Single trial variability in neural activity during a working memory task reveals multiple distinct information processing sequences.

Successful encoding, maintenance, and retrieval of information stored in working memory requires persistent coordination of activity among multiple brain regions. It is generally assumed that the pattern of such coordinated activity remains consistent for a given task. Thus, to separate this task-relevant signal from noise, multiple trials of the same task are completed, and the neural response is averaged across trials to generate an event-related potential (ERP). However, from trial to trial, the neuronal activity recorded with electroencephalogram (EEG) is actually spatially and temporally diverse, conflicting with the assumption of a single pattern of activity for a given task. Here, we show that variability in neuronal activity among single time-locked trials arises from the presence of multiple forms of stimulus dependent synchronized activity (i.e., distinct ERPs). We develop a data-driven classification method based on community detection to identify three discrete spatio-temporal clusters, or subtypes, of trials with different patterns of activation that are further associated with differences in decision-making processes. These results demonstrate that differences in the patterns of neural activity during working memory tasks represent fluctuations in the engagement of distinct brain networks and cognitive processes, suggesting that the brain can choose from multiple mechanisms to perform a given task.

Cognitive skill learning in multiple sclerosis: A meaningful component of the neuropsychological profile.

Cognitive skill learning (CSL) refers to the capacity to improve performance on specific cognitive operations through repeated practice. We hypothesized that high CSL aptitude may promote accumulation of cognitive reserve, and resiliency to cognitive decline, in people with Multiple Sclerosis (MS). Using an adaptive working memory training paradigm, we obtained CSL aptitude indices (amount of improvement on the training task over time) in MS patients for a single session of practice (25-30 min), and longer-term practice (twenty sessions). Neuropsychological performance was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and the Raven's Advanced Progressive Matrices (RAPM). CSL aptitude measures were positively correlated with neuropsychological performance, and had high diagnostic accuracy for classifying cognitive impairment in MS, defined as 1.5 SD below the demographics-corrected normative mean of the SDMT. Positive relationships between CSL aptitude measures and neuropsychological performance tended to be more pronounced for individuals with high estimated cognitive reserve, suggesting that high CSL aptitude is a a factor that promotes the protective effects of cognitive reserve. Furthermore, regression analyses indicated that CSL aptitude is separable from baseline cognitive capacity. The findings suggest that CSL aptitude impacts the neuropsychological profile in MS, and may be a factor underlying variance in cognitive resiliency.

Comparison of neuropsychological impairment and vocational outcomes in systemic lupus erythematosus and multiple sclerosis patients.

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients.

Working memory training and perceptual discrimination training impact overlapping and distinct neurocognitive processes: Evidence from event-related potentials and transfer of training gains.

There is emerging evidence that working memory (WM) can potentially be enhanced via targeted training protocols. However, the differential effects of targeted training of WM vs. training of general attentional processes on distinct neurocognitive mechanisms is not well understood. In the present study, we compared adaptive n-back WM training to an adaptive visual search training task that targeted perceptual discrimination, in the absence of demands on WM. The search task was closely matched to the n-back task on difficulty and participant engagement. The training duration for both protocols was 20 sessions over approximately 4 weeks. Before and after training, young adult participants were tested on a battery of cognitive tasks to examine transfer of training gains to untrained tests of WM, processing speed, cognitive control, and fluid intelligence. Event-related brain potential (ERP) measures obtained during a Letter 3-Back task and a Search task were examined to determine the neural processes that were affected by each training protocol. Both groups improved on measures of cognitive control and fluid intelligence at post- compared to pretest. However, n-back training resulted in more pronounced transfer effects to tasks involving WM compared to search training. With respect to ERPs, both groups exhibited enhancement of P3 amplitude following training, but distinct changes in neural responses were also observed for the two training protocols. The search training group exhibited earlier ERP latencies at post- compared to pretest on the Search task, indicating generalized improvement in processing speed. The n-back group exhibited a pronounced enhancement and earlier latency of the N2 ERP component on the Letter 3-back task, following training. Given the theoretical underpinnings of the N2, this finding was interpreted as an enhancement of conflict monitoring and sequential mismatch identification. The findings provide evidence that n-back training enhances distinct neural processes underlying executive aspects of WM.

Improved cognitive performance and event-related potential changes following working memory training in patients with multiple sclerosis.

BACKGROUND: Few studies of cognitive rehabilitation in multiple sclerosis (MS) have targeted working memory specifically. OBJECTIVE: We examined the effects of n-back working memory training on cognitive performance and brain function in patients with MS. METHODS: Patients with MS (n = 12) and healthy controls (HC; n = 12) underwent 20 sessions of n-back working memory training. Before and after training (pre- and posttest) cognitive event-related potential (ERP) measures were obtained during a 3-back task. In addition, a battery of cognitive tests was administered. RESULTS: Following n-back training, both MS patients and HCs showed significant improvement on tests of working memory, processing speed, complex attention, and reasoning ability. MS and HCs also exhibited an enhancement of N2 ERP component amplitude, and earlier N2 and P3 latencies, following n-back training. CONCLUSIONS: Targeted training of working memory with the n-back task may improve cognitive function in MS. Enhancement of N2 ERP component amplitude and shorter N2 and P3 latency following training in patients with MS is consistent with plasticity of neural processes that are involved in working memory.

Event-related brain potential indices of cognitive function and brain resource reallocation during working memory in patients with Multiple Sclerosis.

OBJECTIVE: To examine event-related brain potentials (ERPs) in Multiple Sclerosis (MS) during a visual n-back working memory (WM) task, and test the hypothesis that compensatory brain function may be associated with variance in task performance in MS patients. METHODS: Midline ERPs for 25MS patients and 18 HCs were obtained for a visual n-back task that placed increasing demands on WM. N-back behavioral measures and neuropsychological performance measures of WM were also obtained. RESULTS: MS patients had slower reaction times (RTs) than HCs during the n-back task. Accuracy on the n-back and on neuropsychological tests did not differ between groups. P3 ERP amplitude decreased for both groups as WM demand increased. MS patients had lower overall P1 and P3 amplitudes compared to HCs. In MS, anteriorization of P3 amplitude was associated with better n-back performance. P1 and P3 amplitudes were also related to neuropsychological test performance in MS. CONCLUSIONS: MS patients had reduced ERP amplitude compared to HCs during the n-back, and changes in ERP anterior-posterior midline amplitude distribution in MS were associated with cognitive performance. SIGNIFICANCE: ERPs, and in particular the P3 component obtained during a visual n-back task, are sensitive to subtle WM dysfunction in MS and may reflect compensatory reallocation of brain resources.

Tone probe event-related potential differences during a face recognition task in prepubertal children and Turner Syndrome girls.

Hormones have been shown to play a role in both cerebral development and neurocognitive function. Turner Syndrome (TS) provides the opportunity to study the effect of the lack of estrogen on neurocognitive development. In this study, event-related potential (ERP) differences were examined among 12 TS girls, 20 prepubertal control girls, and 20 prepubertal control boys during a face recognition memory task. Stage of puberty was determined by Tanner Scale rating and hormonal assay. ERPs to pairs of auditory probe stimuli were recorded from eight scalp sites while participants performed a faced recognition memory (FRM) task. For the N2 component of the ERP (which has previously been associated with evaluation of stimulus information, categorization difficulty, and attention), control boys displayed greater right versus left hemisphere amplitude, control girls displayed greater left versus right hemisphere amplitude, and there was no amplitude asymmetry for TS girls. Further, control girls had greater left hemisphere N2 amplitude than control boys and TS girls, and greater right hemisphere N2 amplitude than TS girls. The results suggest more right hemisphere activation during face recognition in boys, while the opposite pattern was present in control girls. In contrast, TS girls displayed no asymmetry, indicative of more uniform involvement of the left and right hemispheres during face recognition. These findings are consistent with differences in cortical organization related to face recognition memory processing among prepubertal control boys, girls, and TS girls. They also support the notion that sex differences in cognitive function are present prior to pubertal onset, and that lack of endogenous sex hormones (e.g., estrogen) during prenatal/perinatal development (i.e., for TS girls) may influence brain organization and, in turn, neurocognitive processes that relate to face recognition.

Single-trial latency variability of auditory evoked potentials may indicate immediate memory in the albino rat.

Fast habituation (FH) is defined as a decrease in auditory evoked potential (AEP) amplitude in response to the second of a pair of temporally juxtaposed (e.g. 1-s) tones. The degree of FH may depend, in part, on the subject's ability to anticipate the stimulus sequence. This paradigm has been used in our laboratory to study cognitive functioning in human subjects. We have also developed an animal model to investigate, more comprehensively, the anatomical and physiological basis of this phenomenon seen in human subjects. In the present investigation, we wished to determine the relationship between single-trial latency variability and AEP amplitude for two conditions: one for which FH is known to occur and one for which it is not present, due to the length of the interstimulus interval (ISI). Here AEPs were obtained to 40 pairs of 100-ms pure tone stimuli (70-dB SPL, 1- and 5-s ISI, 10-s interpair interval) from 19 chronically implanted, unanesthetized, restrained male Sprague-Dawley rats. The AEP latencies, amplitudes, and the single-trial latency variabilities were obtained for each component (P1, N1, P2 and N2). Findings indicated that FH was present for the 1-s ISI condition but not for the 5-s ISI condition. In addition, single-trial latency variability was negatively correlated with both Tones 1 and 2 AEP amplitudes in the 5-s ISI condition but only with Tone 1 amplitude in the 1-s ISI condition. Thus, single-trial latency variability predicted AEP amplitude only when FH did not occur. These results support earlier findings reported from our laboratory suggesting that the decrease in amplitude during FH is not related to increased variability in the time domain but rather to decreased neuronal output.

The effects of covert attention and stimulus complexity on the P3 response during an auditory continuous performance task.

This study examined the effects of motor responding and stimulus complexity on the event-related potential (ERP) P3 amplitude and latency during an auditory continuous performance task (A-CPT). Subjects were presented with undegraded and degraded syllables during two experimental conditions. In the motor attention (MA) condition participants performed a button press to target syllables. In the covert attention (CA) condition, participants listened for target syllables without responding. The ERP P3 amplitude for targets during MA and CA showed the expected anterior-to-posterior scalp topography, with the greatest amplitude at Pz. Although amplitudes across all scalp sites were greater for MA than CA target P3 responses, both MA and CA targets had greater P3 amplitudes than the P3 for the nontarget syllables (NT). There was no effect of stimulus complexity (degraded vs. undegraded) on P3 amplitude. However, stimulus complexity did affect P3 latency. Degraded syllables elicited longer P3 latency than undegraded syllables for both the MA and CA conditions. The amplitude and topography findings show that when stimulus probability is controlled through the use of a CPT paradigm, a reliable P3 component is present even when the task does not require a motor response to target stimuli.

The effects of exposure to traumatic stressors on inhibitory control in police officers: a dense electrode array study using a Go/NoGo continuous performance task.

Exposure to psychologically stressful and traumatic experiences and the requirement of heightened attention to environmental stimuli are common in police work. Police officers are at increased risk for stress-related disorders such as Post-Traumatic Stress Disorder (PTSD). Traumatic experiences can result in changes to brain structure and function associated with attention and cognitive control processes (such as response inhibition). Despite the significance that these cognitive functions may have on job performance in police officers, few studies have examined the effects of exposure to traumatic events on top-down cognitive control functions in police. In the present study, a dense electrode array system was used to examined the N2 and P3 components of the event-related potential (ERP) during a Go/NoGo continuous performance task (Go/NoGo CPT) in trauma-exposed police officers who did not meet criteria for a current diagnosis of PTSD and in non-trauma exposed civilian controls. Amplitude and latency were obtained to Go, NoGo, and non-target trials. The major between-group findings were for P3 amplitude. There were no group effects for N2. Both groups had an enhanced fronto-central P3 amplitude to NoGo compared to Go trials. However, police had greater P3 amplitude compared to controls for all trial types (Go, NoGo, non-target). PTSD symptom scores in police officers were positively correlated with fronto-central NoGo P3 amplitude, but not with posterior NoGo amplitude. This study provides evidence of heightened attention and/or arousal in police officers as indicated by the generally greater P3 amplitude in police compared to controls during a task requiring sustained attention and inhibitory control. Greater PTSD symptom severity in trauma-exposed individuals may affect frontal cognitive control systems related to response inhibition.

Information processing speed, neural efficiency, and working memory performance in multiple sclerosis: differential relationships with structural magnetic resonance imaging.

Multiple sclerosis (MS), a central nervous system (CNS) neurodegenerative disorder, involves lesions of both white and gray matter and reported cognitive impairments that include processing speed (PS), executive function, and working memory (WM). This study closely examined the specifics of these cognitive deficits and their relationship to structural brain damage. A visual n-back task with 3 WM load conditions was used to assess WM performance (task accuracy), PS (reaction time, RT), and a novel measure of processing efficiency (standard deviation of RT, RTSD) in MS patients and controls. These behavioral measures were related to quantitative magnetic resonance imaging (MRI) measures of white and gray matter integrity. Even when MS patients performed as well as controls, as seen for low WM load (0-back), they responded more slowly and were less efficient in their speed of responding. Accuracy findings indicated that the correct match trials were superior to correct nonmatch trials at differentiating MS patients from controls. Further, decreased accuracy during the highest WM load condition was associated with global damage that included both gray and white matter atrophy, while slowed PS and particularly processing inefficiency were associated primarily with white matter atrophy in MS. Importantly, relationships between PS, processing efficiency, performance accuracy, and structural MRI measures were seen only during the highest WM load condition, the condition that required the most executive control. These findings suggest that the MRI/behavioral relationships that were present exclusively during the 2-back condition may reflect connectivity involving frontal cortical systems, the site for executive control.

The relationship between processing speed and working memory demand in systemic lupus erythematosus: evidence from a visual n-back task.

OBJECTIVE: Working memory (WM) deficits have been reported previously in systemic lupus erythematosus (SLE), but the relationship between information processing speed (PS) and WM deficits in SLE is unknown. This study examined whether or not PS slowing could account for the WM deficits observed in SLE. METHOD: A visual n-back task was used to measure simple and complex PS and WM in 40 SLE patients and 36 healthy controls. Simple PS was defined as reaction time (RT) to correct responses under a very low WM load condition (0-back), while complex PS was defined as RT to correct responses under moderate and high WM load conditions (1 and 2-back). RESULTS: The results showed that SLE patients performed as well as the controls at the lower WM load conditions but had fewer correct responses than controls under the highest WM load condition (2-back). SLE patients had slower RTs than controls under all conditions, but they had relatively greater RT slowing than controls under the higher WM load conditions. Further, when RT for simple PS was subtracted from complex PS, SLE patients still showed slower complex PS for the 1- and 2-back compared with controls. Both simple and complex PS slowing were related to poorer accuracy scores on the 2-back condition, only for the SLE group. CONCLUSIONS: The n-back task provides a sensitive measure of PS and WM. The results suggest that PS deficits alone could not account for the WM deficits in SLE. Disease duration, disease activity, and depression did not appear to account for the observed PS and WM deficits.

Stage and load effects on ERP topography during verbal and spatial working memory.

Frontal-parietal neural networks play a significant role in the functional organization of visual working memory (WM). The relative contribution of material-specific information (e.g., verbal or spatial) on activation of WM circuitry is not fully understood. Process-specific models of WM propose that the activation of WM circuitry is more dependent on the stage of WM than on the type of information being processes. This study investigated the effects of WM information type (verbal, spatial), stage (encoding, maintenance), and load on both the anterior-posterior topography and lateralized scalp distributions of the event-related potential (ERP) P3 amplitude. Seventeen young adults performed verbal and spatial tasks that were equated for stimulus properties and response requirements. Both tasks were presented under 1- and 3-load conditions. The anterior-posterior topography of P3 amplitude at left hemisphere, midline, and right hemisphere scalp locations was affected by the stage of WM and the memory load, but not by the type of information. The encoding stage showed minimal load effects and was associated with a posterior-maximum P3 amplitude distribution. During the maintenance stage, probe letters were presented that were irrelevant to the previously encoded stimuli. Here, higher WM load produced relatively greater frontal and reduced parietal P3 amplitude compared to lower WM load. These anterior-posterior P3 amplitude patterns for encoding and maintenance were similar at left, midline, and right locations. Within the limitations of the study, our results tend to support a process-dependent activation of WM circuits in that P3 amplitude topography only differed as a result of WM stage and load, and not as a result of the type of information (verbal or spatial) presented.

Information processing deficits in multiple sclerosis: a matter of complexity.

This study examined the relationship between processing speed (PS) and working memory (WM), as measured by performance on an n-back task, in relapsing-remitting multiple sclerosis (RRMS) patients. Simple PS was defined as reaction time (RT) on the 0-back task and complex PS was defined as RT on both the 1-back and 2-back tasks. Participants were administered all three n-back tasks (0-, 1-, and 2-back). Total correct responses, total dyads, and RTs were recorded. As expected, RT for all participants slowed as WM load increased. MS patients had slower RTs than controls across all tasks, and the difference between groups for RT was greatest during the 2-back task. When RT for simple PS (0-back) was parsed from the 1- and 2-back tasks, MS patients still showed impaired complex PS compared to controls. MS patients also made significantly fewer total correct responses and had fewer dyads than controls only on the 2-back task. These findings suggest that both WM and PS deficits are present in RRMS, and that as WM demand increases (from 1- to 2-back) both PS and WM deficits become more prominent.

C-reactive protein and cognitive deficits in systemic lupus erythematosus.

OBJECTIVE: Recent studies have highlighted the role of serum C-reactive protein (CRP) as a marker for atherosclerosis, and a predictor for vascular disease and stroke. Systemic lupus erythematosus (SLE) has been associated with (1) higher levels of CRP, (2) cerebrovascular disease, and (3) a "subcortical" pattern of cognitive deficits (eg, lower processing speed, poor working memory). These findings suggest that microvascular changes affect cognition in SLE. To our knowledge, no studies have yet attempted to relate levels of CRP with cognitive deficits in SLE. In the present study, we investigated the relationship between CRP level and measures of working memory/processing speed in SLE. METHODS: The Paced Auditory Serial Addition Test (PASAT), a sensitive measure of processing speed and working memory, was administered as part of a full neuropsychologic battery. CRP levels were obtained from blood collected on the day of cognitive testing. SLE patients were divided into 2 groups: No detectable CRP (No-CRP) and detectable CRP levels (Elevated-CRP). RESULTS: In comparison to the No-CRP group, the Elevated-CRP group performed more poorly on the PASAT. They had fewer correct responses, fewer consecutive correct responses (dyads), and a greater percentage of responses that were obtained by using a less demanding but incorrect "chunking" strategy to perform the PASAT. CONCLUSIONS: Results suggest that CRP may be a sensitive marker for subtle executive dysfunction in SLE, possibly due to central nervous system microvascular autoimmune processes. Early treatment of vasculopathy in SLE may help prevent microvascular disease and associated cognitive dysfunction.

Working memory deficits in multiple sclerosis: comparison between the n-back task and the Paced Auditory Serial Addition Test.

Working memory (WM) deficits are common in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) is used frequently to measure WM in clinical settings. The n-back paradigm is used often in experimental studies of WM. One unique component of the n-back task is that it provides a measure of reaction time (RT), an additional behavioral index of processing speed and task difficulty. Despite the use of both tasks to measure WM, their common variance has not been documented. We tested 32 MS patients and 20 controls; performance measures were obtained for both tasks. Compared with controls, MS patients generally had poorer performance on both the PASAT and n-back task. MS patients also had slower RTs on the n-back than controls and showed more slowing than controls as a function of WM load. Correlational analyses showed a high correspondence between performance measures on the PASAT and n-back. Principal components analysis pointed to a common feature of the PASAT, n-back, and specific other neuropsychological measures, that is, processing speed. Although the PASAT and n-back were shown to have a significant amount of shared variance, each test has specific advantages and disadvantages for use in clinical populations.

Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test.

As many as 66% of systemic lupus erythematosus (SLE) patients have been reported to have cognitive deficits. These deficits are often associated with information processing speed and working memory. Similarly, processing speed and working memory impairments are the hallmark of cognitive dysfunction in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) places high demands on processing speed and working memory. Fisk and Archibald, however, demonstrated that the total score of the PASAT does not accurately reflect impairments in these cognitive processes. They found that MS patients used a chunking strategy to obtain correct responses and reduce the cognitive demands of the task. In the present study, PASAT performance was examined for 45 SLE patients and 27 controls using alternative scoring procedures. Although the total number of correct responses did not differ between SLE and controls at the 2.4 or 2.0 s presentation rates, SLE patients had fewer dyads (correct consecutive responses) than controls at the faster rate, and more chunking responses than controls at both rates. Disease activity, disease duration, depression, fatigue, and corticosteroids could not account for these differences. The findings suggest that SLE patients, like MS patients, chunk responses more often than controls, and that this scoring procedure may better reflect the working memory and processing speed deficits present in SLE.

Covert auditory attention generates activation in the rostral/dorsal anterior cingulate cortex.

The anterior cingulate cortex (ACC) is believed to mediate conscious information processing or high-capacity attention. However, previous functional imaging studies have largely relied on tasks that involve motor function as well as attention. The work from our group utilizing an auditory continuous performance task demonstrated increased activity in a caudal division of the ACC that borders the supplementary motor area (SMA). Activity in this region was attributed to motor responding as well as attention. In the present study, we used (15)O H(2)O positron emission tomography (PET) to map brain activation during nonmotor, covert auditory attention. Our hypothesis was that a different region within the ACC, anterior to the SMA, would be active during covert attention (CA). Six men and six women were asked to monitor aurally presented syllables presented at a 1-sec interstimulus interval. During the CA condition, subjects were asked to continuously discriminate target (.19 probability) from nontarget stimuli. Simultaneous recording of event-related potentials (ERPs) confirmed the discrimination of target and nontarget stimuli and the allocation of attention capacity. Comparison of the monitored versus nonmonitored presentation of stimuli demonstrated significant activity in a rostral/dorsal division of the right ACC, anterior to SMA. Other regions of activation included the lateral prefrontal cortex and posterior superior temporal gyrus in the left hemisphere, consistent with neurocognitive models of language and vigilance. We conclude that a rostral/dorsal subdivision of the right ACC is specific for conscious attention during auditory processing, in contrast to premotor response formation.