recall accuracy after accounting for the influence of age. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in young adults and selective to this group for EM. Our findings suggest that genomic variation maps onto individual differences in frontal brain volumes and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality. [ABSTRACT FROM AUTHOR]

Abstract: A critical feature of higher cognitive functioning is the capacity to flexibly tailor information processing and behaviors to current situational demands. Recent neurocognitive models have been postulated to account for the dynamic nature of human executive processing by invoking two dissociable cognitive control modes, proactive and reactive control. These may involve partially overlapping, but temporally distinct neural implementation in the prefrontal cortex. Prior brain imaging studies exploring proactive control have mainly used tasks requiring only information about single-items to be retained over unfilled delays. Whether proactive control can also be utilized to facilitate performance in more complex working memory tasks, in which concurrent processing of intervening items and updating is mandatory during contextual cue maintenance remains an open question. To examine this issue and to elucidate the extent to which overlapping neural substrates underlie proactive and reactive control we used fMRI and a modified verbal 3-back paradigm with embedded cues predictive of high-interference trials. This task requires context information to be retained over multiple intervening trials. We found that performance improved with item-specific cues predicting forthcoming lures despite increased working memory load. Temporal dynamics of activation in the right inferior frontal gyrus suggest flexible switching between proactive and reactive control in a context-dependent fashion, with greater sustained responses elicited in the 3-back task involving context maintenance of cue information and greater transient responses elicited in the 3-back task absent of cues. [Copyright &y& Elsevier]

Functional brain-imaging data document overlapping sites of activation in prefrontal cortex across memory tasks, suggesting that these tasks may share common executive components. We leveraged this evidence to develop a training regimen and a set of transfer tasks to examine the trainability of a putative executive-control process: interference resolution. Eight days of training on high-interference versions of three different working memory tasks increased the efficiency with which proactive interference was resolved on those particular tasks. Moreover, an improved ability to resolve interference was also transferred to different working memory, semantic memory, and episodic memory tasks, a demonstration of far-transfer effects from process-specific training. Participants trained with noninterference versions of the tasks did not exhibit transfer. We infer that the transfer we demonstrated resulted from increased efficiency of the interference-resolution process. Therefore, this aspect of executive control is plastic and adaptive, and can be improved by training. [ABSTRACT FROM AUTHOR]

Abstract: A resource depletion framework motivated a novel strategy for investigating whether the central executive is unitary or separable into relatively independent subprocesses. The idea that tasks with overlapping neural representations may involve similar executive components was also critical to our approach. Of particular interest were tasks requiring resolution of interference among competing representations. Within a single experimental session intensive training reduced the ability to resolve interference on a transfer task if the training task placed high demands on interference resolution. Negative transfer was absent when interference resolution was minimally required by the task, or when the training and transfer tasks did not rely on overlapping neural representations. These results suggest a nonunitary central executive composed of separable subcomponents, at least one of which mediates interference resolution. Our results are consistent with an executive control process specialized for the selection of task-relevant representations from competitors. The results also agree with the view that higher cognitive processes are resource limited and can be temporarily depleted. [Copyright &y& Elsevier]

Abstract: Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment. [Copyright &y& Elsevier]