Papez’s Forgotten Tract: 80 Years of Unreconciled Findings Concerning the Thalamocingulate Tract

The thalamocingulate tract is a key component of the Papez circuit that connects the anterior thalamic nucleus (ATN) to the cingulum bundle. While the other white matter connections, consisting of the fornix, cingulum bundle and mammillothalamic tract, were well defined in Papez’s original 1937 paper, the anatomy of the thalamocingulate pathway was mentioned only in passing. Subsequent research has been unable to clarify the precise anatomical trajectory of this tract. In particular, the site of thalamocingulate tract interactions with the cingulum bundle have been inconsistently reported. This review aims to synthesize research on this least studied component of the Papez circuit. A systemic approach to reviewing historical anatomical dissection and neuronal tracing studies as well as contemporary diffusion magnetic resonance imaging studies of the thalamocingulate tract was undertaken across species. We found that although inconsistent, prior research broadly encompasses two differing descriptions of how the ATN interfaces with the cingulum after passing laterally through the anterior limb of the internal capsule. The first group of studies show that the pathway turns medially and rostrally and passes to the anterior cingulate region (Brodmann areas 24, 33, and 32) only. A second group suggests that the thalamocingulate tract interfaces with both the anterior and posterior cingulate (Brodmann areas 23 and 31) and retrosplenial region (Brodmann area 29). We discuss potential reasons for these discrepancies such as altering methodologies and species differences. We also discuss how these inconsistencies may be resolved in further research with refinements of terminology for the cingulate cortex and the thalamocingulate tract. Understanding the precise anatomical course of the last remaining unresolved final white matter tract in the Papez circuit may facilitate accurate investigation of the role of the complete Papez circuit in emotion and memory

Virtual Dissection of White Matter Tracts in a Human brain using applied Game Design and Virtual Reality imaging

Visualisation of neural tracts in the human brain has previously been accomplished using two dimensional (2D) representational formats. In most cases, pre-operative visualisation is through the medium of 2D MRI image slices, representing coordinates in the brain through a combination of axial, sagittal, and coronal orthographic viewpoints. Software such as ExploreDTI can visualise off-axis viewpoints, however this method is limited to 2.5D image representations. The use of such 2D representations can require significant training in order to contextualise real-world 3D positions and accurately locate and identify neural tract pathways in the brain. Utilising anonymised tract data and advanced neuroimaging technologies pioneered by Trinity College Institute of Neuroscience (TCIN), the Technological University Dublin (TU Dublin) School of Media created an interactive visualisation environment using the Unity 3D game engine. This virtual reality visualisation utilises the Oculus Rift Virtual Reality (VR) peripheral to realise the first ever virtual dissection of the fornix in-vivo in a highly interactive full 3D environment. Ethical approval was granted by St James/Tallaght Research & Ethics Committee. MRI tract coordinate data in the form of .wrl format 3D objects were converted to game-engine ready formats such as .obj through a 3D editing program (3DS Max) then imported into Unity. A virtual representation of a human brain was created, and scale, position, and rotation manipulation of the VR environment implemented, using natural motion tracking and minimal button usage. Isolation of individual or groups of neural tracts was achieved using hand tracking and spatial selection. Positional data was mapped to MRI image planes in order to overlay traditional MRI images at each position to aid diagnostic accuracy. In summary, virtual dissection of the fornix pathway in the human brain, first individuated by TCIN was transcribed into a 3D VR gaming environment for spatially intuitive visualisation, manipulation, and analysis

Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula’s principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment

A comprehensive regional neurochemical theory in depression: a protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder

Abstract Background Magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that investigates the presence and concentrations of brain metabolites. In the context of major depressive disorder (MDD), MRS has revealed regional biochemical changes in GABA, glutamate, and choline across different brain compartments. Technical and methodological advances in MRS data acquisition, in particular proton-based 1H-MRS, have resulted in a significant increase in the incidence of reports utilizing the technique for psychiatric disorder research and diagnosis. The most recent comprehensive meta-analysis reviewing MRS in MDD stems from 2006. Using contemporary systemic reviews and meta-analysis, the aim is to first test a neurochemical circuit-based theory of depression and then to determine if clinical scores relate to metabolite concentrations before and during treatment. Methods Region-specific metabolite changes in MDD will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria will include participant age (18 to 65), English language studies, known regions of interest, and detailed documentation of 1H-MRS procedures. Reported brain regions will be standardized according neuroanatomical expertise allowing increased power of the meta-analysis. Regions of interest will initially include the hippocampus, thalamus, prefrontal cortex, anterior and posterior cingulate gyri, parietal lobe, and basal ganglia. Exclusion criteria will include comorbid psychiatric illness and drug use. Two independent reviewers will undertake all data extraction, while a third reviewer will check for reviewer discrepancies. Statistical analysis will be performed using STATA supplemented by Metan software and SPSS. Discussion This data will shed new light on the biochemical basis of depression in different brain regions, thereby highlighting the potential of MRS in identifying biomarkers and generating models of MDD and treatment response. Systematic review registration PROSPERO CRD4201809149

MRI volumetric changes in hippocampal subfields in psychosis: a protocol for a systematic review and meta-analysis

Background: The hippocampus has for long been known for its ability to form new, declarative memory. However, emerging findings across conditions in the psychosis spectrum also implicate its role in emotional regulation. Systematic reviews have demonstrated consistent volume atrophic changes in the hippocampus. The aim of the systematic review and metanalysis which will follow from this protocol will be to investigate the volume-based neuroimaging findings across each of the subfields of the hippocampus in psychosis independent of diagnosis. Methods: Volume changes across subfields of the hippocampus in psychotic illnesses will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MRI neuroimaging studies of patients with a definitive diagnosis of psychosis (including brief pre-diagnostic states) will be included. Studies lacking adequate controls, illicit drug use, medical psychosis, history of other significant psychiatric comorbidities, or emphasis on age groups above 65 or below 16 will be excluded. Subfields investigated will include the CA1, CA2/3, CA4, subiculum, presubiculum, parasubiculum, dentate gyrus, stratum, molecular layer, granular cell layer, entorhinal cortex, and fimbria. Two people will independently screen abstracts from the output of the search to select suitable studies. This will be followed by the two reviewers performing a full-text review of the studies which were selected based on suitable abstracts. One reviewer will independently perform all the data extraction, and another reviewer will then systemically check all the extracted information using the original articles to ensure accuracy. Statistical analysis will be performed using the metafor and meta-packages in R Studio with the application of the random-effects model. Discussion: This study will provide insight into the volumetric changes in psychosis of the subfields of the hippocampus, independent of diagnosis. This may shed light on the intricate neural pathology which encompasses psychosis and will open avenues for further exploration of the structures identified as potential drivers of volume change. Systematic review registration: PROSPERO CRD42020199558.</p

Reduced hippocampal volume in adolescents with psychotic experiences: a longitudinal population-based study

Aims: Smaller hippocampal volumes are among the most consistently reported neuroimaging findings in schizophrenia. However, little is known about hippocampal volumes in people who report psychotic experiences. This study investigated differences in hippocampal volume between young people without formal diagnoses who report psychotic experiences (PEs) and those who do not report such experiences. This study also investigated if any differences persisted over two years.Methods: A nested case-control study of 25 adolescents (mean age 13.5 years) with reported PEs and 25 matched controls (mean age 13.36 years) without PEs were drawn from a sample of 100 local schoolchildren. High-resolution T1-weighted anatomical imaging and subsequent automated cortical segmentation (Freesurfer 6.0) was undertaken to determine total hippocampal volumes. Comprehensive semi-structured clinical interviews were also performed including information on PEs, mental diagnoses and early life stress (bullying). Participants were invited for a second scan at two years.Results: 19 adolescents with PEs and 19 controls completed both scans. Hippocampal volumes were bilaterally lower in the PE group compared to the controls with moderate effects sizes both at baseline [left hippocampus p = 0.024 d = 0.736, right hippocampus p = 0.018, d = 0.738] and at 2 year follow up [left hippocampus p = 0.027 d = 0.702, right = 0.048 d = 0.659] throughout. These differences survived adjustment for co-morbid mental disorders and early life stress.Conclusions: Psychotic experiences are associated with total hippocampal volume loss in young people and this volume loss appears to be independent of possible confounders such as co-morbid disorders and early life stress.</p