Autobiographical memory and future thinking impairments in multiple sclerosis: Cognitive and neural mechanisms, functional impact and rehabilitation.

Learning and memory impairments are common in individuals with multiple sclerosis (MS) and have pervasive effects on everyday life functioning. Hence, memory and learning have received particular attention in the cognitive rehabilitation literature in MS. The effectiveness of memory rehabilitation on memory performance is supported by several studies, but the generalisability of the benefits to daily life and memory for real-life events has rarely been examined. Recently, a new line of research focusing on memory for personal life events (i.e., autobiographical memory) has emerged in the MS literature. This approach is complementary to classical learning and memory paradigms and also allows for approaching memory in a broader context, one that considers memory as the ability to remember past episodes and imagine events that may occur in one's personal future (i.e. future thinking). This review provides an overview of the findings in this line of work. The first part summarises current evidence regarding the cognitive and neural mechanisms underlying autobiographical memory and future thinking impairments in MS. It points out that these domains are frequently and early impaired in individuals with MS because of an executive/frontal-related deficit. Individuals with MS are generally aware of these deficits and their negative impact on everyday life, so the development of strategies to alleviate such deficits seems of paramount importance. Thus, in the second part, I present the main outcomes of a cognitive intervention developed by our research group, which has been specifically designed to alleviate autobiographical memory and future thinking impairments in individuals with MS. The implications of these findings for neuropsychological care and well-being of individuals with MS are discussed in the final section, with an emphasis on the functional role of autobiographical memory and future thinking in various domains, including personal identity.

Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children.

The Adverse Outcome Pathways (AOPs) are designed to provide mechanistic understanding of complex biological systems and pathways of toxicity that result in adverse outcomes (AOs) relevant to regulatory endpoints. AOP concept captures in a structured way the causal relationships resulting from initial chemical interaction with biological target(s) (molecular initiating event) to an AO manifested in individual organisms and/or populations through a sequential series of key events (KEs), which are cellular, anatomical and/or functional changes in biological processes. An AOP provides the mechanistic detail required to support chemical safety assessment, the development of alternative methods and the implementation of an integrated testing strategy. An example of the AOP relevant to developmental neurotoxicity (DNT) is described here following the requirements of information defined by the OECD Users' Handbook Supplement to the Guidance Document for developing and assessing AOPs. In this AOP, the binding of an antagonist to glutamate receptor N-methyl-d-aspartate (NMDAR) receptor is defined as MIE. This MIE triggers a cascade of cellular KEs including reduction of intracellular calcium levels, reduction of brain derived neurotrophic factor release, neuronal cell death, decreased glutamate presynaptic release and aberrant dendritic morphology. At organ level, the above mentioned KEs lead to decreased synaptogenesis and decreased neuronal network formation and function causing learning and memory deficit at organism level, which is defined as the AO. There are in vitro, in vivo and epidemiological data that support the described KEs and their causative relationships rendering this AOP relevant to DNT evaluation in the context of regulatory purposes.

Electrocortical Dynamics in Children with a Language-Learning Impairment Before and After Audiovisual Training.

Detecting and discriminating subtle and rapid sound changes in the speech environment is a fundamental prerequisite of language processing, and deficits in this ability have frequently been observed in individuals with language-learning impairments (LLI). One approach to studying associations between dysfunctional auditory dynamics and LLI, is to implement a training protocol tapping into this potential while quantifying pre- and post-intervention status. Event-related potentials (ERPs) are highly sensitive to the brain correlates of these dynamic changes and are therefore ideally suited for examining hypotheses regarding dysfunctional auditory processes. In this study, ERP measurements to rapid tone sequences (standard and deviant tone pairs) along with behavioral language testing were performed in 6- to 9-year-old LLI children (n = 21) before and after audiovisual training. A non-treatment group of children with typical language development (n = 12) was also assessed twice at a comparable time interval. The results indicated that the LLI group exhibited considerable gains on standardized measures of language. In terms of ERPs, we found evidence of changes in the LLI group specifically at the level of the P2 component, later than 250 ms after the onset of the second stimulus in the deviant tone pair. These changes suggested enhanced discrimination of deviant from standard tone sequences in widespread cortices, in LLI children after training.

Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats.

Studies demonstrated that chronic high-dose homocysteine administration induced learning and memory impairment in animals. Atractylenolide III (Aen-III), a neuroprotective constituent of Atractylodis macrocephalae Koidz, was isolated in our previous study. In this study, we investigated potential benefits of Aen-III in preventing learning and memory impairment following chronic high-dose homocysteine administration in rats. Results showed that administration of Aen-III significantly ameliorated learning and memory impairment induced by chronic high-dose homocysteine administration in rats, decreased homocysteine-induced reactive oxygen species (ROS) formation and restored homocysteine-induced decrease of phosphorylated protein kinase C expression level. Moreover, Aen-III protected primary cultured neurons from apoptotic death induced by homocysteine treatment. This study provides the first evidence for the neuroprotective effect of Aen-III in preventing learning and impairment induced by chronic administration of homocysteine. Aen-III may have therapeutic potential in treating homocysteine-mediated cognitive impairment and neuronal injury.

Compound IMM-H004, a novel coumarin derivative, protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia.

AIMS: Compound IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a new synthetic derivative of coumarin, and previous studies showed that it exhibited antioxidant and neuroprotective roles in focal cerebral ischemia. However, we know little about the compound's function in transient global ischemia. This study is to investigate whether compound IMM-H004 can protect against transient global ischemic injury. METHODS: Four-vessel occlusion (4VO) rat model was induced for a 20-min occlusion and different times of reperfusion to mimic transient global cerebral ischemia. IMM-H004 (3, 6, 9 mg/kg) or Edaravone (6 mg/kg) was administered after 30 min of reperfusion. Morris water maze tests were used to estimate the ability of spatial learning and memory. Nissl staining, TUNEL assay and Immunoblot for Bax/Bcl-2 and activated caspase-3 were used to detect hippocampal neuron injury. Immunoblot for PSD-95 and synapsin 1, and electron microscopy were used to observe synaptic function. RESULTS: Compared with vehicle group, IMM-H004 significantly improved the spatial learning performance and exhibited less CA1 neurons loss. The expressions of Bax/Bcl-2 and activated caspase-3 were decreased. IMM-H004 also ameliorated synaptic structure, decreased PSD-95 and increased synapsin 1 expression. CONCLUSION: These findings suggested that IMM-H004 exerted neuroprotective role in global ischemia by reducing apoptosis and maintaining the integrity of synaptic structure.

Quantitative EEG neurofeedback for the treatment of pediatric attention-deficit/hyperactivity disorder, autism spectrum disorders, learning disorders, and epilepsy.

Neurofeedback (NF) using surface electroencephalographic signals has been used to treat various child psychiatric disorders by providing patients with video/audio information about their brain's electrical activity in real-time. Research data are reviewed and clinical recommendations are made regarding NF treatment of youth with attention deficit/hyperactivity disorder, autism, learning disorders, and epilepsy. Most NF studies are limited by methodological issues, such as failure to use or test the validity of a full-blind or sham NF. The safety of NF treatment has not been thoroughly investigated in youth or adults, although clinical experience suggests reasonable safety.

Brainstem response to speech and non-speech stimuli in children with learning problems.

Neuronal firing synchronization is critical for recording auditory responses from the brainstem. Recent studies have shown that both click and/da/synthetic syllable (speech) stimuli perform well in evoking neuronal synchronization at the brainstem level. In the present study, brainstem responses to click and speech stimuli were compared between children with learning problems (LP) and those with normal learning (NL) abilities. The study included 49 children with LP and 34 children with NL. Auditory brainstem response (ABR) to 100-µs click stimulus and speech ABR (sABR) to/da/40-ms stimulus were tested in these children. Wave latencies III, V, and Vn and inter-peak latency (IPL) V-Vn in click ABR and wave latencies I, V, and A and IPL V-A in sABR were significantly longer in children with LP than children with NL. Except IPL of I-III, a significant positive correlation was observed between click ABR and sABR wave latencies and IPLs in children with NL; this correlation was weaker or not observed in children with LP. In this regard, the difference between correlation coefficients of wave latencies I, III, and V and IPLs I-V and V-Vn/V-A was significant in the two groups. Deficits in auditory processing timing in children with LP may have probably affected ABR for both click and speech stimuli. This finding emphasizes the possibility of shared connections between processing timing for speech and non-speech stimuli in auditory brainstem pathways. Weak or no correlation between click and speech ABR parameters in children with LP may have a clinical relevance and may be effectively used for objective diagnoses after confirming its sufficient sensitivity and specificity and demonstrating its acceptable validity with more scientific evidence.

Biological impact of music and software-based auditory training.

Auditory-based communication skills are developed at a young age and are maintained throughout our lives. However, some individuals - both young and old - encounter difficulties in achieving or maintaining communication proficiency. Biological signals arising from hearing sounds relate to real-life communication skills such as listening to speech in noisy environments and reading, pointing to an intersection between hearing and cognition. Musical experience, amplification, and software-based training can improve these biological signals. These findings of biological plasticity, in a variety of subject populations, relate to attention and auditory memory, and represent an integrated auditory system influenced by both sensation and cognition.

Dietary ω-3 polyunsaturated fatty acids improves learning performance of diabetic rats by regulating the neuron excitability.

Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids (PUFA), have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. Sprague-Dawley rats were used in the present study to investigate the effect of fish oil supplementation on spatial learning and memory of streptozotocin (STZ)-induced diabetic rats with the Morris Water Maze. The excitability of CA1 pyramidal neurons and the related ionic currents was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the sodium currents and increased the potassium currents, and further led to the reduction of excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. Fish oil dietary supplementation decreased the transient currents and Kv4.2 expression in the hippocampus and partially improved learning performance of diabetic rats. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Dietary fish oil may modulate the membrane excitability and is a possible strategy for preventing the impairments of diabetes on hippocampal function.

Farmacoterapia para niños con síndrome de Down / No disponible

El campo de la farmacología cognitiva para niños con discapacidad intelectual no existe todavía, pero el reciente desarrollo de la investigación que atiende a este objetivo parece prometedor. La investigación informada por la neurociencia, dirigida a conocer la base neurobiológica de la discapacidad intelectual en el síndrome de Down y otras patologías neurogenéticas está empezando a acumular una masa crítica investigadora con la atracción necesaria para avanzar hacia adelante. Agentes farmacológicos que apuntan a receptores GABA y glutamato y transportadores de dopamina ofrecen perspectivas como para iniciar ensayos clínicos. Las terapias basadas en células e intervenciones biológicas relacionadas con ellas se encuentran todavía en etapas muy inmaduras o ensayo preclínico, pero la infraestructura y los recursos que se necesitan para apoyar estos esfuerzos investigadores están lejos de conseguirse, lo que dificulta el progreso en este campo. La capacidad para convertir hallazgos fundamentales conseguidos desde la neurofarmacología y la neurociencia cognitiva en terapias fundamentadas en dichos hallazgos que mejoren las vidas de los niños con trisomía 21 sigue siendo, pues, todo un reto digno de afrontar (AU)

No disponible

Glabridin as a major active isoflavan from Glycyrrhiza glabra (licorice) reverses learning and memory deficits in diabetic rats.

Cognitive impairment occurs in diabetes mellitus. Glabridin as a major active flavonoids in Glycyrrhiza glabra (licorice) improves learning and memory in mice. In the present study, we investigated the effect of chronic treatment with glabridin (5, 25 and 50 mg/kg, p.o.) on cognitive function in control and streptozotocin (STZ)-induced diabetic rats.Animals were divided into untreated control, glabridin-treated control (5, 25 and 50 mg/kg), untreated diabetic and glabridin treated diabetic (5, 25 and 50 mg/kg) groups. Treatments were begun at the onset of hyperglycemia. Passive avoidance learning (PAL) and memory was assessed 30 days later. Diabetes caused cognition deficits in the PAL and memory paradigm. While oral glabridin administration (25 and 50 mg/kg) improved learning and memory in non-diabetic rats, it reversed learning and memory deficits of diabetic rats. Low dose glabridin (5 mg/kg) did not alter cognitive function in non-diabetic and diabetic groups. Glabridin treatment partially improved the reduced body weight and hyperglycemia of diabetic rats although the differences were not significant. The combination of antioxidant, neuroprotective and anticholinesterase properties of glabridin may all be responsible for the observed effects. These results show that glabridin prevented the deleterious effects of diabetes on learning and memory in rats. Further studies are warranted for clinical use of glabridin in the management of demented diabetic patients.

Ginsenoside Rb1 improves spatial learning and memory by regulation of cell genesis in the hippocampal subregions of rats.

Ginsenoside Rb1 (Rb1) is known to improve learning and memory in hippocampus-dependent tasks. However, the cellular mechanism remains unknown. Cell genesis in hippocampus is involved in spatial learning and memory. In the present study, Rb1 was orally administrated to adult rats for 30days. The behavioral training tests indicated that Rb1 improved spatial cognitive performance of rats in Morris water maze (MWM). Furthermore, we investigated the effects of Rb1 on cell genesis in adult rats' hippocampus, using thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. It has been shown that hippocampal cell genesis can be influenced by several factors such as learning and exercise. In order to avoid the effects of the interfering factors, only the rats treated with Rb1 without training in MWM were used to investigate cell genesis in hippocampus. When BrdU was given to the rats 30days prior to being killed, it was shown that oral administration of Rb1 significantly increased cell survival in dentate gyrus and hippocampal subregion CA3. However, when BrdU was injected 2h prior to sacrifice, the results indicated that Rb1 had no significant influence on cell proliferation in the hippocampal subregions. Thus, an increase of cell survival in hippocampus stimulated by Rb1 may be one of the mechanisms by which ginseng facilitates spatial learning and memory. Our study also indicates that Rb1 may be developed as a therapeutic agent for patients with memory impairment.

Ameliorative effect of traditional Japanese medicine yokukansan on age-related impairments of working memory and reversal learning in rats.

Aging is thought to impair prefrontal cortical (PFC) structure-sensitive cognitive functions and flexibility, such as working memory and reversal learning. A traditional Japanese medicine, yokukansan (YKS), is frequently used to treat age-related neurodegenerative disorders such as Alzheimer's disease in Japan, but its pharmacological properties have not been elucidated. The present study was designed to examine whether YKS improves age-related cognitive deficits using aged rats. YKS was administered to 21-month-old rats for 3 months. The ability to learn initially a reward rule for a T-maze discrimination task (initial learning) was examined in young control (4-month-old), aged control (24-month-old) and YKS-treated aged (24-month-old) rats. Subsequently, working memory and reversal learning were examined in delayed alternation and reversal discrimination T-maze tasks, respectively. Locomotor activity was also measured in new environments. Although performance accuracy in the initial learning procedure did not differ among any experimental groups, accuracy in the delayed alternation task was significantly decreased in aged rats compared to young rats. Aged rats also showed significant decreases in accuracy in the reversal discrimination task. YKS treatment significantly ameliorated the age-related decreases in accuracy in the delayed alternation and reversal discrimination tasks. The ameliorative effects of YKS on impaired delayed alternation performance were reduced by intracranial infusions of a dopamine D1 receptor antagonist, SCH 23390, into the prelimbic cortical region of the PFC, and the YKS effects on impaired reversal learning were done by the infusions into the orbitofrontal cortex (OFC). Locomotor activity did not change in any experimental group. Thus, YKS ameliorated age-related impairments of working memory and reversal learning, which might be mediated by a dopaminergic mechanism in the PFC structure. These investigations provide information important for the treatment of brain dysfunctions in the elderly people.

Single-trial based independent component analysis on mismatch negativity in children.

Independent component analysis (ICA) does not follow the superposition rule. This motivates us to study a negative event-related potential - mismatch negativity (MMN) estimated by the single-trial based ICA (sICA) and averaged trace based ICA (aICA), respectively. To sICA, an optimal digital filter (ODF) was used to remove low-frequency noise. As a result, this study demonstrates that the performance of the sICA+ODF and aICA could be different. Moreover, MMN under sICA+ODF fits better with the theoretical expectation, i.e., larger deviant elicits larger MMN peak amplitude.

(+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia.

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.

Neurocognitive performance in children with ADHD and OCD.

Attention-deficit/hyperactivity Disorder (ADHD) and obsessive-compulsive disorder (OCD) have both been linked to dysfunction in the cortico-striato-thalamo-cortical circuitry (CSTCC). However, the exact nature of neurocognitive deficits remains to be investigated in both disorders. We applied two neuropsychological tasks that tap into different functions associated with the CSTCC, namely a serial reaction time (SRT) task, developed to assess implicit sequence learning, and a delay aversion (DA) task in order to assess abnormal motivational processes. The performance data of boys with ADHD (n=20), OCD (n=20) and healthy controls (n=25), all aged 10-18 years, were compared. Subjects with ADHD less frequently chose the larger, more delayed reward compared to those with OCD and controls, while subjects with OCD showed impaired implicit learning. In contrast, the ADHD group was unimpaired in their implicit learning behavior and the OCD group was not characterized by a DA style. Within the OCD-group, severity of obsessions was associated with implicit learning deficits and impulsive symptoms with DA in the ADHD-group. This double dissociation highlights the distinct cognitive dysfunctions associated with ADHD and OCD and might possibly point to different neural abnormalities in both disorders.

Electroacupuncture pretreatment ameliorates hypergravity-induced impairment of learning and memory and apoptosis of hippocampal neurons in rats.

High-sustained positive acceleration (+Gz) exposures might lead to impairment in cognitive function. Our previous studies have shown that electroacupuncture (EA) pretreatment can attenuate transient focal cerebral ischemic injury in the rats. In this study we aimed to investigate whether EA pretreatment could ameliorate the impairment of learning and memory induced by a sustained +Gz exposure. Using the centrifuge model, rats of experimental groups were exposed to +10 Gz for 5 min. Morris water maze was used for assessing the cognitive ability, and the apoptotic hippocampal CA1 pyramidal neuronal cells were evaluated by caspase-3 activity and TUNEL staining. Our results showed that +Gz exposure significantly caused pyramidal neuronal damage, increased neuronal apoptosis and caspase-3 activity in hippocampal CA1 region, as well as resulted in an impairment of spatial learning and memory, as compared to the sham group animals. Furthermore, the EA pretreatment significantly attenuated the neuronal apoptosis, preserved neuronal morphology and inhibited the caspase-3 activity in hippocampal CA1 region resulted from +Gz exposure. The EA pretreatment also ameliorated the learning and memory function in rats exposed to +Gz. These findings indicate that EA pretreatment provides a novel method to prevent the cognitive damage caused by +Gz, which could significantly protect neuronal damage and impairment of learning and memory.

Astrocyte-mediated hepatocyte growth factor/scatter factor supplementation restores GABAergic interneurons and corrects reversal learning deficits in mice.

Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors.