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1.  Merging Clinical Neuropsychology and Functional Neuroimaging to Evaluate the Construct Validity and Neural Network Engagement of the n-Back Task 
The n-back task is a widely used neuroimaging paradigm for studying the neural basis of working memory (WM); however, its neuropsychometric properties have received little empirical investigation. The present study merged clinical neuropsychology and functional magnetic resonance imaging (fMRI) to explore the construct validity of the letter variant of the n-back task (LNB) and to further identify the task-evoked networks involved in WM. Construct validity of the LNB task was investigated using a bootstrapping approach to correlate LNB task performance across clinically validated neuropsychological measures of WM to establish convergent validity, as well as measures of related but distinct cognitive constructs (i.e., attention and short-term memory) to establish discriminant validity. Independent component analysis (ICA) identified brain networks active during the LNB task in 34 healthy control participants, and general linear modeling determined task-relatedness of these networks. Bootstrap correlation analyses revealed moderate to high correlations among measures expected to converge with LNB (|ρ| ≥0.37) and weak correlations among measures expected to discriminate (|ρ| ≤0.29), controlling for age and education. ICA identified 35 independent networks, 17 of which demonstrated engagement significantly related to task condition, controlling for reaction time variability. Of these, the bilateral frontoparietal networks, bilateral dorsolateral prefrontal cortices, bilateral superior parietal lobules including precuneus, and frontoinsular network were preferentially recruited by the 2-back condition compared to 0-back control condition, indicating WM involvement. These results support the use of the LNB as a measure of WM and confirm its use in probing the network-level neural correlates of WM processing.
PMCID: PMC4290162  PMID: 24963641
Working memory; Convergent validity; Discriminant validity; Divergent validity; Reliability and validity; Bootstrap; fMRI; Independent component analysis; Frontoparietal; Lag task
2.  Age-Related Differences in Working Memory Performance in A 2-Back Task 
The present study aimed to elucidate the neuro-cognitive processes underlying age-related differences in working memory. Young and middle-aged participants performed a two-choice task with low and a 2-back task with high working memory load. The P300, an event-related potential reflecting controlled stimulus–response processing in working memory, and the underlying neuronal sources of expected age-related differences were analyzed using sLORETA. Response speed was generally slower for the middle-aged than the young group. Under low working memory load the middle-aged participants traded speed for accuracy. The middle-aged were less efficient in the 2-back task as they responded slower while the error rates did not differ for groups. An age-related decline of the P300 amplitude and characteristic topographical differences were especially evident in the 2-back task. A more detailed analysis of the P300 in non-target trials revealed that amplitudes in the young but not middle-aged group differentiate between correctly detected vs. missed targets in the following trial. For these trials, source analysis revealed higher activation for the young vs. middle-aged group in brain areas which support working memory processes. The relationship between P300 and overt performance was validated by significant correlations. To sum up, under high working memory load the young group showed an increased neuronal activity before a successful detected target, while the middle-aged group showed the same neuronal pattern regardless of whether a subsequent target will be detected or missed. This stable memory trace before detected targets was reflected by a specific activation enhancement in brain areas which orchestrate maintenance, update, storage, and retrieval of information in working memory.
PMCID: PMC3163893  PMID: 21909328
aging; working memory; 2-back task; event-related potentials; P300
3.  Diffusion tensor imaging differences relate to memory deficits in diffuse traumatic brain injury 
BMC Neurology  2011;11:24.
Memory is one of the most impaired functions after traumatic brain injury (TBI). We used diffusion tensor imaging (DTI) to determine the structural basis of memory deficit. We correlated fractional anisotropy (FA) of the fasciculi connecting the main cerebral regions that are involved in declarative and working memory functions.
Fifteen patients with severe and diffuse TBI and sixteen healthy controls matched by age and years of education were scanned. The neuropsychological assessment included: Letter-number sequencing test (LNS), 2-back task, digit span (forwards and backwards) and the Rivermead profilet. DTI was analyzed by a tract-based spatial statics (TBSS) approach.
Whole brain DTI analysis showed a global decrease in FA values that correlated with the 2-back d-prime index, but not with the Rivermead profile. ROI analysis revealed positive correlations between working memory performance assessed by 2-back d-prime and superior longitudinal fasciculi, corpus callosum, arcuate fasciculi and fornix. Declarative memory assessed by the Rivermead profile scores correlated with the fornix and the corpus callosum.
Diffuse TBI is associated with a general decrease of white matter integrity. Nevertheless deficits in specific memory domains are related to different patterns of white matter damage.
PMCID: PMC3050687  PMID: 21345223
4.  Effects of cannabis on cognition in patients with MS 
Neurology  2014;82(21):1879-1887.
To determine functional and structural neuroimaging correlates of cognitive dysfunction associated with cannabis use in multiple sclerosis (MS).
In a cross-sectional study, 20 subjects with MS who smoked cannabis and 19 noncannabis users with MS, matched on demographic and neurologic variables, underwent fMRI while completing a test of working memory, the N-Back. Resting-state fMRI and structural MRI data (lesion and normal-appearing brain tissue volumes, diffusion tensor imaging metrics) were also collected. Neuropsychological data pertaining to verbal (Selective Reminding Test Revised) and visual (10/36 Spatial Recall Test) memory, information processing speed (Paced Auditory Serial Addition Test [2- and 3-second versions] and Symbol Digit Modalities Test), and attention (Word List Generation) were obtained.
The cannabis group performed more poorly on the more demanding of the Paced Auditory Serial Addition Test tasks (i.e., 2-second version) (p < 0.02) and the 10/36 Spatial Recall Test (p < 0.03). Cannabis users had more diffuse cerebral activation across all N-Back trials and made more errors on the 2-Back task (p < 0.006), during which they displayed increased activation relative to nonusers in parietal (p < 0.007) and anterior cingulate (p < 0.001) regions implicated in working memory. No group differences in resting-state networks or structural MRI variables were found.
Patients with MS who smoke cannabis are more cognitively impaired than nonusers. Cannabis further compromises cerebral compensatory mechanisms, already faulty in MS. These imaging data boost the construct validity of the neuropsychological findings and act as a cautionary note to cannabis users and prescribers.
PMCID: PMC4105254  PMID: 24789863
5.  Processing distinct linguistic information types in working memory in aphasia 
Aphasiology  2007;21(6-8):802-813.
Recent investigations have suggested that adults with aphasia present with a working memory deficit that may contribute to their language-processing difficulties. Working memory capacity has been conceptualised as a single “resource” pool for attentional, linguistic, and other executive processing—alternatively, it has been suggested that there may be separate working memory abilities for different types of linguistic information. A challenge in this line of research is developing an appropriate measure of working memory ability in adults with aphasia. One candidate measure of working memory ability that may be appropriate for this population is the n-back task. By manipulating stimulus type, the n-back task may be appropriate for tapping linguistic-specific working memory abilities.
The purposes of this study were (a) to measure working memory ability in adults with aphasia for processing specific types of linguistic information, and (b) to examine whether a relationship exists between participants’ performance on working memory and auditory comprehension measures.
Method & Procedures
Nine adults with aphasia participated in the study. Participants completed three n-back tasks, each tapping different types of linguistic information. They included the PhonoBack (phonological level), SemBack (semantic level), and SynBack (syntactic level). For all tasks, two n-back levels were administered: a 1-back and 2-back. Each level contained 20 target items; accuracy was recorded by stimulus presentation software. The Subject-relative, Object-relative, Active, Passive Test of Syntactic Complexity (SOAP) was the syntactic sentence comprehension task administered to all participants.
Outcomes & Results
Participants’ performance declined as n-back task difficulty increased. Overall, participants performed better on the SemBack than PhonoBack and SynBack tasks, but the differences were not statistically significant. Finally, participants who performed poorly on the SynBack also had more difficulty comprehending syntactically complex sentence structures (i.e., passive & object-relative sentences).
Results indicate that working memory ability for different types of linguistic information can be measured in adults with aphasia. Further, our results add to the growing literature that favours separate working memory abilities for different types of linguistic information view.
PMCID: PMC2701214  PMID: 19554209
6.  Impairments of working memory in schizophrenia and bipolar disorder: the effect of history of psychotic symptoms and different aspects of cognitive task demands 
Comparisons of cognitive impairments between schizophrenia (SZ) and bipolar disorder (BPD) have produced mixed results. We applied different working memory (WM) measures (Digit Span Forward and Backward, Short-delay and Long-delay CPT-AX, N-back) to patients with SZ (n = 23), psychotic BPD (n = 19) and non-psychotic BPD (n = 24), as well as to healthy controls (HC) (n = 18) in order to compare the level of WM impairments across the groups. With respect to the less demanding WM measures (Digit Span Forward and Backward, Short-delay CPT-AX), there were no between group differences in cognitive performance; however, with respect to the more demanding WM measures (Long-delay CPT-AX, N-back), we observed that the groups with psychosis (SZ, psychotic BPD) did not differ from one another, but performed poorer than the group without a history of psychosis (non-psychotic BPD). A history of psychotic symptoms may influence cognitive performance with respect to WM delay and load effects as measured by Long-delay CPT-AX and N-back tests, respectively. We observed a positive correlation of WM performance with antipsychotic treatment and a negative correlation with depressive symptoms in BPD and with negative symptoms in SZ subgroup. Our study suggests that WM dysfunctions are more closely related to a history of psychosis than to the diagnostic categories of SZ and BPD described by psychiatric classification systems.
PMCID: PMC4246891  PMID: 25506320
schizophrenia; psychotic vs. non-psychotic bipolar disorder; working memory; history of psychosis
7.  Postural Stability and Neuropsychological Deficits After Concussion in Collegiate Athletes 
Journal of Athletic Training  2001;36(3):263-273.
Postural stability and neuropsychological testing are gradually becoming integral parts of postconcussion assessment in athletes. Clinicians, however, sometimes question the viability of instituting preseason baseline testing and the value of these results in making return-to-play decisions. Our purpose was to examine the course of recovery on various postural stability and neuropsychological measures after sport-related concussion. A secondary goal was to determine if loss of consciousness and amnesia, both of which are heavily weighted in most of the concussion classification systems, affect the rate of recovery.
Design and Setting:
All subjects underwent a battery of baseline postural stability and neuropsychological tests before the start of their respective seasons. Any athletes subsequently injured were followed up at postinjury days 1, 3, and 5. Matched control subjects were assessed using the same test battery at the same time intervals.
We studied 36 Division I collegiate athletes who sustained a concussion and 36 matched control subjects.
We assessed postural stability using the Sensory Organization Test on the NeuroCom Smart Balance Master System and the Balance Error Scoring System. Neurocognitive functioning was measured with several neuropsychological tests: Trail-Making Test, Wechsler Digit Span Test, Stroop Color Word Test, and Hopkins Verbal Learning Test.
Injured subjects demonstrated postural stability deficits, as measured on both the Sensory Organization Test and Balance Error Scoring System. These deficits were significantly worse than both preseason scores and matched control subjects' scores on postinjury day 1. Only the results on the Trail-Making Test B and Wechsler Digit Span Test Backward resulted in a logical recovery curve that could explain lowered neuropsychological performance due to concussive injury. Significant differences were revealed between the control and injured groups at day 1 postinjury, but a significant decline between baseline and postinjury scores was not demonstrated. Loss of consciousness and amnesia were not associated with increased deficits or slowed recovery on measures of postural stability or neurocognitive functioning.
Athletes with cerebral concussion demonstrated acute balance deficits, which are likely the result of not using information from the vestibular and visual systems effectively. Neurocognitive deficits are more difficult to identify in the acute stages of concussion, although concentration, working memory, immediate memory recall, and rapid visual processing appear to be mildly affected. More research is necessary to determine the best neuropsychological test battery for assessing sport-related concussion.
PMCID: PMC155417  PMID: 12937495
mild head injury; balance; neurocognitive function
8.  Orbitofrontal Contributions to Human Working Memory 
Cerebral Cortex (New York, NY)  2010;21(4):789-795.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in human memory, the necessity of the orbitofrontal cortex for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether the orbitofrontal cortex is necessary for working memory function, administering subtests of the Wechsler memory scale, the Wechsler adult intelligence scale, and the n-back task to 3 participant groups: orbitofrontal lesions (n = 24), prefrontal lesions not involving orbitofrontal cortex (n = 40), and no brain lesions (n = 54). Orbitofrontal damage was reliably associated with deficits on neuropsychological tests involving the coordination of working memory maintenance, manipulation, and monitoring processes (n-back task) but not on pure tests of working memory maintenance (digit/spatial span forward) or manipulation (digit/spatial span backward and letter–number sequencing). Our findings elucidate a central component of the neural architecture of working memory, providing key neuropsychological evidence for the necessity of the orbitofrontal cortex in executive control functions underlying the joint maintenance, manipulation, and monitoring of information in working memory.
PMCID: PMC3059885  PMID: 20724371
lesion data; orbitofrontal cortex; prefrontal cortex; working memory
9.  A task is a task is a task: putting complex span, n-back, and other working memory indicators in psychometric context 
Frontiers in Psychology  2014;5:1475.
Based on a meta-analysis, Redick and Lindsey (2013) found that complex span and n-back tasks show an average correlation of r = 0.20, and concluded that “complex span and n-back tasks cannot be used interchangeably as working memory measures in research applications” (p. 1102). Here, we comment on this conclusion from a psychometric perspective. In addition to construct variance, performance on a test contains measurement error, task-specific variance, and paradigm-specific variance. Hence, low correlations among dissimilar indicators do not provide strong evidence for the existence, or absence, of a construct common to both indicators. One way to arrive at such evidence is to fit hierarchical latent factors that model task-specific, paradigm-specific, and construct variance. We report analyses for 101 younger and 103 older adults who worked on nine different working memory tasks. The data are consistent with a hierarchical model of working memory, according to which both complex span and n-back tasks are valid indicators of working memory. The working memory factor predicts 71% of the variance in a factor of reasoning among younger adults (83% for among older adults). When the working memory factor was restricted to any possible triplet of working memory tasks, the correlation between working memory and reasoning was inversely related to the average magnitude of the correlations among the indicators, indicating that more highly intercorrelated indicators may provide poorer coverage of the construct space. We stress the need to go beyond specific tasks and paradigms when studying higher-order cognitive constructs, such as working memory.
PMCID: PMC4274887  PMID: 25566149
working memory; latent factors; psychometrics; complex span; n-back; memory updating
10.  Structural correlates of impaired working memory in hippocampal sclerosis 
Epilepsia  2013;54(7):1143-1153.
Temporal lobe epilepsy (TLE) has been considered to impair long-term memory, whilst not affecting working memory, but recent evidence suggests that working memory is compromised. Functional MRI (fMRI) studies demonstrate that working memory involves a bilateral frontoparietal network the activation of which is disrupted in hippocampal sclerosis (HS). A specific role of the hippocampus to deactivate during working memory has been proposed with this mechanism faulty in patients with HS. Structural correlates of disrupted working memory in HS have not been explored.
We studied 54 individuals with medically refractory TLE and unilateral HS (29 left) and 28 healthy controls. Subjects underwent 3T structural MRI, a visuospatial n-back fMRI paradigm and diffusion tensor imaging (DTI). Working memory capacity assessed by three span tasks (digit span backwards, gesture span, motor sequences) was combined with performance in the visuospatial paradigm to give a global working memory measure. Gray and white matter changes were investigated using voxel-based morphometry and voxel-based analysis of DTI, respectively.
Key Findings:
Individuals with left or right HS performed less well than healthy controls on all measures of working memory. fMRI demonstrated a bilateral frontoparietal network during the working memory task with reduced activation of the right parietal lobe in both patient groups. In left HS, gray matter loss was seen in the ipsilateral hippocampus and parietal lobe, with maintenance of the gray matter volume of the contralateral parietal lobe associated with better performance. White matter integrity within the frontoparietal network, in particular the superior longitudinal fasciculus and cingulum, and the contralateral temporal lobe, was associated with working memory performance. In right HS, gray matter loss was also seen in the ipsilateral hippocampus and parietal lobe. Working memory performance correlated with the gray matter volume of both frontal lobes and white matter integrity within the frontoparietal network and contralateral temporal lobe.
Our data provide further evidence that working memory is disrupted in HS and impaired integrity of both gray and white matter is seen in functionally relevant areas. We suggest this forms the structural basis of the impairment of working memory, indicating widespread and functionally significant structural changes in patients with apparently isolated HS.
PMCID: PMC3806272  PMID: 23614459
Temporal lobe epilepsy; Hippocampal sclerosis; Working memory; Voxel-based morphometry; Diffusion tensor imaging
11.  Subjective Rating of Working Memory is Associated with Frontal Lobe Volume in Schizophrenia 
Schizophrenia research  2010;120(1-3):71-75.
Patients with schizophrenia commonly show deficits in working memory on objective neuropsychological measures, and brain imaging studies have documented neural abnormalities during performance of working memory tasks. It remains unclear to what extent such patients are able to accurately gauge the integrity of their working memory in their daily lives. Aims: We evaluated the relationship between subjective rating of working memory integrity in daily life and volumes of the frontal, temporal, and parietal lobes in patients with schizophrenia.
Participants included 29 patients with schizophrenia and 26 healthy comparison subjects. Participants completed a structural magnetic resonance imaging (MRI) scan, the Self Report form of the Behavioral Rating Scale of Executive Function – Adult version (BRIEF-A), and Digit Span Backwards as an objective measure of working memory. Lobar volumes were obtained using an automated processing package and adjusted for total intracranial volume.
The patient group reported worse working memory in daily life, and performed worse on Digit Span Backwards, than the comparison group. Within the patient group, poorer working memory in daily life was associated with smaller left and right frontal lobe volumes. Shorter backwards digit span was associated with smaller left frontal and left and right temporal lobe volumes.
The significant relationship between frontal lobe volumes and subjective working memory in daily life provides some support for the validity of self report measures of cognitive functioning in patients with schizophrenia, and provides further evidence for a contribution of frontal lobe abnormality to executive dysfunction in the illness.
PMCID: PMC2900432  PMID: 20303715
Working Memory; Subjective; Frontal Lobe; MRI; Schizophrenia
12.  The Polarity-Dependent Effects of the Bilateral Brain Stimulation on Working Memory 
Basic and Clinical Neuroscience  2013;4(3):224-231.
Working memory plays a critical role in cognitive processes which are central to our daily life. Neuroimaging studies have shown that one of the most important areas corresponding to the working memory is the dorsolateral prefrontal cortex (DLFPC). This study was aimed to assess whether bilateral modulation of the DLPFC using a noninvasive brain stimulation, namely transcranial direct current stimulation (tDCS), modifies the working memory function in healthy adults.
In a randomized sham-controlled cross-over study, 60 subjects (30 Males) received sham and active tDCS in two subgroups (anode left/cathode right and anode right/cathode left) of the DLPFC. Subjects were presented working memory n-back task while the reaction time and accuracy were recorded.
A repeated measures, mixed design ANOVA indicated a significant difference between the type of stimulation (sham vs. active) in anodal stimulation of the left DLPFC with cathodal stimulation of the right DLPFC [F(1,55)= 5.29, P=0.019], but not the inverse polarity worsened accuracy in the 2-back working memory task. There were also no statistically significant changes in speed of working memory [F(1,55)= 0.458,P=0.502] related to type or order of stimulation.
The results would imply to a polarity dependence of bilateral tDCS of working memory. Left anodal/ right cathodal stimulation of DLPFC could impair working memory, while the reverser stimulation had no effect. Meaning that bilateral stimulation of DLFC would not be a useful procedure to improve working memory. Further studies are required to understand subtle effects of different tDCS stimulation/inhibition electrode positioning on the working memory.
PMCID: PMC4202567  PMID: 25337351
Dorsolateral Prefrontal Cortex; Transcranial Direct Current Stimulation; Working Memory
13.  The Relationship Between Processing Speed and Working Memory Demand in Systemic Lupus Erythematosus: Evidence from a Visual N-Back Task 
Neuropsychology  2011;25(1):45-52.
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.
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).
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 to controls. Both simple and complex PS slowing were related to poorer accuracy scores on the 2-back condition, only for the SLE group.
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.
PMCID: PMC3058546  PMID: 21090896
Systemic Lupus Erythematosus; autoimmune disease; working memory; information processing speed; n-back task
14.  Long-term effects of mild traumatic brain injury on cognitive performance 
Although a proportion of individuals report chronic cognitive difficulties after mild traumatic brain injury (mTBI), results from behavioral testing have been inconsistent. In fact, the variability inherent to the mTBI population may be masking subtle cognitive deficits. We hypothesized that this variability could be reduced by accounting for post-concussion syndrome (PCS) in the sample. Thirty-six participants with mTBI (>1 year post-injury) and 36 non-head injured controls performed information processing speed (Paced Visual Serial Addition Task, PVSAT) and working memory (n-Back) tasks. Both groups were split by PCS diagnosis (4 groups, all n = 18), with categorization of controls based on symptom report. Participants with mTBI and persistent PCS had significantly greater error rates on both the n-Back and PVSAT, at every difficulty level except 0-Back (used as a test of performance validity). There was no difference between any of the other groups. Therefore, a cognitive deficit can be observed in mTBI participants, even 1 year after injury. Correlations between cognitive performance and symptoms were only observed for mTBI participants, with worse performance correlating with lower sleep quality, in addition to a medium effect size association (falling short of statistical significance) with higher PCS symptoms, post-traumatic stress disorder (PTSD), and anxiety. These results suggest that the reduction in cognitive performance is not due to greater symptom report itself, but is associated to some extent with the initial injury. Furthermore, the results validate the utility of our participant grouping, and demonstrate its potential to reduce the variability observed in previous studies.
PMCID: PMC3569844  PMID: 23408228
head injury; minor; post-concussion syndrome; cognition; neuropsychological tests
15.  Neural Correlates of the Difference between Working Memory Speed and Simple Sensorimotor Speed: An fMRI Study 
PLoS ONE  2012;7(1):e30579.
The difference between the speed of simple cognitive processes and the speed of complex cognitive processes has various psychological correlates. However, the neural correlates of this difference have not yet been investigated. In this study, we focused on working memory (WM) for typical complex cognitive processes. Functional magnetic resonance imaging data were acquired during the performance of an N-back task, which is a measure of WM for typical complex cognitive processes. In our N-back task, task speed and memory load were varied to identify the neural correlates responsible for the difference between the speed of simple cognitive processes (estimated from the 0-back task) and the speed of WM. Our findings showed that this difference was characterized by the increased activation in the right dorsolateral prefrontal cortex (DLPFC) and the increased functional interaction between the right DLPFC and right superior parietal lobe. Furthermore, the local gray matter volume of the right DLPFC was correlated with participants' accuracy during fast WM tasks, which in turn correlated with a psychometric measure of participants' intelligence. Our findings indicate that the right DLPFC and its related network are responsible for the execution of the fast cognitive processes involved in WM. Identified neural bases may underlie the psychometric differences between the speed with which subjects perform simple cognitive tasks and the speed with which subjects perform more complex cognitive tasks, and explain the previous traditional psychological findings.
PMCID: PMC3264572  PMID: 22291992
16.  Neurological Assessment and Its Relationship to CSF Biomarkers in Amateur Boxers 
PLoS ONE  2014;9(6):e99870.
Mild traumatic brain injury (TBI) or concussion is common in many sports. Today, neuropsychological evaluation is recommended in the monitoring of a concussion and in return-to-play considerations. To investigate the sensitivity of neuropsychological assessment, we tested amateur boxers post bout and compared with controls. Further the relationship between neuropsychological test results and brain injury biomarkers in the cerebrospinal fluid (CSF) were investigated.
Thirty amateur boxers on high elite level with a minimum of 45 bouts and 25 non-boxing matched controls were included. Memory tests (Rey Osterrieth Complex Figure, Listening Span, Digit Span, Controlled Word Association Test, and computerized testing of episodic memory), tests of processing speed and executive functions (Trail Making, Reaction Time, and Finger Tapping) were performed and related to previously published CSF biomarker results for the axonal injury marker neurofilament light (NFL).
The neurological assessment showed no significant differences between boxers and controls, although elevated CSF NFL, as a sign of axonal injury, was detected in about 80% of the boxers 1–6 days post bout. The investigation of the relationship between neuropsychological evaluation and CSF NFL concentrations revealed that boxers with persisting NFL concentration elevation after at least 14 days resting time post bout, had a significantly poorer performance on Trail Making A (p = 0.041) and Simple Reaction Time (p = 0.042) compared to other boxers.
This is the first study showing traumatic axonal brain injury can be present without measureable cognitive impairment. The repetitive, subconcussive head trauma in amateur boxing causes axonal injury that can be detected with analysis of CSF NFL, but is not sufficient to produce impairment in memory tests, tests of processing speed, or executive functions. The association of prolonged CSF NFL increase in boxers with impairment of processing speed is an interesting observation, which needs to be verified in larger studies.
PMCID: PMC4062456  PMID: 24941067
17.  Comparison of spatial working memory in children with prenatal alcohol exposure and those diagnosed with ADHD; A functional magnetic resonance imaging study 
Alcohol related neurodevelopmental disorder (ARND) falls under the umbrella of fetal alcohol spectrum disorder (FASD), but individuals do not demonstrate the facial characteristics associated with fetal alcohol syndrome (FAS), making diagnosis difficult. While attentional problems in ARND are similar to those found in attention-deficit/hyperactivity disorder (ADHD), the underlying impairment in attention pathways may be different.
Functional magnetic resonance imaging (fMRI) of a working memory (1-back) task of 63 children, 10 to 14 years old, diagnosed with ARND and ADHD, as well as typically developing (TD) controls, was conducted at 3 T. Diffusion tensor imaging (DTI) data were also acquired.
Activations were observed in posterior parietal and occipital regions in the TD group and in dorsolateral prefrontal and posterior parietal regions in the ARND group, whereas the ADHD group activated only dorsolateral prefrontal regions, during the working memory component of the task (1-back minus 0-back contrast). The increases in frontal and parietal activity were significantly greater in the ARND group compared to the other groups. This increased activity was associated with reduced accuracy and increased response time variability, suggesting that ARND subjects exert greater effort to manage short-term memory load. Significantly greater intra-subject variability, demonstrated by fMRI region-of-interest analysis, in the ADHD and ARND groups compared to the TD group suggests that moment-to-moment lapses in attention contributed to their poorer task performance. Differences in functional activity in ARND subjects with and without a diagnosis of ADHD resulted primarily from reduced activation by the ARND/ADHD + group during the 0-back task. In contrast, children with ADHD alone clearly showed reduced activations during the 1-back task. DTI analysis revealed that the TD group had significantly higher total tract volume and number of fibers than the ARND group. These measures were negatively correlated with errors on the 1-back task, suggesting a link between white matter integrity and task performance.
fMRI activations suggest that the similar behavior of children with ARND and ADHD on a spatial working memory task is the result of different cognitive events. The nature of ADHD in children with ARND appears to differ from that of children with ADHD alone.
PMCID: PMC3436669  PMID: 22958510
Fetal Alcohol Spectrum Disorder (FASD); Alcohol related neurodevelopmental disorder (ARND); Attention-deficit/hyperactivity disorder (ADHD); Functional magnetic resonance imaging (fMRI); Spatial working memory; White matter; Gray matter; Diffusion tensor imaging (DTI); Region of interest (ROI)
18.  Characteristics of neuropsychological functions in inpatients with poorly‐controlled type 2 diabetes mellitus 
Aims/Introduction:  It has been suggested that type 2 diabetes is associated with cognitive impairment. We investigated the neuropsychological profile of inpatients with poorly controlled type 2 diabetes and assessed the effects of clinical factors on neuropsychological functions.
Materials and Methods:  Forty‐two patients with type 2 diabetes and 32 non diabetic control subjects were matched for age, sex ratio, and level of education. Attention & working memory, processing speed, verbal memory, visuospatial memory, visuoconstruction, and executive function were tested. Information about physical function, alcohol use, hypertension, dyslipidemia, and myocardial infarction was retrieved from personal interviews and medical records.
Results:  Diabetic patients demonstrated mild cognitive deterioration in attention & working memory, processing speed, verbal memory, and executive function. In particular, neuropsychological decline became prominent when tasks related with speed and verbal stimuli became unstructured and complex. Age was significantly associated with the majority of neuropsychological tests, whereas tasks dealing with working memory and executive function were associated with age only in the diabetic group. Duration of diabetes was associated with Backward Digit Span.
Conclusions:  Accelerated aging had a major influence on cognitive decline in the diabetic group, whereas diminished performance in working memory and executive function might have been more related to diabetes‐related cognitive impairment. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00170.x, 2011)
PMCID: PMC4014957  PMID: 24843583
Neuropsychological function; Poor glycemic control; Type 2 diabetes
19.  A Novel Tool for the Assessment of Pain: Validation in Low Back Pain 
PLoS Medicine  2009;6(4):e1000047.
Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.
Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology.
Methods and Findings
Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%–97%) and specificity (97%; 95% CI 89%–100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs.
We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
Editors' Summary
Pain, although unpleasant, is essential for survival. Whenever the body is damaged, nerve cells detecting the injury send an electrical message via the spinal cord to the brain and, as a result, action is taken to prevent further damage. Usually pain is short-lived, but sometimes it continues for weeks, months, or years. Long-lasting (chronic) pain can be caused by an ongoing, often inflammatory condition (for example, arthritis) or by damage to the nervous system itself—experts call this “neuropathic” pain. Damage to the brain or spinal cord causes central neuropathic pain; damage to the nerves that convey information from distant parts of the body to the spinal cord causes peripheral neuropathic pain. One example of peripheral neuropathic pain is “radicular” low back pain (also called sciatica). This is pain that radiates from the back into the legs. By contrast, axial back pain (the most common type of low back pain) is confined to the lower back and is non-neuropathic.
Why Was This Study Done?
Chronic pain is very common—nearly 10% of American adults have frequent back pain, for example—and there are many treatments for it, including rest, regulated exercise (physical therapy), pain-killing drugs (analgesics), and surgery. However, the best treatment for any individual depends on the exact nature of their pain, so it is important to assess their pain carefully before starting treatment. This is usually done by scoring overall pain intensity, but this assessment does not reflect the characteristics of the pain (for example, whether it occurs spontaneously or in response to external stimuli) or the complex biological processes involved in pain generation. An assessment designed to take such factors into account might improve treatment outcomes and could be useful in the development of new therapies. In this study, the researchers develop and test a new, standardized tool for the assessment of chronic pain that, by examining many symptoms and signs, aims to distinguish between pain subtypes.
What Did the Researchers Do and Find?
One hundred thirty patients with several types of peripheral neuropathic pain and 57 patients with non-neuropathic (axial) low back pain completed a structured interview of 16 questions and a standardized bedside examination of 23 tests. Patients were asked, for example, to choose words that described their pain from a list provided by the researchers and to grade the intensity of particular aspects of their pain from zero (no pain) to ten (the maximum imaginable pain). Bedside tests included measurements of responses to light touch, pinprick, and vibration—chronic pain often alters responses to harmless stimuli. Using “hierarchical cluster analysis,” the researchers identified six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain based on the patterns of symptoms and signs revealed by the interviews and physical tests. They then used “classification tree analysis” to identify the six questions and ten physical tests that discriminated best between pain subtypes and combined these items into a tool for a Standardized Evaluation of Pain (StEP). Finally, the researchers asked whether StEP, which took 10–15 minutes, could identify patients with radicular back pain and discriminate them from those with axial back pain in an independent group of 137 patients with chronic low back pain. StEP, they report, accurately diagnosed these two conditions and was well accepted by the patients.
What Do These Findings Mean?
These findings indicate that a standardized assessment of pain-related signs and symptoms can provide a simple, quick diagnostic procedure that distinguishes between radicular (neuropathic) and axial (non-neuropathic) low back pain. This distinction is crucial because these types of back pain are best treated in different ways. In addition, the findings suggest that it might be possible to identify additional pain subtypes using StEP. Because these subtypes may represent conditions in which different pain mechanisms are acting, classifying patients in this way might eventually enable physicians to tailor treatments for chronic pain to the specific needs of individual patients rather than, as at present, largely guessing which of the available treatments is likely to work best.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Giorgio Cruccu and and Andrea Truini
The US National Institute of Neurological Disorders and Stroke provides a primer on pain in English and Spanish
In its 2006 report on the health status of the US, the National Center for Health Statistics provides a special feature on the epidemiology of pain, including back pain
The Pain Treatment Topics Web site is a resource, sponsored partly by associations and manufacturers, that provides information on all aspects of pain and its treatment for health care professionals and their patients
Medline Plus provides a brief description of pain and of back pain and links to further information on both topics (in English and Spanish)
The MedlinePlus Medical Encyclopedia also has a page on low back pain (in English and Spanish)
PMCID: PMC2661253  PMID: 19360087
20.  Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve 
Brain  2009;133(2):362-374.
The cognitive reserve hypothesis helps to explain the incomplete relationship between brain disease and cognitive status in people with neurologic diseases, including Alzheimer's; disease and multiple sclerosis. Lifetime intellectual enrichment (estimated with education or vocabulary knowledge) lessens the negative impact of brain disease on cognition, such that people with greater enrichment are able to withstand more severe neuropathology before suffering cognitive impairment or dementia. The current research is the first to investigate directly the relationship between intellectual enrichment and an index of cerebral activity (the blood oxygen level dependent signal) in a neurologic sample. Multiple sclerosis patients completed a vocabulary-based estimate of lifetime intellectual enrichment. Disease severity was estimated with brain atrophy. Cognitive status was measured with the Symbol Digit Modalities Test. Cerebral activity (functional magnetic resonance imaging blood oxygen level dependent signal) and behavioural performance (accuracy, reaction time) were recorded during the visual N-Back working memory task (three levels of demand: 0-, 1-, 2-Back). All patients produced perfect/nearly perfect accuracy during lower demands (0- and 1-Back), and reaction time was unrelated to intellectual enrichment; however, voxelwise partial correlations controlling for brain atrophy revealed strong positive correlations between intellectual enrichment and cerebral activity within the brain's; default network (e.g. anterior and posterior cingulate corticies), indicating that patients with greater enrichment were able to maintain resting state activity during cognitive processing better. In turn, intellectual enrichment was negatively associated with prefrontal recruitment, suggesting that patients with lesser enrichment required more cerebral resources to perform the same cognitive task as patients with greater enrichment. This same pattern of enrichment-related cerebral activity was observed when cognitive demands increased (2-Back), and intellectual enrichment was negatively associated with reaction time. Principle components analysis revealed a single cognitive reserve network across tasks (greater default network, lesser prefrontal recruitment). Expression of this network almost fully mediated the positive relationship between intellectual enrichment and cognitive status (Symbol Digit Modalities Test). Also, expression of this network was positively associated with brain atrophy when controlling for cognitive status, indicating that patients with greater expression of this network can withstand more severe brain disease before exhibiting cognition similar to patients with lesser network expression. Of note, similar functional magnetic resonance imaging research with healthy adults has not found an association between intelligence and cerebral efficiency. The unique relationship between intellectual enrichment and cerebral efficiency in neurologic patients is consistent with the cognitive reserve hypothesis, which does not posit that enrichment leads to gains in neurocognitive functioning per se; rather, enrichment protects against neurocognitive decline secondarily to disease.
PMCID: PMC2822636  PMID: 20008455
cognitive reserve; functional MRI; multiple sclerosis; Alzheimer's; disease; default network
21.  Feasibility and Findings from a Novel Working Memory fMRI Paradigm in Multiple Sclerosis 
Functional MRI (fMRI) basic cognitive paradigms such as the n-back have been shown to detect cognitive impairment (CI) in Multiple Sclerosis (MS). The immediate memory task/delayed memory task (IMT/DMT) detects varying degrees of working memory (WM) by alternating three levels of complexity and two levels of WM delay. This paradigm has not been evaluated in MS nor validated against standard neuropsychological (NP) testing.
To evaluate the correlation between WM function and blood oxygen level dependent (BOLD) activation on fMRI in MS patients undergoing the IMT/DMT. To compare IMT/DMT behavioral scores to NP scores.
10 MS patients with no history of CI underwent the Minimal Assessment of Cognitive Function in MS (MACFIMS) and an fMRI session where they performed the IMT/DMT. Working-memory (“wmem”) activation was defined as the BOLD signal during DMT blocks for a particular condition (3, 5, or 7 digits per stimuli) minus the BOLD signal during IMT blocks for that condition. Areas of statistically significant Family Wise Error (FWE) -corrected cluster-level BOLD activation were identified using SPM8 Random Effects t-test. IMT/DMT behavioral data and MACFIMS scores were compared.
The 3-digit as well as the 5-digit wmem showed significant fMRI BOLD activation. The 3-digit wmem, activation was found in portions of the bilateral superior and mid frontal cortex, supplementary motor area, pre and post central gyrus, bilateral superior and inferior parietal lobule, inferolateral pre-frontal cortex, cuneus, insula and cingulate regions. The 5 digit wmen activation was seen in the inferior medial frontal and medial orbitofrontal cortex. IMT/DMT behavioral scores were within normal range and consistent with MACFIMS.
IMT/DMT, a novel fMRI working memory paradigm, is associated with BOLD activation in areas of the brain related to cognitive function in patients with MS. Both MACFIMS and IMT/DMT scores were in agreement and supported intact cognitive function.
PMCID: PMC3996842  PMID: 24772453
Functional MRI; Multiple sclerosis; Cognitive impairment; Working memory
22.  Decrements in cognitive performance in metal inert gas welders exposed to aluminium 
OBJECTIVES: Often little has been discovered of the cognitive functions affected by occupational toxins because many functions cooperate to produce the single performance scores typically reported from neuropsychological tests. To facilitate the interpretation of neuropsychological scores, the issue of occupational exposure to aluminium was examined with an approach intended to increase understanding of those cognitive processes that may be affected. METHODS: The investigation was a cross sectional study of asymptomatic aluminium welders and a reference group of mild steel welders. Based on urinary aluminium concentrations, welders were classified into a reference (n = 28), low (n = 27), and high (n = 24) exposure group. The mean urinary aluminium concentrations were 0.46, 2.25, and 9.98 mumol/l, respectively. A comprehensive neuropsychological examination was undertaken to assess psychomotor function, simple visual reaction time, attention related tasks, verbal and visual or visuospatial abilities as well as verbal and visual learning and memory. RESULTS: Aluminium welders showed no impairment on the finger tapping, Santa Ana dexterity, simple visual reaction times, any of the verbal memory tasks, the similarities subtest of Wechsler adult intelligence scale, or the Stroop task. However, the low exposed group performed poorer on the memory for designs and on more difficult block design items demanding preliminary visuospatial analysis. The time limited synonym task, embedded figures, digit symbol speed, and the backward counting component of the divided attention task showed exposure-response relations. CONCLUSIONS: The impairments found were circumscribed. When the neuropsychological tasks were scored to show some of the underlying theoretical cognitive structures, the results indicated that performance difficulties were mainly detected in tasks requiring working memory, particularly that relating to processing of visuospatial information. There was also evidence that such impairments are more readily found in time limited tasks involving visually presented material, in which effective visual scanning combined with control of working memory is demanded.
PMCID: PMC1757790  PMID: 10615297
23.  Persistent Differences in Patterns of Brain Activation after Sports-Related Concussion: A Longitudinal Functional Magnetic Resonance Imaging Study 
Journal of Neurotrauma  2014;31(2):180-188.
Avoiding recurrent injury in sports-related concussion (SRC) requires understanding the neural mechanisms involved during the time of recovery after injury. The decision for return-to-play is one of the most difficult responsibilities facing the physician, and so far this decision has been based primarily on neurological examination, symptom checklists, and neuropsychological (NP) testing. Functional magnetic resonance imaging (fMRI) may be an additional, more objective tool to assess the severity and recovery of function after concussion. The purpose of this study was to define neural correlates of SRC during the 2 months after injury in varsity contact sport athletes who suffered a SRC. All athletes were scanned as they performed an n-back task, for n=1, 2, 3. Subjects were scanned within 72 hours (session one), at 2 weeks (session two), and 2 months (session three) post-injury. Compared with age and sex matched normal controls, concussed subjects demonstrated persistent, significantly increased activation for the 2 minus 1 n-back contrast in bilateral dorsolateral prefrontal cortex (DLPFC) in all three sessions and in the inferior parietal lobe in session one and two (α≤0.01 corrected). Measures of task performance revealed no significant differences between concussed versus control groups at any of the three time points with respect to any of the three n-back tasks. These findings suggest that functional brain activation differences persist at 2 months after injury in concussed athletes, despite the fact that their performance on a standard working memory task is comparable to normal controls and normalization of clinical and NP test results. These results might indicate a delay between neural and behaviorally assessed recovery after SRC.
PMCID: PMC3900041  PMID: 23914845
concussion; DLPFC; fMRI; n-back task; working memory
24.  Fractionating Verbal Episodic Memory in Alzheimer's Disease 
NeuroImage  2010;54(2):1530-1539.
The aim of this study was to determine the neural correlates of different stages of episodic memory function and their modulation by Alzheimer's Disease (AD). Several decades of work have supported the role of the medial temporal lobes (MTL) in episodic memory function. However, more recent work, derived in part from functional neuroimaging studies, has suggested that other brain structures make up a large-scale network that appear to support successful encoding and retrieval of episodic memories. Furthermore, controversy exists as to whether dissociable MTL regions support qualitatively different aspects of memory (hippocampus: contextual memory or ‘recollection’; perirhinal/lateral entorhinal cortex: item memory or ‘familiarity’). There is limited neuropsychological support for these models and most work in AD only has examined free recall memory measures. We studied the relationship between performance on different stages of the Rey Auditory Verbal Learning Test (AVLT), a 15-item word list learning task, and structural MRI measures in mild AD patients. Structural measures included hippocampal volume and cortical thickness of several ROIs known to undergo atrophy in AD. Correlation and multiple regression analyses, controlling for age, education, and gender, were performed in 146 mild AD patients (MMSE 23.3 ± 2.0). To evaluate the robustness of these relationships, similar analyses were performed with additional standardized verbal memory measures. Early immediate recall trials (e.g. Trial 1 of the AVLT) were not associated with the size of MTL regions, but correlated most strongly with inferior parietal, middle frontal gyrus, and temporal pole ROIs. After repeated exposure (e.g. Trial 5 of the AVLT), immediate recall was correlated with both MTL and a similar distribution of isocortical structures, but most strongly the temporal pole. For delayed recall, only the hippocampus correlated with performance. In contrast, for delayed recognition discrimination, the perirhinal/entorhinal cortex correlated more strongly than hippocampus; no other isocortical regions were strongly associated with performance. Convergent results were found for immediate and delayed trials of the other memory tests. The current results suggest that a richer understanding of the memory deficits in AD can be gained by examining multiple measures, which tap different aspects of memory function. Furthermore, the present findings are consistent with models hypothesizing that different stages of verbal list learning map onto dissociable brain regions. These data have implications for understanding the anatomic basis of processes underlying episodic memory, particularly related to a division of labor within the medial temporal lobes and within the large-scale MTL-cortical memory network.
PMCID: PMC2997155  PMID: 20832485
memory performance; recollection; familiarity; Alzheimer's Disease; medial temporal lobe
25.  Working Memory Related Brain Network Connectivity in Individuals with Schizophrenia and Their Siblings 
A growing number of studies have reported altered functional connectivity in schizophrenia during putatively “task-free” states and during the performance of cognitive tasks. However, there have been few systematic examinations of functional connectivity in schizophrenia across rest and different task states to assess the degree to which altered functional connectivity reflects a stable characteristic or whether connectivity changes vary as a function of task demands. We assessed functional connectivity during rest and during three working memory loads of an N-back task (0-back, 1-back, 2-back) among: (1) individuals with schizophrenia (N = 19); (2) the siblings of individuals with schizophrenia (N = 28); (3) healthy controls (N = 10); and (4) the siblings of healthy controls (N = 17). We examined connectivity within and between four brain networks: (1) frontal–parietal (FP); (2) cingulo-opercular (CO); (3) cerebellar (CER); and (4) default mode (DMN). In terms of within-network connectivity, we found that connectivity within the DMN and FP increased significantly between resting state and 0-back, while connectivity within the CO and CER decreased significantly between resting state and 0-back. Additionally, we found that connectivity within both the DMN and FP was further modulated by memory load. In terms of between network connectivity, we found that the DMN became significantly more “anti-correlated” with the FP, CO, and CER networks during 0-back as compared to rest, and that connectivity between the FP and both CO and CER networks increased with memory load. Individuals with schizophrenia and their siblings showed consistent reductions in connectivity between both the FP and CO networks with the CER network, a finding that was similar in magnitude across rest and all levels of working memory load. These findings are consistent with the hypothesis that altered functional connectivity in schizophrenia reflects a stable characteristic that is present across cognitive states.
PMCID: PMC3358772  PMID: 22654746
schizophrenia; functional connectivity; working memory; cognitive control; cerebellum; task; risk

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