Multi-modal risk factors differentiate suicide attempters from ideators in military veterans with major depressive disorder.

BACKGROUND: The suicide rate for United States military veterans is 1.5× higher than that of non-veterans. To meaningfully advance suicide prevention efforts, research is needed to delineate factors that differentiate veterans with suicide attempt/s, particularly in high-risk groups, e.g., major depressive disorder (MDD), from those with suicidal ideation (no history of attempt/s). The current study aimed to identify clinical, neurocognitive, and neuroimaging variables that differentiate suicide-severity groups in veterans with MDD. METHODS: Sixty-eight veterans with a DSM-5 diagnosis of MDD, including those with no ideation or suicide attempt (N = 21; MDD-SI/SA), ideation-only (N = 17; MDD + SI), and one-or-more suicide attempts (N = 30; MDD + SA; aborted, interrupted, actual attempts), participated in this study. Participants underwent a structured diagnostic interview, neurocognitive assessment, and 3 T-structural/diffusion tensor magnetic-resonance-imaging (MRI). Multinomial logistic regression models were conducted to identify variables that differentiated groups with respect to the severity of suicidal behavior. RESULTS: Relative to veterans with MDD-SI/SA, those with MDD + SA had significantly higher left cingulum fractional anisotropy, decreased attentional control on emotional-Stroop, and faster response time with intact accuracy on Go/No-Go. Relative to MDD + SI, MDD + SA had higher left cingulum fractional anisotropy and faster response time with intact accuracy on Go/No-Go. LIMITATIONS: Findings are based on retrospective, cross-sectional data and cannot identify causal relationships. Also, a healthy control group was not included given the study's focus on differentiating suicide profiles in MDD. CONCLUSIONS: This study suggests that MRI and neurocognition differentiate veterans with MDD along the suicide-risk spectrum and could inform suicide-risk stratification and prevention efforts in veterans and other vulnerable populations.

Neural correlates of impulsivity in bipolar disorder: A systematic review and clinical implications.

Impulsivity is a common feature of bipolar disorder (BD) with ramifications for functional impairment and premature mortality. This PRISMA-guided systematic review aims to integrate findings on the neurocircuitry associated with impulsivity in BD. We searched for functional neuroimaging studies that examined rapid-response impulsivity and choice impulsivity using the Go/No-Go Task, Stop-Signal Task, and Delay Discounting Task. Findings from 33 studies were synthesized with an emphasis on the effect of mood state of the sample and affective salience of the task. Results suggest trait-like brain activation abnormalities in regions implicated in impulsivity that persist across mood states. During rapid-response inhibition, BD exhibit under-activation of key frontal, insular, parietal, cingulate, and thalamic regions, but over-activation of these regions when the task involves emotional stimuli. Delay discounting tasks with functional neuroimaging in BD are lacking, but hyperactivity of orbitofrontal and striatal regions associated with reward hypersensitivity may be related to difficulty delaying gratification. We propose a working model of neurocircuitry dysfunction underlying behavioral impulsivity in BD. Clinical implications and future directions are discussed.

Smaller rostral cingulate volume and psychosocial correlates in veterans at risk for suicide.

Suicide research/clinical work remain in dire need of effective tools that can better predict suicidal behavior. A growing body of literature has started to focus on the role that neuroimaging may play in helping explain the path towards suicide. Specifically, structural alterations of rostral anterior cingulate cortex (rost-ACC) may represent a biological marker and/or indicator of suicide risk in Major Depressive Disorder (MDD). Furthermore, the construct of "grit," defined as perseverance for goal-attainment and shown to be associated with suicidality, is modulated by rost-ACC. The aim was to examine relationships among rost-ACC gray matter volume, grit, and suicidality in U.S. Military Veterans. Participants were age-and-sex-matched Veterans with MDD: with suicide attempt (MDD+SA:n = 23) and without (MDD-SA:n = 37). Groups did not differ in depression symptomatology. Participants underwent diagnostic interview, clinical symptom assessment, and 3T-MRI-scan. A Group (SA-vs.-No-SA) x Cingulate-region (rostral-caudal-posterior) x Hemisphere (left-right) mixed-model-multivariate-ANOVA was conducted. Left-rost-ACC was significantly smaller in MDD+SA, Group x Cingulate-region x Hemisphere-interaction. Lower grit and less left-rost-ACC gray matter each predicted suicide attempt history, but grit level was a more robust predictor of SA. Both structural alterations of rost-ACC and grit level represent potentially valuable tools for suicide risk assessment.

Hyperreactivity and Impaired Habituation of Startle Amplitude During Unpleasant Pictures in Borderline but Not Schizotypal Personality Disorder: Quantifying Emotion Dysregulation.

BACKGROUND: Borderline personality disorder (BPD) is characterized by greater intensity of reactions to unpleasant emotional cues and a slower-than-normal return of these responses to baseline. Habituation is defined as decreased response to repeated stimulation. Affect-modulated startle (AMS), a translational psychophysiological approach, is mediated by the amygdala and used to study emotion processing in both humans and animals. This is the first study to examine the specificity of habituation anomalies in BPD during passive emotional and neutral picture processing. METHODS: A total of 90 participants were studied: patients with BPD (n = 35), patients with schizotypal personality disorder (n = 26; included as a psychopathological comparison group), and healthy control subjects (n = 29). Participants received rigorous clinical assessments, and patients were unmedicated. AMS was examined during a series of intermixed unpleasant, neutral, and pleasant pictures. RESULTS: Compared with the other groups, patients with BPD showed greater overall AMS during unpleasant pictures and prolonged habituation of startle amplitude during unpleasant pictures from early to later trials. The groups did not differ in AMS during neutral or pleasant pictures or self-reported picture valence. Among the patients with BPD, prolonged habituation to unpleasant pictures was associated with greater symptom severity and suicidal/self-harming behavior. CONCLUSIONS: These findings 1) indicate that abnormal processing of and habituation to unpleasant pictures is observed in BPD but not schizotypal personality disorder, suggesting that these deficits are not simply characteristics of personality disorders in general; 2) are consistent with studies showing deficient amygdala habituation to unpleasant pictures in BPD; and 3) have significant implications for clinical assessment and treatment of BPD, e.g., alternative therapies for BPD such as gradual exposure to unpleasant emotional stimuli or amygdala neurofeedback may aid habituation deficits.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Cingulate and temporal lobe fractional anisotropy in schizotypal personality disorder.

BACKGROUND: Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD. AIMS: The study aim was to examine temporal and prefrontal white matter FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls (HCs). We hypothesized that compared with HCs, SPD patients would exhibit lower FA in temporal lobe and anterior cingulum regions but relative sparing in prefrontal regions. METHOD: We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BAs 44, 45, and 46), temporal lobe (BAs 22, 21, and 20), and cingulum (BAs 25, 24, 31, 23, and 29) regions with a series of analyses using multivariate analysis of variance. RESULTS: Compared with HCs, the SPD group had significantly lower FA in the left temporal lobe but not prefrontal regions. In the cingulum, FA was lower in the SPD group in the posterior regions (BAs 31 and 23), higher in the anterior (BA 25) regions and lower overall in the right but not the left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech). CONCLUSIONS: Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.

Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia.

Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI ( patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule.

Anomalous Amygdala Habituation to Unpleasant Stimuli Among Unmedicated Individuals With Borderline Personality Disorder and a History of Self-Harming Behavior.

Self-harming behavior (SB) is one of the diagnostic criteria for borderline personality disorder (BPD). However, it is not exhibited by all individuals with BPD. Furthermore, studies examining the neural correlates of SB in BPD are lacking. Given research showing that BPD patients have difficulty habituating to affective stimuli, this study investigated whether anomalous amygdala activation is specific to BPD patients with SB. The authors used fMRI to compare amygdala activation in BPD patients with SB (n = 15) to BPD patients without SB (n = 18) and healthy controls (n = 32) during a task involving pleasant, neutral, and unpleasant pictures, presented twice. BPD patients with SB demonstrated greater amygdala activity during the second presentation of unpleasant pictures. Results highlight neurobiological differences in BPD patients with and without SB and suggest that anomalous amygdala habituation to unpleasant stimuli may be related to SB.

Diffusion tensor anisotropy in the cingulate gyrus in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting reduced volume, altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a 3T Siemens scanner to acquire structural and diffusion tensor imaging in age-and sex-matched groups of 41 adults with chronic schizophrenia, 6 adults with recent-onset schizophrenia, and 38 healthy control subjects. We manually traced the anterior and posterior cingulate gyri on all subjects and then compared the volume and anisotropy across groups for the left and right anterior and posterior cingulate gyri. The anterior cingulate gyrus was divided axially into six equal segments, and the posterior cingulate gyrus into two segments. Volume was calculated for the anterior and posterior gyri, and average anisotropy was then calculated for each individual segment, looking separately at gray and white matter. We found decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls. Additionally, in both gray and white matter of the cingulate, we found that recent-onset patients had the highest anisotropy, chronic patients had the lowest, and controls were intermediate. These results provide additional evidence for the presence of both white and gray matter abnormalities in the cingulate gyrus, which has been implicated in schizophrenia.

Basal Ganglia activity in pathological gambling: a fluorodeoxyglucose-positron emission tomography study.

BACKGROUND: Pathological gambling (PG) is a disorder classified as an impulse control disorder (DSM-IV) bridging impulsive, compulsive and addictive behaviors. The striatum and thalamus are supposed to be involved in the pathophysiological substrate of these behaviors. An increased relative glucose metabolic rate (rGMR) in patients with a diagnosis of PG had previously been reported in the medial and orbitofrontal cortex. We extended our studies to include functional alterations of the striatum and thalamus in a cohort of patients with PG before and after treatment with lithium. METHODS: Twenty-one patients with PG who met lifetime comorbid bipolar spectrum diagnoses and a comparison group of 21 age- and sex-matched controls underwent a baseline positron emission tomography (PET) scan. Sixteen of these patients entered a randomized double-blind placebo-controlled parallel-group-design trial of lithium and underwent a follow-up PET scan at week 10. Anatomical MRI were obtained and the structures outlined on consecutive axial slices. These individual hand-drawn templates were used to identify structures on the PET scan of each patient, and the rGMR was measured. RESULTS: The PG patients had a decrement of the rGMR in the ventral parts of the striatum and thalamus, and an increment of the rGMR in the dorsal parts as compared with the controls. Lithium treatment increased the ventral caudate rGMR to a trend level in the patients, but had no effect on the metabolism of either the putamen or the thalamus. CONCLUSION: Because of their extensive connectivity to the frontal cortex, striatal and thalamic functional alteration may contribute to faulty decision making processes in PG patients. By increasing the ventral rGMR of the caudate nucleus, lithium treatment may reduce cognitive dysfunction and symptoms in PG patients.

Age and diffusion tensor anisotropy in adolescent and adult patients with schizophrenia.

Findings of white matter pathology as indicated by diffusion tensor anisotropy values in schizophrenia are well established, but the differences in this measure between the onset of the disease and the chronic state are not well known. To investigate the differences between these states in the progression of the disease of schizophrenia we acquired 1.5 T diffusion tensor anisotropy images on 35 adult patients with schizophrenia and schizoaffective disorder, 23 adolescents having their first psychotic episode, and age and sex matched controls (33 adults and 15 adolescents). Regions of interest in major cortical white matter tracts chosen as salient to the prefrontal executive deficit in schizophrenia were assessed using stereotaxic coordinates from the Talairach and Tournoux atlas. Regions of each tract along anterior-posterior and/or inferior-superior directions in both hemispheres were evaluated in multiway ANOVA. Tracts between the frontal lobe and other brain regions, but not temporal, occipital and interhemispheric tracts, showed a differential aging pattern in normals and patients indicating that the white matter pathology in these regions is not stable between the onset and the chronic state in schizophrenia. This suggests that tracts involved in the connectivity of the temporal lobe white matter deficits were already well in place in adolescent patients, while frontal lobe pathology continues to develop from adolescence to adulthood.

Reprint of: F-18Fluorodeoxyglucose positron emission tomography studies of the schizophrenia spectrum: The legacy of Monte S. Buchsbaum, M.D.

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response.

F-18Fluorodeoxyglucose positron emission tomography studies of the schizophrenia spectrum: The legacy of Monte S. Buchsbaum, M.D.

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response.

Short communication: Diffusion tensor anisotropy in the cingulate in borderline and schizotypal personality disorder.

Despite considerable phenomentological differences between borderline personality disorder (BPD) and schizotypal personality disorder (SPD), research increasingly provides evidence that some BPD symptoms overlap with SPD symptoms (e.g., disturbed cognitions). We examined the cingulate, a brain region implicated in the pathophysiology of both disorders, to determine similarities/differences between the groups, and similarities/differences from healthy controls (HC's). 3T structural and diffusion tensor magnetic resonance imaging scans were acquired in BPD (n = 27), SPD (n = 32), HC's (n = 34). Results revealed that BPD patients exhibited significantly lower FA in posterior cingulate white matter compared to HC's (p = 0.04), but SPD patients did not.

Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating.

Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eyeblink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrates that frontal-striatal-thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions-dorsolateral prefrontal cortex (Brodmann areas 46, 9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus. In contrast, schizophrenia patients failed to show differential BOLD responses in FST circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.

Cortical gray and white matter volume in unmedicated schizotypal and schizophrenia patients.

Magnetic resonance imaging (MRI) studies have revealed fronto-temporal cortical gray matter volume reductions in schizophrenia. However, to date studies have not examined whether age- and sex-matched unmedicated schizotypal personality disorder (SPD) patients share some or all of the structural brain-imaging characteristics of schizophrenia patients. We examined cortical gray/white matter volumes in a large sample of unmedicated schizophrenia-spectrum patients (n=79 SPD, n=57 schizophrenia) and 148 healthy controls. MRI images were reoriented to standard position parallel to the anterior-posterior commissure line, segmented into gray and white matter tissue types, and assigned to Brodmann areas (BAs) using a postmortem-histological atlas. Group differences in regional volume of gray and white matter in the BAs were examined with MANOVA. Schizophrenia patients had significantly reduced gray matter volume widely across the cortex but more marked in frontal and temporal lobes. SPD patients had reductions in the same regions but only about half that observed in schizophrenia and sparing in key regions including BA10. In schizophrenia, greater fronto-temporal volume loss was associated with greater negative symptom severity and in SPD, greater interpersonal and cognitive impairment. Overall, our findings suggest that increased prefrontal volume in BA10 and sparing of volume loss in temporal cortex (BAs 22 and 20) may be a protective factor in SPD which reduces vulnerability to psychosis.

FDG-PET study in pathological gamblers. 1. Lithium increases orbitofrontal, dorsolateral and cingulate metabolism.

BACKGROUND: Pathological gambling affects 1-3% of the adult population, and has high comorbidity. Although mood stabilizers and serotonin reuptake inhibitors have shown some efficacy in the treatment of this condition, there is little known about how these pharmacological interventions work. METHODS: Twenty-one patients with pathological gambling, who met lifetime comorbid bipolar spectrum diagnoses, received baseline PET scans. Sixteen of these patients were entered into a randomized double-blind placebo-controlled parallel group design trial of lithium, and received follow-up PET scans at 10 weeks. A comparison group of 32 age- and sex-matched controls was also available. Anatomical MRIs were obtained as a structural template. RESULTS: In patients with pathological gambling, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to normal controls. Lithium increased rGMR further in the orbitofrontal cortex, heightening normal/patient differences, but it also increased the rGMR of the posterior cingulate and the dorsolateral frontal cortex normalizing the metabolic rate in these regions. CONCLUSION: Cortical areas implicated in impulse control disorders show increased rGMR in pathological gambling at baseline. Lithium treatment, while alleviating the symptoms, further increases rGMR in these areas.

Increased white matter metabolic rates in autism spectrum disorder and schizophrenia.

Both autism spectrum disorder (ASD) and schizophrenia are often characterized as disorders of white matter integrity. Multimodal investigations have reported elevated metabolic rates, cerebral perfusion and basal activity in various white matter regions in schizophrenia, but none of these functions has previously been studied in ASD. We used 18fluorodeoxyglucose positron emission tomography to compare white matter metabolic rates in subjects with ASD (n = 25) to those with schizophrenia (n = 41) and healthy controls (n = 55) across a wide range of stereotaxically placed regions-of-interest. Both subjects with ASD and schizophrenia showed increased metabolic rates across the white matter regions assessed, including internal capsule, corpus callosum, and white matter in the frontal and temporal lobes. These increases were more pronounced, more widespread and more asymmetrical in subjects with ASD than in those with schizophrenia. The highest metabolic increases in both disorders were seen in the prefrontal white matter and anterior limb of the internal capsule. Compared to normal controls, differences in gray matter metabolism were less prominent and differences in adjacent white matter metabolism were more prominent in subjects with ASD than in those with schizophrenia. Autism spectrum disorder and schizophrenia are associated with heightened metabolic activity throughout the white matter. Unlike in the gray matter, the vector of white matter metabolic abnormalities appears to be similar in ASD and schizophrenia, may reflect inefficient functional connectivity with compensatory hypermetabolism, and may be a common feature of neurodevelopmental disorders.

Relative glucose metabolic rate higher in white matter in patients with schizophrenia.

OBJECTIVE: There is increasing evidence demonstrating that circuits involving the frontal lobe, striatum, temporal lobe, and cerebellum are abnormal in individuals with schizophrenia, which suggests that metabolic activity in the white matter connecting these areas should be investigated. METHOD: The authors obtained [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and matching T1-weighted magnetic resonance imaging (MRI) on 170 subjects. Participants were 103 normal volunteers and 67 unmedicated patients with schizophrenia (N=61) or schizoaffective disorder (N=6). The images were coregistered and warped to standard space for significance probability mapping. RESULTS: Compared with normal volunteers, patients showed higher relative metabolic rates in the frontal white matter, corpus callosum, superior longitudinal fasciculus, and white matter core of the temporal lobe. Elevated activity in white matter was most pronounced in the center of large white matter tracts, especially the frontal parts of the brain and the internal capsule. The white matter elevation did not appear to be entirely related to changes in gray matter/white matter brain proportions, whole brain metabolic rate bias, or excess head motion in patients, but this cannot be ruled out without absolute glucose determinations. Patients also showed significantly lower relative glucose metabolism in the frontal and temporal lobes, caudate nucleus, cingulate gyrus, and mediodorsal nucleus of the thalamus relative to normal volunteers, which is consistent with earlier studies. CONCLUSIONS: In comparisons of unmedicated schizophrenia patients with normal volunteers, relative metabolic increases are apparent in white matter in patients with schizophrenia as well as decreases in gray matter. Inefficiency in brain circuitry, defects in white matter leading to enhanced energy need, white matter damage, and alterations in axon packing density are among the possible explanations for these schizophrenia-related findings of relatively increased metabolism in white matter.

Amygdala-prefrontal disconnection in borderline personality disorder.

Abnormal fronto-amygdala circuitry has been implicated in impulsive aggression, a core symptom of borderline personality disorder (BPD). We examined relative glucose metabolic rate (rGMR) at rest and after m-CPP (meta-chloropiperazine) with (18)fluorodeoxyglucose (FDG) with positron emission tomography (PET) in 26 impulsive aggressive (IED)-BPD patients and 24 controls. Brain edges/amygdala were visually traced on MRI scans co-registered to PET scans; rGMR was obtained for ventral and dorsal regions of the amygdala and Brodmann areas within the prefrontal cortex (PFC). Correlation coefficients were calculated between rGMR for dorsal/ventral amygdala regions and PFC. Additionally, amygdala volumes and rGMR were examined in BPD and controls. Correlations PFC/amygdala Placebo: Controls showed significant positive correlations between right orbitofrontal (OFC) and ventral, but not dorsal, amygdala. Patients showed only weak correlations between amygdala and the anterior PFC, with no distinction between dorsal and ventral amygdala. Correlations PFC/amygdala: m-CPP response: Controls showed positive correlations between OFC and amygdala regions, whereas patients showed positive correlations between dorsolateral PFC and amygdala. Group differences between interregional correlational matrices were highly significant. Amygdala volume/metabolism: No group differences were found for amygdala volume, or metabolism in the placebo condition or in response to meta-chloropiperazine (m-CPP). We demonstrated a tight coupling of metabolic activity between right OFC and ventral amygdala in healthy subjects with dorsoventral differences in amygdala circuitry, not present in IED-BPD. We demonstrated no significant differences in amygdala volumes or metabolism between BPD patients and controls.