Prefrontal Glutathione Levels in Major Depressive Disorder Are Linked to a Lack of Positive Affect.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.

Evaluation of Prefrontal γ-Aminobutyric Acid and Glutamate Levels in Individuals With Major Depressive Disorder Using Proton Magnetic Resonance Spectroscopy.

Importance: Major depressive disorder (MDD) is one of the most prevalent illnesses worldwide. Perturbations of the major inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate (Glu), respectively, as well as Glx (Glu or glutamine [Gln]) have been extensively reported in a multitude of brain areas of individuals with depression, but few studies have examined changes in Gln, the metabolic counterpart of synaptic Glu. Objective: To investigate changes in GABA, Glx, Glu, and Gln levels in a voxel in the left dorsolateral prefrontal cortex of participants with no, past, and current MDD using proton magnetic resonance spectroscopy (1H-MRS). Design, Setting, and Participants: This community-based study used a cross-sectional design using 3-T 1H-MRS in participants not taking MDD medication recruited from the community. The sample consisted of 251 healthy controls, 98 participants with a history of past MDD, and 47 participants who met the diagnostic criteria for current MDD. Diagnostic groups were comparable regarding age, education, income, and diet. Data were collected from March 2014 to October 2021, and data were analyzed from October 2021 to June 2022. Main Outcomes and Measures: GABA, Glx, Glu, and Gln concentrations in the left dorsolateral prefrontal cortex. Results: Of 396 included participants, 258 (65.2%) were female, and the mean (SD) age was 25.0 (4.7) years. Compared with healthy controls, those with past MDD and current MDD had lower GABA concentrations (mean [SEM] concentration: healthy controls, 2.70 [0.03] mmol/L; past MDD, 2.49 [0.05] mmol/L; current MDD, 2.54 [0.07] mmol/L; 92 with past MDD vs 236 healthy controls: r = 0.18; P = .002; 44 with current MDD vs 236 healthy controls: r = 0.13; P = .04). Compared with healthy controls, those with past MDD also had lower Glu concentrations (mean [SEM] concentration: healthy controls, 7.52 [0.06] mmol/L; past MDD, 7.23 [0.11] mmol/L; 93 with past MDD vs 234 healthy controls: r = 0.16; P = .01) and higher Gln concentrations (mean [SEM] concentration: healthy controls, 1.63 [0.04] mmol/L; past MDD, 1.84 [0.07] mmol/L; 66 with past MDD 153 healthy controls: r = 0.17; P = .04). Conclusions and Relevance: In a large, mostly medication-free community sample, reduced prefrontal GABA concentrations were associated with past MDD, consistent with histopathologic studies reporting reduced glial cell and GABA cell density in the prefrontal cortex in individuals with depression. Patients with MDD also demonstrated increased Gln levels, indicative of increased synaptic Glu release, adding to previous evidence for the Glu hypothesis of MDD.

Associations between heart rate variability, peripheral inflammatory markers and major depressive disorder.

BACKGROUND: Measures for the irregularity of the heartbeat, for example respiratory sinus arrhythmia, have been implicated as a measure for restorative functions of the vegetative nervous system. METHODS: In the current observational study, we investigated 265 subjects, 70 of whom had a lifetime history of major depression, with a plethysmographic heartbeat monitor, blood sampling, as well as a range of psychiatric questionnaires. RESULTS: Subjects with a history of MDE had significantly reduced respiratory sinus arrhythmia (RSA) as compared to never-depressed controls; in the whole sample, higher RSA went with lower anxiety/fear variables, especially in subscores related to cardiac symptoms as well as being afraid of dying. A reduced RSA was also associated with an increased concentration of cytokines (TNFa, IL1a, IL6, IFNg) and thyroid-stimulating hormone in the serum, pointing to a possible triangular relationship between immune system, vegetative nervous system, and emotional dysregulation. LIMITATIONS: We used a plethysmographic device for the measurement of heartbeat instead of an electrocardiogram, and had a single time point only. CONCLUSIONS: This data corroborate the idea that a disequilibrium of the vegetative nervous, especially if accompanied by a dysregulation system in immune function, can increase the risk for depression. Conversely, vagal stimulation and anti-inflammatory treatments may support the treatment with antidepressants.

Cerebral perfusion in depression: Relationship to sex, dehydroepiandrosterone sulfate and depression severity.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disease burden and shows a marked sexual dimorphism. Previous studies reported changes in cerebral perfusion in MDD, an association between perfusion and dehydroepiandrosterone sulfate (DHEAS) levels, and large sex differences in perfusion. This study examines whether perfusion and DHEAS might mediate the link between sex and depressive symptoms in a large, unmedicated community sample. METHODS: The sample included 203 healthy volunteers and 79 individuals with past or current MDD. Depression severity was assessed with the Hamilton Depression Scale (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS). 3 T MRI perfusion data were collected with a pseudocontinuous arterial spin labelling sequence and DHEAS was measured in serum by LC-MS/MS. RESULTS: Large sex differences in perfusion were observed (p < 0.001). Perfusion was negatively correlated with DHEAS (r = -0.23, p < 0.01, n = 250) and with depression severity (HAM-D: r = -0.17, p = 0.01, n = 242; partial Spearman correlation, controlling for age and sex), but not with anxiety. A significant sex*perfusion interaction on depression severity was observed. In women, perfusion showed more pronounced negative correlations with depressive symptoms, with absent or, in the case of the MADRS, opposite effects observed in men. A mediation analysis identified DHEAS and perfusion as mediating variables influencing the link between sex and the HAM-D score. CONCLUSION: Perfusion was linked to depression severity, with the strongest effects observed in women. Perfusion and the neurosteroid DHEAS appear to mediate the link between sex and HAM-D scores, suggesting that inter-individual differences in perfusion and DHEAS levels may contribute to the sexual dimorphism in depression.

Negative association between left prefrontal GABA concentration and BDNF serum concentration in young adults.

BACKGROUND: The brain's major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the brain-derived neurotrophic factor (BDNF) play important roles in several stress-related disorders. Magnetic resonance spectroscopy (MRS) allows for non-invasive quantification of GABA concentration in the brain. We investigated the relationship between GABA concentration in the left dorsolateral prefrontal cortex (DLPFC) and BDNF concentration in the serum in a community-based sample of young subjects. METHODS: For the GABA measurement a single voxel MR spectrum was assessed in the prefrontal lobe (25 × 40 × 30 mm) using the MEGA-PRESS method in 276 subjects. BDNF serum concentrations were assessed with an ELISA kit. For 147 subjects we had both MRS and BDNF serum data, and for 79 subjects we had genotype data on the BDNF rs6265 polymorphism. Depressive psychopathology was assessed using Beck's Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MADRS) and Structured Clinical Interviews for Diagnostic and Statistical Manual of Mental Disorders (SCID) for DSM-IV. RESULTS: GABA concentration in the left DLPFC was negatively associated with BDNF serum concentration (r = -.264, p = .001). This correlation remained significant if corrected for sex (r = -.264, p = .001). BDNF serum concentration was also positively associated with volumes and surface areas of the left prefrontal cortex (p = .048, p = .005). There were no significant associations or interaction with depressive psychopathology (BDI, MADRS, SCID) or rs6265. CONCLUSION: The results of this study suggest that GABA, BDNF and prefrontal brain volumes are interrelated, but do not show a strong association to depressive psychopathology, possibly due to the mild forms of psychiatric conditions present in our community-based sample.

The Association Between Adolescent Residential Mobility and Adult Social Anxiety, BDNF and Amygdala-Orbitofrontal Functional Connectivity in Young Adults With Higher Education.

Background: Large-scale epidemiological studies demonstrate that house moves during adolescence lead to an increase in anxiety and stress-sensitivity that persists into adulthood. As such, it might be expected that moves during adolescence have strong negative and long-lasting effects on the brain. We hypothesized that moves during adolescence impair fear circuit maturation, as measured by the connectivity between amygdala and orbitofrontal cortex, and expression of brain-derived neurotrophic factor (BDNF). Methods: We examined young adults with middle and high economic status recruited from the community using clinical interviews, self-report questionnaires, functional magnetic resonance imaging during an emotional faces task and during a 10 min rest phase, and serum BDNF serum concentration. Results: Out of 234 young adults, 164 did not move between ages 10 and 16 (i.e., moves with change of school), 50 moved once, and 20 moved twice or more than twice. We found relationships between adolescent moving frequency and social avoidance (pcorr = 0.012), right amygdala-orbitofrontal cortex connectivity (pcorr = 0.016) and low serum BDNF concentrations in young adulthood (pcorr = 0.012). Perceived social status of the mother partly mitigated the effects of moving on social avoidance and BDNF in adulthood. Conclusions: This study confirms previous reports on the negative and persistent effects of residential mobility during adolescence on mental health. It suggests that these effects are mediated by impairments in fear circuit maturation. Finally, it encourages research into protecting factors of moving during adolescents such as the perceived social status of the mother.

Tranexamic Acid Reduces Perioperative Blood Loss and Hemarthrosis in Total Ankle Arthroplasty.

Tranexamic acid (TXA) is an effective agent used for reducing perioperative blood loss and decreasing the potential for postoperative hemarthrosis. We hypothesized that patients who had received intraoperative TXA during total ankle arthroplasty (TAA) would have a reduction in postoperative drain output, thereby resulting in a reduced risk of postoperative hemarthrosis and lower wound complication rates. A retrospective review was conducted on 50 consecutive patients, 25 receiving TXA (TXA-TAA) and 25 not receiving TXA (No TXA-TAA), who underwent an uncemented TAA between September 2011 and December 2015. Demographic characteristics, drain output, preoperative and postoperative hemoglobin levels, operative and postoperative course, and minor and major wound complications of the patients were reviewed. Drain output was significantly less in the TXA-TAA group compared to that in the No TXA-TAA group (71.6 ± 60.3 vs 200.2 ± 117.0 mL, respectively, P < .0001). The overall wound complication rate in the No TXA-TAA group was higher (20%, 5/25) than that in the TXA-TAA group (8%, 2/25) (P = .114). The mean change in preoperative to postoperative hemoglobin level was significantly less in the TXA-TAA group compared to that in the No TXA-TAA group (1.5 ± 0.6 vs 2.0 ± 0.4 g/dL, respectively, P = .01). TXA is an effective hemostatic agent when used during TAA. TXA reduces perioperative blood loss, hemarthrosis, and the risk of wound complications.

Medical use of cannabis in Switzerland: analysis of approved exceptional licences.

AIMS OF THE STUDY: In recent years, the Swiss Federal Office of Public Health (FOPH) granted exceptional licenses for the medical use of cannabinoids, typically for 6 months with possible extensions. A systematic review of cannabinoids for medical use commissioned by the FOPH supports the use of cannabinoids for the treatment of chronic pain and spasticity. However, little is known about the patients treated with cannabinoids. We aimed to study medical uses of cannabinoids as part of the FOPH's programme of exceptional licenses. METHODS: We examined all requests for medical use of cannabinoids sent to FOPH in 2013 and 2014. A standardised data sheet was developed to extract data from the files of approved requests. We extracted the duration of the licence, the year it was granted, and the payer of the therapy. At the level of the patient we collected the date of birth, sex, region of residence, diagnosis and the indication. Ethical approval was granted by the Ethics Committee of the Canton of Bern. RESULTS: We analysed 1193 patients licenced for cannabinoid treatment in 2013 or 2014. During 2013, 542 patients were treated under the exceptional licencing programme (332 requesting physicians) compared with 825 in 2014 (446 physicians). Over half of patients (685; 57%) were women. The mean age was 57 years (standard deviation 15.0), chronic pain (49%) and spasticity (40%) were the most common symptoms, and co-medication was reported for 39% of patients. Seventy-eight different diagnoses were recorded, including multiple sclerosis (257 patients, 22%), soft tissue disorders (119, 10%), dorsalgia (97, 8.1%), spinal muscular atrophy (65, 5.5%) and paraplegia/tetraplegia (62, 5.2%). Licence extensions were granted to 143 patients (26.4%) in 2013 and 324 patients (39.3%) in 2014. There were substantial regional variations of the rates of patients treated with cannabinoids. On average, eight patients per 100 000 residents received an exceptional licence. Most patients (1083, 91%) paid out of pocket. CONCLUSIONS: Exceptional licences for medical use of cannabinoids have increased substantially in Switzerland, with the programme including patients with a wide range of conditions.

Weight bearing cone beam CT scan versus gravity stress radiography for analysis of supination external rotation injuries of the ankle.

For AO 44-B2 ankle fractures of uncertain stability, the current diagnostic standard is to obtain a gravity stress radiograph, but some have advocated for the use of weight-bearing radiographs. The primary aim was to compare measures of medial clear space (MCS) on weight-bearing cone beam computed tomography (CBCT) scans versus gravity stress radiographs for determining the state of stability of ankle fractures classified as AO SER 44-B2 or Weber B. The secondary aim was to evaluate the details offered by CBCT scans with respect to other findings that may be relevant to patient care. Nine patients were enrolled in this cross-sectional study between April 2016 and February 2017 if they had an AO SER 44-B2 fracture of uncertain stability, had a gravity stress radiograph, and were able to undergo CT scan within seven days. The width of the MCS was measured at the level of the talar dome on all radiographs and at the mid coronal slice on CT. Wilcoxon signed-ranks tests were used to compare MCS between initial radiographs, gravity stress radiographs and weight-bearing CBCT scans. MCS on weight-bearing CBCT scan (1.41±0.41 mm) was significantly less than standard radiographs (3.28±1.63 mm, P=0.004) and gravity stress radiographs (5.82±1.93 mm, P=0.02). There was no statistically significant difference in MCS measured on standard radiographs versus gravity stress radiographs (P=0.11). Detailed review of the multiplanar CT images revealed less than perfect anatomical reduction of the fractures, with residual fibular shortening, posterior displacement, and fracture fragments in the incisura as typical findings. Similar to weight-bearing radiographs, weight-bearing CBCT scan can predict stability of AO 44-B2 ankle fractures by showing restoration of the MCS, and might be used to indicate patients for non-operative treatment. None of the fractures imaged in this study were perfectly reduced however, and further clinical research is necessary to determine if any of the detailed weight-bearing CBCT findings are related to patient outcomes.

Conditioned place preferences in humans using secondary reinforcers.

The goal of this experiment was to examine whether a conditioned place preference could be established in humans using a secondary reinforcer that provided little obvious reward to the participants. Two experiments were conducted to answer this question. In Experiment 1, 244 undergraduates were placed into a VR environment consisting of two visually distinct rooms connected by a door. Throughout the experiment, one room was randomly paired with occasional point rewards while the other unique room was never paired with rewards. Participants received thee pairings in each room. After a short break, a test session was administered, and participants were given free access to the entire VR environment and no point rewards were administered. On the test day, we observe that participants displayed a significant CPP for the room paired with points, as evidenced by significant differences in rating each of the rooms in terms of enjoyment. In Experiment 2, 77 undergraduates were tested using a biased conditioning approach in which an initial test session was conducted to obtain the participant's preferred room bias, and then the least-preferred room was designated as the points reward room for each participant. Using this biased conditioning approach, participants spent a significantly greater amount of time in the points-paired room. In this case, participants showed preferences based on explicit and implicit measures. These results suggest new approaches to examine the role of secondary reinforcers in nontraditional addictions such as internet, gaming, and gambling dependencies.

A radiographic and clinical comparison of reamer-irrigator-aspirator versus iliac crest bone graft in ankle arthrodesis.

PURPOSE: We evaluated radiographic fusion at follow-up and complication rates in patients who had either iliac crest (ICBG) or femoral reamer-irrigator-aspirator (RIA) bone graft for tibiotalar fusion. METHODS: We retrospectively reviewed charts and radiographs of all patients who had a tibiotalar fusion from August 2007 to February 2011. Records were analysed for patient demographics, complications, and clinical symptoms. Radiographs were reviewed in sequential order by two fellowship-trained foot and ankle surgeons and one orthopaedic surgeon who specialises in foot and ankle surgery to determine radiographic fusion at routine follow-up. Patients were contacted to determine current visual analog scores (VAS) at their graft site. RESULTS: Mean patient age was 49.4 ± 12.1 years in the RIA group and 49.3 ± 15.4 years in the ICBG group (p = .97). Pre-operative characteristics showed no significant differences between groups. The ICBG group had significantly more nonunions than the RIA group (six vs. one, p = 0.04). Two patients in the ICBG had chronic pain at their graft site based on their VAS score; there were none in the RIA group. Radiographic fusion at follow-up was similar between groups, with no significant difference (12.48 ± 3.85 weeks vs.12.21 ± 3.19 weeks, p = .80). CONCLUSIONS: There was a significantly higher nonunion rate in the ICBG group, but both groups had a solid radiographic bony fusion at similar follow-up time points. Our results suggest RIA bone graft is a viable alternative to ICBG for tibiotalar fusion.

Short to midterm clinical and radiographic outcomes of the Salto total ankle prosthesis.

BACKGROUND: Total ankle arthroplasty (TAA) has become an increasingly effective treatment option for tibiotalar arthritis. The purpose of this study was to evaluate the short to midterm clinical and radiographic outcomes of the Salto fixed bearing total ankle prosthesis. METHODS: We retrospectively reviewed the radiographs and patient records of 74 consecutive patients with 75 TAA implants from January 2007 to April 2011. The average age was 60.6 years (range, 41-82) with 41 females and 33 males. The average clinical follow-up was 43 months (range, 24-73 months). Radiographs were reviewed for areas of radiolucency and cystic changes around the talar and tibial implants, as well as for implant migration using standardized tibal, talar, talocalcaneal, and tibial slope angular measurements. The validated Foot and Ankle Outcome Score (FAOS), Short Form-12 (SF-12), and Visual Analog Scale (VAS) were used as subjective patient outcome measures. Kaplan Meier (K-M) curves were created for implant survivorship with revision of components as an endpoint and for return to the operating room for any reason. RESULTS: Total ankle survivorship was 98%. Thirteen patients returned to the operating room for any reason. There was 1 deep infection, and no ankles were converted to an arthrodesis. Average ankle dorsiflexion and plantarflexion improved from 4.3 ± 3.3 to 8.7 ± 5.6 degrees (P = .0008) and 24 ± 11 to 29 ± 7 degrees (P = .04), respectively. Patients showed significant improvements in all subscales of the FAOS (P < .0001). The physical component of the SF-12 significantly improved from 30 ± 8 to 41 ± 13 (P < .0001), but this was not observed with the mental component (52 ± 1 vs 53 ± 1, P = .55). The mean VAS for patient satisfaction was 9 (range, 2-10). Two patients had component migration (1 tibial and 1 talar component), neither of which required a revision procedure. Six ankles had a total of 9 radiolucent lines with a radiographically stable implant, and no patients had cystic changes. CONCLUSION: This is one of the first articles to report clinical and radiographic outcome data for the fixed bearing version of this prosthesis. We observed significant improvements in subjective outcome measures and range of motion with a 98% component survivorship at short to midterm follow-up. Longer follow-up will be necessary to determine the durability of this implant. LEVEL OF EVIDENCE: Level IV, case series.

Donor site morbidity with reamer-irrigator-aspirator (RIA) use for autogenous bone graft harvesting in a single centre 204 case series.

Donor site morbidity and complication rate using the reamer-irrigator-aspirator (RIA) system for intramedullary, non-structural autogenous bone graft harvesting were investigated in a retrospective chart and radiographic review at a University affiliated Level-1 Trauma Centre. 204 RIA procedures in 184 patients were performed between 1/1/2007 and 12/31/2010. RIA-indication was bone graft harvesting in 201 (98.5%), and intramedullary irrigation and debridement in 3 (1.5%) cases. Donor sites were: femur - antegrade 175, retrograde 4, tibia - antegrade 7, retrograde 18. Sixteen patients had undergone two RIA procedures, two had undergone three procedures, all using different donor sites. In 4 cases, same bone harvesting was done twice. Mean volume of bone graft harvested was 47 ± 22ml (20-85 ml). The complication rate was 1.96% (N=4). Operative revisions included 2 retrograde femoral nails for supracondylar femur fractures 6 and 41 days postoperatively (antegrade femoral RIA), 1 trochanteric entry femoral nail (subtrochanteric fracture) 17 days postoperatively (retrograde femoral RIA) and 1 prophylactic stabilization with a trochanteric entry femoral nail for intraoperative posterior femoral cortex penetration without fracture. In our centre, the RIA technique has a low donor site morbidity and has been successfully implemented for harvesting large volumes of nonstructural autogenous bone graft.

Changes in human knee ligament stiffness secondary to osteoarthritis.

Stiffness of the medial (MCL) and lateral (LCL) collateral ligaments was compared between a group of 10 patients undergoing total knee arthroplasty for varus degenerative osteoarthritis (OAP), a group of 10 osteoarthritic cadaveric knees (OAC), and a group of 10 non-osteoarthritic cadaveric knees (NOA). A load-elongation curve was obtained for the medial and lateral compartments of each knee using an instrumented Moreland spreader. A strain gage (SG) was attached to the spreader handle and strain was calibrated to load applied against the spread distance. In extension, medial compartment stiffness of the OAP, OAC, and NOA groups was 60.7+/-16, 52.8+/-9.3 and 21.4+/-5.0 N/mm, respectively. Lateral compartment stiffness in extension was 29.2+/-9.2, 33.3+/-10.3 and 19.5+/-5.3 N/mm, for OAP, OAC, and NOA, respectively. Differences in stiffness between the OAP and OAC groups were not statistically significant (p > 0.05). However, the osteoarthritic groups (OAP and OAC) demonstrated a statistically significantly (p < 0.05) increase in ligament stiffness when compared to the NOA group. Following knee arthroplasty, stiffer medial structures in extension may lead to flexion contracture and accelerated polyethylene wear. Adequate bone resection, in conjunction with soft tissue release may alleviate the threefold increase in stiffness observed in the medial compartment secondary to OA without jeopardizing joint stability.