Sleep Delta power, age, and sex effects in treatment-resistant depression.

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5-4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5-2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2-4 Hz), and Total Delta (0.5-4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD.

Selecting an optimal real-time fMRI neurofeedback method for alcohol craving control training.

Real-time fMRI neurofeedback (rt-fMRI-NF) is a technique in which information about an individual's neural state is given back to them, typically to enable and reinforce neuromodulation. Its clinical potential has been demonstrated in several applications, but lack of evidence on optimal parameters limits clinical utility of the technique. This study aimed to identify optimal parameters for rt-fMRI-NF-aided craving regulation training in alcohol use disorder (AUD). Adults with AUD (n = 30) participated in a single-session study of four runs of rt-fMRI-NF where they downregulated "craving-related" brain activity. They received one of three types of neurofeedback: multi-region of interest (ROI), support vector machine with continuous feedback (cSVM), and support vector machine with intermittent feedback (iSVM). Performance was assessed on the success rate, change in neural downregulation, and change in self-reported craving for alcohol. Participants had more successful trials in run 4 versus 1, as well as improved downregulation of the insula, anterior cingulate, and dorsolateral prefrontal cortex (dlPFC). Greater downregulation of the latter two regions predicted greater reduction in craving. iSVM performed significantly worse than the other two methods. Downregulation of the striatum and dlPFC, enabled by ROI but not cSVM neurofeedback, was correlated with a greater reduction in craving. rt-fMRI-NF training for downregulation of alcohol craving in individuals with AUD shows potential for clinical use, though this pilot study should be followed with a larger randomized-control trial before clinical meaningfulness can be established. Preliminary results suggest an advantage of multi-ROI over SVM and intermittent feedback approaches.

Severity of alcohol use disorder influences sex differences in sleep, mood, and brain functional connectivity impairments.

Growing evidence suggests greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. However, the underlying neurobiological mechanisms are still poorly understood. Here, we examined sex difference in resting state functional connectivity in alcohol use disorder using a whole-brain data driven approach and tested for relationships with mood and self-reported sleep. To examine whether sex effects vary by severity of alcohol use disorder, we studied two cohorts: non-treatment seeking n = 141 participants with alcohol use disorder (low severity; 58 females) from the Human Connectome project and recently detoxified n = 102 treatment seeking participants with alcohol use disorder (high severity; 34 females) at the National Institute on Alcohol Abuse and Alcoholism. For both cohorts, participants with alcohol use disorder had greater sleep and mood problems than healthy control, whereas sex by alcohol use effect varied by severity. Non-treatment seeking females with alcohol use disorder showed significant greater impairments in sleep but not mood compared to non-treatment seeking males with alcohol use disorder, whereas treatment-seeking females with alcohol use disorder reported greater negative mood but not sleep than treatment-seeking males with alcohol use disorder. Greater sleep problems in non-treatment seeking females with alcohol use disorder were associated with lower cerebello-parahippocampal functional connectivity, while greater mood problems in treatment-seeking females with alcohol use disorder were associated with lower fronto-occipital functional connectivity during rest. The current study suggests that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder. The effect of severity on sex differences might reflect neuroadaptive processes with progression of alcohol use disorder and needs to be tested with longitudinal data in the future.

Compounding Vulnerability in the Neurocircuitry of Addiction: Longitudinal Functional Connectivity Changes in Alcohol Use Disorder.

AIMS: The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. METHODS: In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012 to 2020. RESULTS: Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Post hoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. CONCLUSIONS: These findings suggest an increased concordance of networks underlying emotionality and compulsions toward drinking while also a reduction in control network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies.

Charity preferences and perceived impact moderate charitable giving and associated neural response.

Charitable giving depends on individuals' abilities to make altruistic decisions. Previous studies suggest that altruism involves recruitment of neural resources in regions including social processing, reward/reinforcement learning, emotional response, and cognition. Despite evolutionary and social benefits to altruism, we know that humans do not always engage in altruistic behavior, like charitable giving. Understanding the underlying processes leading to decisions to donate is vital to improve prosocial community engagement. The present study examined how characteristics of the charitable giving opportunity influence an individual's decision to give and the neural engagement underlying these features. Twenty-nine participants subjectively rated ten charities on their value, effectiveness, and the subject's personal chance of donating. Participants then completed an fMRI task requiring them to decide to donate to certain charities given the probability of the donation helping, their personal preference for the charity, and whether the donation came at cost to themselves. There was a significant reduction in donating when the probability of helping was low versus high, and subjects were significantly less likely to donate to their lowest-rated charities. Further, probability of a donation being helpful and how much the subject favored a charity moderated PCC and left IFG engagement. Interestingly, reward neurocircuitry did not demonstrate similar sensitivity to these variations. These results may suggest individuals engage motivated reasoning to justify failure to donate, while donations are driven by emotion mentalizing that focuses on the welfare of others. This may provide valuable insight into how to engage individuals in altruistic giving.

Random forest based classification of alcohol dependence patients and healthy controls using resting state MRI.

Currently, classification of alcohol use disorder (AUD) is made on clinical grounds; however, robust evidence shows that chronic alcohol use leads to neurochemical and neurocircuitry adaptations. Identifications of the neuronal networks that are affected by alcohol would provide a more systematic way of diagnosis and provide novel insights into the pathophysiology of AUD. In this study, we identified network-level brain features of AUD, and further quantified resting-state within-network, and between-network connectivity features in a multivariate fashion that are classifying AUD, thus providing additional information about how each network contributes to alcoholism. Resting-state fMRI were collected from 92 individuals (46 controls and 46 AUDs). Probabilistic Independent Component Analysis (PICA) was used to extract brain functional networks and their corresponding time-course for AUD and controls. Both within-network connectivity for each network and between-network connectivity for each pair of networks were used as features. Random forest was applied for pattern classification. The results showed that within-networks features were able to identify AUD and control with 87.0% accuracy and 90.5% precision, respectively. Networks that were most informative included Executive Control Networks (ECN), and Reward Network (RN). The between-network features achieved 67.4% accuracy and 70.0% precision. The between-network connectivity between RN-Default Mode Network (DMN) and RN-ECN contribute the most to the prediction. In conclusion, within-network functional connectivity offered maximal information for AUD classification, when compared with between-network connectivity. Further, our results suggest that connectivity within the ECN and RN are informative in classifying AUD. Our findings suggest that machine-learning algorithms provide an alternative technique to quantify large-scale network differences and offer new insights into the identification of potential biomarkers for the clinical diagnosis of AUD.

Resting-state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence.

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

Smaller right amygdala in Caucasian alcohol-dependent male patients with a history of intimate partner violence: a volumetric imaging study.

Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men (n = 54), ages 24-55, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs (n = 27), non-violent ADs (n = 14) and HCs (n = 13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV.