Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Disrupted white matter integrity in primary insomnia and major depressive disorder: relationships to sleep quality and depression severity.

This study examined the integrity of white matter tracts in 25 participants with primary insomnia (PI), 50 participants with major depressive disorder (MDD), and 25 healthy controls. Seven white matter tracts, selected based on prior research, were quantified by fractional anisotropy (FA) as well as by related measures of diffusivity using diffusion tensor imaging (DTI) on a 3-T scanner. All 100 participants were free of significant medical, psychiatric (excluding the MDD group) and sleep disorders (excluding the PI group), were free of central nervous system medications, and completed an extensive clinical assessment. Subjective and objective sleep measures revealed significant sleep disruption in both the PI and MDD groups. Relative to the controls, both the PI and MDD groups demonstrated impaired integrity in three of the seven white matter tracts: the genu of the corpus callosum (GenuCC), the superior longitudinal fasciculus (SLF), and the inferior longitudinal fasciculus (ILF). We demonstrated reduced FA in the GenuCC, reduced FA and reduced axial diffusivity (AD) in the SLF, as well as reduced AD and radial diffusivity in the ILF. Finally, in an exploratory analysis of the combined cohorts, FA in the GenuCC and FA in the SLF were negatively correlated with depression severity and positively correlated with total sleep time. Abnormalities documented in the GenuCC, SLF and ILF, and present in both the PI and MDD groups may suggest some shared neurobiology.

Increased White Matter Coherence Following Three and Six Months of Medical Cannabis Treatment.

Background: Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD). Methods: As part of a larger, longitudinal investigation, patients interested in treating at least one medical condition with commercially available MC products of their choosing were assessed before initiating MC use (baseline n=37; female=25, male=12) and following three (n=31) and six (n=22) months of treatment. WM coherence was assessed via diffusion tensor imaging for bilateral regions of interest including the genu of the corpus callosum, anterior limb of the internal capsule, external capsule, and anterior corona radiata, as well as an occipital control region not expected to change over time. Results: In MC patients, FA values significantly increased bilaterally in several callosal regions relative to baseline following both 3 and 6 months of treatment; MD values significantly decreased in all callosal regions but only following 6 months of treatment. No significant changes in WM coherence were observed in the control region or in a pilot sample of treatment-as-usual patients (baseline n=14), suggesting that increased WM coherence observed in MC patients may be attributed to MC treatment as opposed to confounding factors. Interestingly, significant reductions in MD values correlated with higher cannabidiol (CBD) exposure but not Δ-9-tetrahydrocannabinol exposure. Conclusions: Overall, MC treatment was associated with increased WM coherence, which contrasts with prior research examining recreational cannabis consumers, likely related to inherent differences between recreational consumers and MC patients (e.g., product choice, age of onset). In addition, increased CBD exposure was associated with reduced MD following 6 months of treatment, extending evidence from preclinical research indicating that CBD may be neuroprotective against demyelination. However, additional research is needed to elucidate the clinical efficacy of MC treatment and the risks and benefits of long-term MC use.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Large-Scale Functional Brain Network Architecture Changes Associated With Trauma-Related Dissociation.

OBJECTIVE: Dissociative experiences commonly occur in response to trauma, and while their presence strongly affects treatment approaches in posttraumatic spectrum disorders, their etiology remains poorly understood and their phenomenology incompletely characterized. Methods to reliably assess the severity of dissociation symptoms, without relying solely on self-report, would have tremendous clinical utility. Brain-based measures have the potential to augment symptom reports, although it remains unclear whether brain-based measures of dissociation are sufficiently sensitive and robust to enable individual-level estimation of dissociation severity based on brain function. The authors sought to test the robustness and sensitivity of a brain-based measure of dissociation severity. METHODS: An intrinsic network connectivity analysis was applied to functional MRI scans obtained from 65 women with histories of childhood abuse and current posttraumatic stress disorder (PTSD). The authors tested for continuous measures of trauma-related dissociation using the Multidimensional Inventory of Dissociation. Connectivity estimates were derived with a novel machine learning technique using individually defined homologous functional regions for each participant. RESULTS: The models achieved moderate ability to estimate dissociation, after controlling for childhood trauma and PTSD severity. Connections that contributed the most to the estimation mainly involved the default mode and frontoparietal control networks. By contrast, all models performed at chance levels when using a conventional group-based network parcellation. CONCLUSIONS: Trauma-related dissociative symptoms, distinct from PTSD and childhood trauma, can be estimated on the basis of network connectivity. Furthermore, between-network brain connectivity may provide an unbiased estimate of symptom severity, paving the way for more objective, clinically useful biomarkers of dissociation and advancing our understanding of its neural mechanisms.

1H MRS Measurement of Cortical GABA and Glutamate in Primary Insomnia and Major Depressive Disorder: Relationship to Sleep Quality and Depression Severity.

BACKGROUND: Both Major Depressive Disorder (MDD) and Primary Insomnia (PI) have been linked to deficiencies in cortical γ-aminobutyric acid (GABA) and glutamate (Glu) thus suggesting a shared neurobiological link between these two conditions. The extent to which comorbid insomnia contributes to GABAergic or glutamatergic deficiencies in MDD remains unclear. METHODS: We used single-voxel proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla to examine GABA+ and Glu relative to creatine (Cr) in the dorsal anterior cingulate cortex (dACC) and in the parieto-occipital cortex (POC) of 51 non-medicated adults with MDD, 24 adults with Primary Insomnia (PI), and 25 age- and sex-matched good sleeper controls (HC). Measures of depression severity and subjective and objective sleep quality were compared with 1H MRS metabolite measures. RESULTS: MDD subjects exhibited a 15% decrease in Glu/Cr in the dACC compared to HC. Within the MDD group, there was a trend inverse correlation between dACC Glu/Cr and anhedonia ratings. We observed no significant association between measures of sleep quality with dACC Glu/Cr in those with MDD. LIMITATIONS: The protocol and data interpretation would have been enhanced by the recruitment of MDD subjects with a broader range of affect severity and a more comprehensive assessment of clinical features. CONCLUSIONS: These findings support the role of cortical glutamatergic mechanisms in the pathophysiology of MDD. Insomnia severity did not further contribute to the relative deficiency of glutamatergic measures in MDD.

Decreased Amygdalar Activation to NSSI-Stimuli in People Who Engage in NSSI: A Neuroimaging Pilot Study.

In healthy individuals, stimuli associated with injury (such as those depicting blood or wounds) tend to evoke negative responses on both self-report and psychophysiological measures. Such an instinctive aversion makes sense from an evolutionary perspective. However, to engage in nonsuicidal self-injury (NSSI), this natural barrier must be overcome. The Benefits and Barriers model of NSSI predicts that people who engage in NSSI will show diminished aversion to NSSI-related stimuli compared to controls who do not engage in NSSI. We tested this hypothesis in a pilot study assessing 30 adults, 15 of whom reported current skin cutting and 15 of whom had no history of NSSI. Functional magnetic resonance imaging (fMRI) data were collected while participants viewed neutral, positive, and negative images selected from the International Affective Picture System. Participants also viewed NSSI images depicting razors, scalpels, or wounds caused by cutting. Compared to healthy control (HC) participants, the NSSI group showed decreased amygdala and increased cingulate cortex (CC) and orbitofrontal cortex (OFC) activation to NSSI and negative images. They also showed increased amygdalar and OFC activation to positive images. Neither the control group nor the NSSI group demonstrated significant activation within regions more typically associated with reward during any of the conditions; however, positive and negative affect ratings collected throughout the course of the task suggested that none of the affective conditions were viewed as rewarding. Although preliminary, these findings are suggestive of reduced limbic and greater cortical processing of NSSI stimuli in those with a history of this behavior. This has potentially important implications for current models of NSSI as well as for its treatment.

Amygdala Resting State Connectivity Differences between Bipolar II and Borderline Personality Disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar II disorder (BD II) have significant clinical overlap, leaving the potential for diagnostic inaccuracies and inadequate treatment recommendations. However, few studies have probed for clinical and neurobiological differences between the two disorders. Clinically, some prior studies have linked BPD with greater impulsivity and more frequent negative affective shifts than BD II, whereas previous neuroimaging studies have highlighted both similar and distinct neural abnormalities in BPD and BD II. Notably, no prior study has specifically targeted cortico-limbic neural differences, which have been hypothesized to underlie these core clinical differences. METHODS: Individuals with BPD (n = 14) and BD II (n = 15) completed various clinical measures and a resting state functional imaging scan at 3T. Whole-brain amygdala resting state functional connectivity (RSFC) was compared between the two groups. RESULTS: Relative to the BD II group, BPD participants reported significantly higher levels of impulsivity, trait anxiety, more frequent negative affective shifts, greater interpersonally reactive affective instability, lower overall functioning, and were characterized by lower amygdala-middle frontal gyrus RSFC. Lower amygdala-middle frontal gyrus RSFC was associated with greater impulsivity, trait anxiety, affective shifts, interpersonal affective reactivity, and functional impairment. LIMITATIONS: The current study consisted of small sample sizes and lacked a control group. CONCLUSIONS: This preliminary study suggests that amygdala-frontal RSFC may distinguish BPD from BD II. These results may guide future work aimed at identifying neural markers that can help disentangle these two disorders, leading to greater diagnostic accuracy and appropriate treatment implementation.

Prefrontal cortex activation during cognitive interference in nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI), deliberate behavior resulting in self-inflicted damage to oneself, is common, particularly among female adolescents, and may be a form of maladaptive emotion regulation. Cognitive interference, a specific type of processing associated with inhibiting prepotent responses in favor of less automatic ones, is utilized in treatment strategies to shift patients' thoughts and behaviors away from maladaptive responses and replace them with more adaptive ones. We examined cognitive interference processing using the Multi-Source Interference Task (MSIT) in females with NSSI behavior (n=15) and healthy control females (n=15). Functional magnetic resonance imaging (fMRI) data were collected concurrently. Results revealed similar between-group performance on the MSIT; however, women with NSSI behavior exhibited altered patterns of neural activation during the MSIT. Specifically, the NSSI group demonstrated increased cingulate cortex (CC) and decreased dorsolateral prefrontal cortex (DLPFC) activation compared to the control group. Further, within the NSSI group, DLPFC activation inversely correlated with emotional reactivity and self-reported impulsivity, suggesting that decreased DLPFC activation is associated with poorer emotional control and increased impulsivity. Taken together, these results indicate that women with NSSI behavior utilize different cortical areas during cognitive interference processing, which may have broader implications regarding the treatment efficacy of cognitive-based therapies.

Depression is associated with dimensional and categorical effects on white matter pathways.

BACKGROUND: Diffusion tensor imaging (DTI) studies report reduced fractional anisotropy (FA) in major depressive disorder (MDD). However, whether FA covaries with key depressive symptoms, such as anhedonia, is unclear. METHODS: Magnetic resonance imaging data were acquired from 38 unmedicated adults with MDD and 52 healthy controls. DTI metrics were extracted from regions of interest that have consistently shown reduced FA in MDD. Analyses focused first on identifying group differences, and then determining whether reduced FA in depressed adults was related to individual differences in anhedonia and depressive severity. To establish specificity to depression, these analyses controlled for symptoms of anxiety. RESULTS: Relative to controls, depressed adults showed reduced FA in the genu of the corpus callosum, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the anterior cingulate cortex, and the uncinate fasciculus (UF). In the depressed group, anhedonia negatively correlated with FA in the genu, cingulum, and UF, but positively correlated with radial diffusivity (RD)-a metric previously linked to demyelination-in the genu and ALIC. Depressive severity positively correlated with RD in the ALIC. These relationships remained significant after accounting for anxiety. CONCLUSION: Anhedonia was positively correlated with reduced FA and increased RD in white matter pathways that connect regions critical for value coding, representing stimulus-reward associations, and guiding value-based action selection. Thus, a cardinal symptom of MDD-anhedonia-was lawfully related to abnormalities in reward network connectivity.

Decreased Cingulate Cortex activation during cognitive control processing in bipolar disorder.

BACKGROUND: Cognitive deficits are well-documented in patients with bipolar disorder (BPD) and may impact the efficacy of psychotherapy. Cognitive control, a form of executive functioning, is often used therapeutically to shift patients' thoughts and behaviors from automatic, maladaptive responses to adaptive coping strategies. This study examined cognitive control processing in patients with BPD using the Multi-Source Interference Task (MSIT). METHOD: Twenty-nine patients diagnosed with BPD and 21 healthy control (HC) subjects completed the MSIT with concurrent functional magnetic resonance imaging (fMRI). RESULTS: Patients with BPD generally performed worse on the MSIT relative to HC participants; the BPD group had significantly lower performance accuracy and made more omission errors. Further, fMRI analyses revealed differential patterns of activation between the groups during the MSIT. Region of interest (ROI) analyses revealed that relative to HC participants, patients with BPD activated significantly fewer voxels within the cingulate cortex (CC) and more voxels within prefrontal cortex (PFC), although the PFC findings did not survive more stringent significance thresholds. LIMITATIONS: Patients and HCs were not matched for age, sex, and premorbid verbal IQ, however, these variables were controlled for statistically. Medication usage in the BPD group may have possibly impacted the results. Given a priori hypotheses, ROI analyses were utilized. CONCLUSIONS: Decreased CC activation and increased PFC activation may be associated with impaired cognitive control, demonstrated by BPD patients when completing the MSIT. Identifying the neural mechanisms which underlie key cognitive abnormalities in BPD may aid in clarifying the pathophysiology of this disorder and inform selection of potential targets for cognition remediation in BPD.

The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment.

The vast majority of states have enacted full or partial medical marijuana (MMJ) programs, causing the number of patients seeking certification for MMJ use to increase dramatically in recent years. Despite increased use of MMJ across the nation, no studies thus far have examined the specific impact of MMJ on cognitive function and related brain activation. In the present study, MMJ patients seeking treatment for a variety of documented medical conditions were assessed prior to initiating MMJ treatment and after 3 months of treatment as part of a larger longitudinal study. In order to examine the effect of MMJ treatment on task-related brain activation, MMJ patients completed the Multi-Source Interference Test (MSIT) while undergoing functional magnetic resonance imaging (fMRI). We also collected data regarding conventional medication use, clinical state, and health-related measures at each visit. Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre-treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use.

Citicoline Treatment Improves Measures of Impulsivity and Task Performance in Chronic Marijuana Smokers: A Pilot BOLD fMRI Study.

OBJECTIVE: Citicoline is an endogenous nucleotide that has historically been used to treat stroke, traumatic brain injury, and cognitive dysfunction. Research has also shown that citicoline treatment is associated with improved cognitive performance in substance-abusing populations. We hypothesized that marijuana (MJ) smokers who received citicoline would demonstrate improvement in cognitive performance as well as increased neural efficiency during tasks of cognitive control relative to those who received placebo. METHOD: The current study tested this hypothesis by examining the effects of citicoline in treatment-seeking chronic MJ smokers. In an 8-week double-blind, placebo-controlled study, 19 MJ smokers were randomly assigned via a double-blind procedure to the citicoline (8 Males, 2 Females) or placebo group (9 Males, 0 Females). All participants completed fMRI scanning at baseline and after 8 weeks of treatment during two cognitive measures of inhibitory processing, the Multi Source Interference Test (MSIT) and Stroop Color Word Test, and also completed the Barratt Impulsiveness Scale (BIS-11), a self-report measure of impulsivity. RESULTS: Following the 8 week trial, MJ smokers treated with citicoline demonstrated significantly lower levels of behavioral impulsivity, improved task accuracy on both the MSIT and Stroop tasks, and exhibited significantly different patterns of brain activation relative to baseline levels and relative to those who received placebo. CONCLUSIONS: Findings suggest that citicoline may facilitate the treatment of MJ use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs.

Elevated Preattentive Affective Processing in Individuals with Borderline Personality Disorder: A Preliminary fMRI Study.

BACKGROUND: Emotion dysregulation is central to the clinical conceptualization of borderline personality disorder (BPD), with individuals often displaying instability in mood and intense feelings of negative affect. Although existing data suggest important neural and behavioral differences in the emotion processing of individuals with BPD, studies thus far have only explored reactions to overt emotional information. Therefore, it is unclear if BPD-related emotional hypersensitivity extends to stimuli presented below the level of conscious awareness (preattentively). METHODS: Functional magnetic resonance imaging (fMRI) was used to measure neural responses to happy, angry, fearful, and neutral faces presented preattentively, using a backward masked affect paradigm. Given their tendency toward emotional hyperreactivity and altered amygdala and frontal activation, we hypothesized that individuals with BPD would demonstrate a distinct pattern of fMRI responses relative to those without BPD during the viewing of masked affective versus neutral faces in specific regions of interests (ROIs). RESULTS: RESULTS indicated that individuals with BPD demonstrated increases in frontal, cingulate, and amygdalar activation represented by number of voxels activated and demonstrated a different pattern of activity within the ROIs relative to those without BPD while viewing masked affective versus neutral faces. CONCLUSION: These findings suggest that in addition to the previously documented heightened responses to overt displays of emotion, individuals with BPD also demonstrate differential responses to positive and negative emotions, early in the processing stream, even before conscious awareness.

Worth the wait: effects of age of onset of marijuana use on white matter and impulsivity.

RATIONALE: Marijuana (MJ) use continues to rise, and as the perceived risk of using MJ approaches an all-time historic low, initiation of MJ use is occurring at even younger ages. As adolescence is a critical period of neuromaturation, teens and emerging adults are at greater risk for experiencing the negative effects of MJ on the brain. In particular, MJ use has been shown to be associated with alterations in frontal white matter microstructure, which may be related to reports of increased levels of impulsivity in this population. OBJECTIVES: The aim of this study was to examine the relationship between age of onset of MJ use, white matter microstructure, and reported impulsivity in chronic, heavy MJ smokers. METHODS: Twenty-five MJ smokers and 18 healthy controls underwent diffusion tensor imaging and completed the Barratt Impulsiveness Scale. MJ smokers were also divided into early onset (regular use prior to age 16) and late onset (age 16 or later) groups in order to clarify the impact of age of onset of MJ use on these variables. RESULTS: MJ smokers exhibited significantly reduced fractional anisotropy (FA) relative to controls, as well as higher levels of impulsivity. Earlier MJ onset was also associated with lower levels of FA. Interestingly, within the early onset group, higher impulsivity scores were correlated with lower FA, a relationship that was not observed in the late onset smokers. CONCLUSIONS: MJ use is associated with white matter development and reported impulsivity, particularly in early onset smokers.

Increased Rostral Anterior Cingulate Cortex Volume in Chronic Primary Insomnia.

BACKGROUND: Recent studies document alterations in cortical and subcortical volumes in patients with chronic primary insomnia (PI) in comparison with normal sleepers. We sought to confirm this observation in two previously studied PI cohorts. METHODS: Two separate and independent groups of unmedicated patients who met Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) criteria for PI were compared with two separate, healthy control groups (Study 1: PI = 20, controls = 15; Study 2: PI = 21, controls = 20). Both studies included 2 weeks of sleep diaries supplemented by wrist actigraphy. The 3.0 T MRI-derived rostral anterior cingulate cortex (rACC) volumes were measured with FreeSurfer image analysis suite (version 5.0) and results normalized to total intracranial volume (ICV). Unpaired t-tests (two-tailed) were used to compare rACC volumes between groups. Post hoc correlations of rACC volumes to insomnia severity measures were performed (uncorrected for multiplicity). RESULTS: Both studies demonstrated increases in normalized rACC volume in PI compared with control patients (Study 1: right side P = 0.05, left side P = 0.03; Study 2: right side P = 0.03, left side P = 0.02). In PI patients from Study 1, right rACC volume was correlated with sleep onset latency (SOL) by both diary (r = 0.51, P = 0.02) and actigraphy (r = 0.50, P = 0.03), and with sleep efficiency by actigraphy (r = -0.57, P = 0.01); left rACC volume was correlated with SOL by diary (r = 0.48, P = 0.04), and wake after sleep onset (WASO) (r = 0.49, P = 0.03) and sleep efficiency (r = -0.49, P = 0.03) by actigraphy. In Study 2, right rACC volume was correlated with SOL by diary (r = 0.44, P = 0.05) in PI patients. CONCLUSIONS: Rostral ACC volumes are larger in patients with PI compared with control patients. Clinical severity measures in PI correlate with rACC volumes. These data may reflect a compensatory brain response to chronic insomnia and may represent a marker of resilience to depressive illness. CITATION: Winkelman JW; Plante DT; Schoerning L; Benson K; Buxton OM; O'Connor SP; Jensen JE; Renshaw PF; Gonenc A. Increased rostral anterior cingulate cortex volume in chronic primary insomnia. SLEEP 2013;36(7):991-998.

Altered affective processing in bipolar disorder: an fMRI study.

BACKGROUND: Previous studies have reported that patients with bipolar disorder (BPD) exhibit altered emotional processing and regulation. However, results remain largely inconsistent across studies. The aim of the current study was to further examine affective processing in patients with bipolar disorder. METHODS: Twenty-three patients diagnosed with BPD (Type I) and 18 healthy matched controls completed a backward-masked affect paradigm while undergoing functional magnetic resonance imaging. Participants also completed a computerized, overt task of facial emotional discrimination after scanning. RESULTS: Results demonstrated altered affective processing of happy and fearful stimuli in bipolar participants in the amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) relative to controls. BPD participants also displayed significant deficits in identifying fearful facial affect. LIMITATIONS: This study has a moderate sample size, and the patients with BPD were significantly older than the healthy control participants; this did not appear to impact results, and although statistically significant, it is not likely biologically significant. CONCLUSIONS: These findings may have implications for patients with BPD, as altered affective processing could result in deficits in reading social cues.

Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T.

The pilot study aimed at examining the neural glutamatergic activity in autism. Seven adolescent males (mean age: 14 ± 1.8; age range: 12-17 years) with intact intellectual capacity (mean IQ: 108 ± 14.26; IQ range: 85-127) suffering from autistic disorder and an equal number of age- and sex-matched healthy controls underwent a two-dimensional magnetic resonance spectroscopy scan at 4T. Results indicated significantly high glutamate (Glu) levels in the anterior cingulate cortex of autistic disorder versus control subjects (paired t test p = 0.01) and a trend for lower Glu in the right medial temporal lobe, which was not statistically different between the groups (paired t test p = 0.06). These preliminary findings support the glutamatergic dysregulation hypothesis in autism and need to be replicated in a larger sample.

A magnetic resonance spectroscopy study of the anterior cingulate cortex in youth with emotional dysregulation.

BACKGROUND: The main aim of this study was to use proton Magnetic Resonance Spectroscopy (MRS) to identify brain biomarkers for emotional dysregulation in youth as measured by subscales of the Child Behavior Checklist (CBCL). METHODS: We measured glutamate (Glu) concentrations in the anterior cingulated cortex (ACC) of 37 pediatric subjects (aged 6-17 years) using high field (4.0 Tesla) proton Magnetic Resonance Spectroscopy (MRS). Subjects were grouped based on combined T scores on three subscales (Anxiety/Depression, Aggression and Attention) of the CBCL previously associated with deficits in the regulation of emotion. Subjects were stratified into those with high (> 180) (N=10) and low (< 180) (N=27) scores. LIMITATIONS: Limitations include small sample size, wide age range studied, focus on Anterior Cingulate Cortex (ACC) only, and that some subjects received psychopharmacological treatments. RESULTS: We found a statistically significant correlation between Glu levels in the ACC and CBCL dysregulation profile scores among subjects with high dysregulation profile scores. CONCLUSIONS: These results suggest that glutamatergic dysregulation in the ACC may represent a useful biomarker of emotional dysregulation in youth. Further investigation into the causality, time line and utility as a predictive metric is warranted.

Age of onset of marijuana use impacts inhibitory processing.

Difficulties in the ability to successfully inhibit impulsive behaviors have been reported in marijuana (MJ) smokers, yet few studies have made direct comparisons between early (prior to age 16) and late (age 16 or later) onset MJ smokers, specifically during behavioral inhibition tasks. The current study utilized the Multi-Source Interference Task (MSIT) during functional magnetic resonance imaging (fMRI) in chronic, heavy MJ smokers and healthy non-MJ smoking controls which revealed a more focal pattern of anterior cingulate activity in controls relative to smokers. Early onset smokers had more focal activation but tended to make more errors of commission relative to late onset smokers, suggesting a possible neural adaptation despite difficulty with behavioral inhibition. Further investigation is warranted, as early exposure to MJ may result in reorganization of critical brain regions.