Kenneth L. Kubos

A two-year longitudinal study of post-stroke mood disorders: findings during the initial evaluation.

A consecutive series of 103 stroke patients capable of undergoing a psychiatric interview were evaluated for mood disorders. Nearly 50% of patients studied in the acute stroke period had clinically significant depressions and one fourth had symptom clusters found in major depressive disorders. We confirmed our previous findings that lesion location is most important in determining frequency and severity of depression. In addition, we have identified other variables including functional physical impairment, intellectual impairment, quality of social support, and age which contribute to or modify depression. Post-stroke depressive disorders are multifactorial in their determination and expression and include both neurophysiological-neurochemical mechanisms and psychological factors in their etiology.

Mood changes in stroke patients: Relationship to lesion location

Abstract During the past several years we have been studying mood changes in stroke patients. 1–9 We have reported recently in a follow-up study of 103 outpatients that the duration of untreated post-stroke depression was at least 7–8 mo in two-thirds of the patients. 1 We also found that during the period from 6 mo to 2 yr post-stroke, there was a significant increase in the prevalence and severity of depression as compared to other post-stroke time periods. 1 In addition, we are presently conducting a 2 yr longitudinal study on a separate group of 103 stroke patients and have reported during the acute stroke period that severity of depression was significantly correlated with the severity of the patients intellectual and functional physical impairment as well as their age and the quality of their social supports. 2 However, the most consistent finding from our studies is the importance of lesion location. 1–5,9 For instance, we have shown that patients with left hemisphere lesions have higher depression scores than those with right hemisphere lesions. However, intrahemispheric lesion location seems to have as great an impact as interhemisphere lesion location. Patients with left anterior lesions were significantly more depressed than patients with left posterior lesions 2–4 even if the patient had bilateral lesions. 9 In addition, we have shown that the closer the lesion was to the left frontal pole the greater the depression score 3,4 even in the presence of bilateral hemisphere strokes. 9 Thus, although multiple factors including severity of impairment and quality of social supports contribute to the development of post-stroke depression, 2 lesion location seems to be one of the most important variables. Therefore, in the present study we wanted to examine the role of lesion location by selecting a group of stroke patients with single stroke lesions and no prior history of psychiatric disorder to determine what clinical symptoms develop in the acute post-stroke period, and we wanted to analyze what relationship these symptoms might have to size or location of the brain lesion.

Polyethylene glycol-conjugated superoxide dismutase fails to augment brain superoxide dismutase activity in piglets.

We studied the effect of intravenously administered polyethylene glycol-conjugated superoxide dismutase (8,000 units/kg) on brain superoxide dismutase activity in 44 1-2-week-old piglets in the absence and presence of global cerebral ischemia and reperfusion. Four groups (n = 6 each) of piglets not exposed to ischemia were studied. Enzyme administration increased plasma superoxide dismutase activity from less than 5 to 142 +/- 8 units/ml (mean +/- SEM) without increasing brain activity (e.g., activities in the caudate were 7.9 +/- 0.5 and 8.1 +/- 0.4 units/mg protein) for up to 2 hours following administration. Four additional groups (n = 5 each) of piglets were given either enzyme or polyethylene glycol 5 minutes prior to 10 minutes of global cerebral ischemia induced by aortic cross-clamping followed by either 5 or 45 minutes of reperfusion. Enzyme administration increased plasma superoxide dismutase activity from less than 5 to 144 +/- 5 units/ml but failed to increase brain activity even after 45 minutes of reperfusion (e.g., activities in the caudate were 8.5 +/- 0.3 and 8.6 +/- 0.6 units/mg protein). We conclude that intravenous polyethylene glycol-conjugated superoxide dismutase does not increase superoxide dismutase activity in the brain despite global ischemia and reperfusion.

Differential and asymmetrical behavioral effects of electrolytic or 6-hydroxydopamine lesions in the nucleus accumbens

Sprague-Dawley rats received either unilateral or bilateral electrolytic or 6-hydroxydopamine (6-OHDA) lesions in the nucleus accumbens (n. acc.) and daily spontaneous activity was measured in home cage running wheels for 30 days postoperatively. Bilateral electrolytic lesions increased activity to 230% of preoperative baseline. Right electrolytic lesions produced a 50% increase in activity while left lesion rats were not significantly different from sham-operated controls. Conversely, 6-OHDA lesions depressed activity. Bilateral 6-OHDA lesions had the greatest depressant effect upon activity while unilateral left or right n. acc. treatments produced relatively less hypoactivity. Results support an asymmetrically organized serial inhibition model of spontaneous locomotor control.

Effect of anterior-posterior lesion location on the asymmetrical behavioral and biochemical response to cortical suction ablations in the rat

Small cortical suction ablations were produced at one of several stereotaxically located sites along the anterior-posterior axis of the right or left hemisphere in the rat. Analysis of variance showed a highly significant effect of lesion location in the right hemisphere on locomotor activity. The most anterior lesions produced both the most hyperactivity and also the greatest reductions in the concentrations of norepinephrine in the ipsilateral and contralateral cortex and locus coeruleus. These results suggest that the effect of cortical lesions on spontaneous activity may be graded across the right hemisphere and that the anatomy of certain neurotransmitter pathways in the cortex may help to explain both the biochemical and behavioral findings.

Intracortical kainic acid induces an assymmetrical behavioral response in the rat

Five nanomolar doses of kainic acid injected into the right frontal cortex of rats produced a significantly greater spontaneous hyperactivity than identical injections into the left hemisphere. Hyperactivity began one week after injection and slowly continued to increase throughout the 30 day postoperative period. These results taken with our previous studies suggest that the neural asymmetry which leads to hyperactivity following right hemisphere lesions may be postsynaptic to cortical noradrenergic terminals.

Cortical undercuts in the rat produce asymmetrical behavioral response without altering catecholamine concentrations

Baseline spontaneous activity of male Sprague-Dawley rats was established in home running wheel cages 3 weeks prior to cortical undercutting. Rats received unilateral 2-mm-diameter circular lesions undercutting layer VI of either the left or right frontal cortex. The right hemisphere lesion group showed a 63% increase in spontaneous activity and rats with left hemisphere lesions were no more active than sham-operated controls. No significant intergroup differences in norepinephrine concentrations were noted in the frontal or posterior cortex or locus ceruleus either ipsilateral or contralateral to the lesion site. In addition, there were no significant group differences in dopamine content of the caudate nucleus. Results suggest that the lateralized neural substrates controlling locomotor asymmetry are probably postsynaptic to cortical norepinephrine fibers and may involve glutamatergic corticostriatal projections.

Asymmetrical effects of cortical island lesions in the rat

Baseline spontaneous activity of male Sprague-Dawley rats was established in home running wheel cages 3 weeks prior to receiving cortical circumscription lesions. Circumscriptions 2 mm in diameter and 2 mm deep were produced by means of a rotating microknife and were centered approximately 9.0 mm anterior to ear bar zero. Circular knife cuts of the right, but not the homologous left cortex produced long-lasting depletions of ipsilateral and contralateral fronto- and posterio-cortical NE. Right hemisphere lesions produced a 35% increase in activity while left hemispheric lesions uniformly decreased spontaneous home cage running wheel activity by 35%. These results are consistent with our hypothesis that injury to transcortical pathways (perhaps noradrenergic fibers) are sufficient to produce lateralized spontaneous hyperactivity. The possible existence of competing excitatory and inhibitory mechanisms in the left frontal cerebral cortex is discussed.

Asymmetrical effects of unilateral cortical suction lesions: behavioral characterization

Behavioral effects of unilateral frontocortical suction lesions in the right and left hemisphere were characterized by a computerized activity monitoring system. Lesions of the right frontal cortex produced postoperative hyperactivity consisting of increases in the total distance traveled, average distance per movement, and average speed of movement. Vertical, rotational, and stereotypic measures were not changed. Animals receiving left hemisphere lesions did not differ from sham-operated controls on any behavioral variable. The lateralized hyperactivity resulting from lesions of the right frontal cortex was confined to increased length and speed of horizontal movement and did not appear to represent a generalized increase in all components of spontaneous activity.

Marked behavioral and biochemical sensitivity to lesion size in the posterior cortex of the rat

Unilateral focal cortical suction lesions of varying diameter from 0.7 to 2.0 mm were made in the right posterior lateral cortex of rats. Only the 1.0 mm lesion size resulted in spontaneous postoperative hyperactivity. This increased activity was accompanied by significant elevations in substantia nigra and caudate nucleus dopamine concentrations. Other lesion sizes did not affect behavior or brain biochemical concentrations in this fashion. These results suggest a functional organization in this area of posterior cortex which affects both neurochemistry and behavior.