Reduction of orbital frontal cortex volume in geriatric depression.

BACKGROUND: Postmortem studies have documented abnormalities in the medial orbital frontal cortex in depressed patients. In this study we evaluated whether atrophy of this region can be identified in older depressed patients using magnetic resonance imaging. METHODS: Twenty elderly patients meeting DSM-IV criteria for major depression and 20 matched control subjects were studied. The orbital frontal cortex was measured in both hemispheres using magnetic resonance imaging. RESULTS: Depressive patients had reduced volume in the total orbital frontal cortex, right orbital frontal cortex, and left orbital frontal cortex. CONCLUSIONS: Our finding of a reduction in orbital frontal cortex volume in both sides of the brain suggests that this region of the brain may have a critical role in the development of depression and raises questions about the etiology of the changes.

Hippocampal volume in geriatric depression.

BACKGROUND: There is a growing literature on the importance of hippocampal volume in geriatric depression. METHODS: We examined hippocampal volume in a group of elderly depressed patients and a group of elderly control subjects (N = 66 geriatric depressed patients and 18 elderly nondepressed control subjects) recruited through Duke's Mental Health Clinical Research Center for the Study of Depression in the Elderly. The subjects received a standardized evaluation, including a magnetic resonance imaging scan of the brain. Patients had unipolar major depression and were free of comorbid major psychiatric illness and neurologic illness. Differences were assessed using t tests and linear regression modeling. RESULTS: Accounting for the effects of age, gender, and total brain volume, depressed patients tended to have smaller right hippocampal volume (p =.014) and left hippocampal volume (p =.073). Among depressed patients, age of onset was negatively but not significantly related to right hippocampal volume (p =.052) and to left hippocampal volume (p =.062). We noted that among subjects with either right or left hippocampal volume of 3 mL or less, the vast majority were patients rather than control subjects. CONCLUSIONS: These results support a role for hippocampal dysfunction in depression, particularly in late-age onset depression. Longitudinal studies examining both depressive and cognitive outcomes are needed to clarify the relationships between the hippocampus, depression, and dementia.

Afferent and efferent connections of the A5 noradrenergic cell group in the rat.

The supraspinal afferent and efferent connections of the A5 noradrenergic cell group were examined in rats. Very small deposits of HRP-WGA were made in the rostral A5 area. Catecholamine histofluorescence techniques were used to confirm that the deposits overlapped the A5 column. Retrogradely labeled cells were present in the perifornical area and paraventricular nucleus of the hypothalamus, the Kölliker-Fuse nucleus, dorsal parabrachial area, intermediate and caudal portions of the nucleus of the solitary tract, and the ventral medullary reticular formation in the areas of the A1 and B1 cell groups. Anterograde HRP-WGA labeling was found in several areas of the subcortical CNS. The contribution of A5 neurons to this labeling was confirmed with retrogradely transported fluorescent latex microspheres combined with catecholamine histofluorescence techniques. The A5 cell group was found to have significant projections to the central nucleus of the amygdala, perifornical area of the hypothalamus, midbrain periaqueductal gray, parabrachial area, and the nucleus of the solitary tract. Other A5 projections include the paraventricular nucleus of the thalamus, the bed nucleus of the stria terminalis, and possibly the zona incerta and lateral and dorsal hypothalamic areas. In addition, A5 neurons may innervate the ventrolateral reticular formation of the medulla. Virtually all of the areas innervated by A5 noradrenergic neurons are involved in cardiovascular regulation. In addition, the A5 area receives afferent input from major cardiovascular regulatory centers of the supraspinal CNS. Thus the A5 cell group has the potential to exert a significant influence on the cardiovascular regulatory system.

Comparative effects of sciatic nerve stimulation, blood pressure, and morphine on the activity of A5 and A6 pontine noradrenergic neurons.

The changes in the firing rate of A5 and A6 (locus coeruleus, LC) noradrenergic neurons induced by sciatic nerve stimulation, norepinephrine-induced elevations of blood pressure (BP) and systemic administration of morphine were studied in rats anesthetized with urethane, paralyzed and ventilated. Stimulation of the contralateral sciatic nerve with single shocks of low intensity (0.2 ms, 0.5 mA) produced a strong excitation of LC neurons with a latency of 14-18 ms. By contrast, shocks of similar intensities were ineffective in driving A5 cells. Higher stimulus intensities produced a low efficacy driving of A5 cells with a very long latency (120-250 ms). The efficacy of the stimulation could be increased by delivering trains of 4-8 stimuli but the latency remained very long. Norepinephrine-induced elevation of arterial pressure (140-160 mm Hg range) silenced the vast majority of A5 neurons. By contrast, the effects of blood pressure on locus coeruleus cells were of small amplitude, poorly reproducible and their time course was generally not correlated with the blood pressure alterations. Finally, the administration of 5 mg/kg of morphine i.v. silenced virtually all LC neurons while the majority of A5 cells were excited by the drug. These results provide evidence for the existence of a differential innervation of the two groups of pontine noradrenergic neurons investigated.

Electrophysiological properties of spinally-projecting A5 noradrenergic neurons.

Spinally-projecting A5 neurons were studied with anatomical and electrophysiological techniques in the rat. A detailed study of the number and distribution of spinally-projecting catecholaminergic (CA) and non-catecholaminergic neurons present in a defined area of ventrolateral pontine reticular formation was performed using a sequential technique for the detection of CA fluorescence and retrogradely transported HRP. Using control animals and rats with 6-hydroxydopamine-induced lesions of spinal CA axons, it was concluded that up to 93% of all noradrenergic (NE) neurons present in the area investigated send an axonal process to the thoracic spinal cord and that NE neurons constitute at least 90% of all spinally-projecting neurons present in the same area. Single unit recordings of spinally-projecting neurons were obtained in the same area of the reticular formation in urethane-anesthetized, paralyzed and respirated rats. Based on the above-mentioned anatomical data, antidromic activation from thoracic spinal cord provided a necessary and sufficient criterion for the identification of A5 NE cells. These neurons had a conduction velocity of 2.5 m/s, a discharge rate of up to 4 spikes/s and all were inhibited by i.v. clonidine or desmethylimipramine (DMI). The inhibition produced by the latter drugs was always reversed by the alpha-2 adrenergic antagonists piperoxan or yohimbine. Antidromic (AD)-activation was followed by a period of inhibition whose duration was increased by raising the intensity of the stimulus or by administration of the NE-uptake inhibitor DMI. The effect of the latter was reversed by administration of the alpha-2 antagonist piperoxan.

A neuroanatomic model for depression.

1. Emotion and mood, once thought to be governed solely by the limbic system of the brain, now are thought to be influenced by numerous nonlimbic central nervous system structures as well. 2. The present review discusses several important brain structures and neuroanatomic pathways thought to be involved in affect and mood disorders, including the amygdala, frontal neocortex, cingulate gyrus, basal ganglia, and the monoamine systems. 3. The authors propose a specific neuroanatomic model for depression that emphasizes that a distributed system of extensively interconnected CNS structures mediates emotion and affect.

Age and sex effects on brain morphology.

1. Brain morphology can be assessed readily in vivo using magnetic resonance imaging (MRI). 2. In this study, the effects of age and sex on whole-brain morphology were examined using an operator-controlled computer-segmentation protocol. 3. Results indicated that age was associated with gray-matter volume reduction. 4. Brain-size differences between males and females were primarily attributable to white-matter volume. 5. This study confirms the importance of controlling for age and sex in brain-morphology studies.

Relative accuracy and reproducibility of regional MRI brain volumes for point-counting methods.

Volumetric magnetic resonance imaging (MRI) methods for the measurement of various neuroanatomical regions are of great interest in studies of neuropsychiatric disorders. Both manual and semiautomated methods have been developed. Manual methods include tracing and point counting. Point counting methods are widely used in post-mortem and microscopy studies. Point counting has been well validated for these purposes. In this article, we report in a series of separate studies the accuracy and reproducibility of point-counting methods. Absolute accuracy was evaluated with a spherical phantom. Accuracy and time efficiency were subsequently assessed with an anatomically realistic phantom and various size grids. The point-counting method was also compared to a tracing method. Finally, the reproducibility of the point-counting method for the caudate and putamen was evaluated on four subjects in a test-retest experiment. These studies provide an estimate of the accuracy and time efficiency of point-counting methods. The test-retest reliability was also high for both caudate and putamen. Findings suggest that point counting is a reliable and efficient method for estimating volumes.

Accuracy and reproducibility of brain and tissue volumes using a magnetic resonance segmentation method.

Magnetic resonance (MR) imaging now allows the qualitative and quantitative assessment of the human brain in vivo. As MR imaging resolution has improved, precise measurement of small brain structures has become possible. Methods of measuring brain regions from MR images include both manual and semiautomated methods. Despite the development of numerous volumetric methods, there have been only limited attempts so far to evaluate the accuracy and reproducibility of these methods. In this study we used phantoms to assess the accuracy of the segmentation process. Our results with simple and complex phantoms indicate an error of 3-5% using either manual or semiautomated techniques. We subsequently used manual and semiautomated volumetric methodologies to study human brain structures in vivo in five normal subjects. Supervised segmentation is a semiautomated method that accomplishes the division of MR images into several tissue types based on differences in signal intensity. This technique requires the operator to manually identify points on the MR images that characterize each tissue type, a process known as seeding. However, the use of supervised segmentation to assess the volumes of gray and white matter is subject to pitfalls. Inhomogeneities of the radiofrequency or magnetic fields can result in misclassification of tissue points during the tissue seeding process, limiting the accuracy and reliability of the segmentation process. We used a structured seeding protocol that allowed for field inhomogeneity that produced reduced variation in measured tissue volumes. We used repeated segmentations to assess intra- and inter-rater reliability, and were able to measure small and large regions of interest with a small degree of variation. In addition, we demonstrated that measurements are reproducible with repeat MR acquisitions, with minimal interscan variability. Segmentation methods can accurately and reliably measure subtle morphometric changes, and will prove a boon to the study of neuropsychiatric disorders.

Limbic circuits and neuropsychiatric disorders. Functional anatomy and neuroimaging findings.

The limbic system seems to be involved in the pathophysiology of neuropsychiatric disorders, including dementia, schizophrenia, affective disorders, and amnestic disorders. These findings are subtle and largely went undetected until the advent of modern neuroimaging. This article discusses some of the neuroimaging findings in these disorders.