Medial temporal lobe atrophy and memory deficits in elderly stroke patients

Medial temporal lobe atrophy (MTA) and its role in memory deficits have been studied extensively in patients with various dementias and non-degenerative neurologic diseases. In stroke patients MTA is a significant risk factor for dementia. However, its role in memory decline in non-demented stroke patients is not yet known. Our aim was to evaluate the relationship between MTA and cognitive functions in a large cohort of elderly patients, who underwent a comprehensive neuropsychologic examination and magnetic resonance imaging 3 months after an ischemic stroke. The study sample (n = 260) was divided into three groups according to the severity of MTA. After adjusting for age, volume of infarcts and cortical atrophy, we found that patients with moderate to severe MTA performed significantly worse in tests of learning, story recall, visual reproduction, block design and mental speed. In contrast, the groups did not differ in tests of digit span, flexibility, verbal fluency and conceptualization. Our conclusion is that in aged stroke patients, MTA is associated with poor performance in specific cognitive domains. The most vulnerable domains are memory and visuospatial functions, whereas verbal and executive functions seem to be unrelated to MTA.     

Sibling risk of anxiety disorders based on hospitalizations in Sweden

Aims: This study used nationwide hospital records to examine sibling risk of any type of anxiety disorder in Sweden over a 40‐year period. Methods: This study, carried out between 1 January 1968 and 31 December 2007, of the entire population of Sweden, linked information on family relationships from the nationwide Multi‐Generation Register with information from the nationwide Swedish Hospital Discharge Register on first diagnosis of anxiety disorder. A total of 42 602 persons hospitalized for anxiety disorders and 2093 affected siblings were identified. Standardized incidence ratios (SIR) were calculated by comparing risk in siblings of persons hospitalized for anxiety disorders with risk in persons whose siblings had no hospital diagnosis of anxiety disorders. Results: The sibling risk was 2.26, which was independent of sex and age differences between siblings. The SIR was highest in siblings <20 years of age (2.83). Analysis of risk by subtype showed that having a sibling diagnosed with any anxiety disorder resulted in increased risks of a number of disorders; the highest increased risk was of social phobia (SIR 3.68, 95% confidence interval, 1.68–7.69). Risk of panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder, and obsessive–compulsive disorder was raised in female but not male siblings. Conclusions: Heritable effects likely play an important role in the cause of anxiety disorders, but the extent of their role remains to be established. Important contributions could be made by studies of gene–environment interactions that have sufficient sample sizes to produce reliable results.     

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age‐related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age‐related neural changes in the human hippocampus using high‐resolution (1.5 mm isotropic) blood‐oxygenation level‐dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging. © 2010 Wiley‐Liss, Inc.     

Limbic structures and networks in children and adolescents with schizophrenia

Studies of adults with schizophrenia provide converging evidence for abnormalities in the limbic system. Limbic structures that show consistent patient/control differences in both postmortem and neuroimaging studies include the anterior cingulate and hippocampus, although differences in the amygdala, parahippocampal gyrus, and fornix have also been observed. Studies of white matter in children and adolescents with schizophrenia tend to show findings that are more focal than those seen in adults. Interestingly, these focal abnormalities in early-onset schizophrenia tend to be more localized to limbic regions. While it is unclear if these early limbic abnormalities are primary in the etiology of schizophrenia, there is evidence that supports a developmental progression with early limbic abnormalities evolving over time to match the neuroimaging profiles seen in adults with schizophrenia. Alternatively, the aberrations in limbic structures may be secondary to a more widespread or global pathological processes occurring with the brain that disrupt neural transmission. The goal of this article is to provide a review of the limbic system and limbic network abnormalities reported in children and adolescents with schizophrenia. These findings are compared with the adult literature and placed within a developmental context. These observations from neuroimaging studies enrich our current understanding of the neurodevelopmental model of schizophrenia and raise further questions about primary vs secondary processes. Additional research within a developmental framework is necessary to determine the putative etiologic roles for limbic and other brain abnormalities in early-onset schizophrenia.     

Hippocampal lesions that abolish spatial maze performance spare object recognition memory at delays of up to 48 hours

The hippocampus is widely considered to be a critical component of a medial temporal lobe memory system, necessary for normal performance on tests of declarative memory. Object recognition memory is thought to be a classic test of declarative memory function. However, previous tests of the effects of hippocampal lesions on object recognition memory have not always supported this view. One possible reason for this inconsistency is that previously reported effects of hippocampal lesions on object recognition memory tasks may have stemmed not from a deficit in object recognition memory per se, but as a result of spatial and contextual confounds in the task. Thus, in the present study, we used a spontaneous object recognition test in a modified apparatus designed to minimize spatial and contextual factors. A group of rats with complete excitotoxic lesions of the hippocampus and a group of control rats were tested on this modified spontaneous object recognition task with retention delays of up to 48 h. These rats were also tested on a spatial nonmatching-to-place task. Spatial memory performance was abolished following hippocampal lesions, whereas performance on the recognition memory task was intact at all delays tested.     

Item recognition is less impaired than recall and associative recognition in a patient with selective hippocampal damage

This article explores the recall, item recognition, and associative recognition memory of patient B.E., whose pattern of retrograde amnesia was reported by Kapur and Brooks (1999; Hippocampus 9:1-8). Structural magnetic resonance imaging (MRI) has shown that B.E. has bilateral damage restricted to the hippocampus. The structural damage he had sustained was accompanied by bilateral hypoperfusion of the temporal lobe, revealed by positron emission tomography (PET), and which single photon emission computed tomography (SPECT) suggested was greater in the left than the right temporal lobe. B.E. showed a global anterograde amnesia for verbal material, but he displayed some sparing of nonverbal item recognition relative to nonverbal recall and associative recognition. His performance on an item recognition task that used the remember/know procedure and another that involved repetition of the test phase, to reduce the difference between the familiarity of the targets and foils, suggested that his relatively spared nonverbal item recognition may have been mainly supported by familiarity. This finding is consistent with the view that the anterior temporal lobe, including the perirhinal cortex, can support familiarity-based memory judgments (Brown and Bashir, 2002; Philos Trans R Soc Lond B 357:1083-1095). B.E.'s data also highlight the importance of functional as well as structural scan information for interpreting the pattern of memory deficits shown by patients with selective hippocampal structural lesions.     

Executive functioning in offspring at risk for depression and anxiety

Background: Executive functioning deficits (EFDs) have been found in adults with major depression and some anxiety disorders, yet it is unknown whether these deficits predate onset of disorder, or whether they reflect acute symptoms. Studies of at‐risk offspring can shed light on this question by examining whether EFDs characterize children at high risk for depression and anxiety who are not yet symptomatic. Methods: This study examined neuropsychological functioning in a sample of 147 children, ages 6–17 years (M age=9.16, SD=1.82), of parents with major depression (MDD) and/or panic disorder (PD) and of controls with neither disorder. Children were assessed via structured diagnostic interviews and neuropsychological measures. Results: Although parental MDD and PD were not associated with neuropsychological impairments, presence of current offspring MDD was associated with poorer performance on several executive functioning and processing speed measures. Children with current generalized anxiety showed poorer verbal memory, whereas children with social phobia had more omissions on a continuous performance task. Conclusions: Findings suggest that EFDs do not serve as trait markers for developing anxiety or depression but appear to be symptomatic of current disorder. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Memory for familiar environments learned in the remote past: fMRI studies of healthy people and an amnesic person with extensive bilateral hippocampal lesions

Preserved remote spatial memory in amnesic people with bilateral hippocampal damage, including the well-studied case K.C., challenges spatial theories, which assume that the hippocampus is needed to support all allocentric spatial representations, old or new. It remains possible, however, that residual hippocampal tissue is functional and contributes to successful performance. Here, we examine brain activity with fMRI during the retrieval of spatial information in K.C. and in healthy controls using landmark and route stimuli from a premorbidly familiar neighborhood that K.C. can navigate normally. In all participants, activity was found in the parahippocampal cortex, but not in the hippocampus itself, during all navigational tasks on which K.C. performs well, even though part of his hippocampus remains viable. The opposite pattern was observed on a house recognition task, which is inconsequential to navigation, and on which K.C. performed poorly. On that task, K.C. recruited the right hippocampus presumably because even "familiar" houses were treated as novel by him, whereas controls recruited occipitotemporal cortex, including parahippocampal cortex. The distinction between recent and remote memory, therefore, may apply as much to spatial theories of hippocampal function as it does to theories emphasizing the role of the hippocampus in other types of explicit memory.     

Evidence for a specific role of the anterior hippocampal region in successful associative encoding

It has been well established that the hippocampal formation plays a critical role in the formation of memories. However, functional specialization within the hippocampus remains controversial. Using functional magnetic resonance imaging (fMRI) during a face-name associative encoding task, followed by a postscan recognition test for face memory and face-name pair memory, we investigated the roles of anterior and posterior hippocampal regions in successful encoding of associations and items. Whole-brain and region of interest (ROI) analyses revealed that the anterior hippocampal formation showed increased activation for subsequently remembered face-name associations compared with pairs that were forgotten. In contrast, the posterior hippocampal formation showed activation above baseline during attempted encoding of face-name pairs, but no evidence of differential activation based on subsequent memory. Furthermore, exploratory whole-brain analyses revealed that a parahippocampal region, most likely corresponding to perirhinal cortex, showed subsequent memory effects for faces. These data provide evidence for functional specialization within the hippocampal formation based on the associative nature of the stimuli and subsequent memory.     

Neuroimaging correlates of anxiety after pediatric traumatic brain injury.

BACKGROUND: Anxiety disorders are common after traumatic brain injury (TBI). Data on the neural correlates of these conditions are lacking. This study examines the relationship between brain damage, particularly to the orbitofrontal cortex (OFC) and temporal lobe, and anxiety symptoms and disorders. METHODS: Ninety-five children and adolescents were followed for one year postinjury. Preinjury and one-year postinjury anxiety status were obtained from the parent. Magnetic resonance imaging was performed to evaluate brain lesions. The primary analysis used regression models to determine relationships between brain lesions and anxiety outcomes. As a secondary analysis, previously reported posttraumatic stress disorder (PTSD) data were reanalyzed using similar methods for purposes of comparison. RESULTS: The primary analysis showed that greater volume and number of OFC lesions correlated with decreased risk for anxiety, whereas lesions in other brain areas did not correlate with anxiety. Consistent with prior data, the secondary analysis showed an inverse correlation between OFC damage and PTSD; temporal lobe damage was positively correlated with PTSD. CONCLUSIONS: After pediatric TBI, greater damage to the OFC is associated with decreased risk for anxiety outcomes. Similar to adult data, these findings implicate OFC dysfunction in childhood anxiety. Temporal lobe damage did not correlate with anxiety, in contrast to the findings for PTSD.     

Dissociable neural responses in the hippocampus to the retrieval of facial identity and emotion: an event-related fMRI study

In studies with brain-damaged patients and experimental animals, the medial temporal lobe, including the hippocampus and parahippocampal gyrus, has been found to play a critical role in establishing declarative or episodic memory. We measured the neural response in these structures, using event-related functional magnetic resonance imaging, while six healthy subjects performed the retrieval task for facial identity and emotion, respectively. Under the identity condition, the subjects participated in a yes/no recognition test for neutral faces learned before the scanning. Under the emotion condition, the subjects learned the faces with positive or negative expression and retrieved their expressions from neutral cue faces. The results showed that the left hippocampus is primarily involved in the identification of learned faces, and that the adjacent parahippocampal gyrus responds more to target than to distracter events. These results indicate a specific engagement of the left hippocampal regions in conscious recollection and identification of physiognomic facial features. The activity in the right hippocampus increased under both the identity and emotion conditions. The present results may relate with the functional model of face recognition in which the left hemisphere contributes to the processing of detailed features and the right hemisphere is efficient in the processing of global features.     

Impaired associative memory in temporal lobe epilepsy subjects after lesions of hippocampus, parahippocampal gyrus, and amygdala

There has been growing interest in the differential role of medial temporal lobe structures in learning and memory. The goal of the present study was to clarify how lesions of hippocampus, parahippocampal gyrus, and amygdala interfere with associative learning and memory. Thirty subjects with pharmacoresistant medial temporal lobe epilepsy (TLE) and temporal lobe removal were compared with 30 matched healthy control subjects. A set of neuropsychological test measures and an associative learning task requiring the learning and recall of objects and faces were administered. The lesions of hippocampus, parahippocampal gyrus, amygdala, and fusiform gyrus of TLE subjects were determined by three-dimensional magnetic resonance imaging (3-D MRI) volumetric assessment. The results indicate that TLE subjects with combined large hippocampal lesions, large parahippocampal gyrus (i.e., perirhinal/entorhinal) lesions, and large amygdala lesions learned and recalled the associative task significantly worse than control subjects or subjects with small lesions of the hippocampus, parahippocampal gyrus, and amygdala. Regression analysis revealed that larger lesions of the parahippocampal gyrus (i.e., perirhinal/entorhinal cortices) were significantly related to increasing deficits on the task, and that hippocampal and amygdala lesion size did not significantly improve the prediction. Our results suggest that perirhinal and entorhinal cortices may contribute predominantly to the associative learning and recall of objects and faces.     

Long‐lasting seizure‐related anxiety in patients with temporal lobe epilepsy and comorbid psychiatric disorders

Ictal anxiety is a frequent epileptic symptom; it is usually brief, associated with objective clinical signs, and is not positively influenced by external factors, in contrast to psychiatric disorders. These criteria can, however, be misleading, especially in patients with psychiatric comorbidities. We report two patients with a history of drug‐resistant right temporal lobe epilepsy, who developed long‐lasting psychiatric symptoms, suggestive of exacerbation of their comorbid anxiety disorder. However, intracranial EEG data and [¹⁸F] FDG‐PET suggested that these symptoms were related to seizure activity, highlighting the difficulties in differentiating ictal symptoms from psychiatric episodes in some patients with epilepsy and comorbid psychiatric disorders. [Published with video sequence]     

Differential contributions of the anterior temporal and medial temporal lobe to the retrieval of memory for person identity information

Although previous studies have suggested the importance of the bilateral anterior temporal (ATL) and medial temporal lobes (MTL) in the retrieval of person identity information, there is little evidence concerning how these regions differentially contribute to the process. Here we investigated this question using functional magnetic resonance imaging (fMRI). Before scanning, subjects learned associations among faces (F), names (N), and job titles (as a form of person-related semantics, S). During retrieval with fMRI, subjects were presented with previously learned and new S stimuli, and judged whether the stimuli were old or new. Successful retrieval (H) trials were divided into three conditions: retrieval of S and associated F and N (HSFN); retrieval of S and associated F (HSF); and retrieval of S only (HS). The left ATL was significantly activated in HSFN, compared to HSF or HS, whereas the right ATL and MTL were significantly activated in HSFN and HSF relative to HS. In addition, activity in bilateral ATL was significantly correlated with reaction time for HSFN, whereas we found no significant correlation between activity in the right MTL and reaction time in any condition. The present findings suggest that the left ATL may mediate associations between names and person-related semantic information, whereas the right ATL mediates the association between faces and person-related semantic information in memory for person identity information. In addition, activation of the right MTL region implies that this area may contribute to a more general relational processing of associative components, including memory for person identity information.     

The hippocampus is involved in mental navigation for a recently learned, but not a highly familiar environment: a longitudinal fMRI study

Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that memory for a large-scale environment is initially dependent on the hippocampus but is later supported by extra-hippocampal structures (e.g., precuneus, posterior parahippocampal cortex, and lingual gyrus) once the environment is well-learned. Participants were scanned during mental navigation tasks initially when they were newly arrived to the city of Toronto, and later after having lived and navigated within the city for 1 yr. In the first session, activation was observed in the right hippocampus, left precuneus, and postcentral gyrus. The second session revealed activation in the caudate and lateral temporal cortex, but not in the right hippocampus; additional activation was instead observed in the posterior parahippocampal cortex, lingual gyrus, and precuneus. These findings suggest that the right hippocampus is required for the acquisition of new spatial information but is not needed to represent this information when the environment is highly familiar.     

Dimensional assessment of anxiety disorders in parents and children for DSM‐5

The current shift in the DSM towards the inclusion of a dimensional component allows clinicians and researchers to demonstrate not only the presence or absence of psychopathology in an individual, but also the degree to which the disorder and its symptoms are manifested. This study evaluated the psychometric properties and utility of a set of brief dimensional scales that assess DSM‐based core features of anxiety disorders, for children and their parents. The dimensional scales and the Screen for Child Anxiety Related Emotional Disorders (SCARED‐71), a questionnaire to assess symptoms of all anxiety disorders, were administered to a community sample of children (n = 382), aged 8–13 years, and their mothers (n = 285) and fathers (n = 255). The dimensional scales assess six anxiety disorders: specific phobia, agoraphobia, panic disorder, social anxiety disorder, generalized anxiety disorder, and separation anxiety disorder. Children rated their own anxiety and parents their child's anxiety. The dimensional scales demonstrated high internal consistency (α > 0.78, except for father reported child panic disorder, for reason of lack of variation), and moderate to high levels of convergent validity (r _s = 0.29–0.73). Children who exceeded the SCARED cutoffs scored higher on the dimensional scales than those who did not, providing preliminary support for the clinical sensitivity of the scales. Given their strong psychometric properties and utility for both child and parent report, addition of the dimensional scales to the DSM‐5 might be an effective way to incorporate dimensional measurement into the categorical DSM‐5 assessment of anxiety disorders in children. Copyright © 2014 American Psychiatric Association. All rights reserved.     

Understanding medial temporal activation in memory tasks: evidence from fMRI of encoding and recognition in a case of transient global amnesia

We used fMRI to examine the activation patterns of patient AE during encoding and recognition of visual scenes during an episode of transient global amnesia (TGA) and 3 months later. Controls (n = 5) showed bilateral (R > L) activation in parahippocampal and fusiform gyri during encoding and right-sided activation in the same regions associated with recognition of previously viewed scenes. AE showed a similar pattern at follow-up. During acute TGA, when performance was profoundly impaired, AE showed no medial temporal activation associated with encoding of new scenes or recognition of old scenes. In both contrasts, the percent signal change in relevant medial temporal regions was more than three standard deviations below the control sample mean. She did, however, show striking bilateral hippocampal activation for recognition attempts (old + new scenes > baseline) even though retrieval was unsuccessful (55% recognition accuracy). This finding was unique to AE on this occasion. This is the first study to document normalization of both encoding and recognition activation patterns in TGA. Furthermore, the strong hippocampal activation during unsuccessful retrieval highlights important issues in interpreting memory-related activations, particularly in dysfunctional systems.     

Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer's disease

The medial temporal lobes (MTL) and frontal cortex have been shown to subserve memory processes. Neurodegenerative diseases, such as Alzheimer's disease (AD), disrupt the neuronal networks that underlie memory processing. The ε4 allele of the apolipoprotein E gene is a genetic risk factor for AD and is associated with decrements in memory and in olfactory function. The present study utilized EQS, a structural equation modeling software program, to examine differences in the neuronal networks between non‐demented ε4 carriers and ε4 noncarriers during a cross‐modal olfactory recognition memory paradigm. Prior to fMRI scanning, participants were presented with 16 odors. During two scans, participants discriminated between names of odors presented before scanning (targets) or not presented (foils). The results indicate significant connections between bilateral frontal lobes and MTL for ε4 carriers when they misidentified a foil as a target. When ε4 noncarriers correctly identified a target, there were greater associations between the amygdala, MTL, and right frontal lobe; these associations also modeled the brain's response when ε4 noncarriers misidentified a foil as a target. During memory retrieval, affective cues may facilitate retrieval in ε4 noncarriers relative to ε4 carriers. Last, no model was found that best represented the functional network used by ε4 carriers when they correctly identified a target, which may reflect variability of neuronal recruitment within this population. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.