Age of onset of obsessive-compulsive disorder differentially affects white matter microstructure.

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Multiomic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines.

The nonpsychoactive cannabinoid, cannabidiol (CBD), is Food and Dug Administration approved for treatment of two drug-resistant epileptic disorders and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multiomic profiling. FRET-based biosensor screening revealed that CBD elicits a sharp rise in cytosolic calcium, and activation of AMP-activated protein kinase in human keratinocyte and neuroblastoma cell lines. CBD treatment leads to alterations in the abundance of metabolites, mRNA transcripts, and proteins associated with activation of cholesterol biosynthesis, transport, and storage. We found that CBD rapidly incorporates into cellular membranes, alters cholesterol accessibility, and disrupts cholesterol-dependent membrane properties. Sustained treatment with high concentrations of CBD induces apoptosis in a dose-dependent manner. CBD-induced apoptosis is rescued by inhibition of cholesterol synthesis and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.

Diagnostic utility of 11 C-methionine PET/CT in primary hyperparathyroidism in a UK cohort: A single-centre experience and literature review.

OBJECTIVE: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45). DESIGN: Retrospective single-center cohort study. PATIENTS AND MEASUREMENTS: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery. RESULTS: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas. CONCLUSIONS: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.

Out-of-hours admissions in patients treated with immune checkpoint inhibitors and their primary management with steroids.

INTRODUCTION: The incidence of immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICI) is well described. However, the impact on emergency care services is not. This study investigated the incidence of irAEs out-of-hours, and the management used to mitigate symptoms and side effects. METHODS: This retrospective cohort study reviewed all emergency presentations triaged by the acute oncology team between December 2021 and June 2022, between 5 pm and 9 am. Patients were identified from triage audit sheets and remaining data points were retrieved from electronic health records. Inclusion criteria included all adult patients admitted on an ICI at one tertiary centre. RESULTS: In 7 months, 970 patients called the acute oncology helpline 11% (n = 109) of patients were on an ICI treatment. After clinical review, 78% (n = 70) resulted in hospital admissions, with length of stay cumulating to 496 bed days. 56% (n = 39) of patients delayed reporting symptoms, ranging between 12 hours and 10 days from symptom onset to seeking support. 49% (n = 34) patients received steroids to manage suspected irAEs. Dexamethasone was the most common steroid used in 71% (n = 24) of patients, and variation was found in prescribed doses. CONCLUSIONS: These results underline the urgent need to address patient and staff education on adverse effects related to ICI. Patients require a comprehensive understanding of the symptoms and importance of prompt reporting. Staff education on recognition and treatment management is needed to reduce variation in practice. Further research is needed to identify barriers in symptom reporting and focus on realtime reporting to reduce the out-of-hours burden on services.

Subcortical shape in pediatric and adult obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) implicates alterations in cortico-striato-thalamo-cortical and fronto-limbic circuits. Building on prior structural findings, this is the largest study to date examining subcortical surface morphometry in OCD. METHODS: Structural magnetic resonance imaging data were collected from 200 participants across development (5-55 years): 28 youth and 75 adults with OCD and 27 psychiatrically healthy youth and 70 adults. General linear models were used to assess group differences and group-by-age interactions on subcortical shape (FSL FIRST). RESULTS: Compared to healthy participants, those with OCD exhibited surface expansions on the right nucleus accumbens and inward left amygdala deformations, which were associated with greater OCD symptom severity ([Children's] Yale-Brown Obsessive-Compulsive Scale). Group-by-age interactions indicated that accumbens group differences were driven by younger participants and that right pallidum shape was associated inversely with age in healthy participants, but not in participants with OCD. No differences in the shape of other subcortical regions or in volumes (FreeSurfer) were detected in supplementary analyses. CONCLUSIONS: This study is the largest to date examining subcortical shape in OCD and the first to do so across the developmental spectrum. NAcc and amygdala shape deformation builds on extant neuroimaging findings and suggests subtle, subregional alterations beyond volumetric findings. Results shed light on morphometric alterations in OCD, informing current pathophysiological models.

Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction.

Standard fear extinction relies on the ventromedial prefrontal cortex (vmPFC) to form a new memory given the omission of threat. Using fMRI in humans, we investigated whether replacing threat with novel neutral outcomes (instead of just omitting threat) facilitates extinction by engaging the vmPFC more effectively than standard extinction. Computational modeling of associability (indexing surprise strength and dynamically modulating learning rates) characterized skin conductance responses and vmPFC activity during novelty-facilitated but not standard extinction. Subjects who showed faster within-session updating of associability during novelty-facilitated extinction also expressed better extinction retention the next day, as expressed through skin conductance responses. Finally, separable patterns of connectivity between the amygdala and ventral versus dorsal mPFC characterized retrieval of novelty-facilitated versus standard extinction memories, respectively. These results indicate that replacing threat with novel outcomes stimulates vmPFC involvement on extinction trials, leading to a more durable long-term extinction memory.SIGNIFICANCE STATEMENT Psychiatric disorders characterized be excessive fear are a major public health concern. Popular clinical treatments, such as exposure therapy, are informed by principles of Pavlovian extinction. Thus, there is motivation to optimize extinction strategies in the laboratory so as to ultimately develop more effective clinical treatments. Here, we used functional neuroimaging in humans and found that replacing (rather than just omitting) expected aversive events with novel and neutral outcomes engages the ventromedial prefrontal cortex during extinction learning. Enhanced extinction also diminished activity in threat-related networks (e.g., the insula, thalamus) during immediate extinction and a 24 h extinction retention test. This is new evidence for how behavioral protocols designed to enhance extinction affects neurocircuitry underlying the learning and retention of extinction memories.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort.

BACKGROUND: Primary hyperparathyroidism (PHPTH) is a common endocrine disorder and an estimated 10% of cases are hereditary, related to syndromes including; multiple endocrine neoplasia (MEN) type 1, MEN type 4, MEN2A and hereditary hyperparathyroidism-jaw tumour syndrome. Establishing the underlying genetic cause for PHPTH allows for personalized and cost-effective management. Familial hypocalicuric hypercalcaemia (FHH) is a benign disorder of hypercalcaemia associated with an inappropriately low urinary calcium excretion, which is quantified by the calcium creatinine clearance ratio (CCCR). Recent NHS England National Genomic Test Directory testing criteria for familial hyperparathyroidism state testing patients presenting with PHPTH and CCCR > 0.02 presenting (i) <35 years of age, or (ii) <45y with one of (a) multiglandular disease, or (b) hyperplasia on histology, or (c) ossifying fibroma(s) of the maxilla and/ or mandible, or (d) a family history of unexplained PHPTH. The testing criterion for FHH is a CCCR < 0.02. AIMS AND METHODS: A retrospective review of patients referred for genetic testing over a 4 year period for suspected hereditary HPTH was performed. Genetic analysis was performed by next-generation sequencing of the following genes; MEN1, CDC73, CASR, CDKN1A, CDKN1B, CDKN2B, CDKN2C, RET, GCM2, GNA11, and AP2S1 in NHS-accredited Regional Genetic laboratories. Aims of this study were to better define testing criteria for suspected hereditary PHPTH in a UK cohort. RESULTS: A total of 121 patients were included in this study (92 female) with a mean age of 41 years (SD 17). A pathogenic germline variant was identified in 16% (n = 19). A pathogenic variant was identified in the PHPTH genes CDC73 in a single patient and MEN1 in six patients (6% of total), in the FHH genes, CASR in 11 patients and AP2S1 in a single paediatric case (10% of total). A variant of uncertain significance (VUS) was identified in eight patients (6%) but over the course of this study familial segregation studies and computational analysis enabled re-classification of four of the variants, with two VUS's in the CASR gene being upgraded to likely pathogenic variants. Age at diagnosis and multiglandular disease as sole risk factors were not predictive of a pathogenic germline variant in this cohort but a positive family history was strongly predictive (P = .0002). A significant difference in the mean calcium creatinine clearance ratio (CCCR) in those patients with an identified CASR pathogenic variant versus those without (P = .0001) was demonstrated in this study. Thirty-three patients were aged over 50 years and the diagnostic rate of a pathogenic variant was 15.1% in those patients >50 years of age compared to 15.9% in those <50 years. Five patients >50 years and with a CCCR of <0.01, were diagnosed with a pathogenic variant in CASR. CONCLUSION: Family history was the strongest predictor of hereditary PHPTH in this cohort. This study has highlighted the importance of re-evaluating VUS's in order to inform patient management and enable appropriate genetic counselling. Finally, this study has demonstrated the need to consider genetic testing for PHPTH in patients of any age, particularly those with additional risk factors.

Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study.

BACKGROUND: Preclinical data implicate the endocannabinoid system in the pathology underlying obsessive-compulsive disorder (OCD), while survey data have linked OCD symptoms to increased cannabis use. Cannabis products are increasingly marketed as treatments for anxiety and other OCD-related symptoms. Yet, few studies have tested the acute effects of cannabis on psychiatric symptoms in humans. METHODS: We recruited 14 adults with OCD and prior experience using cannabis to enter a randomized, placebo-controlled, human laboratory study to compare the effects on OCD symptoms of cannabis containing varying concentrations of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on OCD symptoms to placebo. We used a within-subjects design to increase statistical power. Across three laboratory sessions, participants smoked three cannabis varietals in random order: placebo (0% THC/0% CBD); THC (7.0% THC/0.18% CBD); and CBD (0.4% THC/10.4% CBD). We analyzed acute changes in OCD symptoms, state anxiety, cardiovascular measures, and drug-related effects (e.g., euphoria) as a function of varietal. RESULTS: Twelve participants completed the study. THC increased heart rate, blood pressure, and intoxication compared with CBD and placebo. Self-reported OCD symptoms and anxiety decreased over time in all three conditions. Although OCD symptoms did not vary as a function of cannabis varietal, state anxiety was significantly lower immediately after placebo administration relative to both THC and CBD. CONCLUSIONS: This is the first placebo-controlled investigation of cannabis in adults with OCD. The data suggest that smoked cannabis, whether containing primarily THC or CBD, has little acute impact on OCD symptoms and yields smaller reductions in anxiety compared to placebo.

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative.

BACKGROUND: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. METHODS: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. DISCUSSION: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Can delay discounting deliver on the promise of RDoC?

The National Institute of Mental Health launched the Research Domain Criteria (RDoC) initiative to better understand dimensions of behavior and identify targets for treatment. Examining dimensions across psychiatric illnesses has proven challenging, as reliable behavioral paradigms that are known to engage specific neural circuits and translate across diagnostic populations are scarce. Delay discounting paradigms seem to be an exception: they are useful for understanding links between neural systems and behavior in healthy individuals, with potential for assessing how these mechanisms go awry in psychiatric illnesses. This article reviews relevant literature on delay discounting (or the rate at which the value of a reward decreases as the delay to receipt increases) in humans, including methods for examining it, its putative neural mechanisms, and its application in psychiatric research. There exist rigorous and reproducible paradigms to evaluate delay discounting, standard methods for calculating discount rate, and known neural systems probed by these paradigms. Abnormalities in discounting have been associated with psychopathology ranging from addiction (with steep discount rates indicating relative preference for immediate rewards) to anorexia nervosa (with shallow discount rates indicating preference for future rewards). The latest research suggests that delay discounting can be manipulated in the laboratory. Extensively studied in cognitive neuroscience, delay discounting assesses a dimension of behavior that is important for decision-making and is linked to neural substrates and to psychopathology. The question now is whether manipulating delay discounting can yield clinically significant changes in behavior that promote health. If so, then delay discounting could deliver on the RDoC promise.

Impaired generalization of reward but not loss in obsessive-compulsive disorder.

BACKGROUND: Generalizing from past experiences can be adaptive by allowing those experiences to guide behavior in new situations. Generalizing too much, however, can be maladaptive. For example, individuals with pathological anxiety are believed to overgeneralize emotional responses from past threats, broadening their scope of fears. Whether individuals with pathological anxiety overgeneralize in other situations remains unclear. METHODS: The present study (N = 57) used a monetary sensory preconditioning paradigm with rewards and losses to address this question in individuals with obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD), comparing them to healthy comparison subjects (HC). In all groups, we tested direct learning of associations between cues and reward vs. loss outcomes, as well as generalization of learning to novel choice options. RESULTS: We found no differences between the three groups in the direct learning of stimuli with their outcomes: all subjects demonstrated intact stimulus-response learning by choosing rewarding options and avoiding negative ones. However, OCD subjects were less likely to generalize from rewards than either the SAD or HC groups, and this impairment was not found for losses. Additionally, greater deficits in reward generalization were correlated with severity of threat estimation, as measured by a subscale of the Obsessive Beliefs Questionnaire, both within OCD and across all groups. CONCLUSIONS: These findings suggest that a compromised ability to generalize from rewarding events may impede adaptive behavior in OCD and in those susceptible to high estimation of threat.

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders.

OBJECTIVE: Refractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive-compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016. DESIGN: Here we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses. CONCLUSION: Interest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.

Hyaluronic Acid Filler Injections Under the Metatarsal Heads Provide a Significant and Long-Lasting Improvement in Metatarsalgia From Wearing High-Heeled Shoes.

BACKGROUND: Metatarsalgia is a common overuse injury that may be caused by wearing high-heeled shoes. OBJECTIVE: To evaluate the decrease in metatarsalgia using a hyaluronic acid dermal filler. METHODS: A 6-month, open study was conducted in 15 subjects with metatarsalgia because of regularly wearing high-heeled shoes. Hyaluronic acid (20 mg/mL) with lidocaine hydrochloride (3 mg/mL) was injected under the metatarsal heads at baseline. Pain (on a 0-10 scale) under the metatarsal heads when walking in high heels was recorded in a weekly subject diary. RESULTS: At 6 months after injections, 5 subjects (33.3%) reported no metatarsalgia pain. For subjects with pain, they were able to wear high heels for significantly longer than before the injections (7.2 hours at 6 months vs 3.4 hours at baseline). Significant improvements from baseline were observed at Month 6 for time to onset of pain (3.5 hours longer), time between onset of pain and intolerable pain (1.9 hours longer), and pain sensation (-2.2 grades at onset and -3.8 grades at shoe removal). No adverse events were reported. CONCLUSION: Injection of hyaluronic acid filler to the forefeet provided a significant effective, long-lasting, and well-tolerated improvement in metatarsalgia because of wearing high-heeled shoes.

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance.

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.

Abnormal hippocampal structure and function in clinical anxiety and comorbid depression.

Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2-3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation-structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression-mediated through its impact on abnormal hippocampal threat processing. Collectively, our findings show a strong association between changes in hippocampal microstructure and threat processing, which together may present a common neural pathway to comorbidity of anxiety and depression.

Abnormal reward circuitry in anorexia nervosa: A longitudinal, multimodal MRI study.

Anorexia nervosa (AN) is a debilitating illness and existing interventions are only modestly effective. This study aimed to determine whether AN pathophysiology is associated with altered connections within fronto-accumbal circuitry subserving reward processing. Diffusion and resting-state functional MRI scans were collected in female inpatients with AN (n = 22) and healthy controls (HC; n = 18) between the ages of 16 and 25 years. Individuals with AN were scanned during the acute, underweight phase of the illness and again following inpatient weight restoration. HC were scanned twice over the same timeframe. Based on univariate and multivariate analyses of fronto-accumbal circuitry, underweight individuals with AN were found to have increased structural connectivity (diffusion probabilistic tractography), increased white matter anisotropy (tract-based spatial statistics), increased functional connectivity (seed-based correlation in resting-state fMRI), and altered effective connectivity (spectral dynamic causal modeling). Following weight restoration, fronto-accumbal structural connectivity continued to be abnormally increased bilaterally with large (partial η2 = 0.387; right NAcc-OFC) and moderate (partial η2 = 0.197; left NAcc-OFC) effect sizes. Increased structural connectivity within fronto-accumbal circuitry in the underweight state correlated with severity of eating disorder symptoms. Taken together, the findings from this longitudinal, multimodal neuroimaging study offer converging evidence of atypical fronto-accumbal circuitry in AN. Hum Brain Mapp 37:3835-3846, 2016. © 2016 Wiley Periodicals, Inc.

Incidence of pituitary dysfunction following traumatic brain injury: A prospective study from a regional neurosurgical centre.

Patients with traumatic brain injury (TBI) may develop pituitary dysfunction. Although, there is now increasing awareness of and investigations into such post-traumatic hypopituitarism (PTHP), the exact prevalence and incidence remain uncertain. Here, we aim to identify the incidence of PTHP in a selected population of TBI patients deemed at risk of PTHP at a regional neurosurgical centre in the UK. A total of 105 patients have been assessed in two cohorts: (i) 58 patients in serial cohort and (ii) 47 patients in cross-sectional late cohort. We found that in serial cohort, 10.3% (6/58) of TBI patients had abnormalities of the pituitary-adrenal axis in the acute phase (Day 0-7 post injury). In comparison, in cross-sectional late cohort, 21.3% (10/47) of the patients developed dysfunction in at least one of their pituitary axes at 6 months or more post-TBI, with hypogonadotrophic hypogonadism being the most common. Twenty-two patients from these two cohorts had their growth hormone assessment at 12 months or more post-TBI and 9.1% (2/22) were found to have growth hormone deficiency. Our results suggest that PTHP is a common condition amongst sufferers of TBI, and appropriate measures should be taken to detect and manage it.