Deborah Yurgelun-Todd

Network anticorrelations, global regression, and phase‐shifted soft tissue correction

Synchronized low‐frequency BOLD fluctuations are observed in dissociable large‐scale, distributed networks with functional specialization. Two such networks, referred to as the task‐positive network (TPN) and the task‐negative network (TNN) because they tend to be active or inactive during cognitively demanding tasks, show reproducible anticorrelation of resting BOLD fluctuations after removal of the global brain signal. Because global signal regression mandates that anticorrelated regions to a given seed region must exist, it is unclear whether such anticorrelations are an artifact of global regression or an intrinsic property of neural activity. In this study, we demonstrate from simulated data that spurious anticorrelations are introduced during global regression for any two networks as a linear function of their size. Using actual resting state data, we also show that both the TPN and TNN become anticorrelated with the orbits when soft tissues are included in the global regression algorithm. Finally, we propose a technique using phase‐shifted soft tissue regression (PSTCor) that allows improved correction of global physiological artifacts without global regression that shows improved anatomic specificity to global regression but does not show significant network anticorrelations. These results imply that observed anticorrelations between TNN and TPN may be largely or entirely artifactual in the resting state. These results also imply that differences in network anticorrelations attributed to pathophysiological or behavioral states may be due to differences in network size or recruitment rather than actual anticorrelations. Hum Brain Mapp, 2011.

ALTERED PREFRONTAL AND INSULAR CORTICAL THICKNESS IN ADOLESCENT MARIJUANA USERS

INTRODUCTIONnThere are limited data regarding the impact of marijuana (MJ) on cortical development during adolescence. Adolescence is a period of substantial brain maturation and cortical thickness abnormalities may be indicative of disruptions of normal cortical development. This investigation applied cortical-surface based techniques to compare cortical thickness measures in MJ using adolescents compared to non-using controls.nnnMETHODSnEighteen adolescents with heavy MJ use and 18 non-using controls similar in age received MRI scans using a 3T Siemens scanner. Cortical reconstruction and volumetric segmentation was performed with FreeSurfer. Group differences in cortical thickness were assessed using statistical difference maps covarying for age and gender.nnnRESULTSnCompared to non-users, MJ users had decreased cortical thickness in right caudal middle frontal, bilateral insula and bilateral superior frontal cortices. Marijuana users had increased cortical thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions. In the MJ users, negative correlations were found between frontal and lingual regions for urinary cannabinoid levels and between age of onset of use and the right superior frontal gyrus.nnnCONCLUSIONnThis is one of the first studies to evaluate cortical thickness in a group of adolescents with heavy MJ use compared to non-users. Our findings are consistent with prior studies that documented abnormalities in prefrontal and insular regions. Our results suggest that age of regular use may be associated with altered prefrontal cortical gray matter development in adolescents. Furthermore, reduced insular cortical thickness may be a biological marker for increased risk of substance dependence.

Altered affective response in marijuana smokers: An FMRI study

More than 94 million Americans have tried marijuana, and it remains the most widely used illicit drug in the nation. Investigations of the cognitive effects of marijuana report alterations in brain function during tasks requiring executive control, including inhibition and decision-making. Endogenous cannabinoids regulate a variety of emotional responses, including anxiety, mood control, and aggression; nevertheless, little is known about smokers responses to affective stimuli. The anterior cingulate and amygdala play key roles in the inhibition of impulsive behavior and affective regulation, and studies using PET and fMRI have demonstrated changes within these regions in marijuana smokers. Given alterations in mood and perception often observed in smokers, we hypothesized altered fMRI patterns of response in 15 chronic heavy marijuana smokers relative to 15 non-marijuana smoking control subjects during the viewing of masked happy and fearful faces. Despite no between-group differences on clinical or demographic measures, smokers demonstrated a relative decrease in both anterior cingulate and amygdalar activity during masked affective stimuli compared to controls, who showed relative increases in activation within these regions during the viewing of masked faces. Findings indicate that chronic heavy marijuana smokers demonstrate altered activation of frontal and limbic systems while viewing masked faces, consistent with autoradiographic studies reporting high CB-1 receptor density in these regions. These data suggest differences in affective processing in chronic smokers, even when stimuli are presented below the level of conscious processing, and underscore the likelihood that marijuana smokers process emotional information differently from those who do not smoke, which may result in negative consequences.

Altered frontal cortical volume and decision making in adolescent cannabis users.

Anticipating future outcomes is central to decision making and a failure to consider long-term consequences may lead to impulsive choices. Adolescence is a vulnerable period during which underdeveloped prefrontal cortical systems may contribute to poor judgment, impulsive choices, and substance abuse. Conversely, substance abuse during this period may alter neural systems involved in decision making and lead to greater impulsivity. Although a broad neural network which supports decision making undergoes extensive change during adolescent development, one region that may be critical is the medial prefrontal cortex. Altered functional integrity of this region may be specifically related to reward perception, substance abuse, and dependence. In the present investigation, we acquired structural magnetic resonance images (MRI), using a 3T Siemens Trio scanner, from 18 cannabis abusing adolescents (CA; 2 female and 16 male subjects; mean age, 17.7 years; range 16–19 years), and 18 healthy controls (HC; 6 female and 12 male subjects; mean age, 17.2 years; range 16–19 years). In order to measure medial orbital prefrontal cortex (moPFC) morphology related to substance abuse and impulsivity, semi-automated cortical reconstruction and volumetric segmentation of MRIs was performed with FreeSurfer. Impulsivity was evaluated with the Barratt Impulsiveness Scale (BIS). Our results indicate that cannabis abusing adolescents have decreased right moPFC volume compared to controls, pu2009=u20090.01, du2009=u20090.92, CI0.95u2009=u20090.21, 1.59. Cannabis abusing adolescents also show decreased future orientation, as indexed by the BIS non-planning subscale, when compared to controls, pu2009=u20090.01, du2009=u20090.89, CI0.95u2009=u20090.23, 1.55. Moreover, total moPFC volume was positively correlated with age of first use r (18)u2009=u20090.49, pu2009<u20090.03, suggesting that alterations in this region may be related to initiation of cannabis use or that early initiation may lead to reduced moPFC volume.

Striatal structure and function in mood disorders: a comprehensive review.

OBJECTIVESnu2002 A large and diverse literature has implicated abnormalities of striatal structure and function in both unipolar and bipolar disorder. Recent functional imaging studies have greatly expanded this body of research. The aim of this review is to provide a comprehensive and critical appraisal of the relevant literature.nnnMETHODSnu2002 A total of 331 relevant articles were reviewed to develop an integrated overview of striatal function in mood disorders.nnnRESULTSnu2002 There is compelling evidence from multiple studies that functional abnormalities of the striatum and greater corticostriatal circuitry exist in at least some forms of affective illness. The literature does not yet provide data to determine whether these aberrations represent primary pathology or they contribute directly to symptom expression. Finally, there is considerable evidence that bipolar disorder may be associated with striatal hyperactivity and some suggestion that unipolar illness may be associated with hypoactivation.nnnCONCLUSIONSnu2002 Additional research investigating striatal function in affective disorders will be critical to the development of comprehensive models of the neurobiology of these conditions.

The possible effect of altitude on regional variation in suicide rates.

In the United States, suicide rates consistently vary among geographic regions; the western states have significantly higher suicide rates than the eastern states. The reason for this variation is unknown but may be due to regional elevation differences. States suicide rates (1990-1994), when adjusted for potentially confounding demographic variables, are positively correlated with their peak and capital elevations. These findings indicate that decreased oxygen saturation at high altitude may exacerbate the bioenergetic dysfunction associated with affective illnesses. Should such a link exist, therapies traditionally used to treat the metabolic disturbances associated with altitude sickness may have a role in treating those at risk for suicide.

Neurochemical alterations in adolescent chronic marijuana smokers: A proton MRS study

Converging evidence from neuroimaging and neuropsychological studies indicates that heavy marijuana use is associated with cingulate dysfunction. However, there has been limited human data documenting in vivo biochemical brain changes after chronic marijuana exposure. Previous proton magnetic resonance spectroscopy studies have demonstrated reduced basal ganglia glutamate and dorsolateral prefrontal cortex N-acetyl aspartate levels in adult chronic marijuana users. Similar studies have not been reported in adolescent populations. The present study used proton magnetic resonance spectroscopy to determine whether reductions in glutamate, N-acetyl aspartate and/or other proton metabolite concentrations would be found in the anterior cingulate cortex (ACC) of adolescent marijuana users compared with non-using controls. Adolescent marijuana users (N=17; average age 17.8 years) and similarly aged healthy control subjects (N=17; average age 16.2 years) were scanned using a Siemens 3T Trio MRI system. Proton magnetic resonance spectroscopy data were acquired from a 22.5 mL voxel positioned bilaterally within the ACC. Spectra were fitted using commercial software and all metabolite integrals were normalized to the scaled unsuppressed water integral. Analysis of variance and analysis of covariance were performed to compare between-group metabolite levels. The marijuana-using cohort showed statistically significant reductions in anterior cingulate glutamate (-15%, p<0.01), N-acetyl aspartate (-13%, p=0.02), total creatine (-10%, p<0.01) and myo-inositol (-10%, p=0.03). Within-voxel tissue-type segmentation did not reveal any significant differences in gray/white matter or cerebrospinal fluid content between the two groups. The reduced glutamate and N-acetyl aspartate levels in the adolescent marijuana-using cohort are consistent with precedent human (1)H MRS data, and likely reflect an alteration of anterior cingulate glutamatergic neurotransmission and neuronal integrity within these individuals. The reduced total creatine and myo-inositol levels observed in these subjects might infer altered ACC energetic status and glial metabolism, respectively. These results expand on previous functional MRI data reporting altered cingulate function in individuals with marijuana-abuse.

Reduced insular volume in attention deficit hyperactivity disorder.

The aim of this study was to evaluate whether structural differences in the insula and anterior cingulate cortex (ACC), two critical areas of the salience network, co-exist in adolescents with attention deficit hyperactivity disorder (ADHD) compared with healthy controls (HC). In addition we aimed to determine if structural changes within these regions correlate with attention and inhibitory function. Nineteen adolescents with ADHD and 25 HC received MRI scans on a 3T magnet. Morphometric analysis was performed with FreeSurfer. Youths with ADHD were found to have a bilateral reduction in anterior insular (AIC) gray matter volumes compared to HC. Furthermore, the left AIC was found to positively correlate with oppositional symptoms, while the right AIC was found to associate with both attention problems and inhibition. To our knowledge this is the first report of a bilateral reduction in AIC volumes in ADHD. Our findings suggest a role for the insula in modulating attention and inhibitory capacity in ADHD.

Abnormal striatal circuitry and intensified novelty seeking among adolescents who abuse methamphetamine and cannabis

It has been hypothesized that changes in striatal-mediated dopamine modulation during adolescence may increase the risk for initiating substance abuse as a result of its fundamental role in arbitrating reward sensitivity and motivation during learning and decision making. However, substance abuse during adolescence may also significantly modify striatal structure and function and concomitantly alter reward sensitivity and action control while this brain region is undergoing remodeling. In the present investigation, to assess the relationship of methamphetamine (Meth) or Meth and cannabis (CA) abuse to regional striatal morphology, we acquired structural magnetic resonance images, using a 3T Siemens Trio scanner, from three groups of adolescents composed of healthy controls (n = 10), Meth abusers (n = 9) and combined Meth and CA abusers (Meth+CA, n = 8). We also assessed novelty seeking using the novelty seeking subscale of Cloninger’s Tridimensional Character Inventory. The results indicate that adolescent Meth+CA abusers have increased regional striatal volume and show intensified novelty seeking in contrast to the controls. The degree of Meth exposure was also positively correlated with regional striatal volume and novelty seeking in both the Meth and Meth+CA users. These preliminary findings support theories that propose a role for the striatum in adolescent substance abuse and further indicate that novelty seeking may be related to the initiation of, or sustained, drug use.

Posterior cerebellar vermal deficits in bipolar disorder

BACKGROUNDnBased on growing evidence of the crucial role of the cerebellum in emotional regulation, we sought to identify cerebellar structural deficits in a large sample of patients with bipolar disorder (BD).nnnMETHODSnCerebellar gray matter density was examined in 49 BD patients (24 medication-naive and 25 medication-treated) and 50 carefully matched healthy individuals, using voxel-based morphometry with a high-resolution spatially unbiased atlas template of the human cerebellum. This recently developed methodology is specifically optimized for the assessment of cerebellar structures. We further explored whether antimanic treatment could attenuate cerebellar structural deficits.nnnRESULTSnBD patients showed a greater reduction in gray matter density of the posterior cerebellar regions, including the bilateral vermi and the right crus relative to healthy individuals (corrected p<.05). A stepwise linear reduction in gray matter density was observed in bilateral vermal regions between healthy individuals, medication-treated, and medication-naive BD patients. Furthermore, positive correlations of longer duration of illness with bilateral vermal gray matter deficits were observed only in medication-naive BD patients, but not in patients with medication history.nnnLIMITATIONSnThis study adopted a cross-sectional design. The automatic intensity-normalization method for the measurement of cerebellar gray matter density may have a limitation in providing detailed anatomical information at a cerebellar folia level.nnnCONCLUSIONSnThe current findings suggest that BD-related deficits in the posterior cerebellar regions, which appear to progress over the course of illness, could potentially be ameliorated by proper treatment with mood stabilizers.