Magnetic resonance evidence of increased iron content in subcortical brain regions in asymptomatic Alzheimer's disease.

While iron over-accumulation has been reported in late stage Alzheimer's disease (AD), whether this occurs early in the asymptomatic stage of AD remains unknown. We aimed to assess brain iron levels in asymptomatic AD using quantitative MR relaxometry of effective transverse relaxation rate (R2*) and longitudinal relaxation rate (R1), and recruited 118 participants comprised of three groups including healthy young participants, and cognitively normal older individuals without or with positive AD biomarkers based on cerebrospinal fluid (CSF) proteomics analysis. Compared with the healthy young group, increased R2* was found in widespread cortical and subcortical regions in the older groups. Further, significantly higher levels of R2* were found in the cognitively normal older subjects with positive CSF AD biomarker (i.e., asymptomatic AD) compared with those with negative AD biomarker in subcortical regions including the left and right caudate, left and right putamen, and left and right globus pallidus (p < .05 for all regions), suggesting increased iron content in these regions. Subcortical R2* of some regions was found to significantly correlate with CSF AD biomarkers and neuropsychological assessments of visuospatial functions. In conclusion, R2* could be a valuable biomarker for studying early pathophysiological changes in AD.

Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults.

Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (D-ßHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of D-ßHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of D-ßHB compared to active control glucose (N = 26). Effect of age and blood levels of D-ßHB and glucose were used to further explore the effect of D-ßHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of D-ßHB. Importantly, the effect was specific to D-ßHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of D-ßHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.

Multimodal magnetic resonance imaging reveals distinct sensitivity of hippocampal subfields in asymptomatic stage of Alzheimer's disease.

While hippocampal atrophy and its regional susceptibility to Alzheimer's disease (AD) are well reported at late stages of AD, studies of the asymptomatic stage of AD are limited but could elucidate early stage pathophysiology as well as provide predictive biomarkers. In this study, we performed multi-modal magnetic resonance imaging (MRI) to estimate morphometry, functional connectivity, and tissue microstructure of hippocampal subfields in cognitively normal adults including those with asymptomatic AD. High-resolution resting-state functional, diffusion and structural MRI, cerebral spinal fluid (CSF), and neuropsychological evaluations were performed in healthy young adults (HY: n = 40) and healthy older adults with negative (HO-: n = 47) and positive (HO+ : n = 25) CSF biomarkers of AD. Morphometry, functional connectivity, and tissue microstructure were estimated from the structural, functional, and diffusion MRI images, respectively. Our results indicated that normal aging affected morphometry, connectivity, and microstructure in all hippocampal subfields, while the subiculum and CA1-3 demonstrated the greatest sensitivity to asymptomatic AD pathology. Tau, rather than amyloid-ß, was closely associated with imaging-derived synaptic and microstructural measures. Microstructural metrics were significantly associated with neuropsychological assessments. These findings suggest that the subiculum and CA1-3 are the most vulnerable in asymptomatic AD and tau level is driving these early changes.

Frontal Metabolites and Alzheimer's Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment.

BACKGROUND: Women account for two thirds of the prevalence and incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aß1-42) and tau, for which early detection is crucial in prevention of the disease. OBJECTIVE: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aß1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. METHODS: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aß1-42 and tau and scores of general cognition were also obtained. RESULTS: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. CONCLUSION: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aß1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Relationships between frontal metabolites and Alzheimer's disease biomarkers in cognitively normal older adults.

Elevated expression of ß-amyloid (Aß1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of Aß1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/tCr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.

Abnormalities of the late positive potential during emotional processing in individuals with psychopathic traits: a meta-analysis.

BACKGROUND: Individuals with psychopathic traits display deficits in emotional processing. A key event-related potential component involved in emotional processing is the late positive potential (LPP). In healthy controls, LPP amplitude is greater in response to negative stimuli than to positive or neutral stimuli. In the current study, we aimed to compare LPP amplitudes between individuals with psychopathic traits and control subjects when presented with negative, positive or neutral stimuli. We hypothesized that LPP amplitude evoked by emotional stimuli would be reduced in individuals with psychopathic traits compared to healthy controls. METHODS: After a systematic review of the literature, we conducted a meta-analysis to compare LPP amplitude elicited by emotional stimuli in individuals with psychopathic traits and healthy controls. RESULTS: Individuals with psychopathic traits showed significantly reduced LPP amplitude evoked by negative stimuli (mean effect size = -0.47; 95% CI -0.60 to -0.33; p < 0.005) compared to healthy controls. No significant differences between groups were observed for the processing of positive (mean effect size = -0.15; 95% CI -0.42 to 0.12; p = 0.28) and neutral stimuli (mean effect size = -0.12; 95% CI 0.31 to 0.07; p = 0.21). CONCLUSIONS: Measured by LPP amplitude, individuals with psychopathic traits displayed abnormalities in the processing of emotional stimuli with negative valence whereas processing of stimuli with positive and neutral valence was unchanged as compared with healthy controls.

Online Effects of Transcranial Direct Current Stimulation in Real Time on Human Prefrontal and Striatal Metabolites.

BACKGROUND: Studies have reported that transcranial direct current stimulation (tDCS) can modulate human behaviors, symptoms, and neural activity; however, the neural effects during stimulation are unknown. Most studies compared the effects of tDCS before and after stimulation. The objective of our study was to measure the neurobiological effect of a single tDCS dose during stimulation. METHODS: We conducted an online and offline protocol combining tDCS and magnetic resonance spectroscopy (MRS) in 17 healthy participants. We applied anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) and cathodal tDCS over the right DLPFC for 30 minutes, one of the most common montages used with tDCS. We collected MRS measurements in the left DLPFC and left striatum during tDCS and an additional MRS measurement in the left DLPFC immediately after the end of stimulation. RESULTS: During stimulation, active tDCS, as compared with sham tDCS, elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine but did not induce significant differences in prefrontal or striatal gamma-aminobutyric acid level. Immediately after stimulation, active tDCS, as compared with sham tDCS, did not significantly induce differences in glutamate + glutamine, N-acetylaspartate, or gamma-aminobutyric acid levels in the left DLPFC. CONCLUSIONS: These observations indicate that tDCS over the DLPFC has fast excitatory effects, acting on prefrontal and striatal transmissions, and these effects are short lived. One may postulate that repeated sessions of tDCS might induce similar longer lasting effects of elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine levels, which may contribute to its behavioral and clinical effects.

Noninvasive brain stimulation to suppress craving in substance use disorders: Review of human evidence and methodological considerations for future work.

Substance use disorders (SUDs) can be viewed as a pathology of neuroadaptation. The pharmacological overstimulation of neural mechanisms of reward, motivated learning and memory leads to drug-seeking behavior. A critical characteristic of SUDs is the appearance of craving, the motivated desire and urge to use, which is a main focus of current pharmacological and behavioral therapies. Recent proof-of-concept studies have tested the effects of noninvasive brain stimulation on craving. Although its mechanisms of action are not fully understood, this approach shows interesting potential in tuning down craving and possibly consumption of diverse substances. This article reviews available results on the use of repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES) in SUDs, specifically tobacco, alcohol and psychostimulant use disorders. We discuss several important factors that need to be addressed in future works to improve clinical assessment and effects of noninvasive brain stimulation in SUDs. Factors discussed include brain stimulation devices and parameters, study designs, brain states and subjects' characteristics.

Co-registration of magnetic resonance spectroscopy and transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a widely used tool for noninvasive modulation of brain activity, that is thought to interact primarily with excitatory and inhibitory neurotransmitter systems. Neurotransmitters such as glutamate and GABA can be measured by magnetic resonance spectroscopy (MRS). An important prerequisite for studying the relationship between MRS neurotransmitter levels and responses to TMS is that both modalities should examine the same regions of brain tissue. However, co-registration of TMS and MRS has been little studied to date. This study reports on a procedure for the co-registration and co-visualization of MRS and TMS, successfully localizing the hand motor cortex, as subsequently determined by its functional identification using TMS. Sixteen healthy subjects took part in the study; in 14 of 16 subjects, the TMS determined location of motor activity intersected the (2.5cm)(3) voxel selected for MRS, centered on the so called 'hand knob' of the precentral gyrus. It is concluded that MRS voxels placed according to established anatomical landmarks in most cases agree well with functional determination of the motor cortex by TMS. Reasons for discrepancies are discussed.

The use of virtual reality in craving assessment and cue-exposure therapy in substance use disorders.

Craving is recognized as an important diagnosis criterion for substance use disorders (SUDs) and a predictive factor of relapse. Various methods to study craving exist; however, suppressing craving to successfully promote abstinence remains an unmet clinical need in SUDs. One reason is that social and environmental contexts recalling drug and alcohol consumption in the everyday life of patients suffering from SUDs often initiate craving and provoke relapse. Current behavioral therapies for SUDs use the cue-exposure approach to suppress salience of social and environmental contexts that may induce craving. They facilitate learning and cognitive reinforcement of new behavior and entrain craving suppression in the presence of cues related to drug and alcohol consumption. Unfortunately, craving often overweighs behavioral training especially in real social and environmental contexts with peer pressure encouraging the use of substance, such as parties and bars. In this perspective, virtual reality (VR) is gaining interest in the development of cue-reactivity paradigms and practices new skills in treatment. VR enhances ecological validity of traditional craving-induction measurement. In this review, we discuss results from (1) studies using VR and alternative virtual agents in the induction of craving and (2) studies combining cue-exposure therapy with VR in the promotion of abstinence from drugs and alcohol use. They used virtual environments, displaying alcohol and drugs to SUD patients. Moreover, some environments included avatars. Hence, some studies have focused on the social interactions that are associated with drug-seeking behaviors and peer pressure. Findings indicate that VR can successfully increase craving. Studies combining cue-exposure therapy with virtual environment, however, reported mitigated success so far.

Overlap of food addiction and substance use disorders definitions: analysis of animal and human studies.

Food has both homeostatic and hedonic components, which makes it a potent natural reward. Food related reward could therefore promote an escalation of intake and trigger symptoms associated to withdrawal, suggesting a behavioral parallel with substance abuse. Animal and human theoretical models of food reward and addiction have emerged, raising further interrogations on the validity of a bond between Substance Use Disorders, as clinically categorized in the DSM 5, and food reward. These models propose that highly palatable food items, rich in sugar and/or fat, are overly stimulating to the brain's reward pathways. Moreover, studies have also investigated the possibility of causal link between food reward and the contemporary obesity epidemic, with obesity being potentiated and maintained due to this overwhelming food reward. Although natural rewards are a hot topic in the definition and categorization of Substance Use Disorders, proofs of concept and definite evidence are still inconclusive. This review focuses on available results from experimental studies in animal and human models exploring the concept of food addiction, in an effort to determine if it depicts a specific phenotype and if there is truly a neurobiological similarity between food addiction and Substance Use Disorders. It describes results from sugar, fat and sweet-fat bingeing in rodent models, and behavioral and neurobiological assessments in different human populations. Although pieces of behavioral and neurobiological evidence supporting a food addiction phenotype in animals and humans are interesting, it seems premature to conclude on its validity.

Modulation of smoking and decision-making behaviors with transcranial direct current stimulation in tobacco smokers: a preliminary study.

BACKGROUND: Most tobacco smokers who wish to quit fail to reach their goal. One important, insufficiently emphasized aspect of addiction relates to the decision-making system, often characterized by dysfunctional cognitive control and a powerful drive for reward. Recent proof-of-principle studies indicate that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) can transiently modulate processes involved in decision-making, and reduce substance intake and craving for various addictions. We previously proposed that this beneficial effect of stimulation for reducing addictive behaviors is in part mediated by more reflective decision-making. The goal of this study was to test whether nicotine intake and decision-making behaviors are modulated by tDCS over the DLPFC in tobacco smokers who wished to quit smoking. METHODS: Subjects received two five-day tDCS regimens (active or sham). Stimulation was delivered over the right DLPFC at a 2 mA during 30 min. Nicotine cravings, cigarette consumption and decision-making were assessed before and after each session. RESULTS: Main findings include a significant decrease in the number of cigarettes smoked when participants received active as compared to sham stimulation. This effect lasted up to four days after the end of the stimulation regimen. In regards to decision-making, smokers rejected more often offers of cigarettes, but not offers of money, after they received active as compared to sham stimulation at the Ultimatum Game. No significant change was observed at the Risk Task with cigarettes or money as rewards. CONCLUSION: Overall, these findings suggest that tDCS over the DLPFC may be beneficial for smoking reduction and induce reward sensitive effects.