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.

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.

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.

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.

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.

Regulation of axonal HCN1 trafficking in perforant path involves expression of specific TRIP8b isoforms.

The functions of HCN channels in neurons depend critically on their subcellular localization, requiring fine-tuned machinery that regulates subcellular channel trafficking. Here we provide evidence that regulatory mechanisms governing axonal HCN channel trafficking involve association of the channels with specific isoforms of the auxiliary subunit TRIP8b. In the medial perforant path, which normally contains HCN1 channels in axon terminals in immature but not in adult rodents, we found axonal HCN1 significantly increased in adult mice lacking TRIP8b (TRIP8b(-/-)). Interestingly, adult mice harboring a mutation that results in expression of only the two most abundant TRIP8b isoforms (TRIP8b[1b/2](-/-)) exhibited an HCN1 expression pattern similar to wildtype mice, suggesting that presence of one or both of these isoforms (TRIP8b(1a), TRIP8b(1a-4)) prevents HCN1 from being transported to medial perforant path axons in adult mice. Concordantly, expression analyses demonstrated a strong increase of expression of both TRIP8b isoforms in rat entorhinal cortex with age. However, when overexpressed in cultured entorhinal neurons of rats, TRIP8b(1a), but not TRIP8b(1a-4), altered substantially the subcellular distribution of HCN1 by promoting somatodendritic and reducing axonal expression of the channels. Taken together, we conclude that TRIP8b isoforms are important regulators of HCN1 trafficking in entorhinal neurons and that the alternatively-spliced isoform TRIP8b(1a) could be responsible for the age-dependent redistribution of HCN channels out of perforant path axon terminals.

Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment.

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.

Brain activity associated with chronic cancer pain.

BACKGROUND: The number of neuroimaging studies that examine chronic pain are relatively small, and it is clear that different chronic pain conditions activate diverse regions of the brain. OBJECTIVE: Cancer patients presenting for diagnostic positron emission tomography (PET) imaging were asked to rate their spontaneous baseline pain score. Twenty patients with either no pain (NRS = 0) or with moderate to severe pain (NRS = 4) were invited to participate in this study to determine the difference in brain activity in cancer patients with moderate to severe chronic pain versus no pain. STUDY DESIGN: Prospective, non-randomized, observational report. SETTING: Academic medical center. METHODS: Patients had a 2-D PET scan with the radionuclide 18F-fluoro-2-deoxyglucose (FDG) at a dose of approximately 20 mCi. Each individual raw PET scan was coregistered and normalized to standard stereotactic space. Differences in regional glucose metabolism were then statistically compared between patients with moderate-to-severe pain and patients with no pain. RESULTS: The NRS pain score in the patients with moderate to severe pain (n = 11) was 4.5 [4.0-6.0] (median [interquartile range]) versus 0.0 [0.0-0.0] (p < 0.001) in the group with no pain (n = 9). Compared to patients with no pain, patients with moderate to severe pain had increased glucose metabolism bilaterally in the prefrontal cortex, BA 9-11. Unilateral activation was found in the right parietal precuneus cortex, BA 7. There were no areas of the brain in which there was decreased activity due to moderate to severe pain. CONCLUSIONS: Our results showing a preferential activation of the prefrontal cortex are consistent with results from studies showing that affective pain perception and negative emotions play an important part in the chronic pain experience. LIMITATIONS: This was not a randomized clinical trial. Patient medication was not controlled.

Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease.

The concept of amnestic mild cognitive impairment (MCI) describes older people who show a decline predominantly in memory function, but who do not meet criteria for dementia. Because such individuals are at high risk for developing Alzheimer's disease, they are of great interest for understanding the prodromal stages of the disease process. The mechanism underlying memory dysfunction in people with MCI is not fully understood. The present study uses quantitative, high-resolution structural MRI techniques to investigate, in vivo, the anatomical substrate of memory dysfunction associated with MCI. Changes in brain structures were assessed with two imaging techniques: (i) whole-brain, voxel-based morphometry to determine regions of reduced white matter volume and (ii) sensitive volumetric segmentation of the entorhinal cortex and hippocampus, gray matter regions that are critically important for memory function. In participants with amnestic MCI, compared with age-matched controls, results showed a significant decrease in white matter volume in the region of the parahippocampal gyrus that includes the perforant path. There was also significant atrophy in both the entorhinal cortex and the hippocampus. Regression models demonstrated that both hippocampal volume and parahippocampal white matter volume were significant predictors of declarative memory performance. These results suggest that, in addition to hippocampal atrophy, disruption of parahippocampal white matter fibers contributes to memory decline in elderly individuals with MCI by partially disconnecting the hippocampus from incoming sensory information.