Anteroposterior Gradient Research Articles

Control of innate olfactory valence by segregated cortical amygdala circuits.

Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

Multiple focal pulvinar projection fields in the macaque cortex

Abstract The pulvinar, the largest nucleus of the thalamus, is functionally heterogeneous and involved in multiple cognitive functions. It has been proposed to act as a functional hub of cortical processes due to its extensive reciprocal connectivity with the cortex. However, its role in cognition is not fully understood yet. Here, we posit that an improved understanding of its functional connectivity with the cortex is needed to better capture the cognitive functions of this nucleus. To address this question, we characterize the pulvino-cortical functional connectivity along the ventro-dorsal, antero-posterior, and medio-lateral axes, using awake resting-state data from 10 adult macaques. We first report two global cortical functional connectivity gradients along the antero-posterior and ventro-dorsal pulvinar gradients that match remarkably well the structural connectivity gradients described by anatomical approaches. In addition to these global gradients, multiple local cortical pulvinar projection fields can be identified at the sulci level such as in the lateral sulcus (LS), the intraparietal sulcus (IPS), the principal sulci (PS), and the anterior cingulate cortex (ACC). For most sulci, we show that functional pulvino-cortical projection fields follow the major anatomical axis of these different sulci (e.g., the ventro-dorsal axis for the LS and the antero-posterior axis for the IPS). Other sulci, such as the superior temporal sulcus, the posterior cingulate cortex, or the central sulcus, display multiple projection fields from the pulvinar. Although substantial inter-individual differences exist, the general functional connectivity patterns are remarkably consistent across hemispheres and individuals. Overall, we propose that these multiple pulvinar projection fields correspond to a fundamental principle of pulvino-cortical connectivity and that a better understanding of this connectional organization will shed light on the function of pulvino-cortical interactions and the role of the pulvinar in cognition at large.

Predictors associated with the rate of progression of nigrostriatal degeneration in Parkinson's disease.

Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.

Differential Effects of Aging on Regional Corpus Callosum Microstructure and the Modifying Influence of Pulse Pressure.

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested the effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age-pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed nonlinear components and occurred along an anteroposterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Superagers Resist Typical Age-Related White Matter Structural Changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age, 81.9; 59% women) and 55 typical older adults (mean age, 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed the better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibers and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus, and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional aging pattern is in line with the last-in-first-out hypothesis.

Distinct Spectral Profiles of Awake Resting EEG in Disorders of Consciousness: The Role of Frequency and Topography of Oscillations.

The prolonged disorders of consciousness (PDOC) pose a challenge for an accurate clinical diagnosis, mainly due to patients' scarce or ambiguous behavioral responsiveness. Measurement of brain activity can support better diagnosis, independent of motor restrictions. Methods based on spectral analysis of resting-state EEG appear as a promising path, revealing specific changes within the internal brain dynamics in PDOC patients. In this study we used a robust method of resting-state EEG power spectrum parameter extraction to identify distinct spectral properties for different types of PDOC. Sixty patients and 37 healthy volunteers participated in this study. Patient group consisted of 22 unresponsive wakefulness patients, 25 minimally conscious patients and 13 patients emerging from the minimally conscious state. Ten minutes of resting EEG was acquired during wakefulness and transformed into individual power spectra. For each patient, using the spectral decomposition algorithm, we extracted maximum peak frequency within 1-14Hz range in the centro-parietal region, and the antero-posterior (AP) gradient of the maximal frequency peak. All patients were behaviorally diagnosed using coma recovery scale-revised (CRS-R). The maximal peak frequency in the 1-14Hz range successfully predicted both neurobehavioral capacity of patients as indicated by CRS-R total score and PDOC diagnosis. Additionally, in patients in whom only one peak within the 1-14Hz range was observed, the AP gradient significantly contributed to the accuracy of prediction. We have identified three distinct spectral profiles of patients, likely representing separate neurophysiological modes of thalamocortical functioning. Etiology did not have significant influence on the obtained results.

Brain microstate spatio-temporal dynamics as a candidate endotype of consciousness

Consciousness can be defined as a phenomenological experience continuously evolving. Current research showed how conscious mental activity can be subdivided into a series of atomic brain states converging to a discrete spatiotemporal pattern of global neuronal firing. Using the high temporal resolution of EEG recordings in patients with a severe Acquired Brain Injury (sABI) admitted to an Intensive Rehabilitation Unit (IRU), we detected a novel endotype of consciousness from the spatiotemporal brain dynamics identified via microstate analysis. Also, we investigated whether microstate features were associated with common neurophysiological alterations. Finally, the prognostic information comprised in such descriptors was analysed in a sub-cohort of patients with prolonged Disorder of Consciousness (pDoC). Occurrence of frontally-oriented microstates (C microstate), likelihood of maintaining such brain state or transitioning to the C topography and complexity were found to be indicators of consciousness presence and levels. Features of left–right asymmetric microstates and transitions toward them were found to be negatively correlated with antero-posterior brain reorganization and EEG symmetry. Substantial differences in microstates’ sequence complexity and presence of C topography were found between groups of patients with alpha dominant background, cortical reactivity and antero-posterior gradient. Also, transitioning from left-right to antero-posterior microstates was found to be an independent predictor of consciousness recovery, stronger than consciousness levels at IRU’s admission. In conclusions, global brain dynamics measured with scale-free estimators can be considered an indicator of consciousness presence and a candidate marker of short-term recovery in patients with a pDoC.

EEG-based spatiotemporal dynamics of fast ripple networks and hubs in infantile epileptic spasms.

Infantile epileptic spasms (IS) are epileptic seizures that are associated with increased risk for developmental impairments, adult epilepsies, and mortality. Here, we investigated coherence-based network dynamics in scalp EEG of infants with IS to identify frequency-dependent networks associated with spasms. We hypothesized that there is a network of increased fast ripple connectivity during the electrographic onset of clinical spasms, which is distinct from controls. We retrospectively analyzed peri-ictal and interictal EEG recordings of 14 IS patients. The data was compared with 9 age-matched controls. Wavelet phase coherence (WPC) was computed between 0.2 and 400 Hz. Frequency- and time-dependent brain networks were constructed using this coherence as the strength of connection between two EEG channels, based on graph theory principles. Connectivity was evaluated through global efficiency (GE) and channel-based closeness centrality (CC), over frequency and time. GE in the fast ripple band (251-400 Hz) was significantly greater following the onset of spasms in all patients (P < 0.05). Fast ripple networks during the first 10s from spasm onset show enhanced anteroposterior gradient in connectivity (posterior > central > anterior, Kruskal-Wallis P < 0.001), with maximum CC over the centroparietal channels in 10/14 patients. Additionally, this anteroposterior gradient in CC connectivity is observed during spasms but not during the interictal awake or asleep states of infants with IS. In controls, anteroposterior gradient in fast ripple CC was noted during arousals and wakefulness but not during sleep. There was also a simultaneous decrease in GE in the 5-8 Hz range after the onset of spasms (P < 0.05), of unclear biological significance. We identified an anteroposterior gradient in the CC connectivity of fast ripple hubs during spasms. This anteroposterior gradient observed during spasms is similar to the anteroposterior gradient in the CC connectivity observed in wakefulness or arousals in controls, suggesting that this state change is related to arousal networks.

Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

Electroencephalographic Characterization by Covariance Analysis in Men with Parkinson’s Disease Reveals Sex- and Age-Related Differences

Parkinson’s disease (PD) is the fastest growing neurological disease associated with ageing; its symptomatology varies between sexes. Several quantitative electroencephalography analyses have been used to study the early stages and progression of PD. In this study, we aim to characterize the brain activity by considering the five brainwaves in an eyes-closed resting state, using covariance wavelet analysis (CWA) of electroencephalographic records (EEGs) to analyze the influence of sex and age. To effectively eliminate artifacts from the EEG dataset and extract pertinent brain activity, we employ the inverse wavelet analysis. EEGs from men with PD were divided into two age groups (PD &lt; 60 and PD &gt; 60 years old) with their respective age-matched controls (CL). Brain activity patterns in frequency and power domains were analyzed with the CWA. Main frequency profiles, global wavelet curves, power anomalies, and power per brainwave were used to illustrate the CWA patterns. Power anomalies were used to generate anteroposterior power gradients. In PD &lt; 60 men, frequency and power for the α brainwave decreased, while the δ brainwave increased. The θ brainwave increased and was dominant over the α brainwave in PD &gt; 60 men. The anteroposterior power gradient in PD &lt; 60 men had a positive slope, but it was negative in CL. In both PD and CL &gt; 60 men, the anteroposterior gradient was negative. In PD &gt; 60 men, the θ brainwave increased and became dominant. Men with PD had twice the θ brainwave increase. An inverse relationship between α and δ brainwaves was detected in a PD &lt; 60 sex comparison. A conventional EEG spectral analysis using CWA indicated significant differences in brain activity patterns in the PD/CL groups affected by sex and age, yielding previously unknown information.

Three-dimensional micromorphology of human midpalatal suture and pterygomaxillary articular complex.

Sutures exist in the craniofacial area, and the pattern of maturation and synostosis of facial sutures is largely unknown. For a comprehensive understanding of the three-dimensional circummaxillary suture micromorphology, human midpalatal suture (MPS) and pterygomaxillary articular complex from eight subjects' (five males, three females, 72-88 years old) autopsies were longitudinally scanned with microcomputed tomography. Additional histology was performed for hematoxylin and eosin staining. Sutural micromorphology was assessed by interdigitation index (II), obliteration index (OI) and obliteration number. Intergroup comparisons were performed with Kruskal-Wallis and Mann-Whitney U with Bonferroni correction (α=0.005). Correlation with anteroposterior and craniocaudal gradients was assessed with Spearman's correlation test (α=0.05). Maxillary region of MPS presented a higher II 1.50 (0.61) and obliteration number per slice 8 (9) (P < 0.005). OI was increased in palatomaxillary 35% (47%) followed by pterygopalatine suture 25% (49%) (P < 0.005). The II and OI of the MPS exhibited only a weak anteroposterior gradient, with relatively low correlations. Obliteration areas were found sporadically along the entire MPS. Based on these findings, it is conceivable that the success of nonsurgical maxillary expansion largely depends on individual variations in sutural morphology and maturation rather than appliance design.

Betaglycan promoter activity is differentially regulated during myogenesis in zebrafish embryo somites.

Betaglycan, also known as the TGFβ type III receptor (Tgfbr3), is a co-receptor that modulates TGFβ family signaling. Tgfbr3 is upregulated during C2C12 myoblast differentiation and expressed in mouse embryos myocytes. To investigate tgfbr3 transcriptional regulation during zebrafish embryonic myogenesis, we cloned a 3.2 kb promoter fragment that drives reporter transcription during C2C12 myoblasts differentiation and in the Tg(tgfbr3:mCherry) transgenic zebrafish. We detect tgfbr3 protein and mCherry expression in the adaxial cells concomitantly with the onset of their radial migration to become slow-twitch muscle fibers in the Tg(tgfbr3:mCherry). Remarkably, this expression displays a measurable antero-posterior somitic gradient expression. tgfbr3 is transcriptionally regulated during somitic muscle development in zebrafish with an antero-posterior gradient expression that preferentially marks the adaxial cells and their descendants.

Positron emission tomography in autoimmune encephalitis: Clinical implications and future directions.

18 F-fluoro-deoxyglucose position emission tomography (18 F-FDG-PET) has been proven as a sensitive and reliable tool for diagnosis of autoimmune encephalitis (AE). More attention was paid to this kind of imaging because of the shortage of MRI, EEG, and CSF findings. FDG-PET has been assessed in a few small studies and case reports showing apparent abnormalities in cases where MRI does not. Here, we summarized the patterns (specific or not) in AE with different antibodies detected and the clinical outlook for the wide application of FDG-PET considering some limitations. Specific patterns based on antibody subtypes and clinical symptoms were critical for identifying suspicious AE, the most common of which was the anteroposterior gradient in anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis and the medial temporal lobe hypermetabolism in limbic encephalitis. And the dynamic changes of metabolic presentations in different phases provided us the potential to inspect the evolution of AE and predict the functional outcomes. Except for the visual assessment, quantitative analysis was recently reported in some voxel-based studies of regions of interest, which suggested some clues of the future evaluation of metabolic abnormalities. Large prospective studies need to be conducted controlling the time from symptom onset to examination with the same standard of FDG-PET scanning.

Distribution of five clinically important neuroglial proteins in the human brain

Glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), neurofilament light chain (NFL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) are five neuroglial proteins that are used as CSF or blood biomarkers of tissue damage in the nervous system. There is incomplete knowledge of how the concentration of these proteins differs between anatomical regions in the CNS as previous studies have focused on gene expression or non-quantitative protein analyses, limiting the interpretability of these biomarkers. The purpose of this study was to create a map of the tissue content of these proteins in different regions of the CNS. The concentrations of the investigated proteins were determined with ELISA in post mortem tissue homogenates from 17 selected anatomical regions in the CNS from ten deceased donors aged 24 to 50 years. When appropriate, the protein concentrations were adjusted for post-mortem interval. In total, 168 tissue samples were analysed. There was a substantial variation in the concentrations of GFAP, MBP, NFL, tau and UCHL1 between different CNS regions. Highly myelinated areas of the CNS had tenfold higher MBP concentration than cerebral cortex, whereas tau showed an inverse pattern. GFAP, NFL and tau displayed an anteroposterior gradient in cerebral white matter. The cerebellum had low concentrations of all the investigated proteins. In conclusion, the tissue concentrations of GFAP, MBP, NFL, tau and UCHL1 were determined throughout the CNS. This information can be used as a reference when interpreting circulating levels of these biomarkers in relation to the extent and localisation of CNS-damaging processes.

Interrelationship Between Microstructure &amp; Macrostructure in the Growing Hard Palate

Bone strength is the result of microstructure (material properties) and macrostructure (size and shape), and deficiencies in either can produce skeletal fragilities with increased likelihood of injury. The micro‐ and macro‐architecture work together during re/modeling, ensuring that bone is resistant to repetitive loading and fracture. Bone is particularly responsive to loading during the rapid growth occurring in early life. Within the craniofacial complex, the hard palate is a unique structure that undergoes continuous loading due to resting/active tongue pressure and bite force. Because of this, palatal growth is theorized to drive midfacial growth. The aim of this study is to investigate longitudinal changes in palatal micro‐ and macro‐structure in the context of a perturbation to type I collagen (Col1). Col1 is the structural protein that forms osteoid (the precursor to bone), forms a scaffold for bone mineralization, and determines bone toughness. Here we use the OIM mouse (B6C3FE a/a‐Col1a2OIM/J), a strain with a Col1 mutation. We hypothesize that OIM and unaffected wild‐type (WT) mice will be most similar in bone micro‐ and macro‐structure in regions of the palate that experience high loading and therefore necessitate high rates of bone modeling or remodeling to form a structure which can withstand the stress.Mice were micro‐CT scanned at two timepoints: week 4 (juvenile) and week 16 (adult). BMD was collected at 3 regions (anterior, mid, and posterior palate). Mann‐Whitney U tests were used to compare BMD between genotypes. 28 fixed and 10 sliding landmarks were placed across the palate. Geometric morphologic analyses were conducted to determine variation between genotypes in overall shape and curvature throughout growth.Average BMD decreased along an anteroposterior gradient for all mice. While juvenile OIM mice had lower palate BMD than WT mice at all regions, adult OIM mice had significantly lower BMD at only the anterior and posterior regions but not the midpalate. Procrustes ANOVA revealed significant differences in palatal shape between the genotypes at both the juvenile (p=0.001) and adult (p=0.0015) stage. Principal component analyses revealed that juvenile OIM mice had a shorter anterior palate and broader palate compared to WT mice, while adult OIM mice had a shorter posterior palate than WT mice. OI mice had flatter palatal arches in the coronal plane as juveniles, and in the midsagittal plane as juveniles and adults.Results show significant differences in palatal BMD and morphology between genotypes throughout growth, with fewer significant differences at the adult stage. Increased loading of the anterior palate during incisive gnawing may result in the convergence of bone macrostructure among adult mice, while increased strain at the midpalatal suture may necessitate increased BMD even in the presence of a biomineralization defect. Further research is needed to understand the functional significance of the anteroposterior palatal gradient and its relation to soft tissue attachments, particularly given the transition in oral behaviors between juveniles and adults.

Anterior optic pathway pathology in CNS demyelinating diseases.

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.

Syntelencephaly: medial interhemispheric variant of holoprosencephaly

Holoprosencephaly (HPE) is a congenital malformation occurring very early in pregnancy and due to abnormal diverticulation of the prosencephalon. This defect in primary brain cleavage may be total or partial, which explains the anatomopathological variants of holoprosencephaly. The main forms of holoprosencephaly include alobar, semilobar and lobar HPE. Syntelencephaly also known as middle interhemispheric variant (MIHV) is a very rare type of HPE. While in the three most common variants, cleavage defect has antero-posterior gradient of severity, syntelencephaly does not follow this rule. The latter is characterised by abnormal communication between cerebral hemispheres in the posterior and parietal frontal regions, with normal inter-hemispheric separation of the anterior frontal lobes, of the occipital regions and central grey nuclei. The trunk of the corpus callosum is achieved at the level of the knee of the corpus callosum (allowing differentiation from lobar HPE) and of the splenium. An azygos cerebral artery is common, consisting of a fusion of the A1 segments of the anterior cerebral arteries to form a single arterial trunk. Other cerebral malformations may be associated with syntelencephaly, the most frequent being cortical dysplasia and grey matter heterotopia. Facial abnormalities are less common in syntelencephaly compared to classic forms of HPE. Prognosis depends mainly on these malformative associations in the brain and other organs, and even on chromosomal aberrations.

Use of Covariance Analysis in Electroencephalogram Reveals Abnormalities in Parkinson’s Disease

Covariance analysis from wavelet data in electroencephalographic records (EEG) was, for the first time, applied in this study to unravel information contained in the standard EEG, which was previously not taken into consideration due to the mathematical models used. The methodology discussed here could be applied to any neurological condition, including the important early stages of neurodegenerative diseases. In this study, we analyzed EEG from control (CL) participants and participants with diagnosed Parkinson’s disease (PD), who were age-matched women in an eyes-closed resting state, to test the model. PD is predicted to rise over the next decades as the population ages. Furthermore, women are more likely to undergo PD-related complications and worse disability than men. Two groups based on age were considered: under and over 60 years (PD patients &lt;60 and &gt;60; CL &lt;60 and &gt;60). Continuous Wavelet Transform and Cross Wavelet Transform were applied to determine patterns of global wavelet curves, main frequencies, and power analyses. Our results indicate that both CL age groups and PD patients &lt;60 share a main α brainwave and PD patients &gt;60 showed a main δ brainwave. Interestingly, power anomalies analyses show a decreasing anteroposterior gradient in CL, whereas it is increasing in PD patients, which was not previously observed. The brainwave power in PD patients &lt;60 was higher in θ, α and β waves and in &gt;60 group, the δ, θ and β brainwaves were predominant. This methodology offers a tool to reveal abnormal electrical brain activity unseen by a regular EEG analysis. The advent of new models that process EEG, such as the model proposed in this study, promotes renewed interest in electrophysiology of the brain to study the early stages of PD and improve understanding of the origin and progress of the disease.

Novel insights into the clinico-radiological spectrum of phenotypes associated to PIGN mutations.

Autosomic recessive mutations in the PIGN gene have been described in less than 30 subjects to date, in whom multiple congenital anomalies combined with severe developmental delay, hypotonia, epileptic encephalopathy, and cerebellar atrophy have been described as crucial features. A clear-cut neuroradiological characterization of this entity, however, is still lacking. We aim to present three pediatric PIGN mutated cases with an in-depth evaluation of their brain abnormalities. We present the neuroradiological, clinical, and genetic characterization of three Caucasian pediatric subjects with pathogenic/likely pathogenic variants in the PIGN gene revealed by Next Generation Sequencing analysis. We identified three subjects (two siblings, one unrelated case) presenting with encephalopathy with early-onset epilepsy, hypotonia, and severe global developmental delay. No additional severe multiple congenital anomalies were detected. Neuroradiological evaluation showed extensive quantitative reduction of white matter, severe and progressive cortical atrophy, with frontal predominance and an anteroposterior gradient, combined with cerebellar and brainstem atrophy. Our findings broaden and systematize the neuroradiological spectrum of abnormalities in PIGN related encephalopathy. Furthermore, our dataset confirms that mutations in PIGN gene appear to be pan-ethnic and represent an underestimated cause of early-onset encephalopathy.

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1–4 Hz SWA in a region-dependent manner (F2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1–2 Hz SWA (F2, 687 =18.0, p < 0.001). The association of MoCA with 1–2 Hz SWA (and 1–4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1–2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.