Ganglia Regions Research Articles

Abstinence from Chronic Methylphenidate Exposure Modifies Cannabinoid Receptor 1 Levels in the Brain in a Dose-dependent Manner.

Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior measures, and neurochemistry. The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, with the remaining rats underwent a four-week- long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased CB1 binding in several cortical and basal ganglia regions of the brain compared to rats with no abstinence period. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower CB1 binding mainly in the basal ganglia regions and the hindlimb region of the somatosensory cortex compared to rats with no abstinence period. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [3H] SR141716A binding in many of the cortical and basal ganglia regions examined than rats given LD MP. These results highlight the biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels, while abstinence from LD MP seemed to decrease CB1 levels. Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.

Comparison of quantitative susceptibility mapping methods on evaluating radiation-induced cerebral microbleeds and basal ganglia at 3T and 7T.

Quantitative susceptibility mapping (QSM) has the potential for being a biomarker for various diseases because of its ability to measure tissue susceptibility related to iron deposition, myelin, and hemorrhage from the phase signal of a T2 *-weighted MRI. Despite its promise as a quantitative marker, QSM is faced with many challenges, including its dependence on preprocessing of the raw phase data, the relatively weak tissue signal, and the inherently ill posed relationship between the magnetic dipole and measured phase. The goal of this study was to evaluate the effects of background field removal and dipole inversion algorithms on noise characteristics, image uniformity, and structural contrast for cerebral microbleed (CMB) quantification at both 3T and 7T. We selected four widely used background phase removal and five dipole field inversion algorithms for QSM and applied them to volunteers and patients with CMBs, who were scanned at two different field strengths, with ground truth QSM reference calculated using multiple orientation scans. 7T MRI provided QSM images with lower noise than did 3T MRI. QSIP and VSHARP + iLSQR achieved the highest white matter homogeneity and vein contrast, with QSIP also providing the highest CMB contrast. Compared with ground truth COSMOS QSM images, overall good correlations between susceptibility values of dipole inversion algorithms and the COSMOS reference were observed in basal ganglia regions, with VSHARP + iLSQR achieving the susceptibility values most similar to COSMOS across all regions. This study can provide guidance for selecting the most appropriate QSM processing pipeline based on the application of interest and scanner field strength.

Depression, anxiety and health-related quality of life in paediatric intracranial germ cell tumor survivors

BackgroundLittle is known about depression and anxiety among paediatric intracranial germ cell tumour (iGCT) survivors. We aimed to evaluate the risk factors associated with depression, anxiety and health-related quality of life (HRQoL) in paediatric iGCT survivors.MethodsWe recruited 200 iGCT patients (and their parents) from Beijing Tiantan Hospital and assessed their HRQoL using the Paediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales. The Children’s Depression Inventory, Screen for Child Anxiety Related Emotional Disorders, and Symptom Checklist 90 were used to evaluate depression and anxiety. The results were analysed based on disease recurrence, tumour location and treatment strategies.ResultsSurvivors with recurrent tumours had worse HRQoL scores than those with non-recurrent tumours. Patients with tumours involving both the suprasellar and basal ganglia regions had the worst HRQoL scores. A large proportion of survivors had depression or anxiety. Both depression and anxiety scores were highly correlated with the HRQoL emotional functioning scores. The parent proxy-reports (PPR) and child self-reports were highly correlated in all domains.ConclusionsThis study demonstrated the clinical factors affecting paediatric iGCT survivors’ depression, anxiety, and HRQoL. Therefore, psychological interventions should be implemented. It also suggests that the PedsQL PPR would be helpful for routine screening.

Cerebral Blood Perfusion is Improved Regionally After Shunt Surgery in the High-Pressure Hydrocephalic Brain.

To show the abnormal cerebral hemodynamics, in high-pressure hydrocephalic patients, could be restored by shunt surgery, and the tympanic membrane temperature (TMT) could be used to non-invasively monitor this recovery process. One-hundred-and-four patients, with high-pressure hydrocephalus (spinal tap opening pressure > 180 mmH2O), were prospectively enrolled in our study. The computed tomography perfusion (CTP) was scheduled for 7-10 days preand post-shunt surgery. The TMT and Glasgow Coma Scale (GCS) scores were collected during the same session. The CTP after the shunt surgery revealed a significant increase in cerebral blood volume (CBV) in both hemispheres (p < 0.05). More specifically, this CBV increase was observed in the midbrain, cerebellum, basal ganglion, temporal lobe, and frontal lobe regions (all p < 0.05). Simultaneously, patients' post-surgical TMT and GCS scores also increased compared to their pre-surgical scores since the first post-shunt follow-up (p < 0.01). Notably, while the GCS scores continued to increase during the post-shunt follow-up, the TMT exhibited a fluctuation period after the shunt and required seven days to reach a steady state. Our study revealed that a shunt could significantly increase cerebral perfusion in high-pressure hydrocephalic patients in a region-specific manner. During the perioperative period of hydrocephalus, TMT can be used to monitor cerebral hemodynamic changes.

Resting-State Functional Connectivity in Frontostriatal and Posterior Cortical Subtypes in Parkinson's Disease-Mild Cognitive Impairment.

The "dual syndrome hypothesis" distinguished two subtypes in mild cognitive impairment (MCI) in Parkinson's disease: frontostriatal, characterized by attentional and executive deficits; and posterior cortical, characterized by visuospatial, memory, and language deficits. The aim was to identify resting-state functional modifications associated with these subtypes. Ninety-five nondemented patients categorized as having normal cognition (n=31), frontostriatal (n=14), posterior cortical (n=20), or mixed (n=30) cognitive subtype had a 3 T resting-state functional magnetic resonance imaging scan. Twenty-four age-matched healthy controls (HCs) were also included. A group-level independent component analysis was performed to identify resting-state networks, and the selected components were subdivided into 564 cortical regions in addition to 26 basal ganglia regions. Global intra- and inter-network connectivity along with global and local efficiencies was compared between groups. The network-based statistics approach was used to identify connections significantly different between groups. Patients with posterior cortical deficits had increased intra-network functional connectivity (FC) within the basal ganglia network compared with patients with frontostriatal deficits. Patients with frontostriatal deficits had reduced inter-network FC between several networks, including the visual, default-mode, sensorimotor, salience, dorsal attentional, basal ganglia, and frontoparietal networks, compared with HCs, patients with normal cognition, and patients with a posterior cortical subtype. Similar results were also found between patients with a mixed subtype and HCs. MCI subtypes are associated with specific changes in resting-state FC. Longitudinal studies are needed to determine the predictive potential of these markers regarding the risk of developing dementia. © 2021 International Parkinson and Movement Disorder Society.

Metaboreflex Activity is Attenuated by Transcutaneous Electrical Nerve Stimulation and Interferential Electrical Stimulation in Healthy Individuals

Background: Transcutaneous electrical nervous stimulation (TENS) and interferential electrical stimulation (IES) attenuates muscle metaboreflex by sympathetic nervous modulation. Objective: We tested the hypothesis that IES may be more effective than TENS to improves blood flow which may be linked to greater of deep tissue. Methods: Eleven health subjects were randomized to TENS (80 Hz, 150μs), IES (4000 Hz, ΔAMF=25 Hz) or sham stimulation group, during 30 minutes. The acute intervention was applied on stellate ganglion region (C7-T4). Results: Were measured metaboreflex activity by calf vascular resistance (CVR) and calf blood flow (CBF) and HRV during three times: rest, exercise (static handgrip) and postexercise circulatory occlusion (PECO+ and PECO-). At the exercise peak, compared with TENS and Sham, the IES group reduced CVR (36 ± 3 vs 43 ± 3; p&lt;0.05) and increased CBF (p&lt;0.01). Also, IES was associated with a greater reduction on the MMA (IES: 9 ± 2, TENS: 14 ± 4, Sham: 26 ± 5 units; p&lt;0.01). Furthermore, the IES group had a higher reduction of LF/HF ratio during PECO- and PECO+ (p&lt;0.05). Conclusion: The IES over the stellate ganglion region seems to have superior efficacy compared with TENS to attenuate metaboreflex activation and vasodilatory responses during exercise in healthy subjects.

Deep brain stimulation for movement disorder treatment: exploring frequency-dependent efficacy in a computational network model

A large-scale computational model of the basal ganglia network and thalamus is proposed to describe movement disorders and treatment effects of deep brain stimulation (DBS). The model of this complex network considers three areas of the basal ganglia region: the subthalamic nucleus (STN) as target area of DBS, the globus pallidus, both pars externa and pars interna (GPe-GPi), and the thalamus. Parkinsonian conditions are simulated by assuming reduced dopaminergic input and corresponding pronounced inhibitory or disinhibited projections to GPe and GPi. Macroscopic quantities are derived which correlate closely to thalamic responses and hence motor programme fidelity. It can be demonstrated that depending on different levels of striatal projections to the GPe and GPi, the dynamics of these macroscopic quantities (synchronisation index, mean synaptic activity and response efficacy) switch from normal to Parkinsonian conditions. Simulating DBS of the STN affects the dynamics of the entire network, increasing the thalamic activity to levels close to normal, while differing from both normal and Parkinsonian dynamics. Using the mentioned macroscopic quantities, the model proposes optimal DBS frequency ranges above 130 Hz.

Factors associated with motor severity in vascular parkinsonism with normal dopamine transporter imaging

IntroductionTo delineate the determinants of motor severity in vascular parkinsonism (VaP), we investigated the impact of regional white matter intensity (WMH) burden and co-morbidities on the motor score in the patients with VaP and normal dopamine transporter (DAT) imaging. MethodsIn this multicenter, retrospective study, we reviewed the records of 63 patients diagnosed with VaP and normal DAT imaging on 18F-FP-CIT PET. Signal hyperintensities in deep white matter (DWMH), periventricular (PVH), basal ganglia (BG) regions, and infratentorial foci (ITF) were rated according to Scheltens scale, a semi-quantitative visual rating system. Motor severity was assessed with Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Regional hyperintensity scores, patients' demographics, and co-morbidities such as type 2 diabetes, hypertension, dyslipidemia, and previous stroke history were used as starting variables, and stepwise regression analysis was performed to select independent predictors of motor severity. ResultsPVH (R = 0.33, p = 0.008) and DWMH score (R = 0.31, p = 0.015) correlated with the motor severity, while BG and ITF scores did not. Diabetic patients had significantly higher motor scores compared with non-diabetics (34.7 (13.0) vs. 27.5 (12.4), p = 0.008). Other factors such as sex, BMI, hypertension, dyslipidemia, and previous history of stroke did not impact motor severity. In multivariate analysis, PVH scores and diabetes significantly correlated with motor severity. ConclusionPVH burden and diabetes were independent factors associated with motor severity in VaP with normal DAT imaging. Our results suggest that diabetes, along with white matter hyperintensities, may have a significant role in the development of motor symptoms in VaP.

Automated delineation of enlarged perivascular spaces (EPVS)

AbstractBackgroundEnlarged Perivascular Spaces (EPVS) are associated with small vessel disease. The objective of this study was to develop semi‐automated techniques for the quantification of EPVS burden.MethodAn intensity‐based threshold was used to identify EPVS. A threshold of maximum plus two standard deviations of intensities of normal‐appearing white matter in the supratentorial region was used to identify EPVS. To compare the performance of the semi‐automatic approach for EPVS segmentation to visually rated EPVS scores, two regions of interest were outlined in the basal ganglia (BG) region and the centrum semiovale (CS). For both these regions, a score was generated by an experienced neurologist by visually counting the number of EPVS with a score of zero representing the absence of any EPVS, a score of 1 representing 1‐10 EPVS, a score of 2 representing 11‐20 EPVS, a score of 3 representing 21‐40 EPVS, and a score of 4 representing &gt;40 EPVS. The semi‐automatic approach provided a count of the number of EPVS that were converted to grade using the same scaling as the visual approach. Spearman Rank Order Correlation Coefficient was calculated to estimate the correlation between the two methods. Mann‐Whitney U tests of ranks are employed to determine if any group differences are present. Finally, Cohen’s kappa was used to compare the concordance between measures between the two different methods.ResultFigure 2 shows the results of the segmentation in subjects with differing EPVS burden. Spearman Rank Order Correlation analysis showed a significant correlation between the EPVS scores determined visually and those obtained semi‐automatically in 60 subjects (Table 1). Results of the Mann‐Whitney U tests showed that there was no statistically significant (p &gt; 0.05) difference between the EPVS scores obtained visually and using the semi‐automatic approach (Table 2). Cohen's κ test showed that there was moderate agreement between the two estimation methods in the BG (κ = .522, p &lt; .0001) and CS regions (κ = .571, p &lt; .0001).ConclusionThe developed method showed good concordance with expert visual read and can provide quantitative measures of EPVS burden (counts and volume) for evaluation of vascular risk.

Exploring brain glucose metabolic patterns in cognitively normal adults at risk of Alzheimer’s disease: A cross-validation study with Chinese and ADNI cohorts

ObjectiveDisease-related metabolic brain patterns have been verified for a variety of neurodegenerative diseases including Alzheimer’s disease (AD). This study aimed to explore and validate the pattern derived from cognitively normal controls (NCs) in the Alzheimer’s continuum. MethodsThis study was based on two cohorts; one from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the other from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Each subject underwent [18F]fluoro-2-deoxyglucose positron emission tomography (PET) and [18F]florbetapir-PET imaging. Participants were binary-grouped based on β-amyloid (Aβ) status, and the positivity was defined as Aβ+. Voxel-based scaled subprofile model/principal component analysis (SSM/PCA) was used to generate the “at-risk AD-related metabolic pattern (ARADRP)” for NCs. The pattern expression score was obtained and compared between the groups, and receiver operating characteristic curves were drawn. Notably, we conducted cross-validation to verify the robustness and correlation analyses to explore the relationships between the score and AD-related pathological biomarkers. ResultsForty-eight Aβ+ NCs and 48 Aβ- NCs were included in the ADNI cohort, and 25 Aβ+ NCs and 30 Aβ- NCs were included in the SILCODE cohort. The ARADRPs were identified from the combined cohorts and the two separate cohorts, characterized by relatively lower regional loadings in the posterior parts of the precuneus, posterior cingulate, and regions of the temporal gyrus, as well as relatively higher values in the superior/middle frontal gyrus and other areas. Patterns identified from the two separate cohorts showed some regional differences, including the temporal gyrus, basal ganglia regions, anterior parts of the precuneus, and middle cingulate. Cross-validation suggested that the pattern expression score was significantly higher in the Aβ+ group of both cohorts (p < 0.01), and contributed to the diagnosis of Aβ+ NCs (with area under the curve values of 0.696–0.815). The correlation analysis revealed that the score was related to tau pathology measured in cerebrospinal fluid (p-tau: p < 0.02; t-tau: p < 0.03), but not Aβ pathology assessed with [18F]florbetapir-PET (p > 0.23). ConclusionsARADRP exists for NCs, and the acquired pattern expression score shows a certain ability to discriminate Aβ+ NCs from Aβ- NCs. The SSM/PCA method is expected to be helpful in the ultra-early diagnosis of AD in clinical practice.

Basal ganglia correlates of wellbeing in early adolescence

It has been suggested that biological markers that define mental health are different to those that define mental illness. The basal ganglia changes dramatically over adolescence and has been linked to wellbeing and mental health disorders in young people. However, there remains a paucity of research on wellbeing and brain structure in early adolescence. This cross-sectional study examined relationships between grey matter volume (GMV) of basal ganglia regions (caudate, putamen, pallidum and nucleus accumbens) and self-reported wellbeing (COMPAS-W), in a sample of Australian adolescents aged 12 years (N = 49, M = 12.6, 46.9% female). Significant negative associations were found between left hemisphere caudate GMV and scores on ‘total wellbeing’, ‘composure’ and ‘positivity’. The results of this study indicate that smaller caudate GMV at age 12 is linked to increased subjective wellbeing. While seemingly counter-intuitive, our finding is consistent with previous research of decreased GMV in the pons and increased COMPAS-W scores in adults. Our results suggest that protective neurobiological factors may be identifiable early in adolescence and be linked to specific types of wellbeing (such as positive affect and optimism). This has implications for interventions targeted at building resilience against mental health disorders in young people.

Hemichorea in a patient with ipsilateral cortical infarction: a case report

BackgroundHemichorea is usually caused by contralateral deep structures of brain. It rarely results from acute cortical ischemic stroke and that caused by ipsilateral brain lesions is even rarer.Case presentationA 64-year-old female presented with acute obtuseness and left-sided hemichorea. She had a history of right frontal lobe surgery and radiotherapy due to brain metastasis from lung cancer 8 years ago. MRI revealed acute left frontal lobe infarction in addition to an old right frontal lobe lesion. 18FDG PET-CT showed hypometabolism in the left frontal lobe and hypermetabolism in the right basal ganglia region and central sulcus. The choreatic movement remitted after antipsychotic treatment.ConclusionThe mechanism of hemichorea after ipsilateral cortical infarction is poorly understood. We assume both previous contralateral brain lesion and recent ipsilateral ischemic stroke contributed to the strange manifestation in this case.

Arteriovenous malformations in the basal ganglia and thalamus - A rare case of recurrent stroke

Stroke is rare in children when compare to adults. The aetiology, clinical presentation and outcome of stroke also different from adult. Arterio venous malformations are a rare cause of haemorrhagic stroke in children. Clinical features and secerity depends on site of the lesion. They are prone for recurrence and management of deep seated arterio venous malformations is a difficult one even in an experienced hand. We are presenting a rare case of AVM in basal ganglion region presented with recurrent stoke.

Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids

BackgroundHuman cerebral organoids (hCO) are attractive systems due to their ability to model important brain regions and transcriptomics of early in vivo brain development. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Interestingly, one of the main advantages of hCOs are that they provide three dimensionality that better mimics the in vivo environment; yet, despite this central feature it remains unclear how spatial and mechanical properties regulate hCO and neurodevelopment. While biophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment, much of this work investigated two dimensional systems or relied on correlative observations of native developing tissues in three dimensions. Using hCOs to establish links between spatial factors and neurodevelopment will require the use of new approaches and could reveal fundamental principles of brain organogenesis as well as improve hCOs as an experimental model.ResultsHere, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes mimicking several structures from embryogenesis and neurodevelopment and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions. Transcriptomic analysis suggests these mechanotransducive effects may be mediated by integrin and Wnt signaling.ConclusionsThe findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding of in vivo development and differentiation, but also provide important handles with which to advance and improve control over human model systems for in vitro applications.

Direct Rating Estimation of Enlarged Perivascular Spaces (EPVS) in Brain MRI Using Deep Neural Network

In this article, we propose a deep-learning-based estimation model for rating enlarged perivascular spaces (EPVS) in the brain’s basal ganglia region using T2-weighted magnetic resonance imaging (MRI) images. The proposed method estimates the EPVS rating directly from the T2-weighted MRI without using either the detection or the segmentation of EVPS. The model uses the cropped basal ganglia region on the T2-weighted MRI. We formulated the rating of EPVS as a multi-class classification problem. Model performance was evaluated using 96 subjects’ T2-weighted MRI data that were collected from two hospitals. The results show that the proposed method can automatically rate EPVS—demonstrating great potential to be used as a risk indicator of dementia to aid early diagnosis.

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.

Early Cerebrovascular Silent Changes in Long-Standing End-Stage Renal Disease Patients on Hemodialysis Value of Adding Advanced Unenhanced MRI Sequences to Imaging Protocols

Background: End-Stage Renal Disease (ESRD) patients on hemodialysis suffered from many central and peripheral neurological insults. Aim of the work:This study aimed to assess the value of using MRA, MRV, and SWAN sequences in early visualization of the silent cerebrovascular complications in those patients. Patients and Methods: Our study was conducted on forty-five patients with well-documented ESRD on regular hemodialysis for more than 5 years with no neurological manifestation, all undergone unenhanced MRI, DWI with ADC and measuring the ADC value, SWAN, MRA, and MRV. Results: we found that 11% of cases have acute infarction at the basal ganglia region. 36.7% of patients are diagnosed with intracerebral hemorrhage, only 26.7% of them are seen by the conventional MRI, and 16.7% of cases showed microbleeds on SWAN with normal conventional MRI. The sensitivity and specificity of SWAN with ADC value to detect brain hemorrhage are 100% and 88.8% respectively. Conclusion: Visualization of cerebrovascular complications such as infarction, hemorrhage, atherosclerosis, and arterial and venous occlusion using DWI with ADC, MRA, MRV, and SWAN and is very useful in early management and better prognosis of ESRD patients even with silent complications that don’t give up symptoms with high sensitivity and specificity of SWAN in early detection of hemorrhage and microbleeds.

Chronic Alcoholism and HHV-6 Infection Synergistically Promote Neuroinflammatory Microglial Phenotypes in the Substantia Nigra of the Adult Human Brain.

Both chronic alcoholism and human herpesvirus-6 (HHV-6) infection have been identified as promoters of neuroinflammation and known to cause movement-related disorders. Substantia Nigra (SN), the dopaminergic neuron-rich region of the basal ganglia, is involved in regulating motor function and the reward system. Hence, we hypothesize the presence of possible synergism between alcoholism and HHV-6 infection in the SN region and report a comprehensive quantification and characterization of microglial functions and morphology in postmortem brain tissue from 44 healthy, age-matched alcoholics and chronic alcoholics. A decrease in the perivascular CD68+ microglia in alcoholics was noted in both the gray and white matter. Additionally, the CD68+/Iba1− microglial subpopulation was found to be the dominant type in the controls. Conversely, in alcoholics, dystrophic changes in microglia were seen with a significant increase in Iba1 expression and perivascular to diffuse migration. An increase in CD11b expression was noted in alcoholics, with the Iba1+/CD11b− subtype promoting inflammation. All the controls were found to be negative for HHV-6 whilst the alcoholics demonstrated HHV-6 positivity in both gray and white matter. Amongst HHV-6 positive alcoholics, all the above-mentioned changes were found to be heightened when compared with HHV-6 negative alcoholics, thereby highlighting the compounding relationship between alcoholism and HHV-6 infection that promotes microglia-mediated neuroinflammation.

A prolactin-dependent sexually dimorphic mechanism of migraine chronification.

Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms. The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective. Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms. PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females. We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

Prefrontal Cortex Activation and Stopping Performance Underlie the Beneficial Effects of Atomoxetine on Response Inhibition in Healthy Volunteers and Those With Cocaine Use Disorder

BackgroundImpaired response inhibition in individuals with cocaine use disorder (CUD) is hypothesized to depend on deficient noradrenergic signaling in corticostriatal networks. Remediation of noradrenergic neurotransmission with selective norepinephrine reuptake inhibitors such as atomoxetine may therefore have clinical utility to improve response inhibitory control in CUD. MethodsWe carried out a randomized, double-blind, placebo-controlled, crossover study with 26 participants with CUD and 28 control volunteers investigating the neural substrates of stop-signal inhibitory control. The effects of a single dose of atomoxetine (40 mg) were compared with placebo on stop-signal reaction time performance and functional network connectivity using dynamic causal modeling. ResultsWe found that atomoxetine speeded Go response times in both control participants and those with CUD. Improvements in stopping efficiency on atomoxetine were conditional on baseline (placebo) stopping performance and were directly associated with increased inferior frontal gyrus activation. Further, stopping performance, task-based brain activation, and effective connectivity were similar in the 2 groups. Dynamic causal modeling of effective connectivity of multiple prefrontal and basal ganglia regions replicated and extended previous models of network function underlying inhibitory control to CUD and control volunteers and showed subtle effects of atomoxetine on prefrontal-basal ganglia interactions. ConclusionsThese findings demonstrate that atomoxetine improves response inhibition in a baseline-dependent manner in control participants and in those with CUD. Our results emphasize inferior frontal cortex function as a future treatment target owing to its key role in improving response inhibition in CUD.