Autism Heterogeneity in a Densely Sampled U.S. Population: Results From the First 1,000 Participants in the RI-CART Study.

The objective of this study was to establish a large, densely sampled, U.S. population-based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co-occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population-based U.S. cohort with ASD. Given the depth of sampling, the RI-CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474-488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co-occurring medical and psychiatric conditions in affected individuals.

Complex Neurological Phenotype in Female Carriers of NHE6 Mutations.

Mutations in NHE6 (also termed SLC9A6) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased NHE6 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of NHE6 mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.

Neurocognitive deficits in children and adolescents following maltreatment: Neurodevelopmental consequences and neuropsychological implications of traumatic stress.

Childhood maltreatment is a significant risk factor for a host of psychiatric, developmental, medical, and neurocognitive conditions, often resulting in debilitating and long-term consequences. However, there is no available neuropsychological resource reviewing the literature on the associated neurocognitive deficits in children and adolescents. This review comprehensively examines the 23 prior studies that evaluated the intellectual, language, visual-spatial, memory, motor, and/or attention/executive functions in children and adolescents following an experience of childhood abuse and/or neglect. Neurocognitive impairments were frequently reported. Impairments in executive functions were the most frequent and severe reported impairments, although intelligence, language, visual-spatial skills, and memory are also at serious risk for compromised development following maltreatment. However, specific factors such as abuse/neglect duration, severity, type, and timing during development were all associated with neurocognition. This indicates that these factors are of greater importance than just the presence of abuse/neglect in identifying risk for neurocognitive compromise. Such neurocognitive deficits appear to be a consequence to the known neurobiological and brain development abnormalities of this population, suggesting traumatic stress can be a potential cause of neurodevelopmental disorders. These findings have critical implications for the clinical practice and research involving children following childhood maltreatment and other types of traumatic stress.

Cognitive processing speed mediates the effects of cardiovascular disease on executive functioning.

OBJECTIVE: The goal of this study was to examine the hypothesized mediating role of cognitive processing speed (CPS) in the relationship between cardiovascular disease (CVD) and executive functioning (EF). We investigated whether the processing-speed hypothesis in aging also explains the unique contribution that CPS may have to EF deficits in CVD patients. METHOD: A neuropsychological assessment, including multiple measures of CPS and EF, was administered to 21 older adults with a history of CVD and 73 older adults with no history of CVD. Structural equation models were used to measure the indirect associations between CVD and 6 EF task outcomes through a CPS factor. Competing indirect links were assessed using the product-of-coefficients (α*ß) approach with bias-corrected bootstrap confidence intervals. RESULTS: CVD was significantly, negatively related to CPS (ß = -.239, 95% CI [-.457, -.021]). CPS was significantly, positively related to an EF composite score (ß = .566, 95% CI [.368, .688]). CVD was significantly, negatively related to the EF composite score (ß = -.137, 95% CI [-.084, -.211]). The indirect links from CVD to the individual measures of the EF composite score via CPS were all significant. CVD most adversely affected tasks of cognitive flexibility and inhibition indirectly through CPS. CONCLUSION: With the present study, we have demonstrated that the processing-speed hypothesis in aging extends to older adult patients with CVD. Reduced CPS significantly underlies the link between CVD status and poorer EF. Individuals with CVD demonstrated poorer CPS and EF than those without CVD, and CPS was specifically implicated as a CVD-related mechanism leading to worse EF. (PsycINFO Database Record

Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders.

Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype-phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485-1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3' untranslated region (3'-UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3'UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis.

An FMRI-compatible Symbol Search task.

Our objective was to determine whether a Symbol Search paradigm developed for functional magnetic resonance imaging (FMRI) is a reliable and valid measure of cognitive processing speed (CPS) in healthy older adults. As all older adults are expected to experience cognitive declines due to aging, and CPS is one of the domains most affected by age, establishing a reliable and valid measure of CPS that can be administered inside an MR scanner may prove invaluable in future clinical and research settings. We evaluated the reliability and construct validity of a newly developed FMRI Symbol Search task by comparing participants' performance in and outside of the scanner and to the widely used and standardized Symbol Search subtest of the Wechsler Adult Intelligence Scale (WAIS). A brief battery of neuropsychological measures was also administered to assess the convergent and discriminant validity of the FMRI Symbol Search task. The FMRI Symbol Search task demonstrated high test-retest reliability when compared to performance on the same task administered out of the scanner (r=.791; p<.001). The criterion validity of the new task was supported, as it exhibited a strong positive correlation with the WAIS Symbol Search (r=.717; p<.001). Predicted convergent and discriminant validity patterns of the FMRI Symbol Search task were also observed. The FMRI Symbol Search task is a reliable and valid measure of CPS in healthy older adults and exhibits expected sensitivity to the effects of age on CPS performance.

The synergistic effects of anxiety and cerebral hypoperfusion on cognitive dysfunction in older adults with cardiovascular disease.

OBJECTIVES: Anxiety is a risk factor for cardiovascular disease (CVD) and is associated with neurocognitive outcomes. The effect of anxiety on brain perfusion in a CVD population has yet to be examined, and no study has investigated the interactive effects of anxiety and cerebral perfusion on cognition. METHODS: A total of 55 older adults with CVD completed the Beck Anxiety Inventory (BAI) and underwent arterial spin labeling to quantify cortical perfusion and thickness. Participants were administered the Mini-Mental State Examination (MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: Reduced perfusion predicted poorer cognition and decreased cortical thickness. Higher anxiety score predicted worse memory performance and decreased frontal perfusion. Frontal lobe hypoperfusion combined with increased BAI scores exacerbated poorer MMSE performance. CONCLUSIONS: Higher anxiety may exacerbate the effects of cerebral hypoperfusion on cognitive impairment. Longitudinal studies are needed to confirm our findings and determine whether anxiety treatment improves neurocognitive outcomes in CVD.

Cerebrovascular perfusion among older adults is moderated by strength training and gender.

Cerebral perfusion is important in older adults as it is linked to cognitive declines. Physical activity can improve blood flow in the body but little is known about the relationship between physical activity and cerebral perfusion in older adults. In particular, no study has investigated the relation between strength training and cerebral perfusion. We examined whether different types of physical activity (assessed with the Rapid Assessment of Physical Activity questionnaire) were associated with MRI cerebrovascular perfusion in 59 older adults. There was a significant interaction between gender and strength training, such that women who engaged in strength training (weight lifting or calisthenics) at least once per week exhibited significantly greater cerebrovascular perfusion than women who did not. This interaction remained significant after controlling for other physical activity, demographics, and health variables. These findings suggest that regular strength training can be beneficial for cerebrovascular health in women.

Pediatric neuroimaging using magnetic resonance imaging during non-sedated sleep.

BACKGROUND: Etiological studies of many neurological and psychiatric disorders are increasingly turning toward longitudinal investigations of infant brain development in order to discern predisposing structural and/or functional differences prior to the onset of overt clinical symptoms. While MRI provides a noninvasive window into the developing brain, MRI of infants and toddlers is challenging due to the modality's extreme motion sensitivity and children's difficulty in remaining still during image acquisition. OBJECTIVE: Here, we outline a broad research protocol for successful MRI of children under 4 years of age during natural, non-sedated sleep. MATERIALS AND METHODS: All children were imaged during natural, non-sedated sleep. Active and passive measures to reduce acoustic noise were implemented to reduce the likelihood of the children waking up during acquisition. Foam cushions and vacuum immobilizers were used to limit intra-scan motion artifacts. RESULTS: More than 380 MRI datasets have been successfully acquired from 220 children younger than 4 years of age within the past 39 months. Implemented measures permitted children to remain asleep for the duration of the scan and allowed the data to be acquired with an overall 97% success rate. CONCLUSION: The proposed method greatly advances current pediatric imaging techniques and may be readily implemented in other research and clinical settings to facilitate and further improve pediatric neuroimaging.

Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.

IMPORTANCE: Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE: To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS: Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES: Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS: Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. CONCLUSIONS AND RELEVANCE: While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease.

BACKGROUND: It is well established that aging and vascular processes interact to disrupt cerebral hemodynamics in older adults. However, the independent effects of cerebral perfusion on neurocognitive function among older adults remain poorly understood. We examined the associations among cerebral perfusion, cognitive function, and brain structure in older adults with varying degrees of vascular disease using perfusion magnetic resonance imaging (MRI) arterial spin labeling (ASL). MATERIALS AND METHODS: 52 older adults underwent neuroimaging and were administered the Mini Mental State Examination (MMSE), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and measures of attention/executive function. ASL and T1-weighted MRI were used to quantify total brain perfusion, total brain volume (TBV), and cortical thickness. RESULTS: Regression analyses showed reduced total brain perfusion was associated with poorer performance on the MMSE, RBANS total index, immediate and delayed memory composites, and Trail Making Test B. Reduced frontal lobe perfusion was associated with worse executive and memory function. A similar pattern emerged between temporal lobe perfusion and immediate memory. Regression analyses revealed that decreased total brain perfusion was associated with smaller TBV and mean cortical thickness. Regional effects of reduced total cerebral perfusion were found on temporal and parietal lobe volumes and frontal and temporal cortical thickness. DISCUSSION: Reduced cerebral perfusion is independently associated with poorer cognition, smaller TBV, and reduced cortical thickness in older adults. CONCLUSION: Prospective studies are needed to clarify patterns of cognitive decline and brain atrophy associated with cerebral hypoperfusion.

Interactions between white matter asymmetry and language during neurodevelopment.

The human brain is asymmetric in gross structure as well as functional organization. However, the developmental basis and trajectory of this asymmetry is unclear, and its relationship(s) to functional and cognitive development, especially language, remain to be fully elucidated. During infancy and early childhood, in concert with cortical gray matter growth, underlying axonal bundles become progressively myelinated. This myelination is critical for efficient and coherent interneuronal communication and, as revealed in animal studies, the degree of myelination changes in response to environment and neuronal activity. Using a novel quantitative magnetic resonance imaging method to investigate myelin content in vivo in human infants and young children, we investigated gross asymmetry of myelin in a large cohort of 108 typically developing children between 1 and 6 years of age, hypothesizing that asymmetry would predict language abilities in this cohort. While asymmetry of myelin content was evident in multiple cortical and subcortical regions, language ability was predicted only by leftward asymmetry of caudate and frontal cortex myelin content and rightward asymmetry in the extreme capsule. Importantly, the influence of this asymmetry was found to change with age, suggesting an age-specific influence of structure and myelin on language function. The relationship between language ability and asymmetry of myelin stabilized at ∼4 years, indicating anatomical evidence for a critical time during development before which environmental influence on cognition may be greatest.

Gene-environment interaction of ApoE genotype and combat exposure on PTSD.

Factors determining who develops PTSD following trauma are not well understood. The €4 allele of the apolipoprotein E (apoE) gene is associated with dementia and unfavorable outcome following brain insult. PTSD is also associated with dementia. Given evidence that psychological trauma adversely affects the brain, we hypothesized that the apoE genotype moderates effects of psychological trauma on PTSD pathogenesis. To investigate the moderation of the relationship between PTSD symptoms and combat exposure, we used 172 participants with combat trauma sustained during the Vietnam War. PTSD symptoms were the dependent variable and number of combat experiences, apoE genotype, and the combat experiences × apoE genotype interaction were predictors. We also examined the outcome of a diagnosis of PTSD (n = 39) versus no PTSD diagnosis (n = 131). The combat × apoE genotype interaction was significant for both PTSD symptoms (P = .014) and PTSD diagnosis (P = .009). ApoE genotype moderates the relationship between combat exposure and PTSD symptoms. Although the pathophysiology of PTSD is not well understood, the €4 allele is related to reduced resilience of the brain to insult. Our results are consistent with the €4 allele influencing the effects of psychological trauma on the brain, thereby affecting the risk of PTSD.

Left atrial size is independently associated with cognitive function.

Left atrial (LA) diameter is easily attainable from echocardiograph and sensitive to underlying cardiovascular disease severity, although its association with neurocognitive outcomes is not well understood. Fifty older adults (64.50 ± 9.41 years), recruited from outpatient cardiology clinics and local papers who underwent magnetic resonance imaging, were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and completed psychosocial self-report measures. LA diameter was quantified using echocardiogram. Hierarchical regression analyses revealed that greater LA size was independently associated with reduced performance on the following RBANS composites: language, delayed memory, and total index (p < 0.05 for all). Hierarchical regression analysis demonstrated no significant association between LA diameter and whole brain volume (p > 0.05). The current study suggests that greater LA size is associated with cognitive dysfunction in older adults and prospective studies are needed to validate these findings and elucidate underlying mechanisms.

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping.

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or 'disconnectivity') arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the 'normative' developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T(1)) and transverse (T(2)) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T(1), T(2) and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T(1), T(2) and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.

Effects of HIV and early life stress on amygdala morphometry and neurocognitive function.

Both HIV infection and high levels of early life stress (ELS) have been related to abnormalities in frontal-subcortical structures, yet the combined effects of HIV and ELS on brain structure and function have not been previously investigated. In this study we assessed 49 non-demented HIV-seropositive (HIV+) and 47 age-matched HIV-seronegative healthy control (HC) adults. Levels of ELS exposure were quantified and used to define four HIV-ELS groups: HC Low-ELS (N = 20); HC High-ELS (N = 27); HIV+ Low-ELS (N = 24); HIV+ High-ELS (N = 25). An automated segmentation tool measured volumes of brain structures known to show HIV-related or ELS-related effects; a brief neurocognitive battery was administered. A significant HIV-ELS interaction was observed for amygdala volumes, which was driven by enlargements in HIV+ High-ELS participants. The HIV+ High-ELS group also demonstrated significant reductions in psychomotor/processing speed compared with HC Low-ELS. Regression analyses in the HIV+ group revealed that amygdala enlargements were associated with higher ELS, lower nadir CD4 counts, and reduced psychomotor/processing speed. Our results suggest that HIV infection and high ELS interact to increase amygdala volume, which is associated with neurocognitive dysfunction in HIV+ patients. These findings highlight the lasting neuropathological influence of ELS and suggest that high ELS may be a significant risk factor for neurocognitive impairment in HIV-infected individuals.

Cerebral atrophy, apolipoprotein E varepsilon4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment.

BACKGROUND: Patients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E (APOE) genotype are associated with the rate of functional decline in MCI. METHODS: Participants were 164 healthy controls, 258 MCI patients, and 103 patients with mild Alzheimer's disease (AD), enrolled in the Alzheimer's Disease Neuroimaging Initiative. They underwent brain MRI scans, APOE genotyping, and completed up to six biannual Functional Activities Questionnaire (FAQ) assessments. Random effects regressions were used to examine trajectories of decline in FAQ across diagnostic groups, and to test the effects of ventricle-to-brain ratio (VBR) and APOE genotype on FAQ decline among MCI patients. RESULTS: Rate of decline in FAQ among MCI patients was intermediate between that of controls and mild AD patients. Patients with MCI who converted to mild AD declined faster than those who remained stable. Among MCI patients, increased VBR and possession of any APOE varepsilon4 allele were associated with faster rate of decline in FAQ. In addition, there was a significant VBR by APOE varepsilon4 interaction such that patients who were APOE varepsilon4 positive and had increased atrophy experienced the fastest decline in FAQ. CONCLUSIONS: Functional decline occurs in MCI, particularly among patients who progress to mild AD. Brain atrophy and APOE varepsilon4 positivity are associated with such declines, and patients who have elevated brain atrophy and are APOE varepsilon4 positive are at greatest risk of functional degradation. These findings highlight the value of genetic and volumetric MRI information as predictors of functional decline, and thus disease progression, in MCI.

Marriage and Divorce: A genetic perspective.

Marriage is considered one of the most important sources of social support that an individual receives as an adult. Although hypotheses have been formulated as to why individuals may dissolve a marriage, the determinants of marital success or failure are still relatively unknown. Behavioral geneticists have found that both marriage and divorce are, in part, genetically influenced. The goal of this research was to determine the degree of shared genetic and environmental variance between the two marital statuses. Participants were 6,225 twin pairs from the Vietnam Era Twin Registry. Data were obtained on marital history, and if the individual was no longer married, how the marriage ended. Univariate analyses were performed to determine the extent of genetic and environmental influences each of the marital statues (i.e., marriage and divorce), followed by a novel bivariate analysis to test the shared variance between marriage and divorce. Results from this analysis revealed that the two different marital statuses were influenced by entirely distinct genetic and environmental factors.

Effects of nicotine withdrawal on verbal working memory and associated brain response.

Previous literature has reported effects of nicotine withdrawal on brain function during cognitive tasks such as verbal working memory (VWM). Mechanisms of these withdrawal effects have not been clearly identified. Functional neuroimaging offers an objective method to examine brain mechanisms associated with observable behavior and subjective reports. To investigate these mechanisms, 12 smokers were administered a 2-Back VWM challenge during two functional magnetic resonance imaging sessions. Participants abstained from smoking prior to both sessions; however, they applied a nicotine patch before one session and a placebo patch prior to the other. Among regions that exhibited a significant response to the 2-Back during either session, withdrawal was associated with significantly greater deactivation in left and right temporal poles and left medial frontal gyrus. The magnitude of task-related activation showed a significant inverse relationship to craving in the majority of regions during placebo administration. Also, individual brain responses varied more during placebo, suggesting inefficient neural processing. Results suggest that differences in brain response to a VWM challenge during abstinence may be attributed to increased craving. Further deactivation of regions associated with the default network (medial frontal and anterior temporal clusters) during the placebo condition suggests further suspension of default activity, possibly to compensate for inefficient neural processing.