Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study.

Magnetic resonance imaging was used to examine cerebral anatomy in 48 inpatients with severe depression who were referred for electroconvulsive therapy and in 76 normal control subjects. The magnetic resonance imaging measures included determinations of regional cerebral volumes and ratings of the frequency and severity of cortical atrophy, lateral ventricular enlargement, and subcortical hyperintensity. The mean total frontal lobe volume was found to be 7% smaller in the inpatients with severe depression (235.88 mL) than in the normal control subjects (254.32 mL)--a difference that was statistically significant even after adjusting for the effects of age, sex, education, and intracranial size. No group differences were observed in the volumes of the cerebral hemispheres, the temporal lobes, or the amygdala-hippocampal complex, nor in the frequency of cortical atrophy. Neither did the groups differ with respect to the total volumes of the lateral and third ventricles, nor in the frequency of lateral ventricular enlargement. Patients with depression had a significantly higher frequency of subcortical hyperintensity in the periventricular white matter, with an odds ratio of 5.32.

Brain anatomic effects of electroconvulsive therapy. A prospective magnetic resonance imaging study.

To determine prospectively whether electroconvulsive therapy (ECT) produces structural brain changes, 35 inpatients with depression underwent magnetic resonance imaging before and twice after (at 2 to 3 days and at 6 months) completion of a course of brief-pulse, bilateral ECT. The magnetic resonance images were analyzed blindly for evidence of changes in brain structure using two approaches: measurement of regional brain volumes and a pairwise global comparison. Structural brain abnormalities were present in many patients before ECT. The course of ECT produced no acute or delayed (6-month) change in brain structure as measured by alterations of the total volumes of the lateral ventricles, the third ventricle, the frontal lobes, the temporal lobes, or the amygdala-hippocampal complex. In five subjects, the pairwise global comparisons revealed an apparent increase in subcortical hyperintensity, most likely secondary to progression of ongoing cerebrovascular disease during follow-up. Our results confirm and extend previous imaging studies that also found no relationship between ECT and brain damage.

Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold.

We measured initial seizure threshold by means of a structured stimulus dosage titration procedure in a clinical sample of 111 depressed patients undergoing brief-pulse, constant-current electroconvulsive therapy (ECT). Initial seizure threshold was approximately 60 millicoumbs (mc) (10 Joules) on average, but varied widely (6-fold) across patients. Initial seizure threshold was predicted by four variables: electrode placement (higher with bilateral), gender (higher in men), age (higher with increasing age), and dynamic impedance (inverse relationship). Use of neuroleptic medication was associated with a lower seizure threshold. EEG seizure duration was inversely related to initial seizure threshold, but no other relations with seizure duration were found. These findings may have important clinical implications for stimulus dosing strategies in ECT.

Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT.

To measure the anticonvulsant effects of a course of electroconvulsive therapy (ECT), we used a flexible stimulus dosage titration procedure to estimate seizure threshold at the first and sixth ECT treatments in 62 patients with depression who were undergoing a course of brief pulse, constant current ECT given at moderately suprathreshold stimulus intensity. Seizure threshold increased by approximately 47% on average, but only 35 (56%) of the 62 patients showed a rise in seizure threshold. The rise in seizure threshold was associated with increasing age, but not with gender, stimulus electrode placement, or initial seizure threshold. Dynamic impedance decreased by approximately 5% from the first to the sixth ECT treatment, but there was no correlation between the change in dynamic impedance and the rise in seizure threshold. No relation was found between the rise in seizure threshold and either therapeutic response status or speed of response to the ECT treatment course. These findings confirm the anticonvulsant effect of ECT but suggest that such effects are not tightly coupled to the therapeutic efficacy of moderately suprathreshold ECT.

The dexamethasone suppression test and quantitative cerebral anatomy in depression.

To determine whether structural brain abnormalities in patients with depression are related to cortisol state, we examined the relationship between the dexamethasone suppression test (DST) and brain magnetic resonance imaging (MRI) in 40 inpatients with severe depression referred for electroconvulsive therapy (ECT). Prior to ECT, 27 (68%) of the patients exhibited nonsuppression on the DST. Frontal lobe volume was negatively correlated with peak post-dexamethasone cortisone (r = -0.37) and was 13% smaller in DST nonsuppressors than suppressors; these findings were no longer significant after adjustments for age, gender, and cranial size. Lateral and third ventricular volumes were also correlated with peak postdexamethasone cortisol (r = 0.34 and 0.33, respectively), but not after adjustments for age, gender, and cranial size. Subcortical hyperintensity was associated with peak postdexamethasone cortisol and was more common in DST nonsuppressors than suppressors. Again these findings were no longer significant after adjustments for age. Finally, longitudinal DST and brain MRI studies in 11 of these patients revealed no changes in regional brain volumes nor in postdexamethasone cortisol up to six months after ECT. However, within individual patients, postdexamethasone cortisol was positively (and significantly) correlated with frontal lobe volume.

Leukoencephalopathy in elderly depressed patients referred for ECT.

Using brain magnetic resonance imaging (MRI) and high-resolution computed tomography (CT), we identified changes in the subcortical white matter in 44 of 67 elderly depressed inpatients (66%) referred for electroconvulsive therapy (ECT). This "leukoencephalopathy" was frequently associated with other structural brain changes, including cortical atrophy, lateral ventricular enlargement, and lacunar infarctions of the basal ganglia and thalamus. Many (58%) of the patients had developed late-onset depressive disorders, and the majority (86%) had been refractory to and/or intolerant of antidepressant drug therapy. Nevertheless, all but 1 of the 44 patients subsequently responded to a course of ECT, which in general was well tolerated. Although the precise etiology of the leukoencephalopathy remains unclear, clinical data suggest that it may result from arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions. Several lines of evidence suggest that leukoencephalopathy may have implications for the pathophysiology of depressive illness, at least in some elderly patients.

Cardiovascular response to unilateral electroconvulsive therapy.

Few studies have examined the cardiovascular response to pulse unilateral electroconvulsive therapy (ECT) performed using modern techniques. In this study of 30 patients (mean age 62 years) with major depression, we determined the effects of pulse unilateral ECT on cardiac work load using the rate-pressure product (RPP), a product of pulse and systolic blood pressure. The mean RPP across all ECT treatments increased by an average of 96% from pre-ECT baseline, with the maximal RPP occurring typically during the seizure. The amount of increase in RPP did not differ significantly over the course of treatments. The increase in RPP was significantly and inversely related to baseline RPP, such that subjects with the highest baseline RPPs actually had smaller increases in RPP during the ECT treatments. The mean percent change in RPP was not associated with age, sex, presence of cardiovascular disease, ECT stimulus charge, EEG seizure duration, or amnestic side effects. There was a trend (p = 0.06), however, for the mean increase in RPP to be greater in responders (100% increase, n = 25) than in nonresponders (76% increase, n = 5). The potential relationship of clinical outcome to the increase in RPP suggests that both factors may be manifestations of the physiological intensity of the ECT-induced seizure.

Urinary tryptamine excretion in chronic schizophrenics with low platelet MAO activity.

Reduced platelet MAO activity has been previously reported as a biochemical marker for a subgroup of psychiatric patients, including some chronic schizophrenics. As tryptamine metabolism appears to be sensitive to alterations in MAO activity, urinary tryptamine excretion was measured in chronic schizophrenics with low platelet MAO activity, chronic schizophrenics with normal platelet MAO activity, and age-matched and sex-matched controls. The increased urinary tryptamine excretion observed in chronic schizophrenics with low platelet MAO activity may reflect a pathophysiologic mechanism associated with low MAO activity.

Caffeine augmentation of ECT.

In a randomized, double-blind, placebo-controlled pilot study of 40 depressed inpatients, the authors compared two techniques for maintaining seizure duration during pulse unilateral ECT: pretreatment with intravenous caffeine versus electrical stimulus intensity dosing. Both techniques effectively maintained seizure duration, but with caffeine this was accomplished without any increase in mean stimulus intensity over the course of ECT. There were no differences between the two techniques in therapeutic outcome or cognitive side effects from ECT, and caffeine pretreatment was well tolerated. The authors discuss the clinical and research implications of these findings with respect to strategies for maintaining seizure duration during ECT.

Use of caffeine to lengthen seizures in ECT.

During a course of ECT, seizure duration may become too brief for clinical benefit. Use of higher-energy stimuli may lengthen seizures but may also increase the risk of toxicity, and it is not possible when maximum settings are reached. The authors present the cases of six drug-free depressed inpatients whose seizure durations in ECT declined despite maximum settings on three different ECT devices. In all cases, pretreatment with caffeine lengthened seizures (mean increase = 107%), and clinical improvement followed. Caffeine was well tolerated, even in patients with cardiovascular diseases.

"On-off" syndrome treated with lithium carbonate: a case report.

The authors describe a 42-year-old man who developed "on-off" episodes and for whom lithium carbonate proved an effective treatment. They speculate that the predominant effect of lithium in the "on-off" syndrome is to prevent L-dopa desensitization of the dopamine receptor.

Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects.

Subcortical hyperintensity on T2-weighted brain magnetic resonance imaging was significantly more common and more severe in elderly depressed patients referred for ECT than in a matched control group of normal elderly subjects. The potential clinical and research implications of these findings are discussed.

Effects of ECT on brain structure: a pilot prospective magnetic resonance imaging study.

The authors describe a pilot prospective investigation of the effects of ECT on brain structure using magnetic resonance imaging (MRI). In nine patients with major depression, a course of ECT produced no acute changes in brain structure according to blind raters' assessments of cortical atrophy and global comparison of pre- and post-ECT studies. There were also no significant changes in the ventricle-brain ratios. Pre-ECT brain abnormalities were common in these patients yet were also unaffected by ECT. Future MRI studies of ECT should include more subjects and should address long-term changes and subtle brain abnormalities.

Neuropsychological importance of subcortical white matter hyperintensity.

Subcortical hyperintensity on magnetic resonance imaging is a common incidental finding in healthy elderly subjects. The relationship of such changes to cognitive functioning remains unclear, however, because only a small number of studies have examined this issue with conflicting results. We therefore assessed 66 healthy adult volunteers (mean [+/- SD] age, 61.8 +/- 15.8 years) with magnetic resonance imaging scans rated for subcortical hyperintensity, and with two neuropsychological instruments selected a priori on the basis of previous reports in the literature. Findings were highly significant for both the Benton Facial Recognition Test and the Wechsler Adult Intelligence Scale-Revised Digit Symbol. However, in both cases, the majority of variance was accounted for by age and educational level. Effects of subcortical hyperintensity were not significant. We conclude that subcortical hyperintensity in healthy adults does not relate to cognitive functioning, at least with these two instruments.

Sex differences in brain aging: a quantitative magnetic resonance imaging study.

BACKGROUND: Little is known about the effect of sex on age-related changes in brain structure. METHODS: Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained. RESULTS: Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporoparietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex. CONCLUSIONS: Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.

Relation of education to brain size in normal aging: implications for the reserve hypothesis.

OBJECTIVE: To examine the relations between education and age-related changes in brain structure in a nonclinical sample of elderly adults. BACKGROUND: Education may protect against cognitive decline in late life--an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure. METHODS: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores > or =24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained. RESULTS: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mL (p<0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume. CONCLUSIONS: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation.

Myocardial infarction and stroke.

We used a computer data bank to evaluate 740 consecutive patients admitted to a cardiac care unit with myocardial infarction. Stroke occurred in 18 (2.4%) patients in the hospital; the anterior circulation was involved in 76% of strokes. Hospital mortality was 61% in patients with stroke and 13% in patients without stroke. Atrial arrhythmia was a significant (p less than or equal to 0.03) risk factor for stroke, but peak creatine kinase and ventricular arrhythmia were not. Cardiac pump failure, apical or anterior-lateral myocardial infarction, and history of previous stroke were associated with an increased risk of stroke. Clinical and pathologic data suggested an embolic etiology for most strokes that complicate acute myocardial infarction.

Natural history of cerebral complications of coronary artery bypass graft surgery.

We reviewed 1,669 patients who survived coronary artery bypass graft surgery between 1969 and 1981. A total of 75 cerebral complications were identified, including (1) altered mental state, (2) stroke, and (3) seizure in 64 patients (3.8%). Altered mental state (delirium, hypoxic-metabolic encephalopathy) occurred in 57 (3.4%). Postoperative arrhythmias were associated with an increased risk of altered mental state. Cerebral infarction occurred in 13 (0.8%). Patients who suffered stroke had a higher occurrence of carotid bruits and history of peripheral vascular disease. Seizures occurred in five patients (0.3%). Mortality in patients with a neurologic complication was 29%.

Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging.

Seventy-six healthy adults underwent magnetic resonance imaging (1.5 T) to investigate the effects of age on regional cerebral volumes and on the frequency and severity of cortical atrophy, lateral ventricular enlargement, and subcortical hyperintensity. Increasing age was associated with (1) decreasing volumes of the cerebral hemispheres (0.23% per year), the frontal lobes (0.55% per year), the temporal lobes (0.28% per year), and the amygdala-hippocampal complex (0.30% per year); (2) increasing volumes of the third ventricle (2.8% per year) and the lateral ventricles (3.2% per year); and (3) increasing odds of cortical atrophy (8.9% per year), lateral ventricular enlargement (7.7% per year), and subcortical hyperintensity in the deep white matter (6.3% per year) and the pons (8.1% per year). Many elderly subjects did not exhibit cortical atrophy or lateral ventricular enlargement, however, indicating that such changes are not inevitable consequences of advancing age. These data should provide a useful clinical context within which to interpret changes in regional brain size associated with "abnormal" aging.

Caffeine-modified electroconvulsive therapy in depressed patients with medical illness.

Although pretreatment with intravenous caffeine is an effective technique for increasing seizure duration during a course of electroconvulsive therapy (ECT), little has been published regarding the use of this technique in patients with severe medical illness. The authors describe nine depressed inpatients with major cardiovascular or other medical disease or both whose ECT seizure durations declined despite maximal settings on the ECT device. In all cases, caffeine pretreatment lengthened seizures, and clinical improvement followed. The caffeine-modified ECT treatments were well tolerated and were associated with no clinically significant adverse cardiovascular effects.