The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer's disease: results from a randomized controlled trial.

BACKGROUND: Synaptic dysfunction contributes to cognitive impairment in Alzheimer's disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer's disease. METHODS: Thirty-four drug-naive patients with mild Alzheimer's disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio. RESULTS: MRS data from 33 patients (60-86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06-0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00-0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters. CONCLUSIONS: MRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer's disease, in line with findings in preclinical studies. TRIAL REGISTRATION: Netherlands Trial Register, NTR3346 . Registered on 13 March 2012.

Magnetoencephalography for the Detection of Intervention Effects of a Specific Nutrient Combination in Patients with Mild Alzheimer's Disease: Results from an Exploratory Double-Blind, Randomized, Controlled Study.

Synaptic loss is an early pathological finding in Alzheimer's disease (AD) and correlates with memory impairment. Changes in macroscopic brain activity measured with electro- and magnetoencephalography (EEG and MEG) in AD indicate synaptic changes and may therefore serve as markers of intervention effects in clinical trials. EEG peak frequency and functional networks have shown, in addition to improved memory performance, to be sensitive to detect an intervention effect in mild AD patients of the medical food Souvenaid containing the specific nutrient combination Fortasyn® Connect, which is designed to enhance synapse formation and function. Here, we explore the value of MEG, with higher spatial resolution than EEG, in identifying intervention effects of the nutrient combination by comparing MEG spectral measures, functional connectivity, and networks between an intervention and a control group. Quantitative markers describing spectral properties, functional connectivity, and graph theoretical aspects of MEG from the exploratory 24-week, double-blind, randomized, controlled Souvenir II MEG sub-study (NTR1975, http://www.trialregister.nl) in drug naïve patients with mild AD were compared between a test group (n = 27), receiving Souvenaid, and a control group (n = 28), receiving an isocaloric control product. The groups were unbalanced at screening with respect to Mini-Mental State Examination. Peak frequencies of MEG were compared with EEG peak frequencies, recorded in the same patients at similar time points, were compared with respect to sensitivity to intervention effects. No consistent statistically significant intervention effects were detected. In addition, we found no difference in sensitivity between MEG and EEG peak frequency. This exploratory study could not unequivocally establish the value of MEG in detecting interventional effects on brain activity, possibly due to small sample size and unbalanced study groups. We found no indication that the difference could be attributed to a lack of sensitivity of MEG compared with EEG. MEG in randomized controlled trials is feasible but its value to disclose intervention effects of Souvenaid in mild AD patients needs to be studied further.

Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on cerebral glucose metabolism in early Alzheimer's disease.

INTRODUCTION: Alzheimer's disease is associated with early synaptic loss. Specific nutrients are known to be rate limiting for synapse formation. Studies have shown that administering specific nutrients may improve memory function, possibly by increasing synapse formation. This Dutch study explores the Effect of a specific Nutritional Intervention on cerebral Glucose Metabolism in early Alzheimer's disease (NL-ENIGMA, Dutch Trial Register NTR4718, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4718). The NL-ENIGMA study is designed to test whether the specific multinutrient combination Fortasyn Connect present in the medical food Souvenaid influences cerebral glucose metabolism as a marker for improved synapse function. METHODS: This study is a double-blind, randomized controlled parallel-group single-center trial. Forty drug-naive patients with mild cognitive impairment or mild dementia with evidence of amyloid deposition are 1:1 randomized to receive either the multinutrient combination or placebo once daily. Main exploratory outcome parameters include absolute quantitative positron emission tomography with 18F-fluorodeoxyglucose (including arterial sampling) and standard uptake value ratios normalized for the cerebellum or pons after 24 weeks. DISCUSSION: We expect the NL-ENIGMA study to provide further insight in the potential of this multinutrient combination to improve synapse function.

The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study.

BACKGROUND: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS: 179 drug-naïve mild AD patients who participated in the Souvenir II study. INTERVENTION: Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION: Dutch Trial Register NTR1975.

Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol).

RATIONALE: Typical users of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. OBJECTIVES: The aim of the present study was to investigate whether co-administration of alcohol or THC with MDMA differentially affects ongoing electroencephalogram (EEG) oscillations compared to the administration of each drug alone. METHODS: In two separate experiments, 16 volunteers received four different drug conditions: (1) MDMA (100 mg); (2) alcohol clamp (blood alcohol concentration = 0.6‰) or THC (inhalation of 4, 6 and 6 mg, interval of 1.5 h); (3) MDMA in combination with alcohol or THC; and (4) placebo. Before and after drug administration, electroencephalography was recorded during an eyes closed resting state. RESULTS: Theta and alpha power increased after alcohol intake compared to placebo and reduced after MDMA intake. No interaction between alcohol and MDMA was found. Significant MDMA x THC effects for theta and lower-1-alpha power indicated that the power attenuation after the combined intake of MDMA and THC was less than the sum of each drug alone. For the lower-2-alpha band, the intake of MDMA or THC alone did not significantly affect power, but the intake of combined MDMA and THC significantly decreased lower-2-alpha power. CONCLUSIONS: The present findings indicate that the combined intake of MDMA and THC, but not of MDMA and alcohol, affects ongoing EEG oscillations differently than the sum of either one drug alone. Changes in ongoing EEG oscillations may be related to the impaired task performance that has often been reported after drug intake.

The increase in theta/beta ratio on resting-state EEG in boys with attention-deficit/hyperactivity disorder is mediated by slow alpha peak frequency.

Attention-deficit/hyperactivity disorder (ADHD) was found to be characterized by a deviant pattern of electrocortical activity during resting state, particularly increased theta and decreased beta activity. The first objective of the present study is to confirm whether individuals with slow alpha peak frequency contribute to the finding of increased theta activity in ADHD. The second objective is to explore the relation between resting-state brain oscillations and specific cognitive functions. From 49 boys with ADHD and 49 healthy control boys, resting-state EEG during eyes open and eyes closed was recorded, and a variety of cognitive tasks were administered. Theta and beta power and theta/beta ratio were calculated using both fixed frequency bands and individualized frequency bands. As expected, theta/beta ratio, calculated using fixed frequency bands, was significantly higher in ADHD children than control children. However, this group effect was not significant when theta/beta ratio was assessed using individualized frequency bands. No consistent relation was found between resting-state brain oscillations and cognition. The present results suggest that previous findings of increased theta/beta ratio in ADHD may reflect individuals with slow alpha peak frequencies in addition to individuals with true increased theta activity. Therefore, the often reported theta/beta ratio in ADHD can be considered a non-specific measure combining several distinct neurophysiological subgroups such as frontal theta and slowed alpha peak frequencies. Future research should elucidate the functional role of resting-state brain oscillations by investigating neurophysiological subgroups, which may have a clearer relation to cognitive functions than single frequency bands.

The effectiveness of EEG-feedback on attention, impulsivity and EEG: a sham feedback controlled study.

EEG-feedback, also called neurofeedback, is a training procedure aimed at altering brain activity, and is used as a treatment for disorders like Attention Deficit/Hyperactivity Disorder (ADHD). Studies have reported positive effects of neurofeedback on attention and other dependent variables. However, double-blind studies including a sham neurofeedback control group are lacking. The inclusion of such group is crucial to control for unspecific effects. The current work presents a sham-controlled, double-blind evaluation. The hypothesis was that neurofeedback enhances attention and decreases impulsive behavior. Participants (n=27) were students selected on relatively high scores on impulsivity/inattention questionnaires (Barrat Impulsivity Scale and Broadbent CFQ). They were assigned to a neurofeedback treatment or a sham group. (sham)Neurofeedback training was planned for 15 weeks consisting of a total of 30 sessions, each lasting 22 min. Before and after 16 sessions (i.e., interim analyses), qEEG was recorded and impulsivity and inattention was assessed using a stop signal task and reversed continuous performance task and two questionnaires. Results of the interim analyses showed that participants were blind with respect to group inclusion, but no trend towards an effect of neurofeedback on behavioral measures was observed. Therefore in line with ethical guidelines the experiment was ceased. These results implicate a possible lack of effect of neurofeedback when one accounts for non-specific effects. However, the specific form of feedback and application of the sham-controlled double-blind design may have diminished the effect of neurofeedback.

Relation between resting EEG to cognitive performance and clinical symptoms in adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) in children is characterized by elevated levels of slow wave activity and reduced fast wave activity in resting-state electroencephalogram (EEG). In adults with ADHD, resting-state EEG findings are scarce and inconsistent. The present study examined whether the disparate findings are due EEG recording conditions (i.e., eyes-open vs. eyes-closed). A second goal of the current study was to assess relations between EEG spectral indices to performance measures obtained using a stop-signal task, and to behavioral ADHD symptoms. The present study included 24 adults with ADHD and 24 control adults. The EEG results showed a greater reduction in alpha power from eyes-closed to eyes-open (i.e., alpha attenuation) in ADHD compared to controls. In addition, theta/beta ratio was negatively correlated to the speed of responding to choice stimuli. These findings were interpreted vis-à-vis a biophysical model assuming that the hypo-arousal in ADHD is due to an overdrive of the nucleus coeruleus resulting in inhibitory activity of the thalamic reticular nucleus.

Stroop interference and the timing of selective response activation.

OBJECTIVE: To examine the exact timing of selective response activation in a manual color-word Stroop task. METHODS: Healthy individuals performed two versions of a manual color-word Stroop task, varying in the probability of incongruent color-words, while EEG was recorded. RESULTS: Stroop interference effect was manifested as longer reaction times for incongruent relative to congruent color-words, and was larger in a task version where incongruent color-words were presented less frequently. Whereas the congruence between color display and word meaning did not affect average stimulus- and response-locked lateralized readiness potential (LRP) onset latencies nor response-locked LRP amplitudes, P3 peak latencies were longer and stimulus-locked LRPs were smaller for incongruent than congruent trials. CONCLUSIONS: These data are consistent with the idea that behavioral Stroop interference reflects delays in processing stages preceding color-based selective response activation in a subset of trials. They also do not exclude additional delays after color-based selective response activation, at least up until some 200ms before the overt response. SIGNIFICANCE: This chronometric analysis allows for a parcellation of the Stroop interference process that may be applied in psychopathology.

Neural correlates of stopping and self-reported impulsivity.

OBJECTIVE: To examine the relation between self-reported impulsivity, inhibitory control, and the neural correlates of stopping performance within the normal population. METHODS: Healthy individuals scoring high and low on trait impulsivity performed an auditory stop-signal task. Stopping performance and neural correlates of stopping (i.e. N1 and stop P3) were compared between the impulsive groups as well as between participants who were slow and fast in stopping. RESULTS: As expected, N1 and stop P3 were larger for successful relative to failed stops (i.e. N1 and stop P3 effects). Participants scoring high relative to low on impulsivity showed equal stopping performance, had larger stop P3, but similar N1 effects. Slow as compared to fast stoppers had reduced stop P3, but similar N1 effects. CONCLUSIONS: Participants scoring high relative to low on impulsivity may need more effortful inhibitory control to yield equal stopping performance. Slow relative to fast stoppers may have weaker inhibition processes and abnormal error processing. In contrast to ADHD, both high impulsives as well as slow stoppers had an intact N1 effect. SIGNIFICANCE: Subjective impulsivity and slow stopping in healthy individuals cannot be generalized to ADHD.

Stroop interference and attention-deficit/hyperactivity disorder: a review and meta-analysis.

Previous reviews and meta-analyses that addressed abnormal Stroop interference in attention-deficit/hyperactivity disorder (ADHD) yielded mixed results. The authors of the present study argue that the inconsistencies may reflect the problematic nature of 2 frequently used methods to quantify Stroop interference-the difference score and Golden's method (C. J. Golden, 1978). Golden's method correction for base-word reading is inadequate, and the difference score is sensitive to the nature of the outcome variable. The latter can be remedied with a ratio score. Contrasting previous meta-analyses, this meta-analysis covers all age groups and all Stroop test variants, and it excludes studies using the Golden quantification method. Mean effect sizes for interference in ADHD as quantified by difference scores relative to control scores were 0.24 across all studies but 1.11 for time-per-item studies; outcome variable was a significant moderator variable, reflecting the sensitivity of the difference score to this variable. Consistency analysis of ratio scores across 19 studies reveals more interference for the ADHD groups relative to the control groups. It is concluded that interference control is consistently compromised in individuals with ADHD.

Subjective impulsivity and baseline EEG in relation to stopping performance.

Impulsivity is a personality trait within the normal population, but also a feature of many psychiatric disorders that have been associated with poor inhibitory control. The aim of the present study was to examine the relation between subjective impulsivity, theta/beta EEG ratio, and inhibitory control in healthy individuals. In 15 high and 14 low impulsive healthy volunteers (as assessed by the I(7) questionnaire), resting state EEG was recorded during an eyes open condition to obtain estimates for theta and beta activity. Subsequently, a stop-signal task was presented where participants responded to go-signals and had to stop their initiated response to stop-signals. Stopping performance and EEG activity were compared between the impulsive groups as well as between high vs. low theta/beta ratio groups. Results showed that subjective impulsivity was not related to stopping behavior or to theta/beta ratio. In contrast to our expectations that individuals with high theta/beta ratios would show relatively long stopping reaction times, analyses revealed that the low theta/beta ratio group had longer stopping reaction times. Given that increased theta/beta ratio may reflect reduced cortical inhibition over subcortical drives, it is proposed that healthy individuals with relative high theta/beta ratios are more motivated to maximize inhibition-related performance.