Inhibition of subliminally primed responses is mediated by the caudate and thalamus: evidence from functional MRI and Huntington's disease

Abstract

Masked prime tasks have shown that sensory information that has not been consciously perceived can nevertheless trigger the preactivation of a motor response. Automatic inhibitory control processes prevent such response tendencies from interfering with behaviour. The present study investigated the possibility that these inhibitory control processes are mediated by a cortico-striatal-pallidal-thalamic pathway by using a masked prime task with Huntington's disease patients (Experiment 1) and with healthy volunteers in a functional MRI (fMRI) study (Experiment 2). In the masked prime task, clearly visible left- or right-pointing target arrows are preceded by briefly presented and subsequently masked prime arrows. Participants respond quickly with a left or right key-press to each target. Trials are either compatible (prime and target pointing in the same direction) or incompatible (prime and target pointing in different directions). Prior behavioural and electrophysiological results show that automatic inhibition of the initially primed response tendency is reflected in a 'negative compatibility effect' (faster reaction times for incompatible trials than for compatible trials), and is shown to consist of three distinct processes (prime activation, response inhibition and response conflict) occurring within 300 ms. Experiment 1 tested the hypothesis that lesions of the striatum would interrupt automatic inhibitory control by studying early-stage Huntington's disease patients. Findings supported the hypothesis: there was a bimodal distribution for patients, with one-third (choreic) showing disinhibition, manifested as an absent negative compatibility effect, and two-thirds (non-choreic) showing excessive inhibition, manifested as a significantly greater negative compatibility effect than that in controls. Experiment 2 used fMRI and a region of interest (ROI) template-based method to further test the hypothesis that structures of the striatal-pallidal-thalamic pathway mediate one or more of the processes of automatic inhibitory control. Neither prime activation nor response conflict significantly engaged any ROIs, but the response inhibition process led to significant modulation of both the caudate and thalamus. Taken together, these experiments indicate a causal role for the caudate nucleus and thalamus in automatic inhibitory motor control, and the results are consistent with performance of the task requiring both direct and indirect striatal-pallidal-thalamic pathways. The finding that Huntington's disease patients with greater chorea were disinhibited is consistent with the theory that chorea arises from selective degeneration of striatal projections to the lateral globus pallidus, while the exaggerated inhibitory effect for patients with little or no chorea may be due to additional degeneration of projections to the medial globus pallidus.

Fig. 1

Experimental trial design for compatible ISI–150 trial. Trials were ‘compatible’ when prime and target arrows pointed in the same direction, ‘incompatible’ when they pointed in opposite directions, and ‘neutral’ when the prime was a plus sign. In ISI–0 blocks, targets appeared together with (above or below) the mask, i.e. with an ISI of 0 ms after the prime. In ISI–150 blocks, targets appeared 150 ms after offset of the mask, i.e. with an ISI of 150 ms after the prime.

Fig. 2

Lateralized readiness potential from a prior EEG study demonstrating response facilitation (A) and inhibition (I) processes during masked priming. Activation of the correct response for any given trial (the response assigned to the target) is indicated by positive (downward-going) deflections, while incorrect response activation is reflected by negative (upward-going deflections). See Introduction for detailed explanation.

Fig. 3

Reaction time (RT) data for patients with Huntington’s disease compared with healthy controls. The graphic shows that the distribution of patients’ data is bimodal: some patients [Huntington’s disease-PCE (HD–PCE)] show an absent negative-compatibility effect (NCE), indicative of disinhibition; other patients [Huntington’s disease-NCE (HD–NCE)] show the NCE but it is exaggerated relative to controls, indicative of overinhibition and possibly related to clinical rigidity.

Fig. 4

Regions of interest (ROIs) are shown overlaid on a single axial slice, through the basal ganglia, of the structural template image from SPM96. These five separate ROIs form the basis for the analysis of functional imaging data from the healthy volunteers performing the masked priming task.

Fig. 5

Behavioural data acquired during fMRI scanning. Correct mean reaction times are shown for each condition. The data replicate the classic masked priming effect showing faster reaction time (RT) for compatible than for incompatible trials (the positive compatibility effect, PCE) when the prime–target interval is 0 ms, and the reverse, negative compatibility effect (NCE) when the interval is 150 ms.

Fig. 6

Average signal change over regions of interest (ROIs) related to prime activation, response inhibition and response conflict. The caudate (*P = 0.03) and thalamus (**P = 0.001) show a statistically significant effect of response inhibition, but the putamen and pallidum do not (F < 1). Moreover, prime activation and response conflict do not engage any of the ROIs (F < 1). Response inhibition is indicated by a main effect of ISI, i.e. inhibition occurs when ISI = 150 ms (C150–N150 and I150–N150 contrasts) but not when ISI = 0 ms (C0–N0 and I0–N0 contrasts). Average signal change is computed for each of these contrasts for each ROI by summing the values of each voxel in the ROI and dividing by the number of voxels in the ROI.