Disconnection of hippocampal networks contributes to memory dysfunction in individuals with temporal lobe epilepsy.

A deficit in declarative memory function is common among individuals with temporal lobe epilepsy. The purpose of this study is to evaluate the relationship between the volume of the hippocampus, entorhinal cortex along with the surrounding parahippocampal white matter and memory performance in those with temporal lobe epilepsy. T1 weighted MRI scans were acquired using a 3-D pulse sequence in 50 individuals with temporal lobe epilepsy. Hippocampal and entorhinal cortex volumes were derived by manually tracing consecutive coronal slices aligned perpendicular to the long axis of the hippocampus. In addition, parahippocampal white matter volumes were determined using voxel based morphometry. Finally, declarative memory was assessed using immediate and delayed verbal and visual memory tests from the Wechsler Memory Scale third edition. Significant correlations were seen between right and left hippocampal volumes and delayed verbal memory test scores. In addition, left parahippocampal white matter showed positive correlations with immediate and delayed verbal and visual recall. Furthermore, regression models found that the right hippocampus and left parahippocampal white matter were the best predictors of immediate and delayed verbal and visual memory performance. These results show that a decrease in white matter fibers projecting to the hippocampus may cause a disruption of incoming multi-modal sensory information, contributing to the memory decline seen in individuals with temporal lobe epilepsy.

Age is but a number when considering epilepsy surgery in older adults.

BACKGROUND: A quarter of patients with newly diagnosed epilepsy are older, yet they are less likely to be offered resective surgery potentially because of clinical bias that they incur increased surgical risks. There are few peer-reviewed case series that address this cohort and their outcomes. OBJECTIVE: In the context of current literature, the objective of this study was to report on all epilepsy surgeries in patients aged 50 years or older from a tertiary care center over 15 years with an average follow-up period of 6 years. METHODS: Patients with epilepsy who underwent surgery between 2001 and 2016 were reviewed retrospectively. Inclusion criteria were age > 50 at surgery, availability of presurgical evaluation data, and minimum one year of follow-up data. We identified 34 patients. Seizure outcome was evaluated using the Engel classification system. RESULTS: Thirty-four patients aged 50 years and older out of 276 underwent epilepsy surgery. Average age at time of surgery was 55 years, and average duration of epilepsy was 30 years. Average length of follow-up was 6 years (1-15 years). Twenty-two out of 34 patients (64%) were seizure-free (Engel class I) at their last follow-up visit. Patients with lesional pathology on neuroimaging were more likely to achieve seizure freedom (p < 0.02). Parameters associated with poorer outcome included extratemporal epileptogenic focus (p = 0.07) and bitemporal interictal epileptiform activity (p = 0.003). CONCLUSION: Our study cohort is one of the largest and most representative outcome studies of this age group, following the cohort for 6 years. Our findings demonstrated that when considering epilepsy surgery in an older adult, their age should not play a determining role in the decision-a finding that is more common in modern literature.

Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer's disease.

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.

BACKGROUND: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. METHODS: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. RESULTS: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). CONCLUSIONS: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Setting up EEG Source Imaging in Practice.

SUMMARY: Adding EEG source imaging to a clinical practice has clear advantages over visual inspection of EEG. This article offers insight on incorporating EEG source imaging into an EEG laboratory and the best practices for producing optimal source analysis results.

Structural Connectivity of the Human Piriform Cortex: an Exploratory Study.

BACKGROUND AND OBJECTIVES: The piriform cortex (PC) is part of the primary olfactory network in humans. Recent findings suggest that it plays a role in pathophysiology of epilepsy. Therefore, studying its connectivity can further our understanding of seizure propagation in epilepsy. We aimed to explore the structural connectivity of PC using high-quality human connectome project data coupled with segmentation of PC on anatomic MRI. METHODS: Twenty subjects were randomly selected from the human connectome project database, and PC was traced on each hemisphere. Probabilistic whole-brain tractography was then used to visualize PC connectivity. RESULTS: The strongest connectivity was noted between PC and ipsilateral insula in both hemispheres. Specifically, the posterior long gyrus of each insula was predominantly connected to PC. This was followed by connections between PC and basal ganglia as well as orbital frontal cortices. CONCLUSION: The PC has the strongest connectivity with the insula bilaterally. Specifically, the posterior long gyri of insula have the strongest connectivity. This finding may provide additional insight for localizing and treating temporo-insular epilepsy.

Understanding Anxiety in Cervical Dystonia: An Imaging Study.

BACKGROUND: Anxiety may precede motor symptoms in cervical dystonia (CD) and is associated with an earlier onset of dystonia. Our understanding of anxiety in CD is inadequate. OBJECTIVE: To investigate brain networks associated with anxiety in CD. METHODS: Twenty-six subjects with idiopathic CD underwent MRI Brain without contrast. Correlational tractography was derived using Diffusion MRI connectometry. Quantitative Anisotropy (QA) was used in deterministic diffusion fiber tracking. Correlational tractography was then used to correlate QA with State-Trait Anxiety Inventory (STAI) state (STAI-S) and trait (STAI-T) subscales. RESULTS: Connectometry analysis showed direct correlation between state anxiety and QA in tracts from amygdala to thalamus/ pulvinar bilaterally, and trait anxiety and QA in tracts from amygdala to motor cortex, sensorimotor cortex and parietal association area bilaterally (FDR ≤0.05). CONCLUSION: Our efforts to map anxiety to brain networks in CD highlight the role of the amygdala in the pathophysiology of anxiety in CD.

Convolutional Neural Network Algorithm to Determine Lateralization of Seizure Onset in Patients With Epilepsy: A Proof-of-Principle Study.

BACKGROUND AND OBJECTIVES: A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input. METHODS: Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients. RESULTS: Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification. DISCUSSION: These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality.

Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice.

Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization-activated current, I(h), is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reduced I(h) expression in hippocampal pyramidal neurons. Loss of I(h)-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels and I(h) in vivo, and suggest that targeting I(h) may provide a novel approach to treatment of depression.

Entorhinal cortex atrophy differentiates Parkinson's disease patients with and without dementia.

Volumetric measures of mesial temporal lobe structures on MRI scans recently have been explored as potential biomarkers of dementia in patients with PD, with investigations primarily focused on hippocampal volume. Both in vivo MRI and postmortem tissue studies in Alzheimer's disease, however, demonstrate that the entorhinal cortex (ERC) is involved earlier in disease-related pathology than the hippocampus. The ERC, a region integral in declarative memory function, projects multimodal sensory information to the hippocampus through the perforant path. In PD, ERC atrophy, as measured on MRI, however, has received less attention, compared to hippocampal atrophy. We compared ERC and hippocampal atrophy in 12 subjects with PD dementia including memory impairment, 14 PD subjects with normal cognition, and 14 healthy controls with normal cognition using manual segmentation methods on MRI scans. Though hippocampal volumes were similar in the two PD cognitive groups, ERC volumes were substantially smaller in the demented PD subjects, compared to cognitively normal PD subjects (P < 0.05). In addition, normalized ERC and hippocampal volumes for right and left hemispheres were significantly lower in the demented PD group, compared to healthy controls. Our findings suggest that ERC atrophy differentiates demented and cognitively normal PD subjects, in contrast to hippocampal atrophy. Thus, ERC atrophy on MRI may be a potential biomarker for dementia in PD, particularly in the setting of memory impairment.

Hippocampal atrophy and disconnection in incipient and mild Alzheimer's disease.

Quantitative imaging techniques allow the in vivo investigation of age and disease related changes in the brain and their relation to cognitive function. In this chapter we review imaging evidence indicating that the entorhinal cortex and hippocampus show atrophy very early in Alzheimer's disease (AD) and in individuals who are at risk of developing AD compared to age appropriate controls. Furthermore, the extent and rate of atrophy of the entorhinal cortex, a brain region pathologically involved very early in the disease process, can predict who among the elderly will develop AD. Techniques that assess the integrity of white matter further demonstrate that alterations in the parahippocampal white matter in the region that includes the perforant path could partially disconnect the dentate gyrus and other hippocampal subfields from incoming sensory information. Such partial disconnection and degradation in transmission of sensory information in people at risk of AD and in patients with very mild AD could contribute to the memory dysfunction associated with the early stages of the disease.

The use of brain positron emission tomography to identify sites of postoperative pain processing with and without epidural analgesia.

It is not known how different analgesic regimes affect the brain when reducing postoperative pain. We performed positron emission tomography (PET) scans on a 69-yr-old woman in the presence of moderate postoperative pain and then with epidural analgesia producing complete analgesia, during the first 2 days after total knee arthroplasty. Day 2 postsurgery PET scan data (no pain with epidural analgesia) were subtracted from Day 1 postsurgery PET scan data (time of moderate pain without epidural analgesia) to determine the brain regions activated. Postsurgical pain was associated with increased activity in the contralateral primary somatosensory cortex. Other brain regions showing increased postsurgical activity were the contralateral parietal cortex, bilateral pulvinar and ipsilateral medial dorsal nucleus of the thalamus, contralateral putamen, contralateral superior temporal gyrus, ipsilateral fusiform gyrus, ipsilateral posterior lobe, and contralateral anterior cerebellar lobe. This study demonstrates the feasibility of evaluating the central processing of acute postoperative pain using PET.

Magnetoencephalography and New Imaging Modalities in Epilepsy.

The success of epilepsy surgery is highly dependent on correctly identifying the entire epileptogenic region. Current state-of-the-art for localizing the extent of surgically amenable areas involves combining high resolution three-dimensional magnetic resonance imaging (MRI) with electroencephalography (EEG) and magnetoencephalography (MEG) source modeling of interictal epileptiform activity. Coupling these techniques with newer quantitative structural MRI techniques, such as cortical thickness measurements, however, may improve the extent to which the abnormal epileptogenic region can be visualized. In this review we assess the utility of EEG, MEG and quantitative structural MRI methods for the evaluation of patients with epilepsy and introduce a novel method for the co-localization of a structural MRI measurement to MEG and EEG source modeling. When combined, these techniques may better identify the extent of abnormal structural and functional areas in patients with medically intractable epilepsy.

Cortical stimulation parameters for functional mapping.

PURPOSE: There is significant variation in how patients respond to cortical electrical stimulation. It has been hypothesized that individual demographic and pathologic factors, such as age, sex, disease duration, and MRI findings, may explain this discrepancy. The purpose of our study is to identify specific patient characteristics and their effect on cortical stimulation, and discover the extent of variation in behavioral responses that exists among patients with epilepsy. METHOD: We retrospectively analyzed data from 92 patients with medically intractable epilepsy who had extra-operative cortical electrical stimulation. Mapping records were evaluated and information gathered about demographic data, as well as the thresholds of stimulation for motor, sensory, speech, and other responses; typical seizure behavior; and the induction of afterdischarges. RESULTS: Ninety-two patient cortical stimulation mapping reports were analyzed. The average of the minimum thresholds for motor response was 4.15mA±2.67. The average of the minimum thresholds for sensory response was 3.50mA±2.15. The average of the minimum thresholds for speech response was 4.48mA±2.42. The average of the minimum thresholds for afterdischarge was 4.33mA±2.37. Most striking were the degree of variability and wide range of thresholds seen between patients and within the different regions of the same patient. CONCLUSION: Wide ranges of thresholds exist for the different responses between patients and within different regions of the same patient. With multivariate analysis in these series, no clinical or demographic factors predicted physiological response or afterdischarge threshold levels.

Resecting critical nodes from an epileptogenic circuit in refractory focal-onset epilepsy patients using subtraction ictal SPECT coregistered to MRI.

OBJECTIVE The purpose of this study was to assess the positive predictive value of postresection outcomes obtained by presurgical subtracted ictal SPECT in patients with lesional (MRI positive) and nonlesional (MRI negative) refractory extratemporal lobe epilepsy (ETLE) and temporal lobe epilepsy (TLE). Specifically, outcomes were compared between partial versus complete resection of the regions of transient hyperperfusion identified using subtraction ictal SPECT coregistered to MRI (SISCOM) in relation to the ictal onset zone (IOZ) that was confirmed by electrocorticography (ECoG). That is, SISCOM was used to understand the long-term postsurgical outcomes following resection of the IOZ that overlapped with 1 or more regions of ictal onset-associated transient hyperperfusion. METHODS The study cohort included 44 consecutive patients with refractory ETLE or TLE who were treated between 2002 and 2013 and underwent presurgical evaluation using SISCOM. Concordance was determined between SISCOM localization and the IOZ on the basis of ECoG monitoring. In addition, the association between the extent of the resection site overlapping with the SISCOM signal and postresection outcomes were assessed. Postsurgical follow-up was longer than 24 months in 39 of 44 patients. RESULTS The dominant SISCOM signals were concordant with ECoG and overlapped the resection site in 32 of 44 (73%) patients (19 ETLE and 13 TLE patients), and 20 of 32 (63%) patients became seizure free. In all 19 ETLE patients with concordant SISCOM and ECoG results, the indicated location of ictal onset on ECoG was completely resected; 11 of 19 patients (58%) became seizure free (Engel Class I). In all 13 TLE patients with concordant SISCOM and ECoG results, the indicated ECoG focus was completely resected; 9 of 13 patients (69%) became seizure free (Engel Class I). Complete resection of the SISCOM signal was found in 7 of 34 patients (21%). Of these 7 patients, 5 patients (72%) were seizure free (Engel Class I). Partial resection of the SISCOM signal was found in 16 of 34 patients (47%), and 10 of these 16 patients (63%) were seizure free (Engel Class I) after more than 24 months of follow-up. CONCLUSIONS Concordance between 1 or more SISCOM regions of hyperperfusion with ECoG and at least partial resection of the dominant SISCOM signal in this refractory epilepsy cohort provided additional useful information for predicting long-term postresection outcomes. Such regions are likely critical nodes in more extensive, active, epileptogenic circuits. In addition, SPECT scanner technology may limit the sensitivity of meaningful SISCOM signals for identifying the maximal extent of the localizable epileptogenic network.

Relating medial temporal lobe volume to frontal fMRI activation for memory encoding in older adults.

Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.

Differential associations between entorhinal and hippocampal volumes and memory performance in older adults.

Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r= .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r= .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.

Parahippocampal white matter volume predicts Alzheimer's disease risk in cognitively normal old adults.

An in vivo marker of the underlying pathology in Alzheimer's disease (AD) is atrophy in select brain regions detected with quantitative magnetic resonance imaging (MRI). Although gray matter changes have been documented to be predictive of cognitive decline culminating in AD among healthy older adults, very little attention has been given to alterations in white matter as a possible MRI biomarker predictive of AD. In this investigation, we examined parahippocampal white matter (PWM) volume derived from baseline MRI scans in 2 independent samples of 65 cognitively normal older adults, followed longitudinally, to determine if it was predictive of AD risk. The average follow-up period for the 2 samples was 8.5 years. Comparisons between the stable participants (N = 50) and those who declined to AD (N = 15) over time revealed a significant difference in baseline PWM volume (p < 0.001). Furthermore, baseline PWM volume was predictive not only of time to AD (hazard ratio = 3.1, p < 0.05), but also of baseline episodic memory performance (p = 0.041). These results demonstrate that PWM atrophy provides a sensitive MRI biomarker of AD dementia risk among those with normal cognitive function.

Age-related changes in the mesial temporal lobe: the parahippocampal white matter region.

The perforant pathway originates from cells in the entorhinal cortex and relays sensory information from the neocortex to the hippocampus, a region critical for memory function. Imaging studies have demonstrated structural alterations in the parahippocampal white matter in the region of the perforant pathway in people at risk for developing Alzheimer's disease. It is not clear, however, if changes noted in this region are indicative of pathological aging or are a function of the normal aging process. We compared magnetic resonance imaging (MRI)-derived mesial temporal lobe volumes in 51 healthy older individuals and 40 young participants, with an emphasis on the parahippocampal white matter. Yearly clinical evaluations showed that 9 of the older cohort declined in cognitive function. Parahippocampal white matter, hippocampal, and entorhinal cortex volumes were significantly reduced in healthy older people who remained stable over time compared with young participants. These findings suggest that volume differences in mesial temporal lobe gray and white matter structures may take place as a result of the normative aging process.