What does LTP tell us about the roles of CaMKII and PKMζ in memory?

In “Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ),” Lisman proposes that elucidating the mechanism of LTP maintenance is key to understanding memory storage. He suggests three criteria for a maintenance mechanism to evaluate data on CaMKII and PKMζ as memory storage molecules: necessity, occlusion, and erasure. Here we show that when the criteria are tested, the results reveal important differences between the molecules. Inhibiting PKMζ reverses established, protein synthesis-dependent late-LTP, without affecting early-LTP or baseline synaptic transmission. In contrast, blocking CaMKII has two effects: 1) inhibiting CaMKII activity blocks LTP induction but not maintenance, and 2) disrupting CaMKII interactions with NMDARs in the postsynaptic density (PSD) depresses both early-LTP and basal synaptic transmission equivalently. To identify a maintenance mechanism, we propose a fourth criterion — persistence. PKMζ increases for hours during LTP maintenance in hippocampal slices, and for over a month in specific brain regions during long-term memory storage in conditioned animals. In contrast, increased CaMKII activity lasts only minutes following LTP induction, and CaMKII translocation to the PSD in late-LTP or memory has not been reported. Lastly, do the PKMζ and CaMKII models integrate the many other signaling molecules important for LTP? Activity-dependent PKMζ synthesis is regulated by many of the signaling molecules that induce LTP, including CaMKII, providing a plausible mechanism for new gene expression in the persistent phosphorylation by PKMζ maintaining late-LTP and memory. In contrast, CaMKII autophosphorylation and translocation do not appear to require new protein synthesis. Therefore, the cumulative evidence supports a core role for PKMζ in late-LTP and long-term memory maintenance, and separate roles for CaMKII in LTP induction and for the maintenance of postsynaptic structure and synaptic transmission in a mechanism distinct from late-LTP.     

The influence of levetiracetam on psychosocial and behavioral functioning in children: A case–control and follow-up study

BackgroundLevetiracetam, a widely used antiepileptic drug in children, has been associated with psychosocial and behavioral problems, which are also influenced by epilepsy variables, including duration or seizure frequency.PurposeThe objective of this study is to investigate the frequency and timing of treatment-emergent psychosocial and behavioral problems in children receiving levetiracetam, irrespective of seizure variables which are possible confounders.MethodsA prospective, case–control study with a 3-month follow-up was conducted. Consecutive children aged 6 to 16 years with new-onset partial seizures were included in case of starting treatment with either levetiracetam or valproic acid. Psychosocial and behavioral functioning were assessed using a set of standardized questionnaires including Strengths and Difficulties Questionnaire (SDQ) and Children's Depression Inventory (CDI) at baseline, 1 and 3-month follow-up. Patients' baseline scores were compared to healthy subjects. The difference in the follow-up SDQ and CDI scores was evaluated in patients receiving levetiracetam and valproic acid.ResultsA total of 101 participants were analyzed; 32 patients in levetiracetam group, 19 patients in valproic acid group and 50 healthy controls. Baseline SDQ and CDI scores were not statistically different between patients and healthy subjects (p > 0.05). No statistically significant difference was observed in CDI, total and subscale SDQ scores between patients receiving levetiracetam or valproic acid during the study period (p > 0.05). A girl aged 15 years receiving levetiracetam had a CDI score of 18 without suicidal ideation at baseline. She developed suicidal ideation and depression, which resolved after switching of levetiracetam to valproic acid, at the 1-month follow-up. No other psychiatric or behavioral side-effects were observed in other patients.ConclusionPsychosocial and behavioral side-effects of levetiracetam treatment are not frequent and they don't emerge in most of children at lower doses. At this dose, and after 3 months, using these specific instruments, we did not observe any difference between the valproic acid and levetiracetam treatment groups.     

The advantage of reading over listening text comprehension in Down syndrome: what is the role of verbal memory?

The current study was designed to investigate the role played by verbal memory in the advantage shown by individuals with Down syndrome in reading over listening text comprehension (Roch & Levorato, 2009). Two different aspects of verbal memory were analyzed: processing load and coding modality. Participants were 20 individuals with Down syndrome, aged between 11 and 26 years who were matched for reading comprehension with a group of 20 typically developing children aged between 6;3 and 7;3 years. The two groups were presented with a listening comprehension test and four verbal memory tasks in which the degree of processing load and the coding modality were manipulated. The results of the study confirmed the advantage of reading over listening comprehension for individuals with Down syndrome. Furthermore, it emerged that different aspects of verbal memory were related respectively to reading and to listening comprehension: visual memory with low processing load was related to the former and oral memory with high processing load to the latter. Finally, it was demonstrated that verbal memory contributed to explain the advantage of reading over listening comprehension in Down syndrome. The results are discussed in light of their theoretical relevance and practical implications.     

Blindsight in action: what can the different sub-types of blindsight tell us about the control of visually guided actions?

Blindsight broadly refers to the paradoxical neurological condition where patients with a visual field defect due to a cortical lesion nevertheless demonstrate implicit residual visual sensitivity within their field cut. The aim of this paper is twofold. First, through a selective review of the blindsight literature we propose a new taxonomy for the subtypes of residual abilities described in blindsight. Those patients able to accurately act upon blind field stimuli (e.g. by pointing or saccading towards them) are classified as having 'action-blindsight', those whose residual functions can be said to rely to some extent upon attentive processing of blind field stimuli are classified as demonstrating 'attention-blindsight', while finally, patients who have somewhat accurate perceptual judgements for blind field stimuli despite a complete lack of any conscious percept, are classified as having 'agnosopsia'--literally meaning 'not knowing what one sees'. We also address the possible neurological substrates of these residual sensory processes. Our second aim was to investigate the most striking subtype of blindsight, action-blindsight. We review the data relevant to this subtype and the hypotheses proposed to account for it, before speculating on how action-blindsight may inform our normal models of visuomotor control.     

What do we know about dementia?: a survey on knowledge about dementia in the general public of Japan

OBJECTIVE: The importance of early detection of dementia has been highlighted in recent years by the medical and scientific community; however, delays often occur between the recognition of signs or symptoms and a decision by the patient or family to seek professional help. Such delays may be caused by a lack of knowledge about dementia among patients and family members. The aim of this study was to determine the understanding of dementia among the general public. METHODS: We conducted a survey in Japan that asked 11 questions regarding knowledge of 'general' information, 'symptoms', and 'biomedical' issues related to dementia. A quota sampling method was used to select 2,500 participants, 2,115 of who were eligible for the analyses. RESULTS: The average number of correct responses among females was significantly greater than that among the males. A multiple comparisons test demonstrated that middle-aged women were more knowledgeable than younger and older respondents. It was revealed that there was a lack of knowledge on biomedical aspects of dementia, i.e. cause, treatment, and prognosis along with a misunderstanding of dementia as senescence forgetfulness among the general public. CONCLUSIONS: There appeared to be gaps in knowledge on dementia among the general public, which may prevent caregivers from planning upcoming social and financial challenges. Correct information needs to be given by health professionals and care staff. Educational initiatives planned for the general public could be useful, and should target those groups, men and non-middle aged women who have lower knowledge.     

Action modulated cognition: The influence of sensori–motor experience on the global processing bias

Whether we are aware of it or not, cognition is inherently biased. Researchers have attempted to modulate these biases using prism adaptation in both healthy and patient populations. Recent research suggests that prisms themselves might not be necessary; simply interacting with one side of space can produce similar effects (Dupierrix, Alleysson, Ohlmann and Chokron (2008). Brain Research, 1214, 127–135). Here we tested whether sensori–motor interaction with the environment affects aspects of cognition that should at first glance appear to be unrelated. While previous research involved tasks that were largely directional in nature (e.g., line bisection), we chose a task without a directional component, the hierarchical figures task (Navon, (1977). Cognitive Psychology, 9, 353–383). In a sample of healthy young adults, we found that after 5 min of lateralized pointing (pointing solely to the left or right side of space), performance on the hierarchical figures task varied significantly as a function of pointing direction: interference from irrelevant global information increased after interacting with the left side of space and decreased after interacting with the right side of space. We discuss the results in relation to a “hemispheric imbalance” hypothesis. Our findings demonstrate that cognition can be readily influenced by interactions with the environment even without artificially distorting normal perceptuo–motor relationships.     

The influence of online images on self-harm: A qualitative study of young people aged 16–24

To date, research on the role of the Internet in self-harm has focused on young people's interaction via the medium of text, with limited consideration of the effect of images. This qualitative study explores how young people understand and use online images of self-harm. Semi-structured interviews were conducted with a community sample of 21 individuals aged 16–24 living in Wales, UK, with a previous history of self-harm. Interviewees reported the role of the Internet in normalising young people's self-harm. Images rather than textual interactions are the primary reason cited for using the Internet for self-harm purposes. Images invoke a physical reaction and inspire behavioural enactment, with Tumblr, which permits the sharing of images by anonymous individuals, being the preferred platform. Viewing online images serves a vital role in many young people's self-harm, as part of ritualistic practice. Online prevention and intervention need to attend to the importance of images.     

Autoimmune comorbidities in multiple sclerosis: what is the influence on brain volumes? A case–control MRI study

Background

Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes.

Objectives

To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case–control MS population.

Methods

A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX.

Results

The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p?=?0.038) and cortical GM (p?=?0.036) volumes, independent from MS clinical features and related to T1D duration (p?<?0.01), while no association was observed with AT and celiac disease.

Conclusions

Our data support the importance of considering T1D as possible factors influencing the brain atrophy in MS. Further studies are needed to confirm our data and to clarify the underlying mechanisms.

     

The functional neuroanatomy of verbal memory in Alzheimer’s disease: [18F]-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) correlates of recency and recognition memory

Introduction: The objective of this study was to distinguish the functional neuroanatomy of verbal learning and recognition in Alzheimer’s disease (AD) using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning task. Method: In 81 Veterans diagnosed with dementia due to AD, we conducted a cluster-based correlation analysis to assess the relationships between recency and recognition memory scores from the CERAD Word Learning Task and cortical metabolic activity measured using [¹⁸F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Results: AD patients (Mini-Mental State Examination, MMSE mean = 20.2) performed significantly better on the recall of recency items during learning trials than of primacy and middle items. Recency memory was associated with cerebral metabolism in the left middle and inferior temporal gyri and left fusiform gyrus (p < .05 at the corrected cluster level). In contrast, recognition memory was correlated with metabolic activity in two clusters: (a) a large cluster that included the left hippocampus, parahippocampal gyrus, entorhinal cortex, anterior temporal lobe, and inferior and middle temporal gyri; (b) the bilateral orbitofrontal cortices (OFC). Conclusions: The present study further informs our understanding of the disparate functional neuroanatomy of recency memory and recognition memory in AD. We anticipated that the recency effect would be relatively preserved and associated with temporoparietal brain regions implicated in short-term verbal memory, while recognition memory would be associated with the medial temporal lobe and possibly the OFC. Consistent with our a priori hypotheses, list learning in our AD sample was characterized by a reduced primacy effect and a relatively spared recency effect; however, recency memory was associated with cerebral metabolism in inferior and lateral temporal regions associated with the semantic memory network, rather than regions associated with short-term verbal memory. The correlates of recognition memory included the medial temporal lobe and OFC, replicating prior studies.     

Neuropsychological predictors of BOLD response during a spatial working memory task in adolescents: what can performance tell us about fMRI response patterns?

The relationship between standardized neuropsychological test performance and functional magnetic resonance imaging (fMRI) response during cognitive tasks is largely unknown. This exploratory investigation examined the relationship between neuropsychological test performance and fMRI response to a spatial working memory (SWM) task among 49 typically developing adolescents. Participants were administered a variety of neuropsychological tests in the domains of working memory, visuospatial skills, executive functioning, attention, learning and memory, visuomotor skills and processing speed, and language functioning. Neuropsychological domain scores were used to predict fMRI response during a SWM task. Results suggest that in many brain regions, neuropsychological performance negatively predicts fMRI response, suggesting that those teens with better neuropsychological abilities required fewer neural resources to adequately perform the task. This study provides further understanding of how neuropsychological abilities relate to neural activity during fMRI tasks, and provides an important link between neuropsychological and fMRI research.     

The influence of 4–week treatment with sertraline on the combined T3/TRH test in depressed patients

In the present study, the influence of a 4–week treatment with sertraline on the regulation of hypothalamic–pituitary–thyroid (HPT) axis activity in depression was investigated, in particular the impact of sertraline on the thyroid receptor (TR)–mediated negative feedback control as measured by the combined T3/TRH test. In 20 drug–free patients (8 men,12 women) suffering from a major depressive episode according to DSM-IV criteria the single TRH–stimulation test (administration of 200 μg TRH at 09:00h) was carried out followed by a combined T3/TRH test (pre–treatment with 40 μg 3,5,3’–triiodothyronine [T3] the night before; administration of 200 μg TRH at 09:00h the next day). After 4 weeks of treatment with sertraline at a standard dosage of 50 mg/day, both the single TRH test and the combined T3/TRH test were repeated in the depressed patients. Using repeated–measures ANOVA for statistical analysis, antidepressant therapy with sertraline did not have any significant impact on the TRH–induced TSH and prolactin stimulation (ΔTSH, ΔPRL) during the single TRH test nor during the combined T3/TRH test, neither in responders (n = 10) nor in non–responders (n = 10). Moreover, the percentage suppression of TRH–induced TSH stimulation (ΔTSH) after pre–treatment with 40 μg T3 was comparable before (–61.07 %) and after the 4–week treatment with sertraline (–58.92 %). Apparently, the therapeutic efficacy of antidepressants such as sertraline is not related to the regulation of HPT axis activity in depressed patients.     

The 100 most-cited articles about the role of neurovascular unit in stroke 2001–2020: A bibliometric analysis

BackgroundThe neurovascular unit (NVU) is emerging as a potential therapeutic target in neurological conditions, such as stroke, brain injury, Alzheimer''s disease, and Parkinson''s disease; meanwhile, stroke is the second leading cause of death globally. The purpose of the study is to analyze the most influential articles, authors, countries, and topics in the role of NVU in stroke.MethodsThe Web of Science (WoS) database was used for bibliometric analysis using the search terms “Stroke” and “Neurovascular unit” on January 1st, 2021. Data were extracted from the WoS database to identify collaborations between authors, countries, organizations, and keywords using VOSviewer (1.6.16 mac). Two bibliometric indicators, the activity index (AI) and category normalized citation impact (CNCI), were computed. The keywords of bursts were also identified by CiteSpace.ResultsA total of 770 articles were analyzed by VOSviewer. AIs and CNCIs were computed of the eighteen countries according to VOSviewer co‐authorship analysis results. The majority of authors mainly came from the United States and Japan. Romania, Hungary, and Poland have emerged as rising‐star countries. In the 100 most‐cited articles, the number of citations ranged from 1873 to 69, with a total of 15,758 citations. Most articles were published in 2011 and 2012 (n = 13 each), followed by 2009 (n = 11) and 2013, 2014, and 2015 (n = 8 each). Stroke and Journal of Cerebral Blood Flow and Metabolism were the two top journals. EH Lo from Harvard University/ Massachusetts General Hospital was the top first author and corresponding author. Harvard University/Massachusetts General Hospital was the most productive affiliated institution with 15 publications.ConclusionThere has been growing attention and efforts made in the field of stroke and NVU. The merit of the above findings may help to shape the research policy in ischemic stroke both at the country and institutional level.     

The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: A case–control study

PurposeThe present study aimed to assess the impact of the ketogenic diet on arterial morphology and endothelial function of the big vessels of the neck and on cardiac diastolic function, in a cohort of epileptic children and young adults treated with the ketogenic diet.MethodsPatients were recruited based on the following inclusion criteria: (1) patients who were or had been on the ketogenic diet for a time period of at least six months. Each patient underwent measurement of carotid intima media thickness, carotid artery stiffness, echocardiography, and diastolic function assessment. Patients with drug resistant epilepsy, matched for number, age and sex and never treated with ketogenic diet, were recruited as controls.ResultsThe population study was composed by 43 epilepsy patients (23 males), aged between 19 months and 31 years (mean 11 years). Twenty-three patients were or had been treated with ketogenic diet, and 20 had never been on it (control group). Subjects treated with the ketogenic diet had higher arterial stiffness parameters, including AIx and β-index and higher serum levels of cholesterol or triglycerides compared to those who had never been on the diet (control group) (p < 0.001).ConclusionsArterial stiffness is increased in children and young adults treated with the ketogenic diet, before the increase of the intima media thickness. This supports that arterial stiffness is an early marker of vascular damage.     

Case–control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics

The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with Schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.     

Trends in Psychiatric Inpatient Rates from 1991–1995 in the State of Washington: The Effect of Insurance Type on Utilization

This study examined whether there have been changes in inpatient psychiatric use among publicly and privately insured patients by analyzing trends in adult psychiatric hospitalizations from 1991 through 1995 in the State of Washington. A state-wide Comprehensive Hospital Abstract Reporting System (CHARS) was used to track psychiatric hospital utilization patterns. The results show a significant growth in psychiatric hospitalizations among the publicly insured patients due to their high proportion of severe and persistent mental illness. There was a flat trend in psychiatric hospitalizations suggesting that private insurers aggressively monitor the costly use of hospitalizations for mentally ill patients.     

Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: The role of kallikrein–kinin system

Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by down-regulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B₁R mRNA expression occurred selectively in the hippocampus, whereas protein level was up-regulated in both brain areas. Genetic deletion of kinin B₁R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-γ in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B₁R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein–kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.