Cerebellar responses during anticipation of noxious stimuli in subjects recovered from depression: Functional magnetic resonance imaging  study

Background Subjects recovered from depression have a substantial risk for recurrence of depression, suggesting persistent abnormalitiesin brain activity.

Aims To test whether women recovered from depression show abnormal brain activity in functional magnetic resonance imaging (fMRI)during a conditioning paradigm with a noxious pain stimulus.

Method Ten unmedicated women who had recovered from major depression and eight healthy control women each received either noxioushot or non-noxious warm stimuli, the onset of which was signalledby a specific coloured light during 3-tesla echo planar imaging-basedfMRI.

Results Similar patterns of brain activation were found during painful stimulation for both patients and healthy controls.However, relative to healthy controls, subjects recovered fromdepression showed a reduced response in the cerebellum duringanticipation of the noxious stimulus compared with anticipationof the non-noxious stimulus.

Conclusions Our data suggest that abnormal cerebellar functioncould be a marker of vulnerability to recurrent depression.This could provide a new target for therapeutic interventions.

INTRODUCTION

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INTRODUCTION

Depression is a common disorder (Blazer et al, 1994) and recurrentdepression is a major cause of disability (Hays et al, 1995).Whereas personal and psychosocial risk factors for the developmentof depression have been elucidated (Kendler, 1998), the neurobiologicalmechanisms involved in mediating vulnerability have not been well defined. Study of conditioned responses to aversive stimuliallows investigation of the neural circuits related to emotionalexperiences (Buchel et al, 1998; LaBar et al, 1998; Morris et al, 1998)and we previously have adapted approaches to allowdynamic monitoring of responses to thermal pain and its anticipationusing functional magnetic resonance imaging (fMRI) (Ploghauset al, 1999). Given the recognised potential for conditioning responses to define traits relevant to depression (Eysenck et al, 1976),we have employed our fMRI conditioning paradigmto contrast responses of healthy controls with those of subjectswho had a history of recurrent depression and who had madea full recovery and were off antidepressant medication in aneffort to identify a potential marker of vulnerability to depression.

METHOD

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METHOD

Subjects
Eighteen right-handed women underwent fMRI. Ten of these hada history of recurrent major depressive disorder and had sufferedat least two episodes of DSM-IV depressive disorder (American Psychiatric Association, 2001)but had been recovered and off medication for at least 6 months. The remaining eight subjects(healthy controls) had no history of psychiatric disorder andwere medication-free. Psychiatric history and current statewere assessed at interview using the Structured Clinical Interviewfor DSM-IV (Spitzer et al, 1987). Current depressive symptomatologywas assessed with the Beck Depression Inventory (BDI; Becket al, 1961).

Behavioural procedure
A Peltier thermode was used to apply thermal stimuli to thedorsum of the left hand, as described previously (Ploghaus et al, 1999).Stimulus intensities were chosen with the subjectin the scanner, and for each subject individually; two stimulithat were consistently described by the subjects as ‘painfullyhot’ and ‘clearly warm, but not hot’ werechosen. Three coloured light-emitting diodes (LEDs) (red, green,blue) were mounted at the subjects' feet and could be viewedthrough a mirror in the magnet bore. During the experiment,subjects received seven noxious and seven comfortable warmstimulations in pseudorandom order. Each type of stimulationwas signalled consistently by a certain colour LED for eachsubject, randomised across subjects (Fig. 1). The colouredLED signals preceded the onset of thermal stimulation by apseudo-randomly varied interval with a mean of 7.5 s (s.d.=5s) and stayed on during thermal stimulation, which was appliedfor 11 s. Between conditioning trials subjects had a rest periodthat also was pseudo-randomly varied (mean duration=26.5 s, s.d.=9 s) and signalled by the third coloured LED. Subjectswere instructed to work out the contingency between LED colourand thermal stimulation.

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Fig. 1 Diagrammatic representation of study method (light-emitting diode (LED) colours were randomised across subjects).

Subjects rated their mood before the experiment, immediatelyafter (in the scanner) and at the end of the scan using visualanalogue rating scales. After the experiment, subjects ratedthe two thermal stimuli on intensity and unpleasantness usinga 7-point modified form of the McGill pain scale (Melzack, 1975).Neuroticism was assessed at baseline using the EysenckPersonality Questionnaire (Eysenck et al, 1985).

Data acquisition
We used a 3-tesla Varian INOVA magnetic resonance imaging system(Palo Alto, CA, USA) with a multislice gradient echo planarimaging (EPI) sequence (repetition time, TR=3000 ms, echo time,TE=30 ms, flip angle=90°, field of view, FOV=256 mm², matrix=64²,21 6-mm axial slices). We also acquired a high-resolution T1-weightedanatomical scan for each subject.

Image processing and statistical analysis
Image analysis was performed within MEDx (Sensor Systems, Inc.,Sterling, VA, USA). Each subject's data was first motion correctedusing AIR (http://www.loni.ucla.edu/NCRR/Software/AIR.html), spatially filtered using a Gaussian kernel of full width athalf maximum of 5 mm, global (volumetric) mean intensity normalised,and high-pass filtered (period=180.0 s). Statistical analysiswas then carried out using FMRIB's Easy Analysis Tool (FEAT) (www.fmrib.ox.ac.uk/fsl) to localise regions of significantchange. Differences in signal responses to noxious pain andcomfortable warm stimulations were localised, as were differencesin their preceding anticipation periods, during the conditioning experiment. The parameter estimate images for each subject werewarped into the Montreal Neurological Institute 152 averagebrain space using FMRIB's Linear Image Registration Tool (FLIRT)and a random-effects statistic was used to generate group Z-statisticimages. Cluster detection was applied to the group Z-statisticimages (Z>2.3, P<0.1; Poline et al, 1997).

RESULTS

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RESULTS

Subject characteristics
There were no significant differences in age between the twogroups. As expected, the subjects recovered from depressionhad a higher overall rating of neuroticism. BDI scores werealso higher in this group, although all BDI scores were withinthe normal range (Table 1).

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Table 1 Baseline characteristics of subjects

Ratings of mood and experience of pain
There were no significant differences between groups in ratingsof mood or of the intensity or affective quality of the painfuland warm stimuli. There were also no differences between groupsfor visual analogue ratings of happy, sad and anxious (datanot shown). Interviews after the experiment confirmed thatall subjects learned the correct relation between the colouredlight cues and the temperature of the subsequent thermal stimulation(noxious heat or warm).

Neuroimaging results
A contrast of responses during noxious heat with non-noxiouswarm stimulation in both groups showed activations in brainregions previously reported in neuro-imaging studies of pain (Table 2 & Fig. 2). No significant differences in activationextent, magnitude or localisation, or site of activation werefound between the control group and the recovered depression subjects.

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Table 2 Brain volumes activated by noxious pain v. non-noxious warm stimulation in controls. Coordinates of centre of mass and maximum Z-score for each of the neuroanatomically defined regions are given

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Fig. 2 Fixed-effects analysis of the response to thermal pain (painful heat v. non-noxious warm stimulus) in the healthy control subjects. The group response has been overlaid onto one subject's structural image. Activation responses are seen in areas previously identified to respond to pain: 1, secondary somatosensory cortex; 2, primary sensorimotor cortex; 3, insular cortex; 4, anterior cingulate cortex; 5, thalamus; 6, basal ganglia; 7, premotor cortex; 8, prefrontal cortex; 9, precuneus. Cerebellar activation also was seen but is not shown here.

To investigate differences between the two groups in activationto noxious heat and non-noxious warm stimulation during theconditioning period, an analysis was performed comparing activationduring anticipation of painful stimulation with activationduring anticipation of non-noxious warm stimulation for thetwo groups. Direct contrast identified significant differencesbetween controls and subjects recovered from depression in the lateral cerebellum and the cerebellar vermis (Fig. 3). Directmeasurement of the absolute signal intensities revealed a highercerebellar response with anticipation of pain relative to warmth(mean signal intensity increase in group images, 0.4%) in thecontrols relative to those recovered from depression (meansignal intensity increase, 0%).

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Fig. 3 Fixed-effects analysis of the differences in group responses between healthy controls and subjects recovered from depression to the noxious (painful) and non-noxious (warm) stimuli during the conditioning phase. The activation differences are shown on (a) sagittal and (b) axial slices. These differences demonstrate a reduced conditioning phase response in the subjects that had recovered from depression.

A possible confound could have been greater movement duringscanning by the subjects recovered from depression, which coulddecrease the magnitude of response. Indices of movement derivedfrom the motion correction were therefore tested for differencesin subject motion between the two groups. The index used foreach subject was the mean (over time points) of the relative motion from each time point to the next, where this motion issummarised as the mean displacement (in mm) over all brainvoxels. Mean displacements during scanning for the individualcontrol subjects (0.08, 0.07, 0.18, 0.11, 0.14, 0.06, 0.07and 0.17 mm) were not significantly different (2-tailed t-test,P=0.29; Wilcoxon rank sum test, P=0.36) from those for subjectsrecovered from depression (0.16, 0.16, 0.15, 0.20, 0.05, 0.13,0.09, 0.11, 0.16 and 0.12 mm).

DISCUSSION

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DISCUSSION

Neuroticism, depression and classical conditioning
Not unexpectedly, the group that had recovered from depressionshowed greater neuroticism than the healthy controls. Neuroticismis a known risk factor for depression and subjects with a historyof major depression have an increased risk of experiencingfurther episodes (Kendler, 1998). This conclusion is supportedby theories of classical conditioning (Eysenck et al, 1976; Graeff et al, 1996).

Responses to pain and its anticipation
The conditioning model employed here has been used previouslywith normal volunteers to distinguish brain regions involvedin the processing of pain and its anticipation (Ploghaus etal, 1999). Patients recovered from depression were similarto controls in their responses to thermal pain; this is notunexpected, as the groups did not report differences in theconditioning response or pain perception. However, there wasa significant difference in processing the anticipation of the noxious heat relative to the non-noxious warm stimulus;subjects recovered from depression had a reduced response inthe cerebellum. This was noted both in the cerebellar vermisand right hemisphere.

The cerebellum and emotional processing
Lateral cerebellar activation in healthy controls during thethermal pain conditioning task was noted in our previous study (Ploghaus et al, 1999) but it was unclear whether this representedpart of a motor-related response (e.g. suppression of handwithdrawal) or was an intrinsic element of the primary conditionedresponse to pain. The cerebellum clearly plays a cognitiverole in forms of conditioning, potentially consistent withthe latter hypothesis (Schmahmann, 1997).

Previous studies have suggested that the cerebellum could showfunctional abnormalities in patients with depression. A singlephoton emission computed tomography (SPECT) study of patientswith depression showed increased cerebellar blood flow afterantidepressant treatment (Halloran et al, 1999). Such changescould be related to specific elements within the broader spectrumof symptoms of depression. For example, as anxiety levels increasein patients with depression, cerebellar glucose metabolism decreases (Osuch et al, 2000). In addition, subjects with depressionshow attenuated activation of the cerebellum during the Towerof London planning task (Elliott et al, 1997). Both of thelatter observations would be consistent specifically with our observation of a decreased response in those recovered fromdepression.

Modulation of cerebellar circuits by depression is also givencredence by studies suggesting a role for the cerebellum inemotional processing (Rapoport et al, 2000). There are extensiveanatomical and functional connections between the cerebellumand limbic structures, including the hippocampus and amygdala(Heath et al, 1978). Stimulation of the cerebellum, particularlythe vermis, can reduce aggression and produce pleasure reactionsin animals. In humans, acute stimulation of the cerebellumcan induce emotional states, including fear and anxiety, whereaschronic stimulation appears to reduce anxiety and depression (Cooper et al, 1978). Induction of sadness in healthy volunteersis associated with increased blood flow in the cerebellar vermis(Mayberg et al, 1999).

Implications for the pathophysiology of depression
Subjects recovered from depression have a substantial risk forrecurrence (Kendler, 1998). From our results and those ofothers, it appears that patients recovered from depressionhave a number of differences in brain function relative to healthy controls (Goodwin, 1996). We have shown a specific differencein brain activity during a conditioning response to a noxiousv. a non-noxious stimulus. This difference could be more thansimply a marker or ‘scar’ from the previous illness.A persistent processing abnormality of this kind could contributeto making subjects that have recovered from depression morevulnerable to abnormal mood regulation in the presence of aversivestimuli, as might occur, for example, during stressful lifecircumstances. If confirmed in a larger group, such a differencecould help to identify those at risk of recurrent depression.Our observations suggest further that treatments modifying brain networks involved in conditioning responses to noxious stimulicould provide useful strategies for the treatment of depression.

Clinical Implications and Limitations

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Clinical Implications and...

CLINICAL IMPLICATIONS

Subjects with a history of recurrent depressive disorder showa reduced relative cerebellar activation response during anticipationof noxious v. a non-noxious stimulation.
In conjunction withprevious work, these observations suggestthat abnormal cerebellarfunction could be a vulnerabilitymarker of liability to recurrent depression.
Treatments modifying brain networks involved inconditioningresponses to noxious stimuli therefore could providea novelstrategy for the treatment of depression.

LIMITATIONS

The present study included only women: the findings cannot necessarilybe extrapolated to men.
Although a random effects analysiswas employed to allow generalisationof conclusions beyondthe specific population studied, theresults are based on a relatively small number of subjects.
It is uncertain whetherthe abnormality in cerebellar activityidentified is itselfspecifically relevant to the pathophysiologyof depression oris merely a potential biological marker.

REFERENCES

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