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Working Memory: How Important Is White Matter?

Lazar, Mariana
Working memory, the ability to transiently keep, process, and use information as part of ongoing mental processes is an essential feature of cognitive functioning. The largest number of items that people can hold in their working memory, referred to as the capacity of working memory, is limited and varies substantially among individuals. Uncovering the biological factors that underlie these two defining properties of working memory capacity remains a key undertaking of modern cognitive neuroscience since capacity strongly predicts how well we reason, learn, and even do math. In this work we review data that highlights the role white matter, which provides the wiring of the extensive neural networks that activate during working memory tasks, may play in interindividual variations in capacity. We also describe advanced diffusion imaging methods, which may be uniquely suited in capturing those white matter features that are most relevant to capacity. Finally, we discuss several possible mechanisms through which white matter may both contribute to and limit working memory.
PMID: 30231842
ISSN: 1089-4098
CID: 3301542

Metabolic Abnormalities in the Hippocampus of Patients with Schizophrenia: A 3D Multivoxel MR Spectroscopic Imaging Study at 3T

Meyer, E J; Kirov, I I; Tal, A; Davitz, M S; Babb, J S; Lazar, M; Malaspina, D; Gonen, O
BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 +/- 10.1 years; mean disease duration, 19.5 +/- 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 +/- 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms) 1H-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mIns concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 +/- 2.2 versus 7.4 +/- 1.2 mmol/L (P < .05); showing no differences, concentrations in NAA were 8.8 +/- 1.6 versus 8.7 +/- 1.2 mmol/L; in Cho, 2.3 +/- 0.7 versus 2.1 +/- 0.3 mmol/L; and in mIns, 6.1 +/- 1.5 versus 5.2 +/- 0.9 (all P > .1). There was a positive correlation between mIns and Cr in patients (r = 0.57, P = .05) but not in controls. The mean bilateral hippocampal volume was approximately 10% lower in patients: 7.5 +/- 0.9 versus 8.4 +/- 0.7 cm3 (P < .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them.
PMCID:5161606
PMID: 27444940
ISSN: 1936-959x
CID: 2185592

Zoomed echo-planar diffusion tensor imaging for MR tractography of the prostate gland neurovascular bundle without an endorectal coil: a feasibility study

Ream, Justin M; Glielmi, Christopher; Lazar, Mariana; Campbell, Naomi; Pfeuffer, Josef; Schneider, Rainer; Rosenkrantz, Andrew B
PURPOSE: The purpose of this study was to assess the feasibility of zoomed echo-planar imaging (EPI) diffusion tensor imaging (DTI) with 2-channel parallel transmission (pTx) for MR tractography of the periprostatic neurovascular bundle (NVB) without an endorectal coil, and to compare its performance to that of conventionally acquired DTI. METHODS: 8 healthy males (28.9 +/- 4.6 years) underwent pelvic phased-array coil prostate MRI on a 3T system using both zoomed-EPI DTI (z-DTI) with 2-channel pTx and conventional single-shot spin-echo EPI DTI (c-DTI) acquisitions with 6 encoding directions and b-values of 0 and 1000 s/mm(2). Fractional anisotropy (FA) maps and tractography analysis incorporating 3D visualization of the NVB were performed from each acquisition. Fiber tract counts, estimated signal-to-noise ratio (eSNR), and image quality measures of the FA maps and NVB tractography were compared. Quantitative and image quality measures were compared using Wilcoxon signed rank tests. RESULTS: 3 of 8 subjects had no tracts detected with c-DTI acquisition, while all 8 had tracts detected with z-DTI. z-DTI acquisition yielded significantly more fiber tracts (c-DTI: 77 +/- 116 tracts; z-DTI: 430 +/- 228 tracts; p = 0.019) and higher eSNR (c-DTI: 2.9 +/- 1.2; z-DTI: 13.17 +/- 9.9; p = 0.014). Relative to c-DTI acquisitions, z-DTI FA maps showed significantly reduced artifact (p = 0.008) and reduced anatomic distortion of the prostate (p = 0.010), while z-DTI tractography showed significantly better overall visual quality (p = 0.011), tract symmetry (p = 0.010), tract coherence (p = 0.011), and subjective similarity to the actual NVB (p = 0.011). CONCLUSION: Zoomed-EPI DTI acquisition for tractography of the prostate gland NVB improves quantitative and qualitative measures of image and tract fiber quality, allowing tractography of the NVB at 3T without using an endorectal coil.
PMID: 27193790
ISSN: 2366-0058
CID: 2111792

Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity

Malaspina, Dolores; Kranz, Thorsten M; Heguy, Adriana; Harroch, Sheila; Mazgaj, Robert; Rothman, Karen; Berns, Adam; Hasan, Sumya; Antonius, Daniel; Goetz, Raymond; Lazar, Mariana; Chao, Moses V; Gonen, Oded
Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (chi2=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.
PMCID:4894496
PMID: 26925801
ISSN: 1573-2509
CID: 2009242

Hypo-metabolism of the rostral anterior cingulate cortex associated with working memory impairment in 18 cases of schizophrenia

Mazgaj, Robert; Tal, Assaf; Goetz, Raymond; Lazar, Mariana; Rothman, Karen; Messinger, Julie Walsh; Malaspina, Dolores; Gonen, Oded
Working memory (Work-Mem), the capacity to hold and manipulate information, activates the anterior cingulate cortex (ACC), especially its caudal subregion. Impaired Work-Mem and structural and functional abnormalities of the ACC are reported in schizophrenia. This study aims to elucidate the pathogenesis of Work-Mem dysfunction in schizophrenia by comparing metabolite concentrations across ACC subregions. This retrospective study of 18 schizophrenia cases and 10 matched controls used proton magnetic resonance spectroscopic imaging (1H-MRSI, TR/TE = 1800/35 ms, 0.5 cm3 spatial resolution) to test whether the Work-Mem Index of the Wechsler Adult Intelligence Scale, third edition is associated with differences in the rostral to caudal ACC ratios of N-acetylaspartate (NAA) and creatine (Cr). Higher caudal:rostral ACC Cr (but not NAA) concentrations were associated with decreased Work-Mem Index in cases (r = -0.6, p = 0.02), with a similar trend in controls (r = -0.56, p = 0.10), although caudal:rostral ACC Cr correlated with NAA in cases and controls (r = 0.67 and 0.62, p < 0.05 for both). NAA and Cr ratios did not correlate with myo-inositol, excluding gliosis as the underlying process. Subjects' sex and age had no effects on these relationships. The findings suggest that rostral ACC energy hypo-metabolism, possibly arising from neurodevelopmental processes, is associated with working memory impairment in schizophrenia. Changes in the rostral (not the expected caudal) subregion underscore the interconnections between the ACC subregions and may offer laboratory markers for treatment trials, etiology studies, and perhaps even enhanced identification of prodromal "at risk" subjects.
PMCID:4583324
PMID: 25804309
ISSN: 1931-7565
CID: 1514002

Mode of Anisotropy Reveals Global Diffusion Alterations in Attention-Deficit/Hyperactivity Disorder

Yoncheva, Yuliya N; Somandepalli, Krishna; Reiss, Philip T; Kelly, Clare; Di Martino, Adriana; Lazar, Mariana; Zhou, Juan; Milham, Michael P; Castellanos, F Xavier
OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.
PMCID:4760693
PMID: 26802781
ISSN: 1527-5418
CID: 1955332

Precuneal and amygdala spontaneous activity and functional connectivity in war-zone-related PTSD

Yan, Xiaodan; Lazar, Mariana; Shalev, Arieh Y; Neylan, Thomas C; Wolkowitz, Owen M; Brown, Adam D; Henn-Haase, Clare; Yehuda, Rachel; Flory, Janine D; Abu-Amara, Duna; Sodickson, Daniel K; Marmar, Charles R
Abnormality in the "fear circuitry" has been known as a major neural characteristic of posttraumatic stress disorder (PTSD). Recent studies also revealed decreased functional connectivity in the default mode network in PTSD. The present study aims to investigate, in war-zone-related PTSD, the spontaneous activity and functional connectivity of the amygdala and the precuneus, which are two representative brain regions of the two networks, respectively. Two groups of 52 male US Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans (PTSD vs. controls), well matched on age and ethnicity, were clinically assessed and then studied in a resting state functional magnetic resonance imaging (fMRI) procedure. Functional connectivity analysis was conducted on the resting state fMRI data with the amygdala and precuneus as seeds. Compared with controls, veterans with PTSD had lower functional connectivity in the default mode network, as well as lower amygdala-frontal functional connectivity. Both the PTSD and the control group had a significant positive precuneal-amygdala functional connectivity without a significant group difference. The magnitudes of spontaneous activity of the amygdala and the precuneus were negatively correlated in the PTSD group and showed significant quadratic relationships with the amount of emotional abuse in early life trauma. These findings may improve our understanding about the relationships between fear circuitry and the default mode network in the context of war-zone-related PTSD.
PMID: 25561375
ISSN: 0165-1781
CID: 1428912

Constrained by Our Connections: White Matter's Key Role in Interindividual Variability in Visual Working Memory Capacity

Golestani, Ali M; Miles, Laura; Babb, James; Castellanos, F Xavier; Malaspina, Dolores; Lazar, Mariana
Visual working memory (VWM) plays an essential role in many perceptual and higher-order cognitive processes. Despite its reliance on a broad network of brain regions, VWM has a capacity limited to a few objects. This capacity varies substantially across individuals and relates closely to measures of overall cognitive function (Luck and Vogel, 2013). The mechanisms underlying these properties are not completely understood, although the amplitude of neural signal oscillations (Vogel and Machizawa, 2004) and brain activation in specific cortical regions (Todd and Marois, 2004) have been implicated. Variability in VWM performance may also reflect variability in white matter structural properties. However, data based primarily on diffusion tensor imaging approaches remain inconclusive. Here, we investigate the relationship between white matter and VWM capacity in human subjects using an advanced diffusion imaging technique, diffusion kurtosis imaging. Diffusion kurtosis imaging provides several novel quantitative white mater metrics, among them the axonal water fraction (faxon), an index of axonal density and caliber. Our results show that 59% of individual variability in VWM capacity may be explained by variations in faxon within a widely distributed network of white matter tracts. Increased faxon associates with increased VWM capacity. An additional 12% in VWM capacity variance may be explained by diffusion properties of the extra-axonal space. These data demonstrate, for the first time, the key role of white matter in limiting VWM capacity in the healthy adult brain and suggest that white matter may represent an important therapeutic target in disorders of impaired VWM and cognition.
PMCID:4220025
PMID: 25378158
ISSN: 0270-6474
CID: 1341442

Whole-brain White Matter Microstructure in Adults with Attention-deficit/hyperactivity Disorder [Meeting Abstract]

Yoncheva, Yuliya; Somandepalli, Krishna; Kelly, Clare; Di Martino, Adriana; Lazar, Mariana; Milham, Michael P; Castellanos, FXavier
ISI:000334101802273
ISSN: 1873-2402
CID: 1015272

Diffusional kurtosis imaging of the developing brain

Paydar, A; Fieremans, E; Nwankwo, J I; Lazar, M; Sheth, H D; Adisetiyo, V; Helpern, J A; Jensen, J H; Milla, S S
BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an extension of DTI but includes non-Gaussian diffusion effects, allowing more comprehensive characterization of microstructural changes during brain development. Our purpose was to use diffusional kurtosis imaging to measure age-related microstructural changes in both the WM and GM of the developing human brain. MATERIALS AND METHODS: Diffusional kurtosis imaging was performed in 59 subjects ranging from birth to 4 years 7 months of age. Diffusion metrics, fractional anisotropy, and mean kurtosis were collected from VOIs within multiple WM and GM structures and subsequently analyzed with respect to age. Diffusional kurtosis tractography images at various stages of development were also generated. RESULTS: Fractional anisotropy and mean kurtosis both showed age-related increases in all WM regions, reflecting progression of diffusional anisotropy throughout development, predominantly in the first 2 years of life (eg, 70% and 157% increase in fractional anisotropy and mean kurtosis, respectively, from birth to 2 years for the splenium). However, mean kurtosis detected continued microstructural changes in WM past the fractional anisotropy plateau, accounting for more delayed isotropic changes (eg, 90% of maximum fractional anisotropy was reached at 5 months, whereas 90% of maximum mean kurtosis occurred at 18 months for the external capsule). Mean kurtosis may also provide greater characterization of GM maturation (eg, the putamen showed no change in fractional anisotropy but an 81% change in mean kurtosis from birth to 4 years 7 months). CONCLUSIONS: Mean kurtosis detects significant microstructural changes consistent with known patterns of brain maturation. In comparison with fractional anisotropy, mean kurtosis may offer a more comprehensive evaluation of age-related microstructural changes in both WM and GM and is potentially a valuable technique for studying brain development.
PMID: 24231848
ISSN: 0195-6108
CID: 881582