John P. Hatch

Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder

Our knowledge about the neurobiology of suicide is limited. It has been proposed that suicidal behavior generally requires biological abnormalities concomitant with the personality trait of impulsivity/aggression, besides an acute psychiatric illness or psychosocial stressor. We investigated fronto-limbic anatomical brain abnormalities in suicidal and non-suicidal adult female patients with unipolar depression. Our sample consisted of seven suicidal unipolar patients, 10 non-suicidal unipolar patients and 17 healthy female comparison subjects. The criterion for suicidality was one or more documented lifetime suicide attempts. A 1.5T GE Signa Imaging System running version Signa 5.4.3 software was used to acquire the magnetic resonance imaging images. All anatomical structures were measured blindly, with the subjects’ identities and group assignments masked. We used analysis of covariance with age and intracranial volume as covariates and the Tukey–Kramer procedure to compare suicidal patients, non-suicidal patients and healthy comparison subjects. Suicidal patients had smaller right and left orbitofrontal cortex gray matter volumes compared with healthy comparison subjects. Suicidal patients had larger right amygdala volumes than non-suicidal patients. Abnormalities in the orbitofrontal cortex and amygdala in suicidal patients may impair decision-making and predispose these patients to act more impulsively and to attempt suicide.

Reduced left anterior cingulate volumes in untreated bipolar patients

BACKGROUNDnFunctional and morphologic abnormalities of the cingulate cortex have been reported in mood disorder patients. To examine the involvement of anatomic abnormalities of the cingulate in bipolar disorder, we measured the volumes of this structure in untreated and lithium-treated bipolar patients and healthy control subjects, using magnetic resonance imaging (MRI).nnnMETHODSnThe volumes of gray matter at the right and left anterior and posterior cingulate cortices were measured in 11 bipolar patients not taking any psychotropic medications (aged 38 +/- 11 years, 5 women), 16 bipolar patients treated with lithium monotherapy (aged 33 +/- 11 years, 7 women), and 39 healthy control subjects (aged 37 +/- 10 years, 14 women). Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T, and were done blindly.nnnRESULTSnUsing analysis of covariance with age and intracranial volume as covariates, we found that untreated bipolar patients had decreased left anterior cingulate volumes compared with healthy control subjects [2.4 +/-.3 cm3 and 2.9 +/-.6 cm3, respectively; F(1,58) = 6.4, p =.042] and compared with lithium-treated patients [3.3 +/-.5 cm3; F(1,58) = 11.7, p =.003]. The cingulate volumes in lithium-treated patients were not significantly different from those of healthy control subjects.nnnCONCLUSIONSnOur findings indicate that anatomic abnormalities in left anterior cingulate are present in bipolar patients. Furthermore, our results suggest that lithium treatment might influence cingulate volumes in bipolar patients, which could possibly reflect postulated neuroprotective effects of lithium.

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age±s.d.=34.3±11.5 years) and 15 healthy comparison subjects (37.7±12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.

Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder.

BACKGROUNDnIn vivo imaging studies in adult bipolar patients have suggested enlargement of the amygdala. It is not known whether this abnormality is already present early in the illness course or whether it develops later in life. We conducted a morphometric MRI study to examine the size of specific temporal lobe structures in adolescents and young adults with bipolar disorder and healthy control subjects, as well as their relationship with age, to examine possible neurodevelopmental abnormalities.nnnMETHODSnSubjects included 16 DSM-IV bipolar patients (16 +/- 3 years) and 21 healthy controls (mean age +/- SD = 17 +/- 4 years). Measures of amygdala, hippocampus, temporal gray matter, temporal lobe, and intracranial volumes (ICV) were obtained.nnnRESULTSnThere was a trend to smaller left amygdala volumes in patients (mean volumes +/- SD = 1.58 +/- .42 mL) versus control subjects (1.83 +/- .4 mL; F = 3.87, df = 1,32, p = .06). Bipolar patients did not show significant differences in right or left hippocampus, temporal lobe gray matter, temporal lobe, or right amygdala volumes (analysis of covariance, age, gender, and ICV as covariates, p > .05) compared with healthy control subjects. Furthermore, there was a direct correlation between left amygdala volumes and age (r =. 50, p = .047) in patients, whereas in healthy controls there was an inverse correlation (r = -.48, p = .03).nnnCONCLUSIONSnThe direct correlation between left amygdala volumes and age in bipolar patients, not present in healthy control subjects, may reflect abnormal developmental mechanisms in bipolar disorder.

Smaller cingulate volumes in unipolar depressed patients

BACKGROUNDnThe anterior cingulate cortex is a key structure in brain networks involved in mood regulation. Abnormalities in this brain region are possibly implicated in the pathophysiology of depression. This anatomical magnetic resonance imaging (MRI) study compared cingulate cortex volumes in unipolar depressed patients and age- and gender-matched healthy control subjects.nnnMETHODSnThirty-one unmedicated DSM-IV unipolar patients (24 female, aged 39.2 +/- 11.9 years [mean +/- SD]) and 31 healthy control subjects (24 female, aged 36.7 +/- 10.7 years) were studied in a 1.5-T GE Signa magnet (General Electric Medical Systems, Milwaukee, Wisconsin). Cingulate volumes were compared by analysis of covariance with intracranial volume as the covariate.nnnRESULTSnThe unipolar patients had significantly smaller anterior and posterior cingulate volumes bilaterally compared with healthy control subjects. When patients were divided into currently depressed (n = 21) and remitted (n = 10) subgroups, currently depressed patients had significantly smaller anterior and posterior cingulate volumes bilaterally compared with healthy control subjects, whereas remitted patients had significantly smaller left anterior cingulate volumes compared with healthy individuals.nnnCONCLUSIONSnGray matter abnormalities in the cingulate cortex are implicated in the pathophysiology of unipolar depression. Smaller cingulate volumes in currently depressed patients support the hypothesis that cingulate cortex abnormalities are state dependent, whereas changes in left anterior cingulate might be trait related.

Abnormal left superior temporal gyrus volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study

Abnormalities in left superior temporal gyrus (STG) have been reported in adult bipolar patients. However, it is not known whether such abnormalities are already present early in the course of this illness. Magnetic resonance imaging (MRI) morphometric analysis of STG was performed in 16 DSM-IV children and adolescents with bipolar disorder (mean age+/-SD 15.5+/-3.4 years) and 21 healthy controls (mean age+/-SD 16.9+/-3.8 years). Subjects underwent a 3D spoiled gradient recalled acquisition MRI examination. Using analysis of covariance with age, gender and intra-cranial brain volume as covariates, we found significantly smaller left total STG volumes in bipolar patients (12.5+/-1.5 cm(3)) compared with healthy controls (13.6+/-2.5 cm(3)) (F=4.45, d.f.=1, 32, P=0.04). This difference was accounted for by significantly smaller left and right STG white matter volumes in bipolar patients. Decreased white matter connections may be the core of abnormalities in STG, which is an important region for speech, language and communication, and could possibly underlie neurocognitive deficits present in bipolar patients.

Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study

The objective of this study was to test the hypothesis that 4 weeks of lithium administration would be associated with changes in brain gray and white matter volumes in healthy individuals. Thirteen right-handed healthy volunteers (6 females, mean age=25.9+/-10.0 years) were studied. 3D SPGR MRIs (TR=25 ms, TE=5 ms, slice-thickness=1.5 mm) were acquired using a 1.5 T GE Signa Imaging System, at baseline and after 4 weeks of lithium administration at therapeutically relevant doses. Optimized voxel-based morphometry (VBM) analyses were conducted. Left and right dorsolateral prefrontal cortex and left anterior cingulate gray matter volumes increased significantly following lithium administration. Total white matter volume was increased, whereas total brain volume and total gray matter volume were not significantly changed following 4 weeks of lithium. Lithium treatment resulted in prefrontal regional gray matter volume increases in healthy volunteers, as well as increases in total white matter volume. Whether these changes are mediated by neurotrophic/neuroprotective or osmotic effects remains unknown.

Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients

The dorsolateral prefrontal cortex (DLPFC) plays an essential role in mood regulation and integration of cognitive functions that are abnormal in major depressive disorder (MDD). Few neuroimaging studies have evaluated the still maturing DLPFC in depressed children and adolescents. We conducted single voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left DLPFC in 14 depressed children and adolescents (13.3 +/- 2.3 years old, 10 males) and 22 matched healthy controls (13.6 +/- 2.8 years old, 13 males). Depressed subjects had significantly lower levels of glycerophosphocholine plus phosphocholine (GPC + PC; or choline-containing compounds) and higher myo-inositol levels in the left DLPFC compared to healthy controls. In the depressed subjects, we found significant inverse correlations between glutamate levels and both duration of illness and number of episodes. In healthy controls there was a significant direct correlation between age and glutamine levels, which was not present in the patient group. Lower GPC + PC levels in pediatric MDD may reflect lower cell membrane content per volume in the DLPFC. Increased myo-inositol levels in MDD may represent a disturbed secondary messenger system. GPC + PC and myo-inositol abnormalities further demonstrate the involvement of DLPFC in pediatric MDD.

Psychological distress in childhood trauma survivors who abuse drugs

The relationships between the level of childhood maltreatment and current psychological distress were examined in a community sample of 676 substance abusing men and women using a validated self-report instrument (the Childhood Trauma Questionnaire) designed to measure physical, emotional, and sexual abuse and physical and emotional neglect. Current levels of self-reported psychological distress/symptoms were measured using a 53-item Brief Symptom Inventory. Prevalence of early trauma ranged from 44% for emotional neglect to 65% for sexual abuse. The severity of all forms of childhood maltreatment were directly associated with current psychological distress.

Medial temporal lobe abnormalities in pediatric unipolar depression

In vivo anatomical magnetic resonance imaging (MRI) studies in adults with major depressive disorder (MDD) have implicated neurocircuitries involved in mood regulation in the pathophysiology of mood disorders. Specifically, abnormalities in the medial temporal lobe structures have been reported. This study examined a sample of children and adolescents with major depressive disorder to investigate anatomical abnormalities in these key medial temporal brain regions. Nineteen children and adolescents with DSM-IV major depression (mean age +/- S.D.=13.0 +/- 2.4 years; 10 unmedicated) and 24 healthy comparison subjects (mean age +/- S.D.=13.9 +/- 2.9 years) were studied using a 1.5T Philips MRI scanner. We measured hippocampus and amygdala gray matter volumes. MRI structural volumes were compared using analysis of covariance with age and total brain volumes as covariates. Pediatric depressed patients had significantly smaller left hippocampal gray matter volumes compared to healthy controls (1.89 +/- 0.16 cm(3) versus 1.99 +/- 0.18 cm(3), respectively; F=5.0, d.f.=1/39, p=0.03; effect size: eta2(p) =0.11). Unmedicated depressed patients showed a trend towards smaller left hippocampal volumes compared to medicated patients and healthy subjects (F=2.8, d.f.=2/38, p=0.07; effect size: eta2(p) =0.13). There were no statistically significant differences in mean volumes for left or right amygdala. Smaller left hippocampal volumes in children and adolescents with MDD are in agreement with findings from adult studies and suggest that such abnormalities are present early in the course of the illness. Amygdala volumes are not abnormal in this age group. Smaller hippocampal volumes may be related to an abnormal developmental process or HPA axis dysfunction.