Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

Dissociable patterns of medial prefrontal and amygdala activity to face identity versus emotion in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder demonstrate abnormal social function. Neuroimaging studies in bipolar disorder have shown functional abnormalities in neural circuitry supporting face emotion processing, but have not examined face identity processing, a key component of social function. We aimed to elucidate functional abnormalities in neural circuitry supporting face emotion and face identity processing in bipolar disorder. METHOD: Twenty-seven individuals with bipolar disorder I currently euthymic and 27 healthy controls participated in an implicit face processing, block-design paradigm. Participants labeled color flashes that were superimposed on dynamically changing background faces comprising morphs either from neutral to prototypical emotion (happy, sad, angry and fearful) or from one identity to another identity depicting a neutral face. Whole-brain and amygdala region-of-interest (ROI) activities were compared between groups. RESULTS: There was no significant between-group difference looking across both emerging face emotion and identity. During processing of all emerging emotions, euthymic individuals with bipolar disorder showed significantly greater amygdala activity. During facial identity and also happy face processing, euthymic individuals with bipolar disorder showed significantly greater amygdala and medial prefrontal cortical activity compared with controls. CONCLUSIONS: This is the first study to examine neural circuitry supporting face identity and face emotion processing in bipolar disorder. Our findings of abnormally elevated activity in amygdala and medial prefrontal cortex (mPFC) during face identity and happy face emotion processing suggest functional abnormalities in key regions previously implicated in social processing. This may be of future importance toward examining the abnormal self-related processing, grandiosity and social dysfunction seen in bipolar disorder.

FDG-PET in inflammatory bowel disease.

Accurate, inexpensive, non-invasive studies in evaluation of inflammatory bowel disease (IBD) would represent a significant advancement in identifying and measuring disease activity. There is new evidence that positron emission tomography (PET) scanning can fulfill many of these criteria. The aim of this review is to report the studies pertaining to the use of PET in IBD and provide an evidence-based approach on how to use PET clinically in IBD. Searching Medline and the Cochrane Database of Clinical Trails on July 18, 2008 identified 12 relevant manuscripts for review. Types of studies of PET in IBD include the incidental identification of IBD during studies performed for other indications, the evaluation of suspected IBD and the assessment of known IBD. PET has been studied in both children and adults and has shown excellent sensitivity for detecting active bowel inflammation, but with poor specificity in some studies. PET alone appears sufficient for the evaluation of ulcerative colitis, but PET/computed tomography provides considerably more information over PET alone in the evaluation of Crohn's disease. Current clinical applications for PET in IBD include its use in the early evaluation of IBD, especially in children who may not tolerate an invasive test such as colonoscopy; and its use in differentiating between a flare of IBD versus the onset of a non-inflammatory process causing similar symptoms in patients with known IBD. Many unanswered questions remain, but PET appears to be a promising tool in the non-invasive evaluation of IBD.

Whole body positron emission tomography imaging of activated lymphoid tissues during acute simian-human immunodeficiency virus 89.6PD infection in rhesus macaques.

Mechanisms of acute retroviral pathogenesis have been examined during primary infection of rhesus macaques with simian-human immunodeficiency virus 89.6PD (SHIV(89.6PD)). During acute infection, between initial exposure and establishment of antigen-specific immune responses that stabilize the virus burden, rapid immune system changes influence the viral set-point and dictate subsequent steps in disease progression. In a previous study, we described specific patterns of lymphocyte activation during acute SHIV(89.6PD) infection. We now extend these studies to describe lymphoid tissue activation, using whole body positron emission tomography (PET) and the radioactive tracer 2-[(18)F]fluorodeoxyglucose (FDG). Within a few days after primary infection by intravenous, intrarectal, or intravaginal routes, PET-FDG imaging revealed a distinct pattern of lymphoid tissue activation centered on axillary, cervical, and mediastinum lymph nodes. Increased tissue FDG uptake preceded fulminant virus replication at these sites, suggesting that a diffusible factor of host or viral origin was responsible for lymphoid tissue changes. These data show that activation of lymphoid tissues in the upper body is an early response to virus infection and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies.

Six-month test-retest reliability of MRI-defined PET measures of regional cerebral glucose metabolic rate in selected subcortical structures.

Test-retest reliability of resting regional cerebral metabolic rate of glucose (rCMR) was examined in selected subcortical structures: the amygdala, hippocampus, thalamus, and anterior caudate nucleus. Findings from previous studies examining reliability of rCMR suggest that rCMR in small subcortical structures may be more variable than in larger cortical regions. We chose to study these subcortical regions because of their particular interest to our laboratory in its investigations of the neurocircuitry of emotion and depression. Twelve normal subjects (seven female, mean age = 32.42 years, range 21-48 years) underwent two FDG-PET scans separated by approximately 6 months (mean = 25 weeks, range 17-35 weeks). A region-of-interest approach with PET-MRI coregistration was used for analysis of rCMR reliability. Good test-retest reliability was found in the left amygdala, right and left hippocampus, right and left thalamus, and right and left anterior caudate nucleus. However, rCMR in the right amygdala did not show good test-retest reliability. The implications of these data and their import for studies that include a repeat-test design are considered.

Preoperative FDG-PET temporal lobe hypometabolism and verbal memory after temporal lobectomy.

OBJECTIVE: To examine the relationship of preoperative fluorodeoxyglucose (FDG)-PET asymmetry in temporal lobe metabolism and memory outcome after anterior temporal lobectomy (ATL). METHODS: In a university-based epilepsy surgery center, 60 ATL patients (27 left, 33 right) were divided into two groups: no/mild (n = 21) or moderate/ severe (n = 39) asymmetry in temporal lobe hypometabolism as determined by FDG-PET. All patients were nonretarded, at least 18 years of age, left-hemisphere speech dominant, without MRI abnormalities other than hippocampal atrophy, and with unilateral temporal lobe origin of intractable complex partial seizures. Neuropsychological measures of intelligence and verbal and visual memory function were assessed preoperatively and 6 months postoperatively. RESULTS: Left ATL patients with no/mild asymmetry in FDG-PET temporal lobe metabolism exhibited significantly greater verbal memory decline compared with left ATL patients with moderate/severe hypometabolism. There was no significant relationship between PET asymmetry and pre- to postsurgical IQ change. No significant relationship was observed between extent of PET hypometabolism and memory outcome for right ATL patients. CONCLUSIONS: FDG-PET asymmetry can be added to the preoperative clinical markers that appear useful in predicting verbal memory decline after left ATL.

Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients.

BACKGROUND: EEG alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The hypothesis that the thalamus serves as a neuronal oscillator of alpha rhythms has been supported by studies in animals, but only minimally by studies in humans. METHODS: In the current study, PET-derived measures of regional glucose metabolism, EEG, and structural MRI were obtained from each participant to assess the relation between thalamic metabolic activity and alpha power in depressed patients and healthy controls. The thalamus was identified and drawn on each subject's MRI. The MRI was then co-registered to the corresponding PET scan and metabolic activity from the thalamus extracted. Thalamic activity was then correlated with a 30-min aggregated average of alpha EEG power. RESULTS: Robust inverse correlations were observed in the control data, indicating that greater thalamic metabolism is correlated with decreased alpha power. No relation was found in the depressed patient data. CONCLUSIONS: The results are discussed in the context of a possible abnormality in thalamocortical circuitry associated with depression.

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

Relations between PET-derived measures of thalamic glucose metabolism and EEG alpha power.

Electroencephalogram (EEG) alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The thalamus has been proposed as an important site for modulation of rhythmic alpha activity. Studies in animals have suggested that cortical alpha rhythms are correlated with alpha rhythms in the thalamus. However, little empirical evidence exists for this relation in humans. In the current study, resting EEG and a fluorodeoxyglucose positron emission tomography scan were measured during the same experimental session. Over a 30-min period, average EEG alpha power across 28 electrodes from 27 participants was robustly inversely correlated with glucose metabolic activity in the thalamus. These data provide the first evidence for a relation between alpha EEG power and thalamic activity in humans.

The impact of the Massachusetts Managed Mental Health/Substance Abuse Program on outpatient mental health clinics.

Medicaid managed care initiatives pose special challenges to outpatient providers. During the first two full years of the Massachusetts Mental Health/Substance Abuse initiative, an analysis of cost and utilization data showed that outpatient mental health utilization and expenditures dropped slightly, although far less than did expenditures and utilization for inpatient facilities. In a telephone survey of a stratified random sample of outpatient providers, they reported that access, appropriate utilization, quality of care, the severity of their clients and aftercare coordination increased, while length of stay for these clients decreased. In their clinical practices, agencies shifted toward more emphasis on group and family care and brief therapies. As organizations, they made substantial operational changes. As a result, some agencies did better, while others did worse, under this new system.

The synthesis of fluorine-18 lomefloxacin and its preliminary use in human studies.

Lomefloxacin is a new fluorine-containing antibiotic that has recently been approved for general use. Fluorine-18 lomefloxacin has been prepared by fluoride exchange between fluorine-18 fluoride and lomefloxacin in DMSO. Both time and temperature of the reaction have been optimized and conditions developed for the isolation and purification of the labeled product in a form suitable for oral administration. The exchange reaction provides sufficient labeled material for human studies with pharmacologically relevant quantities of the drug. We have performed preliminary human studies with this compound using positron emission tomography to estimate the tissue distribution of the compound and show the distribution of the compound into the liver and lungs.

Whole body positron emission tomography imaging of simian immunodeficiency virus-infected rhesus macaques.

Pathogenesis of simian immunodeficiency virus (SIV) infection in rhesus macaques begins with acute viremia and then progresses to a distributed infection in the solid lymphoid tissues, which is followed by a process of cellular destruction leading to terminal disease and death. Blood and tissue specimens show the progress of infection at the cellular level but do not reveal the pattern of infection and host responses occurring throughout the body. The purpose of this investigation was to determine whether positron emission tomography (PET) imaging with intravenous 2-18F-2-deoxyglucose (FDG) could identify activated lymphoid tissues in a living animal and whether this pattern would reflect the extent of SIV infection. PET images from SIV-infected animals were distinguishable from uninfected controls and revealed a pattern consistent with widespread lymphoid tissue activation. Significant FDG accumulation in colon along with mesenteric and ileocaecal lymph nodes was found in SIV infection, especially during terminal disease stages. Areas of elevated FDG uptake in the PET images were correlated with productive SIV infection using in situ hybridization as a test for virus replication. PET-FDG images of SIV-infected animals correlated sites of virus replication with high FDG accumulation. These data show that the method can be used to evaluate the distribution and activity of infected tissues in a living animal without biopsy. Fewer tissues had high FDG uptake in terminal animals than midstage animals, and both were clearly distinguishable from uninfected animal scans.

Acute cholecystitis in an animal model: findings on color Doppler sonography.

OBJECTIVE: The purpose of our study was to evaluate the color Doppler findings of acute cholecystitis in a controlled canine model. MATERIALS AND METHODS: Fourteen animals had a laparotomy: cystic duct ligation was done in eight, and incision with closure was performed in six control subjects. Animals were scanned in a blinded fashion preoperatively, immediately postoperatively, and on postoperative days 1-5. On postoperative day 5, a hepatobiliary scan was done with 2 mCi (74 MBq) 99mTc-mebrofenin. Blinded histopathology was performed and correlated with imaging. RESULTS: Flow was seen in the wall of each gallbladder at some point during the postoperative course, demonstrating vascular patency. Hepatobiliary scintigraphy confirmed cystic duct status in 12 cases; two animals died before radionuclide imaging was complete. Color Doppler signal decreased in the gallbladder wall in ligated dogs from postoperative day 1 to postoperative day 3 (p = .03 versus controls at postoperative day 2) and increasingly returned by postoperative day 5. Hyperemia was seen in only two cases (both with severe necrotizing cholecystitis) and only at postoperative day 5. Although not statistically significant, a weak trend of increasing flow with more severe pathologic grades of cholecystitis was observed (p = .20). CONCLUSIONS: In this animal model, loss of vascular signal (not hyperemia) at postoperative day 2 was the finding to diagnose early acute cholecystitis, although lack of flow can also be seen in some normal subjects. Flow tended to return by postoperative day 5, and it increased in some of the more severe cases of cholecystitis. Hyperemia was a somewhat useful sign of acute necrotizing cholecystitis.

Effect of nicotinic acid on exogenous myocardial glucose utilization.

UNLABELLED: Clinical assessment of myocardial glucose uptake with 18F-fluorodeoxyglucose (18F-FDG) and PET requires the control of circulating substrates to achieve acceptable image quality. METHODS: To determine the efficacy of the hypolipemic effect of oral niacin upon myocardial 18F-FDG uptake, five volunteers were studied with 18F-FDG and PET in the fasting state, with and without treatment with niacin. Levels of glucose, fatty acids, insulin and catecholamines were measured at baseline and before and after 18F-FDG administration by programmed infusion. RESULTS: No significant changes in glucose or insulin levels occurred with niacin. A significant decrease in fatty acid levels with niacin treatment was associated with a two- to three-fold increase in myocardial glucose utilization rates relative to the fasting state. Furthermore, regional variation in tracer distribution with greater uptake in the lateral wall than the septum or anterior wall in the fasting studies was not present after niacin treatment. CONCLUSION: As determined by programmed infusion of 18F-FDG and PET imaging, niacin treatment in normal volunteers was associated with an increase in exogenous glucose utilization by the heart and a decrease in the cardiac regional variation of 18F-FDG. Further studies are needed to compare the relative value of niacin therapy and oral glucose loading for determination of myocardial exogenous glucose utilization rates.

Technetium 94m-labeled methoxyisobutyl isonitrile: dosimetry and resting cardiac imaging with positron emission tomography.

BACKGROUND: Development of a positron-emitting form of technetium has allowed the imaging of technetium radiopharmaceuticals with positron emission tomography (PET). We used 94mTc to compare the distribution of the myocardial perfusion agent sestamibi at rest with the conventional PET perfusion tracer 13N-labeled ammonia (13N-ammonia). METHODS AND RESULTS: Dosimetry calculations were performed with the known whole-body distribution of 99mTc-labeled sestamibi. Dynamic PET imaging of 13N-ammonia and 94mTc-labeled sestamibi (94mTc-sestamibi) for 32 minutes was performed in eight patients with previous myocardial infarction. Initial myocardial and extramyocardial distribution of 94mTc-sestamibi was compared with that of 13N-ammonia by qualitative and quantitative analysis. Quantitative comparison of the two tracers was performed with region-of-interest analysis and circumferential profiles. Qualitatively, the cardiac distribution of the tracers was similar in normal and infarcted myocardium. A decrease in the definition of the epicardial and endocardial borders of the heart was seen with 94mTc-sestamibi, presumably because of the lower dose of radionuclide injected. Quantitatively, there was no difference in infarct size, defined prospectively as tracer activity less than 20% of maximum activity for the section, between the two tracers. Circumferential profile analysis with 12-degree radial sections similarly demonstrated no difference in regional cardiac distribution of the tracers. CONCLUSIONS: These results revealed no significant difference in myocardial uptake compared with 13N-ammonia suggesting that the myocardial uptake of sestamibi correlates with that of myocardial perfusion.

Visualization of dopamine nerve terminals by positron tomography using [18F]fluoro-beta-fluoromethylene-m-tyrosine.

[18F]-6-Fluoro-beta-fluoromethylene-m-tyrosine ([18F]FFMMT) was evaluated as a potential imaging agent for dopamine nerve terminals using positron emission tomography (PET). Biodistribution and time course of this tracer in mice after i.p. injection was consistent with the distribution of dopamine. PET imaging studies involving rhesus macaques showed specific uptake in the dopamine-rich caudate-putamen region. This specific localization was blocked by inhibiting the enzyme L-aromatic amino acid decarboxylase and the transport of the tracer into brain was shown to be stereospecific. These results show the promise of L-[18F]FFMMT as a PET tracer in monitoring degeneration of the CNS dopamine system.

Radionuclide ventriculography in severely underweight anorexia nervosa patients before and during refeeding therapy.

Congestive heart failure is a well-recognized complication of refeeding therapy in underweight patients with anorexia nervosa but there are few data describing cardiac function during the critical refeeding period. This prospective study examined left ventricular function with conventional electrocardiographic-gated radionuclide ventriculography (RVG) in severely underweight anorexia nervosa patients both before and during refeeding therapy. Eight patients underwent rest and exercise RVG at admission and after regaining approximately 5% to 10% of their ideal body weight. With the admission study serving as a control, the left ventricular ejection fraction and regional wall motion analysis were analyzed before and after refeeding and weight gain. Resting left ventricular ejection fractions were not significantly different between the first and second RVGs (64 +/- 11% vs. 62 +/- 8%, respectively; P greater than .05). Likewise, the left ventricular ejection fraction with maximal exercise did not significantly differ when comparing the first or the second RVG (74 +/- 10% vs. 72 +/- 8%, P greater than .05). During the baseline RVG, the left ventricular ejection fraction increased from 64 +/- 11% (rest) to 74 +/- 10% (maximal exercise) (P less than .001). During the second RVG, the ejection fraction increased from 62 +/- 8% (rest) to 72 +/- 8% (maximal exercise) (P = .003). However, the left ventricular exercise ejection fraction in the second RVG in one patient increased only by one absolute percentage point. Four of the eight patients had regional wall motion abnormalities detected during resting and/or exercise RVG. Abnormal cardiac function occurs in asymptomatic patients with anorexia nervosa undergoing refeeding therapy.