Variability in blood oxygen level dependent (BOLD) signal in patients with stroke-induced and primary progressive aphasia.

Although fMRI is increasingly used to assess language-related brain activation in patients with aphasia, few studies have examined the hemodynamic response function (HRF) in perilesional, and contralesional areas of the brain. In addition, the relationship between HRF abnormalities and other variables such as lesion size and severity of aphasia has not been explored. The objective of this study was to investigate changes in HRF signal during language-related neural activation in patients with stroke-induced aphasia (SA). We also examined the status of the HRF in patients with aphasia due to nonvascular etiology, namely, primary progressive aphasia (PPA). Five right handed SA patients, three PPA patients, and five healthy individuals participated in the study. Structural damage was quantified with T1-weighted MR images. Functional MR imaging was performed with long trial event-related design and an overt naming task to measure BOLD signal time to peak (TTP) and percent signal change (ΔS). In SA patients, the average HRF TTP was significantly delayed in the left hemisphere regions involved in naming compared to healthy participants and PPA patients. However, ΔS was not different in SA patients compared to the other two groups. Delay in HRF TTP in the left hemisphere naming network of SA patients was correlated with lesion size and showed a negative correlation with global language function. There were no significant differences in the HRF TTP and ΔS in the right hemisphere homologues of the naming network or in the left and the right occipital control regions across the three groups. In PPA patients, HRF had a normal pattern. Our results indicate that abnormal task-related HRF is primarily found in the left hemisphere language network of SA patients and raise the possibility that abnormal physiology superimposed on structural damage may contribute to the clinical deficit. Follow-up investigations in a larger sample of age-matched healthy individuals, SA, and PPA patients will be needed to further confirm and extend our findings.

Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers.

BACKGROUND: Fibrillar amyloid deposition preferentially affects the frontal lobes, temporal pole/neocortex, and posterior cingulate by age 65 years in APOE ε4 carriers prior to the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), but is it impairing frontally mediated neuropsychological performance? METHODS: A total of 71 ε4 homozygotes (HMZ), 194 ε4 heterozygotes (HTZ), and 356 ε4 noncarriers (NC) who did not differ significantly in mean age (56.6 years), years of education (15.6), gender (70% women), or follow-up duration (6.3 years) had neuropsychological testing every 2 years including the Auditory Verbal Learning Test (AVLT) and frontal/executive tasks sensitive to psychomotor speed, working memory, problem solving, and activity. A subset also received the Iowa Gambling Task (IGT). Findings were then tested in a clinical sample of 27 patients with incident MCI and AD. RESULTS: APOE ε4 carriers had greater acceleration of decline (quadratic effect) than NC on the AVLT (p = 0.04) but not on any frontal test. APOE ε4 HMZ had greater velocity of decline (linear effects) than NC on all mental arithmetic tests: paced auditory serial attention task (PASAT) 3 second (p = 0.01) and 2 second (p = 0.004) versions; and Wechsler Adult Intelligence Scale-Revised arithmetic (p = 0.048). IGT performance did not differ between 12 ε4 HMZ, 27 ε4 HTZ, and 44 NC. Among 27 patients with incident MCI and AD, the PASAT showed progressive decline preceding diagnosis in 50%. CONCLUSIONS: No frontal cognitive effects were as robust as memory decline. APOE ε4 HMZ declined more quickly than NC on mental arithmetic tests related to frontal lobe-mediated working memory ability.

Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes.

OBJECTIVE: To characterize the effects of cerebrovascular (CV) risk factors on preclinical memory decline in cognitively normal individuals at 3 levels of genetic risk for Alzheimer disease (AD) based on APOE genotype. METHODS: We performed longitudinal neuropsychological testing on an APOE ε4 enriched cohort, ages 21-97. The long-term memory (LTM) score of the Auditory Verbal Learning Test (AVLT) was the primary outcome measure. Any of 4 CV risk factors (CVany), including hypercholesterolemia (CHOL), prior cigarette use (CIG), diabetes mellitus (DM), and hypertension (HTN), was treated as a dichotomized variable. We estimated the longitudinal effect of age using statistical models that simultaneously modeled the cross-sectional and longitudinal effects of age on AVLT LTM by APOE genotype, CVany, and the interaction between the two. RESULTS: A total of 74 APOE ε4 homozygotes (HMZ), 239 ε4 heterozygotes (HTZ), and 494 ε4 noncarriers were included. APOE ε4 carrier status showed a significant quadratic effect with age-related LTM decline in all models as previously reported. CVany was associated with further longitudinal AVLT LTM decline in APOE ε4 carriers (p=0.02), but had no effect in noncarriers. When ε4 HTZ and HMZ were considered separately, there was a striking effect in HMZ (p<0.001) but not in HTZ. In exploratory analyses, significant deleterious effects were found for CIG (p=0.001), DM (p=0.03), and HTN (p=0.05) in APOE ε4 carriers only that remained significant only for CIG after correction for multiple comparisons. CONCLUSION: CV risk factors influence age-related memory decline in APOE ε4 HMZ.

Crossover by line length and spatial location.

It is well known that line length has a systematic influence on line bisection error in neglect. Most patients with neglect misbisect long lines on the same side of true center as their brain lesion but then cross over on short lines, misbisecting them on the opposite side (i.e., crossover by line length). What is less recognized is that the spatial location of lines relative to the viewer can similarly induce a crossover effect when one considers line bisection error scores that have been averaged across individual line lengths. Patients with right hemisphere injury and neglect classically make averaged line bisection errors that fall right of true center on lines located either at midline or to the left of the viewer; however, we observed that the averaged line bisection error can fall left of true center when lines are located to the right of the viewer (i.e., crossover by spatial location). We hypothesized that crossover by both line length and spatial location stem from systematic errors in magnitude estimation, i.e., perceived line length. We tested predictions based on this hypothesis by examining how the crossover effect by line length is altered by the spatial location of lines along a horizontal axis relative to the viewer. Participants included patients with unilateral lesions of the right and left cerebral hemispheres and age-appropriate normal subjects. All groups demonstrated a crossover effect by line length at the midline location but the effect was altered by placing lines to the right and left of the viewer. In particular, patients with right hemisphere injury and neglect crossed-over across a broader range of line lengths when the lines were located to the right of the viewer rather than at either midline or left of the viewer. It is proposed that mental representations of stimulus magnitude are altered in neglect, in addition to mental representations of space, and that traditional accounts of neglect can be enhanced by including the psychophysical concept of magnitude estimation.

Face memory impairments in patients with frontal lobe damage.

OBJECTIVE: To determine whether damage to prefrontal cortex is associated with face memory impairment. BACKGROUND: Neurophysiologic and functional imaging studies suggest that prefrontal cortex is a key component of a distributed neural network that mediates face recognition memory. However, there have been few attempts to examine the impact of frontal lobe damage on face memory performance. METHODS: Patients with focal frontal lobe lesions and normal control subjects were administered two-alternative forced-choice and single-probe "yes/no" tests of recognition memory for novel faces. Retrograde memory was assessed by using famous faces as stimuli. RESULTS: Compared with control subjects, patients with frontal lobe lesions showed evidence of marked anterograde and relatively mild retrograde face memory impairment. In addition, patients with right frontal lesions demonstrated increased susceptibility to false recognition, consistent with the breakdown of strategic memory retrieval, monitoring, and decision functions. CONCLUSIONS: Prefrontal cortex plays an important role in the executive control of face memory encoding and retrieval. Left and right prefrontal regions seem to make different contributions to recognition memory performance.

Object memory effects on figure assignment: conscious object recognition is not necessary or sufficient.

In three experiments we investigated whether conscious object recognition is necessary or sufficient for effects of object memories on figure assignment. In experiment 1, we examined a brain-damaged participant, AD, whose conscious object recognition is severely impaired. AD's responses about figure assignment do reveal effects from memories of object structure, indicating that conscious object recognition is not necessary for these effects, and identifying the figure-ground test employed here as a new implicit test of access to memories of object structure. In experiments 2 and 3, we tested a second brain-damaged participant, WG, for whom conscious object recognition was relatively spared. Nevertheless, effects from memories of object structure on figure assignment were not evident in WG's responses about figure assignment in experiment 2, indicating that conscious object recognition is not sufficient for effects of object memories on figure assignment. WG's performance sheds light on AD's performance, and has implications for the theoretical understanding of object memory effects on figure assignment.

Fear recognition deficits after focal brain damage: a cautionary note.

OBJECTIVE: To test the hypothesis that fear recognition deficits in neurologic patients reflect damage to an emotion-specific neural network. BACKGROUND: Previous studies have suggested that the perception of fear in facial expressions is mediated by a specialized neural system that includes the amygdala and certain posterior right-hemisphere cortical regions. However, the neuropsychological findings in patients with amygdala damage are inconclusive, and the contribution of distinct cortical regions to fear perception has only been examined in one study. METHODS: We studied the recognition of six basic facial expressions by asking subjects to match these emotions with the appropriate verbal labels. RESULTS: Both normal control subjects (n = 80) and patients with focal brain damage (n = 63) performed significantly worse in recognizing fear than in recognizing any other facial emotion, with errors consisting primarily of mistaking fear for surprise. Although patients were impaired relative to control subjects in recognizing fear, we could not obtain convincing evidence that left, right, or bilateral lesions were associated with disproportionate impairments of fear perception once we adjusted for differences in overall recognition performance for the other five facial emotion categories. The proposed special role of the amygdala and posterior right-hemisphere cortical regions in fear perception was also not supported. CONCLUSIONS: Fear recognition deficits in neurologic patients may be attributable to task difficulty factors rather than damage to putative neural systems dedicated to fear perception.

Classification learning in Alzheimer's disease.

Previous research has demonstrated that explicit recognition of dot patterns is impaired in amnesic patients with damage to the limbic-diencephalic memory system, while implicit categorization of the same kind of stimuli is preserved. The aim of the present study was to investigate the relationship between recognition and categorization performances in patients with Alzheimer's disease. Consistent with the findings in amnesic subjects, our results revealed that the explicit recognition of dot patterns was significantly impaired in Alzheimer's disease. However, implicit categorization functions were also disrupted. This was selective for the prototype stimuli; the categorization of non-prototype dot patterns was spared. The impaired category learning is likely to reflect the damage of modality-specific neocortical areas in Alzheimer's disease.

Age-related hemispheric asymmetry in object discrimination.

Young and elderly observers judged whether two sequentially presented images in either the left or right visual field (LVF or RVF) were the same or different. The two objects depicted were always from the same entry-level category, but could differ only in viewpoint (a "same" trial--observers were instructed to ignore viewpoint changes) and/or in exemplar (a "different" trial). Young observers showed no difference in sensitivity across visual fields. Elderly observers were less sensitive overall than young observers, and were less sensitive to stimuli presented in the LVF-RH than in the RVF-LH. The results of this experiment support the hypothesis that one type of visual cognitive functioning declines with age faster in the right hemisphere than in the left hemisphere.

A search for the optimal stimulus.

How do stimulus size and item number relate to the magnitude and direction of error on center estimation and line cancellation tests? How might this relationship inform theories concerning spatial neglect? These questions were addressed by testing twenty patients with right hemisphere lesions, eleven with left hemisphere lesions and eleven normal control subjects on multiple versions of center estimation and line cancellation tests. Patients who made large errors on these tests also demonstrated an optimal or pivotal stimulus value, i.e., a particular size center estimation test or number of lines on cancellation that either minimized error magnitude relative to other size stimuli (optimal) or marked the boundary between normal and abnormal performance (pivotal). Patients with right hemisphere lesions made increasingly greater errors on the center estimation test as stimuli were both larger and smaller than the optimal value, whereas those with left hemisphere lesions made greater errors as stimuli were smaller than a pivotal value. In normal subjects, the direction of errors on center estimation stimuli shifted from the right of true center to the left as stimuli decreased in size (i.e., the crossover effect). Right hemisphere lesions exaggerated this effect, whereas left hemisphere lesions diminished and possibly reversed the direction of crossover. Error direction did not change as a function of stimulus value on cancellation tests. The demonstration of optimal and pivotal stimulus values indicates that performances on center estimation and cancellation tests in neglect are only relative to the stimuli used. In light of other studies, our findings indicate that patients with spatial neglect grossly overestimate the size of small stimuli and underestimate the size of large stimuli, that crossover represents an "apparent" shift in error direction that actually results from normally occurring errors in size perception, and that the left hemisphere is specialized for one aspect of size estimation, whereas the right performs dual roles.

Dissociation between verbal and autonomic measures of memory following frontal lobe damage.

OBJECTIVE: The objective of this study was to contrast overt verbal versus covert autonomic responses to facial stimuli in a patient with false recognition following frontal lobe damage. BACKGROUND: False recognition has been linked to frontal lobe dysfunction. However, previous studies have relied exclusively on overt measures of memory and have not examined whether or not patients with false recognition continue to demonstrate preserved covert discrimination of familiar and unfamiliar items. METHODS: We recorded skin conductance responses (SCRs) in a patient with frontal lobe damage and in normal control subjects while they performed a familiarity decision task using famous and unfamiliar faces as stimuli. RESULTS: Patient J.S. produced significantly more overt false recognition errors and misidentifications in response to unfamiliar faces than control subjects. However, similar to the control subjects, he showed accurate covert autonomic discrimination of truly familiar faces from unfamiliar ones. Furthermore, SCRs to falsely recognized unfamiliar faces were not significantly different from SCRs generated to unfamiliar faces that J.S. correctly rejected. CONCLUSIONS: Our findings provide further neuropsychological evidence that overt and covert forms of face recognition memory are dissociable. In addition, the failure to detect an autonomic correlate for the false recognition errors and misidentifications in J.S. suggests that these memory distortions were not related to the spurious activation of stored memory representations for specific familiar faces. Instead, these incorrect responses may have been driven by the sense of familiarity evoked by novel faces that had a general resemblance to faces encountered previously. We propose that false recognition in J.S. resulted from the breakdown of strategic frontal memory retrieval, monitoring, and decision functions critical for attributing the experience of familiarity to its appropriate source.

Selective deficit of praxis imagery in ideomotor apraxia.

We studied imagery for learned, skilled movements (praxis imagery) in a patient with severe ideomotor apraxia and intact language abilities. This patient, who made predominantly spatial and movement errors when performing transitive movements demonstrating the use of tools (transitive gestures), was also impaired in her ability to answer imagery questions about joint movement or the spatial position of the hands during action. However, visual object imagery was spared. The finding of parallel praxis production and praxis imagery deficits in this patient suggests that the same representations used for gesture production are also activated during imagery of motor acts. Our findings also suggest that certain aspects of motor imagery may be dissociable from general object imagery.

Contributions of the left and right cerebral hemispheres to line bisection.

Thirty-one right-hemisphere lesioned (RHL) patients, 11 left-hemisphere lesioned patients (LHL) and 10 normal controls (NC) bisected lines in three spatial location and four directional cuing conditions. The error direction and error size were analyzed as separate and combined variables. Seventy-seven percent of RHL patients and 45% of LHL patients made abnormally large errors in line bisection. Right-hemisphere lesioned patients were more sensitive to spatial location and directional cuing than NC subjects. In contrast, LHL patients were less sensitive to either condition than NCs. The error direction and error size emerged as dissociable components of line bisection. Right-hemisphere lesioned patients and NC subjects bisected lines consistently to one side of the true center. Left-hemisphere lesioned patients bisected lines equally often on both sides of the true center. Both RHL and LHL patients made larger absolute bisection errors than NC subjects, but the RHL patient's errors were larger than those of the LHL patients. We propose that the greater sensitivity of RHL patients to spatial location and directional cues and the directional consistency of their bisection errors represent contributions of the intact left cerebral hemisphere to line bisection. In contrast, the LHL patient's unrestrained ability to orient to both ends of the line reflects a contribution of the intact right cerebral hemisphere to line bisection. The failure of both groups to accurately bisect lines reflects a common visuospatial processing deficit that is more pronounced following RHLs than LHLs.

False recognition of unfamiliar faces following right hemisphere damage: neuropsychological and anatomical observations.

False recognition of unfamiliar faces was investigated in patients with focal right hemisphere damage (RHD) in order to define the neuropsychological and anatomical correlates of the recognition impairment and examine its relationship to prosopagnosia. Findings are discussed within the framework of the Bruce and Young (1986) model of face processing. Although false recognition and prosopagnosia were both present in some RHD patients, the two types of face recognition impairments were dissociable in others. Processing deficits in subjects with both false recognition and prosopagnosia were associated with posterior right hemisphere lesion sites and included severe face perception impairment and partial damage to face recognition units (FRUs). Prosopagnosia without false recognition was seen following near complete destruction of FRUs, but this type of dissociation could also occur when FRUs become disconnected. The opposite dissociation, false recognition without prosopagnosia, was observed following right prefrontal damage. We propose that false recognition in frontal patients results from the breakdown of strategic decision making and monitoring functions critical for determining whether a face is indeed that of a familiar person or whether there is merely a resemblance to a known individual. False recognition following prefrontal damage may also be related to confabulation, in which case familiarity or even specific identity are erroneously attributed to facial stimuli without the activation of an underlying memory representation.

Posttranslational modifications of brain and erythrocyte band 3 during aging and disease.

Band 3 performs the same structural and functional activities in adult brain as it does in erythrocytes. It ages as cells and tissues age Our studies, to date, indicate that the anion transport ability of band 3 decreases in brains and lymphocytes from old mice. This decreased transport ability precedes obvious structural changes, such as band 3 degradation and generation of SCA and is the earliest change thus far detected in band 3. The following changes occur in lymphocytes, erythrocytes and brain band 3 with aging: 1) a decreased efficiency of anion transport (decreased Vmax) in spite of an increase in number of anion binding sites (increased K(m)), 2) a decreased glucose transport, 3) 32P labeling in vitro, 4) an increased degradation to smaller fragments as detected by quantitative binding of antibodies to band 3 breakdown products and residue 812-830, and 5) a binding of physiologic IgG autoantibodies in situ. The latter three findings indicate that posttranslational changes occur. In addition, the anion transporter, band 3, undergoes an as yet undefined change that results in binding of "980" antibodies to aged band 3. Posttranslational changes in AD include decreased brain and RBC phosphorylation of a M(r) = 135, 113 and 45 kDa band 3 polypeptides due to the phosphorylation site being already occupied, increased degradation of band 3, alterations in band 3 recognized by antibodies, and decreased anion and glucose transport by blood cells. Band 3 in erythrocytes of AD patients has a different immunological identity from normal band 3 as evidenced by the binding of antibodies described in this study. AD may be preferentially manifested in the brain because neurons accumulate damage throughout the lifetime as they do not regenerate or undergo cell division. We suspect, and our data indicate, that the same mechanism(s) of AD occurs in all cells, but that the manifestations differ due to different cell proteins and functions.

Representations in learning new faces: evidence from prosopagnosia.

We report the performance of a prosopagnosic patient on face learning tasks under different encoding instructions (i.e., levels of processing manipulations). R.J. performs at chance when given no encoding instructions or when given "shallow" encoding instruction to focus on facial features. By contrast, he performs relatively well with "deep" encoding instructions to rate faces in terms of personality traits or when provided with semantic and name information during the study phase. We propose that the improvement associated with deep encoding instructions may be related to the establishment of distinct visually derived and identity-specific semantic codes. The benefit associated with deep encoding in R.J., however, was found to be restricted to the specific view of the face presented at study and did not generalize to other views of the same face. These observations suggest that deep encoding instructions may enhance memory for concrete or pictorial representations of faces in patients with prosopagnosia, but that these patients cannot compensate for the inability to construct abstract structural codes that normally allow faces to be recognized from different orientations. We postulate further that R.J.'s poor performance on face learning tasks may be attributable to excessive reliance on a feature-based left hemisphere face processing system that operates primarily on view-specific representations.

Progressive ideomotor apraxia: evidence for a selective impairment of the action production system.

We report a patient with slowly progressive bilateral limb apraxia associated with an asymmetrical focal degenerative process of the parietal lobes. Clinical assessment of praxis production suggested a striking deficit in controlling the spatiotemporal attributes of purposeful skilled limb movements, consistent with ideomotor apraxia. The precise nature of the action production impairment was further defined by objective three-dimensional computergraphic analysis of transitive movements which demonstrated significant kinematic deficits in spatial accuracy, timing, spatiotemporal coupling, and joint coordination. Gesture comprehension and discrimination were spared. Furthermore, detailed evaluation of the conceptual praxis system revealed that despite an almost complete inability to perform transitive movements accurately, abstract knowledge of tool function and action was remarkably well preserved. The critical dissociation between intact conceptual knowledge of action and impaired movement execution documented in this case points to a fundamental competence/performance dichotomy in apraxia and provides empirical support for cognitive models of praxis that divide the action system into distinct conceptual and production subcomponents. Within this theoretical framework, our patient's severe ideomotor apraxia is interpreted to represent a selective disruption of the action production system.

False recognition and misidentification of faces following right hemisphere damage.

We report two patients who, following massive damage to the right hemisphere, showed a striking tendency for false recognition and misidentification of faces. Neuropsychological investigations revealed that excessive reliance on a feature-based left hemisphere strategy in face processing, combined with an inability to evaluate critically the output generated by the dysfunctional face recognition system, played a major role in the recognition errors and misidentifications. Our findings suggest that the feature based left hemisphere face recognition system is potentially error-prone, presumably because component facial features are likely to be shared among several different individuals, and that reliable recognition and identification of faces is critically dependent upon the efficient processing of configurational facial information by the right hemisphere. We propose further that decision making and monitoring functions relevant to the operations of the face recognition system are primarily lateralized to the right frontal lobe.