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Biomedical subjects

Pradeep J Nathan

Publications and source records attributed to Pradeep J Nathan.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pindolol augmentation of selective serotonin reuptake inhibitors: accounting for the variability of results of placebo-controlled double-blind studies in patients with major depression.

Co-administration of pindolol with SSRIs in patients with depression has been suggested as a way to both hasten and augment antidepressant response. Clinical trials have examined the efficacy of this treatment regime and conflicting results have been reported. The present review briefly presents the results of placebo-controlled double-blind trials of pindolol augmentation of SSRIs in patients with major depression, and focuses on factors that may account for the variability of findings. Additionally, a profile of the subset of patients who may most benefit from pindolol augmentation is outlined. Methodological factors such as qualitative differences in definitions of antidepressant response, the timing of pindolol administration and heterogeneous clinical characteristics of patient samples may contribute to the variability in the results of clinical trials to date. Similarly, individual differences in neuropathology, neurophysiology and genotype may also account for some of the inconsistencies in the findings. Finally, the results of recent neuroimaging studies suggest that the 2.5 mg t.i.d. dose of pindolol that has been used in all but one of these investigations may be suboptimal for achieving reliable and significant occupancy of 5-HT1A autoreceptors and may explain the contradictory nature of the results of investigations of pindolol augmentation.

Adrenergic beta-Antagonists↗
PubMed2005

Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans.

Working memory impairments in the n-back task in schizophrenia have been linked to sustained deficiency in mesocortical dopamine function. More recently, abnormalities in the cholinergic system have also been documented in schizophrenia, with cortical reductions in both nicotinic and muscarinic receptors. While the cholinergic hypothesis of memory is well established, the role of cholinergic receptors in modulating n-back working memory is not known. We investigated the effects of selective and simultaneous muscarinic and nicotinic antagonism on spatial and object n-back working memory performance. The study was a double-blind, placebo-controlled repeated-measures design in which 12 healthy subjects were tested under four acute treatment conditions; placebo (P), mecamylamine (M), scopolamine (S) and mecamylamine+scopolamine (MS). Muscarinic antagonism with scopolamine significantly impaired both object and spatial n-back working memory, whereas nicotinic antagonism with mecamylamine had little effect. Simultaneous antagonism of both muscarinic and nicotinic receptors produced greater impairments in both object and spatial n-back working memory performance than muscarinic or nicotinic antagonism alone. These results suggest that: (1) both muscarinic and nicotinic receptors may functionally interact to synergistically modulate n-back working memory, and (2) that n-back working memory impairments in schizophrenia may in part be due to reductions in both muscarinic and nicotinic receptors.

Adult↗
PubMed2004

Neural correlates of internally-generated disgust via autobiographical recall: a functional magnetic resonance imaging investigation.

Converging lines of evidence suggest the involvement of the insula and basal ganglia in the processing of disgust, an important primary emotion that guides the avoidance of potential physical contamination and disease. Prior human lesion and functional brain imaging studies have employed exteroceptive sensory stimuli such as facial expressions of disgust, and disgust-eliciting pictures. Thus, the neural substrates underlying the internal experience of disgust remain unknown. The present fMRI study examined the neural correlates of self-induced disgust aided by the recall and re-experience of personally salient life events. Subjects were scanned while they recalled and re-experienced either a recent situation that evoked intense disgust or a time-matched, equally vivid neutral/non-emotional event. Relative to the emotionally neutral condition, self-induced disgust was associated with activation of the insula, hippocampus, anterior and posterior cingulate cortex, basal ganglia, thalamus, and primary visual cortex. These findings suggest that areas previously associated with the perception of disgust (e.g., insula, basal ganglia) are also involved interoceptive experience of disgust.

Adult↗
PubMed2004

Simultaneous depletion of tryptophan, tyrosine and phenylalanine as an experimental method to probe brain monoamine function in humans.

Brain monoamines are important regulators of affective and cognitive processes and are involved in the aetiology of a number of psychiatric disorders. While methods to probe serotonin and catecholamine function are established, limited methods are available to probe monoamine function as a whole in humans. In the current study, we examined if simultaneous depletion of monoamine precursors can be used as a possible probe of monoamine function. Ten healthy subjects were tested under two treatment conditions; balanced control (B) condition and combined monoamine depletion (CMD) condition. Monoamine precursor depletion was associated with significant reductions in plasma-free tryptophan (46%), tyrosine (74%) and phenylalanine (78%). Greater reductions were achieved for ratios of each precursor to other large neutral amino acids (LNAA); tryptophan/LNAA (86%), tyrosine/LNAA (94%) and phenylalanine/LNAA (94%). Findings suggest that simultaneous depletion of monoamine precursors can achieve significant plasma monoamine depletion in the range expected to affect brain monoamine function.

Adolescent↗
PubMed2004

Selective effects of simultaneous monoamine depletion on mood and emotional responsiveness.

Monoamines play a significant role in the regulation of mood and emotion. While the selective effects of serotonin and catecholamine depletion on mood have been described, the effects of simultaneous monoamine depletion on subjective measures of mood and emotional responsiveness are yet to be examined. The current study aimed to investigate the effects of simultaneous monoamine depletion on mood and emotional responsiveness in healthy participants. Twenty female participants completed a randomized, double-blind, placebo-controlled study, under a balanced control condition (B), and a combined monoamine depletion condition (CMD; via tryptophan, tyrosine and phenylalanine depletion). Mood ratings Visual Analogue Mood Scale (VAMS) and Profile Of Mood States (POMS) and measures of emotional responsiveness (Emotional Stroop and International Affective Picture System) were examined at baseline and 5 h post-depletion. Following CMD, participants rated themselves as feeling sadder, more antagonistic, and mentally slower on three VAMS subscales. There were no significant mood changes found on the POMS or measures of emotional responsiveness. These findings suggest that simultaneous depletion of all monoamines may have selective effects on mood. The findings provide evidence that the simultaneous monoamine depletion technique may be a useful experimental method to probe central monoamine function in humans.

Adolescent↗
PubMed2004

Acute augmentation of serotonin suppresses cardiovascular responses to emotional valence.

A key component in visceral reactivity to emotional states is heart rate (HR), however little is known about how HR response to emotional stimuli is modulated by neurochemicals. The present study investigated the way in which acute enhancement of serotonin (5-HT) function with a selective serotonin reuptake inhibitor (SSRI) modulates the HR associated with differently valent images (pleasant, neutral, unpleasant). Sixteen healthy participants viewed 75 images whilst HR was recorded. Participants were tested under two single-dose treatment conditions: placebo and citalopram (20 mg). Our findings suggest: (1) HR is able to differentiate differently valent images during placebo treatment and, (2) administration of citalopram suppresses the differences in HR between differently valent images. These results suggest that 5-HT may modulate the cardiovascular HR response to visual emotional stimuli and indicate that 5-HT may have a protective effect on the cardiovascular responses to emotional stimuli.

Adult↗
PubMed2004

Effects of a combined extract of Ginkgo biloba and Bacopa monniera on cognitive function in healthy humans.

Extracts of Ginkgo biloba and Bacopa monniera have been shown to produce positive effects on cognitive function in healthy subjects. While the exact mechanisms are not known, it has been suggested that antioxidant properties and cholinergic modulation may play a role. In the current study the sub-chronic (2 weeks) and chronic (4 weeks) effects of an extract containing Ginkgo biloba (120 mg) and Bacopa monniera (300 mg) (Blackmores Ginkgo Brahmi) on cognitive function were examined. The study was a randomized, double-blind, placebo-controlled, independent group design in which 85 healthy subjects were allocated to one of two treatment conditions (placebo or combined Ginkgo biloba and Bacopa monniera extract). Testing was conducted at baseline and 2 and 4 weeks post treatment. The results showed that the combined extract relative to placebo did not demonstrate any significant effects on tests investigating a range of cognitive processes including attention, short-term and working memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness and decision making. These findings suggest that at least within the current treatment duration and doses, an extract containing Ginkgo biloba and Bacopa monniera had no cognitive enhancing effects in healthy subjects.

Adult↗
PubMed2004

The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans.

L-Theanine (delta-glutamylethylamide) is one of the predominant amino acids ordinarily found in green tea, and historically has been used as a relaxing agent. The current study examined the acute effects of L-theanine in comparison with a standard benzodiazepine anxiolytic, alprazolam and placebo on behavioural measures of anxiety in healthy human subjects using the model of anticipatory anxiety (AA). Sixteen healthy volunteers received alprazolam (1 mg), L-theanine (200 mg) or placebo in a double-blind placebo-controlled repeated measures design. The acute effects of alprazolam and L-theanine were assessed under a relaxed and experimentally induced anxiety condition. Subjective self-reports of anxiety including BAI, VAMS, STAI state anxiety, were obtained during both task conditions at pre- and post-drug administrations. The results showed some evidence for relaxing effects of L-theanine during the baseline condition on the tranquil-troubled subscale of the VAMS. Alprazolam did not exert any anxiolytic effects in comparison with the placebo on any of the measures during the relaxed state. Neither L-theanine nor alprazalam had any significant anxiolytic effects during the experimentally induced anxiety state. The findings suggest that while L-theanine may have some relaxing effects under resting conditions, neither L-theanine not alprazolam demonstrate any acute anxiolytic effects under conditions of increased anxiety in the AA model.

Adult↗
PubMed2004

Augmentation of serotonin enhances pleasant and suppresses unpleasant cortical electrophysiological responses to visual emotional stimuli in humans.

The serotonergic system is one of the major systems targeted in the pharmacological treatment of a wide range of mood disorders including depression; however, little is known about the neurophysiological mechanisms underlying the effects of serotonin (5-HT) on affective phenomena including emotional behaviours, mood and emotional processing. The aim of the current study was to investigate how 5-HT acutely modulates steady-state visually evoked potentials (SSVEP), heart rate (HR) and verbal ratings associated with the viewing of differently valent emotional images. In a randomised double-blind, placebo-controlled design, 17 healthy subjects were tested under two acute treatment conditions: placebo and citalopram (20 mg) (a selective serotonin re-uptake inhibitor, or SSRI). Participants were tested 2 h post treatment whilst viewing 75 images (categorised as pleasant, neutral or unpleasant). Results indicate that under placebo treatment, processing of unpleasant valence [unpleasant (-) neutral images] was associated with decreases in SSVEP amplitude and latency in frontal and occipital cortices, whereas processing of pleasant valence [pleasant (-) neutral images] was associated with amplitude decreases and latency increases within frontal and left temporoparietal cortices. Decreases in both amplitude and latency are both interpreted as surrogate measures of cortical activation or excitation. Citalopram relative to placebo attenuated the electrophysiological activation to unpleasant valence within frontal and occipital cortices, but potentiated electrophysiological activation (amplitude only) to pleasant valence within parietooccipital cortices. Citalopram relative to placebo also suppressed differences in heart rate associated with the viewing of pleasant and unpleasant images, but did not alter subject's subjective responses to emotional images. Results suggest that responsiveness to pleasant and unpleasant stimuli following neurochemical modulation may vary across different response systems (i.e. self-report, HR and SSVEP). Electrophysiological findings suggest that acute serotonergic augmentation with citalopram modulates cortical processing of emotionally valent stimuli such that response to pleasant valence is potentiated and response to unpleasant valence is suppressed. The findings suggest a possible neurophysiological mechanism underlying antidepressant drug action on emotion.

Adult↗
PubMed2004

Simultaneous depletion of serotonin and catecholamines impairs sustained attention in healthy female subjects without affecting learning and memory.

Monoamine neurotransmitters, serotonin, noradrenaline and dopamine modulate many important cognitive processes such as attention, learning and memory. While the selective effects of serotonin and catecholamine depletion on such processes have been investigated, the effects of simultaneous depletion of these monoamines on cognition remain unclear. This is of particular interest given that multiple neurotransmitter abnormalities have been implicated in many psychiatric disorders. The aim of the current study was to examine the effects of lowered brain monoamine function on cognitive performance, using the technique of amino acid precursor depletion. The study was a double-blind, placebo-controlled design in which 20 healthy female subjects were tested under a combined monoamine depletion condition (CMD) and a balanced control condition (B). Cognitive testing was conducted at baseline and 5 h post-depletion. The CMD condition relative to the B condition resulted in deficits in digit vigilance (accuracy and reaction time), a measure of sustained attention. There were no effects on measures of learning and memory or psychomotor function. These findings suggest that simultaneously depleting the availability of brain serotonin and catecholamines in healthy female subjects selectively impairs sustained attention, without affecting other cognitive domains.

Adolescent↗
PubMed2004

Selective effects of acute serotonin and catecholamine depletion on memory in healthy women.

There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.

Adult↗
PubMed2003

Drug-induced modification of the system properties associated with spontaneous human electroencephalographic activity.

The benzodiazepine (BZ) class of minor tranquilizers are important modulators of the gamma-amino butyric acid (GABA(A))/BZ receptor complex that are well known to affect the spectral properties of spontaneous electroencephalographic activity. While it is experimentally well established that the BZs reduce total alpha band (8-13 Hz) power and increase total beta band (13-30 Hz) power, it is unclear what the physiological basis for this effect is. Based on a detailed theory of cortical electrorhythmogenesis it is conjectured that such an effect is explicable in terms of the modulation of GABAergic neurotransmission within locally connected populations of excitatory and inhibitory cortical neurons. Motivated by this theory, fixed order autoregressive moving average (ARMA) models were fitted to spontaneous eyes-closed electroencephalograms recorded from subjects before and approximately 2 h after the oral administration of a single 1 mg dose of the BZ alprazolam. Subsequent pole-zero analysis revealed that BZs significantly transform the dominant system pole such that its frequency and damping increase. Comparisons of ARMA derived power spectra with fast Fourier transform derived spectra indicate an enhanced ability to identify benzodiazepine induced electroencephalographic changes. This experimental result is in accord with the theoretical predictions implying that alprazolam enhances inhibition acting on inhibitory neurons more than inhibition acting on excitatory neurons. Further such a result is consistent with reported cortical neuronal distributions of the various GABA(A) receptor pharmacological subtypes. Therefore physiologically specified fixed order ARMA modeling is expected to become an important tool for the systematic investigation and modeling of a wide range of cortically acting compounds.

Alprazolam↗