Long-term efficacy and cognitive effects of voltage-based deep brain stimulation for drug-resistant essential tremor.

OBJECTIVES: To analyze the long-term efficacy and cognitive effects of voltage-based deep brain stimulation (DBS) for drug-resistant essential tremor (ET). PATIENTS AND METHODS: Patients with drug-resistant ET and treated by voltage-based DBS of the ventral intermediate nucleus (VIM-DBS) were continuously enrolled. Seizure outcomes were assessed by blinded observers using the Tremor Rating Scale (TRS). The full-scale intelligence quotient, full-scale memory quotient, Hamilton Depression Scale, Hamilton Anxiety Scale, and Quality of Life in Essential Tremor Questionnaire were assessed as measures of cognitive function. RESULTS: Eleven patients met the inclusion criteria, and two of them were excluded because of loss to follow-up. The patient follow-up times ranged from 48 to 66 months (median 51 months). TRS scores decreased by 60.4% and 46.0% at the 12- and 48-month follow-ups, respectively. Both changes were highly significant. During the follow-up period, the patients' intelligence and memory had not significantly changed; depression, anxiety, and quality of life significantly improved. After long-term follow-up, the stimulation efficacy and quality of life gradually decreased, and the depression and anxiety levels increased. CONCLUSION: For patients with drug-resistant ET, voltage-based DBS can provide acceptable benefits on tremor, cognitive function, and quality of life. However, the efficacy of VIM-DBS decreased over time.

Prolactin response to immobilization stress and hemorrhage: the effect of hypothalamic deafferentations and posterior pituitary denervation.

The roles of posterior and anterolateral connections to the mediobasal hypothalamus (MBH) as well as innervation of the posterior pituitary in the PRL response to immobilization (IMO) and hemorrhage (HEM) were studied by means of surgical isolation, performed 6-9 days before stress exposure. Male rats bearing indwelling tail artery cannulae subjected to 120-min IMO reached peak PRL secretion in 5-20 min. HEM of 25% elicited a significant rise of PRL levels. A posterior cut in the MBH, performed without damaging the serotonergic fibers from the brain stem, attenuated the PRL response to 25% HEM, whereas the PRL elevation due to IMO remained unaffected. An anterolateral cut around the MBH eliminated both the IMO- and HEM-induced stimulation of PRL. Posterior lobe denervation reduced by about 27% the PRL response to IMO and eliminated the response to HEM. These results suggest the following conclusions. The neural structures located posteriorly to the MBH are involved in the transfer of signals triggering PRL secretion due to hypovolemia. Intact anterolateral pathways to the MBH and stalk-median eminence region are essential for the PRL-releasing activity under both stimuli. The posterior lobe may be an important link in the PRL stress response in male rats.

Galanin-R1 receptor in anterior and mid-hypothalamus: distribution and regulation.

The distribution and regulation of galanin-R1 receptor (GAL-R1-R) mRNA has been studied in the anterior and mid-diencephalon by using in situ hybridization. Moreover, possible colocalization of GAL-R1-R mRNA and prepro-galanin or vasopressin mRNAs has been analyzed at the cellular level using double in situ hybridization methodology. Many nuclei in the hypothalamus expressed GAL-R1-R mRNA, including the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). Strong expression was also seen in the same sections in various areas outside of the diencephalon. The distribution patterns are similar to those described in earlier studies. Double labeling experiments showed GAL-R1-R mRNA in vasopressin neurons in the PVN and SON. Moreover, GAL-R1-R mRNA and prepro-galanin mRNA were colocalized in several hypothalamic nuclei. GAL-R1-R mRNA levels showed a high degree of plasticity. Thus, salt loading resulted in a marked increase in GAL-R1-R mRNA levels in the PVN and SON and a moderate decrease was seen during lactation. In contrast, hypophysectomy caused a decrease in GAL-R1-R mRNA levels. Differential effects of colchicine were recorded with a decrease of GAL-R1-R mRNA in the magnocellular hypothalamic neurons. After salt loading or during lactation, GAL-R1-R mRNA and prepro-galanin mRNA were regulated in parallel, whereas their levels changed in opposite directions after hypophysectomy and colchicine injection. In conclusion, GAL-R1-Rs are present in several hypothalamic nuclei, partly in neurons synthesizing galanin. The receptors are regulated in a specific fashion in the various nuclei, depending on the stimulus applied. The results suggest that the effect of galanin in the hypothalamus partly depends on the state of receptor expression.

Metabolic regulation as a control for lipid disorders. I. Influence of (--)-hydroxycitrate on experimentally induced obesity in the rodent.

The feasibility of treating obesity by metabolic regulation has been explored in this study by examining the effect of (--)-hydroxycitrate on three types of experimentally induced obesity in the rodent.(--)-Hydroxycitrate was utilized because it depressed fatty acid and cholesterol synthesis in vivo through its activity as a potent competitive inhibitor of APT citrate lyase. In all models, the mature rat, the goldthioglucose-induced obese mouse, and the ventromedial hypothalmic lesioned obese rat, food intake and body weight gain were reduced signficantly by the chronic oral administration of a nontoxic dose of (--)-hydroxcitrate. Body composition analyses of mature rats treated with (--)-hydroxycitrate demonstrated a significant depression of body lipid levels and an unaltered body protein content. However, a citrate administration produced no significant effects on weight gain, food intake, or body lipid or protein levels when compared to controls.

The effects of ileal transposition on food intake and body weight loss in VMH-obese rats.

Rats were made obese by VMH knife-cuts and then a 5 or 10 cm segment of terminal ileum was transposed to the duodenum. After surgery, the food moved from the stomach into upper duodenum and then traveled through the transposed ileal segment to lower duodenum and continued down the remaining normal digestive tract. Ileal transposition caused a significant reduction in food intake and a substantial loss of body weight. There was no difference in weight loss with 5 and 10 cm ileal transpositions in obese rats, but weight loss was much less in lean rats. Weight loss was accompanied by a considerable loss in dissectable body fat and an increase in the actual weight of the pancreas and small intestine. These changes are probably caused by the unusual stimulation of a short segment of terminal ileum with undigested food and pancreatic enzymes and may have been mediated by the release of ileal hormones. Changes in plasma levels of metabolites, intracellular enzymes, and protein are presented and the importance of this surgery for the treatment of human obesity is evaluated.

Possible involvement of the central nervous system in graft rejection.

Electrolytic lesions were produced in the tuberal hypothalamus and amygdala of male Fischer and female BNLF1 rats, and in male Fischer and female BNLF1 rats that had received antecedent hypophysectomies. Skin grafts from Lewis rats survived less well on tuberal-lesioned male Fischer rats than similar grafts on sham-operated and amygdala-lesioned male Fischer rats. Lewis skin graft survival was also curtailed in male Fischer rats that had received hypophysectomies followed by tuberal lesions. These differences were not apparent across the male to female (H-Y) BNLF1 histocompatibility barrier. We conclude: (1) that tuberal hypothalamic lesions stimulate allograft reactivity in rats, (2)that this response is greater when the immunogenetic disparity between donor and host is greater, and (3) that the mechanism governing this response involves a direct neural pathway which bypasses the hypothalamic-hypophyseal axis.

Rapid changes in growth hormone regulation and hypothalamic somatostatin after transection of anterolateral pathways to the medial-basal hypothalamus in the rat.

Plasma and pituitary GH content, in-vitro GH release and somatostatin-like immunoreactivity (SLI) in the stalk-median eminence were studied up to 7 days after making an anterolateral cut (ALC) around the medial-basal hypothalamus. Plasma GH concentration increased within 15 min to a very high level, then fell to a high level which was unchanged for several hours. The GH concentration then steadily decreased between days 2 and 7. The SLI content in the stalk-median eminence decreased to 3.5% of the control value within 3 days. The GH content of the anterior pituitary gland was 58.8% of the control value by 1 week after the operation but the in-vitro sensitivity to somatostatin of the GH cells failed to change. Pentobarbitone injection stimulated GH release in the sham-operated controls but decreased it in the rats with an ALC. These findings suggest that transection of somatostatin-containing fibres is followed by a rapid rise and a lasting high concentration of plasma GH which slowly returns towards lower levels in parallel with a marked depletion of pituitary GH content. In rats with transected somatostatin innervation of the median eminence, sodium pentobarbitone probably decreases GH secretion by depressing the secretion of GH-releasing hormone.

Caloric intake stimulates growth hormone secretion in food-deprived rats with anterolateral deafferentation of the medial basal hypothalamus or administered antiserum to somatostatin.

In rats, food deprivation inhibits episodic growth hormone (GH) secretion. On the basis of previous studies, we hypothesized that during a recovery from prolonged fasting, caloric intake stimulates the release of GH-releasing factor (GRF) and this process does not depend on the specific macronutrients in the meal, while protein in the meal acts to restore characteristic ultradian rhythmicity of GH secretion. To test this hypothesis, the effect of caloric intake on GH secretion was examined in fasted adult male Wistar rats devoid of somatostatin (SS) influence on GH secretion either by anterolateral deafferentation (ALC) of the medial basal hypothalamus (MBH) or administration of anti-SS goat serum (ASS). Rats were provided with an indwelling right atrial cannula and were deprived of food for 72 h. ALC was performed 2 weeks prior to the study. ASS was given i.v. 8 h and 7 h prior to refeeding, respectively. Serial blood specimens were collected every 10 min. In rats with ALC (ALC rats) or rats given ASS (ASS rats), the blood GH level revealed irregularly occurring small fluctuations, instead of the usual high bursts and low trough level. The baseline GH level and the mean GH level of fasted ALC rats or fasted ASS rats were significantly lower than those of fed ALC rats or fed ASS rats. Feeding the isocaloric mixed meal, the protein meal or the protein-deficient meal increased the GH pulse frequency, the pulse amplitude, the baseline GH level and the mean GH level in 72-h fasted ALC rats. These changes in GH secretory pattern persisted during the period of observation and were independent of the type of meal ingested. Following feeding the mixed meal, similar changes in the GH secretory pattern demonstrated in 72-h fasted ALC rats were also observed in 72-h fasted ASS rats, suggesting that the stimulation of GH secretion following caloric intake is not limited to ALC rats. Since the influence of SS on GH secretion has been largely eliminated in ALC or ASS rats, it is highly unlikely that the augmentation of GH secretion following feeding after prolonged food deprivation was the consequence of inhibition of SS secretion. Although GRF measurement was not performed, it is conceivable that the signal of caloric intake is conveyed to the MBH and acts to stimulate GRF release.

Improved yield of obese rats using a double coordinate system to locate the ventromedial or paraventricular nucleus.

This article describes a highly efficient method for making VMH and PVN-lesioned obese rats by using a newly developed coordinate system. In previous methods, the coordinates for creating VMH and PVN lesions were determined from single point, either the interaural line or the bregma. Because skull size varies, the use of two reference points resulted in greater consistency. We therefore developed a system for making VMH- and PVN-lesioned obese rats using both the interaural line and the bregma. With this new double coordinate system the success rate for producing obese rats varied from 52% to 92% for VMH lesions and from 36% to 61% for PVN lesions.

Recovery of mating behavior in the female rat following VMH lesions.

On the day of proestrus, female rats were given large electrolytic lesions aimed at the ventromedial nucleus of the hypothalamus (VMH). Following a postoperative period of extended diestrus the vaginal smears showed irregular periods of vaginal cornification with a tendency toward prolonged periods of cornified smears. Sexual receptivity, measured in terms of the lordosis-to-mount ratio (L% = L/M X 100) was low on the evening of the first postsurgical proestrus, but improved markedly in subsequent mating sessions. Although the lordosis response was present, the intromission frequency remained below that observed during mating sessions with control females. Findings at autopsy together with the prolonged periods of vaginal cornification suggest that VMH lesions result in blocked or delayed ovulation. The behavioral data contradict previous reports of blocked mating behavior in VMH females based upon indirect measures of receptivity, i.e., the presence of vaginal plugs or sperm on the morning following overnight caging with sexually active males.

VMH lesions facilitate baitshyness in the rat.

Normal rats and rats with lesions of the ventromedial hypothalamus were compared on the acquisition of a single trial, long CS-US interval, conditioning task (baitshyness). The rats with hypothalamic damage exhibited facilitated baitshyness when tested both shortly after surgery and several months after surgery. The magnitude of the suppression observed in these animals could not be related to either specific anatomical structures within the hypothalamus or to the amount of obesity exhibited following the lesions. Similarities and differences between the results of the present study and previous studies are discussed.

Potentiation of amphetamine-induced arousal by food deprivation: effect of hypothalamic lesions.

Locomotor activity was studied in rats with lesions of the basomedial hypothalamus following food deprivation (0, 1, 2, and 4 days) and amphetamine (0, .5, 1.0, and 2.0 mg/kg). Control animals showed the normal potentiation of amphetamine-induced locomotor activity by starvation. Animals with lesions, however, did not differ, when deprived, from satiated control animals in their response to amphetamine. These results suggest that behavioral arousal produced by food deprivation is mediated by the basomedial hypothalamus.

Effects of catecholamine agonist and antagonist drugs on acute stomach ulceration induced by medial hypothalamic lesions in rats.

In order to investigate the involvement of catecholamines (CAs) in acute stomach ulceration induced by hypothalamic lesions, rats were given bilateral electrolytic anodal lesions in the medial hypothalamus followed by a single subcutaneous injection of CA agonist or antagonist drugs. As in previous studies, lesioned rats that received no post operative drug treatment showed extensive gastric damage when examined 24 hr after the brain lesion. Chlorpromazine, amphetamine, desipramine and isoproterenol caused significant reductions in the extent (total length) and/or number of erosions induced by the brain lesion. Haloperidol and propranolol did not seem to affect ulcer formation. Clozapine increased the number but not the total length of ulcers. Phentolamine, alone or in combination with propranolol, significantly increased both the number and total length of lesion-induced ulcers. Similarities between these results and those reported for most of these drugs in the context of ulcers induced by various experimental stress procedures suggest a degree of commonality between acute stress ulcers and ulcers induced by hypothalamic lesions. The overall pattern of results obtained is also consistent with evidence indicating a protective role for catecholamines in acute ulcer formation.

Angiotensin II pressor activity depends on medial and lateral anterior hypothalamic pathways.

The preoptic region of hypothalamus was disconnected from caudal structures with two different-size knife cuts in rats to investigate the pathway responsible for the effects of intracerebroventricular (ICV) and intravenous (IV) angiotensin II (ang II) on blood pressure and arginine vasopressin (AVP) release. Seven days after surgery ICV ang II (125 ng) in sham-operated (sham) rats increased mean arterial pressure (MAP) (+23 +/- 3 mmHg) and decreased heart rate (HR) (-58 +/- 5 beats/minute). However, ICV ang II had no effect on MAP or HR of rats with a large (preoptic-hypothalamic disconnection) cut. Both the pressor response (+12 +/- 2 mmHg) and the bradycardia (-39 +/- 6 beats/minute) were significantly reduced by a small (medial preoptic-hypothalamic disconnection) cut. The increased plasma AVP to ICV ang II in sham rats (9.8 +/- 3.6 pg/mL) was abolished in large-cut rats and attenuated in small-cut rats (3.2 +/- 0.7 pg/mL). IV bolus injection of ang II (125 ng) in sham rats increased MAP by 43 mmHg, whereas large-cut rats showed a blunted (25%) pressor response. The pressor response to IV infusion of ang II (8 ng/20 microL/minute for 15 minutes) was diminished in large-cut rats (+4 +/- 1 mmHg) as compared with that in sham rats (+19 +/- 2 mmHg). Both cuts transected the projection between the periventricular tissue surrounding the anteroventral third ventricle and supraoptic nucleus, but the supraoptic-neurohypophyseal pathway was severed only by the large cut.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible role of cingulate cortex in regulating sexual behavior in male rats: effects of lesions and cuts.

The role of the cingulate cortex in regulating male sexual behavior was studied in testosterone propionate-treated castrated male rats. Males with lesions in the anterior part of the cingulate cortex showed lower levels of mount, intromission and ejaculation activities than sham-operated control males and males with lesions in the posterior part of the cingulate cortex or the frontal cortex. In male rats in which lateral connections of the anterior cingulate cortex were bilaterally interrupted by sagittal cuts, the sexual activity was much lower than in the control rats, being comparable to that of the anterior cingulate cortex lesion group, but transection of the anterior connections by a transverse cut made in the anterior part of the anterior cingulate had no effect. These results suggest that the anterior cingulate cortex and its lateral connections are critical in regulating male sexual behavior in male rats.

Restoration of circadian corticosterone rhythm in ventromedial hypothalamic lesioned rats.

The effects of ventromedial hypothalamic (VMH) lesions on the circadian periodicity of blood corticosterone were studied in female rats. The rats were kept on a 12-hour light/12-hour dark illumination regimen and fed ad libitum. Three, 10 and 12 weeks after the VMH lesions, the concentrations of blood corticosterone were measured every 4 h for 48 h in the same unanesthetized rats. Three weeks after the operation, the circadian rhythm in VMH-lesioned rats was disturbed and disappeared. The corticosterone levels at 03:00, 07:00, and 11:00 were significantly higher than those in sham-operated rats. 10 and 12 weeks after the operation, the circadian rhythm, however, was notable (p less than 0.05, p less than 0.05). The elevated mean corticosterone levels over 48 h at 3 weeks after the operation decreased at 10 and 12 weeks. The sham-operated rats showed a significant circadian rhythm at 3, 10 and 12 weeks after the operation (p less than 0.001 in each period) with a peak concentration at 19:00 and through at 07:00. These findings show that the corticosterone circadian rhythms which were disturbed in the dynamic phase after VMH lesions recovered in the static phase of obesity, suggesting that the ventromedial hypothalamus is not an essential biological clock of circadian corticosterone rhythm.

Plasma CRH response to water immersion-restraint stress in rats bearing a hypothalamic knife cut.

We reported earlier that the plasma level of corticotropin-releasing hormone (CRH) remained high 120 min after the onset of such strong sustained stress as ether-laparotomy or water immersion-restraint, which reflected the persistent secretion of CRH from the hypothalamic median eminence (ME). We investigated the change in plasma CRH during water immersion-restraint stress in rats bearing an anterolateral cut around the medial basal hypothalamus (MBH) which cuts the CRH neurons from the PVN to the ME. Concentrations of CRH in the hypothalamus, extrahypothalamic tissues and peripheral blood were measured by radioimmunoassay. Plasma ACTH was measured with an immunoradiometric assay kit. Plasma baseline ACTH and CRH concentrations did not differ significantly in the sham vs. cut groups. At 120 min after the onset of stress, plasma ACTH concentrations were definitely higher in both groups. In the cut group, plasma CRH at 120 min after stress did not differ significantly from the baseline level, whereas plasma CRH at 120 min was definitely higher in the sham group. Baseline CRH concentrations in the ME did not differ greatly in the two groups. CRH concentrations in the ME of both groups had decreased appreciably 120 min after the onset of stress as compared with baseline CRH, and the CRH decrease was greater in the cut group than in the sham group. CRH in the neurointermediate lobe (NIL) and adrenal gland of both groups showed no significant change at 120 min, compared with the control. These findings confirm that the continuous CRH increase in plasma during sustained stress is derived mainly from the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of selective vagotomy on circadian rhythms of plasma glucose, insulin and food intake in control and ventromedial hypothalamic (VMH) lesioned rats.

Effects of hepatic and celiac vagotomy on circadian rhythms of plasma glucose, insulin, and food intake were examined in sham-operated (control) and ventromedial hypothalamic (VMH) lesioned rats. Rats were acclimated to the condition with a 12-hour light-dark cycle for 1 week before surgery. One week after VMH lesions, control and VMH lesioned rats were divided into three groups: sham vagotomy, hepatic vagotomy, and celiac vagotomy. Three days after vagotomy, food intake was measured at 6-hour intervals. Seven days after vagotomy, plasma glucose and insulin were measured at the midpoint of each feeding period. In control rats, hepatic vagotomy destroyed circadian rhythms of plasma glucose and insulin probably due to removal of afferent function. In VMH lesioned rats, celiac vagotomy destroyed circadian rhythm of food intake due to the reduction of plasma insulin by removal of efferent function without affecting the loss of circadian rhythms of plasma glucose and insulin.

Obesity and diabetes - a possible experimental model of maturity-onset-type diabetes.

This study aimed to acquire a possible experimental model of obese non-insulin-dependent diabetes. Around 230 g Sprague-Dawley female rats were divided into 4 gp: (1) sham ventromedial hypothalamic (VMH) lesioned rats fed low-fat diet (control rats); (2) VMH lesioned rats fed low-fat diet; (3) sham VMH lesioned rats fed high-fat diet and (4) VMH lesioned rats fed high fat diet, and they were observed for 10 weeks (Exp. 1). This experiment was repeated using rats treated by small doses of streptozotocin (5 mg/kg) (Exp. 2). Body weight was measured weekly, blood glucose, every other week and serum insulin, at the end of the experiments. VMH obese rats fed low-fat diet showed normal levels of fasting blood glucose with hyperinsulinemia. VMH obese rats fed high-fat diet showed mildly elevated levels of fasting blood glucose (155 +/- 8 mg/dl as compared to 125 +/- 3 mg/dl of controls) with hyperinsulinemia (5.92 +/- 0.61 ng/ml). Streptozotocin treated VMH obese rats fed low-fat diet did not show increasing levels of fasting blood glucose, while streptozotocin treated VMH obese rats fed high-fat diet showed marked elevation of fasting blood glucose (229 +/- 23 mg/dl). The latter group of rats also had hyperinsulinemia (3.82 +/- 0.45 ng/ml compared to 1.36 +/- 0.14 ng/ml of controls), although concentrations of serum insulin were decreased by streptozotocin treatment compared to levels of VMH obese rats fed high-fat diet. These results demonstrated that VMH obese rats fed high-fat diet showed milk hyperglycemia with hyperinsulinemia. Following treatment of small doses of streptozotocin, VMH obese rats fed high fat diet showed marked hyperglycemia with hyperinsulinemia. The profile of these rats resembles that of maturity onset-type diabetes which accompanies with obesity and hyperinsulinemia.

The effect of dopamine on the release of prolactin in sheep with lesions of the hypothetical centre producing prolactin inhibiting factor (PIF).

It has been demonstrated in our previous papers that in the anterior part of medial basal hypothalamus (AM BH) in sheep a stimulating, while in the caudal part of MBH (CMBH) an inhibiting centre of prolactin release are situated. These results suggested that CMBH might be the site of PIF production and prompted us to investigate the effect of dopamine (DA) on the concentration of prolactin in the peripheral blood (p.bl.) in animals in which CMBH had been previously lesioned and this concentration was very high. Microinfusion of L-dopamine into the third cerebral ventricle (c.v.) or into the internal maxillary artery in intact as well as in lesioned lactating ewes depressed distinctly the prolactin level in the p.bl. This action of DA suggests that in the CMBH exists dopaminergic system which itself plays an inhibitory role in the control of prolactin release without involvement of PIF.