J.J. Mann

Evaluation of volume-based and surface-based brain image registration methods

Establishing correspondences across brains for the purposes of comparison and group analysis is almost universally done by registering images to one another either directly or via a template. However, there are many registration algorithms to choose from. A recent evaluation of fully automated nonlinear deformation methods applied to brain image registration was restricted to volume-based methods. The present study is the first that directly compares some of the most accurate of these volume registration methods with surface registration methods, as well as the first study to compare registrations of whole-head and brain-only (de-skulled) images. We used permutation tests to compare the overlap or Hausdorff distance performance for more than 16,000 registrations between 80 manually labeled brain images. We compared every combination of volume-based and surface-based labels, registration, and evaluation. Our primary findings are the following: 1. de-skulling aids volume registration methods; 2. custom-made optimal average templates improve registration over direct pairwise registration; and 3. resampling volume labels on surfaces or converting surface labels to volumes introduces distortions that preclude a fair comparison between the highest ranking volume and surface registration methods using present resampling methods. From the results of this study, we recommend constructing a custom template from a limited sample drawn from the same or a similar representative population, using the same algorithm used for registering brains to the template.

Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt

BACKGROUND Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. METHOD Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n = 72) were compared to medication-free depressed subjects with no history of suicidal behavior (n = 80) and healthy volunteers (n = 56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se.

Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression

Alterations in a number of neurobiological systems have been associated with suicidal behavior including the serotonergic and noradrenergic systems and the hypothalamic-pituitary-adrenal axis. Altered functioning of these systems may stem from both genetic and developmental causes. Adversity in early-life has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in functioning of neurobiological systems. Moreover, the interaction of early-life experiences of adversity and genetic vulnerability is increasingly thought to play a role, including via epigenetic mechanisms.

Bipolar I and II versus unipolar depression: clinical differences and impulsivity/aggression traits

OBJECTIVE To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular. METHODS Six hundred and eighty-five (n=685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n=455), Bipolar I (BP-I) disorder (n=151), and Bipolar II (BP-II) (n=79) disorder were compared in terms of their socio-demographic and clinical characteristics. RESULTS Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP-I patients were significantly more often unemployed that UP patients. CONCLUSION Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics.

The effect of social adjustment and attachment style on suicidal behaviour.

Lizardi D, Grunebaum MF, Burke A, Stanley B, Mann JJ, Harkavy‐Friedman J, Oquendo M. The effect of social adjustment and attachment style on suicidal behaviour.

Clinical features of depressed patients with or without a family history of alcoholism

Objective:  To compare clinical features of depressed subjects without alcoholism but with a family history of alcoholism to a depressed group without alcoholism and without a family history of alcoholism.

Personality disorder assessments in acute depressive episodes: stability at follow-up.

Abstract Assessment of personality disorders during the acute phase of major depression may be invalidated by the potential distortion of personality traits in depressed mood states. However, few studies have tested this assumption. We examined the stability of personality disorder diagnoses during and then after a major depressive episode (MDE). Subjects with major depression (N = 82) completed the 17-item Hamilton Depression Scale (HAM-17) and the Structured Clinical Interview for Axis II both at baseline during an MDE and at 3-month follow-up. We compared subjects who continued to meet DSM-IV criteria for the same Axis II diagnoses with patients whose diagnosis changed and patients with no DSM-IV personality disorder to determine the relationship to major depression and its severity. Sixty-six percent of subjects met DSM-IV criteria for at least one Axis II diagnosis at baseline and 80% had the same personality disorder diagnoses at follow-up. Thirty-four percent had a full remission of MDE at 3-month follow-up. Instability of Axis II diagnosis was associated with number of Axis II diagnoses at baseline (p = .036) and Hispanic ethnicity (p = .013). HAM-17 score change was unrelated to differences in the number of symptoms of personality disorders from baseline to follow-up, nor was remission from MDE on follow-up. Axis II diagnoses in acutely depressed patients reassessed after 3 months are often stable and not associated with remission of or improvement in major depression.

An improved method for voxel-based partial volume correction in PET and SPECT

The limited spatial resolution of PET and SPECT leads to partial volume effects (PVE) that limit the quantification accuracy of these modalities. Partial volume correction (PVC) methods have been developed in the past utilizing high-resolution MRI images in combination with the known point-spread function (PSF) of the system. These methods can be broadly divided into voxel-based and volume of interest (VOI)-based methods. The voxel-based approach (Meltzer et al., JCAT, 1990, 14: 561–70) is based on segmentation of the MRI images into regions corresponding to gray matter (GM), white matter (WM) and cerebrospinal fluid. The correction is performed by assuming a uniform distribution within each region. A separate estimate of the WM value is required, and corrected values are obtained for voxels in the GM region only (target region). We have developed a new voxel-based PVC method in which a larger number of regions can be used, thereby reducing any bias introduced by the uniformity assumption. Also, with our new method, no estimate of the WM value is needed, and corrected values are obtained for each voxel in the whole image — not just one target region. Our new method (Multi-Target Correction (MTC)) involves an initial step using a VOI-based PVC method (Rousset et al. JNM, 1998, 39: 904–11). For the purpose of evaluation, simulated PET images were generated using a digital brain phantom, assuming a Gaussian PSF with 6 mm FWHM. The sensitivity of the method to various factors, such as errors in PSF determination, PET/MRI co-registration, and MRI segmentation, was determined. In addition, we examined the effects of tissue heterogeneity and noise. MTC was also applied to a PET study performed on a cylindrical phantom with 6 spherical inserts (diameters: 10, 12, 16, 20, 25, 32 mm, insert-to-background ratio 6) using an ECAT HR+ scanner (Siemens, Knoxville, TN, USA). MTC was performed using 7 VOIs. The simulations showed that MTC was reasonably robust with respect to errors in FWHM ( 2 mm), co-registration errors (<4.5 mm, or <6-), GM region dilation, as well as to region heterogeneity and noise. It was, however, quite sensitive to GM region erosion. Results from the phantom study are presented in the Fig. 1 below, showing that the whole image is corrected with improved contrast and definition of all the inserts. Further evaluations with human PET data are required before MTC can be used routinely.

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

Gamma‐amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non‐attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA‐seq was used to assay isoform‐level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non‐suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

An effective suicide prevention program in the Israeli Defense Forces: A cohort study

OBJECTIVE To evaluate the effectiveness of the IDF Suicide Prevention Program, implemented since 2006. DESIGN Quasi-experimental (before and after) cohort study. PARTICIPANTS Two cohorts of IDF mandatory service soldiers: the first inducted prior to (1992-2005, n=766,107) and the second subsequent to (2006-2012, n=405,252) the launching of the intervention program. EXPOSURE The IDF Suicide Prevention Program is a population-based program, incorporating: reducing weapon availability, de-stigmatizing help-seeking behavior, integrating mental health officers into service units, and training commanders and soldiers to recognize suicide risk factors and warning signs. MAIN OUTCOME MEASURE Suicide rate and time to suicide in cohorts before and after exposure to the Suicide Prevention Program. RESULTS Trend analysis showed lower suicide rates in the cohort after intervention. The hazard ratio for the intervention effect on time to suicide was 0.44 (95% CI=0.34-0.56, P<.001) among males. Lower risk was associated with: male gender; born in Israel; higher socio-economic status; higher intelligence score; and serving in a combat unit (HR=0.43: 95% CI=0.33-0.55). CONCLUSIONS There was a 57% decrease in the suicide rate following the administration of the IDF Suicide Prevention Program. The effect of the intervention appears to be related to use of a weapon, and being able to benefit from improved help-seeking and de-stigmatization. Future efforts should seek to extend the programs prevention reach to other demographic groups of soldiers. The success of the IDF program may inform suicide prevention in other military organizations and in the civilian sector.