how to see what you are looking for in fmri and pet—or the crucial baseline condition

J Neurol (2006) 253 : 551–555DOI 10.1007/s00415-006-0087-1 ENS REVIEW

T. Brandt How to see what you are looking for in fMRI and PET – or the crucial baseline condition

Introduction

In human brain activation studies the stimulus- or task-related actual pattern of activated areas is determinedby subtracting the activity of a baseline condition.

The conscious resting state of subjects, who havebeen instructed to avoid systematic thoughts and lie re-laxed in darkness and silence (REST), is frequently usedas a baseline condition in PET and fMRI studies to as-sess a particular brain activation pattern during con-trolled sensorimotor or cognitive tasks.Clearly the iden-tification of a baseline or control state is fundamental forthe interpretation of brain activation studies [5]. Anumber of neuroimaging studies have shown that activ-ity during rest is greater than in some cognitive tasks,and if activity resulting from unconstrained cognitiveactivity is present in the brain during periods of rest,REST should not be used as a baseline [for review see13].

Mazoyer et al. [8] conducted a meta-analysis of ninePET studies dealing with different cognitive tasks buthaving REST as a common control state.They found thatREST was sustained by a large-scale network of hetero-

modal, associative, parietal, and frontal cortical areas,which they assigned to episodic working memory andexecutive functions. When Binder et al. [1] contrastedREST with auditory, perceptual, or semantic tasks infMRI, they found a parieto-frontal network in the lefthemisphere which exhibited equal activity during RESTand the semantic task, but was reduced during the per-ceptual task. This finding was interpreted as indicatingmental activity of a “conceptual processing” nature.

The resting state offers the advantage of being able toserve as a reference in all cognitive tasks, but its mentalstate varies both from one subject to another and withinthe same subject [14]. Further, the effects of experimen-tal PET on brain activity during the resting state wereidentified in four PET studies that employed differenttasks, identical resting states, and the same objects [12].Resting regional cerebral blood flow was significantlyaffected by the task being studied. Moreover, the pre-dictability of stimulus onsets in the baseline conditionalso modulates the activity in brain structures responsi-ble for processes involved in time-keeper functions dur-ing the performance of a visually keyed motor synchro-nization task [2].

JON

2087

Received: 2 July 2005Received in revised form:15 September 2005Accepted: 4 October 2005Published online: 18 May 2006

Th. Brandt (�)Department of NeurologyUniversity of MunichMarchioninistr. 1581377 Munich, GermanyTel.: +49-89/7095-2571Fax: +49-89/7095-8883E-Mail:[email protected]

■ Abstract The identification of abaseline or control state is funda-mental for the interpretation oftask- or stimulation-induced brainactivation patterns. The consciousresting state in darkness is a fre-quently used, but ill-defined mentalstate. The mere transition from, forexample, lid closed to lid open indarkness causes major changes inbrain activity, which can mask ormimic a stimulus-dependent brainactivation. Contradictory results of

seemingly identical brain activa-tion studies may be attributed tothe choice of different baselineconditions. Therefore, control con-ditions that are closest to the stim-ulus or task condition should beused as baseline in most fMRI andPET studies rather than absoluterelaxation in darkness and silence(REST).

■ Key words fMRI · PET · baselinecondition · resting state

551_555_Brandt_JON_2087 11.05.2006 7:53 Uhr Seite 551

552

The default mode hypothesis

Raichle et al. [11] have suggested that an organized de-fault mode of brain function exists, which is suspendedduring goal-directed behavior. They argued that espe-cially the location of deactivations,which sometimes ap-pear to be largely task-independent, vary little across awide range of tasks. Furthermore, they wonderedwhether these unexplained deactivations merely arisefrom unrecognized activations, which are present onlyin the “control state”.

Does such a resting-state network exist in the humanbrain? Is it modulated during simple sensory process-ing? How is it modulated during cognitive processing?These were the questions that Greicius et al. [3] ad-dressed. They found significant inverse correlationsamong three lateral prefrontal regions and the posteriorcingulate cortex, suggesting a mechanism: the attenua-tion of default-mode network activity during cognitiveprocessing. This was evidence for the existence of a co-hesive default-mode network. Patients with Alzheimer’sdisease show decreased resting-state activity in the pos-terior cingulate and hippocampus, indicating that a dis-rupted connectivity between these two regions accountsfor the posterior cingulate hypometabolism commonlydetected in PET studies in early Alzheimer’s disease [4].

Eyes open or closed during rest in darkness?

The following may serve as an example of how minimaldifferences in the rest condition may cause majorchanges in brain activity. The conditions of eyes open oreyes closed in complete darkness have frequently servedas REST in human brain imaging studies. However, themere transition from lid closed to lid open could theo-retically have nontrivial differential effects on brain ac-tivity without there being any change in external sen-sory stimulation or behavioral tasks. As a matter of fact,the lid drives the brain to regularly and repeatedly acti-vate different cortical networks.

In order to identify the pattern of brain activationtypical for the two conditions – eyes open versus eyesclosed in darkness – we applied statistical parametricmethods to compare the mean blood oxygenation level-dependent (BOLD) signal differences in fMRI [6]. Dur-ing non-changing external stimulation, ocular motorand attentional systems were activated when the eyeswere open; in contrast, the visual, somatosensory,vestibular, and auditory systems were activated whenthe eyes were closed. These data suggest that there aretwo different states of mental activity: an “interoceptive”state with the eyes closed which is characterized byimagination and multisensory activity, and an “extero-ceptive” state with the eyes open which is characterizedby attention and ocular motor activity (Fig. 1).

In a subsequent study the impact of the chosen RESTcondition – eyes open or eyes closed in complete dark-ness – on the pattern of brain activations during visualstimulation was evaluated in healthy volunteers [7].When a subject fixated a single LED in darkness, the ac-tivation of the visual cortex was larger with the eyes-open REST condition than with the eyes-closed RESTcondition. However, activation of the lateral geniculatenucleus (LGN) was smaller. The LGN has been shown toact as a gateway for sensory information [10]. Attentionalone increases its activity even without visual stimuli.Thus, when the activation pattern during the eyes-opencondition – which increases attention – was subtractedfrom the pattern of LED fixation, only minimal activa-tion remained. Activations that can be assigned to ocu-lar motor structures, such as the prefrontal cortex,parietal and frontal eye fields, cerebellar vermis, thethalamus, and basal ganglia were larger with the eyes-closed REST condition than with the eyes-open RESTcondition (Fig. 2). Cortical areas that represent visual,somatosensory, auditory, and vestibular functionsshowed decreases of BOLD signals when the pattern ofeyes closed was subtracted from the pattern of LED fix-ation.

REST condition may mask or mimic stimulus-dependent brain activations

Thus, the choice of the REST condition is critical for de-termining the actual stimulus-induced brain activationpatterns. The example presented above of the powerfuleffect of simply blinking in the dark convincingly illus-trates what others have long suspected – namely that thechoice of different baseline conditions may resolve thecontroversies surrounding the putative brain networkinvolved in identical tasks [7]. It was quite unexpectedthat cortical ocular motor structures are activated withthe eyes open in complete darkness. Not only the ocularmotor activity necessary to fixate an LED will go unde-tected if the eyes-open condition is selected as baseline,but the deactivations of several sensory cortical areasmay be mimicked by unrecognized increases of thesame areas in the eyes-closed condition. Newman et al.[9] showed earlier that discrepancies in the patterns ofcortical activation across studies may be attributable todifferences in baseline tasks. Three baseline conditions(rest, tone monitoring, and passive listening) systemati-cally affected the amount of activation observed in anidentical phoneme task, and major effects were ob-served in Broca’s area, the left posterior superior tempo-ral gyrus, and the left and right inferior parietal regions.


553

Conclusion

Although the conscious resting state is frequently usedin most brain activation studies, it is not an optimalbaseline condition. Rather than a resting condition, itwould be best to use a control condition as baseline tomake comparisons with task or stimulation. Moreover,this control condition should differ as little as possiblefrom the stimulus condition and then only in single

known aspects, e.g., fixation of a stationary target indarkness (control) versus pursuit of a moving target indarkness (stimulation). Sometimes it may be helpful touse different baseline conditions for identical tasks orstimulations, such as described above (eyes open or eyesclosed) during REST.

■ Acknowledgement I am grateful to Judy Benson for critically read-ing the manuscript.

Fig. 1 Left BOLD-signal increases obtained by statistical group analysis for the comparison eyes closed minus eyes open in darkness. Activations are projected onto a stan-dard template brain (P < 0.001, n = 12) for sagittal, coronal, and transverse sections (16 mm below, 10 and 50 mm above the anterior-posterior commissural line). Num-bers indicate clusters that anatomically can be attributed to visual [2], somatosensory [3], vestibular and auditory [5, 9], and frontopolar [1] areas bilaterally.Right BOLD-signal increases obtained by statistical group analysis for the comparison eyes open minus eyes closed in darkness. Activations are projected onto a standardtemplate brain (P < 0.01, n = 12) for sagittal, coronal, and transverse sections (48 mm below, 10 and 20 mm above anterior-posterior commissural line). Numbers indicateclusters that can be attributed to ocular motor structures such as the dorsolateral prefrontal cortex [1, 2] supplementary [1], and parietal eye fields (not shown on selectedslices), thalamus [1, 13], and the cerebellar vermis [4]. Activations are also seen in the cerebellar hemispheres [3, 7, 9] and in the right hemisphere [1], including the pre-frontal and precentral cortex. The latter structures are known to subserve attentional function (modified from 6)


554

Fig. 2 BOLD-signal increases obtained by statistical group analysis for the comparison fixation of LED minus eyes open in darkness (A) and fixation of LED minus eyes closedin darkness (B). Activations are projected onto a standard template brain (P < 0.001, n = 14). Transverse sections are shown. Activation of visual areas [4]: the occipital andinferior temporal gyri were large with eyes open as rest condition as compared to eyes closed. Activation of lateral geniculate nucleus (5b) was more prominent with eyesclosed than with eyes open as rest condition. Activations that may represent ocular motor activity (vermis [1], cerebellar hemisphere [2], thalamus (5a), basal ganglia (5c),dorsolateral prefrontal cortex [6], frontal [7] and parietal eye field [8]) and activation in the orbitofrontal cortex [3] are seen in the comparison of LED minus eyes closed(modified from 7)

References

1. Binder JR et al. (1999) Conceptual pro-cessing during the conscious restingstate: A functional MRI study. J CognNeurosci 11:80–93

2. Cerasa A et al. (2005) Visually cuedmotor synchronization: modulation offMRI activation patterns by baselinecondition. Neurosci Lett 373:32–37

3. Greicius MD et al. (2003) Functionalconnectivity in the resting brain: Anetwork analysis of the default modehypothesis. PNAS 100:253–258


555

4. Greicius MD et al. (2004) Default-modenetwork activity distinguishesAlzheimer’s disease from healthy ag-ing: evidence from functional MRI.PNAS 101:4637–4642

5. Gusnard DA, Raichle ME (2001)Searching for a baseline: functionalimaging and the resting human brain.Nat Rev Neurosci 2:685–694

6. Marx E et al. (2003) Eye closure indarkness animates sensory systems.NeuroImage 19:924–934

7. Marx E et al. (2004) Eyes open and eyesclosed as rest conditions: impact onbrain activation patterns. NeuroImage21:1818–1824

8. Mazoyer B et al. (2001) Cortical net-works for working memory and execu-tive functions sustain the consciousresting state in man. Brain Res Bull54:287–298

9. Newman SD et al. (2001) Baseline con-ditions and subtractive logic in neu-roimaging. Hum Brain Mapp 14:228–235

10. O’Connor DH et al. (2002)Attentionmodulates responses in the humanlateral geniculate nucleus. Nat Neu-rosci 5:1203–1209

11. Raichle ME et al. (2001) A defaultmode of brain function. PNAS 98:676–682

12. Sidtis JJ et al. (2004) The effect of seton the resting state in functional imag-ing: a role for the striatum? NeuroIm-age 22:1407–1413

13. Stark CEL, Squire LR (2001) Whenzero is not zero: The problem ofambiguous baseline conditions infMRI. PNAS 98:12760–12766

14. Wicker B et al. (2003) A relationbetween rest and the self in the brain?Brain Res Brain Res Rev 43:224–230


how to see what you are looking for in fmri and pet—or the crucial baseline condition

Documents