Glutamate imbalance in key structure of the default mode network in adults with attention-deficit/hyperactivity disorder.

The default mode network (DMN) is atypically active in patients with ADHD, likely contributing to the inattention patterns observed in patients with the disorder. Nonetheless, magnetic resonance spectroscopy (MRS) studies have rarely targeted the posterior cingulate cortex, a key DMN region, and little is known about the biochemical setting within this network in patients with ADHD. We aimed to assess the differences in metabolite profiles of the posterior cingulate cortex-a key region of the DMN-between patients with ADHD and controls. Five brain metabolites-glutamate, inositol, N-acetyl aspartate, choline, and creatine-were measured through MRS in the posterior cingulate cortex of patients and controls in a 3.0 T scanner. Between-group comparison of neurometabolite concentrations in PCC was performed using multivariate analysis of covariance. A total of 88 patients and 44 controls were included in the analysis. Patients with ADHD showed lower levels of glutamate in the posterior cingulate cortex compared to controls (p = 0.003). Lower concentrations of glutamate in the posterior cingulate cortex suggest that a glutamatergic imbalance within the posterior cingulate cortex might play a role in the pathogenesis of ADHD. Further understanding of the causes and consequences of such glutamate decrease might help explain how some glutamate-related drug effects impact on ADHD symptomatology.

Dual role of α7 nicotinic acetylcholine receptors in the retrosplenial cortex for aversive memory acquisition and retrieval.

In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

Dopamine D1/D5 Receptors in the Retrosplenial Cortex Are Necessary to Consolidate Object Recognition Memory.

The retrosplenial cortex (RSC) has been widely related to spatial and contextual memory. However, we recently demonstrated that the anterior part of the RSC (aRSC) is required for object recognition (OR) memory consolidation. In this study, we aimed to analyze the requirement of dopaminergic inputs into the aRSC for OR memory consolidation in male rats. We observed amnesia at 24-h long-term memory when we infused SCH23390, a D1/D5 dopamine receptors antagonist, into aRSC immediately after OR training session. However, the same infusion had no effect on OR short-term memory. Then, we analyzed whether the ventral tegmental area (VTA) is necessary for OR consolidation. VTA inactivation by intra-VTA administration of muscimol, a GABAA agonist, immediately after an OR training session induced amnesia when animals were tested at 24 h. Moreover, we observed that this VTA inactivation-induced amnesia was reversed by the simultaneous intra-aRSC delivery of SKF38393, a D1/D5 receptor agonist. Altogether, our results suggest that VTA dopaminergic inputs to aRSC play an important modulatory role in OR memory consolidation.

An alternative path to atrial lesions through a contralateral interhemispheric transfalcine transcingular infra-precuneus approach: A case report.

BACKGROUND: The surgical management of lesions located in the trigone of the lateral ventricle remains a neurosurgical challenge. Previously described approaches to the atrium include the transtemporal, parietal transcortical, parietal trans intraparietal sulcus, occipital transcingulate, posterior transcallosal, and transfalcine transprecuneus. However, reaching this area specifically through the cingulate cortex below the subparietal sulcus has not been described thus far. CASE DESCRIPTION: We present here the removal of a left atrial meningioma through a right parietal "contralateral interhemispheric transfalcine transcingular infra-precuneus" approach and compare it with previously described midline approaches to the atrium. To accomplish this, a right parietal craniotomy was performed. After the left subprecuneus cingulate cortex was exposed through a window in the falx, a limited corticotomy was performed, which allowed the tumor to be reached after deepening the bipolar dissection by 8 mm. Postoperative magnetic resonance imaging showed complete resection of the lesion sparing the corpus callosum, forceps major, and sagittal stratum. Although this approach disrupts the posterior cingulate fasciculus, no deficits have been described so far after unilaterally disrupting the posterior cingulate cortex or the posterior part of the cingulate fasciculus. In fact, a thorough postoperative cognitive examination did not show any deficits. CONCLUSION: The "contralateral interhemispheric transfalcine transcingular infra-precuneus" approach combines the advantages of several previously described approaches. Since it conserves the major white matter tracts that surround the atrium and has a shorter attack angle than the contralateral transfalcine transprecuneus approach, we believe that it could be a potentially new alternative path to reach atrial lesions.

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.

Posterior cingulate gyri metabolic alterations in HIV-positive patients with and without memory deficits / Alterações metabólicas no giro do cíngulo posterior em pacientes HIV-positivos com e sem déficit de memória

Abstract 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.

Resumo 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.

Non-classical behavior of the default mode network regions during an information processing task.

The default mode network (DMN) efficient deactivation and suppressed functional connectivity (FC) during goal-directed tasks, which require attentional resources, have been considered essential to healthy brain cognition. However, recent studies have shown that DMN regions do not always show the expected behavior. Then, we aimed to investigate the functional activation and connectivity of DMN nodes in young, healthy controls during a goal-directed task. We used an adaptation of the symbol digit modalities test (SDMT) to evaluate the information processing speed (IPS). Twenty-four subjects (10 women, age: 29 ± 7 years) underwent two functional Magnetic Resonance Imaging experiments: one during resting-state and one during a block-designed SDMT paradigm. We superimposed the templates of the DMN on the group activation map and observed the reorganization of the network. For the posterior cingulate cortex (PCC) node of the DMN, which is spatially extensive, comprising the precuneus (dorsal portion) and the posterior cingulate gyrus (PCG, ventral portion), the extent of each region was different between conditions, suggesting different functional roles for them. Therefore, for the functional connectivity (FC) analysis, we split the DMN-PCC region into two regions: left precuneus (BA 7) and PCG. The left precuneus (BA 7) was positively correlated with the left lingual gyrus (BA 17), a task-positive region, and negatively associated with the DMN nodes when comparing task performance with the resting-state condition. The other DMN regions presented the classical antagonistic role during the attentional task. In conclusion, we found that the activation and functional connectivity of the DMN is, in general, suppressed during the information processing. However, the left precuneus BA 7 presented a context-dependent modulatory behavior, working as a transient in-between hub connecting the DMN to task-positive areas. Such findings support studies that show increased activation and excitatory functional connectivity of DMN portions during goal-directed tasks. Moreover, our results may contribute to defining more precise functional correlates of IPS deficits in a wide range of clinical and neurological diseases.

Digging deeper in the proteome of different regions from schizophrenia brains.

Schizophrenia is a psychiatric disorder that affects 21 million people worldwide. Despite several studies having been shown that some brain regions may play a critical role in the pathophysiology of schizophrenia, the molecular basis to explain this diversity is still lacking. The cerebellum (CER), caudate nucleus (CAU), and posterior cingulate cortex (PCC) are areas associated with negative and cognitive symptoms in schizophrenia. In this study, we performed shotgun proteomics of the aforementioned brain regions, collected postmortem from patients with schizophrenia and compared with the mentally healthy group. In addition, we performed a proteomic analysis of nuclear and mitochondrial fractions of these same regions. Our results presented 106, 727 and 135 differentially regulated proteins in the CAU, PCC, and CER, respectively. Pathway enrichment analysis revealed dysfunctions associated with synaptic processes in the CAU, transport in the CER, and in energy metabolism in the PCC. In all brain areas, we found that proteins related to oligodendrocytes and the metabolic processes were dysregulated in schizophrenia. SIGNIFICANCE: Schizophrenia is a complex and heterogeneous psychiatric disorder. Despite much research having been done to increase the knowledge about the role of each region in the pathophysiology of this disorder, the molecular mechanisms underlying it are still lacking. We performed shotgun proteomics in the postmortem cerebellum (CER), caudate nucleus (CAU) and posterior cingulate cortex (PCC) from patients with schizophrenia and compared with healthy controls. Our findings suggest that each aforementioned region presents dysregulations in specific molecular pathways, such as energy metabolism in the PCC, transport in the CER, and synaptic process in the CAU. Additionally, these areas presented dysfunctions in oligodendrocytes and metabolic processes. Our results may highlight future directions for the development of novel clinical approaches for specific therapeutic targets.

Comprometimento cognitivo vascular: leucoaraiose, hipocampos e espectroscopia de prótons ? Estudo preliminar / Vascular cognitive impairment: leucoaraiosis, hippocampi, and proton spectroscopy – Preliminary study

Introdução: O continuum do comprometimento cognitivo vascular (CCV) compreende segmento não demência (CCV-ND), segmento demência (CCV-D ou DV), sendo o subtipo mais frequente o CCV subcortical, e inclui, ainda, formas mistas (CCV + DA). Ressonância magnética (RM) do cérebro é o método mais apropriado para avaliação das lesões vasculares, dimensão dos hipocampos e do espectro de prótons (1HMRS). Objetivo: Comparar os valores de metabólitos dos hipocampos (HC) e da região do cíngulo posterior (CP) em grupos de casos de CCV subcortical. Métodos: Casos (n = 55) foram selecionados a partir do banco de dados sobre CCV. Imagens obtidas por equipamento Signa Horizon LX-GE de 1,5T, com protocolo-padrão para aquisição estrutural (incluindo FLAIR, T2 e aquisição para 1H-MRS). Metabólitos estudados (relações) incluíram: Naa/Cr, Co/Cr e mI/Cr. Os casos foram definidos radiologicamente (leucoaraiose grau 3 pela escala de Fazekas modificada) e subdivididos de acordo com a escala de Leon (0-3) em dois em grupos hipocampais (grHC): grHC [0+1] e grHC [2+3]. Análise estatística pelo ANOVA e Tukey. Resultados: A relação Naa/Cr nos HC mostrou diferença significativa entre o grHC [0+1] e o grHC [2+3], o que representa diminuição de integridade (perda) neuronal no segundo, enquanto os CP desses grupos mantiveram os valores estáveis. Houve diferença significativa entre o grHC [2+3] em relação aos CP de ambos os grupos, enquanto o grHC [0+1] ficou compatível com os valores dos CP. Comparação dos valores obtidos em estudos anteriores em CCL e DA mostrou o Naa/Cr com valor intermediário entre os do CCL e da DA nos HC e equivalência de valores nos CP. Conclusão: A 1HMRS possibilita analisar o grau de perda neuronal, além de alterações de membrana e neuroglial dessas regiões. Assim, podem ser obtidas informações para melhor compreender o continuum CCV subcortical (que pode incluir CCV + DA), visando determinar a contribuição dessas duas patologias, caso haja, ao comprometimento cognitivo...

Introduction: Vascular cognitive impairment (VCI) continuum comprisesno-dementia segment (VCI-ND), dementia segment (VCI-D or VaD), with subcortical VCI as the most frequent subtype, and additionally mixed forms (VCI + AD). Magnetic resonance imaging (MRI) of the brain is the most proper method for vascular lesions, hippocampal size, and proton spectrum (1HMRS) assessment. Objective: Comparison of the values of metabolites at the hippocampi (HC) and posterior cingulate (PC) region of groups of cases of subcortical VCI. Methods: Cases (n = 55) were selected from a database on VCI. Images were obtained with Signa Horizon LX-GE de 1.5T equipment and a standard protocol for structural and 1H-MRS acquisitions. Studied metabolites (reasons) were: Naa/Cr, Coh/Cr e mI/Cr. The cases were radiologically defined (grade 3 leucoaraiosis on modified Fazekas scale), and according de Leon?s scale (0-3) subdivided in two hippocampal groups (grHC): grHC[0+1] and grHC[2+3]. Statistical analysis with ANOVA and Tukey. Results: The reason Naa/Cr at the HC showed a significant difference between the grHC[0+1] and grHC[2+3], that represents a reduction of neuronal integrity (loss) in the latter, while at PC these groups maintained stable values. There was a significant difference between grHC [2+3] in relation to PC of both groups, while grHC [0+1] remained compatible with PC values. The comparison of the values obtained from previous studies on MCI and AD showed Naa/Cr with intermediate values between MCI and AD at the HC, and equivalence at the PC. Conclusion: 1HMRS allows for the analysis of the degree of neuronal loss, besides membrane and neuroglial changes of these regions. Thus, information may be obtained for a better understanding of the subcortical VCI continuum (that may include VCI + AD), aiming to determine the contribution of these two pathologies, if present, to the cognitive impairment...

Mini-Mental State Examination and proton spectroscopy of the posterior cingulate in Alzheimer disease.

To compare metabolite ratios in the posterior cingulate with the Mini-Mental State Examination (MMSE) test scores in patients with mild or moderate Alzheimer disease and in controls. METHODS: We evaluated 29 patients with mild or moderate Alzheimer disease and 15 controls by proton spectroscopy with the voxel located in the posterior cingulate. The MMSE was applied to all patients and controls. The metabolic ratios: N-acetyl-aspartate/creatine (Naa/Cr), mio-inositol/creatine (mI/Cr) and mio-inositol/N-acetyl-aspartate (mI/Naa) were obtained and then post-processed using the MRUI software (magnetic resonance user interface). RESULTS: Correlation between Naa/Cr and mI/Naa ratios in the posterior cingulate with the MMSE was observed, and a positive correlation with Naa/Cr and negative correlation with mI/Naa were seen. The mI/r ratio presented no correlation with MMSE scores. CONCLUSION: The positive correlation with Naa/Cr, and negative correlation with mI/Naa may corroborate that neuronal density/viability is associated to a higher MMSE score.

Comparar as razões dos metabólitos obtidas no giro do cíngulo posterior e os escores do Mini-Exame do Estado Mental (MEEM) em pacientes com doença de Alzheimer leve e moderada em controles cognitivamente normais. MÉTODOS: Nós avaliamos 29 pacientes com doença de Alzheimer leve e moderada e 15 controles utilizando espectroscopia de prótons com volume de interesse único localizado no cíngulo posterior. Os escores do teste MEEM foram aplicados em todos os pacientes e controles. As razões dos metabólitos N-acetil-aspartato/creatina (Naa/Cr), mio-inositol/creatina (mI/Cr) e mio-inositol/-acetil-aspartato (mI/Naa) foram obtidas e pós-processadas usando o software MRUI (magnetic resonance user interface). RESULTADOS: Foram encontradas correlações entre as razões Naa/Cr e mI/Naa obtidas no cíngulo posterior e os escores do teste MEEM, sendo a correlação positiva com o Naa/Cr e negativa com a razão mi/Naa. A razão mio-inositol/creatina não teve correlação com os escores do teste MEEM. CONCLUSÃO: A correlação positiva entre o Naa/cr e negativa entre o mI/Naa podem corroborar a hipótese de que a densidade/viabilidade neuronal está associada a maiores escores no teste MEEM.