Neurolipidomics in schizophrenia: A not so well-oiled machine.

Most patients with schizophrenia (SCZ) do not exhibit violent behaviors and are more likely to be victims rather than perpetrators of violent acts. However, a subgroup of forensic detainees with SCZ exhibit tendencies to engage in criminal violations. Although numerous models have been proposed, ranging from substance use, serotonin transporter gene, and cognitive dysfunction, the molecular underpinnings of violence in SCZ patients remains elusive. Lithium and clozapine have established anti-aggression properties and recent studies have linked low cholesterol levels and ultraviolet (UV) radiation with human aggression, while vitamin D3 reduces violent behaviors. A recent study found that vitamin D3, omega-3 fatty acids, magnesium, and zinc lower aggression in forensic population. In this review article, we take a closer look at aryl hydrocarbon receptor (AhR) and the dysfunctional lipidome in neuronal membranes, with emphasis on cholesterol and vitamin D3 depletion, as sources of aggressive behavior. We also discuss modalities to increase the fluidity of neuronal double layer via membrane lipid replacement (MLR) and natural or synthetic compounds. This article is part of the Special Issue on "Personality Disorders".

Copaifera langsdorffii Desf. tree oleoresin-induced antinociception recruits µ1- and κ -opioid receptors in the ventrolateral columns of the periaqueductal gray matter.

Popular medicine has been using oleoresin from several species of copaíba tree for the treatment of various diseases and its clinical administration potentially causes antinociception. Electrical stimulation of ventrolateral (vlPAG) and dorsolateral (dlPAG) columns of the periaqueductal gray matter also causes antinociception. The aim this study was to verify the antinociceptive effect of oleoresin extracted from Copaifera langsdorffii tree and to test the hypothesis that oleoresin-induced antinociception is mediated by µ1- and κ-opioid receptors in the vlPAG and dlPAG. Nociceptive thresholds were determined by the tail-flick test in Wistar rats. The copaíba tree oleoresin was administered at different doses (50, 100 and 200 mg/kg) through the gavage technique. After the specification of the most effective dose of copaíba tree oleoresin (200 mg/kg), rats were pretreated with either the µ1-opioid receptor selective antagonist naloxonazine (at 0.05, 0.5 and 5 µg/ 0.2 µl in vlPAG, and 5 µg/ 0.2 µl in dlPAG) or the κ-opioid receptor selective antagonist nor-binaltorphimine (at 1, 3 and 9 nmol/ 0.2 µl in vlPAG, and 9 nmol/ 0.2 µl in dlPAG). The blockade of µ1 and κ opioid receptors of vlPAG decreased the antinociception produced by copaíba tree oleoresin. However, the blockade of these receptors in dlPAG did not alter copaíba tree oleoresin-induced antinociception. These data suggest that vlPAG µ1 and κ opioid receptors are critically recruited in the antinociceptive effect produced by oleoresin extracted from Copaifera langsdorffii.

Multi-tensor diffusion abnormalities of gray matter in an animal model of cortical dysplasia.

Focal cortical dysplasias are a type of malformations of cortical development that are a common cause of drug-resistant focal epilepsy. Surgical treatment is a viable option for some of these patients, with their outcome being highly related to complete surgical resection of lesions visible in magnetic resonance imaging (MRI). However, subtle lesions often go undetected on conventional imaging. Several methods to analyze MRI have been proposed, with the common goal of rendering subtle cortical lesions visible. However, most image-processing methods are targeted to detect the macroscopic characteristics of cortical dysplasias, which do not always correspond to the microstructural disarrangement of these cortical malformations. Quantitative analysis of diffusion-weighted MRI (dMRI) enables the inference of tissue characteristics, and novel methods provide valuable microstructural features of complex tissue, including gray matter. We investigated the ability of advanced dMRI descriptors to detect diffusion abnormalities in an animal model of cortical dysplasia. For this purpose, we induced cortical dysplasia in 18 animals that were scanned at 30 postnatal days (along with 19 control animals). We obtained multi-shell dMRI, to which we fitted single and multi-tensor representations. Quantitative dMRI parameters derived from these methods were queried using a curvilinear coordinate system to sample the cortical mantle, providing inter-subject anatomical correspondence. We found region- and layer-specific diffusion abnormalities in experimental animals. Moreover, we were able to distinguish diffusion abnormalities related to altered intra-cortical tangential fibers from those associated with radial cortical fibers. Histological examinations revealed myelo-architectural abnormalities that explain the alterations observed through dMRI. The methods for dMRI acquisition and analysis used here are available in clinical settings and our work shows their clinical relevance to detect subtle cortical dysplasias through analysis of their microstructural properties.

Changes in brain gray matter volume in nasopharyngeal carcinoma patients after radiotherapy in long-term follow-up

Abstract Objectives The aim of this study was to examine the changes in gray matter in nasopharyngeal carcinoma patients with normal hearing (Group 1) and nasopharyngeal carcinoma patients with hearing loss (Group 2) after radiotherapy using voxel-based morphological analysis and to analyze the relationship with the radiation doses of the temporal lobe. Methods 21 patients in Group 1, 14 patients in Group 2, and 21 healthy volunteers were selected. All participants underwent an otologic examination and three-dimensional magnetization preparatory rapid acquisition gradient echo sequence scan. The correlation between the variation of whole brain gray matter volume and the doses of the temporal lobe was analyzed by Data Processing & Analysis for Brain Imaging software. Results Compared with the normal control group, the brain areas with reduced gray matter volume in nasopharyngeal carcinoma patients after radiotherapy were mainly in the left posterior cerebellar lobe (T = −8.797), left insular lobe (T = −7.96), and the right insular lobe (T = −6.632). Compared to Group 1, the brain areas of Group 2 patients with reduced gray matter volume were mainly in the left superior temporal gyrus (T = −2.366), left olfactory bulb (T = −2.52), left Rolandic operculum (T = −2.431), and right olfactory bulb (T = −3.100). Compared with Group 1, the brain areas of Group 2 patients with increased gray matter volume were mainly in the left calcarine sulcus (T = 3.425) and right calcarine sulcus (T = 3.169). There were no correlations between the changes of brain gray matter volume and the radiation doses of the temporal lobe in both Group 1 and Group 2. Conclusions The radiotherapy may cause the changes of brain areas associated with cognitive function in nasopharyngeal carcinoma in a long-term follow-up. At the same time, nasopharyngeal carcinoma patients with the radiation-induced hearing loss had abnormal gray matter volumes in the auditory center and other sensory centers. Our findings might provide new understanding into the pathogenesis of radiation-induced brain damage in normal-appearing brain tissue. Yet this exploratory study should be taken with caution.

Changes in brain gray matter volume in nasopharyngeal carcinoma patients after radiotherapy in long-term follow-up.

OBJECTIVES: The aim of this study was to examine the changes in gray matter in nasopharyngeal carcinoma patients with normal hearing (Group 1) and nasopharyngeal carcinoma patients with hearing loss (Group 2) after radiotherapy using voxel-based morphological analysis and to analyze the relationship with the radiation doses of the temporal lobe. METHODS: 21 patients in Group 1, 14 patients in Group 2, and 21 healthy volunteers were selected. All participants underwent an otologic examination and three-dimensional magnetization preparatory rapid acquisition gradient echo sequence scan. The correlation between the variation of whole brain gray matter volume and the doses of the temporal lobe was analyzed by Data Processing & Analysis for Brain Imaging software. RESULTS: Compared with the normal control group, the brain areas with reduced gray matter volume in nasopharyngeal carcinoma patients after radiotherapy were mainly in the left posterior cerebellar lobe (T = -8.797), left insular lobe (T = -7.96), and the right insular lobe (T = -6.632). Compared to Group 1, the brain areas of Group 2 patients with reduced gray matter volume were mainly in the left superior temporal gyrus (T = -2.366), left olfactory bulb (T = -2.52), left Rolandic operculum (T = -2.431), and right olfactory bulb (T = -3.100). Compared with Group 1, the brain areas of Group 2 patients with increased gray matter volume were mainly in the left calcarine sulcus (T=3.425) and right calcarine sulcus (T=3.169). There were no correlations between the changes of brain gray matter volume and the radiation doses of the temporal lobe in both Group 1 and Group 2. CONCLUSIONS: The radiotherapy may cause the changes of brain areas associated with cognitive function in nasopharyngeal carcinoma in a long-term follow-up. At the same time, nasopharyngeal carcinoma patients with the radiation-induced hearing loss had abnormal gray matter volumes in the auditory center and other sensory centers. Our findings might provide new understanding into the pathogenesis of radiation-induced brain damage in normal-appearing brain tissue. Yet this exploratory study should be taken with caution.

Indicadores morfométricos de la corteza cerebral frontal de gazapos de ratas Wistar con diabetes pregestacional

Introducción: La diabetes es una enfermedad que afecta el embarazo provoca complicaciones fetales; dentro de ellas son frecuentes las malformaciones congénitas. Por la imposibilidad práctica y ética de estudiar este proceso en gestantes es imprescindible realizar estudios experimentales empleando procedimientos morfométricos para determinar si la diabetes afecta el neurodesarrollo. Objetivo: Caracterizar morfométricamente la sustancia gris de gazapos de ratas Wistar normales y con diabetes mellitus pregestacional. Métodos: Se realizó un estudio experimental básico de serie de casos a 20 gazapos de ratas Wistar de los cuales 10 eran descendientes de diabetes pregestacional. Se caracterizaron indicadores morfométricos del tejido nervioso como espesor de corteza e indicadores nucleares como el perímetro. Resultados: La media de la altura de la sustancia gris cortical mostró un valor de 1,224 ± 303,7 μm para el grupo control y 1,014 ± 376,0 para los casos, al aplicar el test de diferencias de medias se encontró diferencia significativa (p ≤ 0,05) a favor del grupo control. Los valores de la media del perímetro nuclear en el grupo control fue de 42,80 ± 7,23 μm y en el grupo experimental el promedio fue de 39,68 ± 6,52 μm, al aplicar el test de diferencias de medias se encontró diferencia significativa (p ≤ 0,05) a favor del grupo control al presentar mayor perímetro nuclear. Conclusiones: El mayor espesor cortical y perímetro nuclear correspondió al grupo control evidenciándose el efecto deletéreo de la diabetes mellitus en el neurodesarrollo.

Introduction: Diabetes is a disease that affects pregnancy causing fetal complications; within them congenital malformations are frequent. Due to the practical and ethical impossibility of studying this process in pregnant women, it is essential to carry out experimental studies using morphometric procedures to determine if diabetes affects neurodevelopment. Objective: To characterize morphometrically the gray matter of kits from normal Wistar rats and those with pregestational diabetes mellitus. Methods: A basic experimental study of a series of cases was carried out on 20 young Wistar rats, of which 10 were descendants of pregestational diabetes. Morphometric indicators of the nervous tissue were characterized as thickness of the cortex and nuclear indicators such as perimeter. Results: The average height of the cortical gray matter showed a value of 1.224 ± 303.7 μm for the control group and 1.014 ± 376.0 μm for the cases. When applying the mean difference test, a significant difference was found (p ≤ 0.05) in favor of the control group. The values of the measurement of the nuclear perimeter in the control group was 42.80 ± 7.23 μm and in the experimental group the average was 39.68 ± 6.52 μm. When applying the mean different test, a significant difference was found (p ≤ 0.05) at favor of control group presenting greater nuclear perimeter. Conclusions: The greatest cortical thickness and nuclear perimeter corresponded to the control group, evidencing the deleterious effect os diabetes mellitus on neurodevelopment.

Investigating Tissue-Specific Abnormalities in Alzheimer's Disease with Multi-Shell Diffusion MRI.

BACKGROUND: Most studies using diffusion-weighted MRI (DW-MRI) in Alzheimer's disease (AD) have focused their analyses on white matter (WM) microstructural changes using the diffusion (kurtosis) tensor model. Although recent works have addressed some limitations of the tensor model, such as the representation of crossing fibers and partial volume effects with cerebrospinal fluid (CSF), the focus remains in modeling and analyzing the WM. OBJECTIVE: In this work, we present a brain analysis approach for DW-MRI that disentangles multiple tissue compartments as well as micro- and macroscopic effects to investigate differences between groups of subjects in the AD continuum and controls. METHODS: By means of the multi-tissue constrained spherical deconvolution of multi-shell DW-MRI, underlying brain tissue is modeled with a WM fiber orientation distribution function along with the contributions of gray matter (GM) and CSF to the diffusion signal. From this multi-tissue model, a set of measures capturing tissue diffusivity properties and morphology are extracted. Group differences were interrogated following fixel-, voxel-, and tensor-based morphometry approaches while including strong FWE control across multiple comparisons. RESULTS: Abnormalities related to AD stages were detected in WM tracts including the splenium, cingulum, longitudinal fasciculi, and corticospinal tract. Changes in tissue composition were identified, particularly in the medial temporal lobe and superior longitudinal fasciculus. CONCLUSION: This analysis framework constitutes a comprehensive approach allowing simultaneous macro and microscopic assessment of WM, GM, and CSF, from a single DW-MRI dataset.

Failure of AAV retrograde tracer transduction in hypothalamic projections to the periaqueductal gray matter.

Connectomics is an important field of neuroscience that examines how neurons are connected and form functional circuits that underly the brain's functions. Conventional tracers based on dye have led to great advances in mapping these connections, and now, neurotropic viruses are contributing to connectomics. In this work, two retrograde adeno-associated virus failed to transduce in projections from hypothalamic neurons to periaqueductal gray matter (PAG) but worked well in cortical connections to PAG. One of this virus also marked a substantial amount of PAG efferent projections, therefore working as an anterograde tracer. We also used hydroxystilbamidine (FluoroGold™) as a gold standard in retrograde tracing for comparison with the projections shown by the retrograde virus. As determined in past works, FluoroGold™ shows connections from the hypothalamus and cortex to the PAG. Also, an anterograde AAV was compared with one of the retrograde AAV, which showed a similar pattern of axonal projections and terminal fields. Hence, although neurotropic viruses are revolutionizing connectomics and other areas, their mechanism, neurotropism, and cell invasion need to be addressed. Their use is a great challenge and requires further studies to clarify their interaction with the nervous system's cells.

Ventrolateral periaqueductal gray matter integrative system of defense and antinociception.

Defensive responses are neurophysiological processes crucial for survival during threatening situations. Defensive immobility is a common adaptive response, in rodents, elaborated by ventrolateral periaqueductal gray matter (vlPAG) when threat is unavoidable. It is associated with somatosensory and autonomic reactions such as alteration in the sensation of pain and rate of respiration. In this study, defensive immobility was assessed by chemical stimulation of vlPAG with different doses of NMDA (0.1, 0.3, and 0.6 nmol). After elicitation of defensive immobility, antinociceptive and respiratory response tests were also performed. Results revealed that defensive immobility was followed by a decrease in the nociceptive perception. Furthermore, the lowest dose of NMDA induced antinociceptive response without eliciting defensive immobility. During defensive immobility, respiratory responses were also disturbed. Interestingly, respiratory rate was increased and interspersed with prolonged expiratory phase of breathing. These findings suggest that vlPAG integrates three different defensive behavioral responses, contributing to the most effective defensive strategies during threatening situations.

Functional activation of the periaqueductal gray matter during conditioned and unconditioned fear in guinea pigs confronted with the Boa constrictor constrictor snake

The periaqueductal gray matter (PAG) is an essential structure involved in the elaboration of defensive responses, such as when facing predators and conspecific aggressors. Using a prey vs predator paradigm, we aimed to evaluate the PAG activation pattern evoked by unconditioned and conditioned fear situations. Adult male guinea pigs were confronted either by a Boa constrictor constrictor wild snake or by the aversive experimental context. After the behavioral test, the rodents were euthanized and the brain prepared for immunohistochemistry for Fos protein identification in different PAG columns. Although Fos-protein-labeled neurons were found in different PAG columns after both unconditioned and conditioned fear situations at the caudal level of the PAG, we found greater activation of the lateral column compared to the ventrolateral and dorsomedial columns after predator exposure. Moreover, the lateral column of the PAG showed higher Fos-labeled cells at the caudal level compared to the same area at the rostral level. The present results suggested that there are different activation patterns of PAG columns during unconditioned and conditioned fear in guinea pigs. It is possible to hypothesize that the recruitment of specific PAG columns depended on the nature of the threatening stimulus.

Enhanced responsiveness to hypoxic panicogenic challenge in female rats in late diestrus is suppressed by short-term, low-dose fluoxetine: Involvement of the dorsal raphe nucleus and the dorsal periaqueductal gray.

BACKGROUND: Acute hypoxia, which is panicogenic in humans, also evokes panic-like behavior in male rats. Panic disorder is more common in women and susceptibility increases during the premenstrual phase of the cycle. AIMS: We here investigated for the first time the impact of hypoxia on the expression of panic-like escape behavior by female rats and its relationship with the estrous cycle. We also evaluated functional activation of the midbrain panic circuitry in response to this panicogenic stimulus and whether short-term, low-dose fluoxetine treatment inhibits the hyper-responsiveness of females in late diestrus. METHODS: Male and female Sprague Dawley rats were exposed to 7% O2. Females in late diestrus were also tested after short-term treatment with fluoxetine (1.75 or 10 mg/kg, i.p.). Brains were harvested and processed for c-Fos and tryptophan hydroxylase immunoreactivity in the periaqueductal gray matter (PAG) and dorsal raphe nucleus (DR). RESULTS: Acute hypoxia evoked escape in both sexes. Overall, females were more responsive than males and this is clearer in late diestrus phase. In both sexes, hypoxia induced functional activation (c-Fos expression) in non-serotonergic cells in the lateral wings of the DR and dorsomedial PAG, which was greater in late diestrus than proestrus (lowest behavioral response to hypoxia). Increased responding in late diestrus (behavioral and cellular levels) was prevented by 1.75, but not 10 mg/kg fluoxetine. DISCUSSION: The response of female rats to acute hypoxia models panic behavior in women. Low-dose fluoxetine administered in the premenstrual phase deserves further attention for management of panic disorders in women.

Effects of seizure burden on structural global brain networks in patients with unilateral hippocampal sclerosis.

BACKGROUND AND PURPOSE: Temporal lobe epilepsy secondary to hippocampal sclerosis is related to epileptogenic networks rather than a focal epileptogenic source. Graph-theoretical gray and white matter networks may help to identify alterations within these epileptogenic networks. METHODS: Twenty-seven patients with hippocampal sclerosis and 14 controls underwent magnetic resonance imaging, including 3D-T1, fluid-attenuated inversion recovery, and diffusion tensor imaging. Subject-specific structural gray and white matter network properties (normalized path length, clustering, and small-worldness) were reconstructed. Group differences and differences between those with higher and lower seizure burden (<4 vs. ≥4 average monthly seizures in the last year) in network parameters were evaluated. Additionally, correlations between network properties and disease-related variables were calculated. RESULTS: All patients with hippocampal sclerosis as one group did not have altered gray or white matter network properties (all p > .05). Patients with lower seizure burden had significantly lower gray matter small-worldness and normalized clustering compared to controls and those with higher seizure burden (all p < .04). A higher number of monthly seizures was significantly associated with increased gray and white matter small-worldness, indicating a more rigid network. CONCLUSION: Overall, there were no differences in network properties in this group of patients with hippocampal sclerosis. However, patients with lower seizure burden had significantly lower gray matter network indices, indicating a more random organization. The correlation between higher monthly seizures and a more rigid network is driven by those with higher seizure burden, who presented a more rigid network compared to those with a lower seizure burden.

Associations between brain structure and sleep patterns across adolescent development.

STUDY OBJECTIVES: Structural brain maturation and sleep are complex processes that exhibit significant changes over adolescence and are linked to many physical and mental health outcomes. We investigated whether sleep-gray matter relationships are developmentally invariant (i.e. stable across age) or developmentally specific (i.e. only present during discrete time windows) from late childhood through young adulthood. METHODS: We constructed the Neuroimaging and Pediatric Sleep Databank from eight research studies conducted at the University of Pittsburgh (2009-2020). Participants completed a T1-weighted structural MRI scan (sMRI) and 5-7 days of wrist actigraphy to assess naturalistic sleep. The final analytic sample consisted of 225 participants without current psychiatric diagnoses (9-25 years). We extracted cortical thickness and subcortical volumes from sMRI. Sleep patterns (duration, timing, continuity, regularity) were estimated from wrist actigraphy. Using regularized regression, we examined cross-sectional associations between sMRI measures and sleep patterns, as well as the effects of age, sex, and their interaction with sMRI measures on sleep. RESULTS: Shorter sleep duration, later sleep timing, and poorer sleep continuity were associated with thinner cortex and altered subcortical volumes in diverse brain regions across adolescence. In a discrete subset of regions (e.g. posterior cingulate), thinner cortex was associated with these sleep patterns from late childhood through early-to-mid adolescence but not in late adolescence and young adulthood. CONCLUSIONS: In childhood and adolescence, developmentally invariant and developmentally specific associations exist between sleep patterns and gray matter structure, across brain regions linked to sensory, cognitive, and emotional processes. Sleep intervention during specific developmental periods could potentially promote healthier neurodevelopmental outcomes.

Pitch and Duration Mismatch Negativity are Associated With Distinct Auditory Cortex and Inferior Frontal Cortex Volumes in the First-Episode Schizophrenia Spectrum.

BACKGROUND: Pitch and duration mismatch negativity (pMMN/dMMN) are related to left Heschl's gyrus gray matter volumes in first-episode schizophrenia (FESz). Previous methods were unable to delineate functional subregions within and outside Heschl's gyrus. The Human Connectome Project multimodal parcellation (HCP-MMP) atlas overcomes this limitation by parcellating these functional subregions. Further, MMN has generators in inferior frontal cortex, and therefore, may be associated with inferior frontal cortex pathology. With the novel use of the HCP-MMP to precisely parcellate auditory and inferior frontal cortex, we investigated relationships between gray matter and pMMN and dMMN in FESz. METHODS: pMMN and dMMN were measured at Fz from 27 FESz and 27 matched healthy controls. T1-weighted MRI scans were acquired. The HCP-MMP atlas was applied to individuals, and gray matter volumes were calculated for bilateral auditory and inferior frontal cortex parcels and correlated with MMN. FDR correction was used for multiple comparisons. RESULTS: In FESz only, pMMN was negatively correlated with left medial belt in auditory cortex and area 47L in inferior frontal cortex. Duration MMN negatively correlated with the following auditory parcels: left medial belt, lateral belt, parabelt, TA2, and right A5. Further, dMMN was associated with left area 47L, right area 44, and right area 47L in inferior frontal cortex. CONCLUSIONS: The novel approach revealed overlapping and distinct gray matter associations for pMMN and dMMN in auditory and inferior frontal cortex in FESz. Thus, pMMN and dMMN may serve as biomarkers of underlying pathological deficits in both similar and slightly different cortical areas.

Different patterns of gray matter atrophy in behavioral variant frontotemporal dementia with and without episodic memory impairment.

BACKGROUND: Differentiating patients with behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) is important as these two conditions have distinct treatment and prognosis. Using episodic impairment and medial temporal lobe atrophy as a tool to make this distinction has been debatable in the recent literature, as some patients with bvFTD can also have episodic memory impairment and medial temporal lobe atrophy early in the disease. OBJECTIVES: To compare brain atrophy patterns of patients with bvFTD with and without episodic memory impairment to that of patients with AD. METHODS: We analyzed 19 patients with bvFTD, 21 with AD and 21 controls, matched by age, sex, and years of education. They underwent brain MRI and the memory test from the Brief Cognitive Battery (BCB) to assess episodic memory. We then categorized the bvFTD group into amnestic (BCB delayed recall score <7) and non-amnestic. RESULTS: The amnestic bvFTD group (n = 8) had significant gray matter atrophy in the left parahippocampal gyrus, right cingulate and precuneus regions compared with the nonamnestic group. Compared with AD, amnestic bvFTD had more atrophy in the left fusiform cortex, left insula, left inferior temporal gyrus and right temporal pole, whereas patients with AD had more atrophy in the left hippocampus, left frontal pole and left angular gyrus. CONCLUSIONS: There is a group of amnestic bvFTD patients with episodic memory dysfunction and significant atrophy in medial temporal structures, which poses a challenge in considering only these features when differentiating bvFTD from AD clinically.

Cortical thickness as predictor of response to exercise in people with Parkinson's disease.

We previously showed that dual-task cost (DTC) on gait speed in people with Parkinson's disease (PD) improved after 6 weeks of the Agility Boot Camp with Cognitive Challenge (ABC-C) exercise program. Since deficits in dual-task gait speed are associated with freezing of gait and gray matter atrophy, here we performed preplanned secondary analyses to answer two questions: (a) Do people with PD who are freezers present similar improvements compared to nonfreezers in DTC on gait speed with ABC-C? (b) Can cortical thickness at baseline predict responsiveness to the ABC-C? The DTC from 39 freezers and 43 nonfreezers who completed 6 weeks of ABC-C were analyzed. A subset of 51 participants (21 freezers and 30 nonfreezers) with high quality imaging data were used to characterize relationships between baseline cortical thickness and delta (Δ) DTC on gait speed following ABC-C. Freezers showed larger ΔDTC on gait speed than nonfreezers with ABC-C program (p < .05). Cortical thickness in visual and fronto-parietal areas predicted ΔDTC on gait speed in freezers, whereas sensorimotor-lateral thickness predicted ΔDTC on gait speed in nonfreezers (p < .05). When matched for motor severity, visual cortical thickness was a common predictor of response to exercise in all individuals, presenting the largest effect size. In conclusion, freezers improved gait automaticity even more than nonfreezers from cognitively challenging exercise. DTC on gait speed improvement was associated with larger baseline cortical thickness from different brain areas, depending on freezing status, but visual cortex thickness showed the most robust relationship with exercise-induced improvements in DTC.

Cortical Morphometry is Associated with Neuropsychological Function in Healthy 8-Year-Old Children.

BACKGROUND AND PURPOSE: Cortical development is essential for children's neurocognition. In this study, we evaluated how variations in cortical morphometry in normal children are associated with outcome differences in multiple domains of cognition. METHODS: Eight-year-old children were recruited for a brain MRI followed by a battery of neuropsychological assessments. The MRI scan included 3D-T1-weighted imaging for cortical morphometry in 34 regions defined by the Desikan atlas. The neuropsychological assessments included the Reynolds Intellectual Assessment Scales (RIAS) for IQ, Clinical Evaluation of Language Fundamentals (CELF-4) for language, Children's Memory Scale (CMS) for memory, Wide Range Achievement Test (WRAT-4) for academic skills, and Behavior Rating Inventory of Executive Function (BRIEF) for executive functions. The relationships between MRI measured cortical features, including gray matter volume, surface area, and cortical thickness for different brain regions and neuropsychological test scores, were evaluated using partial correlation analyses controlled for age and sex. RESULTS: RIAS/CELF-4/CMS/WRAT-4/BRIEF scores showed significant correlations (R: [.38-.44], P: [.005-.046]) with gray matter volume, surface area, or cortical thickness in multiple brain regions. Gray matter volume in the medial orbitofrontal/ventromedial prefrontal cortex appeared to be a sensitive marker for overall neurocognition as it significantly correlated with IQ, language, memory, and executive function behaviors. The superior temporal gyrus and banks of superior temporal sulcus appeared to be most sensitive to reflect overall language function as their cortical features consistently correlated with language-related test scores. CONCLUSIONS: Cortical morphometry significantly correlated with neuropsychological function in healthy children; certain regions/features may serve as sensitive imaging markers.

Common disbalance in the brain parenchyma of dementias: Phospholipid profile analysis between CADASIL and sporadic Alzheimer's disease.

Sporadic Alzheimer's disease (SAD) is the most common form of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary ischemic small vessel disease of the brain. Relevant biomarkers or specific metabolic signatures could provide powerful tools to manage these diseases. Therefore, the main goal of this study was to compare the postmortem frontal cortex gray matter, white matter and cerebrospinal fluid (CSF) between a cognitively healthy group and CADASIL and SAD groups. We evaluated 352 individual lipids, belonging to 13 lipid classes/subclasses, using mass spectrometry, and the lipid profiles were subjected to multivariate analysis to discriminate between the dementia groups (CADASIL and SAD) and healthy controls. The main lipid molecular species showing greater discrimination by partial least squares-discriminant analysis (PLS-DA) and a higher significance multivariate correlation (sMC) index were as follows: phosphatidylserine (PS) PS(44:7) and lysophosphatidylethanolamine (LPE) LPE(18:2) in gray matter (GM); phosphatidylethanolamine (PE) PE(32:2) and phosphatidylcholine PC PC(44:6) in white matter (WM), and ether PE (ePE) ePE(38:2) and ether PC (ePC) ePC(34:3) in CSF. Common phospholipid molecular species were obtained in both dementias, such as PS(44:7) and lyso PC (LPC) LPC(22:5) in GM, PE(32:2) in WM and phosphatidic acid (PA) PA(38:5) and PC(42:7) in CFS. Our exploratory study suggests that phospholipids (PLs) involved in neurotransmission alteration, connectivity impairment and inflammation response in GM, WM and CSF are a transversal phenomenon affecting dementias such as CADASIL and SAD independent of the etiopathogenesis, thus providing a possible common prodromal phospholipidic biomarker of dementia.

Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice.

Growing evidence suggests an important role of fluoxetine with serotonin 5-HT1A and 5-HT2C receptors in the modulation of emotion and nociception in brain areas such as the amygdala and periaqueductal gray (PAG). Acute fluoxetine impairs 5-HT2C (but not 5-HT1A) receptor activation in the amygdaloid complex. Given that fluoxetine produces its clinical therapeutic effects only when given chronically, this study investigated the effects of chronic treatment with fluoxetine on the effects produced by 5-HT1A or 5-HT2C receptors activation in the amygdala or PAG on fear-induced antinociception. We recorded the effects of chronic fluoxetine on serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels as well as serotonin turnover; 5-HT1A and 5-HT2C receptor protein levels in the amygdala and PAG. Also, we evaluated the effects of chronic fluoxetine combined with intra-amygdala or intra-PAG injection of MK-212 (a 5-HT2C agonist; 0.63 nmol) or 8-OH-DPAT (a 5-HT1A agonist; 10 nmol) on the antinociceptive response in mice confined in the open arm of the elevated plus-maze (EPM). Nociception was assessed with the writhing test induced by intraperitoneal injection of 0.6% acetic acid. Results showed that fluoxetine (20 mg/kg, s.c.) enhanced the open-arm induced antinociception (OAA) and reduced the number of writhes in mice confined in the enclosed arm, featuring an analgesic effect. In addition, fluoxetine increased the expression of 5-HT2C receptors and 5-HT levels whereas reduced its turnover in the amygdala. While fluoxetine did not change 5-HT and 5-HIAA levels, and its turnover in the PAG, it up-regulated 5HT1A and 5-HT2C receptors in this midbrain area. Chronic fluoxetine (5.0 mg/Kg, an intrinsically inactive dose on nociception) antagonized the enhancement of OAA produced by intra-amygdala or intra-PAG injection of MK-212. Fluoxetine also impaired the attenuation of OAA induced by intra-amygdala injection of 8-OH-DPAT and totally prevented OAA in mice that received intra-PAG 8-OH-DPAT. These results suggest that (i) 5-HT may facilitate nociception and intensify OAA, acting at amygdala 5-HT1A and 5-HT2C receptors, respectively, and (ii) fluoxetine modulates the OAA through activation of 5-HT2C receptors within the PAG. These findings indicate that chronic fluoxetine impairs the effects of 5-HT1A and 5-HT2C receptors activation in the amygdala and PAG on fear-induced antinociception in mice.

Differential white and gray matter damage in highly active multiple sclerosis: A prospective cohort study.

We analyze the differential brain volume changes in highly active multiple sclerosis (HAMS) vs. non-HAMS patients during the disease onset. METHODS: HAMS was defined as: a) patients with 1 relapse in the previous year and at least 1 T1 gadolinium-enhancing lesion or 9 or more T2 lesions while on therapy with other disease modifying treatment (DMD); or b) patients with 2 or more relapses in the previous year, whether on DMD or not. High-resolution T1 weighted MRI scans were acquired at onset and every 12 months for 2 years. Lesion load and brain volume measurements were determined. At onset, gray matter volume (GMV) and white matter volume (WMV) tissue volumes were calculated using the SIENAX. Longitudinal changes were estimated by using SIENA to calculate the percentage of brain volume loss. Differences between volumes per group at onset and at the end of the follow up were established. RESULTS: 64 patients, mean age 38.4 years, 35 (57%) women were included. A total of 14 (21%) were classified as HAMS. At onset, HAMS patients showed lower GMV and WMV volume compared with non-HAMS patients (p = 0.003 and p = 0.01, respectively). During the follow up, HAMS patients showed a higher decrease in GM volume compared with non-HAMS patients (-0.61 vs. - 0.77, p < 0.001) independent from new lesion as well as relapse rate activity during follow up. CONCLUSION: HAMS increased rates of GMV atrophy over 24 months compared to non-HAMS patients independent from relapse rate and new T2 lesions.