Mechanisms of Cognitive Impairment in Temporal Lobe Epilepsy

Summary

Principal Investigator: Barbara Jobst
Abstract: DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is the most common epilepsy in humans undergoing epilepsy surgery. Many of these patients have associated cognitive impairments, particularly in the domain of memory which is an essential, higher cognitive function required for continuity in time, personal history and awareness. The cognitive impairments are no doubt a result of a combination of the brain abnormalities responsible for the disorder, although the mechanisms of this relation remain a mystery. Our laboratory has recently pursued the underlying mechanisms responsible for dynamic cognitive dysfunction in the lithium-pilocarpine model of TLE finding that interictal spikes (IIS), dysfunctions in network oscillation activity (EEG rhythms) and uncoordinated single-neuron firing impact the performance of the animal in a hippocampal- dependent task. We now propose to investigate whether similar mechanisms are at play in humans. These data will ultimately be important for informing therapeutic strategies designed to minimize the cognitive effects of TLE, as well as a better understanding of the pathophysiology of epilepsy on a dynamic level. Three integrated specific aims are proposed. In the first specific aim we will determine the transient effects of IIS on memory, reaction time and related hippocampal oscillations during a hippocampal-dependent memory task in humans. We hypothesize that IIS contribute to memory impairment in patients with TLE through direct impairment of neural processes underlying memory and by disruption of hippocampal oscillations. In the second aim we will investigate the relationships between single unit neural activity and hippocampal oscillations and performance in patients with TLE. Owing to extensive animal work, we hypothesize that deficits in spatial cognition and memory in patients with TLE are due to impaired single unit firing and temporal coding of action potentials. Based on animal data showing impaired coherence in rats with a prior history of seizures, in the third aim we will determine the impact of TLE and related IIS on neuronal network oscillation and cognition, hypothesizing that deficits in working memory in patients with TLE are due to impaired coherence in hippocampal-prefrontal cortex pathways and additional transient coherence disturbances due to IIS. Taken together these three aims will provide considerable insight into the mechanisms of cognitive impairment in TLE. Armed with this information, therapeutic strategies with a scientific basis will be used to treat this devastating comorbidity.
Funding Period: 2011-08-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome
    Alex C Bender
    Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Hanover, NH 03756, USA
    Epilepsy Behav 23:177-86. 2012
  2. ncbi Brain connectivity in West syndrome
    Scott A Burroughs
    Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
    Seizure 23:576-9. 2014
  3. pmc Transitory effect of spike and spike-and-wave discharges on EEG power in children
    Swayamprabha Nair
    Department of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Hanover, NH, United States
    Brain Dev 36:505-9. 2014
  4. ncbi Speed modulation of hippocampal theta frequency correlates with spatial memory performance
    Gregory R Richard
    Department of Neurology, Geisel School of Medicine, Hanover, New Hampshire
    Hippocampus 23:1269-79. 2013
  5. ncbi EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy
    Gregory L Holmes
    Department of Neurology, Neuroscience Center at Dartmouth, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03756, USA
    Epilepsia 54:60-2. 2013
  6. pmc Focal Scn1a knockdown induces cognitive impairment without seizures
    Alex C Bender
    Department of Neurology, Neuroscience Center at Dartmouth, Geisel School of Medicine at Dartmouth, Hanover, NH03756, USA
    Neurobiol Dis 54:297-307. 2013
  7. pmc Searching for new targets for treatment of pediatric epilepsy
    Yoav Noam
    Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA
    Epilepsy Behav 26:253-60. 2013
  8. pmc Thrombin facilitates seizures through activation of persistent sodium current
    Elena Isaeva
    Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, NH, USA
    Ann Neurol 72:192-8. 2012
  9. pmc Electrolyte therapy reduces spike-and-wave discharges in the WAG/Rij rat model of absence epilepsy
    Arkadij N Talnov
    Department of Physiology of Movements, Bogomoletz Institute of Physiology, Kiev, Ukraine
    Epilepsy Behav 24:399-402. 2012
  10. ncbi Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information
    A S Titiz
    Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
    Hippocampus 24:1129-45. 2014

Detail Information

Publications10

  1. pmc SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome
    Alex C Bender
    Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Hanover, NH 03756, USA
    Epilepsy Behav 23:177-86. 2012
    ..We hypothesize that disruptions in GABAergic firing may directly contribute to the poor cognitive outcomes in children with DS, and discuss the therapeutic implications of this possibility...
  2. ncbi Brain connectivity in West syndrome
    Scott A Burroughs
    Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
    Seizure 23:576-9. 2014
    ..While this severely aberrant pattern would suggest severe abnormalities in connectivity, coherence has not yet been systematically assessed in hypsarrhythmia...
  3. pmc Transitory effect of spike and spike-and-wave discharges on EEG power in children
    Swayamprabha Nair
    Department of Neurology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Hanover, NH, United States
    Brain Dev 36:505-9. 2014
    ..Whether interictal epileptiform discharges have lasting effects on EEG activity in humans is not known...
  4. ncbi Speed modulation of hippocampal theta frequency correlates with spatial memory performance
    Gregory R Richard
    Department of Neurology, Geisel School of Medicine, Hanover, New Hampshire
    Hippocampus 23:1269-79. 2013
    ..Therefore, variations in the coordination of theta frequency with speed may participate in learning and memory processes. Impairments of this function could explain at least partially memory deficits in epilepsy...
  5. ncbi EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy
    Gregory L Holmes
    Department of Neurology, Neuroscience Center at Dartmouth, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03756, USA
    Epilepsia 54:60-2. 2013
    ..Effective treatment of pharmacoresistant epilepsy needs to target not only the overt seizures but interictal electroencephalography (EEG) abnormalities as well...
  6. pmc Focal Scn1a knockdown induces cognitive impairment without seizures
    Alex C Bender
    Department of Neurology, Neuroscience Center at Dartmouth, Geisel School of Medicine at Dartmouth, Hanover, NH03756, USA
    Neurobiol Dis 54:297-307. 2013
    ..We propose that the underlying etiology responsible for Dravet syndrome may directly contribute to cognitive impairment in a manner that is independent from seizures...
  7. pmc Searching for new targets for treatment of pediatric epilepsy
    Yoav Noam
    Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA
    Epilepsy Behav 26:253-60. 2013
    ..In this review, we focus on mechanisms of early-life seizures, such as hypoxia-ischemia, and novel molecular targets, including the hyperpolarization-activated cyclic nucleotide-gated channels...
  8. pmc Thrombin facilitates seizures through activation of persistent sodium current
    Elena Isaeva
    Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, NH, USA
    Ann Neurol 72:192-8. 2012
    ..In the present study, we tested the hypothesis that thrombin increases neuronal excitability in the immature brain through alteration of voltage-gated sodium channels...
  9. pmc Electrolyte therapy reduces spike-and-wave discharges in the WAG/Rij rat model of absence epilepsy
    Arkadij N Talnov
    Department of Physiology of Movements, Bogomoletz Institute of Physiology, Kiev, Ukraine
    Epilepsy Behav 24:399-402. 2012
    ..We suggest that the antiepileptic effect of rice-based oral electrolyte hydration therapy can be at least in part due to hyperosmolarity of the ingested solution...
  10. ncbi Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information
    A S Titiz
    Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
    Hippocampus 24:1129-45. 2014
    ..We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats...

Research Grants30

  1. In vivo measurement of dopamine transmission in schizophrenia
    Rajesh Narendran; Fiscal Year: 2013
    ..In this proposal we seek to better understand the neurobiology underlying the cognitive abnormalities in schizophrenia;with the hope that, in turn, this will advance the development of novel treatments for these cognitive impairments. ..
  2. The Effect of Bipolar Disorder and its Comorbidities on Cognition in Older Adults
    ARIEL GERARD GILDENGERS; Fiscal Year: 2013
    ..The knowledge gained from this research may benefit not only patients with Bipolar Disorder, but the broader population of older adults at high risk for disorders associated with neurodegeneration and premature cognitive decline. ..
  3. MRI Structural and Functional Connectivity Changes in Temporal Lobe Epilepsy
    Victoria L Morgan; Fiscal Year: 2013
    ..Furthermore, the proposed approach may be expanded and applied to other forms of focal epilepsy in both adults and children to increase the utilization of surgical treatment for these patients. ..
  4. Physiological mechanisms responsible for cognitive impairments in Dravet Syndrome
    Pierre Pascal Lenck-Santini; Fiscal Year: 2013
    ..It would suggest that additional treatment strategies focusing on cognitive function, other than traditional antiepileptic drugs may be necessary to recover normal cognitive function in affected children. ..
  5. Mechanisms of Cognitive Impairment Following Early-Life Seizures
    Gregory L Holmes; Fiscal Year: 2013
    ..In this proposal we will determine if abnormalities of hippocampal oscillations following early-life seizures are responsible for the intellectual deficits seen in children with epilepsy. ..
  6. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  7. Early Experience, Stress and Neurobehavioral Development Center
    Megan R Gunnar; Fiscal Year: 2013
    ..Our Center also includes a cross-training program in basic developmental science and developmental psychopathology &prevention science. ..