Longitudinal hippocampal subfield development associated with psychotic experiences in young people.

Hippocampal volumetric reductions are observed across the psychosis spectrum, with interest in the localisation of these reductions within the hippocampal subfields increasing. Deficits of the CA1 subfield in particular have been implicated in the neuropathophysiology of psychotic disorders. Investigating the trajectory of these abnormalities in healthy adolescents reporting sub-threshold psychotic experiences (PE) can provide insight into the neural mechanisms underlying psychotic symptoms without the potentially confounding effects of a formal disorder, or antipsychotic medication. In this novel investigation, a sample of 211 young people aged 11-13 participated initially in the Adolescent Brain Development study. PE classification was determined by expert consensus at each timepoint. Participants underwent neuroimaging at 3 timepoints, over 6 years. 78 participants with at least one scan were included in the final sample; 33 who met criteria for a definite PE at least once across all the timepoints (PE group), and 45 controls. Data from bilateral subfields of interest (CA1, CA2/3, CA4/DG, presubiculum and subiculum) were extracted for Linear Mixed Effects analyses. Before correction, subfield volumes were found to increase in the control group and decrease in the PE group for the right CA2 and CA2/3 subfields, with moderate to large effect sizes (d = -0.61, and d = -0.79, respectively). Before correction, right subiculum and left presubiculum volumes were reduced in the PE group compared to controls, regardless of time, with moderate effect sizes (d = -0.52, and d = -0.59, respectively). However, none of these effects survived correction. Severity of symptoms were not associated with any of the noted subfields. These findings provide novel insight to the discussion of the role of hippocampal subfield abnormalities in the pathophysiology underlying psychotic experiences.

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

Introduction: Chronic 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. Methods: This 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. Results: 73 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. Discussion: This 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 message: This 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.

A Pilot Study of Adolescents with Psychotic Experiences: Potential Cerebellar Circuitry Disruption Early Along the Psychosis Spectrum.

A berrant connectivity in the cerebellum has been found in psychotic conditions such as schizophrenia corresponding with cognitive and motor deficits found in these conditions. Diffusion differences in the superior cerebellar peduncles, the white matter connecting the cerebellar circuitry to the rest of the brain, have also been found in schizophrenia and high-risk states. However, white matter diffusivity in the peduncles in individuals with sub-threshold psychotic experiences (PEs) but not reaching the threshold for a definitive diagnosis remains unstudied. This study investigates the cerebellar peduncles in adolescents with PEs but no formal psychiatric diagnosis.Sixteen adolescents with PEs and 17 age-matched controls recruited from schools underwent High-Angular-Resolution-Diffusion neuroimaging. Following constrained spherical deconvolution whole-brain tractography, the superior, inferior and middle peduncles were isolated and virtually dissected out using ExploreDTI. Differences for macroscopic and microscopic tract metrics were calculated using one-way between-group analyses of covariance controlling for age, sex and estimated Total Intracranial Volume (eTIV). Multiple comparisons were corrected using Bonferroni correction.A decrease in fractional anisotropy was identified in the right (p = 0.045) and left (p = 0.058) superior cerebellar peduncle; however, this did not survive strict Bonferroni multiple comparison correction. There were no differences in volumes or other diffusion metrics in either the middle or inferior peduncles.Our trend level changes in the superior cerebellar peduncle in a non-clinical sample exhibiting psychotic experiences complement similar but more profound changes previously found in ultra-high-risk individuals and those with psychotic disorders. This suggests that superior cerebellar peduncle circuitry perturbations may occur early along in the psychosis spectrum.

Longitudinal Gray Matter Development Associated With Psychotic Experiences in Young People.

Background: Gray matter abnormalities are observed across the psychosis spectrum. The trajectory of these abnormalities in healthy adolescents reporting subthreshold psychotic experiences (PEs) may provide insight into the neural mechanisms underlying psychotic symptoms. The risk of psychosis and additional psychopathology is even higher among these individuals who also report childhood adversity/DSM-5 diagnoses. Thus, the aims of this longitudinal study were to investigate PE-related volumetric changes in young people, noting any effects of childhood adversity/DSM-5 diagnosis. Methods: A total of 211 young people 11 to 13 years of age participated in the initial Adolescent Brain Development study. PE classification was determined by expert consensus at each time point. Participants underwent neuroimaging at 3 time points over 6 years. A total of 76 participants with at least one scan were included in the final sample; 34 who met criteria for PEs at least once across all the time points (PE group) and 42 control subjects. Data from 20 bilateral regions of interest were extracted for linear mixed-effects analyses. Results: Right hippocampal volume increased over time in the control group, with no increase in the PE group (p = .00352). DSM-5 diagnosis and childhood adversity were not significantly associated with right hippocampal volume. There was no significant effect of group or interaction in any other region. Conclusions: These findings further implicate right hippocampal volumetric abnormalities in the pathophysiology underlying PEs. Furthermore, as suggested by previous studies in those at clinical high risk for psychosis and those with first-episode psychosis, it is possible that these deficits may be a marker for later clinical outcomes.

Microstructural changes along the cingulum in young adolescents with psychotic experiences: An along-tract analysis.

Psychotic experiences (PEs) such as hallucinations and delusions are common among young people without psychiatric diagnoses and are associated with connectivity and white matter abnormalities, particularly in the limbic system. Using diffusion magnetic resonance imaging (MRI) in adolescents with reported PEs and matched controls, we examined the cingulum white matter tract along its length rather than as the usually reported single indivisible structure. Complex regional differences in diffusion metrics were found along the bundle at key loci following Bonferroni significance adjustment (p < .00013) with moderate to large effect sizes (.11-.76) throughout all significant subsegments. In this prospective community-based cohort of school-age children, these findings suggest that white matter alterations in the limbic system may be more common in the general non-clinical adolescent population than previously thought. Such white matter alternations may only be uncovered using a similar more granular along-tract analysis of white matter tracts.

Childhood Trauma, the HPA Axis and Psychiatric Illnesses: A Targeted Literature Synthesis.

Studies of early life stress (ELS) demonstrate the long-lasting effects of acute and chronic stress on developmental trajectories. Such experiences can become biologically consolidated, creating individual vulnerability to psychological and psychiatric issues later in life. The hippocampus, amygdala, and the medial prefrontal cortex are all important limbic structures involved in the processes that undermine mental health. Hyperarousal of the sympathetic nervous system with sustained allostatic load along the Hypothalamic Pituitary Adrenal (HPA) axis and its connections has been theorized as the basis for adult psychopathology following early childhood trauma. In this review we synthesize current understandings and hypotheses concerning the neurobiological link between childhood trauma, the HPA axis, and adult psychiatric illness. We examine the mechanisms at play in the brain of the developing child and discuss how adverse environmental stimuli may become biologically incorporated into the structure and function of the adult brain via a discussion of the neurosequential model of development, sensitive periods and plasticity. The HPA connections and brain areas implicated in ELS and psychopathology are also explored. In a targeted review of HPA activation in mood and psychotic disorders, cortisol is generally elevated across mood and psychotic disorders. However, in bipolar disorder and psychosis patients with previous early life stress, blunted cortisol responses are found to awakening, psychological stressors and physiological manipulation compared to patients without previous early life stress. These attenuated responses occur in bipolar and psychosis patients on a background of increased cortisol turnover. Although cortisol measures are generally raised in depression, the evidence for a different HPA activation profile in those with early life stress is inconclusive. Further research is needed to explore the stress responses commonalities between bipolar disorder and psychosis in those patients with early life stress.

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.

Amygdala substructure volumes in Major Depressive Disorder.

The role of the amygdala in the experience of emotional states and stress is well established. Connections from the amygdala to the hypothalamus activate the hypothalamic-pituitaryadrenal (HPA) axis and the cortisol response. Previous studies have failed to find consistent whole amygdala volume changes in Major Depressive Disorder (MDD), but differences may exist at the smaller substructural level of the amygdala nuclei. High-resolution T1 and T2-weighted-fluid-attenuated inversion recovery MRIs were compared between 80 patients with MDD and 83 healthy controls (HC) using the automated amygdala substructure module in FreeSurfer 6.0. Volumetric assessments were performed for individual nuclei and three anatomico-functional composite groups of nuclei. Salivary cortisol awakening response (CAR), as a measure of HPA responsivity, was measured in a subset of patients. The right medial nucleus volume was larger in MDD compared to HC (p = 0.002). Increased right-left volume ratios were found in MDD for the whole amygdala (p = 0.004), the laterobasal composite (p = 0.009) and in the central (p = 0.003) and medial (p = 0.014) nuclei. The CAR was not significantly different between MDD and HC. Within the MDD group the left corticoamygdaloid transition area was inversely correlated with the CAR, as measured by area under the curve (AUCg) (p ≤ 0.0001). In conclusion, our study found larger right medial nuclei volumes in MDD compared to HC and relatively increased right compared to left whole and substructure volume ratios in MDD. The results suggest that amygdala substructure volumes may be involved in the pathophysiology of depression.

Blame it on the pump.

Although intrathecal pumps may lead to spinal symptoms that are likely related to the pump itself, the case presented herein underscores the importance of casting a broad differential diagnosis at the time of initial presentation.

The Growth Response to Beta-Hydroxybutyrate in SH-SY5Y Neuroblastoma Cells is Suppressed by Glucose and Pyruvate Supplementation.

Neuroblastoma (NB) is a childhood malignancy of the sympathetic nervous system and is commonly studied using the SH-SY5Y cell line. Its neoplastic and neurodevelopmental manifestations are characterised by a high glucose demand which maintains its high proliferative capacity. This metabolic phenotype may be utilised in dietary therapies such as the ketone diet which alter substrate availability and thus starve NB cells of their preferred biosynthetic requirements. However, the effects of ketone metabolism on cancer growth remain poorly understood due to the involvement of other metabolic substrates in experimental paradigms and complexities underlying the Warburg effect. We investigated how the primary ketone body beta-hydroxybutyrate (ßOHB) affects the growth of SH-SY5Y NB cells in the presence or absence of culture metabolic substrates. We demonstrated that while glucose deprivation reduced the growth and viability of SH-SY5Y cells, they proliferated and were initially unaffected by the addition of ßOHB. However, a growth response to ßOHB was subsequently revealed in media containing low levels of glucose, as well as in glucose and pyruvate deprived conditions. These data shed light on the roles of metabolic substrate availability as key determinants of the responses of SH-SY5Y NB cells to ketone supplementation.

Hippocampal and Amygdalar Volume Changes in Major Depressive Disorder: A Targeted Review and Focus on Stress.

Medial temporal lobe structures have long been implicated in the pathogenesis of major depressive disorder. Although findings of smaller hippocampal and amygdalar volumes are common, inconsistencies remain in the literature. In this targeted review, we examine recent and significant neuroimaging papers examining the volumes of these structures in major depressive disorder. A targeted PubMed/Google Scholar search was undertaken focusing on volumetric neuroimaging studies of the hippocampus and amygdala in major depressive disorder. Where possible, mean volumes and accompanying standard deviations were extracted allowing computation of Cohen's ds effect sizes. Although not a meta-analysis, this allows a broad comparison of volume changes across studies. Thirty-nine studies in total were assessed. Hippocampal substructures and amygdale substructures were investigated in 11 and 2 studies, respectively. The hippocampus was more consistently smaller than the amygdala across studies, which is reflected in the larger cumulative difference in volume found with the Cohen's ds calculations. The left and right hippocampi were, respectively, 92% and 91.3% of the volume found in controls, and the left and right amygdalae were, respectively, 94.8% and 92.6% of the volume of controls across all included studies. The role of stress in temporal lobe structure volume reduction in major depressive disorder is discussed.

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.

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 retroflexus. The first component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fibers 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 retroflexus. 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 first review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retroflexus, with particular focus on their anatomy, function and development.

Over the Cuckoo's Nest: Does Experiencing Electroconvulsive Therapy Change Your Mind? A Mixed Methods Study of Attitudes and Impact of Electroconvulsive Therapy on Patients and Their Relatives.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder, but some aspects remain controversial. Few studies have taken an in-depth mixed methods approach toward the study of attitudes, and there are no significant studies that explore the change of attitudes before and after treatment. The aim was to compare attitudes of patients and their relatives before and after ECT using quantitative and qualitative methods. METHODS: One hundred twenty-three participants were recruited. Forty-one patient/relative participants were recruited from 2 accredited ECT centers along with 82 age- and sex-matched general population controls. A validated 22-item survey about attitudes toward ECT was administered. Patient/relative participants completed the survey before treatment with ECT and engaged in a repeat survey and a semistructured interview 1 month after completion of ECT. Control participants completed the survey on a single occasion. RESULTS: Control versus pre-ECT surveys and pre-ECT versus post-ECT surveys both demonstrated statistically and clinically significant positive attitudinal differences (Cohen d = 1.37, P < 0.001; Cohen d = 1.2, P < 0.001). These differences were maintained for both the patient and relative pre/post subgroups (Cohen d = 1.15, P < 0.001; Cohen d = 1.33, P < 0.001). Qualitative analysis identified 13 attitudinal transitions in cognition, emotion, and imagery domains. CONCLUSIONS: This is the first study to examine a change in attitudes toward ECT of patients, their relatives, and with controls using mixed methods. The findings suggest a 2-phase positive attitudinal change, in which accurate information (phase 1) and experiential learning (phase 2) are both key components. These findings address stigma through accurate knowledge and experiential learning, with a positive outcome through changed attitudes.

Magnetic resonance diffusion weighted imaging using constrained spherical deconvolution-based tractography of the extracranial course of the facial nerve.

OBJECTIVE: To evaluate the accuracy of magnetic resonance diffusion weighted imaging (DWI) featuring constrained spherical deconvolution-based tractography in tracking the extracranial course of the facial nerve to provide a reliable facial nerve map to facilitate well-tolerated and effective tumor resection. STUDY DESIGN: Magnetic resonance DWI was conducted on 2 parotid-healthy cadaveric patients with various protocols to identify the best representation of the extracranial facial nerve tract. This was subsequently correlated to dissection of the facial nerves to ascertain anatomic validation. These protocols were applied to 2 live, parotid-healthy patients to assess feasibility of in vivo facial nerve tract identification. RESULTS: Correlations between imaged tracts and the anatomic course of the extracranial facial nerve were identified to an accuracy of 1 mm. The main trunk and bifurcation tracts were identified on imaging. Fractional anisometry values in cadaveric and live patients were within the range expected for the facial nerve within the parotid gland. CONCLUSIONS: Our results indicated the potential for accurate 3-dimensional visualization of the extracranial course of the facial nerve, which could have diagnostic implications in differentiating benign from malignant tumors and, crucially, neural involvement. Preoperative planning applications of DWI could help in planning surgical approaches and providing focused counseling.

Functional EEG connectivity is a neuromarker for adult attention deficit hyperactivity disorder symptoms.

OBJECTIVE: Altered brain functional connectivity has been shown in youth with attention-deficit/hyperactivity disorder (ADHD). However, relatively little is known about functional connectivity in adult ADHD, and how it is linked with the heritability of ADHD. METHODS: We measured eyes-open and eyes-closed resting electroencephalography (EEG) from 38 adults with ADHD, 45 1st degree relatives of people with ADHD and 51 healthy controls. Functional connectivity among all scalp channels was calculated using a weighted phase lag index for delta, theta, alpha, beta and gamma frequency bands. A machine learning analysis using penalized linear regression was used to identify if connectivity features (10,080 connectivity pairs) could predict ADHD symptoms. Furthermore, we examined if EEG connectivity could accurately classify participants into ADHD, 1st degree relatives and/or control groups. RESULTS: Hyperactive symptoms were best predicted by eyes-open EEG connectivity in delta, beta and gamma bands. Inattentive symptoms were predicted by eyes-open EEG connectivity in delta, alpha and gamma bands, and eyes-closed EEG connectivity in delta and gamma bands. EEG connectivity features did not reliably classify participants into groups. CONCLUSIONS: EEG connectivity may represent a neuromarker for ADHD symptoms. SIGNIFICANCE: EEG connectivity may help elucidate the neural basis of adult ADHD symptoms.

Assessing Public Attitudes to Electroconvulsive Therapy: Validation of the Modified ECT Attitudes Questionnaire Using a Systematic Analysis.

INTRODUCTION: Electroconvulsive therapy (ECT) is an established treatment for major depressive disorder, yet it remains controversial. Attitudes toward ECT have been studied in members of the public and service users, with diverse findings. There is no systematically validated scale to quantify attitudes. OBJECTIVES: The aim of this study was to validate a scale measuring attitudes toward ECT using a systematic analysis. METHODS: Validation consisted of 3 stages: item generation, theoretical analysis, and psychometric analysis. A total of 196 members of the public were surveyed, and the findings were used to perform principal component analysis, Cronbach alpha (CA), and interitem correlation. RESULTS: The Modified ECT Attitudes Questionnaire (EAQ) is a 22-item participant-rated questionnaire (0-44) consisting of 2 principal components: "moral and ethical perceptions of ECT" and "ECT as a last resort treatment." There was adequate reliability for the total EAQ (CA, 0.873) and each of the components (component 1 CA, 0.907; component 2 interitem correlation, 0.389). Among the 196 members of the public, the mean score was 20.4 (SD, 8.4), which equates to 46% positive responses. Component 1 elicited 39% positive responses; component 2 elicited 52% positive responses. The emotion components of attitudes elicited particularly negative responses. CONCLUSIONS: The EAQ is a validated and reliable scale for the measurement of attitudes toward ECT. Application of this scale to 196 members of the public indicates that negative attitudes are rooted in individuals' moral and ethical objections to ECT, particularly the emotion components of such attitudes. This scale can be applied to other groups, including service users, to further characterize attitudes that underlie the stigma toward ECT.

EEG spectral power, but not theta/beta ratio, is a neuromarker for adult ADHD.

Adults with attention-deficit/hyperactivity disorder (ADHD) have been described as having altered resting-state electroencephalographic (EEG) spectral power and theta/beta ratio (TBR). However, a recent review (Pulini et al. 2018) identified methodological errors in neuroimaging, including EEG, ADHD classification studies. Therefore, the specific EEG neuromarkers of adult ADHD remain to be identified, as do the EEG characteristics that mediate between genes and behaviour (mediational endophenotypes). Resting-state eyes-open and eyes-closed EEG was measured from 38 adults with ADHD, 45 first-degree relatives of people with ADHD and 51 unrelated controls. A machine learning classification analysis using penalized logistic regression (Elastic Net) examined if EEG spectral power (1-45 Hz) and TBR could classify participants into ADHD, first-degree relatives and/or control groups. Random-label permutation was used to quantify any bias in the analysis. Eyes-open absolute and relative EEG power distinguished ADHD from control participants (area under receiver operating characteristic = 0.71-0.77). The best predictors of ADHD status were increased power in delta, theta and low-alpha over centro-parietal regions, and in frontal low-beta and parietal mid-beta. TBR did not successfully classify ADHD status. Elevated eyes-open power in delta, theta, low-alpha and low-beta distinguished first-degree relatives from controls (area under receiver operating characteristic = 0.68-0.72), suggesting that these features may be a mediational endophenotype for adult ADHD. Resting-state EEG spectral power may be a neuromarker and mediational endophenotype of adult ADHD. These results did not support TBR as a diagnostic neuromarker for ADHD. It is possible that TBR is a characteristic of childhood ADHD.

Magnetic resonance spectroscopy across chronic pain disorders: a systematic review protocol synthesising anatomical and metabolite findings in chronic pain patients.

BACKGROUND: Chronic pain is pain greater than 3 months duration that may result from disease, trauma, surgery, or unknown origin. The overlap between the psychological, behavioural, and management aspects of pain suggest that limbic brain neurochemistry plays a role in chronic pain pathology. Proton magnetic resonance spectroscopy (1H-MRS) can evaluate in vivo brain metabolites including creatine, N-acetylaspartate, myo-inositol, choline, glutamate, glutamine, and gamma-aminobutyric acid in chronic pain; however, a comprehensive systemic review of metabolite expression patterns across all brain areas has yet to be performed. METHODS AND ANALYSIS: Online databases including PubMed/MEDLINE, Google Scholar, EMBASE, the Cochrane Library, OVID, and PsycINFO will be searched for articles relating to 1H-MRS and chronic pain. Study inclusion criteria will include ages of between 18 and 65 years with a definite diagnosis of chronic pain, no comorbidities, clearly stated brain volumes of interest, and imaging protocols, with comparisons to healthy controls. Two reviewers will extract data relating to volumes of interest, metabolites, study participant demographics, diagnostic method and pain scores, treatments and duration of treatment, scanner information, 1H-MRS acquisition protocols, and spectral processing software. Where possible, volumes of interest will be reassigned as regions of interest consistent with known regional anatomical and functional properties to increase the power and relevance of the analysis. Statistical analyses will then be conducted using STATA. A central common pathway may exist for chronic pain due to the behavioural manifestations and management similarities between its different types. The goal of this systemic review is to generate a comprehensive neurochemical theory of chronic pain in different brain compartments. SYSTEMATIC REVIEW REGISTRATION: This study is registered with PROSPERO CRD42018112640.

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.