Cortico-cerebellar abnormalities in adolescents with heavy marijuana use.

There are currently no studies that have evaluated the motor network, including the cerebellum, in adolescent marijuana (MJ) smokers. The current study aimed to evaluate whether there were activation differences in Brodmann's area 4 (BA4), Brodmann's area 6 (BA6), cingulate (CG) and cerebellum between MJ-using adolescents and healthy controls (HC) on a functional magnetic resonance imaging (fMRI) bilateral finger-tapping task. Twenty-four adolescents (aged 18.2 ± 0.7 years) with heavy MJ use and 24 HC (18.0 ± 1.9) had MRI scans on a 3T Siemens scanner, including a standard bilateral fMRI finger-tapping sequence. Imaging data were analyzed using SPM5 in Matlab. As regions of interest, BA4, BA6, cingulate (CG) and cerebellum were selected, and significant clusters of activity were thresholded at p<0.05, corrected. Healthy controls had significantly greater activation than MJ users for the CG and cerebellum. In addition, activation of the cerebellum and CG correlated with lifetime MJ smokes. This is one of the first studies to evaluate cortico-cerebellar circuits in adolescents with heavy MJ use. The study, which used a bilateral finger-tapping fMRI task, provides evidence for both CG and cerebellar dysfunction in MJ abuse and indicates that lifetime MJ use may impact the developing brain.

Adolescents at risk for alcohol abuse demonstrate altered frontal lobe activation during Stroop performance.

BACKGROUND: Children and adolescents, family history positive (FH+) for alcoholism, exhibit differences in brain structure and functional activation when compared to family history negative (FH-) counterparts. Given that frontal brain regions, and associated reciprocal connections with limbic structures, undergo the most dramatic maturational changes during adolescence, the objective of this study was to compare functional brain activation during a frontally mediated test of response inhibition in 32 adolescents separated into low-risk (FH-) and high-risk (FH+) groups. METHODS: Functional magnetic resonance (fMRI) blood oxygen level-dependent data were acquired at 1.5 Tesla during performance of Stroop Color Naming, Word Reading, and Interference. Preprocessing and statistical analyses, covaried for age, were conducted in SPM99 using a search territory that included superior, middle, and inferior frontal gyri (trigone region), anterior cingulate gyrus (CG), and left and right amygdala. RESULTS: Significantly greater activation in the fronto-limbic search territory was observed in FH+ relative to FH- subjects during Stroop Interference. In addition, a significant regression between brain activation and family history density was observed, with a greater density being associated with increased activation in regions including middle frontal gyrus (BA9) and CG (BA24). CONCLUSIONS: These data demonstrate a significant influence of FH status on brain activation during the performance of a response inhibition task, perhaps reflecting a neurobiological vulnerability associated with FH status that may include reduced neuronal efficiency and/or recruitment of additional neuronal resources. These findings are important given that the adolescent developmental period is already associated with reduced inhibitory capacity, even prior to the onset of alcohol use.

A preliminary study of sex differences in brain activation during a spatial navigation task in healthy adults.

The hippocampus plays a significant role in spatial memory processing, with sex differences being prominent on various spatial tasks. This study examined sex differences in healthy adults, using functional magnetic resonance imaging (fMRI) in areas implicated in spatial processing during navigation of a virtual analogue of the Morris water-maze. There were three conditions: learning, hidden, and visible control. There were no significant differences in performance measures. However, sex differences were found in regional brain activation during learning in the right hippocampus, right parahippocampal gyrus, and the cingulate cortex. During the hidden condition, the hippocampus, parahippocampal gyrus, and cingulate cortex were activated in both men and women. Additional brain areas involved in spatial processing may be recruited in women when learning information about the environment, by utilizing external cues (landmarks) more than do men, contributing to the observed sex differences in brain activation.

The value of research on sexual dimorphism in neuroimaging.

Spets and Slotnick (in Press) applied activation likelihood estimation meta-analysis to examine sex differences in regional brain activation during long-term memory retrieval. Based on their analyses, each of the eight studies they analyzed showed greater activity for males than females during long-term memory retrieval. These results suggest that analyses of magnetic resonance imaging data should not be collapsed by sex and expand this discussion to the challenge of meta-analysis on studies with small to modest sample sizes in favor of larger imaging studies with more rigorous thresholds.

Functional connectivity of the anterior cingulate cortex in Veterans with mild traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is one of the most prevalent injuries in the military with mild traumatic brain injury (mTBI) accounting for approximately 70-80 % of all TBI. TBI has been associated with diffuse and focal brain changes to structures and networks underlying cognitive-emotional processing. Although the anterior cingulate cortex (ACC) plays a critical role in emotion regulation and executive function and is susceptible to mTBI, studies focusing on ACC resting state functional connectivity (rs-fc) in Veterans are limited. METHODS: Veterans with mTBI (n = 49) and with no history of TBI (n = 25), ages 20-54 completed clinical assessments and an 8-minute resting state functional magnetic resonance imaging (rs-fMRI) on a 3 T Siemens scanner. Imaging results were analyzed with left and right ACC as seed regions using SPM8. Regression analyses were performed with time since injury. RESULTS: Seed-based analysis showed increased connectivity of the left and right ACC with brain regions including middle and posterior cingulate regions, preceneus, and occipital regions in the mTBI compared to the non-TBI group. CONCLUSIONS: The rs-fMRI results indicate hyperconnectivity in Veterans with mTBI. These results are consistent with previous studies of recently concussed athletes showing ACC hyperconnectivity. Enhanced top-down control of attention networks necessary to compensate for the microstructural damage following mTBI may explain ACC hyperconnectivity post-mTBI.

Neurobiological evidence of sexual dimorphism in limbic circuitry of US Veterans.

BACKGROUND: Female Veterans are an increasing patient population in the Department of Veterans Affairs and may have distinct clinical and neurobiological features compared to males. METHODS: Nineteen female and 19 male Veterans who met diagnostic criteria for depression/posttraumatic stress disorder (MDD/PTSD) completed diagnostic interviews, symptom measures, and resting-state neuroimaging. Participants completed clinical measures of mood and aggression in addition to magnetic resonance imaging on a 3.0 Tesla Siemens scanner. RESULTS: Females showed increased functional connectivity between the left and right basolateral amygdala (BLA) and the left and right cerebellar and occipital lobes. Sex differences also were evident in the relationship between affective and clinical symptoms with BLA connectivity. Females showed a correlation between revenge planning and decreased connectivity between the left BLA and left occipital lobe and also a correlation between aggression and decreased connectivity between the right BLA and right mid cingulate, right and left medial frontal lobe, and right frontal lobe. Males evidenced a relationship between increased depressive symptoms and increased connectivity between the left BLA and right and left occipital lobe, left calcarine, and other areas associated with visual memory and processing, and interpretation of sensory information. Additionally, males reported higher levels of physical aggression and revenge planning compared to females. LIMITATIONS: This study included neuroimaging and self-report clinical measures. Further studies will benefit from multimodal measures, including behavioral measures of aggression. CONCLUSIONS: Results suggest that male Veterans report more aggression than females and symptoms of aggression and mood are differentially related to BLA connectivity by sex.

Cortico-limbic response to personally challenging emotional stimuli after complete recovery from depression.

People vulnerable to depression are at increased risk of relapse if they live in highly critical family environments. To explore this link, we used neuroimaging methods to examine cortico-limbic responding to personal criticisms in healthy participants and participants with known vulnerability to major depression. Healthy controls and fully recovered participants with a past history of major depression were scanned while they heard praising, critical, and neutral comments from their own mothers. Prior to scanning, the formerly depressed and the control participants were indistinguishable with respect to self-reported positive, negative, or anxious mood. They also reported similar mood changes after being praised or criticized. However, formerly depressed participants responded to criticism with greater activation in the amygdala and less activation in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) than did controls. During praise and neutral commentary, amygdala activation was comparable in both groups, although lower levels of activation in the DLPFC and ACC still characterized formerly depressed participants. Vulnerability to depression may be associated with abnormalities in cortico-limbic activation that are independent of mood state and that remain even after full recovery. Criticism may be a risk factor for relapse because it activates the amygdala and perturbs the affective circuitry that underlies depression.

Cortico-limbic response to personally challenging emotional stimuli after complete recovery from depression.

People vulnerable to depression are at increased risk of relapse if they live in highly critical family environments. To explore this link, we used neuroimaging methods to examine cortico-limbic responding to personal criticisms in healthy participants and participants with known vulnerability to major depression. Healthy controls and fully recovered participants with a past history of major depression were scanned while they heard praising, critical, and neutral comments from their own mothers. Prior to scanning, the formerly depressed and the control participants were indistinguishable with respect to self-reported positive, negative, or anxious mood. They also reported similar mood changes after being praised or criticized. However, formerly depressed participants responded to criticism with greater activation in the amygdala and less activation in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) than did controls. During praise and neutral commentary, amygdala activation was comparable in both groups, although lower levels of activation in the DLPFC and ACC still characterized formerly depressed participants. Vulnerability to depression may be associated with abnormalities in cortico-limbic activation that are independent of mood state and that remain even after full recovery. Criticism may be a risk factor for relapse because it activates the amygdala and perturbs the affective circuitry that underlies depression.

Cannabis and motor function: fMRI changes following 28 days of discontinuation.

The authors hypothesized that supplementary motor cortex (SMA) and anterior cingulate cortex (ACC) activation in chronic cannabis users, studied 4 to 36 hours after their last episode of use, would disappear by Day 28 of abstinence during finger-tapping tests. Eleven cannabis users and 16 comparison subjects were scanned during right (RFT) and left (LFT) finger-tapping tasks on a GE 1.5 Tesla scanner retrofitted with a whole body echo planar coil. Image analyses were conducted in SPM99 using an ROI approach to define each Brodmann area (BA). Differences in cerebral activation were examined in the left and right primary motor cortex (BA4), SMA (BA6), and ACC (BA24 and BA32 separately). The authors found diminished activation for contralateral BA6 from Day 0 to Day 28. For LFT, the authors also found: ipsilaterally diminished BA6 activation on Day 7, but not Day 0 or Day 28; ipsilaterally diminished BA32 activation on Day 0, but not Day 7 or Day 28; contralaterally diminished BA 4 activation on Day 28, but not Day 0 or Day 7; and contralaterally diminished BA32 activation on Day 0 and Day 28, but not Day 7. For RFT, the authors found ipsilaterally diminished BA32 activation on Days 0 and 7 but not on Day 28; contralaterally diminished BA32 activation on Days 0, 7, and 28; and ipsilaterally diminished BA6 activation on Days 0, 7, and 28. These results suggest that residual diminished brain activation is still observed after discontinuing cannabis use in motor cortical circuits.

Increased amygdala fMRI activation after secretin administration.

It has recently been reported that secretin activates gene expression in the central nucleus of the amygdala in rats. To examine the neurophysiological effects of secretin on amygdalar activation in humans, the authors measured Blood Oxygen Level Dependent functional magnetic resonance imaging signal change during facial affect processing in a placebo-controlled double-blind study. The authors studied 12 healthy male subjects who were presented with three stimulus conditions: viewing happy, fearful, and neutral faces, before and after infusion with either secretin or placebo. To test whether treatment was associated with distinct patterns of activation, the two conditions (Pre and Post) were subjected to a subtraction analyses in SPM99 and hypotheses regarding the activation of the left and right amygdala were tested using a region-of-interest approach. Subtraction of treatment minus baseline activation during the fear condition yielded significant (p=.001) activation in the right amygdala and a nonsignificant increase in activation in the left amygdala. No significant differences were seen between the treatment conditions for the amygdala when viewing happy or neutral faces. These preliminary findings indicate that secretin may alter responsivity to affective stimuli. The presence of increased activation of the amygdala during the viewing of fearful faces is consistent with findings from animal studies and suggests a mechanism by which secretin may modulate social behavior.

Orbitofrontal connectivity is associated with depression and anxiety in marijuana-using adolescents.

BACKGROUND: Prevalence of marijuana (MJ) use among adolescents has been on the rise. MJ use has been reported to impact several brain regions, including frontal regions such as the orbitofrontal cortex (OFC). The OFC is involved in emotion regulation and processing and has been associated with symptoms of depression and anxiety. Therefore, we hypothesized that adolescent MJ users would show disruptions in OFC connectivity compared with healthy adolescents (HC) which would be associated with symptoms of mood and anxiety. METHODS: 43 MJ-using and 31 HC adolescents completed clinical measures including the Hamilton Anxiety Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D). Resting-state functional magnetic resonance imaging data was also acquired for all participants. RESULTS: In MJ users, increased depressive symptoms were associated with increased connectivity between the left OFC and left parietal regions. In contrast, lower ratings of anxiety were associated with increased connectivity between right and left OFC and right occipital and temporal regions. These findings indicate significant differences in OFC connectivity in MJ-using adolescents, which correlated with mood/anxiety. LIMITATIONS: Future studies with an increased number of female participants is required to address potential sex differences in connectivity patterns related to symptoms of depression and anxiety. CONCLUSIONS: This study highlights the association between OFC connectivity, MJ use, and symptoms of depression and anxiety in adolescents. These findings provide further insight into understanding the neural correlates that modulate the relationship between comorbid MJ use and mood disorders and could potentially help us better develop preventive and treatment measures.

Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke.

After brain injury, neuroblast cells from the subventricular zone (SVZ) expand and migrate toward damaged tissue. The mechanisms that mediate these neurogenic and migratory responses remain to be fully dissected. Here, we show that bromodeoxyuridine-labeled and doublecortin-positive cells from the SVZ colocalize with the extracellular protease matrix metalloproteinase-9 (MMP-9) during the 2 week recovery period after transient focal cerebral ischemia in mice. Treatment with the broad spectrum MMP inhibitor GM6001 significantly decreases the migration of doublecortin-positive cells that extend from the SVZ into the striatum. These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury.

Recognition of happy facial affect in panic disorder: an fMRI study.

BACKGROUND: This study investigated activation of the anterior cingulate cortex (ACC) and amygdala during the presentation of happy facial affect images in patients with panic disorder (PD) as measured by blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS: Eight patients with PD and eight sex-matched controls were recruited for the study. Scanning was performed on a general electric (GE) Signa 1.5T scanner retrofitted with a whole body echo planar coil. Using a quadrature head coil, echo planar images and high-resolution MR images were acquired. RESULTS: After covarying for age, examination of group differences revealed greater ACC activation bilaterally in patients with PD compared to controls in response to happy faces. However, there were no differences in amygdala activation between the groups. These findings contrasted with regional brain activation in response to neutral faces where there were was also greater bilateral ACC activation in the PD group, but only 44 ACC voxels showed significant increases as opposed to 509 voxels for the happy condition. There were no between group differences in activation in the amygdala. CONCLUSION: This is the first fMRI study to our knowledge that demonstrates ACC abnormalities in response to happy facial affect recognition in PD.

fMRI of fearful facial affect recognition in panic disorder: the cingulate gyrus-amygdala connection.

BACKGROUND: This study investigated cingulate cortex (CC) and amygdala response to fearful facial affect recognition in patients with panic disorder (PD) as measured by BOLD fMRI during the presentation of static facial images. METHODS: Eight patients with PD and eight controls were studied. Scanning was performed on a GE Signa 1.5-T scanner. Echo planar and high-resolution MR images were acquired. RESULTS: Controls produced greater CC activation compared to patients with PD in response to fearful faces. Furthermore, patients with PD produced less amygdala activation than controls in response to fearful faces. During the neutral face condition, overall activation for the CC was significantly greater in PD patients although anterior cingulate cortex (ACC) activation was not as markedly different between both groups. There were no between group differences in amygdala activation on exposure to the neutral face. Only left CC activation was significantly correlated negatively with HAM-A in PD patients in the fearful facial affect condition. LIMITATIONS: Although comparable to similar studies, the sample size is small enough to warrant further investigation. Also, the effects of medication need to be considered when interpreting these results. CONCLUSIONS: Patients with PD activate the ACC and amygdala significantly less than controls when asked to identify fearful facial affect during fMRI. The higher the anxiety, the lower the left CC activation. Thus, chronic hyperarousal in PD may diminish attentional resources and emotional response reflected in reduced ACC and amygdala activation. Even if these are medication effects, the differences from controls are clinically relevant.

Structural group classification technique based on regional fMRI BOLD responses.

This paper presents a new multigroup classification method based on subtle differences in regional brain activity during the completion of a functional magnetic resonance imaging (fMRI) challenge paradigm. Classification is performed based on features derived from BOLD time intensity curves in selected regions of interest (ROI). For each ROI, a mean time intensity curve [called mean regional response (MRR)] is calculated from realigned and normalized datasets. The overall subject performance is characterized with a vector of features obtained using nonlinear modeling of all subject's MRRs with a mixture of time shifted Gaussian functions. The classification is performed in the reduced-dimension optimal discrimination space, obtained through canonical transformations of original feature space. In order to demonstrate feasibility of the proposed method, classification of three groups of subjects is presented. The three groups are defined as heavy marijuana smokers after 24 hours of abstinence, heavy marijuana smokers after 28 days of abstinence, and healthy nonusing controls. The proposed method can be useful as an analytic tool for the discrimination of different groups of subjects based on temporal features of functional magnetic resonance imaging activation.

Sex differences in orbitofrontal connectivity in male and female veterans with TBI.

More female soldiers are now serving in combat theaters than at any other time. However, little is known about possible sex differences underlying the neuropathology and manifestation of one of modern war's signature injuries, traumatic brain injury (TBI). The paucity of information regarding sex differences in TBI is particularly evident when examining changes in executive function and emotion regulation associated with post concussive events. The current study objective was to observe whether patterns of orbitofrontal (OFC) functional connectivity would differ between female veterans with TBI and their male counterparts. The study further sought to determine whether OFC connectivity might be differentially associated with clinical measures of aggression and hostility. Seventeen female veterans and 24 male veterans, age 18 to 25, who met criteria for TBI completed resting state magnetic resonance imaging (MRI) and clinical assessment measures. Imaging data were analyzed using left and right seed regions of the OFC, and regression analyses were conducted to observe the relationship between resting state connectivity and self-reported aggression. Females and males in this study differed in OFC connectivity, with females demonstrating greater connectivity between left and right OFC and parietal and occipital regions and males demonstrating greater connectivity between left and right OFC and frontal and temporal regions. Significant associations between resting state connectivity and clinical measures were found only in male veterans. These findings suggest that TBI may interact with sex-specific patterns of brain connectivity in male and female veterans and exert divergent effects on clinical profiles of aggression post-injury.

Aberrant orbitofrontal connectivity in marijuana smoking adolescents.

INTRODUCTION: Orbitofrontal (OFC) circuits have been implicated in the pathophysiology of substance use disorders. The current study examined OFC functional connectivity differences in marijuana-using adolescents (MJ) and non-using healthy controls (HC). METHODS: Functional magnetic resonance imaging (fMRI) resting-state data were obtained on a 3T MRI scanner on 31 HC and 43 heavy MJ smokers. Image analyses were performed between groups (MJ, HC) for the left and right OFC separately. Regression analyses between OFC functional connectivity and lifetime MJ use, age of first MJ use and impulsivity also were performed. RESULTS: Increased OFC functional connectivity to frontal and motor regions was observed in heavy MJ users compared to HC. Earlier age of first MJ use was associated with increased functional connectivity of the right OFC to motor regions. High lifetime MJ use was associated with increased OFC functional connectivity to posterior brain regions in MJ youth. DISCUSSION: Findings indicate atypical OFC functional connectivity patterns in attentional/executive, motor and reward networks in adolescents with heavy MJ use. These anomalies may be related to suboptimal decision making capacities and increased impulsivity. Results also suggest different OFC connectivity patterns may be present in adolescents with early onset of MJ use and high lifetime exposure to MJ.

Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study.

RATIONALE: Many neuropsychological studies have documented deficits in working memory among recent heavy cannabis users. However, little is known about the effects of cannabis on brain activity. OBJECTIVE: We assessed brain function among recent heavy cannabis users while they performed a working memory task. METHODS: Functional magnetic resonance imaging was used to examine brain activity in 12 long-term heavy cannabis users, 6-36 h after last use, and in 10 control subjects while they performed a spatial working memory task. Regional brain activation was analyzed and compared using statistical parametric mapping techniques. RESULTS: Compared with controls, cannabis users exhibited increased activation of brain regions typically used for spatial working memory tasks (such as prefrontal cortex and anterior cingulate). Users also recruited additional regions not typically used for spatial working memory (such as regions in the basal ganglia). These findings remained essentially unchanged when re-analyzed using subjects' ages as a covariate. Brain activation showed little or no significant correlation with subjects' years of education, verbal IQ, lifetime episodes of cannabis use, or urinary cannabinoid levels at the time of scanning. CONCLUSIONS: Recent cannabis users displayed greater and more widespread brain activation than normal subjects when attempting to perform a spatial working memory task. This observation suggests that recent cannabis users may experience subtle neurophysiological deficits, and that they compensate for these deficits by "working harder"-calling upon additional brain regions to meet the demands of the task.

Neurophysiology of motor function following cannabis discontinuation in chronic cannabis smokers: an fMRI study.

The objective of this study was to identify the differences in cerebral activation between chronic cannabis smokers and controls in response to finger sequencing. We hypothesized that attentional areas related to motor function as well as primary and supplementary motor cortices would show diminished activation in chronic cannabis smokers. Nine cannabis smokers and 16 controls were included in these analyses. Scanning was performed on a GE 1.5T scanner. Echo planar images and high-resolution MR images were acquired. The challenge paradigm included left and right finger sequencing. Group differences in cerebral activation were examined for Brodmann areas (BA) 4, 6, 24, and 32 using ROI analyses in SPM. Cannabis users, tested within 4-36 h of discontinuation, exhibited significantly less activation than controls in BA 24 and 32 bilaterally during right- and left-sided sequencing and for BA 6 in all tasks except for left-sided sequencing in the left hemisphere. There were no statistically significant differences for BA 4. None of these regional activations correlated with urinary cannabis concentration and verbal IQ for smokers. These results suggest that recently abstinent chronic cannabis smokers produce reduced activation in motor cortical areas in response to finger sequencing compared to controls.

Decreased activation of the anterior cingulate in bipolar patients: an fMRI study.

BACKGROUND: Previous neuroimaging investigations of patients with bipolar disorder have reported abnormalities of the frontal subcortical network. The role of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) in bipolar disorder are not clear, although both regions have been shown to be components of a neural network which plays a critical role in the completion of tasks requiring self-monitoring and inhibition, functions often noted to be altered in bipolar patients. fMRI studies have helped clarify the role of specific subdivisions of the ACC and the DLPFC during the performance of cognitive challenges, including the Stroop color word test. To date, studies that have examined ACC function in bipolar patients have not differentiated subregions within this area, nor have they examined changes in these subregions in relation with DLPFC activation. METHODS: To help clarify the specific roles of these regions in bipolar patients, we examined stable patients and control subjects during performance of the Stroop test using BOLD fMRI techniques. We hypothesized that bipolar patients would demonstrate reduced activation of two subdivisions of the ACC (AAA and VOA), as well as altered activation of the DLPFC, during the interference condition. RESULTS: Results indicate that relative to controls, bipolar patients demonstrated significantly reduced signal intensity within the right AAA subdivision (p=0.011), which accompanied an increase in the DLPFC (p=0.049) during the task. LIMITATIONS: The study sample was somewhat small (11 patients, 10 controls) which limits the generalizability of the study findings, however, the patient sample consisted of well-diagnosed, stable, chronic individuals with bipolar disorder and the sample size provided enough power to detect between-group differences. CONCLUSIONS: These findings suggest differential processing strategies of bipolar patients and support the theory of altered frontal systems in these patients during the performance of cognitive tasks.