Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers.

BACKGROUND AND PURPOSE: Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. MATERIALS AND METHODS: We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. RESULTS: Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with "abnormal findings with follow-up recommended." The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. CONCLUSIONS: Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.

Working memory as an emergent property of the mind and brain.

Cognitive neuroscience research on working memory has been largely motivated by a standard model that arose from the melding of psychological theory with neuroscience data. Among the tenets of this standard model are that working memory functions arise from the operation of specialized systems that act as buffers for the storage and manipulation of information, and that frontal cortex (particularly prefrontal cortex) is a critical neural substrate for these specialized systems. However, the standard model has been a victim of its own success, and can no longer accommodate many of the empirical findings of studies that it has motivated. An alternative is proposed: Working memory functions arise through the coordinated recruitment, via attention, of brain systems that have evolved to accomplish sensory-, representation-, and action-related functions. Evidence from behavioral, neuropsychological, electrophysiological, and neuroimaging studies, from monkeys and humans, is considered, as is the question of how to interpret delay-period activity in the prefrontal cortex.

The where and how of attention-based rehearsal in spatial working memory.

Rehearsal in human spatial working memory is accomplished, in part, via covert shifts of spatial selective attention to memorized locations ("attention-based rehearsal"). We addressed two outstanding questions about attention-based rehearsal: the topography of the attention-based rehearsal effect, and the mechanism by which it operates. Using event-related fMRI and a procedure that randomized the presentation of trials with delay epochs that were either filled with a flickering checkerboard or unfilled, we localized the effect to extrastriate areas 18 and 19, and confirmed its absence in striate cortex. Delay-epoch activity in these extrastriate regions, as well as in superior parietal lobule and intraparietal sulcus, was also lateralized on unfilled trials, suggesting that attention-based rehearsal produces a baseline shift in areas representing the to-be-remembered location in space. No frontal regions (including frontal eye fields) demonstrated lateralized activity consistent with a role in attention-based rehearsal.

Behavioral and neurophysiological correlates of episodic coding, proactive interference, and list length effects in a running span verbal working memory task.

Updating refers to (1) discarding items from, (2) repositioning items in, and (3) adding items to a running working memory span. Our behavioral and fMRI experiments varied three factors: trial length, proactive interference (PI), and group integrity. Group integrity reflected whether the grouping of items at the encoding stage was violated at discarding. Behavioral results were consistent with the idea that updating processes have a relatively short refractory period and may not fatigue, and they revealed that episodic information about group context is encoded automatically in working memory stimulus representations. The fMRI results did not show evidence that updating requirements in a task recruit executive control processes other than those supporting performance on nonupdating trials. They did reveal an item-accumulation effect, in which signal increased monotonically with the number of items presented during the trial, despite the insensitivity of behavioral measures to this factor. Behavioral and fMRI correlates of PI extended previous results and rejected an alternative explanation of PI effects in working memory.

Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies.

Working memory refers to the short-term retention of information that is no longer accessible in the environment, and the manipulation of this information, for subsequent use in guiding behavior. In this review, we will present data from a series of event-related functional magnetic-resonance-imaging (fMRI) studies of delayed-response tasks that were designed to investigate the role of different regions of the prefrontal cortex (PFC) during different working-memory component processes. From these data, we conclude that: (1) lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information; and (2) consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding- and response-related processes as well as mnemonic and nonmnemonic processes that are engaged during the temporary maintenance of information. Thus, lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation.

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.

Using event-related fMRI to assess delay-period activity during performance of spatial and nonspatial working memory tasks.

Event-related experimental design and analysis techniques for functional magnetic resonance imaging (fMRI) take advantage of the intrinsic temporal resolution of fMRI to permit investigation of complex human behaviors on the time scale over which they can occur. The protocol described in this report permits the effective isolation and assessment of variance in the fMRI signal that is attributable solely to the delay portion of delayed-response tasks. It permits, therefore, evaluation of the purely mnemonic portions of working memory tasks without requiring the "cognitive subtraction" of nonmnemonic components of such tasks, such as visual processing and motor output. Features of this event-related fMRI technique include the empirical derivation of an impulse response function (IRF) from each subject participating in the experiment, single-subject and random effects group analyses, use of t-values of dependent measures, and the use of regions of interest (ROI) to improve the sensitivity of a priori contrasts. This report provides a detailed exposition of the research methodology of our event-related fMRI technique, the rationale behind many of its critical features, and examples of its application to two empirical datasets.

Activity in human frontal cortex associated with spatial working memory and saccadic behavior.

We examined, with event-related fMRI, two hypotheses about the organization of human working memory function in frontal cortex: (1) that a region immediately anterior to the frontal eye fields (FEF) (superior frontal cortex, SFC) is specialized for spatial working memory (Courtney, et al., 1998); and (2) that dorsolateral prefrontal cortex (PFC) plays a privileged role in the manipulation of spatial stimuli held in working memory (Owen, et al., 1996; Petrides 1994). Our delayed-response task featured 2-D arrays of irregularly arranged squares that were highlighted serially in a random sequence. The Forward Memory condition required maintenance of the spatio-temporal sequence, the Manipulate Memory condition required reordering this sequence into a new spatially defined order, the Guided Saccade condition required saccades to highlighted squares in the array, but no memory, and the Free Saccade condition required self-paced, horizontal saccades. The comparison of fMRI signal intensity associated with 2-D saccade generation (Guided Saccades) versus fMRI signal intensity associated with the delay period of the working memorials condition revealed no evidence for greater working memory-related activity than saccade-related activity in SFC in any individual subject, nor at the level of the group, and greater 2-D saccade than delay-period activity in three of five subjects. These results fail to support the hypothesis that spatial working memory-related activity is represented preferentially in a region of SFC anterior to the FEF (Courtney, et al., 1998). The comparison of maintenance versus manipulation of spatio-temporal information in working memory revealed significantly greater activity associated with the latter in dorsolateral PFC, but not in ventrolateral PFC or in SFC. These results suggest that the delay-related function of SFC is limited to the maintenance of spatial information, and that this region does not support the nonmnemonic executive control functions supported by dorsolateral PFC. These results also indicate that the preferential recruitment of dorsolateral PFC for the manipulation of information held in working memory applies to tasks employing spatial stimuli, as well as to tasks employing verbal stimuli (D'Esposito, et al., 1999); Petrides et al., 1993; Postle et al., 1999).

An evaluation of the concurrent discrimination task as a measure of habit learning: performance of amnesic subjects.

Habit learning has been defined as an association between a stimulus and a response that develops slowly and automatically through repeated reinforcement. Concurrent discrimination (CD) learning, in which subjects learn to choose the rewarded objects in a series of pairs, is believed to be an example of habit learning in monkeys. Studies of human amnesic subjects, however, have produced equivocal results, revealing impaired or absent learning on the same CD tasks that monkeys with medial temporal-lobe (MTL) lesions learn normally. One possible explanation for impaired performance in human amnesic subjects is that, unlike monkeys, human subjects use explicit memory to solve CD problems. To test this hypothesis, we administered a 10-object pair CD learning task to two amnesic subjects, HM and PN, and normal control subjects (NCS). Both amnesic subjects have severe anterograde amnesia with little ability to form explicit memories. On the CD task, they demonstrated little or no learning and acquired no explicit knowledge of the task procedures or reward contingencies. In contrast, NCS learned the task quickly and easily using explicit memory strategies. These results suggest that CD tasks cannot be learned by habit in human subjects, and emphasize the discrepancies between the human and monkey literature on habit learning.

"What"-Then-Where" in visual working memory: an event-related fMRI study.

Behavioral studies indicate that spatial and object working memory are computed by dissociable subsystems. We investigated the neural bases of this dissociation with a whole-brain fMRI design and analysis technique that permitted direct assessment of delay-period activity, uncontaminated by other components of the trial. The task employed a "what"-then-"where" design, with an object and a spatial delay period incorporated in each trial; within-trial order of delay conditions was balanced across each scan. Our experiment failed to find evidence, at the single-subject level and at the group level, for anatomical segregation of spatial and object working memory function in the frontal cortex. Delay-period activity in the caudate nucleus revealed a sensitivity to position in the trial in the spatial, but not the object, condition. In posterior regions, spatial delay-period activity was associated with preferential recruitment of extrastriate areas falling within Brodmann's area 19 and, less reliably, the superior parietal lobule. Object-specific delay-period activity was found predominantly in ventral regions of the posterior cortex and demonstrated more topographic variability across subjects than did spatial working memory activity.

The dependence of span and delayed-response performance on prefrontal cortex.

Theoretical and empirical research on the cognitive functions of the prefrontal cortex have established that this region mediates what have been called 'executive' processes that can influence working and long-term memory. Despite the accumulation of such empirical evidence, the dependence of purely mnemonic portions of memory tasks on PFC remains unresolved. To address this issue, we performed an analysis of reports of performance on tests of working memory of patients with lesions of the dorsolateral prefrontal cortex, focusing on published reports in the literature of simple span and delayed-response tasks. We found that none of the eleven studies of forward verbal and spatial span in patients with prefrontal cortical lesions that we reviewed (reflecting the performance of 166 individual patients) demonstrated a statistically significant deficit relative to normal controls. In contrast, our review of the delayed-response literature indicated that there are conditions under which PFC lesions disrupt delayed-response performance. Based on the results of our review of the literature, we present testable hypotheses about the working memory functions of the PFC.

Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance.

We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task: memory storage and memory manipulation. Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets (to identify load-sensitive regions) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets (to identify manipulation-sensitive regions). Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity (as contrasted with alphabetization-sensitive voxels in this region in only one subject) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity (as contrasted with load-sensitive voxels in this region in two subjects). This double dissociation was reliable at the group level. These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated. More broadly, they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes.

Maintenance versus manipulation of information held in working memory: an event-related fMRI study.

One model of the functional organization of lateral prefrontal cortex (PFC) in primates posits that this region is organized in a dorsal/ventral fashion subserving spatial and object working memory, respectively. Alternatively, it has been proposed that a dorsal/ventral subdivision of lateral PFC instead reflects the type of processing performed upon information held in working memory. We tested this hypothesis using an event-related fMRI method that can discriminate among functional changes occurring during temporally separated behavioral subcomponents of a single trial. Subjects performed a delayed-response task with two types of trials in which they were required to: (1) retain a sequence of letters across the delay period (maintenance) or (2) reorder the sequence into alphabetical order across the delay period (manipulation). In each subject, activity during the delay period was found in both dorsolateral and ventrolateral PFC in both types of trials. However, dorsolateral PFC activity was greater in manipulation trials. These findings are consistent with the processing model of the functional organization of working memory in PFC.

Dissociation of human caudate nucleus activity in spatial and nonspatial working memory: an event-related fMRI study.

We employed a novel event-related fMRI design and analysis technique to explore caudate nucleus contributions to spatial and nonspatial working memory. The spatial condition of a delayed-response task revealed greater mnemonic activation in four of six subjects when the delay period preceded immediately a probe stimulus requiring an overt motor response, as contrasted with a probe requiring no response. This effect was not seen in frontal or parietal cortical areas, and was seen in the caudate nucleus in a formally identical object condition in just one of six subjects. We hypothesized that this pattern of activity represented spatially dependent motor preparation. A second experiment confirmed this hypothesis: delay-period activity of the caudate nucleus showed greater time dependence in a task that featured spatial and motoric memory demands than in a comparable nonspatial task that featured the same response contingencies. These results suggest an important subcortical locus of the dissociation between spatial and nonspatial working memory, and a role for the human caudate nucleus in the integration of spatially coded mnemonic information with motor preparation to guide behavior.

The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional MRI.

Research on the prefrontal cortex (PFC) of monkeys and humans indicates that this region supports a heterogeneous repertoire of mental processes that contribute to many complex behaviors, such as working memory. Anatomical evidence for some of these processes derives from functional neuroimaging experiments using blocked experimental designs, which average signal across all components of many trials and therefore cannot dissociate distinct processes with different time courses. Using event-related functional MRI, we were able to isolate temporally the neural correlates of processes contributing to the target presentation, delay, and probe portions of an item-recognition task. Two types of trials were of greatest interest: those with Recent Negative probes that matched an item from the target set of the previous, but not the present, two trials, and those with Nonrecent Negative probes that did not match a target item from either the present or the two previous trials. There was no difference between the two trial types in target presentation (i.e., encoding) or delay-period (i.e., active maintenance) PFC activation, but there was significantly greater activation for Recent Negatives than Nonrecent Negative activation associated with the probe period within left ventrolateral PFC. These findings characterize spatially and temporally a proactive interference effect that may reflect the operation of a PFC-mediated response-inhibition mechanism that contributes to working memory performance.

Manipulation of familiarity reveals a necessary lexical component of the word-stem completion priming effect.

These experiments were motivated by the idea that many types of nondeclarative memory are by-products arising from the plasticity that is inherent in much of the nervous system. We hypothesized that two types of repetition priming, word-stem completion (WSC) priming and perceptual identification (PI) priming, rely on different mechanisms because the WSC task and the PI task engage different cognitive and brain processes. We tested this hypothesis by manipulating word familiarity. The results, impaired WSC priming but intact PI priming with unfamiliar words, indicate that WSC priming relies primarily on a modification mechanism, whereas PI priming relies primarily on an acquisition mechanism. Our conclusions are consistent with component processes theories of nondeclarative memory.

Impaired word-stem completion priming but intact perceptual identification priming with novel words: evidence from the amnesic patient H.M.

We hypothesized that word-stem completion (WSC) priming and perceptual identification (PI) priming, two types of repetition priming, rely on different cognitive and neural mechanisms: WSC priming on a modification mechanism that influences lexical retrieval, and PI priming on plasticity in pre-lexical perceptual systems. We compared the priming performance of the amnesic patient H.M. with words that came into common usage after the onset of his amnesia, and thus were novel to him (post-1965 words), and with familiar (pre-1953) words. We also tested age- and education-matched normal control subjects (NCS) and a patient with anterograde amnesia of recent onset (P.N.). The modification hypothesis predicted that H.M. would fail to show WSC priming with post-1965 words because pre-existing lexical representations of the test stimuli would be necessary for priming to occur. H.M.'s WSC priming score in the post-1965 condition did not differ from 0, and was inferior to the performance of NCS and of P.N. In contrast, H.M. displayed normal WSC priming in the pre-1953 condition. H.M. also showed robust and equivalent levels of PI priming in both conditions. A final experiment demonstrated preserved post-1965 word PI priming in H.M. when his baseline performance was matched with his post-1965 WSC priming baseline score. Our results challenge models that assume that most kinds of verbal repetition priming rely on the same or similar perceptual mechanisms.

The time course of spatial and object learning in Parkinson's disease.

Parkinson's disease (PD) is characterized by spatial memory dysfunction, but the selectivity of the deficit remains unclear. We addressed this issue by comparing performance on spatial and object variants of a conditional associative learning task, and by analysing the data with time series analytical techniques. The 11 PD subjects and 15 normal control subjects learned stimulus-stimulus pairings through trial-and-error learning. PD subjects were selectively impaired on the spatial condition: they required more trials to achieve criterion, learned at a slower rate and displayed a working memory deficit. The groups did not differ in the object condition. These results suggest a distinction between material-specific spatial and object visual memory systems. Further, they indicate that spatial learning and memory are selectively impaired in early PD, suggesting that interactions between the basal ganglia and prefrontal cortex are important for the mediation of high-level cognition.

Spatial, but not object, delayed response is impaired in early Parkinson's disease.

The authors hypothesized that the pathophysiology of early Parkinson's disease (PD) may selectively target structures that support visual working memory for spatial relations but leave structures that support working memory for featural characteristics of objects relatively intact. Fifteen PD and 15 normal control participants took a visual delayed-response test with a spatial condition and a (nonspatial) object condition, equating the perceptual difficulty of the tests for each participant. The stimuli were irregular polygons presented at different locations on a computer screen. Results revealed a selective impairment of spatial delayed response in PD, indicating a disruption of spatial working memory unconfounded by sensory processing difficulties. The selectivity of this deficit may reflect the circumscribed nature of pathophysiological change affecting the caudate nucleus in early PD.

Intact implicit memory for novel patterns in Alzheimer's disease.

Repetition priming is a kind of implicit memory (learning without awareness) that does not depend on the medial temporal-lobe system. For example, the amnesic patient H.M., who underwent bilateral medial temporal-lobe resection, shows intact priming with novel patterns, suggesting that perceptual priming with nonverbal material does not depend on areas critical for explicit memory. A logical candidate for the neural substrate that supports this kind of priming is the peristriate cortex, an area that is relatively spared in Alzheimer's disease (AD). We therefore predicted that AD subjects would be unimpaired on pattern priming. Subjects copied each of six target figures onto dot patterns. After performing a 3-min distractor task, they were given the same dot patterns (without lines) and asked to draw the first figure that came to mind by connecting the dots with straight lines. Subsequently, in a test of recognition (explicit) memory, subjects viewed each of the six patterns of dots that they had copied previously and were asked to indicate which of four possible completions corresponded to the figure that they had copied 3 min earlier. The AD and control groups achieved comparable priming scores, but AD subjects were significantly impaired in recognizing the patterns explicitly. Our finding of intact pattern priming in AD provides, for the first time, evidence that pattern priming depends on the peristriate cortex.