Prefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder.

OBJECTIVES: Although generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, very little is known about the neurobiology of worry, the hallmark symptom of GAD in adults over the age of 60. This study investigated the neurobiology and neural circuitry of worry in older GAD patients and controls. METHOD: Twenty older GAD patients and 16 age-matched controls (mean age = 67.88) were compared on clinical measures and neural activity during worry using functional magnetic resonance imaging. RESULTS: As expected, worry elicited activation in frontal regions, amygdala, and insula within the GAD group, with a similar but less prominent frontal pattern was observed in controls. Effective connectivity analyses revealed a positive directional circuit in the GAD group extending from ventromedial through dorsolateral prefrontal cortices, converging on the amygdala. A less complex circuit was observed in controls with only dorsolateral prefrontal regions converging on the amygdala; however, a separate circuit passing through the orbitofrontal cortex converged on the insula. CONCLUSION: Results elucidate a different neurobiology of pathological versus normal worry in later life. A limited resource model is implicated wherein worry in GAD competes for the same neural resources (e.g. prefrontal cortical areas) that are involved in the adaptive regulation of emotion through cognitive and behavioral strategies.

Predictors of unsuccessful magnetic resonance imaging scanning in older generalized anxiety disorder patients and controls.

A thorough understanding of the neurobiology of late life anxiety is likely to depend on the use of brain imaging techniques such as magnetic resonance imaging (MRI). Generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, and is thus a focus for neurobiological studies using MRI. This study tested 1-3 weeks predictors of unsuccessful scan outcomes (i.e., scan trials in which the participant moved excessively or prematurely terminated the scan) in older adults with GAD (n = 39) and age- and sex-matched nonanxious controls (n = 21). It was hypothesized that successful completion of a prior MRI scan, clinical status (GAD versus control), and scores on the Anxiety Sensitivity Index (ASI; Peterson et al. 1986), a measure tapping psychological aspects of medical interventions, would predict scan outcome when current diagnoses of claustrophobia were controlled. In logistic regression analyses, unsuccessful scan outcome was predicted by prior MRI completion and ASI Mental Concerns subscale scores, but not clinical status. This model correctly classified 91% of successful and 71% of unsuccessful scans. An alternative model that included a single ASI item rather than Mental Concerns subscale scores showed similar performance, and a model including categorical anxiety sensitivity groups was also effective but slightly less accurate. Implications for improving the success rates of MRI with older adults are discussed.

Task-dependent individual differences in prefrontal connectivity.

Recent advances in neuroimaging have permitted testing of hypotheses regarding the neural bases of individual differences, but this burgeoning literature has been characterized by inconsistent results. To test the hypothesis that differences in task demands could contribute to between-study variability in brain-behavior relationships, we had participants perform 2 tasks that varied in the extent of cognitive involvement. We examined connectivity between brain regions during a low-demand vigilance task and a higher-demand digit-symbol visual search task using Granger causality analysis (GCA). Our results showed 1) Significant differences in numbers of frontoparietal connections between low- and high-demand tasks 2) that GCA can detect activity changes that correspond with task-demand changes, and 3) faster participants showed more vigilance-related activity than slower participants, but less visual-search activity. These results suggest that relatively low-demand cognitive performance depends on spontaneous bidirectionally fluctuating network activity, whereas high-demand performance depends on a limited, unidirectional network. The nature of brain-behavior relationships may vary depending on the extent of cognitive demand. High-demand network activity may reflect the extent to which individuals require top-down executive guidance of behavior for successful task performance. Low-demand network activity may reflect task- and performance monitoring that minimizes executive requirements for guidance of behavior.

The relation of worry to prefrontal cortex volume in older adults with and without generalized anxiety disorder.

Despite the widespread prevalence of generalized anxiety disorder (GAD) in later life, almost nothing is known about the neural aspects of worry in adults over the age of 60. Given the ongoing rapid increase in the older adult population, the relatively poor response rates to current interventions for late life GAD, and the effects of age-related changes to the brain, additional research on worry neurobiology is needed. The study group comprised 15 older GAD patients and 15 matched controls who were compared on clinical measures and brain volumes. It was expected that prefrontal cortex (PFC) volumes [medial orbital cortex (mOFC), dorsolateral cortex (DLPFC)] would show positive relations to worry scores, and weaker relations to more general measures of anxiety and depression. Negative relations were expected between amygdala volumes and worry scores. As expected, mOFC volumes were positively related to worry scores; however, DLPFC and amygdala volumes were not. The mOFC is involved in emotional decision-making under uncertain conditions and has the ability to suppress the amygdala, both of which are hypothesized functions of worry. Results are partly consistent with GAD theory and suggest that worry may involve neural areas that are also involved in the successful control of anxiety.

Age-related differences in activation-performance relations in delayed-response tasks: a multiple component analysis.

We used event-related functional magnetic resonance imaging (fMRI) to measure prefrontal cortex (PFC) activity while younger and older adults performed an item-recognition task in which the memory-set size varied between 1 and 8 letters. Each trial was composed of a 4-sec encoding period in which subjects viewed random letter strings, a 12-sec retention period and a 2-sec retrieval period in which subjects decided whether a single probe letter was or was not part of the memory set. For both groups, reaction-time (RT) increased and accuracy decreased with increasing memory set-size. Analyses of individual subjects' performance and cortical activity indicated that speed and accuracy accounted for variance in different task periods in dorsal and ventral PFC. Age-related differences in accuracy-activation relations were observed in dorsal PFC during encoding and ventral PFC during maintenance. Age-related differences in RT-activation relations were observed in dorsal PFC during retrieval. These results and additional fMRI data we have collected during performance of a speeded processing task, directly support a model of cognitive slowing in which processing rate is related to neural efficiency.

Evidence for multiple manipulation processes in prefrontal cortex.

The prefrontal cortex (PFC) is known to subserve working memory (WM) processes. Brain imaging studies of WM using delayed response tasks (DRTs) have shown memory-load-dependent activation increases in dorsal prefrontal cortex (PFC) regions. These activation increases are believed to reflect manipulation of to-be-remembered information in the service of memory-consolidation. This speculation has been based on observations of similar activation increases in tasks that overtly require manipulation by instructing participants to reorder to-be-remembered list items. In this study, we tested the assumption of functional equivalence between these two types of WM tasks. Participants performed a DRT under two conditions with memory loads ranging from 3 to 6 letters. In an "item-order" condition, participants were required to remember letters in the order in which they were presented. In a "reordering" condition, participants were required to remember the letters in alphabetical order. Load-related activation increases were observed during the encoding and maintenance periods of the order maintenance condition, whereas load-related activation decreases were observed in the same periods of the reordering condition. These results suggest that (1) the neural substrates associated with long-list retention and those associated with reordering are not equivalent, (2) cognitive processes associated with long-list retention may be more closely approximated by item-order maintenance than by reordering, and (3) multiple forms of WM manipulation are dissociable on the basis of fMRI data.

Altered brain tissue composition in heavy marijuana users.

Marijuana is the most widely used illicit substance in the United States; however, previous imaging studies have not detected altered brain structure in marijuana users compared to non-users. Voxel-based morphometry was used to investigate possible differences in brain tissue composition in a group of 11 heavy marijuana users and a group of 8 non-users. All participants were male. Statistical comparisons were made at the voxel level on T1-weighted magnetic resonance images to determine differences in gray matter and white matter tissue density. Compared to non-users, marijuana users had lower gray matter density in a cluster of voxels in the right parahippocampal gyrus (P = 0.0001), and greater density bilaterally near the precentral gyrus and the right thalamus (P < 0.04). Marijuana users also had lower white matter density in the left parietal lobe (P = 0.03), and higher density around the parahippocampal and fusiform gyri on the left side compared to non-users (P < 0.002). Longer duration of marijuana use (in years) was significantly correlated with higher white matter tissue density in the left precentral gyrus (P = 0.045). Our preliminary results suggest evidence of possible structural differences in the brain of heavy marijuana users, and localize regions for further investigation of the effects of marijuana in the brain.

Neural substrates of faulty decision-making in abstinent marijuana users.

Persistent dose-related cognitive decrements have been reported in 28-day abstinent heavy marijuana (MJ) users. However, the neural substrates of these decrements in cognitive performance are not known. This study aimed to determine if 25-day abstinent MJ users show persistent dose-related alterations in performance and brain activity using PET H(2)(15)O during the Iowa Gambling Task-IGT (a decision-making task). Eleven heavy MJ users and 11 non-drug users participated. The MJ group resided in an inpatient research unit at the NIH/NIDA-IRP for 25 days prior to testing to ensure abstinence. A dose-related association was found between increased MJ use and lower IGT performance and alterations in brain activity. The MJ group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex (OFC) and the right dorsolateral prefrontal cortex (DLPFC) than the Control group. When the MJ group was divided into Moderate (8-35 joints/week) and Heavy users (53-84 joints/week), the Heavy MJ group showed less activation in the left medial OFC and greater activation in the left cerebellum than the Moderate group. However, brain activity and task performance were similar between the Moderate MJ users and the Control group, suggesting a "threshold effect". These preliminary findings indicate that very heavy users of MJ have persistent decision-making deficits and alterations in brain activity. Specifically, the Heavy MJ users may focus on only the immediate reinforcing aspects of a situation (i.e., getting high) while ignoring the negative consequences. Thus, faulty decision-making could make an individual more prone to addictive behavior and more resistant to treatment. Finally, it is unclear if these neurologic findings will become progressively worse with continued heavy MJ use or if they will resolve with abstinence from MJ use.

Abnormal brain activity in prefrontal brain regions in abstinent marijuana users.

We used PET (15)O and a modified version of the Stroop task to determine if 25-day abstinent heavy marijuana (MJ) users have persistent deficits in executive cognitive functioning (ECF) and brain activity. Performance on a modified version of the Stroop task and brain activity was compared between 25-day abstinent, heavy marijuana users (n = 11), and a matched comparison group (n = 11). The 25-day abstinent marijuana users showed no deficits in performance on the modified version of the Stroop task when compared to the comparison group. Despite the lack of performance differences, the marijuana users showed hypoactivity in the left perigenual anterior cingulate cortex (ACC) and the left lateral prefrontal cortex (LPFC) and hyperactivity in the hippocampus bilaterally, when compared to the comparison group. These results suggest that marijuana users display persistent metabolic alterations in brain regions responsible for ECF. It may be that marijuana users recruit an alternative neural network as a compensatory mechanism during performance on a modified version of the Stroop task. These differences in brain activity may be a common denominator in the evolution of maladaptive behaviors such as substance abuse and other neuropsychiatric disorders.

Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study.

Cocaine abusers exhibit impairment of executive cognitive functions that are mediated by the frontal cortex. This work tested for structural (i.e., tissue composition) abnormalities that may underlie such performance deficits. Research participants were cocaine abusers (n = 14) abstinent for 20 days and a non-drug-using comparison group (n = 11), who underwent magnetic resonance imaging (T1-weighted scans of the brain). Gray matter and white matter tissue densities were determined using voxel-based morphometry with small volume correction based on a priori hypotheses derived from functional imaging of the same subjects. Cocaine abusers had significantly lower gray matter tissue density than did the non drug users in 10 of 13 small volumes analyzed in the frontal cortex [bilateral anterior cingulate gyrus (infragenual and perigenual regions) and medial orbitofrontal cortex and the lateral orbitofrontal cortex and middle/dorsal cingulate gyrus in the right hemisphere]. No group differences were found in white matter density of the frontal cortex. These results extend our previous findings of defective frontal cortical activation (indexed by cerebral blood flow) in cocaine abusers to include abnormalities in gray matter tissue density in the same frontal cortical regions.