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Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T1-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24–43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was −15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24–47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was −11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection. [ABSTRACT FROM PUBLISHER]

Platelets and monocytes are involved in atherothrombosis via tissue factor expression. Moreover, they are activated in hypercholesterolemia, a classic risk factor for atherothrombosis. Cholesterol-lowering drugs (statins) reduce cardiovascular risk either by decreasing cholesterol or non-lipidic actions, such as platelet and monocyte activity. The aim of our study was to evaluate the effect of several statins on platelet and monocyte activity in hypercholesterolemic subjects. Platelet activity (P-selectin, cytofluorimetric detection), tissue factor levels (ELISA) and activity (detected in whole blood and cellular preparations by a specific clotting assay) were measured in hypercholesterolemic subjects (41 males, 23 females, aged 34–65 years, total cholesterol 6.86±0.60 mmol/l) treated with atorvastatin 10 mg, simvastatin 20 mg, fluvastatin 40 mg, or pravastatin 40 mg for 6 weeks. P-selectin and tissue factor expression in whole blood and isolated cells were increased in hypercholesterolemic subjects with respect to controls (all P<0.001). Simvastatin, atorvastatin, and fluvastatin reduced monocyte procoagulant activity in whole blood and P-selectin (P<0.01). Tissue factor antigen and activity in isolated cells were further reduced (all P<0.05) independently of cholesterol lowering. Pravastatin decreased tissue factor expression in whole blood in direct relationship to reduction of P-sel and cholesterol (P<0.05). Our data show a different impact of several statins on monocyte tissue factor expression in whole blood, suggesting a possible role of decreased platelet activity and a direct action on monocytes. In contrast, pravastatin decreased monocyte procoagulant activity with relation to cholesteroldependent modifications of platelet function. [ABSTRACT FROM AUTHOR]

Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12-18 months of a child's life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H Frail, R O’Halloran, F Padormo, M Poorman, J Rogers, L Sacolick, K Siddiqui, R Teixeira, M Traughber are employees of Hyperfine.io W Hollander, T. Karaulanov, and C Weiant are employees of CaliberMRI. C Akgun, and P Velasco are employees of Flywheel.io, (Copyright © 2024. Published by Elsevier Ltd.)

Background: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria., Methods: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability., Results: A decrease in global CBF and CMRO 2 was observed after acutely administrating MB to all participants. Greater regional CMRO 2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO 2 in those regions were primarily driven by patients with longer disease duration and higher mood instability., Limitations: Sample size; medications potentially impacting on response to MB., Conclusions: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

One of the most prominent symptoms in multiple sclerosis is pathological fatigue, often described by sufferers as one of the most debilitating symptoms, affecting quality of life and employment. However, the mechanisms of both, physical and cognitive fatigue in multiple sclerosis remain elusive. Here, we use behavioural tasks and quantitative MRI to investigate the neural correlates of interoception (the ability to sense internal bodily signals) and metacognition (the ability of the brain to assess its own performance), in modulating cognitive fatigue. Assuming that structural damage caused by multiple sclerosis pathology might impair the neural pathways subtending interoception and/or metacognition, we considered three alternative hypotheses to explain fatigue as a consequence of, respectively: (i) reduced interoceptive accuracy, (ii) reduced interoceptive insight or (iii) reduced global metacognition. We then explored associations between these behavioural measures and white matter microstructure, assessed by diffusion and magnetisation transfer MRI. Seventy-one relapsing-remitting multiple sclerosis patients participated in this cross-sectional study (mean age 43, 62% female). Patient outcomes relevant for fatigue were measured, including disability, disease duration, depression, anxiety, sleepiness, cognitive function, disease modifying treatment and quality of life. Interoceptive and metacognitive parameters were measured using heartbeat tracking and discrimination tasks, and metacognitive visual and memory tasks. MRI was performed in 69 participants, including diffusion tensor MRI, neurite orientation dispersion and density imaging and quantitative magnetisation transfer. Associations between interoception and metacognition and the odds of high cognitive fatigue were tested by unconditional binomial logistic regression. The odds of cognitive fatigue were higher in the people with low interoceptive insight ( P = 0.03), while no significant relationships were found between fatigue and other interoceptive or metacognitive parameters, suggesting a specific impairment in interoceptive metacognition, rather than interoception generally, or metacognition generally. Diffusion MRI-derived fractional anisotropy and neurite density index showed significant ( P < 0.05) negative associations with cognitive fatigue in a widespread bilateral white matter network. Moreover, there was a significant ( P < 0.05) interaction between cognitive fatigue and interoceptive insight, suggesting that the poorer the white matter structure, the lower the interoceptive insight, and the worse the fatigue. The results point towards metacognitive impairment confined to the interoceptive domain, in relapsing-remitting patients with cognitive fatigue. The neural basis of this impairment is supported by a widespread white matter network in which loss of neurite density plays a role., Competing Interests: I.D. received travel and study support from Biogen, Merck, Novartis and Sanofi-Genzyme. M.B. received travel support from Biogen and Merk, and research support from the Italian Ministry of Health. M.C. received royalties from Taylor and Francis from the publication of a book, research funding from Wellcome Trust, Motor Neuron Disease Association, and the Academy of Medical Sciences. She also received institutional support from the University of Sussex and the University of Brighton. D.L. has received speaker bureau fees, honoraria and research grants from Biogen, Novartis, Merck, Roche, Sanofi, TEVA and BMS. All other authors report no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The relationship between obesity and human brain structure is incompletely understood. Using diffusion-weighted MRI from ∼30,000 UK Biobank participants, we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal/temporal/striatal system associated with ISOVF and a medial temporal/occipital/striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (r g = 0.026, P = 0.36) and ICVF (r g = 0.112, P < 9×10 -4 ) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF ( P <0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation., Competing Interests: MK, DM, RB, RD, RR, VW, JS, OD, FT, MC, EB, NH No competing interests declared, (© 2023, Kitzbichler et al.)

Background: Inflammation rapidly reorients motivational state, mood is impaired, pleasurable activities avoided and sensitivity to negative stimuli enhanced. When sustained, this can precipitate major depressive episodes. In humans, this has been linked to opposing actions of inflammation on striatal/insula reward/punishment learning signals while in rodents, motivational impairments can be attenuated with minocycline, implicating a mechanistic role for microglia. Here we investigated whether minocycline also inhibits the reorienting effects of lipopolysaccharide (LPS) on reward/punishment sensitivity in humans. Methods Using a crossover design, fifteen healthy volunteers underwent two experimental sessions in which they each received LPS (1 ng/kg) and placebo. Half (N = 8) received minocycline (100 mg bd) and half (N = 7) an identical looking placebo for 3½ days before each session. Six hours post-injection participants completed a probabilistic instrumental learning task in which they had to learn to select high probability reward (win £1) and avoid high probability punishment (lose £1) stimuli to maximise their gains and minimize losses. Physiological and sickness responses were sampled hourly and blood sampled at baseline, 3 and 6 h post-injection. Results LPS induced robust peripheral physiological: temperature, heart rate and immune: differential white cell, IL-6, TNF-α, IL-8, IL-10 responses (all condition × time interactions: p < 0.005), none were significantly modulated by minocycline (p > 0.1). LPS also biased behavior, enhancing punishment compared with reward sensitivity (F (1,13)  = 6.10, p = 0.028). Minocycline significantly attenuated this inflammation-induced shift in reward versus punishment sensitivity (F (1,13)  = 4.28, p = 0.033). Conclusions These data replicate the previous finding that systemic inflammation rapidly impairs sensitivity to rewards versus punishments in humans and extend this by implicating activated microglia in this acute motivational reorientation with implications for the development of microglial-targeted immune-modulatory therapies in depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The brain has a unique macroscopic waste clearance system, termed the glymphatic system which utilises perivascular tunnels surrounded by astroglia to promote cerebrospinal-interstitial fluid exchange. Rodent studies have demonstrated a marked increase in glymphatic clearance during sleep which has been linked to a sleep-induced expansion of the extracellular space and concomitant reduction in intracellular volume. However, despite being implicated in the pathophysiology of multiple human neurodegenerative disorders, non-invasive techniques for imaging glymphatic clearance in humans are currently limited. Here we acquired multi-shell diffusion weighted MRI (dwMRI) in twenty-one healthy young participants (6 female, 22.3 ± 3.2 years) each scanned twice, once during wakefulness and once during sleep induced by a combination of one night of sleep deprivation and 10 mg of the hypnotic zolpidem 30 min before scanning. To capture hypothesised sleep-associated changes in intra/extracellular space, dwMRI were analysed using higher order diffusion modelling with the prediction that sleep-associated increases in interstitial (extracellular) fluid volume would result in a decrease in diffusion kurtosis, particularly in areas associated with slow wave generation at the onset of sleep. In line with our hypothesis, we observed a global reduction in diffusion kurtosis (t 15 =2.82, p = 0.006) during sleep as well as regional reductions in brain areas associated with slow wave generation during early sleep and default mode network areas that are highly metabolically active during wakefulness. Analysis with a higher-order representation of diffusion (MAP-MRI) further indicated that changes within the intra/extracellular domain rather than membrane permeability likely underpin the observed sleep-associated decrease in kurtosis. These findings identify higher-order modelling of dwMRI as a potential new non-invasive method for imaging glymphatic clearance and extend rodent findings to suggest that sleep is also associated with an increase in interstitial fluid volume in humans., Competing Interests: Declaration of Competing Interests None., (Copyright © 2023. Published by Elsevier Inc.)

The aim of this work was to extend the VERDICT-MRI framework for modelling brain tumours, enabling comprehensive characterisation of both intra- and peritumoural areas with a particular focus on cellular and vascular features. Diffusion MRI data were acquired with multiple b-values (ranging from 50 to 3500 s/mm 2 ), diffusion times, and echo times in 21 patients with brain tumours of different types and with a wide range of cellular and vascular features. We fitted a selection of diffusion models that resulted from the combination of different types of intracellular, extracellular, and vascular compartments to the signal. We compared the models using criteria for parsimony while aiming at good characterisation of all of the key histological brain tumour components. Finally, we evaluated the parameters of the best-performing model in the differentiation of tumour histotypes, using ADC (Apparent Diffusion Coefficient) as a clinical standard reference, and compared them to histopathology and relevant perfusion MRI metrics. The best-performing model for VERDICT in brain tumours was a three-compartment model accounting for anisotropically hindered and isotropically restricted diffusion and isotropic pseudo-diffusion. VERDICT metrics were compatible with the histological appearance of low-grade gliomas and metastases and reflected differences found by histopathology between multiple biopsy samples within tumours. The comparison between histotypes showed that both the intracellular and vascular fractions tended to be higher in tumours with high cellularity (glioblastoma and metastasis), and quantitative analysis showed a trend toward higher values of the intracellular fraction (fic) within the tumour core with increasing glioma grade. We also observed a trend towards a higher free water fraction in vasogenic oedemas around metastases compared to infiltrative oedemas around glioblastomas and WHO 3 gliomas as well as the periphery of low-grade gliomas. In conclusion, we developed and evaluated a multi-compartment diffusion MRI model for brain tumours based on the VERDICT framework, which showed agreement between non-invasive microstructural estimates and histology and encouraging trends for the differentiation of tumour types and sub-regions.

Background: Alzheimer's disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid., Objective: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals., Methods: 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC., Results: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately., Conclusions: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.

Introduction: Whiplash-associated disorder grade 2 (WAD2) is characterised by musculoskeletal pain/tenderness but no apparent nerve injury. However, studies have found clinical features indicative of neuropathy and neuropathic pain. These studies may indicate peripheral nerve inflammation, since preclinical neuritis models found mechanical sensitivity in inflamed, intact nociceptors. The primary aim of this study is to establish the contribution of peripheral neuroinflammation to WAD2 and its role in prognosis. Participants will be invited to participate in a sub-study investigating the contribution of cutaneous small fibre pathology to WAD2., Methods and Analysis: 115 participants within 1 month following whiplash injury and 34 healthy control participants will be recruited and complete validated questionnaires for pain, function and psychological factors. Data collection will take place at the Universities of Sussex and Oxford, UK. Clinical examination, quantitative sensory testing and blood samples will be undertaken. MRI scans using T2-weighted and diffusion tensor images of the brachial plexus and wrist will determine nerve inflammation and nerve structural changes. Skin biopsies from a substudy will determine structural integrity of dermal and intraepidermal nerve fibres. At 6 months, we will evaluate recovery using Neck Disability Index and a self-rated global recovery question and repeat the outcome measures. Regression analysis will identify differences in MRI parameters, clinical tests and skin biopsies between participants with WAD2 and age/gender-matched controls. Linear and logistic regression analyses will assess if nerve inflammation (MRI parameters) predicts poor outcome. Mixed effects modelling will compare MRI and clinical measures between recovered and non-recovered participants over time., Ethics and Dissemination: Ethical approval was received from London-Brighton and Sussex Research Ethics Committee (20/PR/0625) and South Central-Oxford C Ethics Committee (18/SC/0263). Written informed consent will be obtained from participants prior to participation in the study. Results will be disseminated through publications in peer-reviewed journals, presentations at national/international conferences and social media., Trial Registration Number: NCT04940923., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The hippocampus is a morphologically complex region of the brain limbic system centrally involved in important cognitive, affective, and behavioural regulatory roles. It has exquisite vulnerability to neuroinflammatory processes, with some of its subregions found to be specific sites of neuroinflammatory pathology in ex-vivo studies. Optimizing neuroimaging correlates of hippocampal neuroinflammation would enable the direct study of functional consequences of hippocampal neuroinflammatory pathology, as well as the definition of therapeutic end-points for treatments targeting neuroinflammation, and their related affective or cognitive sequelae. However, in vivo traditional imaging of the hippocampus and its subregions is fraught with difficulties, due to methodological challenges deriving from its unique anatomical characteristics. The main objective of this review is to provide a current update on the characterization of quantitative neuroimaging correlates of hippocampal neuroinflammation by focusing on three prototypical autoimmune neuro-inflammatory conditions [multiple sclerosis (MS), systemic lupus erythematosus (SLE), and autoimmune encephalitis (AE)]. We focused on studies employing TSPO-targeting positron emission tomography (PET), quantitative magnetic resonance imaging (MRI), and spectroscopy techniques assumed to be sensitive to neuroinflammatory tissue changes. We found 18 eligible studies (14, 2, and 2 studies in MS, AE, and SLE, respectively). Across conditions, the largest effect was seen in TSPO PET and diffusion-weighted MRI studies. No study examined neuroinflammation-related changes at the hippocampal subfield level. Overall, results were largely inconsistent due to heterogeneous imaging methods, small sample sizes, and different population studies. We discuss how these data could inform future study design and conclude by suggesting further methodological directions aimed at improving the precision and sensitivity of neuroimaging techniques to characterize hippocampal neuroinflammatory pathology in the human brain., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Bipolar disorder (BD) is a major mental illness characterized by periods of (hypo) mania and depression with inter-episode remission periods. Functional studies in BD have consistently implicated a set of linked cortical and subcortical limbic regions in the pathophysiology of the disorder, also including the cerebellum. However, the cerebellar role in the neurobiology of BD still needs to be clarified. Seventeen euthymic patients with BD type1 (BD1) (mean age/SD, 38.64/13.48; M/F, 9/8) and 13 euthymic patients with BD type 2 (BD2) (mean age/SD, 41.42/14.38; M/F, 6/7) were compared with 37 sex- and age-matched healthy subjects (HS) (mean age/SD, 45.65/14.15; M/F, 15/22). T1 weighted and resting-state functional connectivity (FC) scans were acquired. The left and right dentate nucleus were used as seed regions for the seed based analysis. FC between each seed and the rest of the brain was compared between patients and HS. Correlations between altered cerebello-cerebral connectivity and clinical scores were then investigated. Different patterns of altered dentate-cerebral connectivity were found in BD1 and BD2. Overall, impaired dentate-cerebral connectivity involved regions of the anterior limbic network specifically related to the (hypo)manic states of BD. Cerebello-cerebral connectivity is altered in BD1 and BD2. Interestingly, the fact that these altered FC patterns persist during euthymia, supports the hypothesis that cerebello-cerebral FC changes reflect the neural correlate of subthreshold symptoms, as trait-based pathophysiology and/or compensatory mechanism to maintain a state of euthymia., (© 2021. The Author(s).)

Background: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood., Methods: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment., Results: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms., Conclusions: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration., Objective: The present study investigated the effect of CR in modulating brain cortical architecture., Methods: 278 individuals [110 Alzheimer's disease (AD), 104 amnestic mild cognitive impairment (aMCI) due to AD, 64 healthy subjects (HS)] underwent a neuropsychological evaluation and 3T-MRI. Cortical thickness (CTh) and fractal dimension (FD) were assessed. Years of formal education were used as an index of CR by which participants were divided into high and low CR (HCR and LCR). Within-group differences in cortical architecture were assessed as a function of CR. Associations between cognitive scores and cortical measures were also evaluated., Results: aMCI-HCR compared to aMCI-LCR patients showed significant decrease of CTh in the right temporal and in the left prefrontal lobe. Moreover, they showed increased FD in the right temporal and in the left temporo-parietal lobes. Patients with AD-HCR showed reduced CTh in several brain areas and reduced FD in the left temporal cortices when compared with AD-LCR subjects. HS-HCR showed a significant increase of CTh in prefrontal areas bilaterally, and in the right parieto-occipital cortices. Finally, aMCI-HCR showed significant positive associations between brain measures and memory and executive performance., Conclusion: CR modulates the cortical architecture at pre-dementia stage only. Indeed, only patients with aMCI showed both atrophy (likely due to neurodegeneration) alongside richer brain folding (likely due to reserve mechanisms) in temporo-parietal areas. This opposite trend was not observed in AD and HS. Our data confirm the existence of a limited time-window for CR modulation at the aMCI stage.

Background: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPS-induced glial activation., Methods: Seven healthy male volunteers, (mean 25.3 ± 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-5½ hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter., Results: Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R 2  = 0.83; p = 0.004)., Conclusions: DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation., (Copyright © 2021. Published by Elsevier Inc.)

Inflammation is associated with depressive symptoms and innate immune mechanisms are likely causal in some cases of major depression. Systemic inflammation also perturbs brain function and microstructure, though how these are related remains unclear. We recruited N = 46 healthy controls, and N = 83 depressed cases stratified by CRP (> 3 mg/L: N = 33; < 3 mg/L: N = 50). All completed clinical assessment, venous blood sampling for C-reactive protein (CRP) assay, and brain magnetic resonance imaging (MRI). Micro-structural MRI parameters including proton density (PD), a measure of tissue water content, were measured at 360 cortical and 16 subcortical regions. Resting-state fMRI time series were correlated to estimate functional connectivity between individual regions, as well as the sum of connectivity (weighted degree) of each region. Multiple tests for regional analysis were controlled by the false discovery rate (FDR = 5%). We found that CRP was significantly associated with PD in precuneus, posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC); and with functional connectivity between pC/pCC, mPFC and hippocampus. Depression was associated with reduced weighted degree of pC/pCC, mPFC, and other nodes of the default mode network (DMN). Thus CRP-related increases in proton density-a plausible marker of extracellular oedema-and changes in functional connectivity were anatomically co-localised with DMN nodes that also demonstrated significantly reduced hubness in depression. We suggest that effects of peripheral inflammation on DMN node micro-structure and connectivity may mediate inflammatory effects on depression., (© 2021. The Author(s).)

Recent developments in performance and practicality of optically-pumped magnetometers (OPMs) have enabled new capabilities in non-invasive brain function mapping through magnetoencephalography. In particular, the lack of cryogenic operating conditions allows for more flexible placement of sensor heads closer to the brain, leading to improved spatial resolution and source localisation capabilities. Through recording visually evoked brain fields (VEFs), we demonstrate that the closer sensor proximity can be exploited to improve temporal resolution. We use OPMs, and superconducting quantum interference devices (SQUIDs) for reference, to measure brain responses to flash and pattern reversal stimuli. We find highly reproducible signals with consistency across multiple participants, stimulus paradigms and sensor modalities. The temporal resolution advantage of OPMs is manifest in a twofold improvement, compared to SQUIDs. The capability for improved spatio-temporal signal tracing is illustrated by simultaneous vector recordings of VEFs in the primary and associative visual cortex, where a time lag on the order of 10-20 ms is consistently found. This paves the way for further spatio-temporal studies of neurophysiological signal tracking in visual stimulus processing, and other brain responses, with potentially far-reaching consequences for time-critical mapping of functionality in healthy and pathological brains., (© 2021. The Author(s).)

Network models based on structural connectivity have been increasingly used as the blueprint for large-scale simulations of the human brain. As the nodes of this network are distributed through the cortex and interconnected by white matter pathways with different characteristics, modeling the associated conduction delays becomes important. The goal of this study is to estimate and characterize these delays directly from the brain structure. To achieve this, we leveraged microstructural measures from a combination of advanced magnetic resonance imaging acquisitions and computed the main determinants of conduction velocity, namely axonal diameter and myelin content. Using the model proposed by Rushton, we used these measures to calculate the conduction velocity and estimated the associated delays using tractography. We observed that both the axonal diameter and conduction velocity distributions presented a rather constant trend across different connection lengths, with resulting delays that scale linearly with the connection length. Relying on insights from graph theory and Kuramoto simulations, our results support the approximation of constant conduction velocity but also show path- and region-specific differences., (© 2021. The Author(s).)

Background: brainstem monoaminergic (dopaminergic, noradrenergic, and serotoninergic) nuclei (BrMn) contain a variety of ascending neurons that diffusely project to the whole brain, crucially regulating normal brain function. BrMn are directly affected in multiple sclerosis (MS) by inflammation and neurodegeneration. Moreover, inflammation reduces the synthesis of monoamines. Aberrant monoaminergic neurotransmission contributes to the pathogenesis of MS and explains some clinical features of MS. We used resting-state functional MRI (RS-fMRI) to characterize abnormal patterns of BrMn functional connectivity (FC) in MS., Methods: BrMn FC was studied with multi-echo RS-fMRI in n = 68 relapsing-remitting MS patients and n = 39 healthy controls (HC), by performing a seed-based analysis, after producing standard space seed masks of the BrMn. FC was assessed between ventral tegmental area (VTA), locus coeruleus (LC), median raphe (MR), dorsal raphe (DR), and the rest of the brain and compared between MS patients and HC. Between-group comparisons were carried out only within the main effect observed in HC, setting p<0.05 family-wise-error corrected ( FWE )., Results: in HC, VTA displayed FC with the core regions of the default-mode network. As compared to HC, MS patients showed altered FC between VTA and posterior cingulate cortex (p<0.05 FWE ). LC displayed FC with core regions of the executive-control network with a reduced functional connection between LC and right prefrontal cortex in MS patients (p<0.05 FWE ). Raphe nuclei was functionally connected with cerebellar cortex, with a significantly lower FC between these nuclei and cerebellum in MS patients, as compared to HC (p<0.05 FWE )., Conclusions: our study demonstrated in MS patients a functional disconnection between BrMn and cortical/subcortical efferent targets of central brain networks, possibly due to a loss or a dysregulation of BrMn neurons. This adds new information about how monoaminergic systems contribute to MS pathogenesis and suggests new potential therapeutic targets., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium., Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries., Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing., Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Our ability to interact with those around us plays an important role in our relationships, mental well being and ability to successfully navigate the complex social society in which we live. Research in social cognitive neuroscience aims to understand the underlying neurobiology of our social behaviours and interactions with others. Myotonic dystrophy type 1 (DM1) is a genetically inherited neuromuscular disorder characterized by mytonia with systemic manifestations such as cardiac disease, respiratory insufficiency, ophthalmic complications, diabetes and frontal balding among others. Individuals with myotonic dystophy have been found to have widespread changes throughout the brain in both grey and white matter territories. They have been noted to experience difficulty with social cognitive function, and to more frequently display atypical personality traits leading to often unrecognized difficulties with everyday life. In this mini review we explore the anatomical basis of social cognition, current techniques for measuring and investigating this impairment including facial emotion recognition and theory of mind. We examine the evidence for general cognitive dysfunction, autism spectrum and personality disorders in DM1. Throughout the review we discuss neuroimaging highlights relevant to social cognition in DM1. Finally, we discuss practical implications relevant to managing people with myotonic dystrophy and highlight future research needs., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A third of patients receiving Interferon-α (IFN-α) treatment for Hepatitis-C develop major depressive disorder (MDD). Conversely, anti-Tumor Necrosis Factor (TNF) therapies improve depression providing key empirical support for the "inflammatory theory" of depression. Heightened amygdala reactivity (particularly to negatively valanced stimuli) is a consistent finding within MDD; can predict treatment efficacy and reverses following successful treatment. However, whether IFN-α and anti-TNF enhance/attenuate depressive symptoms through modulation of amygdala emotional reactivity is unknown. Utilizing a prospective study design, we recruited 30 patients (mean 48.0 ± 10.5 years, 21 male) initiating IFN-α treatment for Hepatitis-C and 30 (mean 50.4 ± 15.7 years, 10 male) anti-TNF therapy for inflammatory arthritis. All completed an emotional face-processing task during fMRI and blood sampling before and after their first IFN-α (4-h) or anti-TNF (24-h) injection and follow-up psychiatric assessments for 3 months of treatment. IFN-α significantly increased depression symptoms (Hamilton Depression Rating Scale HAM-D) at 4 weeks (p < 0.001) but not 4-h after first dose (p > 0.1). Conversely, anti-TNF significantly improved depressive symptoms (Hospital Anxiety and Depression Rating Scale HADS) at both 24-h (P = 0.015) and 12 weeks (p = 0.018). In support of our a-priori hypothesis, both IFN-α and anti-TNF significantly modulated amygdala reactivity with IFN-α acutely enhancing right amygdala responses to sad (compared with neutral) faces (p = 0.032) and anti-TNF conversely decreasing right amygdala reactivity (across emotional valence) (p = 0.033). Furthermore, these changes predicted IFN-induced increases in HAM-D 4 weeks later (R 2  = 0.17, p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R 2  = 0.23, p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms., (© 2020. The Author(s).)