Functional connectivity between ventral prefrontal cortex and amygdala at low frequency in the resting state in bipolar disorder.

Trait abnormalities in bipolar disorder (BD) within the ventral prefrontal cortex (vPFC) and the amygdala suggest dysfunction in their connectivity. This study employed low frequency resting state functional magnetic resonance imaging (LFRS-fMRI) to analyze functional connectivity between the vPFC and the amygdala in BD. LFRS-fMRI identified a negative correlation in vPFC-amygdala activity, and the magnitude of this correlation was greater in healthy participants than in subjects with BD. Additionally, whole-brain analysis revealed higher correlations between left and right vPFC in BD, as well as with ventral striatum.

Age-related cognitive gains are mediated by the effects of white matter development on brain network integration.

A fundamental, yet rarely tested premise of developmental cognitive neuroscience is that changes in brain activity and improvements in behavioral control across adolescent development are related to brain maturational factors that shape a more efficient, highly-interconnected brain in adulthood. We present the first multimodal neuroimaging study to empirically demonstrate that maturation of executive cognitive ability is directly associated with the relationship of white matter development and age-related changes in neural network functional integration. In this study, we identified specific white matter regions whose maturation across adolescence appears to reduce reliance on local processing in brain regions recruited for conscious, deliberate cognitive control in favor of a more widely distributed profile of functionally-integrated brain activity. Greater white matter coherence with age was associated with both increases and decreases in functional connectivity within task-engaged functional circuits. Importantly, these associations between white matter development and brain system functional integration were related to behavioral performance on tests of response inhibition, demonstrating their importance in the maturation of optimal cognitive control.

Effects of alcohol on performance on a distraction task during simulated driving.

BACKGROUND: Prior studies report that accidents involving intoxicated drivers are more likely to occur during performance of secondary tasks. We studied this phenomenon, using a dual-task paradigm, involving performance of a visual oddball (VO) task while driving in an alcohol challenge paradigm. Previous functional MRI (fMRI) studies of the VO task have shown activation in the anterior cingulate, hippocampus, and prefrontal cortex. Thus, we predicted dose-dependent decreases in activation of these areas during VO performance. METHODS: Forty healthy social drinkers were administered 3 different doses of alcohol, individually tailored to their gender and weight. Participants performed a VO task while operating a virtual reality driving simulator in a 3T fMRI scanner. RESULTS: Analysis showed a dose-dependent linear decrease in Blood Oxygen Level Dependent activation during task performance, primarily in hippocampus, anterior cingulate, and dorsolateral prefrontal areas, with the least activation occurring during the high dose. Behavioral analysis showed a dose-dependent linear increase in reaction time, with no effects associated with either correct hits or false alarms. In all dose conditions, driving speed decreased significantly after a VO stimulus. However, at the high dose this decrease was significantly less. Passenger-side line crossings significantly increased at the high dose. CONCLUSIONS: These results suggest that driving impairment during secondary task performance may be associated with alcohol-related effects on the above brain regions, which are involved with attentional processing/decision-making. Drivers with high blood alcohol concentrations may be less able to orient or detect novel or sudden stimuli during driving.

BOLD activity during mental rotation and viewpoint-dependent object recognition.

We measured brain activity during mental rotation and object recognition with objects rotated around three different axes. Activity in the superior parietal lobe (SPL) increased proportionally to viewpoint disparity during mental rotation, but not during object recognition. In contrast, the fusiform gyrus was preferentially recruited in a viewpoint-dependent manner in recognition as compared to mental rotation. In addition, independent of the effect of viewpoint, object recognition was associated with ventral areas and mental rotation with dorsal areas. These results indicate that the similar behavioral effects of viewpoint obtained in these two tasks are based on different neural substrates. Such findings call into question the hypothesis that mental rotation is used to compensate for changes in viewpoint during object recognition.

Measuring brain connectivity: diffusion tensor imaging validates resting state temporal correlations.

Diffusion tensor imaging (DTI) and resting state temporal correlations (RSTC) are two leading techniques for investigating the connectivity of the human brain. They have been widely used to investigate the strength of anatomical and functional connections between distant brain regions in healthy subjects, and in clinical populations. Though they are both based on magnetic resonance imaging (MRI) they have not yet been compared directly. In this work both techniques were employed to create global connectivity matrices covering the whole brain gray matter. This allowed for direct comparisons between functional connectivity measured by RSTC with anatomical connectivity quantified using DTI tractography. We found that connectivity matrices obtained using both techniques showed significant agreement. Connectivity maps created for a priori defined anatomical regions showed significant correlation, and furthermore agreement was especially high in regions showing strong overall connectivity, such as those belonging to the default mode network. Direct comparison between functional RSTC and anatomical DTI connectivity, presented here for the first time, links two powerful approaches for investigating brain connectivity and shows their strong agreement. It provides a crucial multi-modal validation for resting state correlations as representing neuronal connectivity. The combination of both techniques presented here allows for further combining them to provide richer representation of brain connectivity both in the healthy brain and in clinical conditions.

Brain connectivity related to working memory performance.

Several brain areas show signal decreases during many different cognitive tasks in functional imaging studies, including the posterior cingulate cortex (PCC) and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex (MFG/vACC). It has been suggested that these areas are components in a default mode network that is engaged during rest and disengaged during cognitive tasks. This study investigated the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels between the regions. The two regions were functionally connected in both conditions. In addition, performance on the working memory task was positively correlated with the strength of this functional connection not only during the working memory task, but also at rest. Thus, it appears these regions are components of a network that may facilitate or monitor cognitive performance, rather than becoming disengaged during cognitive tasks. In addition, these data raise the possibility that the individual differences in coupling strength between these two regions at rest predict differences in cognitive abilities important for this working memory task.

A developmental fMRI study of self-regulatory control in Tourette's syndrome.

OBJECTIVE: Disturbances in the maturation of neural systems that mediate self-regulatory processes may contribute to the development of Tourette's syndrome by releasing motor and vocal tics from regulatory control. The purpose of this study was to examine the age correlates of functional activity in neural circuits that subserve self-regulatory control in children and adults with Tourette's syndrome. METHOD: The participants were 136 children and adults, which included 66 Tourette's syndrome patients and 70 healthy comparison subjects. During performance of the Stroop interference task, the authors compared the functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent response in patients with Tourette's syndrome with that of healthy comparison subjects. General linear modeling of Stroop-related activations was used to compare the differential effects of age and behavioral performance on changes in self-regulatory control between the two diagnostic groups. RESULTS: Although the correlations of age with behavioral performance on the Stroop task were similar between patients with Tourette's syndrome and healthy comparison subjects, the two groups differed significantly in their correlations of age with the magnitude of regional brain activation during the task. Interactions of age with diagnosis were detected in the ventral prefrontal (Brodmann's areas 10 and 24) and posterior cingulate cortices (Brodmann's area 31), and post hoc analyses indicated that subjects with Tourette's syndrome deactivated these regions less with advancing age. Greater activation of bilateral frontostriatal regions (Brodmann's areas 9/46, 45/46; lenticular nucleus; and thalamus) accompanied poorer performance in the patient group, which-in the presence of normal behavioral performance on the Stroop task-suggests that greater activation of the frontostriatal systems helps to maintain task performance in individuals with Tourette's syndrome. CONCLUSIONS: Normative developmental correlates of activity in frontostriatal circuits that subserve self-regulatory control are disturbed in persons with Tourette's syndrome. These aberrant developmental correlates are likely a consequence of greater anatomical and functional disturbances in these circuits in adults with Tourette's syndrome, which leads to impaired regulation of tic behaviors. Reduced default-mode processing in ventral prefrontal and posterior cingulate cortices in adults with Tourette's syndrome suggests the presence of greater difficulty in engaging mental processes that become active when freed from the demands of more challenging cognitive tasks. However, individuals with Tourette's syndrome appear to co-opt normal developmental processes in circuits that subserve age-related improvement in self-regulatory control while presumably struggling to maintain adequate task performance.

Cue-induced brain activity changes and relapse in cocaine-dependent patients.

This study used functional magnetic resonance imaging (fMRI) to examine the association between brain activation during exposure to cocaine-related cues and relapse to drug use in cocaine-dependent (CD) patients. We imaged 17 CD subjects during a 2-week in-patient stay. The subjects then entered a 10-week outpatient placebo-controlled, double-blind randomized clinical trial where urine toxicologies were assessed three times weekly to calculate the treatment effectiveness score (TES). Worse TES correlated with BOLD activation in the left precentral, superior temporal, and posterior cingulate cortices (PCC), and right middle temporal and lingual cortices (R>0.65; P<0.005). The left PCC activation also distinguished eight nonrelapsers (TES above mean and completed treatment) from nine relapsers. Cocaine-free urines were significantly greater in the nonrelapsers (92%) than in the relapsers (66%), who also remained in treatment for an average of only 3.2 weeks. Self-reports of craving during fMRI did not differ between nonrelapsers and relapsers and did not correlate with TES. Relapse to cocaine abuse was associated with increased activation in the sensory association cortex, the motor cortex, and PCC while viewing images of cocaine-related cues. These results suggest that relapse to cocaine abuse is associated with increased brain activation to cocaine cues in sensory, motor, and cognitive-emotional processing areas. This physiological activation was a better predictor of relapse than subjective reports of craving, and may be a useful target for treatment development.

fMRI activation of the fusiform gyrus and amygdala to cartoon characters but not to faces in a boy with autism.

Abnormal hypoactivation in the amygdala and fusiform gyrus, brain areas that participate in face processing and social cognition, has consistently been demonstrated in persons with autism. We investigated activity in these areas in a boy with autism, DD, who had a special interest in "Digimon" cartoon characters. DD individuates Digimon faster than familiar faces and objects, but he individuates familiar faces no faster than objects. In contrast, a typically developing boy with an interest in "Pokemon" cartoon characters is equally fast at individuating faces and Pokemon and faster at individuating faces and Pokemon than objects and Digimon. In addition, using functional magnetic resonance imaging (fMRI), we show that DD activates his amygdala and fusiform gyrus for perceptual discriminations involving Digimon but not for those involving familiar or unfamiliar faces. This pattern of activation is not seen in the typically developing control with an interest in Pokemon or in a second comparison case who has autism but no interest in Digimon. These results have important implications for our understanding of autism, cortical face specialization, and the possible role of the amygdala in the development of perceptual expertise.

Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study.

OBJECTIVE: Stress is known to increase cocaine craving and relapse risk in cocaine dependence. Identifying neural activity associated with stress and stress-induced cocaine craving is important in understanding the neurobiology of cocaine craving and relapse. METHOD: Blood oxygenation level dependent (BOLD) signal changes were assessed in a functional magnetic resonance imaging (fMRI) session with healthy controls and treatment-engaged, abstinent, cocaine-dependent individuals (patients) as they participated in brief guided imagery and recall of three personal stress and three personal neutral situations. RESULTS: During stress, patients showed significantly less BOLD activation than controls in specific frontal and para-limbic regions, such as the anterior cingulate (AC) region, left hippocampal/parahippocampal region, right fusiform gyrus, and the right postcentral gyrus. On the other hand, patients had increased activity in the caudate and dorsal striatum region during stress, activation that was significantly associated with stress-induced cocaine craving ratings. CONCLUSIONS: Patients failed to activate AC and related circuits during stress, regions associated with control, and regulation of emotion and distress states. Instead, they exhibited greater craving-related activation in the dorsal striatum, a region related to reward pathways and part of the obsessive-compulsive circuitry. Such functional alterations in stress processing may underlie the stress-related vulnerability to cocaine relapse often observed in cocaine-dependent individuals in early recovery.

Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorder.

RATIONALE: Abnormal amygdala and frontocortical responses to emotional stimuli are implicated in bipolar disorder (BD) and have been proposed as potential treatment targets. OBJECTIVES: The aim of this study was to investigate amygdala and frontocortical responses to emotional face stimuli in BD and the influences of mood-stabilizing medications on these responses. METHODS: Functional magnetic resonance imaging was performed while 17 BD participants (5 unmedicated) and 17 healthy comparison (HC) participants viewed faces with happy, sad, fearful, or neutral expressions. RESULTS: The group by stimulus-condition interaction was significant (p<0.01) for amygdala activation, with the greatest effects in the happy face condition. Relative to HC, amygdala increases were greater in unmedicated BD, but lower in medicated BD. Rostral anterior cingulate (rAC) activation was decreased in unmedicated BD compared to HC; however, BD participants taking medication demonstrated rAC activation similar to HC participants. CONCLUSIONS: Although the sample sizes were small, these preliminary results suggest that BD is associated with increased amygdala and decreased rAC response to emotional faces. The findings also provide preliminary evidence that mood-stabilizing medications may reverse abnormalities in BD in the response of an amygdala-frontal neural system to emotional stimuli.

Gambling urges in pathological gambling: a functional magnetic resonance imaging study.

BACKGROUND: Gambling urges in pathological gambling (PG) often immediately precede engagement in self-destructive gambling behavior. An improved understanding of the neural correlates of gambling urges in PG would advance our understanding of the brain mechanisms underlying PG and would help direct research into effective treatments. METHODS: Echoplanar functional magnetic resonance imaging was used to assess brain function during viewing of videotaped scenarios with gambling, happy, or sad content. Participants rated the quality and magnitude of their emotional and motivational responses. RESULTS: Men with PG (n = 10) reported mean +/- SD greater gambling urges after viewing gambling scenarios vs control subjects (n = 11) (5.20 +/- 3.43 vs 0.32 +/- 0.60; chi21,19 = 21.71; P<.001). The groups did not differ significantly in their subjective responses to the happy (P =.56) or sad (P =.81) videotapes. The most pronounced between-group differences in neural activities were observed during the initial period of viewing of the gambling scenarios: PG subjects displayed relatively decreased activity in frontal and orbitofrontal cortex, caudate/basal ganglia, and thalamus compared with controls. Distinct patterns of regional brain activity were observed in specific temporal epochs of videotape viewing. For example, differences localized to the ventral anterior cingulate during the final period of gambling videotape viewing, corresponding to the presentation of the most provocative gambling stimuli. Although group differences in brain activity were observed during viewing of the sad and happy scenarios, they were distinct from those corresponding to the gambling scenarios. CONCLUSIONS: In men with PG, gambling cue presentation elicits gambling urges and leads to a temporally dynamic pattern of brain activity changes in frontal, paralimbic, and limbic brain structures. When viewing gambling cues, PG subjects demonstrate relatively decreased activity in brain regions implicated in impulse regulation compared with controls.

A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices.

BACKGROUND: Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. METHODS: Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. RESULTS: Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005). CONCLUSIONS: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.

Multimodal imaging in Alzheimer's disease: validity and usefulness for early detection.

Alzheimer's disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimer's disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimer's disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimer's disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.

Nicotine effects on brain function and functional connectivity in schizophrenia.

BACKGROUND: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity. METHODS: Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning twice, once after placement of a placebo patch and once after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load. RESULTS: During the most difficult (dichotic 2-back) task condition, nicotine improved performance of schizophrenic subjects and worsened performance of control subjects. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance. CONCLUSIONS: In tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance.

Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation.

BACKGROUND: Disturbed interpersonal relations and emotional dysregulation are fundamental aspects of borderline personality disorder (BPD). The amygdala plays important roles in modulating vigilance and generating negative emotional states and is often abnormally reactive in disorders of mood and emotion. The aim of this study was to assess amygdala reactivity in BPD patients relative to normal control subjects. We hypothesized that amygdala hyperreactivity contributes to hypervigilance, emotional dysregulation, and disturbed interpersonal relations in BPD. METHODS: Using functional magnetic resonance imaging, we examined neural responses to 20-sec blocks of neutral, happy, sad, and fearful facial expression (or a fixation point) in 15 BPD and 15 normal control subjects. The DSM IV-diagnosed BPD patients and the normal control subjects were assessed by a clinical research team in a medical school psychiatry department. RESULTS: Borderline patients showed significantly greater left amygdala activation to the facial expressions of emotion (vs. a fixation point) compared with normal control subjects. Post-scan debriefing revealed that some borderline patients had difficulty disambiguating neutral faces or found them threatening. CONCLUSIONS: Pictures of human emotional expressions elicit robust differences in amygdala activation levels in borderline patients, compared with normal control subjects, and can be used as probes to study the neuropathophysiologic basis of borderline personality disorder.

Disruption of posterior brain systems for reading in children with developmental dyslexia.

BACKGROUND: Converging evidence indicates a functional disruption in the neural systems for reading in adults with dyslexia. We examined brain activation patterns in dyslexic and nonimpaired children during pseudoword and real-word reading tasks that required phonologic analysis (i.e., tapped the problems experienced by dyslexic children in sounding out words). METHODS: We used functional magnetic resonance imaging (fMRI) to study 144 right-handed children, 70 dyslexic readers, and 74 nonimpaired readers as they read pseudowords and real words. RESULTS: Children with dyslexia demonstrated a disruption in neural systems for reading involving posterior brain regions, including parietotemporal sites and sites in the occipitotemporal area. Reading skill was positively correlated with the magnitude of activation in the left occipitotemporal region. Activation in the left and right inferior frontal gyri was greater in older compared with younger dyslexic children. CONCLUSIONS: These findings provide neurobiological evidence of an underlying disruption in the neural systems for reading in children with dyslexia and indicate that it is evident at a young age. The locus of the disruption places childhood dyslexia within the same neurobiological framework as dyslexia, and acquired alexia, occurring in adults.

Neural systems for compensation and persistence: young adult outcome of childhood reading disability.

BACKGROUND: This study examined whether and how two groups of young adults who were poor readers as children (a relatively compensated group and a group with persistent reading difficulties) differed from nonimpaired readers and if there were any factors distinguishing the compensated from persistently poor readers that might account for their different outcomes. METHODS: Using functional magnetic resonance imaging, we studied three groups of young adults, ages 18.5-22.5 years, as they read pseudowords and real words: 1) persistently poor readers (PPR; n = 24); 2) accuracy improved (compensated) readers (AIR; n = 19); and 3) nonimpaired readers (NI, n = 27). RESULTS: Compensated readers, who are accurate but not fluent, demonstrate a relative underactivation in posterior neural systems for reading located in left parietotemporal and occipitotemporal regions. Persistently poor readers, who are both not fluent and less accurate, activate posterior reading systems but engage them differently from nonimpaired readers, appearing to rely more on memory-based rather than analytic word identification strategies. CONCLUSIONS: These findings of divergent neural outcomes as young adults are both new and unexpected and suggest a neural basis for reading outcomes of compensation and persistence in adults with childhood dyslexia.

An FMRI Stroop task study of ventromedial prefrontal cortical function in pathological gamblers.

OBJECTIVE: Function of the ventromedial prefrontal cortex has been implicated in impulse control. The authors used the Stroop paradigm to test attention and response inhibition during the presentation of congruent and incongruent stimuli in male pathological gamblers and a group of comparison subjects. METHOD: Event-related functional magnetic resonance imaging was used to examine ventromedial prefrontal cortex function during Stroop performance. RESULTS: In response to infrequent incongruent stimuli, pathological gamblers demonstrated decreased activity in the left ventromedial prefrontal cortex relative to the comparison subjects. Both groups demonstrated similar activity changes in multiple brain regions, including activation of the dorsal anterior cingulate and dorsolateral frontal cortex. CONCLUSIONS: Pathological gamblers share many neural correlates of Stroop task performance with healthy subjects but differ in a brain region previously implicated in disorders characterized by poor impulse control.

Frontostriatal abnormalities in adolescents with bipolar disorder: preliminary observations from functional MRI.

OBJECTIVE: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. METHOD: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. RESULTS: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. CONCLUSIONS: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence.