Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: an fMRI study

Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits. Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing. Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included. Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto-parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus. The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding.     

Load-related brain activation predicts spatial working memory performance in youth aged 9–12 and is associated with executive function at earlier ages

Spatial working memory is a central cognitive process that matures through adolescence in conjunction with major changes in brain function and anatomy. Here we focused on late childhood and early adolescence to more closely examine the neural correlates of performance variability during this important transition period. Using a modified spatial 1-back task with two memory load conditions in an fMRI study, we examined the relationship between load-dependent neural responses and task performance in a sample of 39 youth aged 9–12 years. Our data revealed that between-subject differences in task performance was predicted by load-dependent deactivation in default network regions, including the ventral anterior cingulate cortex (vACC) and posterior cingulate cortex (PCC). Although load-dependent increases in activation in prefrontal and posterior parietal regions were only weakly correlated with performance, increased prefrontal–parietal coupling was associated with better performance. Furthermore, behavioral measures of executive function from as early as age 3 predicted current load-dependent deactivation in vACC and PCC. These findings suggest that both task positive and task negative brain activation during spatial working memory contributed to successful task performance in late childhood/early adolescence. This may serve as a good model for studying executive control deficits in developmental disorders.     

White matter changes compromise prefrontal cortex function in healthy elderly individuals

Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magnitude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task. We also examined the effects of WMH located in the dorsolateral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior parietal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning.     

Cerebellar fMRI Activation Increases with Increasing Working Memory Demands

The aim of the present study was to explore cerebellar contributions to the central executive in n-back working memory tasks using 7-T functional magnetic imaging (fMRI). We hypothesized that cerebellar activation increased with increasing working memory demands. Activations of the cerebellar cortex and dentate nuclei were compared between 0-back (serving as a motor control task), 1-back, and 2-back working memory tasks for both verbal and abstract modalities. A block design was used. Data of 27 participants (mean age 26.6?±?3.8 years, female/male 12:15) were included in group statistical analysis. We observed that cerebellar cortical activations increased with higher central executive demands in n-back tasks independent of task modality. As confirmed by subtraction analyses, additional bilateral activations following higher executive demands were found primarily in four distinct cerebellar areas: (i) the border region of lobule VI and crus I, (ii) inferior parts of the lateral cerebellum (lobules crus II, VIIb, VIII, IX), (iii) posterior parts of the paravermal cerebellar cortex (lobules VI, crus I, crus II), and (iv) the inferior vermis (lobules VI, VIIb, VIII, IX). Dentate activations were observed for both verbal and abstract modalities. Task-related increases were less robust and detected for the verbal n-back tasks only. These results provide further evidence that the cerebellum participates in an amodal bilateral neuronal network representing the central executive during working memory n-back tasks.     

Practice on conflict tasks promotes executive function of working memory in the elderly

Effects of practice on a conflict task in elderly individuals are examined with a focus on its impact on executive function in working memory. During a short-term practice period, healthy elderly participants practiced switching attention using a Stroop task that involved a conflict between a task relevant stimulus and an irrelevant stimulus. To explore neural substrates underlying practice effects, two working memory tasks were used: a focus reading span test (F-RST) and a non-focus reading span test (NF-RST); the NF-RST test demanded greater switching attention due to a conflict between the relevant task stimulus and an irrelevant task stimulus, thus requiring an attention switch from the latter to the former. Following the Stroop task practice, fMRI data showed that participants who had engaged in practice had significant increases in activation in the anterior cingulate cortex (ACC), the left inferior parietal lobule (IPL), the left dorsolateral prefrontal cortex (DLPFC) and the precuneus regions during the NF-RST. By contrast, a control group, which did not practice, showed no significant increases in these regions. Results suggest that practice on conflict tasks in elderly individuals activated regions related to conflict perceiving and attention switching regions as well as attention-maintenance regions thereby improving performance on tasks requiring a high degree of attention control of working memory.     

Neocortical system abnormalities in autism: an fMRI study of spatial working memory

OBJECTIVE: To test the hypothesis that deficits in spatial working memory in autism are due to abnormalities in prefrontal circuitry. METHODS: Functional MRI (fMRI) at 3 T was performed in 11 rigorously diagnosed non-mentally retarded autistic and six healthy volunteers while they performed an oculomotor spatial working memory task and a visually guided saccade task. RESULTS: Autistic subjects demonstrated significantly less task-related activation in dorsolateral prefrontal cortex (Brodmann area [BA] 9/46) and posterior cingulate cortex (BA 23) in comparison with healthy subjects during a spatial working memory task. In contrast, activation of autistic individuals was not reduced in other regions comprising the neural circuitry for spatial working memory including the cortical eye fields, anterior cingulate cortex, insula, basal ganglia, thalamus, and lateral cerebellum. Autistic subjects also did not demonstrate reduced activation in any brain regions while performing visually guided saccades. CONCLUSION: Impairments in executive cognitive processes in autism may be subserved by abnormalities in neocortical circuitry as evidenced by decreased activation in prefrontal and posterior cingulate circuitry during a spatial working memory task.     

Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.     

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age+/-s.d.=34.3+/-11.5 years) and 15 healthy comparison subjects (37.7+/-12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.     

Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study.

BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness and show deficits on high-load information processing tasks. We used functional magnetic resonance imaging (fMRI) to test whether nonpsychotic relatives show altered functional activation in the prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a working memory task requiring interference resolution. METHODS: Twelve nonpsychotic relatives of persons with schizophrenia and 12 healthy control subjects were administered an auditory, verbal working memory version of the Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS: Compared with control subjects, relatives showed greater task-elicited activation in the PFC and the anterior and dorsomedial thalamus. When task performance was controlled, relatives showed significantly greater activation in the anterior cingulate. When effects of other potentially confounding variables were controlled, relatives generally showed significantly greater activation in the dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study suggests that relatives of persons with schizophrenia have subtle differences in brain function in the absence of psychosis. These differences add to the growing literature identifying neurobiological vulnerabilities to schizophrenia.     

Fatigue in the executive cortical network demonstrated in narcoleptics using functional magnetic resonance imaging--a preliminary study

BACKGROUND AND PURPOSE: To demonstrate dynamic changes in cerebral functional activation during a working memory task in a state of severe excessive daytime sleepiness. PATIENTS AND METHODS: Omitting the usual morning dose of stimulants in three narcoleptics induced sleepiness. Functional magnetic resonance imaging (fMRI) was used to map cerebral activation during the performance of a 2-back verbal working memory task. Repeated 9.5 min scans were performed, until the subjects felt they could not continue. This was the functional imaging equivalent of the maintenance of wakefulness test. RESULTS: Bilateral and widespread activation in known nodes of the executive network were seen during the first scan in all subjects, including the lateral prefrontal, posterior parietal and anterior cingulate cortex. There was a reduction in cerebral activation, especially but not exclusively in the prefrontal cortex, associated with slowing of performance from the first to the last tolerated scan. On stimulants, subjective alertness, activation and objective performance were readily maintained. CONCLUSION: This preliminary study suggests that fatigue in the executive cortical network may be demonstrated by a progressive reduction in regional cerebral activation across scans, which may be prevented by stimulant use. Averaging multiple scan runs, a typical practice in fMRI, could blur important dynamic components of activation.     

Isolated executive impairment and associated frontal neuropathology

Cognitive impairment in the absence of dementia is common in elderly individuals and is most often studied in the context of an isolated impairment in memory. In the current study, we report the neuropsychological and neuropathological features of a nondemented elderly individual with isolated impairment on a test of executive function (i.e., Trail Making Test) and preserved memory, language, and visuospatial function. Postmortem studies indicated that cortical neurofibrillary tangles (NFT) varied considerably, and some regions contained large numbers of neuritic senile plaques. Semiquantitative immunohistochemistry showed higher NFT and amyloid-beta (Abeta) loads in the frontal cortex relative to the temporal, entorhinal, occipital, and parietal cortices. A survey of the entire cingulate gyrus showed a wide dispersion of Abeta42 with the highest concentration in the perigenual part of the anterior cingulate cortex; Abeta appeared to be linked with neuron loss and did not overlap with the heaviest neuritic degeneration. The current case may represent a nonmemory presentation of mild cognitive impairment (executive mild cognitive impairment) that is associated with frontal and anterior cingulate pathology and may be an early stage of the frontal variant of Alzheimer disease.     

Executive dysfunction in patients with spinocerebellar ataxia type 3

The aim of this study was to assess the cognitive functions of patients with spinocerebellar ataxia type 3(SCA3). We examined 15 patients with genetically confirmed SCA3 and 15 healthy control subjects matched for age, years of education, and intellectual ability. We administered verbal memory (word recall and word recognition) and executive function tasks (word fluency test, forward and backward digit and visual span tests, Kana Pick-out Test, Trail Making Test, and conflicting instructions and a Go/NoGo task from the Frontal Assessment Battery). We found that patients with SCA3 had significantly lower scores than the healthy control subjects on the word recall, semantic, and letter fluency, and backward digit span tests, while word recognition was well preserved. The other executive function tests showed preserved functions in the SCA3 group, indicating that visual working memory, and attention and inhibition control were not affected. The patients with SCA3 showed impaired word recall and intact word recognition, and accordingly, episodic memory encoding and storage processes in short-term memory were preserved. In category and letter-fluency tests, impairment was attributable to word-retrieval from semantic memory. Impaired verbal working memory may be involved in the retrieval of verbal information from phonological storage by means of continuous subvocal rehearsal, rather than a deficit in initial phonological encoding. Essential executive dysfunction in patients with SCA3 may be due to damage in the cerebellar cortex–ventral dentate nucleus–thalamus–prefrontal cortex circuits, which are involved in strategic retrieval of verbal information from different modes of memory storage.     

Neural basis for generalized quantifier comprehension

Generalized quantifiers like "all cars" are semantically well understood, yet we know little about their neural representation. Our model of quantifier processing includes a numerosity device, operations that combine number elements and working memory. Semantic theory posits two types of quantifiers: first-order quantifiers identify a number state (e.g. "at least 3") and higher-order quantifiers additionally require maintaining a number state actively in working memory for comparison with another state (e.g. "less than half"). We used BOLD fMRI to test the hypothesis that all quantifiers recruit inferior parietal cortex associated with numerosity, while only higher-order quantifiers recruit prefrontal cortex associated with executive resources like working memory. Our findings showed that first-order and higher-order quantifiers both recruit right inferior parietal cortex, suggesting that a numerosity component contributes to quantifier comprehension. Moreover, only probes of higher-order quantifiers recruited right dorsolateral prefrontal cortex, suggesting involvement of executive resources like working memory. We also observed activation of thalamus and anterior cingulate that may be associated with selective attention. Our findings are consistent with a large-scale neural network centered in frontal and parietal cortex that supports comprehension of generalized quantifiers.     

Pathways to similar executive impairment: Comparison of schizophrenia patients and healthy aging individuals

Executive impairment is prominent in schizophrenia, in conditions such as Parkinson's disease and dementia and in healthy aging. Identifying processes that critically constrain executive function can advance investigation of their biological basis and treatment planning. Recent findings that elderly healthy individuals showed similar impairment on conditional exclusion task as schizophrenia patients raised the question whether similar processes are impaired. To test this we compared 56 schizophrenia patients, 57 elderly and 77 young healthy individuals on three executive tests: conditional exclusion, abstraction and inhibition and tests of working memory and psychomotor speed. Schizophrenia patients performed worse than elderly healthy on abstraction, inhibition and verbal working memory. They were similarly impaired on Penn Conditional Exclusion Test (PCET) outcome measures but differed in performance characteristics. Schizophrenia patients needed relatively more trials to learn the first PCET category than the second or the third. This correlated with other cognitive impairments, particularly in working memory. Elderly healthy individuals found it most difficult to learn the last category. The two groups showed different error patterns. We propose that schizophrenia patients have particular difficulty in early (probabilistic) learning (“what to do”) while aging individuals have selective impairment in executive integration. These constitute distinct targets for customized treatment in the two conditions.     

Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease

BACKGROUND: The prefrontal cortex (PFC) is a heterogeneous cortical structure that supports higher cognitive functions, including working memory and verbal abilities. The PFC is vulnerable to neurodegeneration with healthy aging and Alzheimer disease (AD). OBJECTIVE: We used volumetric magnetic resonance imaging to determine whether any region within the PFC is more vulnerable to deterioration with late aging or AD. METHODS: Volumetric analysis of PFC regions was performed on younger healthy elderly subjects (n = 26; 14 men and 12 women [mean age, 71.7 years] for aging analysis; 12 men and 14 women [mean age, 71.4 years] for AD analysis), oldest healthy elderly (OHE) subjects (n = 22 [11 men and 11 women]; mean age, 88.9 years), and patients with AD (n = 22 [12 men and 10 women]; mean age, 69.8 years). RESULTS: The OHE subjects had less PFC white matter than did young healthy elderly subjects. The orbital region was selectively preserved relative to other PFC regions in the OHE subjects. Subjects with AD had less total PFC gray matter than did age-matched healthy subjects and significantly less volume in the inferior PFC region only. CONCLUSIONS: Orbital PFC is selectively preserved in OHE subjects. In contrast, degeneration within the PFC with AD is most prominent in the inferior PFC region. Thus, degeneration within the PFC has a regionally distinct pattern in healthy aging and AD.     

Atrophy of the left dorsolateral prefrontal cortex is associated with poor performance in verbal fluency in elderly poststroke women

This study aimed to investigate the association between atrophy in the prefrontal cortex with executive function and verbal fluency in elderly male and female patients poststroke. Thirty elderly female patients with non-aphasic ischemic stroke aged ≥ 60 years and 30 age-matched non-aphasic male patients with ischemic stroke were recruited. Automatic magnetic resonance imaging segmentation was used to assess the volume of the whole prefrontal cortex, along with its subdivisions: anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex. The Semantic Verbal Fluency Test was administered at 3 and 15 months poststroke. At 3 months poststroke, left dorsolateral prefrontal cortex volume was significantly correlated with Verbal Fluency Test score in female patients only (partial coefficient = 0.453, P = 0.045), after controlling for age, education, diabetes, neurological deficit, white matter lesions volume, as well as the location and volume of infarcts. At 15 months poststroke, there remained a significant association between the left dorsolateral prefrontal cortex volume and Verbal Fluency Test (partial coefficient = 0.661, P = 0.001) and between the left prefrontal cortex volume and Verbal Fluency Test (partial coefficient = 0.573, P = 0.004) in female patients after the same adjustments. These findings indicate that atrophy of the left dorsolateral prefrontal cortex contributes to the impairment of verbal fluency in elderly female patients with stroke. Sex differences may be present in the neuropsychological mechanisms of verbal fluency impairment in patients with stroke.     

Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression

BACKGROUND: We previously found that children of parents with depression showed impaired performance on a task of emotional categorisation. AIMS: To test the hypothesis that children of parents with depression would show abnormal neural responses in the anterior cingulate cortex, a brain region involved in the integration of emotional and cognitive information. METHOD: Eighteen young people (mean age 19.8 years) with no personal history of depression but with a biological parent with a history of major depression (FH+ participants) and 16 controls (mean age 19.9 years) underwent functional magnetic resonance imaging while completing an emotional counting Stroop task. RESULTS: Controls showed significant activation in the pregenual anterior cingulate cortex to both positive and negative words during the emotional Stroop task. This activation was absent in FH+ participants. CONCLUSIONS: Our findings show that people at increased familial risk of depression demonstrate impaired modulation of the anterior cingulate cortex in response to emotionally valenced stimuli.     

Abnormal parietal cortex activation during working memory in schizophrenia: verbal phonological coding disturbances versus domain-general executive dysfunction

OBJECTIVE: The goal of this study was to determine whether the regions of the prefrontal and parietal cortices showing abnormal activation among individuals with schizophrenia during working memory tasks are associated with either 1) phonological coding processes that may be specific to verbal tasks (i.e., ventral prefrontal and parietal cortices) or 2) domain-general executive processes engaged by verbal and nonverbal tasks (i.e., dorsal prefrontal and parietal cortices). METHOD: The participants were 57 medicated individuals with schizophrenia and 120 healthy subjects. Functional magnetic resonance imaging was used to scan all participants during performance of verbal and nonverbal 2-back working memory tasks. RESULTS: In the healthy subjects there was similar bilateral dorsal prefrontal and inferior parietal cortex activation for both the verbal and nonverbal working memory tasks, but greater left ventral prefrontal and parietal cortex activation during verbal compared to nonverbal working memory. Individuals with schizophrenia showed bilateral deficits in dorsal frontal and parietal activation during both verbal and nonverbal working memory tasks. They also demonstrated the typical pattern of greater activity for verbal, as compared to nonverbal, working memory in ventral prefrontal and parietal regions, although they showed less verbal superiority in a left ventral prefrontal region. CONCLUSIONS: These results support the hypothesis that working memory deficits in individuals with schizophrenia reflect deficits in activation of brain regions associated with the central executive components of working memory rather than domain-specific storage buffers.     

Comparison of adult age differences in verbal and visuo-spatial memory: the importance of 'pure', parallel and validated measures

The study compared age-related decrements in verbal and visuo-spatial memory across a broad elderly adult age range. Twenty-four young (18-25 years), 24 young-old (65-74 years), 24 middle-old (75-84 years) and 24 old-old (85-93 years) adults completed parallel recall and recognition measures of verbal and visuo-spatial memory from the Doors and People Test (Baddeley, Emslie & Nimmo-Smith, 1994). These constituted 'pure' and validated indices of either verbal or visuo-spatial memory. Verbal and visuo-spatial memory declined similarly with age, with a steeper decline in recall than recognition. Unlike recognition memory, recall performance also showed a heightened decline after the age of 85. Age-associated memory loss in both modalities was largely due to working memory and executive function. Processing speed and sensory functioning (vision, hearing) made minor contributions to memory performance and age differences in it. Together, these findings demonstrate common, rather than differential, age-related effects on verbal and visuo-spatial memory. They also emphasize the importance of using 'pure', parallel and validated measures of verbal and visuo-spatial memory in memory ageing research.     

Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: the Vietnam Era twin study of aging

High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggests that cortisol regulation is likely to be associated with prefrontally-mediated executive function abilities. We hypothesized that elevated cortisol levels would be associated with poorer frontal-executive function in addition to episodic memory. We assessed cortisol from 15 saliva samples paralleling individual diurnal rhythms across three non-consecutive days in a group of 778 middle-aged twin men ages 51-60. Cognitive domains created from 24 standard measures included: general cognitive ability, verbal and visual-spatial ability, verbal and visual-spatial memory, short-term/immediate memory, working memory, executive function, verbal fluency, abstract reasoning, and psychomotor processing speed. Adjusting for general cognitive ability at age 20, age, race, and multiple health and lifestyle indicators, higher levels of average area-under-the-curve cortisol output across three days were significantly associated with poorer performance in three domains: executive (primarily set-shifting) measures, processing speed, and visual-spatial memory. In a 35-year longitudinal component of the study, we also found that general cognitive ability at age 20 was a significant predictor of midlife cortisol levels. These results possibly support the notion that glucocorticoid exposure is associated with cognitive functions that are mediated by frontal-striatal systems, and is not specific to hippocampal-dependent memory. The results also suggest that the direction of effect is complex.