A Randomized Controlled Trial on the Effects of a 12-Week High- vs. Low-Intensity Exercise Intervention on Hippocampal Structure and Function in Healthy, Young Adults.

Physical exercise affects hippocampal structure and function, but the underlying neural mechanisms and the effects of exercise intensity remain incompletely understood. Therefore, we undertook a comprehensive, multi-modal 3T and 7T MRI randomized controlled trial (Netherlands Trial Register - NL5847) in which we randomized 52 young, non-athletic volunteers to a 12-week low- or high-intensity exercise program. Using state-of-the-art methods, we investigated changes in hippocampal volume, as well as changes in vasculature, neuro-metabolites, and peripheral growth factors as potential underpinnings. Cardiorespiratory fitness improved over time (p < 0.001), but no interaction with exercise intensity was found (p = 0.48). Accordingly, we did not observe significant interactions between exercise condition and time on MRI measures (all p > 0.06). However, we found a significant decrease in right hippocampal volume (p < 0.01), an increase in left hippocampal glutathione (p < 0.01), and a decrease of left hippocampal cerebral blood volume (p = 0.01) over time, regardless of exercise condition. Additional exploratory analyses showed that changes in brain-derived neurotrophic factor (p = 0.01), insulin-like growth-factor (p = 0.03), and dorsal anterior cingulate cortex N-acetyl-aspartate levels (p = 0.01) were positively associated with cardiorespiratory fitness changes. Furthermore, a trend toward a positive association of fitness and gray-matter cerebral blood flow (p = 0.06) was found. Our results do not provide evidence for differential effects between high-intensity (aerobic) and low-intensity (toning) exercise on hippocampal structure and function in young adults. However, we show small but significant effects of exercise on hippocampal volume, neurometabolism and vasculature across exercise conditions. Moreover, our exploratory results suggest that exercise might not specifically only benefit hippocampal structure and function, but rather has a more widespread effect. These findings suggest that, in agreement with previous MRI studies demonstrating moderate to strong effects in elderly and diseased populations, but none to only mild effects in young healthy cohorts, the benefits of exercise on the studied brain measures may be age-dependent and restorative rather than stimulatory. Our study highlights the importance of a multi-modal, whole-brain approach to assess macroscopic and microscopic changes underlying exercise-induced brain changes, to better understand the role of exercise as a potential non-pharmacological intervention.

Effects of prolonged methylphenidate treatment on amygdala reactivity and connectivity: a randomized controlled trial in stimulant treatment-naive, male participants with ADHD.

Background: Problems with emotional processing are widely reported in individuals with attention-deficit/hyperactivity disorder (ADHD). Although methylphenidate (MPH) effectively alleviates inattention and hyperactivity symptoms in ADHD, its effects on emotional processing and internalizing symptoms have remained elusive. While we previously found that acute MPH administration modulated neural mechanisms underlying emotional processing in an age-dependent manner, the effects of prolonged administration remained unknown. Objectives: Therefore, we investigated: (i) whether prolonged MPH treatment influences neural substrates (amygdala reactivity and connectivity) of emotional processing, and (ii) whether these effects are modulated by age. Methods: The "effects of Psychotropic drugs On Developing brain-MPH" ("ePOD-MPH") randomized controlled trial was a 16-week double-blind, placebo-controlled, multi-center trial with MPH in 50 boys (10-12 years of age) and 49 men (23-40 years of age), all stimulant treatment-naive and diagnosed with ADHD. Participants performed an emotional face-matching task during functional magnetic resonance imaging. We assessed their symptoms of ADHD and internalizing symptoms at baseline, during the trial (8 weeks), and 1 week after the trial end (17 weeks). Results and Conclusions: We did not find effects of prolonged MPH treatment on emotional processing, as measured by amygdala reactivity and connectivity and internalizing symptoms in this trial with stimulant treatment-naive participants. This differs from our findings on emotional processing following acute MPH administration and the effects of prolonged MPH treatment on the dopamine system, which were both modulated by age. Interestingly, prolonged MPH treatment did improve ADHD symptoms, although depressive and anxiety symptoms showed a medication-independent decrease. Furthermore, our data indicate that baseline internalizing symptoms may be used to predict MPH treatment effects on ADHD symptoms, particularly in (male) adults with ADHD.

The influence of age-of-onset of antidepressant use on the acute CBF response to a citalopram challenge; a pharmacological MRI study.

Preclinical studies have demonstrated that antidepressant treatment in juvenile rodents affect the ontogeny of the serotonin system. However, whether early antidepressant use has similar effects on the development of the serotonin system in humans remains unknown. Therefore, we investigated whether effects of selective serotonin reuptake inhibitor (SSRI) treatment on the serotonin system are modulated by age. With pharmacological Magnetic Resonance Imaging the cerebral blood flow (CBF) response to an acute citalopram challenge was measured, as a proxy for serotonin function. Fifty-one females with major depressive disorder or anxiety disorder were stratified into three groups: 1) those treated with SSRIs <23 years of age, 2) those treated with SSRIs >23 years of age, and 3) those that were never treated with SSRIs. Additionally, a group of 14 healthy controls was included. CBF decreased after a citalopram challenge in the amygdala, hippocampus and orbitofrontal cortex across the whole sample. However, in contrast to preclinical studies, we did not find any age-dependent effect of SSRI exposure on the CBF response. In view of recent concerns on potential adverse effects of SSRIs administered to children, future studies are needed to replicate our negative findings in larger samples sizes and potentially in a prospective design.

Effects of 16 Weeks of Methylphenidate Treatment on Actigraph-Assessed Sleep Measures in Medication-Naive Children With ADHD.

Methylphenidate (MPH) improves behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Its effects on sleep, however, are insufficiently known, as trials with MPH in medication-naive children were so far restricted to relatively short trial durations. Here, we assessed effects of prolonged MPH treatment on sleep in medication-naive boys in a 16-weeks double-blind, placebo controlled, multicenter clinical trial with immediate-release MPH (ePOD-MPH trial, NTR3103). Seventy-five medication-naive boys, aged 10-12 years, were screened for eligibility using ADHD DSM-IV criteria. Sleep was assessed using actigraphy, diaries and questionnaires prior to randomization, in week 8, and 1 week after trial end. Fifty boys (mean age 11.4y, SD 0.9) were randomized to MPH or placebo. Linear mixed model analysis demonstrated a significant time-by-treatment interaction effect (p = 0.007) on sleep efficiency. Post-hoc analyses demonstrated that the two groups did not differ from each other (p = 0.94) during treatment (week 8), but that sleep efficiency was significantly improved in the MPH (p = 0.005), but not placebo group (p = 0.87) 1 week after trial end. The lack of MPH's negative effects on sleep during treatment differ from most previous studies and could be explained by the relatively long trial duration in our study and the medication-naive status of our sample; suggesting that evaluating sleep problems only shortly after treatment onset presents an incomplete picture, because it might not be representative for sleep quality after longer treatment periods. Our findings of improved sleep after trial end could be due to rebound effects or longer-term effects of MPH treatment and therefore require replication. CLINICAL TRIAL REGISTRATION: Central Committee on Research Involving Human Subjects (an independent registry, identifier NL34509.000.10) before enrollment of the first subject and The Netherlands National Trial Register, identifier NTR3103.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study.

BACKGROUND: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects. AIMS: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT). METHODS: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region). RESULTS: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change. CONCLUSION: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients.

Stimulants are the main pharmacological treatment for patients with attention-deficit/hyperactivity disorder (ADHD). Their current prescription rates are rising, both in children, adolescents and adults. Related to the impulse control phenotype, both preclinical and clinical studies have demonstrated lower γ-amino butyric acid (GABA) levels in prefrontal brain regions in ADHD. Whereas stimulant treatment increases GABA levels, preclinical studies have suggested that stimulant treatment effects may be age-dependent. As the long-term consequences of stimulant use in ADHD children and adolescents have so far been poorly studied, we used magnetic resonance spectroscopy to assess GABA+ and glutamate + glutamine (Glx) levels in the medial prefrontal cortex (mPFC) of adult ADHD patients, both before and after an oral methylphenidate (MPH) challenge. Three groups were studied: 1) ADHD patients who were first treated with stimulants before 16 years of age, i.e. during periods of ongoing brain development (early-stimulant-treated, EST); 2) patients first treated with stimulants in adulthood (i.e. > 23 years) (late-stimulant-treated, LST), and 3) stimulant-treatment-naive (STN) ADHD patients. Reduced basal GABA+ levels were found in EST compared to LST patients (p = 0.04), while after an MPH challenge, only the EST patients showed significant increases in GABA+ (p = 0.01). For Glx, no differences were found at baseline, nor after an MPH challenge. First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.