Reduced hippocampal volume in drug-free depressed patients

A number of studies have used magnetic resonance imaging to examine the volumetric differences in temporal lobe structures especially the hippocampus in patients suffering from major depressive disorder (MDD). Although some studies reported lower hippocampal volume, others did not. It is proposed that the inconsistency among studies may be due to the heterogeneity of patients and antidepressant treatment during scanning. In this study, we aimed to evaluate the hippocampus in drug-free patients. Twenty-four patients (6 males and 18 females) diagnosed as having MDD according to the DSM-IV criteria and 24 healthy controls (6 males and 18 females) were included in the study. Eleven of the patients had their first mood episode and were drug-naïve. Other patients were drug-free for at least 4 weeks. The Hamilton depression rating scale (HAM-D) assessed the severity of depression. Magnetic resonance imaging was performed on a 1.5-T MR unit. The Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal volume. The data were evaluated by a repeated measure of ANOVA and the intracranial volume was taken as a covariate. A significant hippocampal volume difference was observed between the patients and healthy controls (F=4.43, df=1.45, P<0.05); however, laterality had no effect on the volumes (F=0.03, df=1.45, P>0.05). The left hippocampus of patients was significantly lower than those of controls (t=1.98, df=46, P<0.05). Correlation analysis showed a correlation between HAM-D scores and the right hippocampal volume. The results of this study indicate that hippocampus volume is reduced in depressed patients especially in the left side. This finding in the drug-free depressed outpatients without a history of alcohol dependence supports previous studies that have reported lower hippocampal volume.     

The medial temporal lobe in encoding,retention, retrieval and interhemispheric transfer of visual memory in primates

Low-level electrical stimulation through electrodes in the medial temporal lobe (MTL) was used to disrupt the performance of chiasm-split macaques working in a delayed matching-to-sample (DMS) visual memory task. The stimulation was below afterdischarge threshold and did not distract the animals. Nonetheless, stimulation caused severe deficits when delivered either during encoding or retrieval stages. Substantially less deficit appeared when stimulation was delivered during the retention interval. Stimulation levels which led to significant disruption on the DMS task had no effect on a discrimination task using the same kinds of images. Unilateral electrical stimulation delivered to MTL in one hemisphere during encoding and to MTL in the other hemisphere during retrieval produced an effective disruption, suggesting that the unilateral stimulation during the encoding period disrupts the encoding on that side while unilateral stimulation delivered to the opposite side during the retrieval period prevents the retrieval of the (now unilateral) memory. This suggestion is supported by control experiments in which significantly less disruption was caused by unilateral electrical stimulation delivered during both the encoding and the retrieval period if the stimulation was delivered to the same side in both periods. The electrical stimulation was further used to determine that interhemispheric access by one hemisphere to memories placed in the other was excellent. This was done, in these split-chiasm monkeys, by using unilateral stimulation to limit memory formation to just one hemisphere, then testing interhemispheric access by routing the test through the ignorant hemisphere (using just the ipsilateral eye). Successful interhemispheric access was obtained with either the anterior commissure or with the splenium of the corpus callosum (the other interhemispheric forebrain pathways having been cut). The electrical stimulation was also used to determine that the visual inputs even though entering via just one eye and one hemisphere, lead to bilateral memory formation. In this case each hemisphere was tested separately during retrieval by delivering disruptive levels of the electrical stimulation to the MTL of the other hemisphere.     

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.     

The role of the right medial temporal lobe in the control of memory-guided saccades

The role of the hippocampal formation in the control of memory-guided saccades is unclear. We tested two types of memory-guided saccades with short memorization delay in three patients with a lesion affecting the right medial temporal lobe and involving the hippocampal formation. In single memory-guided saccades, testing spatial working memory, the gain of the patient group did not differ from that of an age-matched control group. In contrast, in sequences of memory guided saccades, testing chronological working memory, there was a marked and significant increase in the percentage of erroneous sequences in patients, compared to controls. These results suggest an important role of the hippocampal formation in the memorization of the chronological order of saccade sequences. In contrast, this structure does not appear to be crucial for spatial working memory, used in single memory-guided saccades.     

Midlife memory improvement predicts preservation of hippocampal volume in old age

This study examines whether midlife change in episodic memory predicts hippocampal volume in old age. From the Seattle Longitudinal Study we retrospectively identified 84 healthy, cognitively normal individuals, age 52 to 87, whose episodic memory had reliably declined (n = 33), improved (n = 28) or remained stable (n = 23) over a 14-year period in midlife (age 43-63). Midlife memory improvement was associated with 13% larger hippocampal volume (p < 0.01) in old age (age 66-87), compared with old age individuals whose midlife episodic memory had either declined or remained stable during midlife. Midlife memory change did not predict total hippocampal volume for those currently in late middle age (age 52-65). The pattern of findings was not modified by gender, apolipoprotein ε4 status, education or current memory performance. Change in midlife memory scores over 14 years, but not any single assessment, predicted hippocampal volumes in old age, emphasizing the importance of longitudinal data in examining brain-cognition relationships. These findings suggest that improvement in memory in midlife is associated with sparing of hippocampal volume in later life.     

抗衰益智方Ⅰ对小鼠学习记忆能力以及海马胆碱乙酰转移酶表达的影响

目的：观察抗衰益智方Ⅰ（KYFⅠ）对正常小鼠学习记忆能力和中枢胆碱乙酰转移酶表达的影响。方法:各组小鼠除正常对照组灌服双蒸水外,中药组(分为低、中、高剂量组）灌服相应剂量KYFⅠ,连续灌胃40 d。从第35 d起灌胃结束后进行Morris水迷宫测试,连续5 d。水迷宫测试结束后检测小鼠海马组织胆碱乙酰转移酶（ChAT）和乙酰胆碱酯酶（AChE）的活性,并分别用免疫组化和Western blotting方法观察小鼠海马ChAT阳性神经元的数量变化以及ChAT蛋白的表达。结果:与对照组比较,KYFⅠ高剂量组小鼠水迷宫学习成绩较好;同时,KYFⅠ高剂量组小鼠海马组织内ChAT活性明显增高,AChE活力降低;免疫组化和Western blotting结果显示KYFⅠ高剂量组小鼠海马CA1区ChAT阳性神经元数量增加,ChAT蛋白表达升高。结论:高剂量KYFⅠ可以提高正常小鼠学习记忆能力,其机制可能与KYFⅠ抑制小鼠海马组织AChE活性,提高ChAT活性、升高ChAT蛋白的表达,从而促进脑内乙酰胆碱（ACh）的合成有关。     

Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience

Stress exerts a profound, yet complex, influence on learning and memory and can enhance, impair or have no effect on these processes. Here, we have examined how the administration of stress at different times before learning affects long-term (24-hr) memory for neutral and emotional information. Participants submerged their dominant hand into a bath of ice cold water (Stress) or into a bath of warm water (No stress) for 3 min. Either immediately (Exp. 1) or 30 min (Exp. 2) after the water bath manipulation, participants were presented with a list of 30 words varying in emotional valence. The next day, participants' memory for the word list was assessed via free recall and recognition tests. In both experiments, stressed participants exhibited greater blood pressure, salivary cortisol levels, and subjective pain and stress ratings than non-stressed participants in response to the water bath manipulation. Stress applied immediately prior to learning (Exp. 1) enhanced the recognition of positive words, while stress applied 30 min prior to learning (Exp. 2) impaired free recall of negative words. Participants' recognition of positive words in Experiment 1 was positively associated with their heart rate responses to the water bath manipulation, while participants' free recall of negative words in Experiment 2 was negatively associated with their blood pressure and cortisol responses to the water bath manipulation. These findings indicate that the differential effects of pre-learning stress on long-term memory may depend on the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information.     

Medial temporal lobe volume of nondemented elderly individuals with poor cognitive functions

Poor cognitive performance of elderly individuals with low educational attainment is often difficult to interpret in dementia evaluation. Lack of education, as well as dementia, is often associated with poor cognitive test performance. To elucidate the underlying structural change of low cognitive performance in elderly individuals with low educational attainment, this study examined the relationship between low cognitive performance (LCP) and brain volumes, especially regions vulnerable to Alzheimer's disease, in nondemented elderly Koreans. Individuals with LCP (n=14) were matched on age and education with individuals with normal cognitive performance (n=14). The two groups were compared on the MR-based volumetric measures in the hippocampus, the entorhinal cortex, the amygdala, the temporal lobe, the frontal lobe, the cerebrum, and the intracranial cavity. Intracranial volume (p<.05) and absolute hippocampus (p<.05) and frontal lobe volumes (p<.05) were significantly reduced in individuals with LCP. Normalized volumes of the hippocampus and the frontal lobe did not differ in the two cognitive performance groups. ICV was associated with the K-DRS scores. General cognitive functioning of the LCP individuals, measured with the Korean version of the DRS, did not deteriorate in the 1- or 2-year follow-up cognitive tests. LCP in a nondemented elderly population with limited education appears to be associated with stable lower intelligence rather than increased risk for dementia of the Alzheimer's type.     

Effects of a constant light environment on hippocampal neurogenesis and memory in mice

Because the environmental light–dark cycle is a key factor involved in modulating circadian rhythm in mammals, disruption of cyclic light conditions has a variety of effects on physiology and behavior. In the hippocampus, neurogenesis, which continues to occur throughout life, has been reported to exhibit circadian variation under cyclic light–dark conditions. In the present study, we examined whether a constant light environment affected hippocampal neurogenesis in mice. Half of the animals were exposed to continuous light conditions (L/L group), while the other half remained under normal cyclic light–dark conditions (L/D group). In the L/L group, the number of BrdU-labeled cells (proliferating cells) and that of BrdU and class III β-tubulin double-labeled cells (newborn neurons) in the granule cell layer were significantly decreased compared with the L/D group. Because hippocampal neurogenesis is involved in memory and learning, we also investigated the effects on performance in water maze tasks to assess spatial learning. Exposure to L/L treatment for 3 weeks impaired spatial learning task performance, although there was no difference in the open field behaviors between the groups. These findings demonstrate that the constant light conditions impaired hippocampal neurogenesis as well as cognitive performance, and suggest an important role for the cyclic light–dark environment in appropriate maintenance of the hippocampal system.     

大鼠海马和颞叶一氧化氮合酶阳性神经元在学习记忆时的表达

目的　对获得空间辨别性学习记忆大鼠的海马结构和颞叶皮质内一氧化氮合酶 (NOS)免疫阳性神经元系统的观察 ,为一氧化氮 (NO)在学习记忆活动中的作用提供形态学依据。方法　以经水迷宫训练获得空间辨别性学习记忆的大鼠为模型组 ,建立游水对照组和空白对照组。用免疫组化的方法观察 3组大鼠海马和颞叶的NOS阳性神经元的形态学特征及测定免疫反应阳性产物的光密度值 (OD )。结果　 (1)NOS阳性神经元在 3组大鼠海马和颞叶呈散在分布。在海马CA1、CA2、CA3、CA4及龄状回 (DG)都有少量分布 ,颞叶以Ⅱ、Ⅲ、Ⅴ、Ⅵ层分布为主。神经元胞体形态有锥体形 ,圆形或椭圆形 ,梭形3种。 (2 )模型组大鼠海马和颞叶皮质NOS阳性神经元较对照组明显增多。 (3)其免疫反应阳性产物的OD值也较对照组明显增大。结论　NOS阳性神经元形态发生了可塑性变化 ,参与了学习记忆     

Choline chloride effects on memory in the elderly

Choline chloride (2 g QID) and placebo were administered to 10 subjects over age 60 in a placebo-drug-placebo design. Subjects first took placebo for 7 days, followed by choline for 21 days and finally took placebo for another 21 days. Memory tests were given at the end of both placebo periods and twice during choline administration. Choline did not significantly affect performance on a test of memory storage, a test of retrieval from memory or on the digit span test. In addition, a correlational analysis showed that the difference between memory performance during choline administration and during placebo administration was not significantly related to baseline memory performance. These results, together with results of previous studies indicate that choline is not an effective agent for improving memory in nondemented elderly patients.     

Reduced mammillary body volume in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) patients show compromised emotional and cognitive functions, including anterograde memory deficits. While some memory inadequacies in OSA may result from earlier-described structural deficits in the hippocampus, mammillary body injury also could contribute, since these structures receive projections from the hippocampus via the fornix, project heavily to the anterior thalamus, and have been implicated in other conditions with memory deficiencies, such as Korsakoff's syndrome. However, volume loss in mammillary bodies has not been reported in OSA, likely a consequence of logistic difficulties in size assessment. We evaluated mammillary body volumes in 43 OSA (mean age+/-S.D., 46.9+/-9.2 years; mean apnea-hypopnea-index+/-S.D., 31.2+/-19.9 events/h) and 66 control subjects (age, 47.3+/-8.9 years). Two high-resolution T1-weighted image volumes were collected on a 3.0 T magnetic resonance scanner, averaged to improve signal-to-noise, and reoriented (without warping) into a common space. Brain sections containing both mammillary bodies were oversampled, and the bodies were manually traced and volumes calculated. OSA patients showed significantly reduced left, right, and combined mammillary body volumes compared with control subjects, after partitioning for age, gender, and head size (multivariate linear model, p<0.05). Left-side mammillary bodies showed greater volume reduction than the right side. Diminished mammillary body volume in OSA patients may be associated with memory and spatial orientation deficits found in the syndrome. The mechanisms contributing to the volume loss are unclear, but may relate to hypoxic/ischemic processes, possibly assisted by nutritional deficiencies in the syndrome.     

Functional connections in the human temporal lobe

Summary Connections in the human mesial temporal lobe were investigated using brief, single pulses of electrical stimulation to evoke field potential responses in limbic structures of 74 epileptic patients. Eight specific areas within these structures were stereotactically targeted for study, including amygdala, entorhinal cortex, presubiculum, the anterior, middle and posterior levels of hippocampus and the middle and posterior levels of parahippocampal gyrus. These sites were studied systematically in order to quantitatively assess the response characteristics and reliability of responses evoked during stimulation of pathways connecting the areas. Specific measures included response probability, amplitude, latency and conduction velocities. The results are assumed to be representative of typical human limbic pathways since all recordings were made interictally and response probabilities across sites were not found to differ significantly between non-epileptogenic vs. identified epileptogenic regions. Field potentials ranging in amplitude from less than 0.1 to greater than 6.0 mV were evoked ipsilaterally, with mean onset latencies and conduction velocities ranging from 4.4 ms and 3.64 m/s in the perforant pathway connecting entorhinal cortex to anterior hippocampus to 24.8 ms and 0.88 m/s in the pathway connecting the amygdala and middle hippocampus. Stimulation of presubiculum and entorhinal cortex were most effective in evoking widespread responses in adjacent limbic recording sites, whereas posterior parahippocampal gyrus appeared functionally separated from other limbic sites since its probability of influencing ipsilateral sites was significantly lower than any other area. It was particularly noteworthy that stimulation did not evoke responses in any sites in contralateral hippocampal formation; even though a large number of sites were tested with bilateral implantation of homotopic electrodes. The absence of evidence for a functional contralateral limbic projection in the human brain stands in marked contrast to the anatomical and physiological evidence in lower animals for strong contralateral connections between subfields of the hippocampus via the hippocampal commissure. In addition, it correlates well with anatomical evidence for reduced hippocampal commissural connections in lower primates.     

Place memory and scene memory: effects of fornix transection in the monkey

Summary Five experiments examined the effects of fornix transection upon some spatial and visual learning tasks in monkeys (Macaca fascicularis). For each trial of each task, the monkey was brought to a test tray and allowed to choose between 2 objects on the tray. In different tasks, different cues were provided by the experimenter to guide the monkey's choices. In total 5 different tasks were run (Experiments 1 to 5) and the results showed that the effects of fornix transection varied markedly between tasks: the animals with fornix transection were severely impaired in experiments 1, 3 and 5 but learned normally in experiments 2 and 4. It is concluded that the results cannot be explained by the simple hypothesis of a deficit in place learning, since some forms of place learning are unimpaired by fornix transection. A better general hypothesis is that the memory disrupted by fornix transection is like a snapshot memory, which stores the spatial arrangement of items in a witnessed scene.     

Factors determining the impact of care-giving on caregivers of elderly patients with dementia. A systematic literature review

Introduction

Dementia caregivers suffer a considerable care burden. More than in comparable groups of caregivers or peers, they are confronted with feelings of depression and decreased physical health. Although many studies are set up to determine the link between the stressors in dementia care-giving and the impact on the family caregiver, the results remained inconclusive. Others, depression in caregivers remains the main cause of a premature or acute ending of home care.

Method

The aim of this systematic literature review was to analyse what factors determine the development of depression in caregivers of elderly patients with dementia. Depression was taken as primary outcome as it is shown to be the main reason for caregivers to abandon home care.

Results

Depression occurs in one in three of caregivers and it occurs more frequently in those who care for patients with dementia than in caregivers of patients with other chronic illnesses.

Conclusion

Caregiver characteristics rather than objective care needs of the patients tend to be responsible for the onset of depression. Future research should concentrate on demonstrating links between negative feelings in caregivers and the way the care situation evolves. This can have important implications in home care support.     

Medial temporal lobe abnormalities in pediatric unipolar depression

In vivo anatomical magnetic resonance imaging (MRI) studies in adults with major depressive disorder (MDD) have implicated neurocircuitries involved in mood regulation in the pathophysiology of mood disorders. Specifically, abnormalities in the medial temporal lobe structures have been reported. This study examined a sample of children and adolescents with major depressive disorder to investigate anatomical abnormalities in these key medial temporal brain regions. Nineteen children and adolescents with DSM-IV major depression (mean age +/- S.D.=13.0 +/- 2.4 years; 10 unmedicated) and 24 healthy comparison subjects (mean age +/- S.D.=13.9 +/- 2.9 years) were studied using a 1.5T Philips MRI scanner. We measured hippocampus and amygdala gray matter volumes. MRI structural volumes were compared using analysis of covariance with age and total brain volumes as covariates. Pediatric depressed patients had significantly smaller left hippocampal gray matter volumes compared to healthy controls (1.89 +/- 0.16 cm(3) versus 1.99 +/- 0.18 cm(3), respectively; F=5.0, d.f.=1/39, p=0.03; effect size: eta2(p) =0.11). Unmedicated depressed patients showed a trend towards smaller left hippocampal volumes compared to medicated patients and healthy subjects (F=2.8, d.f.=2/38, p=0.07; effect size: eta2(p) =0.13). There were no statistically significant differences in mean volumes for left or right amygdala. Smaller left hippocampal volumes in children and adolescents with MDD are in agreement with findings from adult studies and suggest that such abnormalities are present early in the course of the illness. Amygdala volumes are not abnormal in this age group. Smaller hippocampal volumes may be related to an abnormal developmental process or HPA axis dysfunction.     

Exercise moderates age-related atrophy of the medial temporal lobe

Regional deterioration of brain structure is a typical feature of aging, but emerging evidence suggests that exercise may mitigate the decline. The purpose of the present investigation was to examine the moderating influence of exercise engagement on cross-sectional estimates of age-related brain atrophy at both global and regional levels. Estimates of exercise engagement over the past 10 years and MRI-based measures of global (gray and white) and regional volumes were obtained in a sample of 52 healthy older adults aged 55-79. Volume estimates were obtained in prefrontal, parietal, temporal, occipital, neostriatal, and medial temporal regions. Higher levels of exercise engagement were related to larger superior frontal volumes. Most critically, exercise engagement selectively moderated age-related medial temporal lobe atrophy. Specifically, significant age-related atrophy was observed for older adults who engaged in low levels of exercise, but not for those who engaged in high levels of exercise. This novel finding extends support for the efficacy of exercise to the potential maintenance of medial temporal lobe integrity in older adults.     

Functional connections in the human temporal lobe

Summary In a previous investigation of functional limbic pathways in the human mesial temporal lobe, we found evidence for strong connections between ipsilateral mesial temporal structures, but none for contralateral functional connections (Wilson et al. 1990). In the present study, we focused specifically upon the question of functional commissural linkages between these structures by systematic stimulation of a total of 390 electrode placements in 74 epileptic patients with temporal lobe depth electrodes implanted for surgical diagnosis. Eight standard electrode placement regions were targeted: amygdala, entorhinal cortex, anterior, middle and posterior hippocampus, subicular cortex, middle parahippocampal gyrus, and posterior parahippocampal gyrus. Three to six electrodes were implanted bilaterally in each patient, and each electrode was individually stimulated while recording from all the other sites. Out of the 390 electrodes stimulated, 78% were effective in evoking clear responses in adjacent ipsilateral structures, and 75% of 581 ipsilateral recording sites were responsive to stimulation. Only one of the stimulated electrode sites was effective in evoking responses in contralateral recording sites, and only two of 511 contralateral recording sites were responsive to that stimulation. The effective stimulation site was in presubicular cortex, and the responsive contralateral recording sites were in entorhinal and presubicular cortices. Response to this stimulation site was intermittent and variable in latency. The relative ease of obtaining functional verification of significant ipsilateral anatomical pathways in the human limbic system, and the sharply contrasting difficulty of functionally activating commissural pathways to contralateral limbic sites are discussed in the context of decreases in hippocampal contribution to commissural pathways in the primate brain compared to sub-primate mammals, and the significance of this change to normal limbic system function as well as to mechanisms of seizure spread in epilepsy.     

Dissociated effects of perirhinal cortex ablation,fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe

Four experiments were performed with macaque monkeys (rhesus, Macaca mulatta, and cynomolgus, M.fascicularis). In experiment 1 six rhesus monkeys learned pre-operatively to perform delayed matching-to-sample, with complex naturalistic scenes as the stimulus material. Three of these monkeys then received bilateral ablations of the perirhinal cortex, while the other three received fornix transection. Both groups showed an impairment postoperatively, but the effect of perirhinal cortex ablation was significantly more severe than the effect of fornix transection. In experiment 2 the same animals, together with three normal, control rhesus monkeys,which had a similar training history, performed simple, spatial discrimination learning in a Wisconsin General Test Apparatus. The animals with fornix transection were impaired, but the animals with ablations of perirhinal cortex were not. In experiment 3 the nine animals from experiment 2 were tested for the acquisition of systematic preferences among four novel foods (apple, lemon, olive, meat). Their results were compared with those from a previously published experiment with normal and amygdalectomized cynomolgus monkeys which had been given the same food preference test. Amygdalectomy produced a significant disruption of food preference learning but the other two lesions (fornix transection and perirhinal cortex ablation) did not. In experiment 4, 16 rhesus monkeys (9 normal controls, 4 with perirhinal cortex ablation, and 3 with fornix transection) learned to discriminate among complex naturalistic scenes, in a task in which each scene was presented only once per day in the main part of the experiment. The two operated groups were impaired, and there was no significant difference between the severity of the impairments. Thus, the effects of perirhinal cortex ablation can be doubly dissociated from the effects of fornix transection (experiments 1 and 2) and both can be dissociated from the effects of amygdalectomy (experiment 3). Furthermore, the results of experiment 4 show that the effects of perirhinal cortex ablation are not limited to tasks of memory over short retention intervals. On the basis of the presently reported data and other known effects of perirhinal cortex ablation, it is suggested that this ablation produces an impairment in knowledge (semantic memory) about objects.