Cognitive Impairment In Epilepsy Research Articles

The association of structural connectome efficiency with cognition in children with epilepsy

ObjectiveCognitive impairment is common in children with epilepsy (CWE), but understanding the underlying pathological processes is challenging. We aimed to investigate the association of structural brain network organisation with cognition. MethodsThis was a retrospective cohort study of CWE without structural brain abnormalities, comparing whole brain network characteristics between those with cognitive impairment and those with intact cognition. We created structural whole-brain connectomes from anatomical and diffusion tensor magnetic resonance imaging using the number of streamlines and tract-averaged fractional anisotropy. We assessed the differences in average path length and global network efficiency between children with cognitive impairment and those without,using multivariable analyses to account for possible clinical group differences. ResultsTwenty-eight CWE and cognitive impairment had lower whole brain network global efficiency compared with 34 children with intact cognition (0.54, standard deviation (SD):0.003 vs. 0.56, SD:0.002, p < 0.001), which is equivalent to longer normalized network average path lengths (1.14, SD:0.05 vs. 1.10, SD:0.02, p = 0.003). In multivariable logistic regression cognitive impairment was not significantly associated with age of onset, duration of epilepsy, or number of antiseizure medications, but was independently associated with daily seizures (p = 0.04) and normalized average path length (p = 0.007). ConclusionsHigher structural network average path length and lower global network efficiency may be imaging biomarkers of cognitive impairment in epilepsy. Understanding what leads to changes in structural connectivity could aid identification of modifiable risk factors for cognitive impairment. These findings are only applicable to the specific cohort studied, and further confirmation in other cohorts is required.

Serum neurofilament light chain in patients with epilepsy and cognitive impairment.

The neurofilament light chain (NfL) is receiving increased attention as a biomarker of neurological diseases, as NfL concentration elevated in the blood and cerebrospinal fluid after neuronal damage. However, few studies have addressed NfL in epilepsy. We aimed to investigate the alteration of serum NfL in adult patients with epilepsy, and the association between this biomarker and cognitive impairment. A total of 38 consecutive patients with epilepsy and 24 controls underwent cross-sectional measurement of serum NfL levels and cognitive testing using the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), the Frontal Assessment Battery (FAB), the Trail-Making Test, and the Stroop Color-Word Test. Statistical analysis was performed with Student's t-test to compare serum NfL levels between the epilepsy group and the control group, and with Spearman's correlation and age-corrected partial correlation analyses to evaluate the association between serum NfL level and cognitive impairment in epilepst patients. There was no difference in serum NfL levels between the epilepsy and control groups (epilepsy [mean ± SD]: 17.3 ± 13.9 pg/mL; control: 17.7 ± 11.5 pg/mL; p = .92); however, the MoCA-J scores were lower in the epilepsy group (26.6 ± 3.1 vs. 28.1 ± 1.6; p = .03). The age-corrected partial correlation analysis showed a correlation between serum NfL level and cognitive test scores in the epilepsy group (MMSE: rs = -.63, p < .01; MoCA-J: rs = -.54, p < .01; FAB: rs = -.68, p < .01), whereas serum NfL levels were correlated exclusively with MMSE scores in the control group (rs = .44, p = .04). In adult epilepsy patients, the serum NfL level was not significantly elevated, but was correlated with cognitive test scores. Our findings suggest that serum NfL concentration could be an indicator of cognitive function in epilepsy patients.

Hippocampal mossy cells exhibit some of the earliest signs of increased excitability in the Tg2576 model of Alzheimer’s disease neuropathology

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative illness characterized by progressive accumulation of amyloid beta (Aβ) and neurofibrillary tangles, with cognitive impairment and altered neural activity. Hyperexcitability in the early stages of AD contribute to Aβ accumulation and cognitive impairment, aggravating the progression of AD. However, the hyperexcitability origin is not clear. This study aimed to test whether mossy cells (MCs), an excitatory cell of the hippocampal dentate gyrus, show increased excitability at early stages of AD and contribute to the increased network excitability generation. Indeed, alterations of MCs contribute to hyperexcitability and cognitive impairment in epilepsy. However, the role of MCs in AD has not been substantially explored.MethodsIntrinsic and synaptic properties of MCs and granule cells (GCs) from WT and Tg2576 mice at early ages (1‐2 m.o.) were characterized by whole‐cell patch‐clamp recordings. Synaptic properties included the frequency and amplitude of spontaneous excitatory postsynaptic potentials (EPSPs) and excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs). Deterioration in MCs morphology was evaluated using Nissl staining and GluR2/3 labeling by light‐ and confocal microscopy. Aβ deposition was evaluated using the McSA1 antibody.ResultsTg2576 GCs did not have any significant difference in their intrinsic properties, as we shown previously in mice ∼3 m.o. However, an enhanced excitatory and inhibitory input to GCs, depicted by augmented IPSC (7.16 vs 14.04 events/s) and NMDA‐mediated EPSC frequencies (0.81 vs 1.41 events/s) were found. Interestingly, Tg2576 MCs had an augmented EPSP frequency (5.75 vs 9.44 events/s), and their intrinsic properties showed a depolarized RMP (‐72.88 vs ‐58.36 mV), and reduced rheobase (145.56 vs 47.14 pA), AP amplitude (98.14 vs 76.66 mV), time‐to‐peak (552.75 vs 266.16 ms) and maximum rise (171.44 vs 88.68 mV/ms) and decay slopes (‐61.17 vs ‐42.38 mV/ms). The correlation between #APs and current injected showed Tg2576 MCs fired significantly more APs (SEZD = 0.34; z = 2.48). Tg2576 MCs showed robust intracellular Aβ aggregation without any significant morphological change.ConclusionsMCs changes in excitability and early accumulation of Aβ suggest that MCs could be the cause of increased excitability occurring later in GCs. In this manner, MCs could be an important contributor to AD.

Interictal discharges delay target-directed eye movements and impair attentional set-shifting in children with epilepsy.

The theory of transient cognitive impairment in epilepsy posits that lapses in attention result from ephemeral disruption of attentional circuitry by interictal events. Eye movements are intimately associated with human attention and can be monitored in real time using eye-tracking technologies. Here, we sought to characterize the associations between interictal epileptiform discharges (IEDs), gaze, and attentional behavior in children with epilepsy. Eleven consecutive children undergoing invasive monitoring with stereotactic electrodes for localization-related epilepsy performed an attentional set-shifting task while tandem intracranial electroencephalographic signals and eye-tracking data were recorded. Using an established algorithm, IEDs were detected across all intracranial electrodes on a trial-by-trial basis. Hierarchical mixed-effects modeling was performed to delineate associations between trial reaction time (RT), eye movements, and IEDs. Hierarchical mixed-effects modeling revealed that both the presence of an IED (β±SE=72.74± 24.21 ms, p= .003) and the frequency of epileptiform events (β±SE=67.54± 17.30 ms, p< .001) were associated with prolonged RT on the attentional set-shifting task. IED occurrence at the time of stimulus presentation was associated with delays in gaze initiation toward the visual targets (p= .017). The occurrence of epileptiform activity in close temporal association with stimulus presentation is associated with delays in target-directed gaze and prolonged response time, hallmarks of momentary lapses in attention. These findings provide novel insights into the mechanisms of transient impairments in children and support the use of visual tracking as a correlate of higher order attentional behavior.

Research Center for Psychotechnics Cognitive Impairments in Patients with Epilepsy

Cognitive impairment in epilepsy is an important problem. The understanding of the pathogenesis of disorders of higher nervous functions is based on the interaction of several factors, which include the form and duration of the disease, gender differences.

Mechanisms for Cognitive Impairment in Epilepsy: Moving Beyond Seizures.

There has been a major emphasis on defining the role of seizures in the causation of cognitive impairments like memory deficits in epilepsy. Here we focus on an alternative hypothesis behind these deficits, emphasizing the mechanisms of information processing underlying healthy cognition characterized as rate, temporal and population coding. We discuss the role of the underlying etiology of epilepsy in altering neural networks thereby leading to both the propensity for seizures and the associated cognitive impairments. In addition, we address potential treatments that can recover the network function in the context of a diseased brain, thereby improving both seizure and cognitive outcomes simultaneously. This review shows the importance of moving beyond seizures and approaching the deficits from a system-level perspective with the guidance of network neuroscience.

Cognitive Impairment in People with Epilepsy.

People with epilepsy frequently have cognitive impairment. The majority of cognitive problems is influenced by a variety of interlinked factors, including the early onset of epilepsy and the frequency, intensity and duration of seizures, along with the anti-epileptic drug treatment. With a systematic review, we investigate significant factors about the cognitive impairment in epilepsy. Most cognitive problems in adult people with epilepsy include memory, attention and executive function deficits. However, which cognitive area is mainly affected highly depends on the location of epileptic activity. Moreover, modifications in signalling pathways and neuronal networks have an essential role in both the pathophysiology of epilepsy and in the mechanism responsible for cognitive impairment. Additionally, studies have shown that the use of polytherapy in the treatment of epilepsy with anti-epileptic drugs (AEDs) heightens the risk for cognitive impairment. It can be challenging to distinguish the contribution of each factor, because they are often closely intertwined.

The organization of functional neurocognitive networks in focal epilepsy correlates with domain-specific cognitive performance.

Understanding and diagnosing cognitive impairment in epilepsy remains a prominent challenge. New etiological models suggest that cognitive difficulties might not be directly linked to seizure activity, but are rather a manifestation of a broader brain pathology. Consequently, treating seizures is not sufficient to alleviate cognitive symptoms, highlighting the need for novel diagnostic tools. Here, we investigated whether the organization of three intrinsic, resting-state functional connectivity networks was correlated with domain-specific cognitive test performance. Using individualized EEG source reconstruction and graph theory, we examined the association between network small worldness and cognitive test performance in 23 patients with focal epilepsy and 17 healthy controls, who underwent a series of standardized pencil-and-paper and digital cognitive tests. We observed that the specific networks robustly correlated with test performance in distinct cognitive domains. Specifically, correlations were evident between the default mode network and memory in patients, the central-executive network and executive functioning in controls, and the salience network and social cognition in both groups. Interestingly, the correlations were evident in both groups, but in different domains, suggesting an alteration in these functional neurocognitive networks in focal epilepsy. The present findings highlight the potential clinical relevance of functional brain network dysfunction in cognitive impairment.

Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3β (GSK-3β). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Ouvrier’s Modified Mini Mental State Examination as a screening test for cognitive impairment in school-aged children with epilepsy

Background Epilepsy may affect children's development, including their cognitive function. The prevalence of cognitive impairment in epilepsy patients is quite high. Weschler Intelligence Scale for Children (WISC) takes a long time to administer and is expensive, so a simpler screening tool for cognitive evaluation is needed in pediatric epilepsy patients.&#x0D; Objective To assess the diagnostic value of Ouvrier’s Modified Mini Mental State Examination (MMSE) for detecting cognitive impairment in children aged 8-11 years with epilepsy.&#x0D; Methods This diagnostic study was conducted in December 2018 to February 2019 at Cipto Mangunkusumo and Fatmawati Hospitals in Jakarta. Data were collected with purposive sampling of children with epilepsy aged 8 to 11 years. Cognitive function was assessed by Ouvrier’s Modified MMSE and WISC. Ouvrier’s Modified MMSE was compared to WISC as and the gold standard. Results were analyzed using a 2x2 table.&#x0D; Results The prevalence of cognitive impairment in 8-11-year-old epilepsy patients was 72.9%. Ouvrier’s Modified MMSE had 83% sensitivity, 85% specificity, 94% positive predictive value, 65% negative predictive value, and 83% accuracy.&#x0D; Conclusions Ouvrier’s Modified MMSE has good diagnostic value, thus it may be useful for early detection of cognitive impairment in pediatric epilepsy.

Ouvrier’s Modified Mini Mental State Examination as a screening test for cognitive impairment in school-aged children with epilepsy

Background Epilepsy may affect children's development, including their cognitive function. The prevalence of cognitive impairment in epilepsy patients is quite high. Weschler Intelligence Scale for Children (WISC) takes a long time to administer and is expensive, so a simpler screening tool for cognitive evaluation is needed in pediatric epilepsy patients.&#x0D; Objective To assess the diagnostic value of Ouvrier’s Modified Mini Mental State Examination (MMSE) for detecting cognitive impairment in children aged 8-11 years with epilepsy.&#x0D; Methods This diagnostic study was conducted in December 2018 to February 2019 at Cipto Mangunkusumo and Fatmawati Hospitals in Jakarta. Data were collected with purposive sampling of children with epilepsy aged 8 to 11 years. Cognitive function was assessed by Ouvrier’s Modified MMSE and WISC. Ouvrier’s Modified MMSE was compared to WISC as and the gold standard. Results were analyzed using a 2x2 table.&#x0D; Results The prevalence of cognitive impairment in 8-11-year-old epilepsy patients was 72.9%. Ouvrier’s Modified MMSE had 83% sensitivity, 85% specificity, 94% positive predictive value, 65% negative predictive value, and 83% accuracy.&#x0D; Conclusions Ouvrier’s Modified MMSE has good diagnostic value, thus it may be useful for early detection of cognitive impairment in pediatric epilepsy.

Alterations of Neuronal Dynamics as a Mechanism for Cognitive Impairment in Epilepsy.

Epilepsy is commonly associated with cognitive and behavioral deficits that dramatically affect the quality of life of patients. In order to identify novel therapeutic strategies aimed at reducing these deficits, it is critical first to understand the mechanisms leading to cognitive impairments in epilepsy. Traditionally, seizures and epileptiform activity in addition to neuronal injury have been considered to be the most significant contributors to cognitive dysfunction. In this review we however highlight the role of a new mechanism: alterations of neuronal dynamics, i.e. the timing at which neurons and networks receive and process neural information. These alterations, caused by the underlying etiologies of epilepsy syndromes, are observed in both animal models and patients in the form of abnormal oscillation patterns in unit firing, local field potentials, and electroencephalogram (EEG). Evidence suggests that such mechanisms significantly contribute to cognitive impairment in epilepsy, independently of seizures and interictal epileptiform activity. Therefore, therapeutic strategies directly targeting neuronal dynamics rather than seizure reduction may significantly benefit the quality of life of patients.

Cognitive Implications in Epilepsy.

Cognitive dysfunction is one of the major contributors to the burden of epilepsy. It can significantly disrupt intellectual development in children and functional status and quality of life in adults. There is major evidence confirms that cognitive impairment can appear or worsen with early and chronic progressive neurologic changes in epilepsy. It has been increasingly accepted that comorbidity does not indicate causality. Certainly, cognitive impairment in epileptic patients warrant crucial evaluation and mitigation from the time of diagnosis and treatment of epilepsy. The concept of a bidirectional nature of cognitive impairment in epilepsy represents a change in the paradigm of neuropsychology of epilepsy. It has been suggested that both behavioral and cognitive dysfunction associated with epilepsy are not necessarily the consequence of active epilepsy but in fact can dominate and be associated with factors before emergence of epilepsy. This review discusses different etiologies of cognitive and behavioral comorbidities in epilepsy and tries to clarify the nature of relation between epilepsy and cognition.

The P300 Event-Related Potential Component and Cognitive Impairment in Epilepsy: A Systematic Review and Meta-analysis

Background: Epilepsy is one of the most prevalent chronic brain diseases worldwide and is often accompanied by cognitive impairment. Event-related potentials (ERPs) are an objectively non-invasive approach for studying information processing and cognitive functions in the brain. The P300 is an important and extensively explored late component of ERPs that has been widely applied to assess cognitive function in epilepsy in previous studies. However, consistent conclusions have not yet been reached for various reasons.Objective: We conducted a comprehensive systematic review and meta-analysis of P300-related studies to assess the latency and amplitude of the P300 in epileptic patients.Methods: PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. The standard mean difference (SMD) and the 95% confidence interval (CI) were calculated as the effect size of the P300 component.Results: The main results of the present meta-analysis indicated that epileptic patients have a longer P300 latency and a lower P300 amplitude than controls. Subgroup analysis based on age group demonstrated that these differences can be observed in both children and adult patients compared with healthy controls. In addition, the P300 latency was longer in patients with the five main types of epileptic seizures than in controls.Conclusion: This study revealed that epileptic patients have abnormalities in the P300 component, which may reflect deficits in cognitive function. Thus, the P300 may be a potential objective approach for evaluating cognitive function in epileptic patients.

Transient Cognitive Impairment in Epilepsy.

Impairments of the dialog between excitation and inhibition (E/I) is commonly associated to neuropsychiatric disorders like autism, bipolar disorders and epilepsy. Moderate levels of hyperexcitability can lead to mild alterations of the EEG and are often associated with cognitive deficits even in the absence of overt seizures. Indeed, various testing paradigms have shown degraded performances in presence of acute or chronic non-ictal epileptiform activity. Evidences from both animal models and the clinics suggest that anomalous activity can cause cognitive deficits by transiently disrupting cortical processing, independently from the underlying etiology of the disease. Here, we will review our understanding of the influence of an abnormal EEG activity on brain computation in the context of the available clinical data and in genetic or pharmacological animal models.

The impact of brain-derived neurotrophic factor Val66Met polymorphism on cognition and functional brain networks in patients with intractable partial epilepsy.

Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups. We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE. In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n=276), postoperative cognitive change (n=126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n=37 and 34). mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients. Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE.

Comparison of Montreal Cognitive Assessment (MOCA) with Mini Mental State Examination (MMSE) on association between homocysteine and cognitive status in epilepsy patients with phenytoin monotherapy

ABSTRACTMini Mental State Examination (MMSE) has been used as a tool to detect cognitive impairment in patients treated with antiepileptic drugs, however fail to detect mild cognitive impairment in these patients. Studies report Montreal Cognitive Assessment (MOCA) is more sensitive than MMSE in detecting cognitive status in patients with stroke, parkinsonism, cardiovascular disease and epilepsy. Homocysteine has been implicated in the modulation of cognitive impairment in epilepsy but could not be established clearly as most studies followed MMSE. To investigate the relationship between homocysteine and cognitive status the present study employed MOCA in comparison with MMSE in epilepsy population with phenytoin monotherapy. Our findings suggest MOCA is more sensitive than MMSE in demonstrating the relationship between homocysteine and cognitive impairment in epilepsy.

Psychomotor slowing is associated with anomalies in baseline and prospective large scale neural networks in youth with epilepsy.

PurposePsychomotor slowing is a common but understudied cognitive impairment in epilepsy. Here we test the hypothesis that psychomotor slowing is associated with alterations in brain status reflected through analysis of large scale structural networks. We test the hypothesis that children with epilepsy with cognitive slowing at diagnosis will exhibit a cross-sectional and prospective pattern of altered brain development.MethodsA total of 78 children (age 8–18) with new/recent onset idiopathic epilepsies underwent 1.5 T MRI with network analysis of cortical, subcortical and cerebellar volumes. Children with epilepsy were divided into slow and fast psychomotor speed groups (adjusted for age, intelligence and epilepsy syndrome).ResultsAt baseline, slow-speed performers (SSP) presented lower modularity, lower global efficiency, higher transitivity, and lower number of hubs than fast-speed performers (FSP). Community structure in SSP exhibited poor association between cortical regions and both subcortical structures and the cerebellum while FSP presented well-defined communities. Prospectively, SSP displayed lower modularity but higher global efficiency and transitivity compared to FSP. Modules in FSP showed higher integration between and within themselves compared to SSP. SSP showed hubs mainly from frontal and temporal regions while in FSP were spread among frontal, temporal, parietal, subcortical areas and the left cerebellum.ImplicationsResults suggest the presence of widespread alterations in large scale networks between fast- and slow-speed children with recent onset epilepsies both at baseline and 2 years later. Slower processing speed appears to be a marker of abnormal brain development antecedent to epilepsy onset as well as brain development over the 2 years following diagnosis.

Cognitive impairment in epilepsy: the role of reduced network flexibility.

ObjectiveThe dominant model of cognitive impairment in focal epilepsy has emphasised structural bases for cognitive deficits. Current theories of cognition in the healthy brain emphasise the importance of the reweighting of brain network interactions in support of task performance. Here, we explore the hypothesis that cognitive deficits in epilepsy arise through abnormalities of dynamic functional network interactions.MethodWe studied 19 healthy controls and 37 temporal lobe epilepsy (TLE) patients, using a behavioural measure of verbal fluency (the Controlled Oral Word Association Test) and an fMRI verbal fluency paradigm (Orthographic Lexical Retrieval).ResultsBehaviourally, verbal fluency was significantly impaired in TLE. Psychophysiological interaction analyses of the fMRI data, which capture state‐dependent changes in network connectivity, revealed reduced task‐dependent modulations of connectivity from left superior medial frontal cortex to left middle frontal gyrus in TLE patients. Individual differences in verbal fluency among TLE cases was correlated with task‐dependent changes in connectivity from left posterior cingulate to left superior medial frontal cortex, and from left superior medial frontal cortex to a range of right predominant brain areas.InterpretationThese data reveal that the typical pattern of task‐driven shifts in network connectivity is not observed in TLE. Our observations go beyond simple structure‐function associations and suggest that failure of network flexibility can be an important contributor to cognitive impairment in epilepsy.

Cognitive Impairment in Epilepsy: A Clinical Study

Cognitive Impairment in Epilepsy: A Clinical Study