Influence of natalizumab on resting-state connectivity in patients with multiple sclerosis.

Background: Changes in brain connectivity occur in patients with multiple sclerosis (MS), even in patients under disease-modifying therapies. Using magnetic resonance imaging (MRI) to asses patients treated with disease-modifying therapies, such as natalizumab, can elucidate the mechanisms involved in clinical deterioration in MS. Objectives: To evaluate differences in resting-state functional connectivity among MS patients treated with natalizumab, MS patients not treated with natalizumab, and controls. Design: Single-center retrospective cross-sectional study. Methods: Twenty-three MS patients being treated with natalizumab were retrospectively compared with 23 MS patients who were naïve for natalizumab, and were using first-line medications (interferon-ß and/or glatiramer acetate), and 17 gender- and age-matched control subjects. The MS patient groups were also matched for time since diagnosis and hyperintense lesion volume on FLAIR. All participants underwent brain MRI using a 3 Tesla scanner. Independent component analysis and dual regression were used to identify resting-state functional connectivity using the FMRIB Software Library. Results: In comparison to controls, the MS patients treated with natalizumab presented decreased connectivity in the left orbitofrontal cortex, in the anterior cingulate and orbitofrontal cortex network. The patients not treated with natalizumab presented increased connectivity in the secondary visual, sensorimotor, and ventral attention networks in comparison to controls.Compared to patients treated with natalizumab, the patients not using natalizumab presented increased connectivity in the left Heschl's gyrus and in the right superior frontal gyrus in the ventral attention network. Conclusion: Differences in brain connectivity between MS patients not treated with natalizumab, healthy controls, and patients treated with natalizumab may be secondary to suboptimal neuronal compensation due to prior less efficient treatments, or due to a compensation in response to maladaptive plasticity.

The digiti quinti sign in hemiplegic migraine: An fMRI study.

BACKGROUND AND PURPOSE: The digiti quinti sign (DQS) consists of a wider angle between the fourth and fifth fingers (ANG) indicative of subtle hemiparesis that has been found interictally in hemiplegic migraine (HM), suggesting a permanent subtle motor dysfunction. The aim of this study was to find a possible cortical origin for the DQS using blood oxygen level dependent (BOLD) functional (f) MRI. METHODS: Eight HM patients and 13 controls entered the cross-sectional study. We examined hand dominance, performed handgrip tests with dynamometry, documented the DQS graphically in two consecutive sessions, and used BOLD-fMRI during a motor task specifically designed to measure the evoked activation in the motor cortex (M1). The brain activation at the symptomatic side was compared with the contralateral hemisphere and with both correspondent hemispheres in controls. RESULTS: Subjects had a normal neurological examination, except for DQS in all HM patients. The activation amplitude (beta values) and the cluster extension (mm3 ) of the activation area in M1 was smaller at the affected side. Besides, the cluster extension correlated negatively with the disease time span. The ANG was wider bilaterally in patients and the fMRI signals were reduced in the patient's group. CONCLUSION: The DQS, a relevant clinical finding in HM, indicates a disrupted cortical activation.

Preliminary comparative study of cortical thickness in HIV-infected patients with and without working memory deficit.

PURPOSE: Changes in cerebral cortical regions occur in HIV-infected patients, even in those with mild neurocognitive disorders. Working memory / attention is one of the most affected cognitive domain in these patients, worsening their quality of life. Our objective was to assess whether cortical thickness differs between HIV-infected patients with and without working memory deficit. METHODS: Forty-one adult HIV-infected patients with and without working memory deficit were imaged on a 1.5 T scanner. Working memory deficit was classified by composite Z scores for performance on the Digits and Letter-Number Sequencing subtests of the Wechsler Adult Intelligence Scale (third edition; WAIS-III). Cortical thickness was determined using FreeSurfer software. Differences in mean cortical thickness between groups, corrected for multiple comparisons using Monte-Carlo simulation, were examined using the query design estimate contrast tool of the FreeSurfer software. RESULTS: Greater cortical thickness in left pars opercularis of the inferior frontal gyrus, and rostral and caudal portions of the left middle frontal gyrus (cluster 1; p = .004), and left superior frontal gyrus (cluster 2; p = .004) was observed in HIV-infected patients with working memory deficit compared with those without such deficit. Negative correlations were found between WAIS-III-based Z scores and cortical thickness in the two clusters (cluster 1: ρ = -0.59; cluster 2: ρ = -0.47). CONCLUSION: HIV-infected patients with working memory deficit have regions of greater thickness in the left frontal cortices compared with those without such deficit, which may reflect increased synaptic contacts and/or an inflammatory response related to the damage caused by HIV infection.

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.

Anterior Insular Resting-State Functional Connectivity is Related to Cognitive Reserve in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cognitive dysfunction is common in multiple sclerosis (MS). The dorsal anterior insula (dAI) is a key hub of the salience network (SN) orchestrating access to critical cognitive brain regions. The aim of this study was to assess whole-brain dAI intrinsic functional connectivity (iFC) using resting-state functional MRI (rs-fMRI) in people with MS and healthy controls (HC) and test the relationship between cognitive reserve (CR) and dAI iFC in people with MS. METHODS: We studied 28 people with relapsing-remitting MS and 28 HC. CR index was quantified by combining premorbid IQ, leisure activities, and education level. For whole-brain iFC analyses, the bilateral dAI were used as seeds. Individual subject correlation maps were entered into general linear models for group comparison and to analyze the effect of CR index on dAI iFC, controlling for multiple comparisons. The correlation between CR index and iFC was assessed using a linear regression model. RESULTS: rs-fMRI analyses revealed a negative relationship between CR index and iFC within the left dAI and a left occipital cluster in people with MS including regions of the cuneus, superior occipital gyrus, and parieto-occipital sulcus. The regression analysis showed that people with MS and a higher CR index had a statistically significantly reduced iFC within the left dAI and the cluster. CONCLUSIONS: CR is relevant to functional connectivity within one of the main nodes of the SN, the dAI, and occipital regions in MS. These results have implications for how CR may modulate the susceptibility to cognitive dysfunction in MS.

Posterior cingulate gyri metabolic alterations in HIV-positive patients with and without memory deficits.

OBJECTIVE: We aimed to evaluate whether human immunodeficiency virus (HIV)-positive patients with and without clinically significant memory deficits and healthy control participants differ on in vivo hydrogen-1 magnetic resonance spectroscopy (H-MRS) in the posterior cingulate gyri. MATERIALS AND METHODS: In total, 21 HIV-positive patients with memory deficit (HIV+wMD) were compared with 15 HIV-positive patients without memory deficit (HIV+wOMD) and 22 sex-, age-, and education-matched control participants. Memory impairments were classified based on the participants' performance on the Rey Auditory Verbal Learning Test. Short echo time (30 ms), single-voxel H-MRS was performed using a 1.5-T magnetic resonance scanner. RESULTS: The HIV+wMD and HIV+wOMD groups had higher choline/creatine ratio in the posterior cingulate gyri than the control group. There were no significant metabolite ratio differences between the HIV+wMD and HIV+wOMD groups. CONCLUSION: HIV-positive patients with and without memory deficits had significantly higher choline/creatine ratios than controls in the posterior cingulate gyri, which may reflect cerebral inflammation, altered cell membrane metabolism, microgliosis, and/or astrocytosis.

OBJETIVO: Nós avaliamos se os pacientes HIV-positivos com e sem déficits de memória clinicamente significativos e controles saudáveis diferem na espectroscopia de prótons do giro do cíngulo posterior, por ressonância magnética (RM) cerebral. MATERIAIS E MÉTODOS: Vinte e um pacientes HIV-positivos com déficit de memória foram comparados com 15 pacientes HIV-positivos sem déficit de memória e 22 controles, pareados por sexo, idade e escolaridade. As deficiências de memória foram classificadas por meio do desempenho no Teste de Aprendizagem Auditivo-Verbal de Rey. A espectroscopia de prótons foi realizada com tempo de eco curto (30 ms), por voxel único, no giro do cíngulo posterior, utilizando aparelho de RM de 1,5 T. RESULTADOS: Os pacientes HIV-positivos com e sem déficit de memória apresentaram aumento da relação colina/creatina no giro do cíngulo posterior, comparados aos controles. Não houve diferenças significativas nas relações metabólicas no grupo HIV-positivo com déficit de memória, em relação ao grupo de pacientes HIV-positivo sem déficit. CONCLUSÃO: Pacientes HIV-positivos com e sem déficits de memória apresentaram relações colina/creatina significativamente aumentadas em relação aos controles, no giro do cíngulo posterior, o que pode refletir inflamação cerebral, alteração do metabolismo da membrana celular, microgliose e/ou astrocitose.

Anterior to Midposterior Corpus Callosum Subregions Are Volumetrically Reduced in Male Alcoholics but Only the Anterior Segment Is Associated to Alcohol Use.

Alcohol consumption seems to affect corpus callosum morphometry irrespectively of an alcohol use disorder (AUD) diagnosis. The present study examined the relationship between corpus callosum (CC) subregion volumes and alcohol use patterns in AUD and non-AUD subjects. Twenty-two male AUD patients and 23 healthy matched non-AUD subjects were recruited from March 2016 to July 2017. Volumetric data were acquired through Magnetic Resonance and analyzed by the FreeSurfer software. AUD subjects were in abstinence for 45.1 days ± 36.8 (SD), consumed higher amounts of alcohol and presented higher AUDIT scores than controls (p < 0.0001). A multivariate analysis corrected by age and tobacco use indicated that AUD patients presented smaller CC volumes compared to non-AUD subjects (p < 0.01), except for the posterior subregion. A multiple regression analysis corrected by age and tobacco use including CC volumes from all subjects and the amount of daily alcohol ingestion as variables indicated that anterior CC volume was negatively (p < 0.001) associated to alcohol consumption. This study demonstrated that CC subregions were smaller in AUD subjects, as expected, and that the volume of the anterior segment was inversely associated to increasing daily amounts of alcohol, indicating greater frontal region vulnerability to harmful alcohol effects.

Superparamagnetic iron oxide nanoparticles as a tool to track mouse neural stem cells in vivo.

Cell transplantation offers a promising approach in many neurological disorders. Neural stem (NS) cells are potential candidates for cell therapy. The ability to track the grafted cells in the host tissue will refine this therapy. Superparamagnetic iron oxide nanoparticles (SPION) have been suggested as a feasible method, but there is no consensus about its safety. Here we investigated the feasibility of label NS cells with SPION and track by MRI after transplantation into mouse striatum with SPION cells and its therapeutic effects by grafting the cells into mouse striatum. We demonstrated that SPION-labeled NS cells display normal patterns of cellular processes including proliferation, migration, differentiation and neurosphere formation. Transmission electron microscopy reveals SPION in the cytoplasm of the cells, which was confirmed by microanalysis. Neurons and astrocytes generated from SPION-labeled NS cells were able to carry nanoparticles after 7 days under differentiation. SPION-labeled NS cells transplanted into striatum of mice were detected by magnetic resonance imaging (MRI) and microscopy 51 days later. In agreement with others reports, we demonstrated that NS cells are able to incorporate SPION in vitro without altering the stemness, and can survive and be tracked by MRI after they have been grafted into mice striatum.

Lower Choline Rate in the Left Prefrontal Cortex Is Associated With Higher Amount of Alcohol Use in Alcohol Use Disorder.

Excessive and long-term alcohol consumption produce metabolic changes, such as of choline, in many brain regions in alcohol use disorder (AUD) and in non-AUD subjects as well. This study examined the association of choline proportion in the prefrontal cortex with pattern of alcohol use in AUD patients. The choline metabolite was acquired through a single voxel Proton Magnetic Resonance Spectroscopy (1H MRS). Between-groups comparison corrected by age showed that the ratio of Choline/Creatine (Cho/Cr) was significantly smaller (p = 0.005) in the Left Prefrontal (LPF) of AUD patients when compared to paired non-AUD subjects. A multiple regression analysis corrected by age showed that decreasing ratios of Cho/Cr in the LPF was associated with increasing amount of alcohol consumption in drinks per day (p < 0.01) in AUD patients. Rates of Cho/Cr in the LPF was inversely related to amounts of alcohol consumption possibly indicating the severity of the AUD. Thus, low proportion of Cho/Cr in the LPF could indicate more severe AUD (higher alcohol intake).

White-matter integrity in patients with systemic lupus erythematosus and memory deficits.

PURPOSE: Cognitive dysfunction is common in neuropsychiatric systemic lupus erythematosus (SLE). Memory is a commonly affected cognitive domain. Clinically, however, it is difficult to detect memory deficits. The objective of this study is to evaluate whether normal controls and SLE patients with and without memory deficit differ in terms of white-matter integrity. METHODS: Twenty SLE patients with memory deficit were compared to 47 SLE patients without memory deficit and 22 sex-, age-, and education-matched control individuals. Diffusion tensor imaging (DTI) was performed in a 1.5-Tesla scanner. For tract-based spatial statistics analysis, a white-matter skeleton was created. A permutation-based inference with 5000 permutations with a threshold of p < 0.05 was used to identify abnormalities in fractional anisotropy (FA). The mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were also projected onto the mean FA skeleton. RESULTS: Compared to controls, SLE patients with and without memory deficit had decreased FA in: bilateral anterior thalamic radiation, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, corticospinal tract, genu, and body of the corpus callosum. SLE patients with and without memory deficit also presented increased MD and RD values compared to controls in these areas. Comparison between SLE patients with and without memory deficit did not present significant differences in DTI parameters. CONCLUSION: DTI can detect extensive abnormalities in the normal-appearing white matter of SLE patients with and without memory deficit, compared to controls. However, there was no difference, in terms of white-matter integrity, between the groups of SLE patients.

Increased posterior cingulate cortex efficiency may predict cognitive impairment in asymptomatic HIV patients.

Purpose Despite antiretroviral therapy, approximately half of individuals with human immunodeficiency virus (HIV) will develop HIV-associated neurocognitive disorder (HAND). Efficiency of brain networks is of great importance for cognitive functioning, since functional networks may reorganize or compensate to preserve normal cognition. This study aims to compare efficiency of the posterior cingulate cortex (PCC) between patients with and without HAND and controls. We hypothesize HAND negative (HAND-) patients will show higher PCC efficiency than HAND positive (HAND+) patients. Methods A total of 10 HAND + patients were compared with 9 HAND- patients and 17 gender-, age-, and education-matched controls. Resting-state functional MRI was acquired with a 3 Tesla scanner. Local efficiency, a measure of network functioning, was investigated for PCC. Network differences among HAND + , HAND- patients and controls were tested as well as correlations between network parameters and cognitive test performance in different domains. Results HAND- patients showed significantly increased PCC efficiency compared with healthy controls ( p = 0.015). No differences were observed between HAND + patients and either controls ( p = 0.327) or HAND- patients ( p = 0.152). In HAND- patients, PCC efficiency was positively related with cognitive performance in the attention/working memory domain ( p = 0.003). Conversely, in HAND + patients, PCC efficiency was negatively correlated with performance in the abstraction/executive domain ( p = 0.002). Conclusion HAND- patients showed a higher level of PCC efficiency compared with healthy subjects, and PCC efficiency was positively related to cognitive performance. These results support the functional reorganization hypothesis, that increased PCC efficiency is a compensation technique to maintain cognitive functioning.