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.

Early detection of rejection in pancreas transplantation.

A major dilemma in pancreas transplantation is the lack of reliable methods for the early detection of allograft rejection. Over a 26-mo period, 70 rejection episodes occurred in 36 patients (13 isolated-pancreas, 23 simultaneous pancreas-kidney recipients) with pancreaticoduodenocystostomy. A total of 300 radionuclide pancreas examinations were performed (mean 8.3/patient) utilizing 99mTc-labeled DTPA. Computer analysis generated a quantitative measure of blood flow to the allograft (technetium index, TI). Rejection episodes were defined as isolated pancreas, isolated kidney, or combined pancreas-kidney. Mean urinary amylase (UA) levels and TI during normal allograft function were 30,256 U/L and 0.57%, respectively, whereas levels heralding rejection were 6873 U/L and 0.39% (P less than .05). The treatment of rejection based on kidney dysfunction or combined pancreas-kidney dysfunction resulted in significantly higher graft salvage and a lower incidence of hyperglycemia compared with isolated-pancreas-allograft rejection. After therapy, a TI greater than 0.3% was associated with 95.9% graft survival, whereas levels less than 0.3% resulted in a 72.7% rate of graft loss (P less than .001). Similarly, pancreas allografts with a UA greater than 10,000 U/L had 92.2% functional survival, whereas levels less than 10,000 U/L resulted in a 53.3% rate of graft loss (P less than 0.001). Overall, reversal of rejection occurred in 80% of cases, with 10 pancreas and 2 kidney allografts lost due to rejection. Monitoring pancreas-allograft function by UA, TI, and renal function in simultaneous transplants allows for the timely diagnosis and successful treatment of pancreas-allograft rejection.

Clinical outcome of patients with a 'low probability' of pulmonary embolism on ventilation-perfusion lung scan.

Lung ventilation and perfusion (V/Q) scintigraphy is usually indicated when pulmonary embolism (PE) is a suspected diagnosis. Typically, V/Q scintigraphic interpretation is reported as a "normal," "low," "intermediate," or "high probability" of PE. Although a "low probability" interpretation does not exclude the diagnosis of PE, it significantly reduces the likelihood. We retrospectively analyzed up to one year of follow-up in 90 patients who were clinically suspected of having PE, but in whom V/Q scintigraphy implied a low probability of PE. None of the 90 patients demonstrated clinical evidence of PE subsequent to the V/Q scan. Our findings suggest that significant pulmonary embolism is uncommon and that the clinical course appears to be predictable in patients with a low probability V/Q scan.

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.

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.

Osteosarcoma arising in Paget's disease of the calvarium.

Paget's disease of the bone occasionally transforms into sarcomatous tumors such as osteosarcoma. While Paget's disease demonstrates markedly increased uptake of bone scanning radiopharmaceutical, osteosarcomas complicating this condition often show decreased uptake. An unusual scan appearance of the osteosarcoma is presented in which the tumor showed intense uptake of the tracer on the bone scan. The extent of the sarcoma as delineated by the bone scan corresponded closely to the size of the lesion as seen on computerized tomography and magnetic resonance imaging and was confirmed at surgery.

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.

The rim sign: association with acute cholecystitis.

In a retrospective analysis of 218 hepatobiliary studies in patients clinically suspected of acute cholecystitis, a rim of increased hepatic activity adjacent to the gallbladder fossa (the "rim sign") has been evaluated as a scintigraphic predictor of confirmed acute cholecystitis. Of 28 cases with pathologic confirmation of acute cholecystitis in this series, 17 (60%) demonstrated this sign. When associated with nonvisualization of the gallbladder at 1 hr, the positive predictive value of this photon-intense rim for acute cholecystitis was 94%. When the rim sign was absent, the positive predictive value of nonvisualization of the gallbladder at 1 hr for acute cholecystitis was only 36%. As this sign was always seen during the first hour postinjection, it can, when associated with nonvisualization, reduce the time required for completion of an hepatobiliary examination in suspected acute cholecystitis.

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.

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.

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.

123I-iodoamphetamine SPECT brain imaging in alternating hemiplegia.

Alternating hemiplegia of childhood is an unusual disorder characterized by early onset (occurring before 18 months of age); repeated attacks of hemiplegia involving both sides of the body; other paroxysmal phenomena, such as tonic stiffening, dystonic posturing, choreoathetoid movements, ocular motor abnormalities, and autonomic disturbances, in association with bouts of hemiplegia or occurring independently; and evidence of mental or neurologic deficits. A girl was examined because of left hemiplegia at the age of 16 months. The patient had begun exhibiting episodes of alternating hemiplegia at approximately 4 months of age. They consisted of tonic stiffening and dystonia of the right or left extremities, lasting from 30 min to several hours and followed by residual hemiparesis. They were invariably accompanied by ocular motor abnormalities. Magnetic resonance imaging, computed tomography, and angiography all were normal. Single proton emission computed tomography brain images during an acute episode of right hemiplegia demonstrated hypoperfusion of the left cerebral hemisphere. Following improvement of the hemiplegia, the patient was re-evaluated. The uptake of the radiotracer in the left hemisphere was increased. The scan did not demonstrate significant asymmetry in cerebral perfusion.

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.

The use of socioeconomic data to predict teenage birth rates. An exploratory study in Massachusetts.

In an exploratory study of adolescent fertility in 24 Massachusetts cities, age-specific birth rates constructed specifically for the study constituted the dependable variables. Data from the 1980 U.S. Census provided the independent socioeconomic variables for the analysis. The relationships between birth rates and these independent variables were explored through simple and partial correlation analyses. Results of the analyses confirm the assumption that rates of birth to teenagers vary systematically in relation to socioeconomic variables. They also confirm at the macro level the results of several earlier household survey showing an association between family income on the one hand, and adolescent sexual activity, contraception, and abortion on the other. In the current study, economic variables, particularly the median income of all families in the community, were found to be highly significant predictors of fertility among adolescents 15 to 19 years of age. The fertility of the generation to which the teenagers' mothers belonged (that is, women 35 to 44 years old) was also significantly associated with the teenagers' birth rates. The results for teenage mothers 15 through 17 years old and teenage mothers 18 and 19 years old were similar.

National problems, local solutions: comprehensive services for pregnant and parenting adolescents.

PIP: This study identifies a number of factors associated with the successful development and maintenance of local comprehensive adolescent pregnancy programs in the US. The comprehensive programs were located in communities with relatively well-developed social welfare infrastructures. They received basic state support and were able to tap a wide variety of federal, state, and local resources. These comprehensive programs were managed by skillful administrators and drew upon a broad range of leadership talents. Only a minority of exceptional communities possess the essential prerequisites. Within states, grant mechanisms favor those few localities that can put together the winning proposal or that have the organizational capacity to draw on a variety of funding sources. They are not always the communities with the greatest need. Within communities, even the most comprehensive programs served only a small proportion of the potential clientele. They reflected a brief crisis intervention orientation to a problem that is complex and long-lasting in its origin and consequences. National evaluations and comprehensive programs have found that their benefits are limited and short-lived. The study further demonstrates the political vulnerability of local services for stigmatized and powerless groups in the absence of a strong national mandate. Service providers kept a low profile to avoid the attention of potential opponents. A national strategy based on the sponsorship of a limited number of demonstration projects and the dissemination of information about exceptional, exemplary programs is unlikely to accomplish very much. The evidence suggests that the lack of a national policy commitment to pregnancy prevention contributes to the high rate of adolescent pregnancies.^ieng