β-adrenergic modulation of oddball responses in humans
© Strange and Dolan; licensee BioMed Central Ltd. 2007
Received: 14 March 2007
Accepted: 13 June 2007
Published: 13 June 2007
Detection of salient or motivationally significant stimuli is of adaptive importance. The neurophysiological correlates of this detection have been extensively studied in 'oddball' paradigms. Much theoretical data supports the role of noradrenergic systems in generating oddball responses. We combine psychopharmacology and functional neuroimaging to demonstrate modulation of neuronal responses to oddball nouns by the β-adrenergic antagonist propranolol. Critically, responses in regions implicated in oddball detection, namely right ventrolateral prefrontal cortex and temporoparietal junction (TPJ), were abolished by propranolol. Thus, oddball responses depend on modulatory adrenergic inputs, mediated via β-adrenergic receptors.
Stimuli that violate the prevailing context, oddball stimuli, elicit a P3 event-related potential (ERP). A recent review  has highlighted the similarities between conditions evoking the P3 ERP and those evoking phasic responses in the Locus Coeruleus (LC), which provides the major ascending noradrenergic (NE) projection. Early studies combining animal intracranial recordings, lesion studies and human scalp-recorded ERPs provided evidence for the involvement of the LC-NE system in P3 generation [1, 2]. The human electrophysiological response to oddball stimuli (P3) is dependent on the local and global probability of their occurrence [3, 4]. In addition, P3s are elicited by motivationally significant stimuli, such as emotional stimuli . In parallel, data from animal studies demonstrate increased phasic activity in LC neurones to novel, infrequent or threatening stimuli [6, 7].
Thus, in the context of fMRI scanning, we presented subjects with two types of infrequent oddballs, perceptual and emotional, both known to elicit a P3 [1, 3, 5] and to engage LC in animals [1, 6, 7]. To examine the role of the β-adrenergic system in oddball responses, 24 right-handed, native English speaking subjects were scanned in a double-blind placebo-controlled design with 12 subjects receiving a 40 mg dose of propranolol and 12 placebo. We scanned subjects while viewing nouns presented visually at a rate of one every 3 s. Subjects were presented with 38 lists of 14 nouns and were required to indicate with a push-button whether or not the first letter in the noun had an enclosed space (shallow encoding). For each list, 12 nouns were of the same semantic category, were emotionally neutral and presented in the same font, i.e. neutral control (C) nouns. A perceptual (P) oddball was presented in a novel font but was emotionally neutral and of the same semantic category as the neutral nouns. An emotional (E) oddball was aversive in content but of the same category and perceptually identical to neutral nouns. Thus, both oddball types had a frequency of 1 in 14 (global probability of occurrence 0.07). The first 5 nouns in each list were always neutral nouns, engendering low local probability of oddball occurrence.
Materials and methods
The 24 subjects comprised 12 males (age range 20–39 yrs; mean 29.2) and 12 females (20–29 yrs; 24.7) with drug allocation balanced for gender i.e. 6 males and 6 females received propranolol. All subjects gave informed consent and were free of neurological or psychiatric history. The study had full ethics approval.
Subjects were administered propranolol or placebo at 0730. In view of the kinetics of propranolol's peak plasma concentration (1–2 h), the oddball task started 90 min after drug administration. Blood pressure (BP) was measured at the time of drug/placebo administration and blood samples and BP were taken immediately prior to the encoding scanning session .
Nouns were presented every 3 s (stimulus duration 1 s) in lower case Times font (48 point; 4–10 degrees of horizontal visual angle) except for perceptual oddballs, which appeared in 19 different fonts. Each list of 14 nouns was separated by presentation of the words 'New List'. Instructions for shallow encoding were provided visually at the start of each session. The 38 lists were normed for semantic relatedness and emotional valence by a separate group of 12 subjects [5 male (24–37 yrs; 28.2); 7 female (23–37 yrs; 27.9)]. Control nouns, like oddballs, could not occur within the first 5 nouns of each list and could not immediately follow an oddball or another chosen control noun.
In discussing our oddball-induced activations we refer to the P3 ERP. The P3 complex has been divided on the basis of scalp topography and task correlates into the fronto-central P3a, evoked by novel distractor stimuli and a component of the characteristic response to orienting stimuli, and a later parietal P3b, evoked by infrequent target stimuli. Our experiment was not designed to dissociate these two components.
Placebo vs Propranolol *p < 0.001 uncorrected;† p < 0.05 uncorrected
Coordinates (x, y, z)
Right anterior prefrontal cortex
22, 64, 20
Left occipito-temporal cortex
-52, -70, 0
Right occipito-temporal cortex
50, -62, -4
Left posterior inferior temporal sulcus
-62, -38, 0
Right temporo-parietal junction
42, -68, 12
Right inferior frontal gyrus
48, 44, -14
Right supramarginal gyrus
58, -46, 28
Left supramarginal gyrus
-48, -56, 34
Imaging data were analysed using Statistical Parametric Mapping (SPM99) employing an event-related model with a two stage random effects procedure. The effects of interest were the events corresponding to the E and P nouns and the two randomly selected control nouns. Trial-specific responses were modelled by convolving a delta function that indicated each event onset with a synthetic, canonical haemodynamic response function (HRF) to create regressors of interest. All other nouns, the presentation of the "New List" marker, as well as oddballs or selected control nouns for which encoding responses were incorrect or absent, were modelled separately. Movement parameters and low frequency drifts in signal (cut-off 120 secs) were modelled as nuisance covariates. For the drug group, data from one subject was not included because of poor image quality.
From the 1st level analysis described above, session-specific parameter estimates of the magnitude of the haemodynamic response for each stimulus type were calculated for each voxel in the brain . A contrast of parameter estimates modelling each comparison of interest (e.g. emotional oddballs vs control nouns) was calculated in a voxel-wise manner to produce, for each subject, one contrast image for that particular effect. Two contrast images for each subject were carried forward to the random effects analysis: perceptual and emotional oddballs versus their respective controls were entered into an ANOVA (corrected for non-sphericity) across the 12 placebo and propranolol subjects. We employed a conjunction analysis to test for activation common to both perceptual and emotional oddballs versus their respective controls under placebo as well as for the placebo vs drug comparison. A conjunction analysis tests for a significant main effect in the absence of any interactions among the simple effects. . The whole-brain statistical parametric maps that ensued from the conjunction analyses were thresholded at p < 0.001 uncorrected and examined for evidence of activation. We report P values of the ensuing maxima that survive threshold at p < 0.001 (uncorrected), except for bilateral supramarginal gyrus, which we report descriptively.
We next compared oddball-evoked responses between groups. Fig. 1b (also see table 1) shows responses significantly attenuated by propranolol relative to the placebo group. Oddball responses in bilateral occipitotemporal cortex, right TPJ, right ventrolateral and right anterior prefrontal cortex were abolished by β-adrenergic blockade. Plots of the response estimates clearly demonstrate that activations in regions previously shown to respond to oddballs are engaged by both oddball types and that these responses are selectively abolished by propranolol. Fig. 1a demonstrates oddball-evoked responses in a more superior locus of TPJ bilaterally, in supramarginal gyrus (arrowed). This locus, strongly implicated in oddball detection , showed significantly reduced activation bilaterally by propranolol, albeit at a lower threshold.
Previous investigation of NE modulation of oddball responses in humans has been limited in two respects; 1) pharmacological studies have been limited to scalp-recorded ERPs, which provide limited anatomical specificity, 2) studies have used α2-adrenergic receptor agonists such as clonidine, which, in addition to causing sedation, act on presynaptic autoreceptors to inhibit noradrenaline release. Thus the postsynaptic target receptors mediating NE effects are unknown, with further uncertainty arising from the fact that clonidine also inhibits release of 5-hydoxytryptamine (5-HT) . Despite these potential limitations, our findings accord with a previous study demonstrating a reduction of TPJ activity in response to an alerting cue by the α2-agonist clonidine .
Our data are supported by prior studies of oddball response generators as well as the distribution of NE cortical innervation. It is thought that detection of behaviourally relevant stimuli, particularly when salient, engages a largely right lateralized temporoparietal and ventral prefrontal (including inferior and middle frontal gyri and operculum) cortical network . Scalp-recorded ERPs in brain damaged patients , intracranial recordings from patients with implanted electrodes  as well as neuroimaging studies  have demonstrated oddball-evoked responses in TPJ and prefrontal cortex, particularly in the region of inferior frontal sulcus. NE projections are most dense to inferior parietal cortex, somatosensory cortex, frontal pole and TPJ (see  and  for review). Those regions showing oddball responses in the placebo group, but which were not modulated by drug, namely fusiform cortex, receive relatively weak NE projections.
The areas within which we demonstrate modulation of oddball-evoked responses overlap strongly with regions implicated in oddball detection and with projections of the LC-NE system. We suggest that our data provide direct empirical support for a neurophysiological model that oddball responses are mediated via the NE system , via β-adrenergic receptors.
This work was funded by a Wellcome Trust Programme grant to RJD.
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