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Introduction: Considerable evidence suggests a pathophysiological role of neuroinflammation in psychiatric disorders. Lumbar puncture and positron emission tomography (PET) show increased levels of inflammation in psychiatric disorders. However, the invasive nature of these techniques, as well as their expense, make them undesirable for routine use in patients. Electroencephalography (EEG) is noninvasive, affordable and shows potential as a clinical tool for detection of neuroinflammation., Methods: In this randomized, crossover design, placebo-controlled, double-blind study, typhoid vaccine was administered to 20 healthy volunteers to induce a low level of neuroinflammation. EEG was recorded before and after placebo/vaccine administration during resting-state and during performance of the Attention Network Test (ANT). Resting-state EEG was analyzed using spectral power analysis, and time-frequency analysis was used for the EEG from the ANT. Behavioral data were assessed using linear mixed models and Spearman's correlations., Results: Behavioral results from the ANT showed no decrement in performance following the vaccine, consistent with previous studies. During eyes-open resting, there was a relative decrease in right-frontal delta power in the vaccine condition compared to placebo. There was a trend toward greater alpha power suppression in the alerting response of the attentional network; however, this finding did not reach significance., Conclusion: Decreased resting-state delta power may reflect an unpleasant internal state conferred by the vaccine. Inflammation did not significantly affect attention networks. The absence of significant alterations may be due to an insufficient inflammatory response. Further studies are needed to assess the feasibility of EEG as a technique for detection of neuroinflammation., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo., Methods: This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 μg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures., Discussion: This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants' naturalistic environment. The measures included are designed to assess the drug's safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials., Trial Registration: ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024., (© 2024. The Author(s).)

Objectives: A resurgence of research investigating the administration of psychedelic compounds alongside psychotherapy suggests that this treatment is a promising intervention for anxiety, depression, and existential distress in people with cancer. However, psychedelic treatment that induces a mind-altering experience potentially poses barriers to vulnerable cancer patients, and health-care practitioners may have concerns about referring their patients to trials investigating this approach. The aim of the current study was to investigate the perceptions of cancer health-care practitioners based in New Zealand and the USA related to psychedelic-assisted therapy., Methods: This study utilized a cross-sectional survey of cancer health-care practitioners in New Zealand and the USA via convenience sampling to identify their perceptions about the concept of conducting psychedelic-assisted therapy with cancer patients., Results: Participants perceived that (1) psychedelic-assisted therapy has the potential to provide benefit for cancer patients, (2) research in this area across a variety of domains is important, (3) work should consider spiritual and indigenous perspectives of health, and (4) there was willingness to refer patients to trials in this area, especially patients with advanced disease who were no longer going through curative treatment. Participants in the USA had greater awareness of psychedelics than the New Zealand sample; however, New Zealand participants more strongly believed that spiritual/indigenous factors should be considered in psychedelic-assisted therapy., Significance of Results: Cancer health-care practitioners in our sample considered research investigating the potential for psychedelic-assisted therapies to be important and may be more open to studies that start in palliative and end-of-life contexts.

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3-38.3 min) compared to placebo-with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ; ACTRN12621000436875., (© 2024. The Author(s).)

Background: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2)., Methods: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen., Discussion: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial., Trial Registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The prevalence of nonspecific pyogenic spondylodiskitis, associated with both a high morbidity and a high mortality, has increased in the last few decades. The diagnosis is often delayed because of the nonspecific clinical manifestation at the early stage. The reliability of radiographs is limited, particularly in early stage after the onset of infection. Computed tomography (CT) can reliably assess the bony condition with the possibility of spatial visualization. Contrast enhancement supports the detection of affected soft tissue. Magnetic resonance imaging (MRI) continues to be the gold standard in the diagnosis of spondylodiskitis. Sophisticated investigation protocols supported by gadolinium enhancement secure the diagnosis. MRI has a high resolution without radiation exposure. Different nuclear investigation techniques extend the diagnostic options. Reports of 18F-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) are particularly promising to confirm the diagnosis. The drawback of the reduced image quality with respect to detailed anatomical information can be overcome by a combined simultaneous acquisition of CT or MRI. With respect to one of the greatest challenges, the differentiation between degenerative changes (Modic type 1) and infection at an early stage using differentiated MRI protocols and FDG-PET is promising. This overview presents a concise state-of-the-art look at radiologic investigations in case of suspected nonspecific pyogenic spondylodiskitis with the focus on a pragmatic approach., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To investigate scopolamine's rapid-acting antidepressant effects using an active placebo comparator. Most prior intravenous scopolamine studies reduced depressive symptomatologies compared to saline placebo infusions within 3 days. However, the confounding effect of placebo is unknown given that only saline placebo has been used in prior studies., Methods: In this trial, 40 patients with major depressive disorder were randomized to receive single intravenous doses of either scopolamine hydrobromide (4-6 µg/kg) or glycopyrronium bromide (4 µg/kg) between August 2019 and April 2021 in Auckland, New Zealand. Glycopyrronium was chosen as the active placebo due to its similar antimuscarinic properties to scopolamine but inability to cross the blood-brain barrier. The primary mood outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS) administered pre-infusion and 1, 3, 7, 14, 28, and 42 days post-infusion., Results: Per protocol, this trial was abandoned for futility at n = 40. While scopolamine reduced MADRS scores by 12.6 (± 8.7 SD) points at day 3, glycopyrronium showed similar reductions (11.2 ± 9.6 SD). Frequentist linear mixed models showed no antidepressant effects of scopolamine versus placebo ( d  = 0.17), and Bayesian mixed effect models showed moderate evidence in favor of the null hypothesis at day 3 (Bayes factor = 0.32). Participants remained well-blinded to drug allocation, with 50% of participants correctly guessing their allocation., Conclusions: The observed MADRS improvement was larger than in prior studies, but no antidepressant effects were observed. This study using an active placebo confirms recent studies demonstrating the lack of antidepressant efficacy of scopolamine., Trial Registration : Australian New Zealand Clinical Trials Registry identifier: ACTRN12619000569101., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is a treatment shown to be effective in treating major depressive disorder (MDD). However, the effect of rTMS therapy on functional connectivity within the brains of patients being treated for MDD remains poorly understood. Few studies have investigated the effects of a course of rTMS on resting-state network activity., Methods: In an open-label naturalistic study, resting-state fMRI was collected prior to and following a four-week course of rTMS in 24 participants with MDD and 2 with bipolar disorder. Montgomery-Asberg depression rating scale scores showed a response rate of 42%., Results: Clinical response to rTMS was correlated with reduced functional connectivity from baseline to post-rTMS within the salience network (SN). This indicates SN connectivity may be functionally relevant to how rTMS produces antidepressant effects. In an exploratory inter-network analysis, connectivity between the SN and posterior default mode network (pDMN) was higher following treatment. However this difference was not correlated with the antidepressant response. Local BOLD activity within these networks was also assessed using the fractional amplitude of low-frequency fluctuations (fALFF) technique. Local activity increased in both the SN and pDMN following rTMS. However this increase was also not correlated with antidepressant response., Limitations: The sample population was heterogeneous, continuing current use of medications, and the study lacked a healthy control or sham stimulation comparison group., Conclusions: Together, these results provide evidence for the involvement of the SN in the antidepressant response to rTMS treatment., (Copyright © 2022. Published by Elsevier B.V.)

Prior studies indicate a pathogenic role of neuroinflammation in psychiatric disorders; however, there are no accepted methods that can reliably measure low-level neuroinflammation non-invasively in these individuals. Magnetic resonance spectroscopic imaging (MRSI) is a versatile, non-invasive neuroimaging technique that demonstrates sensitivity to brain inflammation. MRSI in conjunction with echo-planar spectroscopic imaging (EPSI) measures brain metabolites to derive whole-brain and regional brain temperatures, which may increase in neuroinflammation. The validity of MRSI/EPSI for measurement of low level neuroinflammation was tested using a safe experimental model of human brain inflammation - intramuscular administration of typhoid vaccine. Twenty healthy volunteers participated in a double-blind, placebo-controlled crossover study including MRSI/EPSI scans before and 3 h after vaccine/placebo administration. Body temperature and mood, assessed using the Profile of Mood States, were measured every hour up to four hours post-treatment administration. A mixed model analysis of variance was used to test for treatment effects. A significant proportion of brain regions (44/47) increased in temperature post-vaccine compared to post-placebo (p < 0.0001). For temperature change in the brain as a whole, there was no significant treatment effect. Significant associations were seen between mood scores assessed at 4 h and whole brain and regional temperatures post-treatment. Findings indicate that regional brain temperature may be a more sensitive measure of low-level neuroinflammation than whole-brain temperature. Future work where these measurement techniques are applied to populations with psychiatric disorders would be of clinical interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alterations in levels of neurotransmitters γ-aminobutyric acid (GABA) and glutamate may underlie the mechanism by which repetitive transcranial magnetic stimulation (rTMS) has efficacy as a treatment for major depressive disorder (MDD). This study used proton magnetic resonance spectroscopy (H 1 MRS) to investigate the effect of rTMS on levels of GABA and combined glutamate/glutamine measure (Glx). Treatment-resistant, currently depressed individuals participated in a naturalistic open-label study with rTMS treatment administered at 10 Hz and 120% of resting motor threshold to the left dorsolateral prefrontal cortex (DLPFC) for 20 sessions. H 1 MRS measures were collected at baseline and after four weeks of daily treatment. GABA and Glx were measured from both the left DLPFC and a control region (right motor cortex). Twenty-seven participants completed the study and were included in the analysis. Contrary to previous studies, no difference in GABA was observed following treatment. Glx levels were found to significantly increase in both the left DLPFC and right motor cortex voxels but this increase did not correlate with antidepressant response. Glx levels were found to increase following rTMS, not only underlying the site of stimulation but also at a distant control voxel suggesting a degree of non-specificity in response to therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Regular ingestion of sub-hallucinogenic doses of psychedelics, referred to as "microdosing", has gained increasing popularity and attention in the press and in online forums, with reported benefits across multiple cognitive and emotional domains. Rigorously controlled studies to date, however, have been limited in scope and have failed to produce results comparable to those reported in the grey literature., Methods: Eighty healthy male participants will receive 14 doses of placebo or 10 μg lysergic acid diethylamide orally every 3rd day over a 6-week treatment protocol. A battery of personality, creativity, mood, cognition, and EEG plasticity measures, as well as resting-state fMRI imaging, will be administered at baseline and at the end of the protocol. Creativity, mood, and plasticity measures will additionally be assessed in the acute phase of the first dose. Daily functioning will be monitored with questionnaires and a wearable sleep and activity tracker., Discussion: This study will rigorously examine the claims presented in the microdosing grey literature by pairing a comparable dosing protocol with objective measures. Potential therapeutic implications include future clinical trials to investigate microdosed psychedelics as a standalone treatment or as an augmentation of psychotherapy in the treatment of depression, addiction, eating disorders, obsessive-compulsive disorders, and palliative care., Trial Registration: ACTRN12621000436875 . Registered on 19 February 2021.

Background: Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine's potential antidepressant effect remain unknown, such as its dose-response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood-brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine., Methods/design: A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 μg/kg) along with one glycopyrronium bromide 4 μg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants., Discussion: This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose-response profile and washout period of scopolamine's antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects., Trial Registration: The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019.

Purpose: The aim of this study was to evaluate the biomechanical stability and the clinical and radiographic outcomes in patients undergoing transforaminal lumbar interbody fusion (TLIF) using an oblique bridging cage with a particular focus on subsidence., Methods: Finite element models were developed to compare the biomechanics of the oblique cage with conventional posterior lumbar interbody fusion and banana-shaped cages with TLIF. Additionally, a retrospective review of a prospective collected database was performed to investigate the clinical and radiologic results with a focus on the subsidence rate using an oblique polyetheretherketone (PEEK) cage with a bicortical load-bearing design. We included 87 patients with degenerative pathologic conditions of the lumbar spine who underwent TLIF. The clinical outcome was assessed using the Oswestry Low Back Pain Disability Questionnaire and the visual analogue scale. Fusion and subsidence rates were assessed radiographically., Results: The finite element models showed no differences in stability on compression or extension/flexion. The oblique cage differed in terms of the location of the maximal stresses. A total of 105 levels were fused. The level at which fusion was most frequently performed was L4-L5 (59%). The fusion rate was 93.2% after 24 months. Subsidence was found at 4 levels after the last follow-up visit (3.9%). Overall clinical outcome improvement was achieved after 24 months., Conclusion: Regarding fusion, the use of an oblique PEEK cage with a cortical load-bearing design provided highly satisfactory clinical and radiologic results after 2 years. A review of the literature suggests a lower rate of cage subsidence after lumbar interbody fusion using bridging cages rather than single cages., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Non-union of osteoporotic vertebra fractures are a seldom entity. However, when back pain persists in the course of conservatively treated osteoporotic vertebra fractures, a non-union should be considered. We thus sought to validate our diagnostic algorithm in patients with known osteoporotic vertebra fractures presenting persistent back pain and advert to the diagnosis and treatment of vertebral non-unions., Patients and Methods: Patients admitted with preexisting osteoporotic vertebra fractures and therapy-resistant back pain were retrospectively analysed. All admitted patients were subject to standard plain radiographs in erect position and conventional CT or MR imaging of the spine, respectively. In addition, patients with suspected non-union were subject to lateral fulcrum radiographs in supine position., Results: From a total of 172 admitted patients, four patients presented with non-union of a fractured osteoporotic vertebra (2%). The subsequent surgical therapy included cement-augmented rod-and-screw stabilization, with or without additional correction of deformity, and kyphoplasty (N = 3) or kyphoplasty alone (N = 1). All surgical interventions were successful in pain reduction and allowed immediate and improved postoperative mobilisation., Conclusions: Non-union of osteoporotic vertebra fractures must be considered when symptoms outlast conservative treatment. In these cases, plain lateral fulcrum radiographs are a simple and effective adjunct to the conventional diagnostic methods. Surgical stabilization then proves to be the effective treatment of choice.

A heart murmur was detected in a 10 mo old, female New Zealand White rabbit. Auscultation revealed cardiac murmurs both at the left and right hemithorax. Phonocardiography confirmed the systolic-diastolic nature of the left-sided and the systolic character of the right-sided murmur. Electrocardiography showed normal sinus rhythm; tall R waves and large T waves in lead II; and deep S waves in leads II, III, and aVF. Thoracic radiography demonstrated generalized cardiomegaly with prominent pulmonary vasculature. Echocardiography revealed a perimembraneous ventricular septal defect with aortic insufficiency. Signs of biventricular volume overload, relative pulmonic stenosis, and pulmonary valve insufficiency were also seen as consequences of the defect. Necropsy demonstrated a ventricular septal defect just below the aortic valve, a dilated pulmonary trunk, dilated and hypertrophied ventricles, dilated atria, and rightward displacement of the aortic root. Cardiac histopathology showed ventricular cardiomyocyte degeneration (swelling and hypereosinophilia of the cytoplasm with a loss of cross striation, and nuclear hyperchromasia), cartilaginous metaplasia of the aorta, and subendocardial fibrosis of the right ventricular flow tract.

Purpose: Tissue expanders lead to changes in the underlying bone and can cause bone resorption. We investigated whether the insertion of mechanical devices that distribute the load on the bone can influence these effects., Materials and Methods: A total of 28 Lewis rats were assigned to 1 of 4 groups. Hydrogel expanders were placed subcutaneously either directly on the calvaria, on titanium mesh, or on a titanium plate. The fourth group of rats served as the controls. The bone quality and thickness were assessed beneath, and at the periphery of, the expanders using micro-computed tomography and histologic examination., Results: Micro-computed tomography images were obtained before and 21 days after insertion. The images revealed a significant decrease in hydroxyapatite density beneath the expanders in the group with only expanders. This decrease was reduced with the use of titanium mesh and completely prevented with the use of titanium plates. Histologic examination revealed a significant decrease in bone density and marked lacunae beneath the hydrogel expanders in the group with only expanders. In contrast, the titanium mesh decreased the size of the lacunae, and the titanium plates completely prevented both the formation of lacunae and the decrease in bone thickness., Conclusion: The bone resorption caused by hydrogel expanders can be diminished using titanium mesh and completely prevented by the insertion of a titanium plate., (Copyright 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Psychotic symptoms are seen in numerous psychiatric illnesses afflicting the elderly. This article reviews the efficacy of the pharmacologic management of psychotic symptoms in primary psychotic disorders, affective disorders, and neurodegenerative disorders., Method: A comprehensive literature review., Results: Evidence to support the use of pharmacologic interventions to manage psychotic symptoms in elderly patients afflicted with primary psychotic disorders and affective disorders is limited by the absence of randomized, placebo-controlled trials (RCTs). The use of low-dose clozapine is supported by RCTs in Parkinson's disease. The efficacy of risperidone and olanzapine for the treatment of psychotic symptoms has been demonstrated by large RCTs in Alzheimer's disease., Conclusion: There is evidence of the efficacy of antipsychotic medications to manage psychotic symptoms in elderly patients. However, the absence of published evidence from RCTs in primary psychotic and affective disorders, and the limited evidence in the neurodegenerative illnesses, is notable.

Modafinil is a novel wake-promoting agent approved for the treatment of excessive sleepiness associated with narcolepsy that holds significant promise as an alternative treatment to traditional psychostimulants for excessive fatigue associated with medical and psychiatric disorders and as augmentation medication for treatment-resistant depression.