University Department of Psychiatry, Warneford Hospital, Oxford
Department of Clinical Neurology, John Radcliffe Hospital, Oxford
University Department of Psychiatry, Warneford Hospital, Oxford
Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK
Correspondence: Professor Paul Matthews, Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Tel: +44 (0) 1865 222493; fax +44 (0) 1865 222717; e-mail: paul{at}fmrib.ox.ac.uk
Declaration of interest Supported by the Medical Research Council (MRC) (P.M.M.). P.J.C. is a MRC Clinical Scientist. J.M.McC. was a Wellcome Training Fellow.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 noxious hot or non-noxious warm stimuli, the onset of which was signalled by a specific coloured light during 3-tesla echo planar imaging-based fMRI.
Results Similar patterns of brain activation were found during painful stimulation for both patients and healthy controls. However, relative to healthy controls, subjects recovered from depression showed a reduced response in the cerebellum during anticipation of the noxious stimulus compared with anticipation of the non-noxious stimulus.
Conclusions Our data suggest that abnormal cerebellar function could be a marker of vulnerability to recurrent depression. This could provide a new target for therapeutic interventions.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Behavioural procedure
A Peltier thermode was used to apply thermal stimuli to the dorsum of the
left hand, as described previously
(Ploghaus et al,
1999). Stimulus intensities were chosen with the subject in the
scanner, and for each subject individually; two stimuli that were consistently
described by the subjects as painfully hot and clearly
warm, but not hot were chosen. Three coloured light-emitting diodes
(LEDs) (red, green, blue) were mounted at the subjects' feet and could be
viewed through a mirror in the magnet bore. During the experiment, subjects
received seven noxious and seven comfortable warm stimulations in pseudorandom
order. Each type of stimulation was signalled consistently by a certain colour
LED for each subject, randomised across subjects
(Fig. 1). The coloured LED
signals preceded the onset of thermal stimulation by a pseudo-randomly varied
interval with a mean of 7.5 s (s.d.=5 s) and stayed on during thermal
stimulation, which was applied for 11 s. Between conditioning trials subjects
had a rest period that also was pseudo-randomly varied (mean duration=26.5 s,
s.d.=9 s) and signalled by the third coloured LED. Subjects were instructed to
work out the contingency between LED colour and thermal stimulation.
|
Subjects rated their mood before the experiment, immediately after (in the scanner) and at the end of the scan using visual analogue rating scales. After the experiment, subjects rated the two thermal stimuli on intensity and unpleasantness using a 7-point modified form of the McGill pain scale (Melzack, 1975). Neuroticism was assessed at baseline using the Eysenck Personality 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 planar imaging (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-weighted anatomical 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 corrected using AIR
(http://www.loni.ucla.edu/NCRR/Software/AIR.html),
spatially filtered using a Gaussian kernel of full width at half maximum of 5
mm, global (volumetric) mean intensity normalised, and high-pass filtered
(period=180.0 s). Statistical analysis was then carried out using FMRIB's Easy
Analysis Tool (FEAT)
(www.fmrib.ox.ac.uk/fsl)
to localise regions of significant change. Differences in signal responses to
noxious pain and comfortable warm stimulations were localised, as were
differences in their preceding anticipation periods, during the conditioning
experiment. The parameter estimate images for each subject were warped into
the Montreal Neurological Institute 152 average brain space using FMRIB's
Linear Image Registration Tool (FLIRT) and a random-effects statistic was used
to generate group Z-statistic images. Cluster detection was applied to the
group Z-statistic images (Z>2.3, P<0.1;
Poline et al,
1997).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Ratings of mood and experience of pain
There were no significant differences between groups in ratings of mood or
of the intensity or affective quality of the painful and warm stimuli. There
were also no differences between groups for visual analogue ratings of happy,
sad and anxious (data not shown). Interviews after the experiment confirmed
that all subjects learned the correct relation between the coloured light cues
and the temperature of the subsequent thermal stimulation (noxious heat or
warm).
Neuroimaging results
A contrast of responses during noxious heat with non-noxious warm
stimulation in both groups showed activations in brain regions previously
reported in neuro-imaging studies of pain
(Table 2 &
Fig. 2). No significant
differences in activation extent, magnitude or localisation, or site of
activation were found between the control group and the recovered depression
subjects.
|
|
To investigate differences between the two groups in activation to noxious heat and non-noxious warm stimulation during the conditioning period, an analysis was performed comparing activation during anticipation of painful stimulation with activation during anticipation of non-noxious warm stimulation for the two groups. Direct contrast identified significant differences between controls and subjects recovered from depression in the lateral cerebellum and the cerebellar vermis (Fig. 3). Direct measurement of the absolute signal intensities revealed a higher cerebellar response with anticipation of pain relative to warmth (mean signal intensity increase in group images, 0.4%) in the controls relative to those recovered from depression (mean signal intensity increase, 0%).
|
A possible confound could have been greater movement during scanning by the subjects recovered from depression, which could decrease the magnitude of response. Indices of movement derived from the motion correction were therefore tested for differences in subject motion between the two groups. The index used for each subject was the mean (over time points) of the relative motion from each time point to the next, where this motion is summarised as the mean displacement (in mm) over all brain voxels. Mean displacements during scanning for the individual control subjects (0.08, 0.07, 0.18, 0.11, 0.14, 0.06, 0.07 and 0.17 mm) were not significantly different (2-tailed t-test, P=0.29; Wilcoxon rank sum test, P=0.36) from those for subjects recovered 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Responses to pain and its anticipation
The conditioning model employed here has been used previously with normal
volunteers to distinguish brain regions involved in the processing of pain and
its anticipation (Ploghaus et al,
1999). Patients recovered from depression were similar to controls
in their responses to thermal pain; this is not unexpected, as the groups did
not report differences in the conditioning response or pain perception.
However, there was a 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 in the cerebellum. This was noted both
in the cerebellar vermis and right hemisphere.
The cerebellum and emotional processing
Lateral cerebellar activation in healthy controls during the thermal pain
conditioning task was noted in our previous study
(Ploghaus et al,
1999) but it was unclear whether this represented part of a
motor-related response (e.g. suppression of hand withdrawal) or was an
intrinsic element of the primary conditioned response to pain. The cerebellum
clearly plays a cognitive role in forms of conditioning, potentially
consistent with the latter hypothesis
(Schmahmann, 1997).
Previous studies have suggested that the cerebellum could show functional abnormalities in patients with depression. A single photon emission computed tomography (SPECT) study of patients with depression showed increased cerebellar blood flow after antidepressant treatment (Halloran et al, 1999). Such changes could be related to specific elements within the broader spectrum of symptoms of depression. For example, as anxiety levels increase in patients with depression, cerebellar glucose metabolism decreases (Osuch et al, 2000). In addition, subjects with depression show attenuated activation of the cerebellum during the Tower of London planning task (Elliott et al, 1997). Both of the latter observations would be consistent specifically with our observation of a decreased response in those recovered from depression.
Modulation of cerebellar circuits by depression is also given credence by studies suggesting a role for the cerebellum in emotional processing (Rapoport et al, 2000). There are extensive anatomical and functional connections between the cerebellum and limbic structures, including the hippocampus and amygdala (Heath et al, 1978). Stimulation of the cerebellum, particularly the vermis, can reduce aggression and produce pleasure reactions in animals. In humans, acute stimulation of the cerebellum can induce emotional states, including fear and anxiety, whereas chronic stimulation appears to reduce anxiety and depression (Cooper et al, 1978). Induction of sadness in healthy volunteers is 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 for recurrence
(Kendler, 1998). From our
results and those of others, it appears that patients recovered from
depression have a number of differences in brain function relative to healthy
controls (Goodwin, 1996). We
have shown a specific difference in brain activity during a conditioning
response to a noxious v. a non-noxious stimulus. This difference
could be more than simply a marker or scar from the previous
illness. A persistent processing abnormality of this kind could contribute to
making subjects that have recovered from depression more vulnerable to
abnormal mood regulation in the presence of aversive stimuli, as might occur,
for example, during stressful life circumstances. If confirmed in a larger
group, such a difference could help to identify those at risk of recurrent
depression. Our observations suggest further that treatments modifying brain
networks involved in conditioning responses to noxious stimuli could provide
useful strategies for the treatment of depression.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Beck, A. T., Ward, C. H., Mendelson, M., et al (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571.[Medline]
Blazer, D. G., Kessler, R. C., McGonagle, K. A., et al (1994) The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. American Journal of Psychiatry, 51, 979-986.
Buchel, C., Morris, J., Dolan, R., et al (1998) Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron, 20, 947-957.[Medline]
Cooper, I. S., Amin, M. & Cullinan, T. (1978) A long-term follow-up study of cerebellar stimulation for the control of epilepsy. In Cerebellar Stimulation in Man (ed. I. S. Cooper), pp 19-38. New York: Raven Press.
Elliott, R., Baker, S. C., Rogers, R. D., et al (1997) Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychological Medicine, 27, 931-942.[CrossRef][Medline]
Eysenck, S. B., White, O. & Eynsenck, H. J. (1976) Personality and mental illness. Psychology Reports, 39, 1011-1022.
Eysenck, S. B., Eysenck, H. J. & Barrett, P. (1985) A revised version of the psychoticism scale. Personality and Individual Differences, 6, 21-29.[CrossRef]
Goodwin, G. M. (1996) Functional imaging, affective disorder and dementia. British Medical Bulletin, 52, 495-512.[Abstract]
Graeff, F. G., Guimaraes, F. S., De Andrade, T. G., et al (1996) Role of 5-HT in stress, anxiety, and depression. Pharmacology, Biochemistry and Behaviour, 54, 129-141.[CrossRef][Medline]
Halloran, E., Prentice, N., Murray, C. L., et al (1999) Follow-up study of depression in the elderly. Clinical and SPECT data. British Journal of Psychiatry, 175, 252-258.[Abstract]
Hays, R. D., Wells, K. B., Sherbourne, C. D., et al (1995) Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Archives of General Psychiatry, 52, 11-19.[Abstract]
Heath, R. G., Dempesy, C. W., Fontana, C. J., et al (1978) Cerebellar stimulation: effects on septal region, hippocampus, and amygdala of cats and rats. Biological Psychiatry, 13, 501-529.[Medline]
Kendler, K. S. (1998) Anna-Monika-Prize paper. Major depression and the environment: a psychiatric genetic perspective. Pharmacopsychiatry, 31, 5-9.[Medline]
LaBar, K. S., Gatenby, J. C., Gore, J. C., et al (1998) Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron, 20, 937-945.[Medline]
Mayberg, H. S., Liotti, M., Brannan, S. K., et al
(1999) Reciprocal limbic-cortical function and negative mood:
converging PET findings in depression and normal sadness. American
Journal of Psychiatry, 156,
675-682.
Melzack, R. (1975) The McGill pain questionnaire: major properties and scoring methods. Pain, 1, 277-299.[CrossRef][Medline]
Morris, J. S., Ohman, A. & Dolan, R. (1998) Conscious and unconscious emotional learning in the human amygdala. Nature, 39, 467-470.[CrossRef]
Osuch, E. A., Ketter, T. A., Kimbrell, T. A., et al (2000) Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biological Psychiatry, 48, 1020-1023.[CrossRef][Medline]
Ploghaus, A., Tracey, I., Gaiti, J. S., et al
(1999) Dissociating pain from its anticipation in the human
brain. Science, 284,
1979-1981.
Poline, J. B., Worsley, K. J., Evans, A. C., et al (1997) Combining spatial extent and peak intensity to test for activations in functional imaging. NeuroImage, 5, 83-96.[CrossRef][Medline]
Rapoport, M, van Reekum, R. & Mayberg, H.
(2000) The role of the cerebellum in cognition and behaviour:
a selective review. Journal of Neuropsychiatry and Clinical
Neuroscience, 12,
193-198.
Schmahmann, J. D. (1997) The Cerebellum and Cognition. San Diego, CA: Academic Press.
Spitzer, R. L., Williams, J. B. & Gibbon, M. (1987) Structured Clinical Interview for DSM-IV (SCID). New York: Biometrics Research, New York Psychiatric Institute.
Received for publication December 19, 2001. Revision received July 9, 2002. Accepted for publication July 9, 2002.
Related articles in BJP: