Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers

Phillips, Michael A.; Szabadi, E.; Bradshaw, C. M.

doi:10.1007/s002130000398

Cited by 83 publications

(75 citation statements)

References 22 publications

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“…In the present experiment, a single dose of 0.2 mg clonidine reduced both the subjective and the objective level of alertness in healthy volunteers (see Table 1), in agreement with previous reports (Morley et al, 1991;Kumari et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001Phillips et al, 2000d;Hou et al, 2005. Alertness was robustly increased by a single dose of 400 mg modafinil, in contrast to previous reports using a 200-mg single dose where either a small effect (Hou et al, 2005(Hou et al, , 2007 or no effect of modafinil in healthy non-sleep-deprived volunteers was observed.…”

Section: Discussionsupporting

confidence: 92%

“…Clonidine reduced pupil diameter (Bitsios et al, 1996;Phillips et al, 2000c, d;Hou et al, 2005, reduced systolic and diastolic blood pressure in both the supine and the standing positions (Lal et al, 1975;Berlan et al, 1989;Morley et al, 1991;Bitsios et al, 1996;Kumari et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001Arya et al, 1997;Phillips et al, 2000d;Hou et al, 2005, reduced salivation (Bitsios et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001Arya et al, 1997;Phillips et al, 2000d;Hou et al, 2005, and reduced core temperature (Arya et al, 1997;) (see Figure 5 and Table 2). The autonomic effects of clonidine are consistent with the stimulation of inhibitory a 2 -adrenoceptors on central neurons.…”

Section: Discussionmentioning

confidence: 95%

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Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Samuels

Hou

Langley

et al. 2007

Neuropsychopharmacol

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A sudden loud sound evokes an electromyographic (EMG) response from the orbicularis oculi muscle in humans together with an auditory evoked potential (AEP) and an increase in skin conductance (SC). Startle responses are inhibited by weak prepulses (prepulse inhibition, (PPI)) and may also be modified by the level of alertness. We compared the sedative drug clonidine and the alerting drug modafinil on sound-evoked EMG, AEP, and SC responses, on the PPI of these responses and on level of arousal and autonomic functions. Sixteen healthy male volunteers participated in four weekly sessions (clonidine 0.2 mg, modafinil 400 mg, their combination, placebo) in a double-blind, cross-over, balanced design. Responses were evoked by sound pulses of 115 and 85 dB (PPI) for 40 ms and recorded conventionally. Level of alertness, autonomic functions (pupil diameter, blood pressure, heart rate, salivation, temperature) and the plasma levels of the hormones prolactin, thyroid-stimulating hormone and growth hormone were also measured. Data were analyzed with analysis of variance with multiple comparisons. Both prepulses and clonidine attenuated all three startle responses and modafinil antagonized clonidine's effects on the EMG and AEP responses. None of the drugs affected PPI. Clonidine showed sedative and sympatholytic effects, and modafinil showed alerting and sympathomimetic effects. In conclusion, startle responses were susceptible not only to PPI but also to the level of arousal. Keywords: acoustic startle response; auditory evoked potential; skin conductance; prepulse inhibition; clonidine; modafinil INTRODUCTIONThe startle response involves rapid involuntary contractions of facial and skeletal musculature in response to a sudden intense stimulus. In the case of the acoustic startle response, this reaction occurs in response to a sudden loud sound and is measurable in humans as an electromyographic (EMG) response from the orbicularis oculi muscle (eyeblink startle response). This response is believed to be mediated via a pathway below the level of the diencephalon consisting of between three and five central synapses, originating from the sensory receptors and terminating on the motor neurons, where the principal relay is the caudal pontine reticular nucleus (Davis et al, 1982; for review, see Yeomans and Frankland, 1996;Koch, 1999). In addition to this muscular response, changes in electroencephalographic (EEG) activity can be observed in response to the auditory stimulus, and these changes are termed auditory evoked potentials (AEP). In particular, the N1/P2 component of the AEP is measurable following the presentation of the acoustic startle stimulus (for examples, see Abduljawad et al, 1999Abduljawad et al, , 2001 Phillips et al, 2000a, b;Graham et al, 2001Graham et al, , 2004Scaife et al, 2005Scaife et al, , 2006. Both the muscular and the AEP responses are fast responses; longer-latency responding to the startle stimulus can be observed in autonomic activity, in particular in sympathetically mediated skin conductance...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Samuels

Hou

Langley

et al. 2007

Neuropsychopharmacol

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“…For example, changes in pupil responses correspond to changes in locus coeruleus firing rate (Joshi et al, 2016;Murphy et al, 2014;Varazzani et al, 2015), as well as norepinephrine concentrations (Phillips et al, 2000;Warren et al, 2016). Extending recent work (Chmielewski et al, 2017;Dippel et al, 2017;Mückschel et al, 2017), we found that midfrontal theta correlated with pupil dilation responses, suggesting that the mPFC and LC-NE might interact to resolve conflict and respond to surprising events even during choices based on personal preferences.…”

Section: Discussionsupporting

confidence: 80%

Midfrontal theta and pupil dilation parametrically track subjective conflict (but also surprise) during intertemporal choice

et al. 2018

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2 Highlights •Modeled conflict during intertemporal choice and measured EEG and pupil responses.• Midfrontal theta and pupil responses parametrically tracked subjective conflict.• But theta and pupil responses were also large when decisions were surprisingly easy.• These signals may implement adaptive control during value-guided choice.3 AbstractMany everyday choices are based on personal, subjective preferences. When choosing between two options, we often feel conflicted, especially when trading off costs and benefits occurring at different times (e.g., saving for later versus spending now).Although previous work has investigated the neurophysiological basis of conflict during inhibitory control tasks, less is known about subjective conflict resulting from competing subjective preferences. In this pre-registered study, we investigated subjective conflict during intertemporal choice, whereby participants chose between smaller immediate versus larger delayed rewards (e.g., $15 today vs. $22 in 30 days). We used economic modeling to parametrically vary eleven different levels of conflict, and recorded EEG data and pupil dilation. Midfrontal theta power, derived from EEG, correlated with pupil responses, and our results suggest that these signals track different gradations of subjective conflict. Unexpectedly, both signals were also maximally enhanced when decisions were surprisingly easy. Therefore, these signals may track events requiring increased attention and adaptive shifts in behavioral responses, with subjective conflict being only one type of such event. Our results suggest that the neural systems underlying midfrontal theta and pupil responses interact when weighing costs and benefits during intertemporal choice. Thus, understanding these interactions might elucidate how individuals resolve self-control conflicts.

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“…Neuroimaging work has shown that the pupil diameter covaries with fMRI BOLD activity in the LC (Murphy, O'Connell, O'Sullivan, Robertson, & Balsters, 2014) and that both P3 ERP and pupil diameter are sensitive to LC-NE modes of task engagement (Cheadle et al, 2014;Murphy, Robertson, Balsters, & O'Connell, 2011). Converging evidence from electrophysiology (e.g., Rajkowski, Kubiak, & Aston-Jones, 1994) and pharmacology (e.g., Phillips, Szabadi, & Bradshaw, 2000;Koss, 1986) also suggests that pupil diameter correlates with LC activity in animals. The anatomical pathways linking the LC and the pupil are a topic of ongoing research but probably involve α 2 -adrenoreceptormediated inhibition of the parasympathetic EdingerWestphal nucleus responsible for pupil constriction (Samuels & Szabadi, 2008).…”

Section: Introductionmentioning

confidence: 99%

Pupil Diameter Tracks the Exploration–Exploitation Trade-off during Analogical Reasoning and Explains Individual Differences in Fluid Intelligence

Hayes¹,

Petrov²

2016

Journal of Cognitive Neuroscience

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Abstract■ The ability to adaptively shift between exploration and exploitation control states is critical for optimizing behavioral performance. Converging evidence from primate electrophysiology and computational neural modeling has suggested that this ability may be mediated by the broad norepinephrine projections emanating from the locus coeruleus (LC) [Aston-Jones, G., & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403-450, 2005]. There is also evidence that pupil diameter covaries systematically with LC activity. Although imperfect and indirect, this link makes pupillometry a useful tool for studying the locus coeruleus norepinephrine system in humans and in high-level tasks. Here, we present a novel paradigm that examines how the pupillary response during exploration and exploitation covaries with individual differences in fluid intelligence during analogical reasoning on Raven's Advanced Progressive Matrices. Pupillometry was used as a noninvasive proxy for LC activity, and concurrent think-aloud verbal protocols were used to identify exploratory and exploitative solution periods. This novel combination of pupillometry and verbal protocols from 40 participants revealed a decrease in pupil diameter during exploitation and an increase during exploration. The temporal dynamics of the pupillary response was characterized by a steep increase during the transition to exploratory periods, sustained dilation for many seconds afterward, and followed by gradual return to baseline. Moreover, the individual differences in the relative magnitude of pupillary dilation accounted for 16% of the variance in Advanced Progressive Matrices scores. Assuming that pupil diameter is a valid index of LC activity, these results establish promising preliminary connections between the literature on locus coeruleus norepinephrine-mediated cognitive control and the literature on analogical reasoning and fluid intelligence. ■

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Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers

Abstract: These results confirm the alerting effect of the centrally acting noradrenergic activating drug yohimbine and the opposite effect of clonidine, and the suitability of the PST to detect these effects.

Cited by 83 publications

References 22 publications

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Midfrontal theta and pupil dilation parametrically track subjective conflict (but also surprise) during intertemporal choice

Pupil Diameter Tracks the Exploration–Exploitation Trade-off during Analogical Reasoning and Explains Individual Differences in Fluid Intelligence

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