Event-related potential markers of brain changes in preclinical familial Alzheimer disease.

OBJECTIVES: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. METHODS: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. RESULTS: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200-300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. CONCLUSIONS: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD.

Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding.

OBJECTIVE: To investigate the integrity of hippocampal-prefrontal circuitry during episodic encoding in patients with HIV. METHODS: Functional MRI was used to observe changes in blood oxygenation level-dependent (BOLD) signal in 14 HIV-positive participants and 14 age- and education-matched control subjects while performing an episodic encoding task. Subjects also completed neuropsychological measures of attention and memory. RESULTS: Behavioral results revealed no significant differences in neuropsychological performance. The fMRI results revealed that while both groups recruited brain regions known to be important for successful encoding, including bilateral medial temporal lobes and inferior prefrontal gyri, the HIV group demonstrated significantly reduced signal intensity changes in the right posterior hippocampus, right inferior frontal gyrus, and left lingual gyrus. Additionally, the HIV group exhibited more activity within lateral frontal and posterior parietal regions. CONCLUSIONS: This study demonstrates altered integrity of hippocampal-prefrontal regions during episodic encoding in HIV-positive patients. These results extend previous studies that have documented the effects of HIV on fronto-striatal circuits, and suggest the virus functionally impacts the hippocampal system as well.

Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli.

Lesions of parahippocampal structures impair performance of delayed matching tasks in nonhuman primates, suggesting a role for these structures in the maintenance of items in working memory and short-term stimulus matching. However, most human functional imaging studies have not shown medial temporal activation during working memory tasks and have primarily focused on functional magnetic resonance imaging (fMRI) signal intensity changes in the prefrontal and posterior parietal cortex. The goal of this study was to test the hypothesis that the difference between the human and nonhuman primate data results from the use of highly familiar stimuli in human working memory studies and trial-unique stimuli in nonhuman primate studies. We used fMRI to examine prefrontal and temporal lobe activation during performance of a working memory (two-back) task, using blocks of novel and highly familiar complex pictures. Performance of the working memory task with novel complex pictures resulted in greater signal change within medial temporal lobe structures than performance of the task with familiar complex pictures. In contrast, the working memory task with highly familiar stimuli resulted in greater prefrontal activation. These results are consistent without hypothesis that the medial temporal lobe is recruited for the short-term maintenance of information that has no prior representation in the brain, whereas the prefrontal cortex is important for monitoring familiar stimuli that have a high degree of interference. A second set of tasks examined stimulus matching. Subjects performed a target-matching task, during which they identified a single target presented in blocks of novel or familiar stimuli. The results provide evidence of hippocampal and parahippocampal recruitment in the target-matching task with familiar stimuli. These results are consistent with prior animal studies and suggest that prefrontal regions may be important for the monitoring and matching of familiar stimuli which have a high potential for interference, whereas medial temporal regions may become proportionally more important for matching and maintenance of novel stimuli.

Referred phantom sensations and cortical reorganization after spinal cord injury in humans.

To test the hypothesis that cortical remapping supports phantom sensations, we examined referred phantom sensations and cortical activation in humans after spinal-cord injury (SCI) at the thoracic level (T3-T12). Of 12 SCI subjects, 9 reported phantom sensations, and 2 reported referred phantom sensations. In both of these subjects, referred phantom sensations were evoked by contact in reference zones (RZ) that were not adjacent in the periphery and were not predicted to be adjacent in the postcentral gyrus (PoCG), suggesting that representations separated by centimeters of cortical space were simultaneously engaged. This finding was supported by functional MRI (fMRI). In a subject with a T6-level complete SCI, contact in RZ on the left or right forearm projected referred phantom sensations to the ipsilateral chest. During fMRI, contact in either forearm RZ evoked activity in the central PoCG (the position of the forearm representation) and the medial PoCG (the position of the chest representation) with >/=1.6 cm of nonresponsive cortex intervening. In contrast, stimulation in non-RZ forearm and palm regions in this subject and in lesion-matched SCI subjects evoked central but not medial PoCG activation. Our findings support a relation between PoCG activation and the percept of referred phantom sensations. These results, however, present an alternative to somatotopic cortical reorganization, namely, cortical plasticity expressed in coactivation of nonadjacent representations. The observed pattern suggests that somatotopic subcortical remapping, projected to the cortex, can support perceptual and cortical reorganization after deafferentation in humans.

Prefrontal-temporal circuitry for episodic encoding and subsequent memory.

Humans encounter and form memories for multiple types of experiences that differ in content, novelty, and memorability. Critical for understanding memory is determining (1) how the brain supports the encoding of events with differing content and (2) whether neural regions that are sensitive to novelty also influence whether stimuli will be subsequently remembered. This event-related functional magnetic resonance imaging (fMRI) study crossed content (picture/word), novelty (novel/repeated), and subsequent memory (remembered/forgotten) to examine prefrontal and temporal lobe contributions to encoding. Results revealed three patterns of encoding-related activation in anatomically connected inferior prefrontal and lateral temporal structures that appeared to vary depending on whether visuospatial/visuo-object, phonological/lexical, or semantic attributes were processed. Event content also modulated medial temporal lobe activity; word encoding predominantly activated the left hemisphere, whereas picture encoding activated both hemispheres. Critically, in prefrontal and temporal regions that were modulated by novelty, the magnitude of encoding activation also predicted whether an event would be subsequently remembered. These results suggest that (1) regions that demonstrate a sensitivity to novelty may actively support encoding processes that impact subsequent explicit memory and (2) multiple content-dependent prefrontal-temporal circuits support event encoding. The similarities between prefrontal and lateral temporal encoding responses raise the possibility that prefrontal modulation of posterior cortical representations is central to encoding.

Segregation of somatosensory activation in the human rolandic cortex using fMRI.

The segregation of sensory information into distinct cortical areas is an important organizational feature of mammalian sensory systems. Here, we provide functional magnetic resonance imaging (fMRI) evidence for the functional delineation of somatosensory representations in the human central sulcus region. Data were collected with a 3-Tesla scanner during two stimulation protocols, a punctate tactile condition without a kinesthetic/motor component, and a kinesthetic/motor condition without a punctate tactile component. With three-dimensional (3-D) anatomical reconstruction techniques, we analyzed data in individual subjects, using the pattern of activation and the anatomical position of specific cortical areas to guide the analysis. As a complimentary analysis, we used a brain averaging technique that emphasized the similarity of cortical features in the morphing of individual subjects and thereby minimized the distortion of the location of cortical activation sites across individuals. A primary finding of this study was differential activation of the cortex on the fundus of the central sulcus, the position of area 3a, during the two tasks. Punctate tactile stimulation of the palm, administered at 3 Hz with a 5.88(log10.mg) von Frey filament, activated discrete regions within the precentral (PreCG) and postcentral (PoCG) gyri, corresponding to areas 6, 3b, 1, and 2, but did not activate area 3a. Conversely, kinesthetic/motor stimulation, 3-Hz flexion and extension of the digits, activated area 3a, the PreCG (areas 6 and 4), and the PoCG (areas 3b, 1, and 2). These activation patterns were observed in individual subjects and in the averaged data, providing strong evidence for the existence of a distinct representation within area 3a in humans. The percentage signal changes in the PreCG and PoCG regions activated by tactile stimulation, and in the intervening gap region, support this functional dissociation. In addition to this distinction within the fundus of the central sulcus, the combination of high-resolution imaging and 3-D analysis techniques permitted localization of activation within areas 6, 4, 3a, 3b, 1, and 2 in the human. With the exception of area 4, which showed inconsistent activation during punctate tactile stimulation, activation in these areas in the human consistently paralleled the pattern of activity observed in previous studies of monkey cortex.

Activity in ventrolateral and mid-dorsolateral prefrontal cortex during nonspatial visual working memory processing: evidence from functional magnetic resonance imaging.

Whole-brain functional magnetic resonance imaging was used to study five healthy human subjects while they performed two nonspatial visual working memory tasks and one control task. In the first memory task, the subjects were required to view a sequence of three pattern stimuli, randomly selected from a familiar set of four stimuli, and then identify which one of three simultaneously presented stimuli was the one that had not been presented in the previous array. In the other task, the subjects were required to observe an identical sequence of three randomly selected pattern stimuli and then to respond by selecting those same stimuli in the order presented. In comparison to a baseline control task, increases in signal intensity were observed, bilaterally, in the mid-dorsolateral frontal cortex and in the right ventrolateral frontal cortex in both memory tasks. When the two tasks were compared directly, however, the first memory task, which had the higher monitoring requirement, yielded significantly greater signal intensity changes in area 9/46 of the right mid-dorsolateral frontal cortex. These results provide further evidence for the precise functional contribution made by the mid-dorsolateral frontal cortex in visual working memory tasks and concur closely with findings in nonhuman primates.

An fMRI investigation of cortical contributions to spatial and nonspatial visual working memory.

The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.

Bridging the gap: integrating cellular and functional magnetic resonance imaging studies of the hippocampus.

The importance of the medial temporal lobe in memory has been studied extensively at the neuronal, neural ensemble, and systems level. In this report, we discuss recent systems level neuroimaging results in relation to neurophysiological studies of the hippocampus and related structures within the medial temporal lobe. By combining our knowledge across the cellular and systems levels we sought to gain theoretical insight and a better understanding of the function of the hippocampus and related medial temporal lobe structures. The integration of information from studies carried out at the cellular and neural ensemble level with studies at the systems level is difficult because of the vast differences in spatial and temporal resolution of the different research methodologies, differences in neuroanatomy across species, and differences in the types of behavioral and cognitive paradigms used in rat, nonhuman primate, and human studies. Despite these methodological and species-related differences, the neurophysiological studies offer insight into many of the questions raised by recent neuroimaging studies. For instance, there is physiological evidence that suggests that the hippocampal memory system is functionally heterogeneous, which may explain some of the discrepancies in the location and extent of activation reported by different imaging studies of the medial temporal lobe. In addition, we describe recent computational models of the hippocampus which may be useful for bridging the gap between neurophysiological and neuroimaging data.

Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex.

The present study used functional magnetic resonance imaging to demonstrate that performance of visual spatial and visual nonspatial working memory tasks involve the same regions of the lateral prefrontal cortex when all factors unrelated to the type of stimulus material are appropriately controlled. These results provide evidence that spatial and nonspatial working memory may not be mediated, respectively, by mid-dorsolateral and mid-ventrolateral regions of the frontal lobe, as widely assumed, and support the alternative notion that specific regions of the lateral prefrontal cortex make identical executive functional contributions to both spatial and nonspatial working memory.

The hippocampal formation participates in novel picture encoding: evidence from functional magnetic resonance imaging.

Considerable evidence exists to support the hypothesis that the hippocampus and related medial temporal lobe structures are crucial for the encoding and storage of information in long-term memory. Few human imaging studies, however, have successfully shown signal intensity changes in these areas during encoding or retrieval. Using functional magnetic resonance imaging (fMRI), we studied normal human subjects while they performed a novel picture encoding task. High-speed echo-planar imaging techniques evaluated fMRI signal changes throughout the brain. During the encoding of novel pictures, statistically significant increases in fMRI signal were observed bilaterally in the posterior hippocampal formation and parahippocampal gyrus and in the lingual and fusiform gyri. To our knowledge, this experiment is the first fMRI study to show robust signal changes in the human hippocampal region. It also provides evidence that the encoding of novel, complex pictures depends upon an interaction between ventral cortical regions, specialized for object vision, and the hippocampal formation and parahippocampal gyrus, specialized for long-term memory.

Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder.

BACKGROUND: The new technique of functional magnetic resonance imaging was used to investigate the mediating neuroanatomy of obsessive-compulsive disorder symptoms. METHODS: Ten patients with obsessive-compulsive disorder and 5 normal subjects were studied via functional magnetic resonance imaging during control and provoked conditions. Data analysis entailed parametric and nonparametric statistical mapping. RESULTS: Statistical maps (nonparametric; P < 10(-3)) showed activation for 70% or more of patients with obsessive-compulsive disorder in medial orbitofrontal, lateral frontal, anterior temporal, anterior cingulate, and insular cortex, as well as caudate, lenticulate, and amygdala. No normal subjects exhibited activation in any brain region. CONCLUSIONS: Results of functional magnetic resonance imaging were consistent with past studies of obsessive-compulsive disorder that used other functional neuroimaging modalities. However, paralimbic and limbic activations were more prominent in the present study.

The nucleus accumbens in monkeys (Macaca fascicularis): II. Emotion and motivation.

Changes in incentive and emotion have been demonstrated in monkeys with amygdala lesions and monkeys with cingulate and medial frontal lesions. The nucleus accumbens (NA) receives inputs from the amygdala, hippocampus and anterior cingulate cortex. In order to better understand the role of the NA and anterior cingulate cortex in processing emotional and motivational stimuli, studies were undertaken which compared the emotional and motivational behaviour of monkeys with NA lesions or anterior cingulate lesions with previous studies on amygdala-lesioned monkeys. A food preference task, a food vs. non-food discrimination task, and a approach-avoidance task were used with monkeys which received lesions of the NA or lesion of the anterior cingulate and medial frontal cortex. These tasks had previously been used to examine the emotional response of monkeys with amygdala lesions. In addition, the lesioned monkeys were tested on a frustration tasks and a button press acquisition-extinction task. Unlike amygdala-lesioned monkeys (Aggleton, J.P. and Passingham, R.E., J. Comp. Physiol. Psychol., 96 (1981) 961-977 and 96 (1982) 71-77), the NA-lesioned monkeys maintained normal food preferences, did not show signs of hyperorality in the food vs. non-food task, and performed normally on the approach-avoidance tasks. The NA-lesioned monkeys did, however, show an increase in activity, and violent and aggressive behaviour in response to stress in both the frustration task and the button press extinction task. In addition, the NA-lesioned monkeys performed normally during a button press acquisition task, but extinguished faster on a button press extinction task than the control monkeys. The anterior cingulate-lesioned monkeys were also found to exhibit an increased responsiveness to frustration. Results of the food preference, food vs. non-food discrimination, and approach-avoidance tasks were similar to those obtained with NA lesioned. These studies suggest that lesions of the NA or the anterior cingulate cortex result in substantial changes in emotional behavior, however, these changes do not mimic those found following lesions of the amygdala.

Functional MR of brain activity and perfusion in patients with chronic cortical stroke.

PURPOSE: (1) To determine whether functional MR can reliably map functional deficits in patients with stroke in the primary visual cortex; (2) to determine whether functional MR can reliably map perfusion deficits; and (3) to determine whether functional MR can give any additional diagnostic information beyond conventional MR. METHODS: Seven patients who had had a stroke in their primary visual system were examined using two functional MR techniques: (1) dynamic susceptibility contrast imaging, and (2) cortical activation mapping during full-field visual stimulation. Maps of relative cerebral blood volume and activation were created and compared with visual field examinations and conventional T2-weighted images on a quadrant-by-quadrant basis in five of these patients. RESULTS: Visual field mapping matched with both T2-weighted conventional images and activation mapping of 16 of 18 quadrants. In two quadrants, the activation maps detected abnormalities that were present on the visual field examination but not present on the T2-weighted images nor on the relative cerebral blood volume maps, which may indicate abnormal function without frank infarction. In addition, the activation maps demonstrated decreased activation in extrastriate cortex and had normal T2 signal and relative cerebral blood volume but was adjacent to infarcted primary cortex, mapping in vivo how stroke in one location can affect the function of distant tissue. CONCLUSION: Functional MR techniques can accurately map functional and perfusion deficits and thereby provide additional clinically useful information. Additional studies will be needed to determine the prognostic utility of functional MR in stroke patients.

Functional MR in the evaluation of dementia: correlation of abnormal dynamic cerebral blood volume measurements with changes in cerebral metabolism on positron emission tomography with fludeoxyglucose F 18.

PURPOSE: To determine whether magnetic susceptibility functional MR imaging of cerebral blood volumes provides information similar to fludeoxyglucose F 18 positron emission tomography (PET) brain images in patients undergoing evaluation for dementia. METHODS: Ten subjects were studied with both PET and functional MR. Clinical diagnoses included probable Alzheimer disease (n = 5), possible Alzheimer disease (n = 1), Pick disease (n = 2), and primary progressive aphasia (n = 2). The studies were quantitatively evaluated by coregistration of PET and functional MR images followed by regression analyses of corresponding regions of interest. Qualitatively, each brain was categorized into eight regions, and each was classified as normal or abnormal by visual inspection. RESULTS: Correlation coefficients between registered functional MR and PET images were excellent (mean, r = 0.58) in most of the cerebrum. Significant correlations were observed in 72 of 74 brain sections. Qualitatively, 16 brain regions were judged to be abnormal by both MR imaging and PET; 46 regions were normal by both; 10 regions were abnormal by PET only; and 8 regions were abnormal only by functional MR. The concordance between functional MR and PET was 78%, which was highly significant. CONCLUSION: Cerebral blood volumes images derived from magnetic susceptibility (functional MR) provide information similar to fludeoxyglucose F 18 PET images in demented patients undergoing evaluation for dementia.

The nucleus accumbens in monkeys (Macaca fascicularis). III. Reversal learning.

The nucleus accumbens (NA), which receives inputs from limbic structures and projects to the motor system, may be important for the association of reinforcement with action. There are projections to the NA from the amygdala and hippocampus. Discrimination and reversal learning tasks which are known to be disrupted by lesions to these areas in monkeys were given to monkeys with lesions of the NA. Twelve monkeys (Macaca fascicularis) were used in the present study. Six of these received ibotenic acid lesions which resulted in considerable cell loss in the NA; the remaining six acted as controls. The first group of six monkeys were taught a visual discrimination task pre-operatively. Post-operatively, these monkeys were tested on visual and spatial discrimination and reversal tasks. A second group of six monkeys were tested on a motor reversal task. The results indicate that ibotenic acid lesions of the NA transiently impair spatial but not visual reversal learning in monkeys. The NA lesions did not impair a monkey's ability to perform visual or spatial discriminations, or the ability to perform the motor learning or motor reversal tasks. Our results suggest that bilateral lesions of the NA in monkeys do not disrupt the ability to discriminate basic properties of reward-related stimuli or the formation of visual stimulus-reward associations. In addition, our results argue against theories which suggest that the NA is important for behavioural switching or general behavioural flexibility. We conclude that the NA may play a more specific role in the association of temporal and spatial cues with movement and reward.

The functions of the medial premotor cortex. II. The timing and selection of learned movements.

Monkeys with medial premotor cortex (MPC) lesions are impaired on a simple learned task that requires them to raise their arm at their own pace. However, they can succeed on this task if they are given tones to guide performance. In the externally paced task the tones could aid performance in several ways. They tell the animal when to act (trigger), they remind the animal that food is available and so motivate (predictor), and they remind the animal of what to do (instruction). Monkeys with MPC lesions can respond quickly to visual cues (experiment 1), and they can respond as well as normal monkeys when there is no immediate trigger (experiment 2). They are also quick to relearn a task in which external cues tell them what to do (experiment 5). However, they are poor at selecting between movements on a simple motor sequence task (experiment 3), and they are poor at changing between two movements (experiment 4). On these tasks there were cues to act as triggers and predictors, but there were no external instructions. We conclude that the reason why animals with MPC lesions perform better with external cues is that these cues act as instructions. The cues prompt retrieval of the appropriate action. This is true whether the task requires the animal to perform one action (experiments 1 and 2) or to select between actions (experiments 3 and 4).

The functions of the medial premotor cortex. I. Simple learned movements.

We report several studies on the effects of removing the medial premotor cortex (supplementary motor area) in monkeys. The removal of this area alone does not cause either paralysis or akinesia. However, the animals were poor at performing a simple learned task in which they had to carry out an arbitrary action: they were taught to raise their arm in order to obtain food in a foodwell below. They were impaired whether they worked in the light or the dark. They were impaired when they had to perform the movements at their own pace, but much less impaired when a tone paced performance. Monkeys with lesions in the anterior cingulate cortex were as impaired as monkeys with medial premotor lesions at performing this task at their own pace. However, monkeys with lateral premotor lesions were less impaired. We conclude that the medial premotor areas play a crucial role in the performance of learned movements when there is no external stimulus to prompt performance.

The nucleus accumbens in monkeys (Macaca fascicularis): I. The organization of behaviour.

A behavioural comparison was made between six unoperated control monkeys and six monkeys which received bilateral ibotenic acid lesions of the nucleus accumbens. Two of the control monkeys were subsequently given bilateral lesions of the anterior cingulate and medial frontal cortex (areas 24, 25 and 32) and were retested on the behavioural tasks. The NA lesioned monkeys, but not the anterior cingulate lesioned monkeys, were significantly impaired on a hoarding task in which they were required to remove 18 peanuts from their shells and store them in their cheek pouches. These same monkeys were not impaired when the nuts were presented without shells. Evidence is provided which suggests that this deficit is not motivational or due to gross motor impairments. A second task in which the animals were required to search through four boxes to retrieve food revealed a decrease in the tendency for the NA and cingulate lesioned animals to use an organized pattern of searching. Both groups were found to return to a previously opened box more often than controls. However, neither group showed signs of perseverative behaviour. Data from a ten-box version of this task suggest that these return errors were not due to a decrease in working memory. Together these studies suggest that both the NA and the anterior cingulate cortex contribute to the ability to organize behaviour temporally and spatially.