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Sirtuin 1 (SIRT1), the NAD-dependent histone deacetylase, has been extensively investigated due to its cognitive protective effect. Studies suggest microRNAs (miRNAs) and histone modifications are key epigenetic regulators of gene expression and play important role in brain development. We previously showed that cognitive impairment by lead (Pb) was associated with downregulation of SIRT1, but the epigenetic role of this is unclear. Thus, we exposed 4-week-old male mice to 0.2% lead acetate solution for three months, and subsequently extracted brain homogenate from mice cortex and hippocampus at the age of 1, 4, and 16 months, respectively. In this study, we found that the protein level of SIRT1 was inhibited in the hippocampus and cortex of 16-month-old aged mice exposed to Pb. Moreover, changes in the levels of miR-138-5p and miR-141-3p, which were considered to the mechanistic target of SIRT1 by bioinformatic analysis, were negative correlations SIRT1 protein expression. We also found miR-34c-3p expression was increased in the cortex of mice at the age of 16 months. Collectively, our results showed the expression of neural SIRT1 and three selected microRNAs at different age nodes of mice for the first time of following Pb exposure. Our results suggest that additional efforts should focus on the consequences of early Pb exposure from an epigenetic perspective.

The influence of excess iodine on human health has been paid more and more attention. Although numerous studies have reported that excess iodine may cause deleterious effects, the mental damage and its mechanism is yet to be identified. Using Sprague-Dawley rats exposed to excess iodine from pregnancy to 6 months post-delivery as in vivo model, this study explored the impacts of long-term repetitive excess iodine administration on the hippocampus of offspring rats, focusing on mitochondrial apoptosis pathway, with changes in monoamine neurotransmitters. The results showed that excess iodine could increase urinary iodine and brain organ coefficient in offspring of both genders, change the hippocampal cell structure, and damage the spatial learning and memory capacities. Poly ADP-ribose polymerase (PARP), P53, Cleaved Caspase-3, and cytochrome C proteins expression increased and Bcl2 protein expression decreased in hippocampus of excess iodine-treated offspring, indicating that excess iodine could activate the mitochondrial apoptosis pathway. Besides, excess iodine showed different effects on monoamine neurotransmitter in different gender. Collectively, our experimental data indicated that the learning and memory impairment induced by excess iodine may be mediated via mitochondrial apoptotic pathway. Long-term repetitive excess iodine exposure affected monoamine neurotransmitters in hippocampus of offspring rats.

Significance: Transcranial photobiomodulation (PBM) is a noninvasive neuromodulation technique capable of producing changes in the mitochondrial cytochrome c-oxidase (CCO) activity of neurons. Although the application of PBM in clinical practice and as a neurophysiological tool is increasing, less is known about how different treatment time intervals may result in different outcomes. Aim: We evaluated the effects of different PBM treatment intervals on brain metabolic activity through the CCO and proto-oncogene expression (c-Fos). Approach: We studied PBM effects on brain CCO and c-Fos expression in three groups of animals: Control (CN, n = 8), long interval PBM treatment (LI, n = 5), and short interval PBM treatment (SI, n = 5). Results: Increased CCO activity in the LI group, compared to the SI and CN groups, was found in the prefrontal cortices, dorsal and ventral striatum, and hippocampus. Regarding c-Fos expression, we found a significant increase in the SI group compared to LI and CN, whereas LI showed increased c-Fos expression compared to CN in the cingulate and infralimbic cortices. Conclusions: We show the effectiveness of different PBM interval schedules in increasing brain metabolic activity or proto-oncogene expression.

Purpose: Hippocampus contouring for radiotherapy planning is performed on MR image data due to poor anatomical visibility on computed tomography (CT) data. Deep learning methods for direct CT hippocampus auto-segmentation exist, but use MR-based training contours. We investigate if these can be replaced by CT-based contours without loss in segmentation performance. This would remove the MR not only from inference but also from training. Approach: The hippocampus was contoured by medical experts on MR and CT data of 45 patients. Convolutional neural networks (CNNs) for hippocampus segmentation on CT were trained on CT-based or propagated MR-based contours. In both cases, their predictions were evaluated against the MR-based contours considered as the ground truth. Performance was measured using several metrics, including Dice score, surface distances, and contour Dice score. Bayesian dropout was used to estimate model uncertainty. Results: CNNs trained on propagated MR contours (median Dice 0.67) significantly outperform those trained on CT contours (0.59) and also experts contouring manually on CT (0.59). Differences between the latter two are not significant. Training on MR contours results in lower model uncertainty than training on CT contours. All contouring methods (manual or CNN) on CT perform significantly worse than a CNN segmenting the hippocampus directly on MR (median Dice 0.76). Additional data augmentation by rigid transformations improves the quantitative results but the difference remains significant. Conclusions: CT-based training contours for CT hippocampus segmentation cannot replace propagated MR-based contours without significant loss in performance. However, if MR-based contours are used, the resulting segmentations outperform experts in contouring the hippocampus on CT.

Age-related hippocampal formation (HF) atrophy has been documented on MRI studies using volumetric analysis and visual rating scales. This retrospective cross-sectional study aimed to compare linear MRI measurements of the HF between young (1–3 years) and old (>10 years) non-brachycephalic dogs, with normal brain anatomy and cerebrospinal fluid (CSF) analysis. Right and left hippocampal formation height (HFH), height of the brain (HB) and mean HFH/HB ratio were measured by two observers on a transverse T2 fluid-attenuated inversion recovery sequence containing rostral colliculi and mesencephalic aqueduct.119 MRI studies were enrolled: 75 young and 44 old dogs. Left and right HFH were greater (p

Alterations in the relative abundance of synaptic proteins may contribute to hippocampal synaptic dysfunction in Alzheimer’s disease (AD). The extent to which perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remains unclear. We examined protein levels of presynaptic synaptophysin (SYP) and synaptotagmin (SYT), and postsynaptic drebrin (DRB), a marker for dendritic spine plasticity, in the hippocampus of people with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) or mild/moderate AD. Although normalized SYP and SYT levels were preserved, DRB was reduced by approximately 40% in the hippocampus of MCI and AD compared to NCI subjects. This differential alteration of synaptic markers in MCI suggests a selective impairment in hippocampal postsynaptic dendritic plasticity in prodromal AD that likely heralds the onset of memory impairment in symptomatic disease.

Background: Structural neuroimaging studies have consistently shown a pattern of extra-hippocampal atrophy in patients with left and right drug-refractory medial temporal lobe epilepsy (MTLE). However, it is not yet completely understood how extra-hippocampal atrophy is related to hippocampal atrophy. Moreover, patients with left MTLE often exhibit more intense cognitive impairment, and subtle brain asymmetries have been reported in patients with left MTLE versus right MTLE but have not been explored in a controlled study. Objectives: To investigate the association between extra-hippocampal and hippocampal atrophy in patients with MTLE, and the effect of side of hippocampal atrophy on extra-hippocampal atrophy. Methods: Voxel-based morphometry analyses of magnetic resonance images of the brain were performed to determine the correlation between regional extra-hippocampal grey matter volume and hippocampal grey matter volume. The results from 36 patients with right and left MTLE were compared, and results from the two groups were compared with those from 49 healthy controls. Results: Compared with controls, patients with MTLE showed a more intense correlation between hippocampal grey matter volume and regional grey matter volume in locations such as the contralateral hippocampus, bilateral parahippocampal gyri and frontal and parietal areas. Compared with right MTLE, patients with left MTLE exhibited a wider area of atrophy related to hippocampal grey matter loss, encompassing both the contralateral and ipsilateral hemispheres, particularly affecting the contralateral hippocampus. Conclusions: Our results suggest that left hippocampal atrophy is associated with a larger degree of extra-hippocampal atrophy. This may help to explain the more intense cognitive impairment usually observed in these patients.

Background: About 40% of patients with limbic encephalitis do not have detectable CNS antibodies. Some of these patients have immune-mediated limbic encephalitis, but their frequency is unknown. Aims: (1) To determine the spectrum of limbic encephalitis identified on clinical grounds in a single institution, and compare it with that in patients referred for antibody analysis. (2) To correlate clinical outcomes with the cellular location of the autoantigens. Methods: Prospective clinical case studies. Immunohistochemistry with rat brain, live hippocampal neurones, HeLa cells expressing Kv potassium channels and immunoblot. Results: In 4 years, 17 patients were identified in the Hospital of the University of Pennsylvania, Philadelphia, USA, and the serum or CSF samples of 22 patients diagnosed elsewhere were also studied. 9 of our 17 (53%) patients had antibodies to known neuronal antigens (paraneoplastic or voltage gated potassium channels (VGKCs)) and 5 (29%) to novel cell-membrane antigens (nCMAg) typically expressed in the hippocampus and sometimes in the cerebellum. Considering the entire series, 19 of 39 (49%) patients had antibodies to known antigens, and 17 (44%) to nCMAg. Follow-up (2–48 months, median 19 months) was available for 35 patients. When compared with patients with antibodies to intraneuronal antigens, a significant association with response to treatment was found in those with antibodies to cell-membrane antigens in general (VGKC or nCMAg, p = 0.003) or to nCMAg (p = 0.006). Conclusions: (1) 82% of patients with limbic encephalitis prospectively identified on clinical grounds had CNS antibodies; (2) responsiveness to treatment is not limited to patients with VGKC antibodies; (3) in many patients (29% from a single institution), the autoantigens were unknown but were found to be highly enriched in neuronal cell membranes of the hippocampus; and (4) these antibodies are associated with a favourable outcome.

Background: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer’s disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). Objective: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer’s disease, using volumetry and a visual rating scale. Methods: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer’s disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. Results: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer’s disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer’s disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. Conclusions: Hippocampal atrophy is not only a characteristic of Alzheimer’s disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.

Objective: To evaluate interictal language functions in patients with medically intractable left and right sided mesial temporal lobe epilepsy (TLE). Methods: Spontaneous speech, language comprehension, confrontation naming, repetition, reading, writing, and word fluency were examined in 12 patients with left sided TLE and 11 patients with right sided TLE. Results: Four patients out of 23 displayed language deficits in more than one language domain. Three further patients exhibited isolated language deficits. Linguistic deficits were observed in both left TLE and right TLE. In quantitative analyses left and right TLE only differed in spontaneous speech (p = 0.02); no difference was found in other language functions, laterality quotient of Wada test, or overall IQ. Qualitative error analysis of object naming, however, showed typical errors associated only with left TLE. Patients with linguistic deficits were older at testing compared to patients without linguistic deficits (p = 0.003), whereas other factors including side of TLE, handedness, educational level, age at epilepsy onset, and duration of epilepsy did not differ between groups. Conclusions: Possible explanations for these findings include neuronal cell loss and deafferentiation in cortical areas, and disruption of the basal temporal language area pathways. Our study suggests that some patients with chronic mesial TLE exhibit linguistic deficits when specifically tested, and underlines the need to routinely investigate linguistic functions in TLE.

Objective: The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE). Methods: We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p

Background: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. Objective: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number. Methods: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. Results: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. Conclusions: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.

Background: Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at-risk condition for Alzheimer’s disease (AD). Patients and methods: We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI. Results: The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding. Conclusion: These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.

Background: Olfactory dysfunction is common in old age, but its basis is uncertain. Objective: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer’s disease pathology. Methods: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standred deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2–4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid β burden, tangle density and Lewy bodies on the basis of immunohistochemistry. Results: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of τ tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. Conclusion: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.

Background: A comprehensive characterisation of grey and white matter changes in progressive supranuclear palsy (PSP), the second most common extrapyramidal syndrome after Parkinson disease, is still not available. Objective: To evaluate grey and white matter changes in mild PSP patients by voxel based morphometry (VBM) and diffusion tensor imaging (DTI), respectively. Methods: 14 mild PSP patients and 14 healthy controls entered the study and underwent a clinical and neuropsychological evaluation according with a standardised assessment. Each subject had a structural magnetic resonance imaging (MRI) study. Processing analysis of MRI data was carried out according to optimised VBM and fractional anisotropy was determined. Results: Compared with the controls, in PSP patients VBM analysis showed a significant clusters of reduced grey matter in premotor cortex, frontal operculum, anterior insula, hippocampus, and parahippocampal gyrus, bilaterally. With regard to subcortical brain regions, the pulvinar, dorsomedial and anterior nuclei of the thalamus, and superior and inferior culliculum were affected bilaterally. A bilateral decrease in fractional anisotropy in superior longitudinal fasciculus, anterior part of corpus callosum, arcuate fascicolus, posterior thalamic radiations, and internal capsule, probably involving the cortico-bulbar tracts, was present in PSP patients. Conclusions: These data provide evidence for both grey and white matter degeneration in PSP from the early disease stage. These structural changes suggest that atrophy of cortical and subcortical structures and neurodegeneration of specific fibre tracts contribute to neurological deficits in PSP.

Background: Anosognosia is a common manifestation of Alzheimer's disease. There is an association between impaired awareness and frontal-executive cognitive deficits. Anosognosia is also correlated with decreased metabolism in the right hemisphere, particularly in frontal lobe regions. Objective: To investigate pathological correlates of anosognosia in Alzheimer's disease. Design: 41 subjects followed longitudinally in the University of Pittsburgh memory disorders clinic and with necropsy verified Alzheimer's disease were divided into two groups, based on previous clinical assessment: +Aware (n = 23) and –Aware (n = 18). A subset analysis matching subjects for dementia severity using mini-mental state examination scores was also carried out (13 +Aware; 13 –Aware). Histopathological data from necropsy brain tissue consisted of senile plaque (SP) and neurofibrillary tangle (NFT) counts (regional density) from four different brain regions in the right and left hemispheres: superior and middle frontal gyri (SMF), superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), and the entorhinal cortex (EC). Results: SP density was greater in the right PRO region of –Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Significant differences between SP or NFT density were not observed in any other regions. In the subset analysis matching for dementia severity, SP density was again greater in the right PRO region of –Aware subjects than in the other regions (F = 12.72, p = 0.002). Conclusions: Increased SP density in the right PRO region suggests that selective pathological involvement of this area contributes to awareness deficits in Alzheimer's disease. The putative role of the PRO in self appraisal may reflect its interconnections with other medial temporal and prefrontal regions.

Objective: The gross morphology and morphometry of the hippocampus, fornix, and corpus callosum in patients with severe non-missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions was examined and the volumes of these structures were correlated with performance on memory tests. In addition, the predictability of the length of coma from the selected anatomical volumes was examined. Method: High spatial resolution T1 weighted MRI scans of the brain (1 mm 3 ) and neuropsychological evaluations with standardised tests were performed at least 3 months after trauma in 19 patients. Results: In comparison with control subjects matched in terms of gender and age, volume reduction in the hippocampus, fornix, and corpus callosum of the nmTBI patients was quantitatively significant. The length of coma correlated with the volume reduction in the corpus callosum. Immediate free recall of word lists correlated with the volume of the fornix and the corpus callosum. Delayed recall of word lists and immediate recall of the Rey figure both correlated with the volume of the fornix. Delayed recall of the Rey figure correlated with the volume of the fornix and the right hippocampus. Conclusion: These findings demonstrate that in severe nmTBI without obvious neuroradiological lesions there is a clear hippocampal, fornix, and callosal volume reduction. The length of coma predicts the callosal volume reduction, which could be considered a marker of the severity of axonal loss. A few memory test scores correlated with the volumes of the selected anatomical structures. This relationship with memory performance may reflect the diffuse nature of the damage, leading to the disruption of neural circuits at multiple levels and the progressive neural degeneration occurring in TBI.

Objectives: To clarify risk factors for the development of schizophrenia-like psychotic disorders following temporal lobectomy, and to explore the possibility that the early postoperative period is a time of high risk for the onset of such chronic psychotic disorders. Methods: Patients who developed schizophrenia-like psychosis were identified from a series of 320 patients who had a temporal lobectomy for medically intractable epilepsy. The relationship of their disorders to both the operation and subsequent seizure activity was examined. Using a retrospective case–control design, risk factors for the development of schizophrenia-like psychosis were established. Results: Eleven patients who developed schizophrenia-like psychosis postoperatively were identified and compared with 33 control subjects who remained free of psychosis postoperatively. The onset of de novo psychotic symptoms was typically in the first year following the operation. No clear relationship between postoperative seizure activity and fluctuations in psychotic symptoms emerged. Compared with the controls, patients who become psychotic had more preoperative bilateral electroencephalogram (EEG) abnormalities, pathologies other than mesial temporal sclerosis in the excised lobe and a smaller amygdala on the unoperated side. Conclusions: Temporal lobectomy for medically intractable epilepsy may precipitate a schizophrenia-like psychosis. Patients with bilateral functional and structural abnormalities, particularly of the amygdala, may be at particular risk for the development of such psychoses.

The purpose of this study was to define magnetic resonance imaging (MRI) correlates of normal brain ageing, with the specific objective of investigating whether the size of the hippocampus is selectively correlated with age related memory performance in non-demented individuals in their ninth and tenth decades of life.Hippocampal size was estimated using MRI based volumetry and qualitative visual assessment in 102 community dwelling individuals aged between 81 and 94 years. Participants were evaluated on a variety of clinical and experimental instruments, including a comprehensive neuropsychological test battery. All participants underwent neurological examination, an extensive medical history was obtained, and an informant confirmed details of each participant's functional ability.Both visual and volumetric hippocampal measures were identified as robust predictors of memory performance, even when the influence of age related illnesses and sociodemographic variables was accounted for. When the sample was reduced to include the most cognitively healthy participants who were rated by an informant as showing no evidence of cognitive decline, the left hippocampal measures remained significant predictors of delayed retention of verbal material.These findings suggest that hippocampal volumes are selectively correlated with memory functioning in both normal and successful ageing.

Background: Evidence from previous volumetric magnetic resonance studies has revealed that patients with chronic temporal lobe epilepsy show atrophy of distinct subcortical nuclei, predominantly ipsilateral to the focus side. We were interested to find out if there is also selective subcortical atrophy in patients suffering from long standing extratemporal lobe epilepsy. Methods: Thirty one patients in whom pre-surgical evaluation unambiguously localised an extratemporal focus were included in this study. Using high resolution magnetic resonance imaging, the volumes of the caudate nuclei, putamen, pallidum, and thalamus were measured bilaterally in both hemispheres and compared with measurements obtained in 15 healthy volunteers. Results: No significant difference in volumes was found between the two subject groups, or in any subgroup of extratemporal lobe epilepsy patients, nor was there any relation to clinical variables such as age of onset, overall seizure frequency, or disease duration. However, patients who had no or only rare generalised tonic–clonic seizures seemed to differ from the other patients and controls in that they had smaller putamen volumes bilaterally (p

Objective and importance: Resective surgery is an effective treatment for refractory temporal lobe epilepsy. In difficult cases, invasive monitoring may be needed to precisely lateralise and localise seizure foci of mesial temporal origin. The authors present a modified technique for image guided, endoscopic placement of an intraventricular electrode array (IVE) that abuts the amygdalo-hippocampal complex. Methods: Eight patients with suspected mesial temporal lobe epilepsy had placement of an IVE in conjunction with other invasive electrodes. Seven of these patients also had subdural grid or strip electrodes and four had foramen ovale electrodes. Frameless image guidance was used to place a custom 10-contact depth electrode through a rigid neuroendoscope within the atrium of the lateral ventricle. Once proper orientation towards the temporal horn was confirmed, the IVE array was advanced into the temporal horn to the temporal tip. The endoscope was removed and electrode placement was confirmed through an intraoperative lateral skull radiograph and on visual inspection at the time of resection in two cases. Results: The IVE was crucial for localisation in one patient and helped localisation in four others. Surgery was offered to seven patients. The only serious complication of IVE placement was a thalamic contusion presumably from an errant electrode tip. One electrode was inadvertently placed into the frontal horn. There were no deaths and no permanent morbidity associated with the procedure. Conclusion: Endoscopically placed temporal horn, intraventricular electrodes provide an alternative to transcortical depth electrode placement. The technique hopefully can avoid complications associated with multiple depth electrode placements, especially when bilateral amygdalo-hippocampal electrical recordings are desired, although there may be a steep learning curve.

Background: Many reports support the clinical validity of volumetric MRI measurements in Alzheimer's disease. Objective: To integrate functional brain imaging data derived from magnetoencephalography (MEG) and volumetric data in patients with Alzheimer's disease and in age matched controls. Methods: MEG data were obtained in the context of a probe-letter memory task. Volumetric measurements were obtained for lateral and mesial temporal lobe regions. Results: As expected, Alzheimer's disease patients showed greater hippocampal atrophy than controls bilaterally. MEG derived indices of the degree of activation in left parietal and temporal lobe areas, occurring after 400 ms from stimulus onset, correlated significantly with the relative volume of lateral and mesial temporal regions. In addition, the size of the right hippocampus accounted for a significant portion of the variance in cognitive scores independently of brain activity measures. Conclusions: These data support the view that there is a relation between hippocampal atrophy and the degree of neurophysiological activity in the left temporal lobe.

The case is described of a patient who, following cerebral hypoxia, developed severe difficulty in orienting himself in new environments in the context of a mild global amnesic syndrome. Some episodes he related suggested that his main difficulty was remembering the spatial/directional value of landmarks he recognised. A neuroradiological examination documented severe bilateral atrophy of the hippocampi associated with atrophic changes in the cerebral hemispheres, most marked in the dorsal regions. Neuropsychological and experimental evaluation showed a severe deficit of spatial learning with substantially preserved ability to learn verbal and visual-object information. He was also virtually unable to learn a route in a maze task based exclusively on spatial data, but the availability of visual cues substantially improved his learning. Finally, he performed within normal limits on various tests investigating knowledge acquired premorbidly regarding famous buildings, routes in the town he had been living in since childhood, and geography. Topographical disorientation may be subtended by a specific difficulty in storing the spatial/directional value of visual landmarks in novel environments. The hippocampus appears to be involved in the acquisition of new topographical spatial knowledge.

Objective: To examine alterations in patterns of brain activation seen in normal aging and in mild Alzheimer's disease by functional magnetic resonance imaging (fMRI) during an associative encoding task. Methods: 10 young controls, 10 elderly controls, and seven patients with mild Alzheimer's disease were studied using fMRI during a face–name association encoding task. The fMRI paradigm used a block design with three conditions: novel face–name pairs, repeated face–name pairs, and visual fixation. Results: The young and elderly controls differed primarily in the pattern of activation seen in prefrontal and parietal cortices: elderly controls showed significantly less activation in both superior and inferior prefrontal cortices but greater activation in parietal regions than younger controls during the encoding of novel face–name pairs. Compared with elderly controls, the Alzheimer patients showed significantly less activation in the hippocampal formation but greater activation in the medial parietal and posterior cingulate regions. Conclusions: The pattern of fMRI activation during the encoding of novel associations is differentially altered in the early stages of Alzheimer's disease compared with normal aging.

Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure. Methods: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as confounding covariates in analyses. Results: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epileptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epileptogenic zone compared with patients without such a history. Left amygdala volume was also reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral thalamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy. Conclusions: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the presumed epileptogenic zone and may result from recurrent seizures.

Objective: To investigate the relation between atrophy of the hippocampal region and brain functional patterns during episodic memory processing in Alzheimer's disease. Patients and methods: Whole brain structural magnetic resonance imaging (MRI) data and single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF) were obtained during a verbal recognition memory task in nine subjects with mild Alzheimer's disease and 10 elderly healthy controls. Using the statistical parametric mapping approach, voxel based comparisons were made on the MRI data to identify clusters of significantly reduced grey matter concentrations in the hippocampal region in the Alzheimer patients relative to the controls. The mean grey matter density in the voxel cluster of greatest hippocampal atrophy was extracted for each Alzheimer subject. This measure was used to investigate, on a voxel by voxel basis, the presence of significant correlations between the degree of hippocampal atrophy and the rCBF SPECT measures obtained during the memory task. Results: Direct correlations were detected between the hippocampal grey matter density and rCBF values in voxel clusters located bilaterally in the temporal neocortex, in the left medial temporal region, and in the left posterior cingulate cortex during the memory task in the Alzheimer's disease group (p < 0.001). Conversely, measures of hippocampal atrophy were negatively correlated with rCBF values in voxel clusters located in the frontal lobes, involving the right and left inferior frontal gyri and the insula (p < 0.001). Conclusions: Hippocampal atrophic changes in Alzheimer's disease are associated with reduced functional activity in limbic and associative temporal regions during episodic memory processing, but with increased activity in frontal areas, possibly on a compensatory basis.

To investigate whether medial temporal lobe atrophy predicted outcome in patients with minor cognitive impairment and whether assessment of the medial temporal lobe could increase the predictive accuracy of age and delayed recall for outcome. Quantitative and qualitative methods of assessing the medial temporal lobe were also compared.Patients with minor cognitive impairment older than 50 years (n=31) were selected from a memory clinic and were followed up for on average 1.9 years. The medial temporal lobe was assessed in three different ways: volumetry of the hippocampus, volumetry of the parahippocampal gyrus, and qualitative rating of medial temporal lobe atrophy (MTA). Outcome measures were Alzheimer type dementia or cognitive decline at follow up. Delayed recall was tested with a verbal learning test.Ten patients had experienced cognitive decline at follow up, of whom seven had probable Alzheimer type dementia. All medial temporal lobe measurements were associated with cognitive decline at follow up (p trend analysis between 0.001 (hippocampus) and 0.05 (parahippocampal gyrus)). Only the hippocampal volume and MTA score were associated with Alzheimer type dementia at follow up (p trend analysis respectively 0.003 and 0.01). All medial temporal lobe measurements increased the predictive accuracy of age and the delayed recall score for cognitive decline (p increase in predictive accuracy varied between0.001 (hippocampus) and 0.02 (parahippocampal gyrus and MTA score)) and the hippocampal volume and the MTA score increased the predictive accuracy of age and the delayed recall score for Alzheimer type dementia (p= 0.02).The ability to detect patients at high risk for Alzheimer type dementia among those with minor cognitive impairment increases when data on age and memory function are combined with measures of medial temporal lobe atrophy. Volumetry of the hippocampus is preferred, but qualitative rating of medial temporal lobe atrophy is a good alternative.

Schizophrenia is a highly heritable disorder associated with structural brain abnormalities. The aim of this study was to establish if the gene(s) for schizophrenia are associated with specific abnormalities of brain structure.Six sibships from multiple affected families were recruited. Each sibship consisted of one patient with schizophrenia, one "obligate carrier" without the disorder but with an affected child, and one "non-affected non-carrier". Such sibships are very rare, but present a powerful opportunity to separate the associations of genotype and phenotype. Obligates presumably have the gene(s) but not the disorder, affected siblings have both, whereas non-affected non-carrier siblings have neither.Brain MRI was conducted with a semiautomated region of interest analysis. The risk of false positive findings was reduced by collapsing brain regions and sides into five regions and comparing groups by repeated measures analysis of variance.In terms of whole brain volumes and volumes of cortical structures, obligates resembled their non-affected non-carrier siblings, both groups having significantly greater volumes than their schizophrenic siblings (p=0.01 and p=0.04). Obligates also had significantly smaller ventricles than their schizophrenic siblings (p=0.03). However, with respect to the amygdalohippocampal complex, the obligates' brains resembled those of their schizophrenic siblings, both groups showing a significant reduction in volume when compared with their non-affected non-carrier siblings (p=0.001).In the families studied, reductions in volumes of cortical structures and reductions in whole brain volume seem to be associated with the phenotype of schizophrenia. By contrast, reduced volume of the amygdalohippocampal complex seems to be associated with genetic risk for the disorder even in the absence of disease.

Item does not contain fulltext OBJECTIVES: Patients with intractable epilepsy may benefit from epilepsy surgery especially if they have a radiologically demonstrable cerebral lesion. Dedicated magnetic resonance imaging (MRI) protocols as performed at epilepsy surgery centres can detect epileptogenic abnormalities with great sensitivity and specificity. However, many patients with epilepsy are investigated with standard MRI sequences by radiologist outside epilepsy centres ("non-experts"). This study was undertaken to compare standard MRI and epilepsy specific MRI findings in patients with focal epilepsy. METHODS: Comparison of results of standard MRI reported by "non-expert" radiologists, standard MRI evaluated by epilepsy "expert" radiologists, and epilepsy specific MRI read by "expert" radiologists in 123 consecutive patients undergoing epilepsy surgery evaluation between 1996 and 1999. Validation of radiological findings by correlation with postoperative histological examination. RESULTS: Sensitivity of "non-expert" reports of standard MRI reports for focal lesions was 39%, of "expert" reports of standard MRI 50%, and of epilepsy dedicated MRI 91%. Dedicated MRI showed focal lesions in 85% of patients with "non-lesional" standard MRI. The technical quality of standard MRI improved during the study period, but "non-expert" reporting did not. In particular, hippocampal sclerosis was missed in 86% of cases. Neuropathological diagnoses (n=90) were predicted correctly in 22% of "non-expert" standard MRI reports but by 89% of dedicated MRI reports. CONCLUSIONS: Standard MRI failed to detect 57% of focal epileptogenic lesions. Patients without MRI lesion are less likely to be considered candidates for epilepsy surgery. Patients with refractory epilepsy should be referred to an MRI unit with epileptological experience at an early point.

This paper describes a suite of routines using IgorPro, a powerful analysis and graphing software package for the Macintosh computer, to enhance the ability to analyze, manipulate, and display data recorded with the Discovery™ acquisition software marketed by DataWave Technologies. The routines are able to time-align fast and slow data channels, and are especially useful for analyses that involve both neural and behavioral data. The software was designed for eyeblink conditioning and vocalization experiments, but it can easily be used for analyzing other types of neurobehavioral data. The data are first prepared on the PC with routines that inspect the header of the data file and translate the data file into a compact binary format that can be read by IgorPro. An option is also available to splice out data from unnecessary portions of an intertrial interval. The new file is then put on the Macintosh computer for display and analysis by IgorPro. These routines enable both neural and behavioral data to be quickly and easily reduced, manipulated, and statistically and graphically summarized.