Neuroimaging signatures predicting motor improvement to focused ultrasound subthalamotomy in Parkinson's disease.

Subthalamotomy using transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) is a novel and promising treatment for Parkinson's Disease (PD). In this study, we investigate if baseline brain imaging features can be early predictors of tcMRgFUS-subthalamotomy efficacy, as well as which are the post-treatment brain changes associated with the clinical outcomes. Towards this aim, functional and structural neuroimaging and extensive clinical data from thirty-five PD patients enrolled in a double-blind tcMRgFUS-subthalamotomy clinical trial were analyzed. A multivariate cross-correlation analysis revealed that the baseline multimodal imaging data significantly explain (P < 0.005, FWE-corrected) the inter-individual variability in response to treatment. Most predictive features at baseline included neural fluctuations in distributed cortical regions and structural integrity in the putamen and parietal regions. Additionally, a similar multivariate analysis showed that the population variance in clinical improvements is significantly explained (P < 0.001, FWE-corrected) by a distributed network of concurrent functional and structural brain changes in frontotemporal, parietal, occipital, and cerebellar regions, as opposed to local changes in very specific brain regions. Overall, our findings reveal specific quantitative brain signatures highly predictive of tcMRgFUS-subthalamotomy responsiveness in PD. The unanticipated weight of a cortical-subcortical-cerebellar subnetwork in defining clinical outcome extends the current biological understanding of the mechanisms associated with clinical benefits.

Multivariate genomic and transcriptomic determinants of imaging-derived personalized therapeutic needs in Parkinson's disease.

Due to the marked interpersonal neuropathologic and clinical heterogeneity of Parkinson's disease (PD), current interventions are not personalized and fail to benefit all patients. Furthermore, we continue to lack well-established methods and clinical tests to tailor interventions at the individual level in PD. Here, we identify the genetic determinants of individual-tailored treatment needs derived from longitudinal multimodal neuroimaging data in 294 PD patients (PPMI data). Advanced multivariate statistical analysis revealed that both genomic and blood transcriptomic data significantly explain (P < 0.01, FWE-corrected) the interindividual variability in therapeutic needs associated with dopaminergic, functional, and structural brain reorganization. We confirmed a high overlap between the identified highly predictive molecular pathways and determinants of levodopa clinical responsiveness, including well-known (Wnt signaling, angiogenesis, dopaminergic activity) and recently discovered (immune markers, gonadotropin-releasing hormone receptor) pathways/components. In addition, the observed strong correspondence between the identified genomic and baseline-transcriptomic determinants of treatment needs/response supports the genome's active role at the time of patient evaluation (i.e., beyond individual genetic predispositions at birth). This study paves the way for effectively combining genomic, transcriptomic and neuroimaging data for implementing successful individually tailored interventions in PD and extending our pathogenetic understanding of this multifactorial and heterogeneous disorder.

Brain morphometry in adults with gambling disorder.

Little is known regarding the brain substrates of Gambling Disorder, including surface brain morphometry, and whether these are linked to the clinical profile. A better understanding of the brain substrates will likely help determine targets to treat patients. Hence, the aim of this study was two-fold, that is to examine surface-based morphometry in 17 patients with gambling disorder as compared to norms of healthy individuals (2713 and 2790 subjects for cortical and subcortical anatomical scans, respectively) and to assess the clinical relevance of morphometry in patients with Gambling Disorder. This study measured brain volume, surface and thickness in Gambling Disorder. We compared these measures to those of a normative database that controlled for factors such as age and sex. We also tested for correlations with gambling-related behaviors, such as gambling severity and duration, impulsivity, and depressive symptoms (assessed using the South Oaks Gambling Screen, years of gambling, Barratt Impulsiveness Scale, and Beck Depression Inventory, respectively). Patients displayed thinner prefrontal and parietal cortices, greater volume and thickness of the occipital and the entorhinal cortices, and greater volume of subcortical regions as compared to the norms of healthy individuals. There were positive correlations between surface area of occipital regions and depressive symptoms. This work contributes to better characterize the brain substrates of Gambling Disorder, which appear to resemble those of substance use disorders and Internet Gaming Disorder.

Concurrent Transcranial Direct Current Stimulation and Resting-State Functional Magnetic Resonance Imaging in Patients with Gambling Disorder.

Background/Introduction: Transcranial direct current stimulation (tDCS) delivered over the dorsolateral prefrontal cortex (DLPFC) while patients are at rest can decrease craving in patients with substance-related and addictive disorders. Yet, the effects of tDCS on resting-state brain activity remain unknown in this population. This study examined the effects of tDCS on resting-state functional connectivity (rsFC) with concurrent stimulation and functional magnetic resonance imaging in patients with gambling disorder. Methods: This was a randomized, sham-controlled, double-blind, crossover study. The anodal and cathodal electrodes were applied over the right and left DLPFC, respectively. Patients received 30 min of active and sham stimulation on separate days. rsFC was assessed before and during stimulation with seed-based analyses. Results: There was a significant increase of rsFC between the right DLPFC seed and the right superior parietal lobule during active stimulation as compared to during sham stimulation (p = 0.0059, corrected for multiple comparisons). There was also a positive correlation between rsFC change of this frontoparietal network and brain volume of the right DLPFC (p = 0.0042, corrected for multiple comparisons). Discussion: A single session of tDCS targeting the DLPFC strengthened functional connectivity in a frontoparietal circuit, known to be implicated in cognitive control, especially in patients with a greater volume of the region under the anode electrode. Impact statement Transcranial direct current stimulation increased the functional connectivity of a frontoparietal circuit in patients with gambling disorder. These changes were larger in patients with greater volume of the dorsolateral prefrontal cortex. Transcranial direct current stimulation strengthened the connectivity of a brain network known to be associated with cognitive control.

Estrous Cycle Modulation of Feeding and Relaxin-3/Rxfp3 mRNA Expression: Implications for Estradiol Action.

INTRODUCTION: Food intake varies during the ovarian hormone/estrous cycle in humans and rodents, an effect mediated mainly by estradiol. A potential mediator of the central anorectic effects of estradiol is the neuropeptide relaxin-3 (RLN3) synthetized in the nucleus incertus (NI) and acting via the relaxin family peptide-3 receptor (RXFP3). METHODS: We investigated the relationship between RLN3/RXFP3 signaling and feeding behavior across the female rat estrous cycle. We used in situ hybridization to investigate expression patterns of Rln3 mRNA in NI and Rxfp3 mRNA in the hypothalamic paraventricular nucleus (PVN), lateral hypothalamic area (LHA), medial preoptic area (MPA), and bed nucleus of the stria terminalis (BNST), across the estrous cycle. We identified expression of estrogen receptors (ERs) in the NI using droplet digital PCR and assessed the electrophysiological responsiveness of NI neurons to estradiol in brain slices. RESULTS: Rln3 mRNA reached the lowest levels in the NI pars compacta during proestrus. Rxfp3 mRNA levels varied across the estrous cycle in a region-specific manner, with changes observed in the perifornical LHA, magnocellular PVN, dorsal BNST, and MPA, but not in the parvocellular PVN or lateral LHA. G protein-coupled estrogen receptor 1 (Gper1) mRNA was the most abundant ER transcript in the NI. Estradiol inhibited 33% of type 1 NI neurons, including RLN3-positive cells. CONCLUSION: These findings demonstrate that the RLN3/RXFP3 system is modulated by the estrous cycle, and although further studies are required to better elucidate the cellular and molecular mechanisms of estradiol signaling, current results implicate the involvement of the RLN3/RXFP3 system in food intake fluctuations observed across the estrous cycle in female rats.

Eye tracking of smoking-related stimuli in tobacco use disorder: A proof-of-concept study combining attention bias modification with alpha-transcranial alternating current stimulation.

BACKGROUND: Tobacco use disorder (TUD) is characterized by the presence of an attentional bias (AB) towards smoking-related stimuli. We investigated whether combining an AB modification paradigm (ABM) with transcranial alternating current stimulation (tACS) applied over the dorsolateral prefrontal cortex (DLPFC) reduces the AB towards smoking-related stimuli, as well as craving level and impulsive choices. METHODS: In a sham-controlled, crossover preliminary study, 19 subjects with TUD received two stimulation arms: 1) active tACS (10 Hz, 2 mA, 30 min) combined with ABM and 2) sham tACS combined with ABM, in a randomized order, separated by one week. AB towards smoking cues during passive observation of smoking and neutral cues was assessed with an eye-tracking device and reactions times at a visual-probe task. Craving level was measured with the Questionnaire of Smoking Urges. Impulsive choices were assessed with the delay discounting task. RESULTS: Active tACS combined with ABM reduced the amount of time spent looking at smoking-related pictures (p = 0.03), prevented the increase of self-reported desire to smoke (p = 0.026), and reduced the proportion of impulsive choices (p = 0.049), compared to sham tACS combined with ABM. No significant effects were reported on other craving dimensions and on AB based on reaction times. CONCLUSIONS: These preliminary findings suggest that combining tACS with ABM may help smokers who wish to quit by reducing the desire to smoke, attention to smoking-cues, and impulsive decision-making.

Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats.

The neuropeptide relaxin-3 (RLN3) binds with high affinity to its cognate receptor, relaxin-family peptide receptor 3 (RXFP3), and with lower affinity to RXFP1, the cognate receptor for relaxin. Intracerebroventricular (icv) administration of RLN3 in rats strongly increases food and water intake and alters the activity of the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes, but the relative involvement of RXFP3 and RXFP1 in these effects is not known. Therefore, the effects of icv administration of equimolar (1.1 nmol) amounts of RLN3 and the RXFP3-selective agonist RXFP3-A2 on food and water intake, plasma levels of corticosterone, testosterone, and oxytocin and c-fos mRNA expression in key hypothalamic regions in male rats were compared. Food intake was increased by both RLN3 and RXFP3-A2, but the orexigenic effects of RXFP3-A2 were significantly stronger than RLN3, 30 and 60min after injection. Water intake and plasma corticosterone and testosterone levels were significantly increased by RLN3, but not by RXFP3-A2. Conversely, RXFP3-A2 but not RLN3 decreased oxytocin plasma levels. RLN3, but not RXFP3-A2, increased c-fos mRNA levels in the parvocellular (PVNp) and magnocellular (PVNm) paraventricular and supraoptic (SON) hypothalamic nuclei, in the ventral medial preoptic area (MPAv), and in the organum vasculosum of the lamina terminalis (OVLT). A significant increase in c-fos mRNA expression was induced in the perifornical lateral hypothalamic area (LHApf) by RLN3 and RXFP3-A2. These results suggest that RXFP1 is involved in the RLN3 stimulation of water intake and activation of the HPA and HPG axes. The reduced food intake stimulation by RLN3 compared to RXFP3-A2 may relate to activation of both orexigenic and anorexigenic circuits by RLN3.

Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder.

Gambling disorder is characterized by persistent maladaptive gambling behaviors and is now considered among substance-related and addictive disorders. There is still unmet therapeutic need for these clinical populations, however recent advances indicate that interventions targeting the Glutamatergic/GABAergic system hold promise in reducing symptoms in substance-related and addictive disorders, including gambling disorder. There is some data indicating that transcranial direct current stimulation may hold clinical benefits in substance use disorders and modulate levels of brain metabolites including glutamate and GABA. The goal of the present work was to test whether this non-invasive neurostimulation method modulates key metabolites in gambling disorder. We conducted a sham-controlled, crossover, randomized study, blinded at two levels in order to characterize the effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on neural metabolites levels in sixteen patients with gambling disorder. Metabolite levels were measured with magnetic resonance spectroscopy from the right dorsolateral prefrontal cortex and the right striatum during active and sham stimulation. Active as compared to sham stimulation elevated prefrontal GABA levels. There were no significant changes between stimulation conditions in prefrontal glutamate + glutamine and N-acetyl Aspartate, or in striatal metabolite levels. Results also indicated positive correlations between metabolite levels during active, but not sham, stimulation and levels of risk taking, impulsivity and craving. Our findings suggest that transcranial direct current stimulation can modulate GABA levels in patients with gambling disorder which may represent an interesting future therapeutic avenue.

Inhibition in the lateral septum increases sucrose intake and decreases anorectic effects of stress.

Sucrose-overeating rats with decreased anorectic response to stress showed lower stress-induced activation of c-fos expression in the lateral septum (LS). The present study tested a hypothesis that neuronal inhibition in the LS is important for the development and maintenance of the sucrose-overeating phenotype. Sucrose overeating was developed with weekly episodes of food restriction (21 h per day, 4 days per week) followed by 1-h access to sucrose. The anorectic effects of stress on 1-h sucrose intake were estimated using weekly foot shock stress sessions. The development of the sucrose-overeating phenotype was accompanied by a decrease in the anorectic effects of stress and by an increase in LS mRNA expression of a γ-aminobutyric acid (GABA) synthesising enzyme, glutamic acid decarboxylase 67 in stressed rats. Direct recordings of neuronal firing in the LS in rats submitted to repeated weekly cycles of food restriction, sucrose refeeding and stress showed that the development of sucrose overeating increased the percentage of LS neurons inhibited during anticipation and at the start of clusters (CS) of sucrose licking. In addition, the CS-excited LS neurons showed a decrease in responsiveness to sucrose during the development of sucrose overeating. Direct injection of baclofen, an agonist of the GABAB receptor, into the LS decreased the anorectic effects of stress and increased sucrose intake. These results suggest that an increase in inhibitory effects in the LS is important for the development of sucrose overeating and the decreased anorectic effects of stress.

Sex-specific effects of relaxin-3 on food intake and brain expression of corticotropin-releasing factor in rats.

This study compared the effects of relaxin-3 (RLN3) on food intake, plasma corticosterone, and the expression of corticotropin-releasing factor (CRF) in male and female rats. RLN3 was injected into the lateral ventricle at 25, 200, and 800 pmol concentrations. RLN3 at 25 pmol increased food intake (grams) at 30 and 60 minutes after injection in female but not male rats. Female rats also showed higher increase in relative to body weight (BW) food intake (mg/g BW) for all RLN3 concentrations at 30 minutes and for 800 pmol of RLN3 at 60 minutes. Moreover, RLN3 at 800 pmol significantly increased 24-hour BW gain in female but not male rats. At 60 minutes after administration, 800 pmol of RLN3 produced a significant increase in plasma corticosterone and in the expression of CRF and c-fos mRNAs in the parvocellular paraventricular hypothalamic nucleus (PVN) in male but not female rats. The levels of c-fos mRNA in the magnocellular PVN were increased by RLN3 but did not differ between the sexes. Conversely, expression of CRF mRNA in the medial preoptic area was increased in female rats but was not sensitive to 800 pmol of RLN3. In the bed nucleus of the stria terminalis, 800 pmol of RLN3 significantly increased CRF mRNA expression in female but not male rats. Therefore, female rats showed more sensitivity and stronger food intake increase in response to RLN3. The differential effects of RLN3 on CRF expression in the PVN and bed nucleus of the stria terminalis may contribute to the sex-specific difference in the behavioral response.

Activation of GABAA and GABAB receptors in the lateral septum increases sucrose intake by differential stimulation of sucrose licking activity.

The present study was aimed to determine how direct injections into the lateral septum (LS) of muscimol and baclofen, GABAA and GABAB receptor agonists, respectively, affect intake of 10% sucrose and sucrose licking activity in rats. The effects of muscimol and baclofen on the 1-h intake of sucrose and sucrose licking activity were tested at low (350pmol), medium (876pmol), and high (1752pmol) doses. The medium and high doses of muscimol and the high dose of baclofen significantly increased 1-h sucrose intake. The total sucrose lick number was significantly increased by the medium dose of muscimol and the high dose of baclofen. An increase in sucrose licking activity induced by muscimol but not baclofen occurred in the first 15min after injections. The medium and high doses of muscimol but not baclofen significantly decreased latency to initiate the first lick of sucrose. The total licking time calculated as the sum of the duration of all sucrose lick clusters showed a significant increase by the high dose of baclofen but not by any dose of muscimol. Therefore, the GABAA and GABAB LS mechanisms appear to be involved in stimulating sucrose intake, but this stimulation occurs by differential regulation of the sucrose licking activity. Muscimol intra-LS administration led to a short-latency rapid increase in sucrose licking. In contrast, baclofen did not decrease latency to initiate licking, but significantly increased total licking duration.

The medial preoptic nucleus as a site of the thermogenic and metabolic actions of melanotan II in male rats.

The present study was designed to investigate the role of the medial preoptic nucleus (MPO) as a site of the thermogenic and metabolic effects of the α-melanocyte-stimulating hormone analog melanotan II (MTII). We also assessed the involvement of the dorsomedial hypothalamic nucleus (DMH) by investigating the effects of the MPO infusion of MTII in rats with DMH lesions produced by kainic acid. Infusion of MTII in the MPO led to increases in interscapular brown adipose tissue (iBAT) temperature and iBAT uptake of 14C-bromopalmitate. Both increases were blocked by DMH lesions. iBAT temperature increase (area under curve) and 14C-bromopalmitate uptake emerged as two correlated variables (r = 0.63, P < 0.001). DMH lesions also blocked MTII-induced expression of mRNAs coding for proteins involved in 1) thermogenesis [type II iodothyronine deiodinase (Dio2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (Pgc1α)], 2) lipolysis [hormone-sensitive lipase (Hsl)], and 3) lipogenesis [diacylglycerol-O-acyltransferase 2 (Dgat2), fatty acid synthase (Fas)], in iBAT of rats killed 1 h after MPO infusion of MTII. MTII also stimulated expression of genes in iWAT but only in rats with DMH lesions. These genes included glucose transporter member 4 (Glut4), glycerol-3-phosphate acyltransferase 3 (Gpat3), Dgat1, Dgat2, triglyceride lipase (Atgl), Hsl, and carnitine palmitoyltransferase 1ß (Cpt1ß). Altogether, the present results reveal the MPO as a site of the thermogenic and metabolic actions of MTII. They also contribute to establish the MPO-DMH duet as a significant target for melanocortins to modulate energy homeostasis.

Regulation of expression of relaxin-3 and its receptor RXFP3 in the brain of diet-induced obese rats.

An animal model closely related to human obesity is diet-induced obesity in Sprague-Dawley rats. These rats placed on a high-energy (HE) diet show wide distribution in body weight gain with a subset of animals developing diet-induced obesity (DIO) and the remaining animals showing a diet-resistant (DR) phenotype. Once obesity is established, DIO rats strongly defend their increased body weight against caloric restriction. There is evidence that neuropeptide relaxin-3 is involved in food intake regulation, but the levels of expression of relaxin-3 and its receptor have not been yet demonstrated in the DIO model. The present study investigated the brain expression of relaxin-3 and its cognate receptor RXFP3 in DIO and DR rats maintained on an HE diet since weaning. Expression of relaxin-3 and RXFP3 mRNAs was assessed by in situ hybridization in ad libitum, food-deprived (12 h) and refed (1 h) feeding states. The levels of expression of relaxin-3 in the medial portion of the nucleus incertus (NI) were higher in the DIO rats compared to the DR rats in the ad libitum-fed state. Food deprivation increased the levels of expression of relaxin-3 in the medial NI in DR but not DIO rats. The stronger expression of relaxin-3 in the ad libitum-fed state in the DIO rats was accompanied by low expression of the RXFP3 receptor in the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus, central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Refeeding increased expression of RXFP3 in the paraventricular thalamic nucleus, parvocellular PVN, CeA, NI, and NTS in the DIO rats. These results provide evidence that DIO rats show a constitutive increase in relaxin-3 expression in the medial NI and that refeeding after food deprivation may enhance the orexigenic effects of relaxin-3 in DIO rats by rapid upregulation of the expression of RXFP3 in the specific brain regions involved in food intake regulation.

Hypothalamic expression of urocortin 3 and the type 2 corticotropin-releasing factor receptor is regulated according to feeding state in lean but not obese Zucker rats.

Urocortin 3 (Ucn3) is an anorexigenic neuropeptide with high affinity for the type 2 corticotropin-releasing factor receptor (CRF2-R). How the expression of hypothalamic Ucn3 is regulated by fasting and refeeding in genetically obese (fa/fa) Zucker rats is not known. Obese Zucker rats develop early hyperphagia associated with low expression of CRF2-R in the ventromedial hypothalamic nucleus (VMH) in this phenotype. Although lean (Fa/?) Zucker rats have strong basal expression of CRF2-R in the VMH, and normally consume less food compared to their obese littermates, at the beginning of refeeding, the lean rats ingested almost the same amount of food as the obese animals. The present study was designed to investigate the dynamics of the expression of CRF2-R and Ucn3 in the brain of lean and obese Zucker rats fed ad libitum, food-deprived for 48 h, or refed for 1 and 24 h. The levels of expression of Ucn3 mRNA were analyzed in the rostral perifornical hypothalamus (rPFH) and dorsal medial amygdala (MeD), and CRF2-R mRNA in the VMH and lateral septum (LS) using in situ hybridization. The results showed that in the ad libitum-fed state, both phenotypes had comparable levels of expression of rPFH Ucn3, but the obese rats had lower levels of expression of VMH CRF2-R. Food deprivation decreased hypothalamic expression of Ucn3 and CRF2-R in lean but not obese rats. One hour of refeeding triggered expression of rPFH Ucn3 but not VMH CRF2-R in lean rats, and at 24 h of refeeding the levels of hypothalamic expression of Ucn3 and CRF2-R returned to those seen in the ad libitum-fed state in both phenotypes. In the LS, the levels of expression of CRF2-R were not affected by feeding and phenotype. In the MeD, the Ucn3 transcript increased by food deprivation in obese but not lean rats. Therefore, the increase of Ucn3 expression in the MeD in obese food-deprived rats may reflect stronger behavioral effects of food deprivation in this phenotype. The hypothalamic expression of Ucn3 and CRF2)-R was modulated by the feeding states in lean but not obese rats. The low levels of VMH CRF2-R may limit anorexigenic Ucn3 effects in the obese phenotype. The low VMH CRF2-R levels at the beginning of refeeding in lean rats may allow them to ingest a considerable amount of food regardless of the rapidly increased expression of rPFH Ucn3 by refeeding in this phenotype. This article is part of a Special Issue entitled 'Central Control of Food Intake'.