Affective modulation of the startle response in depression: influence of the severity of depression, anhedonia, and anxiety.

BACKGROUND: The amplitude of the startle reflex response is known to be influenced by the concomitant presentation of affect-toned material--if it is positive affect-toned, the reflex is inhibited, and if it is negative affect-toned, the reflex is augmented. Abundant evidence demonstrates the utility of the affect-startle paradigm as a significant tool for measuring both positive and negative emotions. We applied this paradigm to study emotional reactivity in depression, particularly in relation to symptoms of depression, anhedonia, and anxiety. METHODS: Depressed patients (22) and controls (22) were shown a series of film clips, consisting of two clips with positive valence, two with negative valence, and two with relatively neutral valence. The startle response was measured in reaction to the acoustic startle-eliciting stimuli presented three times binaurally during each clip. RESULTS: Highly depressed and anhedonic patients, relative to controls, showed a reduced mood (self-ratings) and a lack of startle modulation in response to affective film clips whereas patients relatively low on depression/anhedonia displayed a reduced mood only with pleasant clips and a normal pattern of affective startle modulation. Anhedonia and depression were highly positively correlated but neither correlated with anxiety. Anxious patients displayed larger reflexes across all clips and showed a reduced mood modulation with pleasant, but not unpleasant, clips. LIMITATIONS: The large majority of patients was medicated with antidepressants which may have influenced the results. CONCLUSIONS. Reactivity to pleasant stimuli is diminished in patients suffering from low levels of depression and/or anhedonia, but reactivity even to unpleasant stimuli seems compromised at high levels of depression and/or anhedonia. Anxiety is associated with hyperstartle responding.

Menstrual cycle effects on hypothalamic dopamine receptor function in women with a history of puerperal bipolar disorder.

Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder.

Enhanced startle reactions to acoustic stimuli in patients with obsessive-compulsive disorder.

OBJECTIVE: Anxiety states induced experimentally or occurring naturally potentiate the startle reflex elicited by sudden sensory stimuli in both animals and human beings. The authors investigated whether patients with obsessive-compulsive disorder (OCD) show exaggerated startle reactions to acoustic probes, especially during negative-affect-toned stimuli, compared with healthy subjects. METHOD: Ten patients with OCD and 10 age- and sex-matched comparison subjects were shown a series of film clips. Two of the film clips had positive valence, two had negative valence, and two had relatively neutral valence. The subjects' eyeblink startle response was measured in reaction to startle-eliciting stimuli presented three times binaurally during each film clip. RESULTS: Patients with OCD produced larger startle reflexes and shorter latencies to onset of startle response than the comparison subjects over the entire session. CONCLUSIONS: Patients with OCD were excessively responsive to startle-eliciting stimuli. This effect may be associated with the development or maintenance of OCD.

Modulation of the acoustic startle reflex by emotionally-toned film-clips.

It has been widely reported that the eyeblink component of the acoustic startle reflex can be modulated by emotionally-toned slide stimuli; pleasant slides reduce eyeblink amplitudes whereas unpleasant slides enhance them. The present study examines the modulation of the acoustic startle reflex by short (2-min) film-clips classified as pleasant, unpleasant or neutral, on the basis of subjective ratings. These film-clips were also evaluated with respect to their test-retest reliability in producing affective states as well as modulating startle reflexes. Overall, results showed significant reduction of startle during pleasant clips and augmentation during unpleasant clips. However, on first showing, one of the two unpleasant clips (a medical demonstration film depicting details of toe surgery) actually inhibited the startle reflex rather than augmented it. This is discussed in terms of the proposition that only stimuli which arouse fear can be guaranteed to augment startle; stimuli that are repulsive may produce perceptual and emotional 'blunting' that reduces startle amplitude.

Functional MRI study of the cognitive generation of affect.

OBJECTIVE: The authors investigated, by whole brain functional magnetic resonance imaging (MRI), the neural substrate underlying processing of emotion-related meanings. METHOD: Six healthy subjects underwent functional MRI while viewing 1) alternating blocks of pairs of pictures and captions evoking negative feelings and the same materials irrelevantly paired to produce less emotion (reference pairs); 2) alternating blocks of picture-caption pairs evoking positive feelings and the same materials irrelevantly paired to produce less emotion; and 3) alternating blocks of picture-caption pairs evoking positive feelings and picture-caption pairs evoking negative feelings. RESULTS: Compared with the reference picture-caption pairs, negative pairs activated the right medial and middle frontal gyri, right anterior cingulate gyrus, and right thalamus. Compared with the reference picture-caption pairs, positive pairs activated the right and left insula, right inferior frontal gyrus, left splenium, and left precuneus. Compared with the negative picture-caption pairs, positive pairs activated the right and left medial frontal gyri, right anterior cingulate gyrus, right precentral gyrus, and left caudate. CONCLUSIONS: Contrasts of both 1) negative and reference picture-caption pairs and 2) positive and negative picture-caption pairs activated networks involving similar areas in the medial frontal gyrus (Brodmann's area 9) and right anterior cingu-late gyrus (areas 24 and 32). The area 9 sites activated are strikingly similar to sites activated in related positron emission tomography experiments. Activation of these same sites by a range of evoked affects, elicited by different methods, is consistent with areas within the medial prefrontal cortex mediating the processing of affect-related meanings, a process common to many forms of emotion production.

Effects of d-amphetamine and haloperidol on latent inhibition in healthy male volunteers.

Latent inhibition (LI) refers to a retardation of learning about the consequences of a stimulus when that stimulus has been passively presented a number of times without reinforcement. Acute positive-symptom schizophrenics, normal volunteers who score high on questionnaire measures of schizotypy and non-patients or animals treated with dopamine agonists show reduced LI. Neuroleptic drugs, such as haloperidol, administered at low doses, potentiate LI and effectively reverse disruption of LI induced by dopamine agonists in animals. However, a high dose of haloperidol, administered on its own, has been found to reduce LI. We examined the effects on LI of acute oral administration of an indirect dopamine-agonist, d-amphetamine (5 mg), and a nonselective dopamine receptor antagonist, haloperidol (5 mg), in normal male volunteers, using an associative learning task. Replicating previous reports, we found that d-amphetamine reduced LI; haloperidol also reduced LI, but only in subjects who scored low on the Psychoticism scale of the Eysenck Personality Questionnaire. In a subsequent study, no effect was found of 2 mg oral haloperidol administration on LI. The effect of 5 mg haloperidol on LI is interpreted as similar to that observed with a high dose of haloperidol in rats.

Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers.

The effects of acute administration of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers on habituation and prepulse inhibition (PPI) of the acoustic startle reflex in two experiments. In Experiment 1, 40 male non-smoker volunteers were tested for habituation and PPI (defined as percentage reduction of the pulse-alone amplitude; prepulses 9 dB above background) before and after double-blind administration of either 2 mg haloperidol or placebo. No influence of haloperidol was observed on either habituation or PPI of the startle reflex in this experiment. In Experiment 2, 60 male volunteers underwent startle testing before and after double-blind administration of a single oral dose of 5 mg haloperidol, 5 mg d-amphetamine or placebo. Habituation and PPI (prepulses 15 dB above background) for the placebo group did not differ significantly from that observed for the d-amphetamine or for the haloperidol group. However, in a subgroup of smoking subjects, both d-amphetamine and haloperidol reduced PPI as compared to that observed prior to drug administration. The implications of these findings in relation to animal pharmacological studies and observed sensorimotor gating deficits in schizophrenia are discussed.

Effect of acute subcutaneous nicotine on prepulse inhibition of the acoustic startle reflex in healthy male non-smokers.

In a double-blind placebo-controlled trial, the effects of two doses (6 micrograms/kg, 12 micrograms/kg) of acute SC nicotine were investigated on prepulse inhibition (PPI) of the acoustic startle reflex in healthy non-smoker male volunteers. Each subject received three injections [placebo (saline), 6 micrograms/kg nicotine, 12 micrograms/kg nicotine] on separate occasions, 2 weeks apart. No influence of either 6 micrograms/kg or 12 micrograms/kg nicotine was observed for the amplitude and habituation of the startle response over pulse-alone stimuli, relative to the saline-treated condition. Percent of PPI (expressed as percent reduction of non-prepulse trials) was significantly greater, but PPI as measured by absolute difference scores was not significantly different, when subjects were given the 12 micrograms/kg dose of nicotine than saline. There was an increase in percent of PPI from saline through low to high doses of nicotine, but PPI observed under the low dose did not differ significantly from either the high dose or placebo. These results provide some support for previous findings showing an enhancement in PPI by cigarette smoking in overnight smoking-deprived smokers and by acutely administered nicotine in experimental animals. The findings indicate that previously observed effects of smoking on percent of PPI in smoking-deprived subjects were not attributable to the restoration of a deficit induced by smoking withdrawal, but represent a direct pharmacological action of nicotine.

Effects of acute administration of d-amphetamine and haloperidol on procedural learning in man.

The effects of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers using a between-subjects double-blind design in a procedural learning task, thought mainly to involve unconscious/automatic learning. The results showed: (1) d-amphetamine facilitated response speed, whereas haloperidol inhibited it, in comparison to placebo; (2) the linear increase in procedural learning corresponded with pharmacological manipulation of degree of dopaminergic activity, i.e. subjects given haloperidol showed the least, and subjects given d-amphetamine the greatest, procedural learning. The implications of these findings are discussed in relation to investigation of abnormalities of procedural learning processes in schizophrenia.

Effect of cigarette smoking on prepulse inhibition of the acoustic startle reflex in healthy male smokers.

The present study investigated the effects of cigarette smoking on prepulse inhibition (PPI) of the acoustic startle reflex in healthy men. Cigarette smoking in a group of overnight smoking-deprived smokers increased PPI as compared to the smoking-deprived condition. This finding is consistent with previous animal studies showing that nicotine increases PPI of the acoustic startle reflex. In addition, cigarette smoking also reduced startle amplitude during the first 6-7 min of the post-smoking session.

The growth hormone response to apomorphine at 4 days postpartum in women with a history of major depression.

We have examined the responsiveness of dopamine sensitive neurones in the postpartum period in woman with a history of major depression who are at high risk of experiencing a recurrence of illness in the postpartum period. Fourteen women were assessed at 36 weeks of pregnancy and during the 3 months following delivery, using the Schedule for Affective Disorders and Schizophrenia, including its change version. They were not depressed at initial assessment. Five of the 14 women went on to experience a postpartum relapse (2 major depressive disorder, 2 generalised anxiety disorder, 1 panic disorder). On the fourth day postpartum, i.e., before relapse, the growth hormone response to the dopamine agonist apomorphine was measured as an index of the functional state of hypothalamic dopamine D2 receptors. Women who subsequently relapsed had a significantly greater growth hormone response to apomorphine than those who remained well. This was particularly marked in women with anxiety/panic. The development of increased sensitivity of hypothalamic dopamine D2 receptors in the postpartum period appears to predict the onset of depressive and anxiety disorders.

Effects of sex steroids on protein synthesis in cultured human lymphocytes.

In cultured human lymphocytes, oestrogen and progesterone at concentrations found in plasma during the normal menstrual cycle, significantly increase the incorporation of [35S] methionine into protein and, in addition, both hormones significantly alter the relative synthesis of certain proteins. At concentrations found in plasma during pregnancy, some changes are augmented while others are reversed. These specific sex-steroid-induced changes in protein synthesis provide possible peripheral biological markers of hormone action which may be tested for their association with predisposition to, and/or onset of, conditions such as postpartum psychiatric illness.

The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles.

In order to investigate mechanisms by which the adrenal 11 beta-hydroxylase inhibitor metyrapone might exert its antidepressant effect, we used gas chromatography to analyse the 24 h urinary steroid profiles from six females with major depression taking part in a trial of metyrapone (2-4 g/day) as an antidepressant. Due to concurrent administration of hydrocortisone (30 mg/day), plasma cortisol levels were not significantly reduced. Treatment with metyrapone resulted in greatly increased urinary excretion of 11-deoxy corticosteroids, including the GABA-modulatory steroid tetrahydro-11-deoxycorticosterone (from 68 +/- 34 to 219 +/- 75 micrograms/24 h, p < .05). Metyrapone also had multiple extra-adrenal effects on corticosteroid metabolism, including inhibition of the peripheral conversion of cortisone to cortisol as demonstrated by a significant decrease in the ratio of 11 beta-hydroxy/11-oxo metabolites of cortisol (from 0.81 +/- 0.08 to 0.46 +/- 0.04, p < .01). The decreased Montgomery-Asberg Depression Rating Scale scores seen during treatment with metyrapone did not correlate with changes in plasma cortisol, but did correlate significantly with total 11-deoxycortisol metabolites (r = 0.778, n = 12, p < .01). We conclude that, in addition to decreased cortisol synthesis, increased secretion of cortisol precursors and reduced local bioavailability of cortisol may play a role in the antidepressant effect of metyrapone.

Effect of clonidine on the human acoustic startle reflex.

The present study investigated in healthy human volunteers whether clonidine reduced the amplitude of the acoustic startle reflex and whether this effect, if found, was due to an accelerated rate of habituation. Subjects were presented with startle-eliciting noise-bursts after intravenous (iv) infusion of clonidine (1.5 microgram/kg) and saline on separate days. Clonidine significantly reduced the amplitude of the acoustic startle reflex (as indexed by the eyeblink component) relative to the saline treated condition. This effect was neither due to an accelerated rate of habituation of the startle reflex nor to the sedative effect of clonidine. These findings complement an earlier report (Morgan et al. 1993) that yohimbine augments the amplitude of the startle reflex in man. Taken together, the two reports indicate a new model for the clinical investigation of central alpha2 adrenoceptor function in humans.

Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency.

BACKGROUND AND OBJECTIVE: Previous studies suggesting effects of metyrapone on extra-adrenal corticosteroid metabolism have involved significant alterations in plasma cortisol. We have therefore studied effects of metyrapone on urinary excretion of steroids in a group of patients treated concurrently with hydrocortisone so that changes in plasma cortisol were minimized. DESIGN: Replacement doses of hydrocortisone (30 mg/day) were given concurrently with metyrapone (2-4 g/day) for 2 weeks. Blood samples were taken and 24-hour urinary steroid collections were made at baseline and after 1 and 2 weeks of treatment. PATIENTS: Subjects were 6 female patients with major depression from a trial of metyrapone as an antidepressant. MEASUREMENTS: Urinary steroid profiles were measured by gas chromatography; plasma cortisol and urinary free cortisol were measured by fluorescence immunoassay. RESULTS: Plasma cortisol levels were not significantly decreased by treatment, while excretion of 11-deoxycortisol metabolites increased eightfold after 2 weeks indicating that concurrent hydrocortisone administration had not suppressed the adrenal. Ratios reflecting 11 beta-hydroxy/11-oxo metabolites of cortisol were significantly decreased, consistent with inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase (11-HSD). Other changes included significant decreases in the rates of 5 alpha vs 5 beta and of 20 alpha vs 20 beta reduction of corticosteroids. CONCLUSIONS: Metyrapone has multiple effects on extra-adrenal corticosteroid metabolism and is the only agent we know of which selectively inhibits 11-oxoreductase. Metyrapone thus provides a model for 11-HSD I deficiency and a tool for in-vitro studies of cortisol-cortisone interconversion. The results also suggest mechanisms whereby corticosteroid effects can be regulated separately from corticosteroid synthesis.

Treatment of major depression with metyrapone and hydrocortisone.

Eight inpatients with Major Depression were treated with metyrapone and hydrocortisone in a balanced order placebo-controlled single-blind cross-over study. The hydrocortisone dose (30 mg daily) was a physiological replacement dose and the metyrapone dose was titrated against plasma cortisol in order to keep cortisol within physiological limits. The treatment resulted in a significant reduction in depressive symptoms. This placebo-controlled study replicates the results of several uncontrolled studies but leaves open for further study the mechanism by which the combined administration of metyrapone and hydrocortisone might exert its antidepressant effect.

Seasonal affective disorder: response to light as measured by electroencephalogram, melatonin suppression, and cerebral blood flow.

This study was designed to test the hypothesis that patients with SAD have significantly different physiological responses to light than healthy age- and sex-matched controls. We studied retinal contrast sensitivity, visual evoked EEG responses, and melatonin suppression by, and cerebral blood flow response to, full-spectrum artificial daylight. There was no significant difference between 10 patients and 11 controls in retinal contrast sensitivity, or amplitude or latency of N2, P2, P100 or P300 on EEG. We compared melatonin suppression in 12 SAD patients and 12 controls. During exposure to 500 lux and 1500 lux artificial daylight both the SAD patients and controls had a significant melatonin percentage suppression; however, the percentage suppression did not differ significantly between the SAD patients and the controls. In addition, we carried out a small pilot study into the effect of light on cerebral blood flow in four SAD patients and four controls. Before exposure to 1500 lux artificial daylight there was no significant difference between patients and controls in global, regional or cerebral hemispheric blood flow. After light exposure the SAD patients and controls had a significantly different percentage change in cerebral blood flow. We suggest that patients with SAD do not have significantly physiological responses to light than controls, except perhaps in cerebral blood flow. Furthermore, mechanisms other than supersensitivity of melatonin suppression must explain both the pathophysiology of the disorder and its response to treatment with light.

Melatonin rhythms in seasonal affective disorder.

We examined 24-hour melatonin rhythms from 20 patients with seasonal affective disorder (SAD) and 20 healthy volunteers. Patients and controls were individually matched for age, sex, and month of study. Plasma samples were taken at hourly intervals, and were assayed for melatonin by radio-immunoassay. The 24-hourly melatonin estimations for each individual were fitted to a cosine curve, and the significance of the curve fits was calculated. Two analyses were performed. In analysis 1 the following were calculated: (a) cosine fit, (b) significance of fits, (c) mean amplitude and acrophase (peak) and (d) mean melatonin levels. The curve fits were highly significant for all but three subjects (two patients, one control), but there were no significant differences in any measure between the two groups. In analysis 2 the comparisons were repeated and restricted to the 18 patients and 19 controls in whom there was a significantly significant melatonin rhythm. Again there were no significant differences between groups. These results suggest that the circadian rhythm of melatonin is not abnormal in SAD, and that the therapeutic effect of light in SAD is not mediated by phase shifts in melatonin secretion.

Cognitive impairments in patients with seasonal affective disorder.

Eleven patients with seasonal affective disorder (SAD) and ten controls matched for age, IQ, and education were tested on a number of computerised tests designed to assess attention, memory, and learning. When depressed, patients showed no deficit in attention but were impaired on spatial memory and learning. They were also significantly slower to respond than controls, with a pattern that suggested slowed information processing centrally, rather than simple sensory or motor slowing. On recovery from depression, improvement was seen in most tests, although impairment remained in latency to respond on a test of spatial memory. This continuing impairment correlated with residual depressive symptoms but not with ventricular brain ratio (VBR).