Severe Working Memory Deficits Research Articles

Cerebrospinal Fluid Biomarkers for the Detection of Autoimmune Depression

The discovery of anti–NMDA receptor encephalitis in 2007 provided enormous boosts to immunological research in neurology and psychiatry. Anti–NMDA receptor encephalitis is associated with severe neurological and a plethora of psychiatric symptoms, including psychotic and affective phenomena (1,2). To date, several more well-characterized neuronal autoantibodies have been described (1,2). According to current international consensus criteria, a diagnosis of possible autoimmune encephalitis (AE) should be considered in the presence of a subacute neuropsychiatric syndrome (with severe working memory deficits, an altered mental state, or psychiatric symptoms) in combination with at least one further organic sign, such as inflammatory cerebrospinal fluid (CSF) changes with an increased white blood cell (WBC) count, suspicious magnetic resonance imaging (MRI) changes, epileptic seizures, or focal neurological signs (2).

Occupational burnout‐like syndrome in early‐onset Alzheimer’s disease

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to non‐amnesic cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients.MethodsWe retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years.ResultsEleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative.ConclusionWe describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis.

Correlation between visuo-spatial working memory and brain Magnetic Resonance Imaging (MRI) lesion five years after Traumatic Brain Injury (TBI)

To describe the changes in fractional anisotropy (FA) measured with Diffusion Tensor Imaging (DTI) and the changes in Regional Homogeneity (ReHo) signal measured with resting state functional MRI on patients with visuo-spatial working memory deficit, 5 years after a severe TBI. We included TBI patients from a neurosurgical intensive care cohort of the Pitié-Salpêtrière Parisian Hospital. Patients were hospitalized between 2005 and 2011. A French version of the Glasgow Outcome Scale Extended (GOSE) assessed the global functional outcome. A large neuropsychological assessment including working memory tests was performed. We present here the results of the backward visuo-spatial span as standard notes. FA were measured on DTI and ReHo were extracted from resting state functional MRI acquisition on a voxel-based approach. Fifty-four patients were included 65 months after their TBI. The median age at evaluation time was 34 years [19–71]. Median Glasgow Coma Score was 8 [3–15]. Seventeen patients had a GOSE score below 6, 18 had a GOSE at 6 and 19 had a GOSE higher than 6. Thirty patients had a standard note on backward visuo-spatial span inferior to 7, which corresponds to a deficit. In this group, FA was lower in the left hemisphere, in the anterior limb of the internal capsule and in the external capsule. Patients also had an increased ReHo in the right hemisphere in the superior temporal gyrus, Heschl's gyrus, putamen, medium frontal gyrus and inferior frontal gyrus triangularis. Despite the fact that axonal lesions observed after TBI are diffuse, decreased FA was predominant in the left hemisphere of patients with the most severe working memory deficits and in whom ReHo appeared higher in the right hemisphere. These observations should open the discussion about contralateral inhibition of hemispheres.

A Meta-Analysis of Working Memory Deficits in Children With Learning Difficulties

Children with learning difficulties suffer from working memory (WM) deficits. Yet the specificity of deficits associated with different types of learning difficulties remains unclear. Further research can contribute to our understanding of the nature of WM and the relationship between it and learning difficulties. The current meta-analysis synthesized research on verbal WM and numerical WM among children with reading difficulties (RD), children with mathematics difficulties (MD), and children with reading and mathematics difficulties (RDMD). A total of 29 studies subsuming 110 comparisons were included. Results showed that compared to typically developing children, all learning difficulty groups demonstrated deficits in verbal WM and numerical WM, with RDMD children showing the most severe WM deficits. MD children and RD children showed comparable verbal WM deficits, but MD children showed more severe numerical WM deficits than RD children. Neither severity of learning difficulties nor type of academic screening emerged as a moderator of WM deficit profiles. Although the findings indicate the domain-general nature of WM deficits in RD, MD, and RDMD children, the numerical WM deficits of children with MD and RDMD may reflect the domain-specific nature of WM deficits.

Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice.

BackgroundSynaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown.ResultsIn this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants.ConclusionsThese findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.

Immature dentate gyrus as a candidate endophenotype of psychiatric disorders

Despite massive research efforts, the exact pathogenesis and pathophysiology of psychiatric disorders, such as schizophrenia and bipolar disorder, remain largely unknown. Animal models can serve as essential tools for investigating the etiology and treatment of such disorders. Some mutant mouse strains were found to exhibit behavioral abnormalities reminiscent of human psychiatric disorders. Here we outline our unique approach of extrapolating findings in mice to humans, and present studies on alpha-CaMKII heterozygous knockout (alpha-CaMKII HKO) mice as examples. Alpha-CaMKII HKO mice have profoundly dysregulated behavior and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. By conducting a series of experiments, we discovered that almost all the neurons in the mutant DG were very similar to the immature DG neurons of normal rodents. In other words, alpha-CaMKII HKO mice have an "immature DG". We proposed that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

S17-04 Alpha-CAMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here I show that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were changed. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neuronsw as dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Statistical clustering of human post-mortem brains using 10 genes derived from the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an “immature DG” in adulthood might serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice

The alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII) is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of α-CaMKII (α-CaMKII+/−) have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG) of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs), c-Fos and Arc, in the brain after a working memory version of the eight-arm radial maze test. c-Fos expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC). However, c-Fos expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using arc promoter driven dVenus transgenic mice demonstrated that arc gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of α-CaMKII in the proper maturation and integration of DG neurons into these circuits.

Intrauterine environment-genome interaction and Children's development (4): Brain-behavior phenotypying of genetically-engineered mice using a comprehensive behavioral test battery on research of neuropsychiatric disorders

Despite massive research efforts, the exact pathogenesis and pathophysiology of psychiatric disorders, such as schizophrenia and bipolar disorder, remain largely unknown. Animal models can serve as essential tools for investigating the etiology and treatment of such disorders. Some mutant mouse strains were found to exhibit behavioral abnormalities reminiscent of human psychiatric disorders. Here we outline our unique approach of extrapolating findings in mice to humans, and present studies on alpha-CaMKII heterozygous knockout (alpha-CaMKII+/-) mice as examples. Alpha-CaMKII+/- mice have profoundly dysregulated behavior and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. By conducting a series of experiments, we discovered that almost all the neurons in the mutant DG were very similar to the immature DG neurons of normal rodents. In other words, alpha-CaMKII+/- mice have an "immature DG". We proposed that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders. The impact of a large-scale mouse phenotyping on studies of psychiatric disorders and the potential utility of an "animal-model-array" of psychiatric disorders for the development of suitable therapeutic agents is also discussed.

Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

A pilot study for rehabilitation of central executive deficits after traumatic brain injury

Primary objective: An impairment of the central executive system (CES) of working memory (WM) is a common consequence of traumatic brain injury (TBI), and may also explain deficits in divided attention, long-term memory and executive functions. Here we investigated the efficacy of a rehabilitative program (working memory training: WMT) targeting the CES in improving WM and other cognitive functions dependent on this system.Methods and procedures: Nine TBI patients with severe WM deficits underwent the WMT (experimental training). The WMT was preceded by a general stimulation training (GST; control training). Patients’ cognitive performance was evaluated at the admission, after the GST and at the end of the WMT.Main outcomes and results: Whereas the GST had no effect on patients’ performance, after the WMT patients improved in all the cognitive functions dependent on the CES, but not in those functions not thought to tap this system. Importantly, a beneficial WMT effect was found on patients’ everyday life functioning.Conclusions: The results support the efficacy of the WMT in recovering CES impairments.

Investigating Gene‐to‐Behavior Pathways in Psychiatric Disorders

We have been investigating the relationships between genes and behaviors by conducting a systematic and well-defined behavioral test battery with mice that have a mutation on a gene of interest. The behavioral test battery covers a relatively broad range of various behavioral domains such as learning and memory, sensory-motor functions, emotion, motivation, and drug sensitivity/preference. Recently, we subjected mice lacking calcineurin (CN), a calcium/calmodulin protein phosphatase, to the comprehensive behavioral test battery. The mutant mice had a severe working memory deficit, increased locomotor activity, decreased social interaction, and impairments in prepulse and latent inhibition. The abnormalities of CN mutant mice were strikingly similar to those described for schizophrenic patients. Consistent with these findings, human genetics studies in a large sample of affected families detected a significant association of the PPP3CC gene, which encodes the CN gamma catalytic subunit with schizophrenia. The idea that abnormalities in the CN signaling pathway are involved in schizophrenia pathogenesis is consistent with traditional theories of schizophrenia and with many facts known about schizophrenia. A tremendous amount of knowledge about CN has accumulated and, by utilizing this information, the studies on the pathogenesis/pathophysiology of schizophrenia and its related mental disorders will be potentially accelerated. We discuss the potential impact of a large-scale mouse phenotyping project on the study of psychiatric disorders.

Acquired Dyslexia after Stroke in the Prereading Stage: A Single Case Treatment Study with f MRI

The authors report a treatment study of a child (CK) who suffered a left-hemisphere stroke at age 6.3 years, a few months before beginning school. Despite complete recovery of spoken language abilities, CK failed to acquire written language abilities. Neurolinguistic assessment 2 years after the stroke revealed marked impairments in working memory, deficits in acquiring a sublexical reading strategy, and a very rudimentary orthographic network. Functional imaging demonstrated activation in posterior language areas during reading of familiar words while the attempt to read unfamiliar words activated peri- and contralesional structures of the anterior language areas. It was assumed that despite sufficient neural plasticity, the acquisition of a sublexical reading strategy was prevented by severe working memory deficits. Therefore, a specific treatment intervention was developed, choosing a compensatory strategy for reading remediation. Reading development was monitored over three months before and three months after an intensive training was conducted. Data showed significant gains in reading performance only after the specific intervention. These gains remained stable in a catamnesis 2 years later.

Unaltered radial maze performance and brain acetylcholine of the endothelial nitric oxide synthase knockout mouse

Proceeding from previous findings of a beneficial effect of endothelial nitric oxide synthase (eNOS) gene inactivation on negatively reinforced water maze performance, we asked whether this improvement in place learning capacities also holds for a positively reinforced radial maze task. Unlike its beneficial effects on the water maze task, eNOS gene inactivation did not facilitate radial maze performance. The acquisition performance over the days of place learning did not differ between eNOS knockout (eNOS−/−) and wild-type mice (eNOS+/+). eNOS−/− mice displayed a slight and eNOS+/+ mice a more severe working memory deficit in the place learning version of the radial maze compared to the genetic background C57BL/6 strain. Possible differential effects of eNOS inactivation, related to differences in reinforcement contingencies between the Morris water maze and radial maze tasks, behavioral strategy requirements, or to different emotional and physiological concomitants inherent in the two tasks are discussed. These task-unique characteristics might be differentially affected by the reported anxiogenic and hypertensional effects of eNOS gene inactivation. Post-mortem determination of acetylcholine concentrations in diverse brain structures revealed that acetylcholine and choline contents were not different between eNOS−/− and eNOS+/+ mice, but were increased in eNOS+/+ mice compared to C57BL/6 mice in the frontal cortex. Our findings demonstrate that phenotyping of learning and memory capacities should not rely on one learning task only, but should include tasks employing both negative and positive reinforcement contingencies in order to allow valid statements regarding differences in learning capacities between rodent strains.

Neurocognitive and symptom correlates of self-reported childhood sexual abuse in schizophrenia spectrum disorders.

This study examined whether self-reported childhood sexual abuse in schizophrenia spectrum disorders is linked with severity of neurocognitive deficits. The Wisconsin Card Sorting Test, California Verbal Learning Test, and select WAIS III subtests were administered to 15 participants with schizophrenia or schizoaffective disorder who had been sexually abused and to 28 participants with no abuse history. Controlling for age and premorbid IQ, a MANCOVA indicated there were group differences (f(9, 31) = 5.53, p < .001). Subsequent ANCOVA indicated that the sexual abuse group performed more poorly on tests of working memory and information processing speed. Childhood sexual abuse is associated with more severe working memory deficits in adults with schizophrenia spectrum disorders.