Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications

Abstract

The neuropsychological basis of attentional set-shifting, task-set switching and stop-signal inhibition is reviewed through comparative studies of humans and experimental animals. Using human functional neuroimaging, plus neuropsychological investigation of patients with frontal damage quantified by structural magnetic resonance imaging, and through parallels with effects of specific lesions of the prefrontal cortex (PFC) and striatum in rats and marmosets, it is possible to define both distinct and overlapping loci for tasks such as extra-dimensional shifting and reversal learning, stop-signal reaction time and task-set switching. Notably, most of the paradigms implicate a locus in the right PFC, specifically the right inferior frontal gyrus, possibly associated with processes of response inhibition. The neurochemical modulation of fronto-striatal circuitry in parallel with effects on task performance has been investigated using specific neuropharmacological agents in animals and by human psychopharmacological investigations, sometimes in conjunction with functional imaging. Evidence is provided for double dissociations of effects of manipulations of prefrontal cortical catecholamine and indoleamine (5-HT) systems that have considerable implications in the treatment of disorders such as Parkinson's disease, attention deficit/hyperactivity disorder and depression, as well as in theoretical notions of how 'fronto-executive' functions are subject to state-dependent influences, probably related to stress, arousal and motivation.

Figures

Figure 1

Compound stimuli used in discrimination learning paradigm. The perceptual dimensions were shapes and lines. Exemplars of these dimensions could occur in combination with one another on successive trials, one exemplar of one dimension being correct. Three types of shift are shown: an intra-dimensional shift (ids) occurs when novel stimuli are used but the relevant stimulus dimension (i.e. shapes or lines) stays the same; an extra-dimensional shift (eds) occurs when an exemplar from the previously irrelevant dimension becomes correct. Reversal learning can occur at several stages, e.g. at the compound discrimination stage or after the id- or ed-shift. Here, the stimuli remain the same, but the exemplar that was previously correct is now incorrect and vice versa. See Dias et al. (1996, 1997) for further details.

Figure 2

(a) Representative coronal sections through the marmoset PFC showing the extent of lesions made to the lateral or orbitofrontal PFC, together with (b) doubly dissociable behavioural deficits on id-shifting, ed-shifting and reversal shifts (rev; *p<0.05, **p<0.01) (reproduced with permission from Dias et al. 1996, modified with permission from the publishers).

Figure 3

Results of an fMRI study on reversal learning, id-shifting and ed-shifting in human subjects. The regional cortical BOLD activations for contrasts involving reversal and ed-shifting are shown. Note the double dissociation between activations for reversal learning and ed-shifting. DLPFC, dorsolateral prefrontal cortex; VLPFC, ventrolateral prefrontal cortex; PPC, posterior parietal cortex. Adapted with permission from Hampshire & Owen (2006) and publishers of Cerebral Cortex, Oxford University Press.

Figure 4

Effects of prefrontal dopamine depletion on the first and fifth stages of a serial id-shifting task, showing deficits in the lesioned group. *p<0.05, **p<0.01.

Figure 5

Effects of selective prefrontal 5-HT (serotonin) depletion on id-shifting, ed-shifting and reversal learning; note the selective effect on the latter: (a) ed-shift, (b) reversal and (c) reversal error type. *p<0.05, **p<0.01. Adapted with permission from the Society for Neuroscience (© 2005) from Clarke et al. (2005).

Figure 6

Versions of tasks used in (a) task switching and (b) stop-signal inhibition paradigms. For task-set switching, the subject moves around the spatial array in positions 1, 2 and 3 on successive trials, cued to respond to the arrow or word. For stop-signal inhibition, on a proportion of trials, an auditory stimulus signals not to respond on that trial of a choice reaction time paradigm. rt, reaction time; ssd, stop-signal delay; iti, inter-trial interval. Modified with permission from the publishers of Brain. The Clarendon Press, Oxford University Press (Aron et al. 2004b) and the Society for Neuroscience © 2006 (Aron & Poldrack 2006).

Figure 7

Main results from Aron et al. (2004a,b). (a) Relationship between stop-signal reaction time (SSRT) and volume of damage to the right pars opercularis. (b) Relationship between residual switch cost (SC resid) and volume of damage to the right pars opercularis. (c) Relationship between volume of damage to the medial gyrus of the left PFC and a measure of task congruency at long response–stimulus intervals. (d) Significant correlation between stop-signal reaction time performance and residual switch cost. Modified from Aron et al. (2004b), with permission from the publishers, The Clarendon Press (Oxford University Press).

Figure 8

Talairach coordinates plotted from six neuroimaging studies of switching, sorting and reversing and boundaries of inferior frontal gyrus (for further details see Aron et al. 2004a,b). Adapted from Aron et al. (2004b), with permission from the publishers, The Clarendon Press (Oxford University Press).