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

Multimodal validation of facial expression detection software for real-­time monitoring of affect in patients with suicidal intent

We sought to test the hypothesis that previously validated biomarkers of high risk for suicide, namely EEG event related potentials (ERP), Galvanic skin response (GSR) and heart rate variability (HRV) can be employed in combination with facial affect and pupil dilation measures, in a novel diagnostic battery that will ultimately increase reliability of clinical evaluations of suicidal persons

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

Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus

The often-overlooked dorsal diencephalic conduction system (DDCS) is a highly conserved pathway linking the basal forebrain and the monoaminergic brainstem. It consists of three key structures; the stria medullaris, the habenula and the fasciculus retrofexus. The frst component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fbers from the basal forebrain that terminate in the triangular eminence of the stalk of the pineal gland, known as the habenula. The habenula acts as a relay hub where incoming signals from the stria medullaris are processed and subsequently relayed to the midbrain and hindbrain monoaminergic nuclei through the fasciculus retrofexus. As a result of its wide-ranging connections, the DDCS has recently been implicated in a wide range of behaviors related to reward processing, aversion and motivation. As such, an understanding of the structure and connections of the DDCS may help illuminate the pathophysiology of neuropsychiatric disorders such as depression, addiction and pain. This is the frst review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retrofexus, with particular focus on their anatomy, function and development

DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse

Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance

Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain

IntroductionChronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic.MethodsThis study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale.Results73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine.DiscussionThis work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key messageThis real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions

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

The hippocampus, amygdala and their principal output tracts in major depressive disorder

Major depressive disorder is a common, debilitating illness. Despite its high prevalence rate and global disease burden, the biological mechanisms underlying this disorder remain largely unknown. Evidence points towards the involvement of the limbic system deep within the brain. This system processes memory, emotion and arousal, all of which are affected by depression symptoms. Two key regions in the limbic system are the hippocampus and the amygdala. The hippocampus is important for memory formation, with the left hippocampus particularly important for episodic memory. The previously well-documented changes in this structure in depression may account for the common global memory and cognition impairments found in this condition. The amygdala has been shown to be fundamental to the generation and recognition of emotional responses, with the right side demonstrating more involvement in negative emotional responses compared to the left side, which processes more positive emotions. Although evidence exists for a role of this structure in depression, this evidence is less extensive than that of the hippocampus. Both of these structures have widespread connections across the entire brain and each has a clearly defined major white matter bundle, or output tract, that connects each structure to its principal downstream effectors. These tracts are the fornix, which conveys processed memory information from the hippocampus, and the stria terminalis, which conducts emotionally-laden output from the amygdala. Both these tracts terminate in the basal forebrain and hypothalamus, regions important for pleasure and stress responses, respectively. There is limited evidence for the involvement of both of these tracts in depression. Using advanced volumetric and diffusion neuroimaging methods, combined with novel bespoke analyses of these images, this study has found noteworthy differences in all four structures in a well-characterised group of eighty-three patients with depression compared to eighty controls. Hippocampal differences were found to be confined to the core processing areas, more so on the left. There was evidence of an extension of pathology in patients with recurrent depression when compared to first presentation patients who exhibited more restrictive structural changes. The amygdala showed an exaggeration in the normal right-left volume imbalance, driven by enlargement of right stress-associated centromedial output areas. Through measurement of the cortisol awakening response in a subset of participants, the right amygdala revealed an association with abnormal stress responses in depression. Both the fornix and the stria terminalis showed localised differences along distinct sections of their tracts suggestive of abnormal axonal connectivity in depression. The aforementioned centromedial areas of the amygdala were found to be predictors of a depression diagnosis. These amygdala areas and a specific substructure within the hippocampus, the CA1 region, were also found to be predictors of disease duration in depression. These findings reinforce a role for these four limbic regions in depression. The lateralised volume differences in each of these structures could account for many of the symptoms of depression, including low mood, anhedonia and cognitive disturbance found in the disorder. While these results are preliminary, they demonstrate the utility of my novel analyses by revealing deeper and more site-specific differences in depression. These findings place altered hippocampal and amygdala volumes at the centre of a limbic network influencing memory, emotion and arousal in depression. Further studies, refining these techniques and exploring the upstream and downstream components of these structures are already underway

Cornu Ammonis Changes Are at the Core of Hippocampal Pathology in Depression

Commentary on: Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, O'Keane V, O'Hanlon E. The Hippocampus in Depression: More Than the Sum of Its Parts? Advanced Hippocampal Substructure Segmentation in Depression. Biol Psychiatry. 2019 Mar 15;85(6):487-497. doi: 10.1016/j.biopsych.2018.08.021. Epub 2018 Sep 6. PubMed PMID: 30528746. The hippocampus is a key cognitive hub implicated in major depressive disorder. However, major depressive disorder neuroimaging studies have used inconsistent anatomical hippocampal definitions to estimate hippocampal volumes, leading to some heterogeneity in findings. In a recent paper, we used a novel reassembly of automated hippocampal substructures (composites) to build alternative anatomical hippocampal definitions and used these to investigate differences in a well-defined cohort of major depressive disorder patients and healthy controls. We found that the most significant differences between major depressive disorder and healthy controls were localized to the core cornu ammonis (CA) regions of the hippocampus. The CA2–4 regions were smaller in first episode major depressive disorder, whereas more widespread differences were found in recurrent/chronic major depressive disorder, suggestive of a potential disease process in major depressive disorder. In this commentary, we also show how new hippocampal composites to investigate sections of the hippocampal circuitry demonstrate that differences in major depressive disorder occur across the input, middle and output circuit nodes of the hippocampal core. Hippocampal pathology localized across the core hippocampal CA circuity may account for the diverse and wide-ranging symptoms often experienced in depression