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1991
D’Esposito.  1991.  The Pharmacology of Memory. Abstract

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1993
D’Esposito, McGlinchey-Berroth R, Alexander M, Verfaellie M, Milberg WP.  1993.  Dissociable cognitive and neural mechanisms of unilateral visual neglect., 1993 Dec. Neurology. 43:2638-44. Abstract

We administered two experimental tasks to 16 patients with neglect following unilateral right hemisphere strokes, designed to probe processing of information in the neglected left visual field. A semantic priming/lexical decision task examined implicit processing of stimuli presented to the neglected field, and a discrimination task required explicit recognition of the same stimuli. We grouped patients according to three patterns of performance: (1) poor discrimination in the left visual field but intact priming, (2) normal priming and discrimination in both fields, and (3) normal priming but poor discrimination in both fields. Although patients in group 1 had posterior lesions, patients in groups 2 and 3 had extensive deep anterior lesions. These results suggest that the clinical phenomenon of unilateral visual neglect can be the surface manifestation of deficits in two different and interacting processes–attentional processes (group 1) and intentional processes (group 2)–or it may be a global attentional disturbance superimposed on these deficits (group 3).

1994
Grossman, M.  1994.  Patterns of cognitive impairment in relapsing-remitting and chronic-progressive multiple sclerosis. Neuropsychiatry, Neuropsychology & Behavioral Neurology. AbstractWebsite

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Wolfe, N, Babikian VL, Linn RT, Knoefel JE, D’Esposito, Albert ML.  1994.  Are multiple cerebral infarcts synergistic?, 1994 Feb Archives of neurology. 51:211-5. Abstract

OBJECTIVE: The goal of this study was to characterize the cumulative effects of multiple strokes on cognition. DESIGN: We conducted a prospective, longitudinal case study with neuropsychological, neurological, and radiological evaluations. SETTING: Research was conducted at the Boston (Mass) Veterans Administration Medical Center, Neurology Service, on successive inpatient hospital admissions. PATIENT: We followed up a 66-year-old right-handed man with multiple subcortical lacunae during a 3.5-year period during which he suffered two additional cortical infarctions. MAIN OUTCOME MEASURES: Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cognitive domains (attention, language, memory, visuospatial functions, response inhibition, and mental flexibility), full neurological examination, and computed tomographic scan. RESULTS: The patient’s stepwise cognitive decline was characterized by unexpected exacerbation of "frontal" neurobehavioral features following the occurrence of two posterior cortical lesions. At initial evaluation, the computed tomographic scan showed bilateral subcortical lacunae in basal ganglia and periventricular white matter, and symptoms included dysarthria and perseveration. The second evaluation, following a left posterior parietal lesion, revealed a range of new frontal features, including impulsivity, pull-to-stimulus, and difficulty shifting set. Following a subsequent right occipital infarct, further frontal lobe impairments emerged: forced grasp reflex and incontinence. CONCLUSIONS: We hypothesize that the cumulative effects of infarcts were synergistic. That is, the posterior cortical infarcts elicited frontal features that would not be expected from a simple sum of these lesions’ effects.

1995
D’Esposito, Alexander M.  1995.  The clinical profiles, recovery and rehabilitation of memory disorders. Neurorehabilitation. Abstract

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Grossman, M, Peltzer L, D'Esposito M, Alavi A, Reivich M.  1995.  Recovery of function after focal cerebral insult: a PET activation study. Neuropsychological Explorations of Memory and Cognition: Essays in Honor of Nelson Butters. , New York: Plenum Press Abstract

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D’Esposito, Verfaellie M, Alexander M, Katz DI.  1995.  Amnesia following traumatic bilateral fornix transection., 1995 Aug. Neurology. 45:1546-50. Abstract1995desposito.pdf

There is controversy regarding the effect of isolated fornix damage on human memory. We report a patient who suffered a traumatic penetrating head injury that resulted in a significant and persistent anterograde amnesia. CT revealed a lesion that involved the region of the proximal, posterior portion of both fornices without evidence of damage to other hippocampal pathways or to other structures known to be critical for memory, such as the hippocampus, thalamus, or basal forebrain. The unique location of the lesion in this patient provides evidence supporting the role of isolated fornix lesions in amnesia.

Biassou, N, Grossman M, Onishi K, Mickanin J, Hughes E, Robinson KM, D’Esposito.  1995.  Phonologic processing deficits in Alzheimer’s disease., 1995 Dec. Neurology. 45:2165-9. Abstract1995biassou.pdf

We investigated phonologic production in patients with mild to moderate Alzheimer’s disease (AD) on a repetition task. AD patients produced significantly more speech errors than age-matched controls. AD patients’ errors, unlike those of controls, resulted in the transformation of real words into pseudowords, occurred disproportionately in word-initial positions, and were not influenced by the phonologic environment. This pattern of errors suggests a lexical phonologic retrieval deficit in AD.

Fischer, R, Alexander M, D’Esposito, Otto R.  1995.  Neuropsychological and neuroanatomical correlates of confabulation., 1995 Feb. Journal of clinical and experimental neuropsychology. 17:20-8. Abstract

In the present exploratory investigation we report nine confabulatory patients of comparable age, education, and general level of intelligence in the acute epoch of recovery after rupture and clipping of ACoA aneurysms. Five of the nine cases had "spontaneous" confabulation, severe anterograde amnesia, markedly poor attentional and executive functions, and denial of illness. These patients all had multiple lesions that involved basal forebrain, ventral frontal lobe, and striatum. The other four patients manifested only "momentary" or "provoked" confabulations. These patients also had severe anterograde amnesia but showed relatively mild deficits in executive functions. These patients had lesions restricted to the basal forebrain except for one who had additional orbital frontal damage. Analysis of these two groups of confabulatory patients suggests that there is a common profile of deficits and anatomic foundation associated with confabulation; "spontaneous" confabulation appears to require extensive, simultaneous disruption of medial basal forebrain and frontal cognitive systems resulting in profound executive and memory deficits, whereas more limited lesions to the basal forebrain or orbital frontal cortex will result in "transient" or "provoked" confabulatory responses and a more restricted profile of cognitive deficits.

D’Esposito, Alexander M.  1995.  Subcortical aphasia: distinct profiles following left putaminal hemorrhage., 1995 Jan. Neurology. 45:38-41. Abstract1995desposito2.pdf

Numerous reports of aphasia after subcortical lesions have produced incomplete agreement about basic clinico-anatomic correlations. Some disagreement has arisen from methodologic differences. To control for some of the common differences, we analyzed 13 patients with left putaminal hemorrhage controlled for location–subcortical but not thalamic, and for time postonset–studied in both acute and postacute epochs. There was no apparent correlation between lesion site and acute language profiles. During the postacute epoch, there were several distinct correlations between lesion site (postacute decreased CT density) and specific aphasia dimensions–nonfluency, impaired comprehension, and perhaps impaired repetition. Our correlations were compatible with comparably controlled cases in the literature. A corollary result of this study is that patients fluent during the early epoch are likely to have a better outcome, and those initially nonfluent have a poor prognosis for language recovery.

D’Esposito.  1995.  Profile of a neurology residency., 1995 Nov. Archives of neurology. 52:1123-6. Abstract1995despoarchneurol.pdf

The pattern and frequency of patient encounters during the Boston (Mass) University adult neurology residency program (1988 to 1991) for one resident was compared with that in general neurology practice as well as with the frequency of neurologic disorders in the US population. A total of 1332 new patients (85% adult, 15% pediatric) were seen during a 3-year period. This total represented 970 inpatients (73% of all patients) and 362 outpatients (27%). The resident encountered more patients in the hospital (7.5 admissions or 13 consultations per week) and fewer patients in the clinic (2.5 new outpatients per week) than does the average community neurologist (two admissions, 8.7 consultations, and 13.2 new outpatients). The most common diagnosis for an admission encounter was acute ischemic infarct; for a consultation, metabolic encephalopathy; and for an outpatient encounter, radiculopathy. Less prevalent neurologic disorders in the United States (eg, cognitive, demyelinating, movement, and neoplastic disorders) were encountered more frequently in residency than were very prevalent neurologic disorders (eg, headache and trauma). This is the first reported summary of all patients one resident actually encountered during neurology training. The patient encounter profile suggests that this residency training overemphasized acute inpatient care of less prevalent neurologic disorders compared with outpatient care of more prevalent disorders commonly seen in a neurology practice. Accumulation of similar data from other residencies and practicing neurologists can help residency directors assess the changing needs of residents in training and guide curriculum in response to changes in practice patterns.

D’Esposito, Detre JA, Alsop D, Shin RK, Atlas S, Grossman M.  1995.  The neural basis of the central executive system of working memory., 1995 Nov 16. Nature. 378:279-81. Abstractdesposito1995_the_neural_basis_of_the_central_executive_system_of_working_memory_nature.pdf

Working memory refers to a system for temporary storage and manipulation of information in the brain, a function critical for a wide range of cognitive operations. It has been proposed that working memory includes a central executive system (CES) to control attention and information flow to and from verbal and spatial short-term memory buffers. Although the prefrontal cortex is activated during both verbal and spatial passive working memory tasks, the brain regions involved in the CES component of working memory have not been identified. We have used functional magnetic resonance imaging (fMRI) to examine brain activation during the concurrent performance of two tasks, which is expected to engage the CES. Activation of the prefrontal cortex was observed when both tasks are performed together, but not when they are performed separately. These results support the view that the prefrontal cortex is involved in human working memory.

Grossman, M, Robinson KM, Onishi K, Thompson H, Cohen J, D’Esposito.  1995.  Sentence comprehension in multiple sclerosis., 1995 Oct. Acta neurologica Scandinavica. 92:324-31. Abstract

INTRODUCTION: Explanations of sentence processing difficulty in aphasia have implicated slowed information processing speed. We tested this hypothesis by evaluating sentence comprehension in multiple sclerosis (MS), and relating comprehension performance to measures of information processing speed. MATERIAL & METHODS: Twenty right-handed, high school-educated, non-demented, native English speakers with clinically definite MS and 16 age- and education-matched control subjects were examined on 3 different sentence comprehension measures that stress grammatical appreciation. Performance was related to quantitative assessments of mental information processing speed. RESULTS: Group-wide analyses demonstrated a trend toward sentence comprehension difficulty in MS. Analyses of individual patient profiles identified a subgroup of MS patients who were consistently impaired to a significant extent across all sentence comprehension tasks. Their sentence comprehension difficulty was associated with selectively compromised mental information processing speed. CONCLUSION: Sentence comprehension difficulty in MS is associated with slowed information processing speed. This finding supports the claim that information processing speed contributes to sentence processing.

1996
Grossman, M, Galetta S, Ding X-S, Morrison D, D’Esposito, Robinson K, Jaggi J, Alavi A, Reivich M.  1996.  Clinical and positron emission tomography studies of visual apperceptive agnosia. Neuropsychiatry, Neuropsychology & Behavioral Neurology. AbstractWebsite

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Kroll, NEA, Knight RT, Metcalfed E, Wolfe ES, Tulving E.  1996.  Cohesion failure as a source of memory illusions. Journal of Memory and Language. Abstract1996kroll.pdf

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McGlinchey-Berroth, R, Milberg W, Verfaellie M, Grande L, D’Esposito, Alexander M.  1996.  Semantic processing and orthographic specificity in hemispatial neglect. Abstract1996mcglincheyberroth.pdf

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White-Devine, T, Grossman M, Robinson K, Onishi K, Biassou N.  1996.  Verb confrontation naming and word-picture matching in Alzheimer’s disease. Neuropsychology. Abstract1996whitedevine.pdfWebsite

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Grossman, M, Mickanin J, Robinson KM, D’Esposito.  1996.  Anomaly judgments of subject-predicate relations in Alzheimer’s disease., 1996 Aug. Brain and language. 54:216-32. Abstract1996grossman.pdf

Claims that patients with probable Alzheimer’s disease (AD) have semantic memory difficulty have received equivocal support. A common assumption has been that defining or core information determines the truth value of word meaning on measures requiring semantic memory such as category membership judgments or confrontation naming, but this assumption may not be valid. In the present study, we assessed the comprehension of subject-predicate sentences independent of their truth value by asking AD patients to judge the coherence of statements such as "The tulip is tall" or "*The tulip is jealous." We found that AD patients are significantly more impaired than controls at judging the coherence of these simple subject-predicate sentences. Moreover, AD patients were more successful at judging the coherence of statements that contain attributes with a narrow scope of reference compared to attributes with a broad scope of reference. These findings support the hypothesis that AD patients have a semantic memory impairment and suggest a specific deficit processing the network of semantic relations underlying word meaning in semantic memory.

Ween, JE, Alexander M, D’Esposito, Roberts M.  1996.  Factors predictive of stroke outcome in a rehabilitation setting., 1996 Aug. Neurology. 47:388-92. Abstract1996ween.pdf

Accurate outcome prediction following stroke is important for proper delivery of poststroke care. It has been difficult to determine specific factors that provide reliable and accurate predictions of outcome, particularly for patients with intermediate deficit severities. Age and severity of deficit have repeatedly been found to be most reliable, but only as rough estimates and for patients at either extreme of the disability spectrum. This paper reports a prospective study of consecutive rehabilitation admissions (N = 536) to determine the influence of preselected factors. Outcome was analyzed in terms of functional improvement and disposition. Patients younger than 55 years or with an admission Functional Independence Measure (FIM) greater than 80 almost universally went home. Admission FIMs less than 40 were associated with nearly certain nursing home discharge. The comprehensive FIM score was a stronger predictor of outcome than motor impairment in isolation. An admission FIM of 60 or greater was associated with a higher probability of functional improvement during rehabilitation. Small-vessel strokes had the best outcome. Intracerebral hemorrhages improved more than ischemic strokes but more slowly. Right hemisphere lesions did worse than left. Comorbidities influenced outcome only when several conditions accumulated. The absence of a committed caregiver at home increased the risk of nursing home discharge. Suggestions for rehabilitation triage are given.

Alsop, D, Detre JA, D’Esposito, Howard RS, Maldjian JA, Grossman M, Listerud J, Flamm ES, Judy KD, Atlas S.  1996.  Functional activation during an auditory comprehension task in patients with temporal lobe lesions., 1996 Aug. NeuroImage. 4:55-9. Abstract1996alsop.pdf

Functional magnetic resonance imaging (fMRI) was used to map regional brain activation during an auditory comprehension task in two normal controls and two patients with left temporal lobe lesions. Activity in the superior temporal and angular gyrus regions was detected in all normal subjects. In the patients, the spatial distribution of activation ipsilateral to the lesions differed from the pattern observed in contralateral cortex or in control subjects. These studies highlight the potential of fMRI for mapping abnormal functional anatomy in the human brain.

Robinson, KM, Grossman M, White-Devine T, D’Esposito.  1996.  Category-specific difficulty naming with verbs in Alzheimer’s disease., 1996 Jul. Neurology. 47:178-82. Abstract1996robinson.pdf

We studied 20 patients with Alzheimer’s disease (AD) on a picture-naming task consisting of frequency-matched pairs of nouns and verbs that were homophonic and homographic (e.g., paint). Intragroup comparisons revealed that verb naming is significantly more difficult for patients with AD than noun naming. An error analysis demonstrated that patients with AD produce significantly more semantic and descriptive errors for verbs than nouns. We correlated verb naming and noun naming with measures of grammatical comprehension, lexical retrieval, and visuoperceptual processing, but there were no selective effects for verbs compared with nouns. Differences in the mental representation of concepts underlying verbs and nouns may account, in part, for the relative difficulty naming with verbs in AD.

Grossman, M, D’Esposito, Hughes E, Onishi K, Biassou N, White-Devine T, Robinson KM.  1996.  Language comprehension profiles in Alzheimer’s disease, multi-infarct dementia, and frontotemporal degeneration., 1996 Jul. Neurology. 47:183-9. Abstract1996grossman4.pdf

We assessed language functioning in 116 age-, education-, and severity-matched patients with the clinical diagnosis of Alzheimer’s disease (AD), multi-infarct dementia (MID) due to small-vessel ischemic disease, or a frontotemporal form of degeneration (FD). Assessments of comprehension revealed that patients with AD are significantly impaired in their judgments of single word and picture meaning, whereas patients with FD had sentence comprehension difficulty due to impaired processing of grammatical phrase structure. Patients with MID did not differ from control subjects in their comprehension performance. Traditional aphasiologic measures did not distinguish between AD, MID, and FD. Selective patterns of comprehension difficulty in patients with different forms of dementia emphasize that language deficits cannot be explained entirely by the compromised memory associated with a progressive neurodegenerative illness.

Maldjian, J, Atlas S, Howard RS, Greenstein E, Alsop D, Detre JA, Listerud J, D’Esposito, Flamm ES.  1996.  Functional magnetic resonance imaging of regional brain activity in patients with intracerebral arteriovenous malformations before surgical or endovascular therapy., 1996 Mar. Journal of neurosurgery. 84:477-83. Abstract1996maldjian.pdf

Functional magnetic resonance (MR) imaging was performed in six patients harboring proven intracerebral arteriovenous malformations (AVMs) using a noninvasive blood oxygen level-dependent technique based on the documented discrepancy between regional increases in blood flow and oxygen utilization in response to regional brain activation. Statistical functional MR maps were generated and overlaid directly onto conventional MR images obtained at the same session. In the six patients studied, a total of 23 separate functional MR imaging activation studies were performed. Of these, two runs were discarded because of motion artifacts. All of the remaining 21 studies demonstrated activation in or near expected regions for the paradigm employed. Qualitatively reproducible regional localizations of functional activity in unexpected sites were also seen. The authors’ findings indicating aberrant mapping of cortical function may be explained on the basis of the plasticity of brain function, in that the developing brain can take over function that would normally have been performed by regions of brain encompassed by the lesion. Preliminary results in this study’s small number of cases also indicate that activity demonstrated within the confines of the apparent AVM nidus may help predict the development of a posttherapy deficit. The authors demonstrate that functional MR imaging can be successfully and reproducibly performed in patients with intracerebral AVMs. Notwithstanding the paucity of normative data using functional MR imaging, the author’ findings support cortical reorganization associated with these congenital lesions. Blood oxygen level-dependent MR imaging is a noninvasive method used to localize areas of eloquent cortex in patients harboring AVMs; it may prove to be of value in treatment planning.

Grossman, M, Mickanin J, Onishi K, Robinson KM, D’Esposito.  1996.  Freehand drawing impairments in probable Alzheimer’s disease., 1996 May. Journal of the International Neuropsychological Society : JINS. 2:226-35. Abstract

We evaluated freehand picture production of familiar objects in patients with probable Alzheimer’s disease. The overall recognizability of their drawings was significantly compromised. Error analyses revealed the production of category violations and the frequent inclusion of incorrect features in a picture that were borrowed from semantically related objects, suggesting difficulty distinguishing between items with overlapping features sets in semantic memory. Analyses of individual patient drawing profiles also revealed that some patients are disproportionately compromised in expressing a particular perceptual feature, implicating difficulty at the level of perceptual processing. Regression analyses demonstrated the contribution of limited visual attentional resources. We conclude that impaired freehand drawing in probable Alzheimer’s disease is multifactorial in nature.

D’Esposito, Alexander M, Fischer R, McGlinchey-Berroth R, O’Connor M.  1996.  Recovery of memory and executive function following anterior communicating artery aneurysm rupture., 1996 Nov. Journal of the International Neuropsychological Society : JINS. 2:565-70. Abstract

We studied the recovery of memory and executive function in 10 patients following anterior communicating artery aneurysm (ACoA) rupture and repair. Patients were tested at 2 consecutive points in time following surgery (approximately at 2 and 3 months). At the first testing, the patients divided into 2 groups based on the severity of impairment on executive measures. Both groups had severe anterograde amnesia, but only patients with severe executive impairments had retrograde amnesia with a temporal gradient. At second testing, both groups had persistent severe anterograde amnesia. The dysexecutive group showed significant improvement in executive deficits and in retrograde amnesia, with attenuation of the temporal gradient. Patients with more severe executive impairments had more extensive bilateral frontal lesions than other patients. These results suggest that the cognitive profile following ACoA rupture changes with time. Time postonset following aneurysm rupture and lesion site are both critical for defining the neuropsychological profile, and determining the underlying cognitive mechanisms in this neurological disorder.

Zorrilla, LT, Aguirre GK, Zarahn E, Cannon TD, D’Esposito.  1996.  Activation of the prefrontal cortex during judgments of recency: a functional MRI study., 1996 Nov 4. Neuroreport. 7:2803-6. Abstract

Animal and human lesion studies have consistently shown that damage to the prefrontal lobe disrupts performance on tasks requiring memory for temporal context. In this study, functional magnetic resonance imaging (fMRI) was used to explore the brain regions associated with judgements of relative recency in healthy humans. Bilateral dorsolateral prefrontal cortex (Brodmann’s area [BA] 9) was more active during a verbal recency judgment task than during a non-mnemonic control task. Activation related to temporal context recognition was also observed in midline supplementary motor area (BA 6) and left precuneus (BA 7). This study provides further evidence that memory for temporal context requires the prefrontal cortex and is the first to demonstrate this association in healthy humans. The current findings also suggest the possibility that recognition of context and recognition of episodic content may involve similar brain systems.

Aguirre, GK, Detre JA, Alsop D, D’Esposito.  1996.  The parahippocampus subserves topographical learning in man., 1996 Nov-Dec. Cerebral cortex (New York, N.Y. : 1991). 6:823-9. Abstract1996aguirre.pdf

The hippocampus has been proposed as the site of neural representation of large-scale environmental space, based upon the identification of place cells (neurons with receptive fields for current position in the environment) within the rat hippocampus and the demonstration that hippocampal lesions impair place learning in the rat. The inability to identify place cells within the monkey hippocampus and the observation that unilateral hippocampal lesions do not selectively impair topographic behavior in humans suggest that alternate regions may subserve this function in man. To examine the contribution of the hippocampus and adjacent medial-temporal lobe structures to topographic learning in the human, a ’virtual’ maze was used as a task environment during functional magnetic resonance imaging studies. During the learning and recall of topographic information, medial-temporal activity was confined to the para- hippocampal gyri. This activity accords well with the lesion site known to produce topographical disorientation in humans. Activity was also observed in cortical areas known to project to the parahippocampus and previously proposed to contribute to a network subserving spatially guided behavior.

McGlinchey-Berroth, R, Bullis DP, Milberg WP, Verfaellie M, Alexander M, D’Esposito.  1996.  Assessment of neglect reveals dissociable behavioral but not neuroanatomical subtypes., 1996 Sep. Journal of the International Neuropsychological Society : JINS. 2:441-51. Abstract

In the current study, we investigated whether standard assessment techniques of visuospatial neglect are sensitive to detecting dissociable subtypes. We administered a battery of tasks commonly used to detect the presence of visuospatial neglect to 120 patients with unilateral right hemisphere infarcts and, in most cases, performed a systematic analysis of their lesions to quantify and localize brain damage. Using a factor analysis, we discovered seven relatively independent constructs, three of which were specifically related to the presence of left hemispatial neglect: Left Attentional Processing, Line Bisection, and Word Reading. Impairments in two of these factors, Left Attentional Processing and Line Bisection, occurred together in most cases but also occurred independently in 38 cases. There were no cases in whom Word Reading was present without concomitant deficits in one or the other two factors. These three factors could not be distinguished neuroanatomically; that is, lesions were equally likely in the temporal/parietal cortex, dorsolateral frontal cortex, or in deep frontal structures. These data confirm the notion that hemispatial neglect is a complex and multifaceted disorder composed of cognitively independent processes. These processes, however, cannot be dissociated neuroanatomically based on currently available assessment techniques.

Ween, JE, Alexander M, D’Esposito, Roberts M.  1996.  Incontinence after stroke in a rehabilitation setting: outcome associations and predictive factors., 1996 Sep. Neurology. 47:659-63. Abstract1996ween2.pdf

Urinary incontinence (UI) after stroke is common and associated with overall poor functional outcomes. There is controversy regarding which factors contribute to incontinence after stroke and which factors may be predictive of recovery of continence. This study investigated consecutive stroke admissions to an inpatient rehabilitation hospital and evaluated the impact of several pre-selected factors on the presence of UI and its recovery. We also studied the impact of UI on outcome in terms of functional abilities with the Functional Independence Measure (FIM) and in terms of disposition. UI on admission was associated with severe functional impairment with large infarctions and was probably caused by general severity rather than specific impairment of neuromicturition control. Patients with less impairment (admission FIM > 60) and small vessel strokes were likely to recover continence. UI on admission had a negative impact on outcome.

Armstrong, C, Onishi K, Robinson K, D’Esposito, Thompson H, Rostami A, Grossman M.  1996.  Serial position and temporal cue effects in multiple sclerosis: two subtypes of defective memory mechanisms., 1996 Sep. Neuropsychologia. 34:853-62. Abstract1996armstrong.pdf

Neurocognitive studies of multiple sclerosis (MS) have identified a robust long-term memory deficit. We hypothesized that this is due in part to the limited representation and use of serial order information. MS patients and controls were studied with a supraspan list learning procedure with post-encoding retrieval and recognition trials. MS patients demonstrated post-encoding negative recency with normal recognition, and word order recall was impaired. These findings appear to be in part to difficulty using temporal order cues in long-term memory. Two dissociable memory deficits were identified, suggesting that there are at least two neurocognitive mechanisms underlying memory impairment in MS.

1997
Kimberg, DY, D’Esposito.  1997.  Cognitive functions in the prefrontal cortex: working memory and executive control. Current Directions in Psychological Science. Abstract1997kimberg.pdfWebsite

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Kimberg, DY, D'Esposito M.  1997.  The frontal lobes: cognitive neuropsychological aspects. Behavioral Neurology and Neuropsychology. : McGraw-Hill Abstract

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D'Esposito, M.  1997.  Specific stroke syndromes. Neurologic Rehabilitation: A Guide to Diagnosis, Prognosis, and Treatment Planning. , Cambridge: Blackwell Science Abstract

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Zarahn, E, Aguirre GK, D’Esposito.  1997.  Empirical analyses of BOLD fMRI statistics. I. Spatially unsmoothed data collected under null-hypothesis conditions., 1997 Apr. NeuroImage. 5:179-97. Abstractempiricalboldii.pdf

Temporal autocorrelation, spatial coherency, and their effects on voxel-wise parametric statistics were examined in BOLD fMRI null-hypothesis, or "noise," datasets. Seventeen normal, young subjects were scanned using BOLD fMRI while not performing any time-locked experimental behavior. Temporal autocorrelation in these datasets was described well by a 1/frequency relationship. Voxel-wise statistical analysis of these noise datasets which assumed independence (i.e., ignored temporal autocorrelation) rejected the null hypothesis at a higher rate than specified by the nominal alpha. Temporal smoothing in conjunction with the use of a modified general linear model (Worsley and Friston, 1995, NeuroImage 2: 173-182) brought the false-positive rate closer to the nominal alpha. It was also found that the noise fMRI datasets contain spatially coherent time signals. This observed spatial coherence could not be fully explained by a continuously differentiable spatial autocovariance function and was much greater for lower temporal frequencies. Its presence made voxel-wise test statistics in a given noise dataset dependent, and thus shifted their distributions to the right or left of 0. Inclusion of a "global signal" covariate in the general linear model reduced this dependence and consequently stabilized (i.e., reduced the variance of) dataset false-positive rates.

Aguirre, GK, Zarahn E, D’Esposito.  1997.  Empirical analyses of BOLD fMRI statistics. II. Spatially smoothed data collected under null-hypothesis and experimental conditions., 1997 Apr. NeuroImage. 5:199-212. Abstractempiricalbold.pdf

In the companion to this paper (E. Zarahn, G. K. Aguirre, and M. D’Esposito, 1997, NeuroImage, 179-197), we describe an implementation of a general linear model for autocorrelated observations in which the voxel-wise false-positive rates in fMRI "noise" datasets were stabilized and brought close to theoretical values. Here, implementations of the model are tested for use with statistical parametric mapping analysis of spatially smoothed fMRI data. Analyses using varying models of intrinsic temporal autocorrelation and either including or excluding a global signal covariate were conducted upon human subject data collected under null hypothesis as well as under experimental conditions. We found that smoothing with an empirically derived impulse response function (IRF), combined with a model of the intrinsic temporal autocorrelation in spatially smoothed fMRI data, resulted in a map-wise false-positive rate which did not exceed a 5% level when a nominal alpha = 0.05 tabular threshold was applied. Use of other models of intrinsic temporal autocorrelation resulted in map-wise false-positive rates that significantly exceeded this level. fMRI data collected while subjects performed a behavioral task were used to examine (a) task-dependent global signal changes and (b) the dependence of sensitivity on the temporal smoothing kernel and inclusion/exclusion of a global signal covariate. The global signal changes within an fMRI dataset were shown to be influenced by the performance of a behavioral task. However, the inclusion of this measure as a covariate did not have an adverse affect upon our measure of sensitivity. Finally, use of an empirically derived estimate of the IRF of the system was shown to result in greater map-wise sensitivity for signal changes than the use of a broader (in time) Poisson (parameter = 8 s) kernel.

Grossman, M, Galetta S, D’Esposito.  1997.  Object recognition difficulty in visual apperceptive agnosia., 1997 Apr. Brain and cognition. 33:306-42. Abstract1997grossman3.pdf

Two patients with visual apperceptive agnosia were examined on tasks assessing the appreciation of visual material. Elementary visual functioning was relatively preserved, but they had profound difficulty recognizing and naming line drawings. More detailed evaluation revealed accurate recognition of regular geometric shapes and colors, but performance deteriorated when the shapes were made more complex visually, when multiple-choice arrays contained larger numbers of simple targets and foils, and when a mental manipulation such as a rotation was required. The recognition of letters and words was similarly compromised. Naming, recognition, and anomaly judgments of colored pictures and real objects were more accurate than similar decisions involving black-and-white line drawings. Visual imagery for shapes, letters, and objects appeared to be more accurate than visual perception of the same materials. We hypothesize that object recognition difficulty in visual apperceptive agnosia is due to two related factors: the impaired appreciation of the visual perceptual features that constitute objects, and a limitation in the cognitive resources that are available for processing demanding material within the visual modality.

Aguirre, GK, D’Esposito.  1997.  Environmental knowledge is subserved by separable dorsal/ventral neural areas., 1997 Apr 1. The Journal of neuroscience : the official journal of the Society for Neuroscience. 17:2512-8. Abstractenvironmental.pdf

Environmental psychology models propose that knowledge of large-scale space is stored as distinct landmark (place appearance) and survey (place position) information. Studies of brain-damaged patients suffering from "topographical disorientation" tentatively support this proposal. In order to determine if the components of psychologically derived models of environmental representation are realized as distinct functional, neuroanatomical regions, a functional magnetic resonance imaging (fMRI) study of environmental knowledge was performed. During scanning, subjects made judgments regarding the appearance and position of familiar locations within a virtual reality environment. The fMRI data were analyzed in a manner that has been empirically demonstrated to rigorously control type I error and provide optimum sensitivity, allowing meaningful results in the single subject. A direct comparison of the survey position and landmark appearance conditions revealed a dorsal/ventral dissociation in three of four subjects. These results are discussed in the context of the observed forms of topographical disorientation and are found to be in good agreement with the human lesion studies. This experiment confirms that environmental knowledge is not represented by a unitary system but is instead functionally distributed across the neocortex.

Grossman, M, Payer F, Onishi K, White-Devine T, Morrison D, D’Esposito, Robinson K, Alavi A.  1997.  Constraints on the cerebral basis for semantic processing from neuroimaging studies of Alzheimer’s disease., 1997 Aug. Journal of neurology, neurosurgery, and psychiatry. 63:152-8. Abstract1997grossman2.pdf

OBJECTIVE: Functional activation studies of semantic processing in healthy adults have yielded conflicting results. The purpose was to evaluate the relative role of the brain regions implicated in semantic processing with converging evidence from imaging studies of patients with impaired semantic processing. METHODS: Semantic memory was assessed in patients with Alzheimer’s disease using two measures, and these performance patterns were related to profiles of reduced cerebral functioning obtained with high resolution single photon emission computed tomography (SPECT). Patients with frontotemporal degeneration were similarly evaluated as a control group. RESULTS: Reduced relative cerebral perfusion was seen in parietal and posterior temporal brain regions of patients with Alzheimer’s disease but not patients with frontotemporal degeneration. Impairments on semantically guided category membership decision tasks were also seen in patients with Alzheimer’s disease but not those with frontotemporal degeneration. Performance on the semantic measures correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere only in Alzheimer’s disease. Relative perfusion was significantly lower in these regions in patients with Alzheimer’s disease with semantic difficulty compared with patients with Alzheimer’s disease with relatively preserved semantic processing. CONCLUSION: These findings provide converging evidence to support the contribution of superior temporal and inferior parietal regions of the left hemisphere to semantic processing.

D’Esposito, Zarahn E, Aguirre GK, Shin RK, Auerbach P, Detre JA.  1997.  The effect of pacing of experimental stimuli on observed functional MRI activity., 1997 Aug. NeuroImage. 6:113-21. Abstractpacing.pdf

Neuroimaging activation studies typically observe signals during two or more periods of differing cognitive activity which are then analyzed by a subtraction to test for localized neuroanatomical dissociations between cognitive tasks. Significant activity found between task conditions is frequently assumed to reflect a novel cognitive process present in one task and not the other. We present a conceptual framework that considers the neural mechanisms underlying such observed neuroimaging changes. We propose that neuroimaging experiments which present stimuli at a fixed pace (where each trial takes the same amount of time) will be sensitive to changes in both duration and intensity of neural processing. In contrast, the signal observed during a self-paced design is derived from neural processing averaged over the reaction time and hence could be less sensitive to differences in duration of neural processing. As an empirical demonstration of these ideas, we studied normal subjects using echoplanar functional MRI during two visuospatial tasks (matching of either ROTATED or NONROTATED stimuli) performed using FIXED and SELF-PACED designs. In both pacing designs, reaction times were greater in the ROTATED than NONROTATED task, interpreted as a greater duration of neural processing during the ROTATED compared to the NONROTATED task. In the FIXED-PACED design, significantly greater signal was present within a parieto-occipital cortical region during the ROTATED task compared to the NONROTATED task. This difference was not observed during the SELF-PACED design. This result illustrates the importance of considering trial pacing in the interpretation of functional neuroimaging activation studies.

Zarahn, E, Aguirre GK, D’Esposito.  1997.  A trial-based experimental design for fMRI., 1997 Aug. NeuroImage. 6:122-38. Abstracttrialbased.pdf

An experimental design for functional MRI (fMRI) is presented whose conceptual units of analysis are behavioral trials, in contrast to blocks of trials. This type of design is referred to as a trial-based (TB) fMRI design. It is explained how TB designs can afford the ability to: (1) randomize the presentation of behavioral trials and (2) utilize intertrial variance in uncontrolled behavioral measures to examine their functional correlates. A particular type of TB design that involves modeling trial-evoked fMRI responses with one or more shifted impulse response functions is described. This design is capable of discriminating functional changes occurring during temporally separated behavioral subcomponents within trials. An example of such a design is implemented and its statistical specificity, functional sensitivity, and functional specificity are tested.

Grossman, M, Mickanin J, Onishi K, Robinson KM, D’Esposito.  1997.  Lexical acquisition in probable Alzheimer’s disease., 1997 Dec. Brain and language. 60:443-63. Abstract1997grossman.pdf

Patients with probable Alzheimer’s disease (pAD) were exposed to a new verb in a naturalistic fashion. We probed their knowledge of the word’s semantic and grammatical characteristics for several minutes following this exposure, and compared this with their performance on parallel measures assessing known words. Significant differences were seen between pAD patients and controls in the acquisition of the new verb’s semantic meaning and its argument structure, but pAD patients did not differ from controls in the acquisition of the new word’s grammatical form class. Individual patient analyses demonstrated parallel deficits restricted to the semantic meaning and argument structure of the new word and known words in several pAD patients, suggesting that a selective language impairment contributed to their word learning deficit. This pattern is consistent with an intimate relationship between semantic meaning and argument structure in semantic memory. Other pAD patients had difficulty learning about all aspects of the new word, despite good performance with known words, suggesting that compromised memory may have limited their lexical acquisition.

Thompson-Schill, SL, D’Esposito, Aguirre GK, Farah MJ.  1997.  Role of left inferior prefrontal cortex in retrieval of semantic knowledge: a reevaluation., 1997 Dec 23. Proceedings of the National Academy of Sciences of the United States of America. 94:14792-7. Abstractschillrole.pdf

A number of neuroimaging findings have been interpreted as evidence that the left inferior frontal gyrus (IFG) subserves retrieval of semantic knowledge. We provide a fundamentally different interpretation, that it is not retrieval of semantic knowledge per se that is associated with left IFG activity but rather selection of information among competing alternatives from semantic memory. Selection demands were varied across three semantic tasks in a single group of subjects. Functional magnetic resonance imaging signal in overlapping regions of left IFG was dependent on selection demands in all three tasks. In addition, the degree of semantic processing was varied independently of selection demands in one of the tasks. The absence of left IFG activity for this comparison counters the argument that the effects of selection can be attributed solely to variations in degree of semantic retrieval. Our findings suggest that it is selection, not retrieval, of semantic knowledge that drives activity in the left IFG.

D’Esposito, Detre JA, Aguirre GK, Stallcup M, Alsop D, Tippet LJ, Farah MJ.  1997.  A functional MRI study of mental image generation., 1997 May. Neuropsychologia. 35:725-30. Abstractimagerot.pdf

The neural substrates of mental image generation were investigated with functional MRI. Subjects listened to words under two different instructional conditions: to generate visual mental images of the words’ referents, or to simply listen to each word and wait for the next word. Analyses were performed which directly compared the regional brain activity during each condition, with the goal of discovering whether mental image generation engages modality-specific visual areas, whether it engages primary visual cortex, and whether it recruits the left hemisphere to a greater extent than the right. Results revealed that visual association cortex, and not primary visual cortex, was engaged during the mental image generation condition. Left inferior temporal lobe (Brodmann’s area 37) was the most reliably and robustly activated area across subjects, had activity which extended superiorly into occipital association cortex (area 19). The results of this experiment support the hypothesis that visual mental imagery is a function of visual association cortex, and that image generation is asymmetrically localized to the left.

Armstrong, C, Lewis T, D’Esposito, Freundlich B.  1997.  Eosinophilia-myalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings., 1997 Nov. Journal of neurology, neurosurgery, and psychiatry. 63:633-41. Abstract1997armstrong.pdf

OBJECTIVE: To identify the specific nature of the neurocognitive impairments of eosinophilia-myalgia syndrome (EMS) in an unselected population, and to present longitudinal patterns. METHODS: A consecutive sample of 23 patients with EMS and 18 age and education matched control subjects were assessed on a comprehensive neuropsychological battery. Longitudinal results were gathered from six patients. RESULTS: Neurocognitive impairments were found which represent a subset of deficits reported in previous group and case study reports. Deficits were limited to complex visual memory, conceptual set shifting, and attention, which suggest a selective dysexecutive syndrome. The motor slowing and verbal memory deficits previously reported were not found. Although depression, fatigue, sleep deprivation, and pain were significant symptoms, they were unassociated with deficits with the exception of an association of depression with one deficit. There was no pattern of overall decline over time in a subset of the group, although considerable heterogeneity in the longitudinal patterns of neurocognitive tests was found. Abnormalities of white matter appeared in the MRI of eight of 12 patients. CONCLUSIONS: The neurocognitive and neuroimaging findings contribute to the evidence which indicates that the neural substrate of EMS is white matter damage.

Kimberg, DY, D’Esposito, Farah MJ.  1997.  Effects of bromocriptine on human subjects depend on working memory capacity., 1997 Nov 10. Neuroreport. 8:3581-5. Abstractkinberg1997.pdf

Pharmacological manipulation of brain dopamine concentration affects visuospatial working memory in humans and in animals, the latter effects localized to the prefrontal cortex. However, the effects of dopamine agonists on humans are poorly understood. We hypothesized that bromocriptine would have an effect on cognitive functions associated with the prefrontal cortex via its effects on cortical dopamine receptors and on subcortical receptors in areas that project to the neocortex. We found that the effect of bromocriptine on young normal subjects depended on the subjects’ working memory capacity. High-capacity subjects performed more poorly on the drug, while low-capacity subjects improved. These results demonstrate an empirical link between a dopamine-mediated working memory system and higher cognitive function in humans.

McDowell, S, Whyte J, D’Esposito.  1997.  Working memory impairments in traumatic brain injury: evidence from a dual-task paradigm., 1997 Oct. Neuropsychologia. 35:1341-53. Abstractimpairments.pdf

Although many individuals with traumatic brain injury (TBI) perform well on standard neuropsychological tests, they often exhibit marked functional difficulties. The functions which are impaired seem to be analogous to the role of the central executive system (CES) in Baddeley’s [Working Memory, 1986, Oxford University Press, New York] widely accepted model of working memory. The purpose of this study was to investigate CES function in individuals with TBI with a dual-task paradigm. We studied 25 non-demented persons who were at various stages in their recovery from severe TBI and compared their performance on a dual-task paradigm to a group of age-matched controls. Our dual-task paradigm measured performance on a simple visual reaction time task both alone (baseline) and during concurrent tasks of articulation or digit span. Subjects were also assessed with other neuropsychological tests of executive function. TBI patients had slower reaction times on the primary task when performed alone (P < 0.05) and greater decrements in performance during dual-task conditions (P < 0.01). They also exhibited significantly greater deficits than control subjects on other measures of executive function. Although correlations between dual-task performance and other executive measures were quite low, principle components analysis suggested that a common factor does exist between these measures. These findings support the conclusion that TBI patients have a working memory impairment that is due to dysfunction of the CES and which may be related to executive function deficits as measured by standard neuropsychological testing.

1998
Detre, JA, Maccotta L, King D, Alsop D, Glosser G, D’Esposito, Zarahn E, Aguirre GK, French JA.  1998.  Functional MRI lateralization of memory in temporal lobe epilepsy., 1998 Apr. Neurology. 50:926-32. Abstract1998detre.pdf

OBJECTIVE: To determine the feasibility of using functional magnetic resonance imaging (fMRI) to detect asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy (TLE). BACKGROUND: Assessment of mesial temporal lobe function is a critical aspect of the preoperative evaluation for epilepsy surgery, both for predicting postoperative memory deficits and for seizure lateralization. fMRI offers several potential advantages over the current gold standard, intracarotid amobarbital testing (IAT). fMRI has already been successfully applied to language lateralization in TLE. METHODS: fMRI was carried out in eight normal subjects and 10 consecutively recruited patients with TLE undergoing preoperative evaluation for epilepsy surgery. A complex visual scene encoding task known to activate mesial temporal structures was used during fMRI. Asymmetry ratios for mesial temporal activation were calculated, using regions of interest defined in normals. Patient findings were compared with the results of IAT performed as part of routine clinical evaluation. RESULTS: Task activation was nearly symmetric in normal subjects, whereas in patients with TLE, significant asymmetries were observed. In all nine patients in whom the IAT result was interpretable, memory asymmetry by fMRI concurred with the findings of IAT including two patients with paradoxical IAT memory lateralization ipsilateral to seizure focus. CONCLUSIONS: fMRI can be used to detect asymmetries in memory activation in patients with TLE. Because fMRI studies are noninvasive and provide excellent spatial resolution for functional activation, these preliminary results suggest a promising role for fMRI in improving the preoperative evaluation for epilepsy surgery.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  An area within human ventral cortex sensitive to "building" stimuli: evidence and implications., 1998 Aug. Neuron. 21:373-83. Abstractaguirre1998.pdf

Isolated, ventral brain lesions in humans occasionally produce specific impairments in the ability to use landmarks, particularly buildings, for way-finding. Using functional MRI, we tested the hypothesis that there exists a cortical region specialized for the perception of buildings. Across subjects, a region straddling the right lingual sulcus was identified that possessed the functional correlates predicted for a specialized building area. A series of experiments discounted several alternative explanations for the behavior of this site. These results are discussed in terms of their impact upon our understanding of the functional structure of visual processing, disorders of topographical disorientation, and the influence of environmental conditions upon neural organization.

Thompson-Schill, SL, Swick D, Farah MJ, D’Esposito, Kan IP, Knight RT.  1998.  Verb generation in patients with focal frontal lesions: a neuropsychological test of neuroimaging findings., 1998 Dec 22. Proceedings of the National Academy of Sciences of the United States of America. 95:15855-60. Abstractschillverb.pdf

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  Neural components of topographical representation., 1998 Feb 3. Proceedings of the National Academy of Sciences of the United States of America. 95:839-46. Abstracttopographical.pdf

Studies of patients with focal brain damage suggest that topographical representation is subserved by dissociable neural subcomponents. This article offers a condensed review of the literature of "topographical disorientation" and describes several functional MRI studies designed to test hypotheses generated by that review. Three hypotheses are considered: (i) The parahippocampal cortex is critically involved in the acquisition of exocentric spatial information in humans; (ii) separable, posterior, dorsal, and ventral cortical regions subserve the perception and long term representation of position and identity, respectively, of landmarks; and (iii) there is a distinct area of the ventral occipitotemporal cortex that responds maximally to building stimuli and may play a role in the perception of salient landmarks. We conclude with a discussion of the inferential limitations of neuroimaging and lesion studies. It is proposed that combining these two approaches allows for inferences regarding the computational involvement of a neuroanatomical substrate in a given cognitive process although neither method can strictly support this conclusion alone.

Grossman, M, Payer F, Onishi K, D’Esposito, Morrison D, Sadek A, Alavi A.  1998.  Language comprehension and regional cerebral defects in frontotemporal degeneration and Alzheimer’s disease., 1998 Jan. Neurology. 50:157-63. Abstract1998grossman.pdf

We related profiles of language comprehension difficulty to patterns of reduced cerebral functioning obtained with high-resolution single photon emission computed tomography (SPECT) in patients with neurodegenerative conditions. We found different patterns of reduced relative cerebral perfusion in patients with frontotemporal degeneration (FD) and patients with Alzheimer’s disease (AD). Cognitive assessments also showed different patterns of impaired comprehension in patients with FD and patients with AD. Grammatical comprehension difficulty in FD correlated with relative cerebral perfusion in left frontal and anterior temporal brain regions; impaired semantic processing in AD correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere. These findings are consistent with the hypothesis that a neural network distributed throughout the left hemisphere subserving different aspects of language comprehension, rather than a single brain region, is responsible for understanding language.

Grossman, M, Robinson K, Biassou N, White-Devine T, D’Esposito.  1998.  Semantic memory in Alzheimer’s disease: representativeness, ontologic category, and material., 1998 Jan. Neuropsychology. 12:34-42. Abstract1998grossman2.pdf

Alzheimer’s disease (AD) patients with semantic memory difficulty and AD patients with relatively preserved semantic memory named pictures and judged the category membership of words and pictures of natural kinds and manufactured artifacts that varied in their representativeness. Only semantically impaired patients were insensitive to representativeness in their category judgments. AD subgroup judgments did not differ for natural kinds compared to manufactured artifacts nor for words compared to pictures. AD subgroup differences could not be explained by dementia severity, memory, reading, and visuoperception. The similarity process for relating coordinate members of a taxonomic category contributes to the normal appreciation of word and picture meaning, and this process is compromised in AD patients with semantic difficulty.

D’Esposito, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J.  1998.  Functional MRI studies of spatial and nonspatial working memory., 1998 Jul. Brain research. Cognitive brain research. 7:1-13. Abstract1998desposito.pdf

Single-unit recordings in monkeys have revealed neurons in the lateral prefrontal cortex that increase their firing during a delay between the presentation of information and its later use in behavior. Based on monkey lesion and neurophysiology studies, it has been proposed that a dorsal region of lateral prefrontal cortex is necessary for temporary storage of spatial information whereas a more ventral region is necessary for the maintenance of nonspatial information. Functional neuroimaging studies, however, have not clearly demonstrated such a division in humans. We present here an analysis of all reported human functional neuroimaging studies plotted onto a standardized brain. This analysis did not find evidence for a dorsal/ventral subdivision of prefrontal cortex depending on the type of material held in working memory, but a hemispheric organization was suggested (i.e., left-nonspatial; right-spatial). We also performed functional MRI studies in 16 normal subjects during two tasks designed to probe either nonspatial or spatial working memory, respectively. A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmann’s area 46) in both spatial and nonspatial [working memory-control] subtractions. Based on another model of prefrontal organization [M. Petrides, Frontal lobes and behavior, Cur. Opin. Neurobiol., 4 (1994) 207-211], a reconsideration of the previous imaging literature data suggested that a dorsal/ventral subdivision of prefrontal cortex may depend upon the type of processing performed upon the information held in working memory.

McDowell, S, Whyte J, D’Esposito.  1998.  Differential effect of a dopaminergic agonist on prefrontal function in traumatic brain injury patients., 1998 Jun. Brain : a journal of neurology. 121 ( Pt 6):1155-64. Abstractdifferential.pdf

We examined the effects of low-dose bromocriptine, a D2 dopamine receptor agonist, on processes thought to be subserved by the prefrontal cortex, including working memory and executive function, in individuals with traumatic brain injury. A group of 24 subjects was tested using a double-blind, placebo-controlled crossover trial, counterbalanced for order. Bromocriptine was found to improve performance on some tasks thought to be subserved by prefrontal function, but not others. Specifically, there was improvement in performance on clinical measures of executive function and in dual-task performance, but not measures that tap the ability to maintain information in working memory without significant executive demands. Also, on control tasks not thought to be dependent on the prefrontal cortex, no improvement on bromocriptine was noted. These results demonstrate a selective effect of bromocriptine on cognitive processes which involve executive control, and provide a foundation for potential therapies for patients with prefrontal damage causing dysexecutive syndromes.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  A critique of the use of the Kolmogorov-Smirnov (KS) statistic for the analysis of BOLD fMRI data., 1998 Mar. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 39:500-5. Abstract1998aguirre.pdf

The use of the Kolmogorov-Smirnov (KS) statistic for testing hypotheses regarding activation in blood oxygenation level-dependent functional MRI data is critiqued on both theoretical and empirical grounds. Theoretically, it is argued that the KS test is formally unable to support inferences of interest to most neuro-imaging studies and has reduced sensitivity compared with parametric alternatives. Empirically, false-positive rates yielded by the KS test in human data collected under the null hypothesis were significantly in excess of tabular values. These excessive false-positive rates could be explained by the presence of temporal autocorrelation. We also present evidence that the distribution of blood oxygenation level-dependent functional MRI data is only slightly nonnormal, questioning the initial impetus for the use of the KS test in this context. Finally, it is noted that parametric alternatives exist that do provide adequate control of the false-positive rate and can support inferences of interest.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The variability of human, BOLD hemodynamic responses., 1998 Nov. NeuroImage. 8:360-9. Abstractvariability.pdf

Cerebral hemodynamic responses to brief periods of neural activity are delayed and dispersed in time. The specific shape of these responses is of some importance to the design and analysis of blood oxygenation level-dependent (BOLD), functional magnetic resonance imaging (fMRI) experiments. Using fMRI scanning, we examine here the characteristics and variability of hemodynamic responses from the central sulcus in human subjects during an event-related, simple reaction time task. Specifically, we determine the contribution of subject, day, and scanning session (within a day) to variability in the shape of evoked hemodynamic response. We find that while there is significant and substantial variability in the shape of responses collected across subjects, responses collected during multiple scans within a single subject are less variable. The results are discussed in terms of the impact of response variability upon sensitivity and specificity of analyses of event-related fMRI designs.

D’Esposito, Ballard D, Aguirre GK, Zarahn E.  1998.  Human prefrontal cortex is not specific for working memory: a functional MRI study., 1998 Oct. NeuroImage. 8:274-82. Abstract

Lesion studies in monkeys have provided evidence that lateral prefrontal cortex is necessary for working memory, the cognitive processes involved in the temporary maintenance and manipulation of information. Monkey electrophysiological studies, however, have also observed prefrontal neuronal activity associated with cognitive processes that are nonmnemonic. We tested the hypothesis that the same regions of human prefrontal cortex that demonstrate activity during working memory tasks would also demonstrate activity during tasks without working memory demands. During echoplanar fMRI imaging, subjects performed a three-condition experiment (working memory task, nonworking memory task, rest). In the working memory task, subjects observed serially presented stimuli and determined if each stimulus was the same as that presented two stimuli back. The nonworking memory task in Experiment 1 required subjects to identify a single predetermined stimulus; in Experiment 2, subjects were required to make a button press to every stimulus. In all subjects in both experiments, the working memory task exhibited greater prefrontal cortical activity compared to either nonworking memory task. In these same prefrontal regions, greater activation was also observed during both nonworking memory tasks compared to rest. We conclude that human lateral prefrontal cortex supports processes in addition to working memory. Thus, reverse inference of the form "if prefrontal cortex is active, working memory is engaged" is not supported.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The inferential impact of global signal covariates in functional neuroimaging analyses., 1998 Oct. NeuroImage. 8:302-6. Abstractinferential.pdf

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Nolde, SF, Johnson MK, D’Esposito.  1998.  Left prefrontal activation during episodic remembering: an event-related fMRI study., 1998 Oct 26. Neuroreport. 9:3509-14. Abstractnolde.pdf

The major current theory relating brain mechanisms in prefrontal cortex (PFC) to memory for discrete events (episodic memory) emphasizes the role of right PFC during retrieval. Using event-related fMRI, we found both right and left PFC activity during episodic remembering, but only the left PFC activity was related to the amount of episodic detail required at test. We suggest that right PFC subserves relatively simple, heuristic, cognitive processes and that left PFC is recruited for more reflectively demanding, systematic, processes. Episodic remembering often requires such systematic processes and, under those circumstances, recruits left, as well as right, PFC.

1999
Aguirre, GK, D'Esposito M.  1999.  Experimental design for brain fMRI. Functional MRI. , Berlin: Springer-Verlag Abstract

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D’Esposito.  1999.  Cognitive aging: new answers to old questions., 1999 Dec 16-30. Current biology : CB. 9:R939-41. Abstract1999desposito.pdf

The use of techniques for functional brain imaging is beginning to provide insights into the psychological and neural mechanisms that underlie age-related changes in cognitive performance.

D’Esposito, Zarahn E, Aguirre GK.  1999.  Event-related functional MRI: implications for cognitive psychology., 1999 Jan. Psychological bulletin. 125:155-64. Abstractdesposito1999.pdf

Functional magnetic resonance imaging (fMRI) has rapidly emerged as a powerful technique in cognitive neuroscience. We describe and critique a new class of imaging experimental designs called event-related fMRI that exploit the temporal resolution of fMRI by modeling fMRI signal changes associated with behavioral trials as opposed to blocks of behavioral trials. Advantages of this method over block designs include the ability to (a) randomize trial presentations, (b) test for functional correlates of behavioral measures with greater power, (c) directly examine the neural correlates of temporally dissociable components of behavioral trials (e.g., the delay period of a working memory task), and (d) test for differences in the onset time of neural activity evoked by different trial types. Consequently, event-related fMRI has the potential to address a number of cognitive psychology questions with a degree of inferential and statistical power not previously available.

Zarahn, E, Aguirre GK, D’Esposito.  1999.  Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI., 1999 Jan. Brain research. Cognitive brain research. 7:255-68. Abstract1999zarahn.pdf

The use of cognitive subtraction to study the neural substrates of the maintenance component of spatial working memory in humans relies upon the assumptions of the pure insertion of cognitive processes and a linear transform of neural activity to neuroimaging signal. Here, functional changes attributable to the memory requiring phase (referred to as the retention delay) of a spatial working memory task were temporally discriminated from those attributable to other behavioral subcomponents within trials using an experimental design that is argued to obviate these assumptions, as well as permit a joint test of their validity. The hypothesis that the assumptions of cognitive subtraction (as applied to neuroimaging) hold in general was not supported. Functional changes attributable to the retention delay were detected in the dorsolateral prefrontal cortex as well as in other cortical regions in a subset of the subjects, and in the right frontal eye field and right superior parietal lobule of all subjects (n=5). These results support models in which these regions are involved in maintaining spatial representations in humans. In addition, nearly all regions that evidenced such functional changes during the retention delay also evidenced functional changes during behaviors that did not require spatial working memory. This result tends to dispute models which posit the existence of gross neuroanatomical regions involved in solely mnemonic function.

Aguirre, GK, Singh R, D’Esposito.  1999.  Stimulus inversion and the responses of face and object-sensitive cortical areas., 1999 Jan 18. Neuroreport. 10:189-94. Abstractinversion.pdf

Behavioral and neuropsychological studies suggest that upright and inverted face stimuli are processed by computationally and anatomically distinct systems. Specifically, inverted faces seem to be addressed by general object perception systems, avoiding face-specific processes. We tested this model by examining the fMRI signal response of a functionally defined fusiform face area and bilateral object-responsive cortical areas during the perception of upright and inverted stimuli (faces and cars). While inversion of face stimuli had no effect upon the magnitude of responses in the fusiform face area, inverted faces evoked greater neural responses compared to upright faces within object regions. This finding supports the assertion that object areas are involved to a greater degree in the perception of inverted vs upright faces.

D’Esposito, Zarahn E, Aguirre GK, Rypma B.  1999.  The effect of normal aging on the coupling of neural activity to the bold hemodynamic response., 1999 Jul. NeuroImage. 10:6-14. Abstractagingeffect.pdf

The use of functional neuroimaging to test hypotheses regarding age-related changes in the neural substrates of cognitive processes relies on assumptions regarding the coupling of neural activity to neuroimaging signal. Differences in neuroimaging signal response between young and elderly subjects can be mapped directly to differences in neural response only if such coupling does not change with age. Here we examined spatial and temporal characteristics of the BOLD fMRI hemodynamic response in primary sensorimotor cortex in young and elderly subjects during the performance of a simple reaction time task. We found that 75% of elderly subjects (n = 20) exhibited a detectable voxel-wise relationship with the behavioral paradigm in this region as compared to 100% young subjects (n = 32). The median number of suprathreshold voxels in the young subjects was greater than four times that of the elderly subjects. Young subjects had a slightly greater signal:noise per voxel than the elderly subjects that was attributed to a greater level of noise per voxel in the elderly subjects. The evidence did not support the idea that the greater head motion observed in the elderly was the cause of this greater voxel-wise noise. There were no significant differences between groups in either the shape of the hemodynamic response or in its the within-group variability, although the former evidenced a near significant trend. The overall finding that some aspects of the hemodynamic coupling between neural activity and BOLD fMRI signal change with age cautions against simple interpretations of the results of imaging studies that compare young and elderly subjects.

Thompson-Schill, SL, D’Esposito, Kan IP.  1999.  Effects of repetition and competition on activity in left prefrontal cortex during word generation., 1999 Jul. Neuron. 23:513-22. Abstractthompsonschill1999.pdf

Neuroimaging studies have revealed an association between word generation and activity in the left inferior frontal gyrus (IFG) that is attentuated with item repetition. The experiment reported here examined the effects of repeated word generation, under conditions in which completion was either decreased or increased, on activity measured during whole-brain echoplanar functional magnetic resonance imaging. Activity in left IFG decreased during repetition conditions that reduced competition but increased during repetition conditions that increased competition; this pattern was contrasted to repetition effects observed in other cortical areas, specifically regions of left temporal cortex. The increase in left IFG activity, which is not predicted by a simple semantic retrieval account of prefrontal function, is consistent with the hypothesis that left IFG subserves the selection of semantic knowledge among competing alternatives.

Postle, BR, D’Esposito.  1999.  Dissociation of human caudate nucleus activity in spatial and nonspatial working memory: an event-related fMRI study., 1999 Jul 16. Brain research. Cognitive brain research. 8:107-15. Abstractdissociation.pdf

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.

Thompson-Schill, SL, Aguirre GK, D’Esposito, Farah MJ.  1999.  A neural basis for category and modality specificity of semantic knowledge., 1999 Jun. Neuropsychologia. 37:671-6. Abstractschillneuralbasis.pdf

Prevalent theories hold that semantic memory is organized by sensorimotor modality (e.g., visual knowledge, motor knowledge). While some neuroimaging studies support this idea, it cannot account for the category specific (e.g., living things) knowledge impairments seen in some brain damaged patients that cut across modalities. In this article we test an alternative model of how damage to interactive, modality-specific neural regions might give rise to these categorical impairments. Functional MRI was used to examine a cortical area with a known modality-specific function during the retrieval of visual and non-visual knowledge about living and non-living things. The specific predictions of our model regarding the signal observed in this area were confirmed, supporting the notion that semantic memory is functionally segregated into anatomically discrete, but highly interactive, modality-specific regions.

D’Esposito, Postle BR, Jonides J, Smith EE.  1999.  The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional MRI., 1999 Jun 22. Proceedings of the National Academy of Sciences of the United States of America. 96:7514-9. Abstractsubstrate.pdf

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.

Rypma, B, D’Esposito.  1999.  The roles of prefrontal brain regions in components of working memory: effects of memory load and individual differences., 1999 May 25. Proceedings of the National Academy of Sciences of the United States of America. 96:6558-63. Abstractroles.pdf

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Postle, BR, D’Esposito.  1999.  "What"-Then-Where" in visual working memory: an event-related fMRI study., 1999 Nov. Journal of cognitive neuroscience. 11:585-97. Abstractwhat.pdf

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.

D’Esposito, Postle BR.  1999.  The dependence of span and delayed-response performance on prefrontal cortex., 1999 Oct. Neuropsychologia. 37:1303-15. Abstractdependence.pdf

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.

D’Esposito, Postle BR, Ballard D, Lease J.  1999.  Maintenance versus manipulation of information held in working memory: an event-related fMRI study., 1999 Oct. Brain and cognition. 41:66-86. Abstractmaintenance.pdf

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.

Postle, BR, Berger JS, D’Esposito.  1999.  Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance., 1999 Oct 26. Proceedings of the National Academy of Sciences of the United States of America. 96:12959-64. Abstractdoubledissociation.pdf

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.

Aguirre, GK, D’Esposito.  1999.  Topographical disorientation: a synthesis and taxonomy., 1999 Sep. Brain : a journal of neurology. 122 ( Pt 9):1613-28. Abstracttopo.pdf

Over the last century, several dozen case reports have presented ’topographically disoriented’ patients who, in some cases, appear to have selectively lost their ability to find their way within large-scale, locomotor environments. A review is offered here that has as its aim the creation of a taxonomy that accurately reflects the behavioural impairments and neuroanatomical findings of this literature. This effort is guided by an appreciation of the models of normative way-finding offered by environmental psychology and recent neuroscience research. It is proposed that several varieties of topographical disorientation exist, resulting from damage to distinct neuroanatomical areas. The particular pattern of impairments that patients evidence is argued to be consonant with the known functions of these cortical regions and with recent neuroimaging results. The conflicting claims of previous reviews of this area are also considered and addressed.

2000
Raye, CL, Johnson MK, Mitchell KJ, Nolde SF, D’Esposito.  2000.  fMRI investigations of left and right PFC contributions to episodic remembering. Psychobiology. Abstract2000raye.pdf

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Kimberg, DY, D'Esposito M.  2000.  Frontal lobes II: cognitive issues. Patient-Based Approaches to Cognitive Neuroscience. : Kluwer Academic Publishers Abstract

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D'Esposito, M.  2000.  The neural basis of working memory: evidence from neuropsychological, pharmacological and neuroimaging studies. Neurobehavior of Language and Cognition: Studies of Normal Aging and Brain Damage. : Kluwer Academic Publishers Abstract

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D'Esposito, M, Postle BR.  2000.  Neural correlates of component processes of working memory: evidence from neuropsychological and pharmacological studies. Control of Cognitive Processes: Attention & Performance XVIII. Abstract

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D'Esposito, M.  2000.  Post-concussive syndrome. Penn Neurology 2000: Management of Common Neurological Problems. Abstract

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Postle, BR, Berger JS, Taich AM, D’Esposito.  2000.  Activity in human frontal cortex associated with spatial working memory and saccadic behavior., 2000. Journal of cognitive neuroscience. 12 Suppl 2:2-14. Abstract

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).

D’Esposito.  2000.  Functional neuroimaging of cognition., 2000. Seminars in neurology. 20:487-98. Abstract

Neuroimaging has, in many respects, revolutionized the study of behavioral neurology and cognitive neuroscience. Early studies of brain-behavior relationships relied on a precise neurological examination as the basis for hypothesizing the site of brain damage that was responsible for a given behavioral syndrome. The advent of structural brain imaging, first with computed tomography (CT) and later with magnetic resonance imaging (MRI), paved the way for more precise anatomical localization of the cognitive deficits that are manifest after brain injury. In recent years, functional neuroimaging, broadly defined as techniques that provide measures of brain activity, has further increased our ability to study the neural basis of behavior. The modern era of functional brain imaging was introduced with the use of positron emission tomography (PET). In more recent years, functional magnetic resonance imaging (fMRI) has rapidly emerged as an extremely powerful technique with many advantages over PET for studying cognition. Thus, the principles underlying fMRI studies of cognition are the focus of this review.

Ances, BM, D’Esposito.  2000.  Neuroimaging of recovery of function after stroke: implications for rehabilitation., 2000. Neurorehabilitation and neural repair. 14:171-9. Abstract

Stroke is a leading cause of morbidity and mortality in individuals. Many patients have good functional recovery after stroke. The mechanisms of recovery remain largely unknown. Neuroimaging of patients recovering from stroke may provide important insight into the mechanisms of recovery as well as assist in the development of new rehabilitation techniques. The first part of this article reviews previous neuroimaging studies that have monitored the reorganization within the motor and language areas after stroke. In the second section, a unifying theory based on John Hughlings Jackson’s "Principles of Compensation" is presented as a possible theory for recovery of function. In the final portion of the article, possible implications and future applications of neuroimaging studies for rehabilitation are presented.

Postle, BR, Zarahn E, D’Esposito.  2000.  Using event-related fMRI to assess delay-period activity during performance of spatial and nonspatial working memory tasks., 2000 Feb. Brain research. Brain research protocols. 5:57-66. Abstractdelay.pdf

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.

Zarahn, E, Aguirre GK, D’Esposito.  2000.  Replication and further studies of neural mechanisms of spatial mnemonic processing in humans., 2000 Jan. Brain research. Cognitive brain research. 9:1-17. Abstract2000zarahn.pdf

Changes in neuronal firing rates during periods of time when subjects are required to remember information (retention delays) have been reported in non-human primates. In humans, tests for such functional changes using hemodynamic markers of neural activity have typically relied on cognitive subtraction. However, the temporal resolution of fMRI allows a more direct test than that afforded by cognitive subtraction of the idea that certain brain regions may increase their neural activity during retention delays in humans. Using a method that exploits this temporal resolution, increased functional activity attributable to a retention delay for spatial information in regions proximate to/within the right frontal eye field and the right superior parietal lobule were detected (in four out of four and three out of four subjects, respectively; this is an internal replication of the results of [E. Zarahn, G.K. Aguirre, M. D’Esposito, Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI, Cognit. Brain Res., 7 (1999) 255-268. ]). Second, a model in which ventral and not dorsal prefrontal cortex in humans is involved in simply maintaining spatial information was tested. The results disputed this model as increases in fMRI signal attributable to the retention delay were detected more frequently in dorsal than ventral prefrontal cortex. Third, a model which posited that the intensity of neural activity is causally related to the accuracy of spatial mnemonic representation was tested by comparing retention delay signal between correct and incorrect trials. The results did not support this model in any of the regions tested.

D’Esposito, Postle BR, Rypma B.  2000.  Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies., 2000 Jul. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. 133:3-11. Abstractdespo2000.pdf

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.

D’Esposito, Weksler ME.  2000.  Brain aging and memory: new findings help differentiate forgetfulness and dementia., 2000 Jun. Geriatrics. 55:55-8,61-2. Abstract

Geriatrics is pleased to highlight the clinical implications of research topics supported by the American Federation for Aging Research (AFAR). AFAR is a leading private organization supporting research on the aging process and diseases of older populations. More than 900 physicians, scientists, and students have received AFAR grants totaling more than $20 million since AFAR was founded by Irving S. Wright, MD, in 1981. The articles in the New Frontiers series are designed to provide primary care physicians with insight into the pathogenesis, diagnosis, prevention, and treatment of the diseases of aging.

Rypma, B, D’Esposito.  2000.  Isolating the neural mechanisms of age-related changes in human working memory., 2000 May. Nature neuroscience. 3:509-15. Abstractisolating.pdf

Working memory (WM), the process by which information is coded into memory, actively maintained and subsequently retrieved, declines with age. To test the hypothesis that age-related changes in prefrontal cortex (PFC) may mediate this WM decline, we used functional MRI to investigate age differences in PFC activity during separate WM task components (encoding, maintenance, retrieval). We found greater PFC activity in younger than older adults only in dorsolateral PFC during memory retrieval. Fast younger subjects showed less dorsolateral PFC activation during retrieval than slow younger subjects, whereas older adults showed the opposite pattern. Thus age-related changes in dorsolateral PFC and not ventrolateral PFC account for WM decline with normal aging.

D’Esposito, Ballard D, Zarahn E, Aguirre GK.  2000.  The role of prefrontal cortex in sensory memory and motor preparation: an event-related fMRI study., 2000 May. NeuroImage. 11:400-8. Abstractballard.pdf

Delayed-response tasks are behavioral paradigms in which subjects must remember stimulus attributes across a delay to subsequently perform the appropriate motor response. Quintana and Fuster (1992), reported that there exist subpopulations of neurons in monkey lateral prefrontal cortex (PFC) whose firing rates during the delay are tuned to either sensorial attributes of the stimulus (i.e., involved in sensory memory) or the direction of a postdelay motor response associated with the stimulus (i.e., involved in motor preparation). We studied human subjects with an event-related fMRI method that would allow us to test the hypothesis that there are regions within the PFC that are recruited during both motor preparation and sensory memory. Subjects performed a delayed-response task with two types of trials that either (1) allowed subjects to prepare during a delay period for a specific motor response or (2) required that subjects maintain a sensory attribute (specifically, color) during a delay period for correct performance postdelay. It was assumed that during the delay periods, the delayed-response trials would engage motor preparation while delayed-match trials would engage sensory memory. Behavioral data supported this assumption. Imaging results support the hypothesis that the PFC is involved in both motor preparation and sensory memory. Furthermore, no selectivity (in terms of intensity of neural representation on the spatial scale of the voxel size <5 mm(3)) for motor preparation over sensory memory (or vice-versa) was detected within the PFC. This latter result fails to support a gross anatomical segregation within the PFC with respect to involvement in these two cognitive processes.

Ranganath, C, Johnson MK, D’Esposito.  2000.  Left anterior prefrontal activation increases with demands to recall specific perceptual information., 2000 Nov 15. The Journal of neuroscience : the official journal of the Society for Neuroscience. 20:RC108. Abstractranganath2000.pdf

Results from neuroimaging studies have led to competing theories regarding the contributions of prefrontal regions to memory formation and retrieval. To investigate this issue, we used event-related functional magnetic resonance imaging to assess prefrontal activation during encoding and retrieval of pictures of objects. Responses to studied and unstudied objects at retrieval were compared between two tests with differing demands for the specificity of information to be retrieved (source vs old-new recognition). Results showed that bilateral ventral [Brodmann’s areas (BA) 44, 45, and 47] and right dorsal (BA 9) prefrontal regions were activated during both encoding and retrieval, but activity in these regions was not reliably modulated by the specificity of information to be retrieved. A region in left anterior prefrontal cortex (BA 10/46) was reliably activated during retrieval trials, and activation in this region increased with demands to retrieve perceptually detailed information about studied objects. Our results show that left anterior prefrontal cortex is engaged during the monitoring and evaluation of specific memory characteristics at retrieval-a process critical for accurate episodic remembering.

Mitchell, KJ, Johnson MK, Raye CL, Mather M, D’Esposito.  2000.  Aging and reflective processes of working memory: binding and test load deficits., 2000 Sep. Psychology and aging. 15:527-41. Abstract2000mitchell.pdf

It was hypothesized that age-related deficits in episodic memory for feature combinations (e.g., B. L. Chalfonte & M. K. Johnson, 1996) signal, in part, decrements in the efficacy of reflective component processes (e.g., M. K. Johnson, 1992) that support the short-term maintenance and manipulation of information during encoding (e.g., F. 1. M. Craik. R. G. Morris. & M. L. Gick, 1990; T. A. Salthouse, 1990). Consistent with this, age-related binding deficits in a working memory task were found in 2 experiments. Evidence for an age-related test load deficit was also found: Older adults had greater difficulty than young adults when tested on 2 features rather than 1, even when binding was not required. Thus, disruption of source memory in older adults may involve deficits in both encoding processes (binding deficits) and monitoring processes (difficulty accessing multiple features, evaluating them, or both).

Mitchell, KJ, Johnson MK, Raye CL, D’Esposito.  2000.  fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory., 2000 Sep. Brain research. Cognitive brain research. 10:197-206. Abstractmitchhippo.pdf

Richly detailed memories for particular events depend on processes that bind individual features of experience together. Previous cognitive behavioral research indicates that older adults have more difficulty than young adults in conditions requiring feature binding. We used functional magnetic resonance imaging (fMRI) during a working memory task to identify neural substrates of this age-related deficit in feature binding. For young, but not older, adults there was greater activation in left anterior hippocampus on combination trials (remember objects together with their locations) than on trials in which participants were told to remember only which objects or only which locations occurred. The results provide neuroimaging evidence for an age-related hippocampal dysfunction in feature binding in working memory.

Kimberg, DY, Aguirre GK, D’Esposito.  2000.  Modulation of task-related neural activity in task-switching: an fMRI study., 2000 Sep. Brain research. Cognitive brain research. 10:189-96. Abstractmodulation.pdf

Task-switching paradigms, in which subjects are typically asked to switch between different S-R mappings, can be considered operationalizations of executive control. Such paradigms are therefore potentially useful in investigating the neural bases of control functions. Here, we present the results of an fMRI study intended to examine two separable components of task-switching: preparation, and the residual shift cost identified by Rogers and Monsell [13]. In analyses restricted to functionally identified regions of interest, we found robust evidence of greater activity for switch trials, compared to repeat trials. This pattern was present both at the time of stimulus presentation and prior to the switch trial. In analyses of the entire brain, we were able to identify one area in the superior parietal lobule that was active during switching but was not part of the apparent network of task-related regions. We conclude that switch trials are neurally distinct from repeat trials in eliciting generally greater neural activity both before and during the performance of a trial.

2001
Rypma, B, D'Esposito M.  2001.  Age-related changes in brain-behavior relationships: evidence from event-related functional MRI studies. Ageing and Executive Control. , Hove, UK: Psychology Press