Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need.

Drugs of abuse are thought to promote addiction in part by "hijacking" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and single-nucleus RNA sequencing, we identified Rheb as a molecular substrate that regulates cell type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic, molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.

Staged breast reconstruction utilizing primary nipple repositioning surgery prior to nipple-sparing mastectomy.

Staged nipple-sparing mastectomy (NSM) following mastopexy or breast reduction has become increasingly utilized in patients with large or ptotic breasts. The safety and efficacy of this approach has been demonstrated in recent years. However, the optimal timing between stages has not been established. The authors provide their experience with this staged approach with emphasis on timing between stages. An institutional review board approved this retrospective study. Data of all patients at a single institution who underwent staged NSM following mastopexy or reduction mammaplasty for therapeutic or prophylactic oncologic surgical management from 2016 to 2020 were reviewed. Timing between stages as well as surgical, oncologic, aesthetic, and patient-reported outcomes were evaluated. Nineteen patients (38 breasts) underwent staged NSM following planned mastopexy/breast reduction. The mean time interval between stages was 25 weeks. No patients developed nipple areolar complex necrosis. Infection and hematoma were seen in one breast (2.6%) and seroma in two (5.3%) after NSM. Delayed wound healing was seen in eight breasts (21.1%) after first stage mastopexy/reduction and in 12 breasts (31.6%) after NSM. Skin flap necrosis was noted in two breasts (5.3%) after NSM. No patients developed oncological recurrence. Mean patient-reported post-operative satisfaction and well-being scores were 63 and 67 out of 100, respectively. The authors describe their experience with staged NSM following nipple repositioning procedures. Their results suggest that this procedure can be performed safely with cosmetically favorable results if surgeons wait an average of 25 weeks between first and second stage procedures.

Seeking satiety: From signals to solutions.

Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to "reduce food and avoid drinking to fullness" and begin "running during the night." Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.

Magnetogenetic cell activation using endogenous ferritin.

The ability to precisely control the activity of defined cell populations enables studies of their physiological roles and may provide therapeutic applications. While prior studies have shown that magnetic activation of ferritin-tagged ion channels allows cell-specific modulation of cellular activity, the large size of the constructs made the use of adeno-associated virus, AAV, the vector of choice for gene therapy, impractical. In addition, simple means for generating magnetic fields of sufficient strength have been lacking. Toward these ends, we first generated a novel anti-ferritin nanobody that when fused to transient receptor potential cation channel subfamily V member 1, TRPV1, enables direct binding of the channel to endogenous ferritin in mouse and human cells. This smaller construct can be delivered in a single AAV and we validated that it robustly enables magnetically induced cell activation in vitro . In parallel, we developed a simple benchtop electromagnet capable of gating the nanobody-tagged channel in vivo . Finally, we showed that delivering these new constructs by AAV to pancreatic beta cells in combination with the benchtop magnetic field delivery stimulates glucose-stimulated insulin release to improve glucose tolerance in mice in vivo . Together, the novel anti-ferritin nanobody, nanobody-TRPV1 construct and new hardware advance the utility of magnetogenetics in animals and potentially humans.

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need.

Addiction prioritizes drug use over innate needs by "hijacking" brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining "FOS-Seq", CRISPR-perturbations, and snRNA-seq, we identify Rheb as a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy.

Regulating the activity of discrete neuronal populations in living mammals after delivery of modified ion channels can be used to map functional circuits and potentially treat neurological diseases. Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity in motor circuits when exposed to magnetic fields. AAV-mediated delivery of a cre-dependent nanobody-TRPV1 calcium channel into the striatum of adenosine 2a (A2a) receptor-cre driver mice led to restricted expression within D2 neurons, resulting in motor freezing when placed in a 3T MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed focal activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus (STN) projection neurons in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and a corresponding improvement in motor rotational behavior during magnetic field exposure. These data demonstrate that AAV delivery of magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in vivo using clinically available devices for both preclinical analysis of circuit effects on behavior and potential human clinical translation.

FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system.

Animals that consume fermenting fruit and nectar are at risk of exposure to ethanol and the detrimental effects of inebriation. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in murine and human liver, stimulates arousal from intoxication without changing ethanol catabolism. Mice lacking FGF21 take longer than wild-type littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduces the time needed for mice to recover from ethanol-induced unconsciousness and ataxia. FGF21 did not counteract sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediates its anti-intoxicant effects by directly activating noradrenergic neurons in the locus coeruleus region, which regulates arousal and alertness. These results suggest that this FGF21 liver-brain pathway evolved to protect against ethanol-induced intoxication and that it might be targeted pharmaceutically for treating acute alcohol poisoning.

Change in medial frontal cerebral metabolite concentrations following bariatric surgery.

Obesity is associated with adverse effects on brain health, including an increased risk of neurodegenerative diseases. Changes in cerebral metabolism may underlie or precede structural and functional brain changes. While bariatric surgery is known to be effective in inducing weight loss and improving obesity-related medical comorbidities, few studies have examined whether it may be able to improve brain metabolism. In the present study, we examined changes in cerebral metabolite concentrations in participants with obesity who underwent bariatric surgery. Thirty-five patients with obesity (body mass index ≥ 35 kg/m2 ) were recruited from a bariatric surgery candidate nutrition class. They completed single voxel proton magnetic resonance spectroscopy at baseline (presurgery) and within 1 year postsurgery. Spectra were obtained from a large medial frontal brain region using a PRESS sequence on a 3-T Siemens Verio scanner. The acquisition parameters were TR = 3000 ms and TE = 37 ms. Tissue-corrected metabolite concentrations were determined using Osprey. Paired t-tests were used to examine within-subject change in metabolite concentrations, and correlations were used to relate these changes to other health-related outcomes, including weight loss and glycated hemoglobin (HbA1c ), a measure of blood sugar levels. Bariatric surgery was associated with a reduction in cerebral choline-containing compounds (Cho; t [34] = - 3.79, p < 0.001, d = -0.64) and myo-inositol (mI; t [34] = - 2.81, p < 0.01, d = -0.47) concentrations. There were no significant changes in N-acetyl-aspartate, creatine, or glutamate and glutamine concentrations. Reductions in Cho were associated with greater weight loss (r = 0.40, p < 0.05), and reductions in mI were associated with greater reductions in HbA1c (r = 0.44, p < 0.05). In conclusion, participants who underwent bariatric surgery exhibited reductions in cerebral Cho and mI concentrations, which were associated with improvements in weight loss and glycemic control. Given that elevated levels of Cho and mI have been implicated in neuroinflammation, reduction in these metabolites after bariatric surgery may reflect amelioration of obesity-related neuroinflammatory processes. As such, our results provide evidence that bariatric surgery may improve brain health and metabolism in individuals with obesity.

Resting-state network functional connectivity before and after bariatric surgery.

BACKGROUND: Bariatric surgery is an increasingly popular treatment for patients with severe obesity and related health issues (e.g., diabetes, cardiovascular disease). Studies have identified alterations in functional connectivity both in obesity and following surgical treatment for severe obesity. OBJECTIVE: This study aimed to assess brain function via resting-state within-network connectivity in bariatric surgery patients with severe obesity. SETTING: University hospital. METHODS: Thirty-four bariatric surgery patients completed functional neuroimaging at baseline and postoperatively (goal, 12 weeks; actual, 16 weeks, on average). They also self-reported health information. Baseline resting-state functional connectivity (RSFC) was predicted by baseline age, body mass index (BMI), continuous positive airway pressure use, and reported history of rheumatoid arthritis and type 2 diabetes. Change in RSFC was assessed using the same predictors. This model was run with and without controlling for baseline RSFC. RESULTS: Higher baseline BMI predicted lower baseline RSFC in 3 networks. Lower baseline RSFC also was related to rheumatoid arthritis and type 2 diabetes. Difference between baseline and follow-up RSFC was strongly negatively associated with baseline RSFC. Controlling for baseline RSFC, type 2 diabetes negatively predicted RSFC difference. CONCLUSIONS: RSFC may reflect brain dysfunction in patients with obesity and related diseases. That less connectivity at baseline predicted greater positive change suggests that RSFC may be a biomarker of neurocognitive improvement following bariatric surgery. Diseases more prevalent in patients with obesity (e.g., rheumatoid arthritis and type 2 diabetes) along with elevated BMI negatively affect RSFC likely through inflammatory pathways.

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction.

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.

Dynamic processing of hunger and thirst by common mesolimbic neural ensembles.

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking. These dynamic clusters also show a nearly complete overlap of individual D1 neurons and extensive overlap among D2 neurons. Modulating D1 and D2 neural activities revealed analogous effects on feeding versus drinking behaviors. In aggregate, these data show that a highly overlapping set of D1 and D2 neurons in NAc detect food and water reward and elicit concordant responses to hunger and thirst. These studies establish a general role of this mesolimbic pathway in mediating instinctive behaviors by controlling motivation-associated variables rather than conferring behavioral specificity.

Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour.

Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2-4. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS-AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS-AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.

Prevalence of Postoperative Micronutrient Deficiencies in Bariatric Surgery Patients Who Use Transdermal Patches for Supplementation: A Pilot Study.

Background Patients require vitamin and mineral supplementation after bariatric surgery to prevent the development of micronutrient deficiencies. Consuming oral supplements is challenging due to gastric volume restriction. A transdermal patch dosage form may provide adequate micronutrient supplementation without pill burden. The study aims to determine the percentage of patients who have two or more nutritional deficiencies one year after surgery and to determine serum nutrient concentrations and gastrointestinal symptoms over time. Methods Patients who planned to undergo bariatric surgery and preferred transdermal patches versus oral supplements were recruited during preoperative office visits. Enrolled patients were instructed to use a transdermal multivitamin patch as per the manufacturer's instructions. Serum nutrient concentrations and Gastrointestinal Symptom Response Scale scores were determined at baseline and three months, six months, and one year after surgery. Results Ninety-two participants completed the study protocol. Twenty-five participants had a full panel of study labs one year after surgery. Among these patients, 19% had two or more micronutrient deficiencies. Vitamin D was the most common deficiency followed by vitamin B6; however, median serum concentrations of both nutrients increased over time. Vitamin B1, folate, and zinc deficiencies were also observed. There were no changes in gastrointestinal symptoms. Conclusions Additional studies, including randomized controlled trials, are required to determine if the PatchMD Multivitamin Plus patch (Pilot Rd. STE. B, Las Vegas) can provide adequate supplementation of vitamins and minerals. The patch was not associated with changes in gastrointestinal symptoms.

Comparative Safety of Sleeve Gastrectomy and Roux-en-Y: A Propensity Score Analysis.

BACKGROUND: Use of bariatric surgery has increased dramatically in the USA. However, there are growing concerns regarding the safety outcomes of different bariatric procedures. We aim to compare the safety of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), which includes hospital readmissions, emergency room (ER) visits, gastrointestinal bleeding, and revisional surgery. METHODS: A retrospective cohort analysis was conducted for adults (≥ 18 years) who received SG and RYGB in the USA. We used Truven MarketScan Commercial and Medicare supplemental claims databases from January 1, 2005, to October 1, 2015. To adjust for baseline demographic and clinical characteristics, we used stabilized inverse probability of treatment weighting using propensity score. Cox proportional hazard models was used to compare safety outcomes between SG and RYGB after bariatric surgery. RESULTS: A total of 194,248 patients met inclusion criteria; 79,813 patients (41%) received SG and 114,435 patients (59%) received RYGB. The use of SG was associated with a significantly lower 30-day hospital readmission rate [adjusted hazard ratios (aHRs) 0.77; 95% confidence interval (CI), 0.74-0.81] and ER visits [aHR, 0.82; 95% CI, 0.80-0.83], and decreased risk of gastrointestinal bleeding [aHR, 0.87; 95% CI, 0.78-0.98] compared to RYGB. However, SG was associated with an increased risk of revisional surgery, compared to RYGB [aHR,1.21; 95% CI, 1.08-1.35]. CONCLUSIONS: Among patients receiving bariatric surgery in a real-world setting, SG was associated with lower complication rate but a higher risk of revisional surgery compared to RYGB. Further longitudinal studies are needed to assess long-term findings.

Drug absorption in bariatric surgery patients: A narrative review.

Background: Despite the increase in the number of bariatric surgeries performed, little is known about the impact of the surgery on drug absorption. Unpredictability is assumed with drugs, given the anatomical changes after surgery. Objective: To evaluate the impact of bariatric surgery on drug absorption based on the type of procedure performed. Methods: We conducted a comprehensive literature review searching PubMed/Medline for published studies (from inception to December 2017) that evaluate the use of drugs and the assessment of drug absorption after bariatric surgery. Pharmacokinetic/pharmacodynamic studies, case reports, and observational studies were included in our review. Results: We found 60 studies addressing drug use after bariatric surgery. Twenty-eight studies reported a decrease in drug absorption after bariatric surgery while only four studies showed an increase in drug absorption. Unchanged absorption of drugs was seen in 23 studies after the surgery. Conclusion: The available information shows variations in drug absorption after bariatric surgery. The unpredictability may result from factors related to the patient, drug, and/or type of surgery. Therefore, pharmacists' involvement and close monitoring of patients after bariatric surgery could be effective to avoid sub-/supratherapeutic responses.

Changes in overactive bladder medication following bariatric surgery: segmented regression analysis.

PURPOSE: Bariatric surgery has shown reductions in overactive bladder (OAB) symptoms; however, the impacts on OAB treatment is unknown. The goal of our study is to evaluate the impact of bariatric surgery on OAB medication utilization. METHODS: We used IBM® MarketScan® commercial databases from 2005 to 2018. We included patients aged ≥ 18 years with 360 days of continuous enrollment before and after bariatric surgery (Roux-en-Y Gastric Bypass and Sleeve Gastrectomy) with at least one fill of an OAB medication in the 360 days prior to bariatric surgery. We evaluated all included patients and stratified by surgery type and patient sex. Segmented regression analyses were used to assess the proportion of patients on OAB medications before and after bariatric surgery. We replicated our findings using hip or knee replacement surgery as a negative control. RESULTS: Among the included patients (n = 3069), 92.2% were females, 58.6% underwent Roux-en-Y Gastric Bypass. Immediately following bariatric surgery, the proportion of patients treated with an OAB medication reduced from 34.8 to 14.1% (p < 0.001) resulting in a 59.5% relative reduction. Patients who underwent Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy (63.8% vs. 55.1%) relative reduction (p = 0.009)) and females versus males [62.3% vs. 52.9% relative reduction (p < 0.001)] had a more pronounced reduction in OAB medication use. There was slight decrease in OAB medication use in the negative control analysis. CONCLUSIONS: A reduction in OAB medication use following bariatric surgery may be associated with a reduction in OAB symptoms suggesting an additional benefit of bariatric surgery.

The Business of Employed Plastic Surgery: Creating Your Seat at the Table.

BACKGROUND: While the landscape of medicine changes, hospital employment continues to gain popularity in surgical specialties. The number of plastic surgeons entering an employed relationship has also grown, offering new opportunities and challenges alike. The authors studied the profitability of plastic surgery to the hospital and the necessity of the specialty to hospital administration through financial net revenue, contribution margin, and payer mix, to help plastic surgeons realize and capitalize on their importance and contribution to the hospital system. METHODS: Facility net revenue and contribution margin from Houston Methodist West Hospital were evaluated. Average net revenue and contribution margin for inpatient and outpatient cases for plastic surgery, orthopedic surgery, and all combined surgical specialties were studied for the 2018 and 2019 fiscal years. RESULTS: The authors demonstrated net increase per year for both outpatient and inpatient revenue in favor of plastic surgery versus orthopedics and combined surgical specialties. Plastic surgery contributed higher facility net revenue when compared to orthopedics, contributing 20 percent more per outpatient case and 86 percent more per inpatient case. A higher contribution margin for each year was realized for inpatient cases versus orthopedics and combined surgical specialties, increasing by 8 percent and 53 percent and 61 percent and 86 percent, respectively. CONCLUSIONS: A surgeon's ability to present objective financial data and develop leadership roles within the hospital system can lead to a favorable outcome for both physician and hospital. An objective dialogue with hospital administration is critical and offers an avenue to negotiate the development of your practice.

Impact of Laparoscopic Sleeve Gastrectomy on Cardiovascular Pharmacotherapy in Left Ventricular Assist Device Patients.

ABSTRACT: Left ventricular assist device (LVAD) implantation is increasingly utilized in patients with advanced heart failure and morbid obesity. Laparoscopic sleeve gastrectomy (LSG) can facilitate weight loss in this population and can ultimately change the pharmacokinetics of heart failure therapeutics. In this study, we aimed to explore the changes in cardiovascular pharmacotherapy post LSG intervention. We conducted a retrospective observational cohort study of morbidly obese LVAD patients between 2013 and 2019 at the University of Florida with available pharmacotherapeutic data at 1 and 6 months. Thirteen post-LSG patients and 13 control subjects were included in the final analysis. In the post-LSG group, the mean body mass index decreased significantly (44 ± 5 vs. 34 ± 4.9, P < 0.001), and 7 patients were successfully bridged to cardiac transplantation. Only 3 patients required adjustment of their LVAD speed. Mean return to flow decreased by 8 mm Hg, despite a 45% reduction in the mean number of vasodilators per patient (1.2 vs. 0.7, P = 0.03). Mean weekly warfarin dose decreased by 35% after 6 months (32.9 ± 20.9 vs. 50.7 ± 26.6, P = 0.01). The use of diuretics, vasodilators, and beta-blockers was significantly reduced by 50%, 45%, and 35%, respectively. None of these changes were observed in the control group at 6-month follow-up post LVAD. In this single-center experience, weight loss post LSG is associated with decreased vasodilator, diuretic, and anticoagulant medication requirements in LVAD patients.

Higher-Order Inputs Involved in Appetite Control.

The understanding of the neural control of appetite sheds light on the pathogenesis of eating disorders such as anorexia nervosa and obesity. Both diseases are a result of maladaptive eating behaviors (overeating or undereating) and are associated with life-threatening health problems. The fine regulation of appetite involves genetic, physiological, and environmental factors, which are detected and integrated in the brain by specific neuronal populations. For centuries, the hypothalamus has been the center of attention in the scientific community as a key regulator of appetite. The hypothalamus receives and sends axonal projections to several other brain regions that are important for the integration of sensory and emotional information. These connections ensure that appropriate behavioral decisions are made depending on the individual's emotional state and environment. Thus, the mechanisms by which higher-order brain regions integrate exteroceptive information to coordinate feeding is of great importance. In this review, we will focus on the functional and anatomical projections connecting the hypothalamus to the limbic system and higher-order brain centers in the cortex. We will also address the mechanisms by which specific neuronal populations located in higher-order centers regulate appetite and how maladaptive eating behaviors might arise from altered connections among cortical and subcortical areas with the hypothalamus.