Here we show that decreases in striatal D2 receptor availability (interpreted as DA increases and hyperstimulation of D2 receptors) were associated with decreased activation in lower occipital cortex and cerebellum (regions activated by the VA task to a greater extent in RW than SD) and with decreased deactivation in CG and insula (regions that did not differ between RW and SD).
Since activation of lower occipital cortex and cerebellum and deactivation in CG and insula were associated with accuracy during SD one interpretation could be that striatal hyperstimulation of D2 receptors by attenuating these regional brain responses contributed to the VA deficit during SD. However, another interpretation is that striatal DA increases reflect counteracting effects to maintain arousal as the drive to sleep increases (greater fatigue greater DA increases), masking DA true effects. In the former interpretation the association between striatal ΔD2R and blunted regional brain responses may reflect the mechanisms by which DA interferes with VA attention during SD, while in the latter interpretation this may reflect DA's counteracting effects on the drive to sleep in order to maintain arousal.
The regions where striatal ΔD2R were positively correlated with ΔBOLD (occipital cortex and cerebellum) are regions that are not typically considered main targets for DA innervation or regulation, which could be taken to suggest that the association reflects parallel processes rather than processes that are causally linked. However, the association could reflect either downstream effects from regions modulated by DA or direct DA modulation since, though low, there are D2 receptors in occipital cortex (Gil-Martin et al., 1994
; Lidow and Goldman-Rakic, 1994
; Meador-Woodruff et al., 1997
; Parkinson, 1989
; Mukherjee et al., 2002
), and in cerebellum (Pinborg et al., 2007
Regions in the occipital cortex where ΔBOLD correlated positively with striatal ΔD2R included both areas deactivated (upper and middle occipital) and activated (lower occipital) by the VA task and these responses were attenuated during SD (). The association between ΔD2R and ΔBOLD showed an opposite pattern in upper and middle occipital (larger ΔD2R greater deactivation and hence less differences between SD and RW) than in the inferior occipital (larger ΔD2R less activation and hence greater differences between SD and RW) (). This most likely reflects the functional heterogeneity of the visual cortex (Grill-Spector and Malach, 2004
) and its impairment by SD (Corsi-Cabrera et al., 1999
; Chuah and Chee, 2008
; Chee et al., 2008
Higher activity in the middle occipital cortex has been associated with lower arousal (Hofle et al., 1997
). Thus it is possible that higher activity in the upper and middle occipital cortex associated with decreased arousal during SD could have interfered with the deactivation required for maintaining performance with increasing task difficulty (). Interestingly transcranial magnetic stimulation (rTMS) of the upper middle occipital cortex, but not the lower occipital, during SD was shown to remediate the deficits in a visual working memory task (Luber et al., 2008
Decreased activation of the inferior occipital cortex while performing a VA task during SD, has been reported by others (Chee et al., 2008
). Moreover, it has been suggested that it is contingent on the engagement of selective attention since decreased activation during SD was not observed with passive visual stimulation (Chee et al., 2008
). Cholinergic neurotransmission, which plays a key role in regulating the visual cortex (Sato et al., 1987
) and is reduced with prolonged wakefulness (Jones, 2005
) was shown to contribute to the reduced activation of the visual system during SD (Chuah and Chee, 2008
). Our finding suggests that DA neurotransmission (directly or indirectly) may also contribute to decreased activation of the visual system during SD.
The association between striatal ΔD2R and cerebellar activation most likely reflects striatal modulation of cerebellar activity (Perciavalle et al., 1987
). The correlation with ΔD2R was centered in the inferior posterior hemisphere () where its activation by the VA task during SD was associated with performance accuracy (). This is consistent with prior imaging studies linking the activity of the cerebellar hemispheres with VA processes (Dieterich et al., 2000
). Similarly, in patients with attention deficit hyperactivity disorders (ADHD) and dyslexia the cerebellar abnormalities (including posterior cerebellar hemispheres) have been linked with symptoms of inattention (Mackie et al., 2007
; Ashtari et al., 2005
; Kibby et al., 2008
). Thus striatal hyperstimulation of D2 receptors may have contributed to impairments in VA by disrupting cerebellar activation.
The anterior CG where striatal ΔD2R was negatively correlated with ΔBOLD is a target of the DA mesocortical system (Hurd et al., 2001
) and plays a key role in attention (Rueda et al., 2005
; Mason et al., 2007
). The association could reflect direct or indirect modulation via striato-thalamo-cortical pathways (Alexander et al., 1990
). The area in the CG that correlated with ΔD2R corresponded to BA 24 and BA 32. BA 24 has been shown to deactivate during cognitive tasks in proportion to emotional interference (Bush et al., 2003
; Simpson et al., 2001a
). Though deactivation of the CG did not differ for the RW and SD conditions, individual analysis revealed that subjects with the largest ΔD2R showed less BOLD differences in CG between SD and RW whereas subjects with less or no ΔD2R deactivated more during SD than RW (). Since CG deactivation was associated with performance accuracy during SD this suggests that striatal hyperstimulation of D2 receptors by interfering with further CG deactivation was detrimental for performance.
In the insula, striatal ΔD2R was also negatively correlated with ΔBOLD (). The insula is implicated in the awareness of the physiological condition of the physical body (interoception) (Craig, 2002
). Thus awareness of fatigue and sleepiness may have contributed to the blunted deactivation of the insula during SD. The insula has very low levels of D2 receptors (Hurd et al., 2001
) and thus the association with striatal ΔD2R most likely reflects the striatal connectivity with the insula (Postuma and Dagher, 2006
). The role of DA and/or of striato-insular pathways in interoceptive function to our knowledge has not been investigated.
Studies on the role of DA on SD-induced cognitive impairment
The deterioration in performance in the VA task with SD, which is consistent with prior studies (Durmer and Dinges, 2005
) was associated with decreases in striatal ΔD2R (interpreted as DA increases). This finding may seem paradoxical since it is opposite to the beneficial effects that stimulant medications can have on attention during SD (Bonnet et al., 2005
). However, stimulant medication and DA agonists are not always beneficial and in some subjects they impair performance (Oranje et al., 2006
). Also, the beneficial effects of stimulant drugs in attention are believed to reflect its dopaminergic as well as its noradrenergic effects on the prefrontal cortex rather than the striatum (Berridge et al., 2006
; Corbetta et al., 2008
) and to require the stimulation of D1 receptors (or D1 and D2) (Levy, 2008
) whereas here we show DA stimulation of D2 receptors in striatum with SD. Indeed, microdialysis studies in rodents showed that low doses of methylphenidate that improved cognitive function but were devoid of locomotor effects increased DA and norepinephrine in prefrontal cortex with minimal effects in striatum (Berridge et al., 2006
). In contrast, high doses of stimulant medications, which induce robust DA increases in striatum, impair attention (Martinez and Sarter, 2008
Moreover, since SD has been shown to disrupt prefrontal activity (Horne, 1993
) and this disruption has also been associated with cognitive impairment (Thomas et al., 2000
) it is possible that the association between VA performance and striatal ΔD2R reflects reduced prefrontal activity occurring concomitantly to striatal hyperstimulation of D2 receptors with SD. Indeed, D2 receptor blockade (using sulpiride) was shown to alleviate the impairment in attention in prefrontal lesioned animals, but not in intact animals, suggesting that striatal hyperstimulation of D2 receptors may contribute to attention deficits in the prefrontal damaged animal (Passetti et al., 2003
). Inasmuch as the prefrontal cortex regulates DA cell firing and its damage increases striatal DA (Bertolino et al., 2000
) further studies are required to assess if decreases in prefrontal activity during SD contribute to the striatal DA increases.
However, it is also possible that striatal DA increases reflect a counteracting effect to maintain arousal as the drive to sleep increases. Thus greater fatigue would produce greater striatal DA increases. This might mask the effect of DA increases, or even make them appear to be opposite to the true effects. Thus even though the effect of DA may be to improve performance, it may be associated with decreased performance due to the correlated and greater effect of SD onto which the DA effects are superimposed.
(1) The limited sensitivity of the [11
C]raclopride did not allow us to measure DA changes in the prefrontal cortex nor did it allow us to assess regions predominantly modulated by D1 receptors, which are crucial for attention. (2) The [11
C]raclopride method does not allow us to ascertain if changes in binding reflect changes in DA, in D2 receptor levels or in affinity (Gjedde et al., 2005
). (3) In our subjects we did not obtain electroencephalographic measures nor did we obtain information on chronotype, the Epworth score, nor on sleep latencies. These would have provided additional information on sleeping patterns of our subjects that may have been relevant to understanding the intersubject variability in the responses to SD. (4) The PET and the fMRI were done sequentially (2 h apart from each other) and we cannot necessarily assume that the state of the brain was the same at both measurements. This is relevant since alertness and cognitive performance fluctuate with SD and may deteriorate abruptly after 30 h of wakening (Doran et al., 2001
). Indeed our data showed fluctuation in alertness during the SD condition. However, since prior imaging studies did not show regional brain activation differences during a working memory task performed after 24 h versus 35 h of SD (Chee et al., 2006
) it is unlikely that the 2 hour time difference invalidates our findings. In the future with the development of dual PET-MRI scanners it will be possible to simultaneously assess these two measures, which will eliminate this confound.
Striatal DA increases during SD were associated with decreased activation in cerebellum and lower occipital cortex and with decreased deactivation of CG while performing the VA task (). Since performance accuracy during the VA task correlated with activation of the cerebellum and lower occipital cortex and with deactivation of CG () this suggests that striatal hyperstimulation of D2 receptors may contribute to VA impairment by attenuating the regional brain activation responses necessary for optimal task performance. The mechanism(s) by which striatal hyperstimulation of D2 receptors during SD result in attenuated activation responses to the VA task require further investigation.