Clinical breast exam contribution to breast cancer diagnosis in BRCA mutation carriers vs. average to intermediate risk women.

PURPOSE: The contribution of clinical breast exam (CBE) to breast cancer diagnosis in average risk women undergoing regular screening mammography is minimal. To evaluate the role of CBE in high-risk women, we compared BC diagnosis by CBE in BRCA mutation carriers undergoing regular BC surveillance to average to intermediate risk women undergoing regular breast cancer screening. METHODS: A retrospective chart review of all consecutive screening visits of BRCA mutation carriers (January 2012-October 2022) and average to intermediate risk women (November 2016-December 2022) was completed. Women with histologically confirmed BC diagnosis were included. Additional CBE yield for BC diagnosis, defined as the percentage of all BC cases detected by CBE alone, was assessed in both groups. RESULTS: Overall, 12,997 CBEs were performed in 1,328 BRCA mutation carriers in whom 134 BCs were diagnosed. In 7,949 average to intermediate risk women who underwent 15,518 CBEs, 87 BCs were diagnosed. CBE contributed to BC diagnosis in 3 (2%) BRCA mutation carriers and 3 (4%) non-carriers. In both groups, over 4,000 CBEs were needed in order to diagnose one cancer. In all 3 BRCA mutation carriers BC was palpated during the surveillance round that did not include MRI. In the average to intermediate risk group, 2 of 3 cancers diagnosed following CBE findings were in a different location from the palpable finding. CONCLUSIONS: The contribution of CBE to BC diagnosis is marginal for all women including BRCA mutation carriers. In BRCA mutation carriers, CBE appears redundant during the MRI surveillance round.

Breast cancer diagnosed after age 70 years in Israeli BRCA1/BRCA2 pathogenic sequence variant carriers: a single institution experience.

PURPOSE: A semi-annual surveillance scheme from age 25 to 30 years is offered to BRCA1/BRCA2 pathogenic sequence variants (PSVs) carriers for early detection of breast cancer (BC). There is a paucity of data on the yield of adhering to this scheme beyond 70 years of age. METHODS: Female BRCA1/BRCA2 PSV carriers followed at the Meirav high-risk clinic, Sheba Medical center, Israel were eligible. Type and frequencies if use of Imaging modalities, breast biopsies and histological outcomes for participants after age 70 years were retrieved and analyzed. RESULTS: Overall, the study encompassed 88 consenting participants (46 BRCA1 carriers) mean age ± SD 73.7 ± 3.3 years (range 70-90 years), followed for an average of 3.8 years (range 1-11 years). Ten carriers (11.3%) were diagnosed with BC after age 70 years (mean age at diagnosis 72 ± 2 years) and an additional case was diagnosed with breast lymphoma. The imaging modality that has led to most diagnoses was MRI (8/11 cases). Eight of these ten cases were previously diagnosed with BC prior to age 70 and in six, BC past 70 years was in the contralateral breast. The lesions size averaged 1.29 ± 0.75 cm, with IDC and DCIS diagnosed in five cases each, and none had lymph node involvement. CONCLUSION: In ~10% of BRCA1/BRCA2 PSV carriers BC is diagnosed by breast imaging after age 70 years. If these results are validated in a larger study, the guidelines for the maximum age for BC surveillance in high risk women should be revisited and set at 75 years.

Sex differences in methylphenidate-induced dopamine increases in ventral striatum.

Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).

Variations in Practice and Geographic Disparities Between Dedicated Multidisciplinary Clinics for BRCA1/BRCA2 Mutation Carriers in Israel.

BACKGROUND: Population screening for the BRCA mutations in Ashkenazi Jewish women was recently implemented in Israel and is expected to lead to a 10-fold increase in the diagnosis of asymptomatic carriers. Performing the screening follow-up within multidisciplinary dedicated clinics for carriers is recommended for early detection and risk reduction. OBJECTIVES: : To determine the availability, capacity, and practices of dedicated screening clinic for BRCA carriers in Israel. METHODS: A telephone-based survey of all public hospitals in Israel was conducted October 2020 to August 2021 to determine whether they had a dedicated clinic. Dedicated clinics were defined as multidisciplinary screening clinics offering at least breast and gynecological screening and risk reducing services on site. The clinic director or nurse navigator answered a questionnaire about screening practices followed by a semi-structured interview. RESULTS: Of the ten dedicated BRCA clinics found in Israel, nine participated. Approximately 4500 BRCA carriers are currently being followed. No specialized clinics are available in the southern district or in the northernmost half of the northern district of Israel, leading to a disparity between periphery and center. Screening recommendations, although asserted as adhering to international guidelines, vary among clinics including age at initiating of clinical exam, use of adjunct imaging modalities, and follow-up during lactation and after risk reducing surgery. CONCLUSIONS: There is a suboptimal distribution of dedicated clinics for BRCA carriers in Israel. Nationally centralized attempt to create guidelines that will unify screening practices is warranted, especially considering the expected increase in demand.

Accelerated Aging of the Amygdala in Alcohol Use Disorders: Relevance to the Dark Side of Addiction.

Here we assessed changes in subcortical volumes in alcohol use disorder (AUD). A simple morphometry-based classifier (MC) was developed to identify subcortical volumes that distinguished 32 healthy controls (HCs) from 33 AUD patients, who were scanned twice, during early and later withdrawal, to assess the effect of abstinence on MC-features (Discovery cohort). We validated the novel classifier in an independent Validation cohort (19 AUD patients and 20 HCs). MC-accuracy reached 80% (Discovery) and 72% (Validation). MC features included the hippocampus, amygdala, cerebellum, putamen, corpus callosum, and brain stem, which were smaller and showed stronger age-related decreases in AUD than HCs, and the ventricles and cerebrospinal fluid, which were larger in AUD and older participants. The volume of the amygdala showed a positive association with anxiety and negative urgency in AUD. Repeated imaging during the third week of detoxification revealed slightly larger subcortical volumes in AUD patients, consistent with partial recovery during abstinence. The steeper age-associated volumetric reductions in stress- and reward-related subcortical regions in AUD are consistent with accelerated aging, whereas the amygdalar associations with negative urgency and anxiety in AUD patients support its involvement in the "dark side of addiction".

Ductal Carcinoma In Situ (DCIS) Diagnosed by MRI-Guided Biopsy among BRCA1/BRCA2 Mutation Carriers.

Background: While BRCA1/BRCA2 pathogenic sequence variants (PSVs) clearly confer an increased risk for invasive breast cancer, the extent to which these mutant alleles increase DCIS risk is less clear. Objective: To assess the rate of detection over a 5-year period, and MRI imaging features of pure noncalcified DCIS in a cohort of Israeli BRCA1/BRCA2 PSV carriers attending a high-risk clinic from 2015 to 2020. Materials and Methods: All female BRCA1/BRCA2 PSV-carriers followed at the Meirav High-risk clinic from 2015 to 2020 were eligible if they underwent semiannual breast imaging (MRI/mammography) and MRI-guided biopsy-proven pure DCIS. Clinical data, pathology information, and imaging characteristics were retrieved from the computerized archiving system. Results: 18/121 (15.2%) participating BRCA1 PSV carriers and 8/81 (10.1%) BRCA2 PSV-carriers who underwent MRI-guided biopsy were diagnosed with DCIS. The median age of BRCA1 carriers and BRCA2 carriers was 49.8 years and 60.6 years, respectively (p = 0.55). Negative estrogen-receptor tumors were diagnosed in 13/18 (72%) BRCA1 and 2/8 (25%) BRCA2 PSV carriers (p < 0.05). Thirteen (13/18-72%) BRCA1 carriers had intermediate to high-grade or high-grade DCIS compared with 4/8 (50%) of BRCA2 carriers (p = 0.03). Over the 5-year study period, 29/1100 (2.6%) BRCA1/BRCA2 PSV carriers were diagnosed with DCIS seen on MRI only. Conclusion: MRI-detected noncalcified DCIS is more frequent in BRCA1 PSV carriers compared with BRCA2 carriers, unlike the BRCA2 predominance in mammography-detected calcified DCIS. BRCA1-related DCIS is diagnosed earlier, more likely to be estrogen receptor-negative and of higher grade compared with BRCA2-related DCIS. Future prospective studies should validate these results and assess the actual impact they might have on clinical management of BRCA PSV carriers.

Time trends in uptake rates of risk-reducing mastectomy in Israeli asymptomatic BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The rate of risk-reducing bilateral mastectomy (RRBM) among cancer-free Israeli female BRCA1/BRCA2 mutation carriers was reportedly 13% in 2010. Current RRBM rates in Israel and factors seemingly associated with opting for RRBM were reevaluated. METHODS: Israeli female cancer-free BRCA1/BRCA2 mutation carriers, who were followed at the high-risk clinic at Sheba Medical Center between January 2011 and April 2020 were eligible. Univariate Cox regression and log-rank test were used to study the crude association between potential predictors and performance of RRBM. RESULTS: Overall, 427 cancer-free BRCA1 (n = 218) or BRCA2 (n = 209) mutation carriers were included. Median age at genotyping was 33.6 years (interquartile range 26.8-41.8 years), median follow-up 4.4 years (range 0.1-7.6 years). Overall, 41/427 (9.6%) participants underwent RRBM, all of them within 5 years of genotyping. Being married (HR-2.57, p = 0.017) and having a first degree relative with breast cancer (BC) (HR-2.19, p = 0.017) were positively associated with RRBM, whereas any previous benign breast biopsy was negatively associated (HR-0.48, p = 0.029) with performing RRBM. CONCLUSIONS: RRBM is still infrequently elected by Israeli BRCA1/BRCA2 mutation carriers, with married women with one relative with BC who have not undergone previous breast biopsy more likely to opt for RRBM.

Brain Network Segregation and Glucose Energy Utilization: Relevance for Age-Related Differences in Cognitive Function.

The human brain is organized into segregated networks with strong within-network connections and relatively weaker between-network connections. This "small-world" organization may be essential for maintaining an energetically efficient system, crucial to the brain which consumes 20% of the body's energy. Brain network segregation and glucose energy utilization both change throughout the lifespan. However, it remains unclear whether these processes interact to contribute to differences in cognitive performance with age. To address this, we examined fluorodeoxyglucose-positron emission tomography and resting-state functional magnetic resonance imaging from 88 participants aged 18-73 years old. Consistent with prior work, brain network segregation showed a negative association with age across both sensorimotor and association networks. However, relative glucose metabolism demonstrated an interaction with age, showing a negative slope in association networks but a positive slope in sensorimotor networks. Overall, brain networks with lower segregation showed significantly steeper age-related differences in glucose metabolism, compared with highly segregated networks. Sensorimotor network segregation mediated the association between age and poorer spatial cognition performance, and sensorimotor network metabolism mediated the association between age and slower response time. These data provide evidence that sensorimotor segregation and glucose metabolism underlie some age-related changes in cognition. Interventions that stimulate somatosensory networks could be important for treatment of age-related cognitive decline.

Post-mastectomy surveillance of BRCA1/BRCA2 mutation carriers: Outcomes from a specialized clinic for high-risk breast cancer patients.

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4-28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.

Risk of falling among hospitalized patients with high modified Morse scores could be further Stratified.

BACKGROUND: Falls during hospitalization harbor both clinical and financial outcomes. The modified Morse fall scale [MMFS] is widely used for an in-hospital risk-of-fall assessment. Nevertheless, the majority of patients at risk of falling, i.e. with high MMFS, do not fall. The aim of this study was to ascertain our study hypothesis that certain patients' characteristics (e.g. serum electrolytes, usage of a walking device etc.) could further stratify the risk of falls among hospitalized patients with MMFS. METHODS: This was a retrospective cohort analysis of adult patients hospitalized in Internal Medicine departments. RESULTS: The final cohort included 428 patients aged 76.8±14.0 years. All patients had high (9 or more) MMFS upon admission, and their mean MMFS was 16.2±6.1. A group of 139 (32.5%) patients who fell during their hospitalization was compared with a control group of 289 (67.5%) patients who did not fall. The fallers had higher MMFS, a higher prevalence of mild dependence, and a greater use of a cane or no walking device. Regression analysis showed the following patients' characteristics to be independently associated with an increased risk of falling: mild dependence (OR=3.99, 95% CI 1.97-8.08; p<0.0001), treatment by anti-epileptics (OR=3.9, 95% CI 1.36-11.18; p=0.011), treatment by hypoglycemic agents (OR=2.64, 95% CI 1.08-6.45; p= 0.033), and hypothyroidism (OR=3.66, 05%CI 1.62-8.30; p=0.002). In contrast to their role in the MMFS, the use of a walker or a wheelchair was found to decrease the risk of falling (OR=0.3, 95% CI 0.13-0.69; p=0.005 and OR=0.25, 95% CI 0.11-0.59; p= 0.002). CONCLUSIONS: Further risk stratification of hospitalized patients, already known to have a high MMFS, which would take into account the characteristics pointed out in this study, should be attained.

An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers.

Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed.

Risk-behaviour screening for identifying adolescents with mental health problems in Europe.

Indicated prevention of mental illness is an important public health concern among youth. The aim of this study was to establish a European school-based professional screening among adolescents, which included variables on both a broad range of risk-behaviours and psychopathology; and to investigate the indicative value of adolescent risk-behaviour and self-reported psychopathology on help-seeking and psychological problems that required subsequent mental healthcare. A two-stage professional screening approach was developed and performed within the multi-centre study "Saving and Empowering Young Lives in Europe" (SEYLE). The first stage of screening comprised a self-report questionnaire on a representative sample of 3,070 adolescents from 11 European countries. In the second stage, students deemed at-risk for mental health problems were evaluated using a semi-structured clinical interview performed by healthcare professionals. 61 % of participants (n = 1,865) were identified as being at-risk in stage one. In stage two, 384 participants (12.5 % of the original sample) were found to require subsequent mental healthcare during semi-structured, clinical assessment. Among those, 18.5 % of pupils were identified due to screening for psychopathology alone; 29.4 % due to screening for risk-behaviours alone; and 52.1 % by a combination of both. Young age and peer victimization increased help-seeking, while very low body mass index, depression, suicidal behaviour and substance abuse were the best predictors of referral to mental healthcare. Screening of risk-behaviours significantly increased the number of detected students requiring subsequent mental healthcare. Screening of risk-behaviours added significant value in identifying the significant amount of European pupils with mental health problems. Therefore, attention to adolescent risk-behaviours in addition to psychopathology is critical in facilitating prevention and early intervention. Identifying factors that increase compliance to clinical interviews are crucial in improving screening procedures.

Pregnancy Associated Breast Cancer Among Israeli BRCA1/BRCA2 Carriers in a High-Risk Clinic.

RATIONALE AND OBJECTIVES: Female carriers of pathogenic sequence variants (PSVs) in the BRCA1 /BRCA2 (Breast Cancer gene - BRCA) genes are at a substantially high-risk for developing breast cancer (BC), hence are offered active surveillance scheme based on semiannual breast exam and imaging from age 25 years to facilitate BC early detection (mammography/breast ultrasound depending on the age, and MRI). However, there are not specific guidelines for screening in case of pregnancy or lactation. In the current study, we summarize the experience at the largest high-risk clinic in Israel. MATERIALS AND METHODS: Data of consecutive BRCA-PSV carriers undergoing surveillance as well as diagnostic ultrasound at the Meirav high-risk clinic from January 2014 to 2021 who were pregnant and/or breastfeeding at time of follow-up were identified. Relevant clinical data including results of breast exam, breast ultrasonography, biopsies and histological results were retrieved. Percentage of biopsies with malignancy, cancer detection rate and positive predictive values were calculated. Data is presented in descriptive statistics. RESULTS: A total of 263 BRCA-carriers were included. Of these, 593 breast-ultrasonograms were performed in 263 BRCA-carriers for 292 pregnancies and 409 breast-ultrasonograms for 175 breastfeeding carriers. Of 36 breast biopsies in 292 pregnancies, 4 (PPV = 11%) had BC diagnosed (high grade invasive). Of 175 breastfeeding women, 25 biopsies were performed and 2 (PPV = 8%) were high grade invasive BC. Five of 6 BC were diagnosed in BRCA1 carriers, and 4/6 were screen detected. The rate of pregnancy-associated breast cancer was 6/292 (2.05%). CONCLUSION: The overall detection rate of pregnancy-associated BC in BRCA-carriers is relatively low (2.05%), but still much higher than that in the general population. Two thirds of the BC were detected by screening. Therefore, despite the changes of the glandular breast tissue at time of pregnancy and breastfeeding, screening plays an important role in early detection. Ultrasound should be considered as a screening tool during this period of life of high-risk patients.

Neural circuit selective for fast but not slow dopamine increases in drug reward.

The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported 'high' in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual 'high' ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled 'high' ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward.

Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans.

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.

Suicide prevention for youth--a mental health awareness program: lessons learned from the Saving and Empowering Young Lives in Europe (SEYLE) intervention study.

BACKGROUND: The Awareness program was designed as a part of the EU-funded Saving and Empowering Young Lives in Europe (SEYLE) intervention study to promote mental health of adolescents in 11 European countries by helping them to develop problem-solving skills and encouraging them to self-recognize the need for help as well as how to help peers in need. METHODS: For this descriptive study all coordinators of the SEYLE Awareness program answered an open-ended evaluation questionnaire at the end of the project implementation. Their answers were synthesized and analyzed and are presented here. RESULTS: The results show that the program cultivated peer understanding and support. Adolescents not only learned about mental health by participating in the Awareness program, but the majority of them also greatly enjoyed the experience. CONCLUSIONS: Recommendations for enhancing the successes of mental health awareness programs are presented. Help and cooperation from schools, teachers, local politicians and other stakeholders will lead to more efficacious future programs.

Effect of detoxification on N3 sleep correlates with brain functional but not structural changes in alcohol use disorder.

BACKGROUND: Sleep disturbances are very common in alcohol use disorder (AUD) and contribute to relapse. Detoxification appears to have limited effects on sleep problems. However, inter-individual differences and related brain mechanisms have not been closely examined. METHODS: We examined N3 sleep and the associated brain functional and structural changes in 30 AUD patients (9 Females, mean age: 42 years) undergoing a 3-week inpatient detoxification. Patients' N3 sleep, resting state functional connectivity (RSFC), grey matter volume (GMV) and negative mood were measured on week 1 and week 3. RESULTS: AUD patients did not show significant N3 sleep recovery after 3-weeks of detoxification. However, we observed large variability among AUD patients. Inter-individual variations in N3 increases were associated with increases in midline default mode network (DMN) RSFC but not with GMV using a whole-brain approach. Exploratory analyses revealed significant sex by detoxification effects on N3 sleep such that AUD females showed greater N3 increases than AUD males. Further, N3 increases fully mediated the effect of mood improvement on DMN RSFC increases. CONCLUSIONS: We show a significant relationship between N3 and DMN functional changes in AUD over time/abstinence. The current findings may have clinical implications for monitoring brain recovery in AUD using daily sleep measures, which might help guide individualized treatments. Future investigations on sex differences with a larger sample and with longitudinal data for a longer period of abstinence are needed.

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward.

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

Sleep disturbances are associated with cortical and subcortical atrophy in alcohol use disorder.

Sleep disturbances are prominent in patients with alcohol use disorder (AUD) and predict relapse. So far, the mechanisms underlying sleep disruptions in AUD are poorly understood. Because sleep-related regions vastly overlap with regions, where patients with AUD showed pronounced grey matter (GM) reduction; we hypothesized that GM structure could contribute to sleep disturbances associated with chronic alcohol use. We combined sleep EEG recording and high-resolution structural brain imaging to examine the GM-sleep associations in 36 AUD vs. 26 healthy controls (HC). The patterns of GM-sleep associations differed for N3 vs. REM sleep and for AUD vs. HC. For cortical thickness (CT), CT-sleep associations were significant in AUD but not in HC and were lateralized such that lower CT in right hemisphere was associated with shorter N3, whereas in left hemisphere was associated with shorter REM sleep. For the GM density (GMD), we observed a more extensive positive GMD-N3 association in AUD (right orbitofrontal cortex, cerebellum, dorsal cingulate and occipital cortex) than in HC (right orbitofrontal cortex), and the GMD-REM association was positive in AUD (midline, motor and paralimbic regions) whereas negative in HC (the left supramarginal gyrus). GM structure mediated the effect of chronic alcohol use on the duration of N3 and the age by alcohol effect on REM sleep. Our findings provide evidence that sleep disturbances in AUD were associated with GM reductions. Targeting sleep-related regions might improve sleep in AUD and enhance sleep-induced benefits in cognition and emotional regulation for recovery.

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents.

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.