Macroscopic resting state model predicts theta burst stimulation response: A randomized trial.

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 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.

Habitual caffeine consumption moderates the antidepressant effect of dorsomedial intermittent theta-burst transcranial magnetic stimulation.

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 (ß = 0.62, p = 0.043), but no main effects of treatment group (ß = 0.22, p = 0.140) or caffeine consumption (ß = -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.

Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging.

In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.

Preserved hippocampus activation in normal aging as revealed by fMRI.

The hippocampus is deteriorated in various pathologies such as Alzheimer's disease (AD) and such deterioration has been linked to memory impairment. By contrast, the structural and functional effects of normal aging on the hippocampus is a matter of debate, with some findings suggesting deterioration and others providing evidence of preservation. This constitutes a crucial question since many investigations on AD are based on the assumption that the deterioration of the hippocampus is the breaking point between normal and pathological aging. A growing number of fMRI studies specifically aimed at investigating hippocampal engagement in various cognitive tasks, notably memory tasks, but the results have been inconclusive. Here, we optimized the episodic face-name paired-associates task in order to test the functioning of the hippocampus in normal aging. Critically, we found no difference in the activation of the hippocampus between the young and a group of older participants. Analysis of individual patterns of activation substantiated this impression. Collectively, these findings provide evidence of preserved hippocampal functioning in normal aging.

Increased risk of phosphorus limitation at higher temperatures for Daphnia magna.

Invertebrate herbivores frequently face growth rate constraints due to their high demands for phosphorus (P) and nitrogen (N). Temperature is a key modulator of growth rate, yet the interaction between temperature and P limitation on somatic growth rate is scarcely known. To investigate this interaction, we conducted a study on the somatic growth rate (SGR) of the cladoceran Daphnia magna, known to be susceptible to P-limitation. We determined the SGR across a broad range of dietary P content of algae (carbon (C):P ratios (125-790), and at different temperatures (10-25°C). There was a strong impact of both temperature and C:P ratio on the SGR of D. magna, and also a significant interaction between both factors was revealed. The negative effect of dietary C:P on growth rate was reduced with decreased temperature. We found no evidence of P limitation at lowest temperature, suggesting that enzyme kinetics or other measures of food quality overrides the demands for P to RNA and protein synthesis at low temperatures. These findings also indicate an increased risk of P limitation and thus reduced growth efficiency at high temperatures.

Longitudinal evidence for diminished frontal cortex function in aging.

Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.

The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers.

RATIONALE: The use of herbal remedies, such as Ginkgo biloba and Ginseng, for improving cognitive performance has become increasingly popular during recent years. Several previous studies have indicated that administration of Ginkgo biloba and Ginseng may improve aspects of learning and memory in healthy volunteers. These results, however, are generally not supported by well-controlled clinical studies. Also, positive results have often been reported from studies investigating effects related to short-term, chronic administration of the extract. Nonetheless, both Ginkgo biloba and Ginseng are marketed as having the capacity to enhance cognitive functions, such as memory and learning, in the long term. OBJECTIVE: This study aimed at investigating whether the use of Ginkgo biloba and Ginseng for a long period of time has positive effects on performance on learning and memory. METHODS: Community-dwelling volunteers ( n=3500) from The Betula prospective cohort study: memory, health, and aging were included in the study. RESULTS: It was found that the use of neither Ginkgo biloba ( n=40) nor Ginseng ( n=86) was associated with enhanced memory performance in any of the eight memory tests examined, relative to control groups either using or not using nutritional supplements. CONCLUSIONS: These findings indicate that use of Ginkgo biloba or Ginseng does not provide any quantifiable beneficial effects on memory performance in the long-term in healthy adult volunteers.