You are here

Article Text

Article menu

Download PDFPDF

Paper
Functional imaging of the cerebral olfactory system in patients with Parkinson’s disease
  1. B Westermann1,2,
  2. E Wattendorf2,3,
  3. U Schwerdtfeger2,
  4. A Husner2,
  5. P Fuhr4,
  6. O Gratzl1,
  7. T Hummel5,
  8. D Bilecen6,
  9. A Welge-Lüssen2
  1. 1
    Neurosurgical University Clinic, University Hospital Basel, Switzerland
  2. 2
    University Clinic of Otorhinolaryngology, University Hospital Basel, Switzerland
  3. 3
    Institute of Anatomy, Department of Neuroanatomy, University of Basel, Switzerland
  4. 4
    Neurological University Clinic, University Hospital Basel, Switzerland
  5. 5
    Smell and Taste Clinic, Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany
  6. 6
    Institute of Radiology, University Hospital Basel, Switzerland
  1. Dr B Westermann, Neurosurgical University Clinic, University Hospital Basel, Spitalstrasse 21, Switzerland; Birgit.Westermann{at}unibas.ch

Abstract

Background: Olfactory dysfunction is a frequent non-motor symptom in Parkinson’s disease (PD) and is considered to be an early manifestation of the disease.

Objective: To establish the cortical basis of olfactory function in patients with PD.

Method: Functional magnetic resonance imaging (fMRI) was used to investigate brain activity related to olfactory processing in patients with hyposmic PD at mild to moderate stages of the disease (n = 12, median Hoehn and Yahr stage 2.0) and in healthy, age-matched controls (n = 16) while passively perceiving a positively valenced (rose-like) odorant.

Results: In both patients with PD and healthy controls, olfactory stimulation activated brain regions relevant for olfactory processing (ie the amygdaloid complex, lateral orbitofrontal cortex, striatum, thalamus, midbrain and the hippocampal formation). In controls, a bilateral activation of the amygdala and hippocampus was observed, whereas patients with PD involved these structures in the left hemisphere only. Group comparison showed that regions of higher activation in patients with PD were located bilaterally in the inferior frontal gyrus (BA 44/45) and anterior cingulate gyrus (BA 24/32), and the left dorsal and right ventral striatum.

Conclusions: In patients with PD, results obtained under the specific conditions used suggest that neuronal activity in the amygdala and hippocampus is reduced. Assuming an impact on olfactory-related regions early in PD, our findings support the idea that selective impairment of these brain regions contributes to olfactory dysfunction. Furthermore, neuronal activity in components of the dopaminergic, cortico-striatal loops appears to be upregulated, indicating that compensatory processes are involved. This mechanism has not yet been demonstrated during olfactory processing in PD.

  • Parkinson’s disease
  • olfactory dysfunction
  • laterality
  • functional magnetic resonance imaging (fMRI)

https://doi.org/10.1136/jnnp.2006.113860

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Olfactory impairment has been described as a frequent, non-motor symptom in Parkinson’s disease (PD). Research on non-motor deficits in PD1 indicates that olfactory dysfunction, in addition to gastrointestinal and autonomous deficits, may be considered to be an early clinical feature of the disease—preceding motor symptoms by years.2 3 Using standardised psychophysical tests,4 5 olfactory loss has been reliably demonstrated to occur in PD.6

    However, the relationship of olfactory impairment with the clinical disease pattern of PD is not clear. Although several studies were unable to correlate measures of olfactory function with clinical signs7 or the duration of the disease,8 other work suggests a correlation between the ability to discriminate odours and motor symptoms9 or the latency of olfactory event-related potentials and the severity of the disease.10 Furthermore, using TRODAT-1 SPECT imaging, reduced dopamine transporter binding in the striatum has been shown to correlate with olfactory impairment in patients with early PD.11 In addition, a post-mortem study revealed an increase of dopaminergic neurons in the olfactory bulb of patients with PD, indicating that pathophysiological changes involve the olfactory system.12 Moreover, the presence of Lewy bodies (LBs) and Lewy neurites (LNs) in dopaminergic-regulated brain regions known to be involved in olfactory processing—such as the amygdaloid complex, hypothalamus, cingulate gyrus and the hippocampal formation—shows that these structures are the earliest to be affected.1 13 14

    In the present study, olfactory function in patients with PD and healthy subjects was examined using functional magnetic resonance imaging (fMRI). Results were expected to provide further insight into the disease-related modulation of olfaction—in particular, in dopaminergic-regulated brain regions, including the orbitofrontal cortex15, cingulate gyrus15 and the striatum.16 To the authors’ knowledge, the present study is the first to investigate brain functions associated with olfactory impairment in PD using fMRI.

    METHODS

    Subjects

    We investigated 12 patients with PD (9 men and 3 women; age range: 44–71 years, mean: 57.1±2.2 years) diagnosed according to the UK PD Society Brain Bank diagnostic criteria17 and 16 age-matched healthy controls (10 men and 6 women; age range: 54–75 years, mean: 64.7±1.4 years). None of the control subjects had a history or signs of neurological disorders. Written informed consent was obtained from all participants. The study was approved by the Ethics Committee of the University Hospital of Basel, Switzerland.

    According to the Hoehn and Yahr scale,18 all patients were in mild to moderate stages of the disease (4 patients  =  1.5, 7 patients ⩾ 2.0, 1 patient  =  3.0; median: 2.0). The median duration of disease was 3.3 years (range: 0.3–11 years). Onset of motor symptoms was right-sided in 9 patients and left-sided in 3 patients. The median Unified Parkinson’s Disease Rating Scale (UPDRS)19 score was 28 (range: 9–48). All subjects were non-demented (Mini-Mental State Examination20, MMSE score >28) and did not exhibit significant signs of depression (Beck Depression Inventory21, BDI score <15).

    Data acquisition

    Imaging was performed on a 1.5 T Siemens Sonata MR scanner (Siemens, Erlangen, Germany). Functional images were obtained using a T2*-weighted echo planar imaging (EPI) sequence (repetition time: 2 s, echo time: 40 ms, flip angle: 90°) covering the whole brain with 25 contiguous axial slices (resolution: 3.4 × 3.4 × 4.0 mm). Images were additionally tilted by 16° relative to the anterior/posterior commissure (AC-PC) line to minimise susceptibility artifacts. Left- and right-sided olfactory stimulation was measured in separate sessions (288 scans per session). After completion of fMRI sessions, a high-resolution structural T1-weighted image was obtained (magnetisation-prepared rapid gradient echo [MPRAGE] sequence, resolution: 1 × 1 × 1 mm).

    Olfactory testing

    Prior to fMRI, olfactory function of all subjects was assessed birhinally using the standardised “Sniffin’ Sticks” test battery (Burghart, Wedel, Germany) that included odour threshold (T), discrimination (D) and identification (I) tests.5 22 Based on the composite TDI score, olfactory function is classified as normosmic (TDI >30), hyposmic (TDI 16–30) and functionally anosmic (TDI ⩽15). To ensure comparable performance of both groups during the fMRI task, subjects had to perceive the olfactory stimulus during scanning. Accordingly, 12 patients of the initial PD group (n = 25) and all subjects of the control group (n = 16) were selected for the present study. On average, patients with PD were hyposmic (mean TDI score: 23.6, range: 13.3–32.5). Controls were, on average, normosmic (mean TDI score: 33.3, range: 27.0–39.5). Assuming that olfactory abilities in patients with PD are not influenced by dopaminergic drugs,23 patients were not withdrawn from their regular medication.

    Olfactory stimulation in the MRI scanner

    Separate left- and right-sided olfactory stimulation was performed using a computer-controlled olfactometer OM2S (Burghart) based on the principles of air-dilution olfactometry (total flow 7 l/min, 37°C, 80% relative humidity). For stimulation, the rose-like odour (Phenyl-Ethyl-Alcohol, Fluka, Switzerland; 40% v/v) was used. This odour is considered to be pleasant and produces little or no trigeminal activation.

    fMRI activation task

    Subjects were informed that periods of olfactory stimulation alternated with periods of no stimulation (fig 1). During each of the eight olfactory stimulation periods, six stimuli with a duration of 1 s each and an inter-stimulus interval (ISI) of 6 s were delivered.16 Although adaptation to the stimulus throughout the fMRI session cannot be completely ruled out, such effects were expected to occur similarly in both groups.24 Subjects were instructed to pay attention to the odour. To prevent participants from mental imaging of the odorant, which is known to activate regions related to olfactory processing,25 the olfactory stimulus was not announced in advance. For the same reason, attention of the subjects was consistently directed towards a non-olfactory semantic retrieval task during the entire session. In this task, subjects had to produce words matching three successively presented target articles or target pronouns (ISI: 12 s, duration: 6 s). From each olfactory period, only olfactory events not coinciding with the semantic retrieval task (three of the six stimuli; see fig 1) were further analysed.

    Figure 1
    Figure 1 Olfactory stimulation sequence applied during functional MRI sessions. ISI, inter-stimulus interval.

    Data analysis

    Using the Statistical Parametric Mapping software (SPM2),26 functional images were corrected for movements, co-registered to the structural image, normalised to the standard brain template and smoothed by a 9 × 9 × 12 mm Gaussian kernel. An event-related analysis was used to separately identify neuronal activity following olfactory stimuli, olfactory stimuli with concurrent semantic retrieval, and the semantic retrieval task during both left- and right-sided olfactory stimulation in each subject. All events were modelled by convolving the regressors comprising the onset times of the respective stimuli with the canonical haemodynamic response function (duration: 1 s for all olfactory events and 6 s for the semantic retrieval task). To examine olfactory processing, the random effect model included only contrast estimates obtained from the olfactory events—i.e. those without semantic retrieval. Correspondingly, contrast estimates of left- and right-sided olfactory stimulation for each group were entered into a 2 × 2 ANOVA model to assess statistical inference of group effects and differences. Group effects were reported using a correction for multiple comparisons across the entire brain volume with a false discovery rate (FDR) of p<0.02 for clusters with an extent of 10 voxels.

    According to our hypothesis, statistical inference of group differences was restricted to dopaminergic-modulated regions contributing to olfactory processing. Concerning previous studies using comparable olfactory stimuli and tasks, the following brain regions were predicted a priori: the anterior cingulate gyrus,15 16 the inferior frontal gyrus27 and the striatum16. To assess the statistical significance, a spherical volume of interest was centred around the activation maxima in each pre-defined anatomical region and adapted to its extent. Accordingly, the diameter of the search volume for striatal subregions and the anterior cingulate gyrus was 16 mm, and for the left and right inferior frontal gyrus 24 and 20 mm, respectively (see table 1). Regions were considered significant at a family-wise error of p<0.05 after a correction for multiple comparisons across small volumes of interest had been performed.28 All activation maxima were reported as Z scores and coordinates in the Talairach/Tornoux space.

    View this table:
    Table 1 Brain regions with higher (PD>C) and reduced activity (PD<C) in patients with PD in comparison to controls

    RESULTS

    Brain regions activated in both patients with PD and controls

    Left-sided olfactory stimulation elicited higher neuronal activity than right-sided stimulation, specifically in patients with PD (table 2). Here, right-sided stimulation activated the right insula only. Overall, however, activation was observed in the lateral orbitofrontal cortex (inferior frontal gyrus, BA 47), amygdaloid complex, hippocampal formation with adjacent fornix and the thalamus (fig 2A,B). In more posterior regions, neuronal responses included the superior temporal gyrus (BA 22), parietal operculum (BA 43), inferior parietal lobe (BA 40) and the occipital lobe (BA 18/31). Subcortically, activity concerned the midbrain and caudate nucleus (tail). Furthermore, activation of the insula, including the claustrum (BA 13) and cerebellum, was observed.

    Figure 2
    Figure 2 Activated regions during left-sided olfactory stimulation (from left to right): the lateral orbitofrontal cortex (BA 47), the amygdala and the hippocampal formation for (A) controls and (B) patients with PD. Group differences (C). Higher neuronal activity in patients with PD compared with controls (PD>C) in the left striatum and left inferior frontal gyrus (BA 44/45) during left-sided olfactory stimulation.
    View this table:
    Table 2 Brain regions activated in both patients with PD (n = 12) and controls (n = 16)

    Notably, in patients with PD, activation was reduced to the left hemisphere in regions associated with olfactory processing, the amygdala and hippocampal formation (table 3). The activation was similarly reduced in several regions usually not related to the olfactory system—such as the inferior parietal lobe (BA 40) and the parietal operculum (BA 43).

    View this table:
    Table 3 Lateralisation index

    The piriform cortex was not significantly activated at the group level, probably due to low signal changes in addition to a certain anatomical variability.16 In the single subject analysis, however, activation in this region could be shown in almost all participants.

    Comparison of patients with PD and controls

    According to the expected changes in dopaminergic-regulated brain regions, significant group differences in frontal and striatal regions were identified (table 1, fig 2c).

    DISCUSSION

    Pattern of activation in patients with PD and controls

    Olfactory stimulation revealed a distinct pattern of cortical and subcortical activation, characterising patients with PD and healthy controls. In both groups, olfactory stimulation activated brain regions that are essentially involved in the processing of chemosensory information—that is, the amygdaloid complex,29 hippocampus,15 thalamus16 and portions of the lateral orbitofrontal cortex.15 Most importantly, activity induced by left-sided stimulation showed that responses of the amygdala and hippocampus in patients with PD were restricted to left-hemispheric structures only, but occurred bilaterally in controls. This phenomenon of reduced activation could be related to cortical changes associated with neuropathological processes in early stages of PD that have been shown to involve primary olfactory regions, including the anterior olfactory nucleus14 and the olfactory bulb.12 As for the amygdala, a substantial cell loss, accompanied by high densities of LBs and LNs has been shown, in particular in the cortical nucleus.13 Major connections of the cortical nucleus to the olfactory bulb and olfactory-related regions raise the possibility that pathological changes in this structure influence olfactory function.

    Reduced activation in patients with PD compared with controls has also been observed in posterior areas, such as the inferior parietal lobe (BA 40). Considering that this region integrates stimuli from multiple modalities,30 the higher and more bilateral activity in controls may indicate that, in this group, processing of the olfactory stimulus allows association with other sensory attributes of the stimulus.

    Interestingly, patients with PD and controls activated targets of dopaminergic projections, the midbrain, lateral orbitofrontal cortex (BA 47) and striatum in response to olfactory stimulation. Co-activation of these structures has been observed in other studies using comparable olfactory stimuli and tasks.15 16 As far as cognitive tasks are concerned, this pattern of activation indicates stimulus reinforcement via the mesocortico-limbic loop31 that was previously shown to be active during processing of the incentive value of olfactory stimuli in non-human primates.32 The results of the present study suggest that patients with PD, like healthy controls, are able to assess the salience of the olfactory stimuli using dopaminergic-mediated reinforcement.33 One explanation for this finding could be that, in early PD, mesocortico-limbic circuits are less affected by dopamine depletion than nigrostriatal circuits and may even be upregulated in earlier stages of the disease.34 Even the similar activation of the cerebellum35 and insular cortex15 16 in both groups might be related to the higher arousal elicited by the olfactory condition.

    Another important finding of the present study was that higher responses were elicited by left-sided than by right-sided stimulation in both groups. This different activation might have been influenced by the hedonic properties of positively valenced odorant. Specifically, electrophysiological measurements showed that the event-related potential to vanillin is of greater amplitude and longer latency when the left nostril is stimulated, whereas hydrogen sulphide produces a larger amplitude and longer latency when the right nostril is stimulated.36 The differences between the two sides of stimulation were even more pronounced in patients with PD. This is in line with studies showing that olfactory function is less severely impaired with left-sided than right-sided stimulation in PD.6 23

    Focusing on dopaminergic-regulated brain regions, additional differences between patients with PD and controls have been identified at the level of group comparisons.

    Regions of higher activation in PD patients (PD > C)

    Analysing activity following left-sided stimulation, patients with PD exhibited higher activation than controls bilaterally in the inferior frontal gyrus (BA 44/45) and in the anterior cingulate gyrus (BA 24/32), in anterior portions of the left striatum (head of the nucleus caudatus and putamen) and the right ventral striatum (nucleus accumbens). In patients with PD, upregulated activity in regions participating in cortico-striatal loops has been reported as a characteristic phenomenon during motor37, cognitive38 and linguistic39 tasks. It seems to be part of a compensatory mechanism mediated by brain areas that are not affected by the nigrostriatal dopamine deficit.38 As it concerns olfaction, upregulated activity indicates that compensatory mechanisms may support the processing of olfactory stimuli in PD.

    Regions of reduced activation in PD patients (PD < C)

    Neuronal activity in patients with PD was significantly decreased in the left posterior putamen during right-sided stimulation. Decreased activity in the posterior putamen may be related to the finding that dopamine depletion is most advanced in this region.40

    To summarise, the pattern of activation indicates that patients with PD can mobilise a substantial part of the olfactory network. However, activity has been reduced to the left in important olfactory relays, notably the amygdala. In line with the previously reported neuronal loss in the cortical amygdaloid nucleus, our findings suggest that this brain region is implicated in olfactory dysfunction in PD. Furthermore, higher neuronal activity in components of cortico-striatal loops indicates involvement of compensatory mechanisms. Both effects describe the altered olfactory processing in PD. Compensatory mechanisms that are possibly engaged during olfactory processing in PD may be subject to different explanations. Compensation may be a consequence of the deficient stimulus processing at early stages of its evaluation, as indicated by the reduced (unilateral) activation of the amygdala; as such, the higher frontal activity in PD could be related to stimulus reinforcement. Alternatively, it could reflect more general changes to adapt to nigrostriatal-dopamine deficits in PD. In this respect, olfactory deficits in PD should be further differentiated from those occurring in other patient groups to characterise compensatory mechanisms that are specifically engaged in PD.

    Acknowledgments

    The authors thank Prof. Dr Martin Lotze (University of Greifswald, Germany) for his expert suggestions during the preparation of this manuscript, and Prof. Dr Klaus Scheffler and Dr Markus Klarhöfer (University Hospital Basel, MR-Physics, Switzerland) for implementation of the MRI sequences.

    REFERENCES

    1. ↵
      1. Braak H,
      2. Rub U,
      3. Gai WP,
      4. et al
      . Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 2003;110:517–36.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Ponsen MM,
      2. Stoffers D,
      3. Booij J,
      4. et al
      . Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004;56:173–81.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Sommer U,
      2. Hummel T,
      3. Cormann K,
      4. et al
      . Detection of presymptomatic Parkinson’s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 2004;19:1196–202.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Doty RL,
      2. Shaman P,
      3. Dann M
      . Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32:489–502.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Hummel T,
      2. Sekinger B,
      3. Wolf SR,
      4. et al
      . ‘Sniffin’ Sticks’: Olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 1997;22:39–52.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Daum RF,
      2. Sekinger B,
      3. Kobal G,
      4. et al
      . Olfactory testing with “sniffin’ sticks” in idiopathic Parkinsonism. Nervenarzt 2000;71:643–50.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Doty RL,
      2. Riklan M,
      3. Deems DA,
      4. et al
      . The olfactory and cognitive deficits of Parkinsons disease—evidence for independence. Ann Neurol 1989;25:166–71.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Doty RL,
      2. Deems DA,
      3. Stellar S
      . Olfactory dysfunction in parkinsonism—a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988;38:1237–44.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Tissingh G,
      2. Berendse HW,
      3. Bergmans P,
      4. et al
      . Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord 2001;16:41–6.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Chase T,
      2. Bedrad P
      1. Hummel T
      . Olfactory evoked potentials as a tool to measure progression of Parkinson’s Disease. In: Chase T, Bedrad P, eds. Focus on Medicine Vol. 14—New developments in the drug therapy of Parkinson’s disease. Oxford: Blackwell Science, 1999:47–53.
    11. ↵
      1. Siderowf A,
      2. Newberg A,
      3. Chou KL,
      4. et al
      . [Tc-99m] TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 2005;64:1716–20.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Huisman E,
      2. Uylings HBM,
      3. Hoogland PV
      . A 100% increase of 687 dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson’s disease. Mov Disord 2004;19:687–92.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Harding AJ,
      2. Stimson E,
      3. Henderson JM,
      4. et al
      . Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 2002;125:2431–45.
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Pearce RKB,
      2. Hawkes CH,
      3. Daniel SE
      . The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 1995;10:283–7.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Royet JP,
      2. Plailly J,
      3. Delon-Martin C,
      4. et al
      . fMRI of emotional responses to odors: influence of hedonic valence and judgment, handedness, and gender. Neuroimage 2003;20:713–28.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Poellinger A,
      2. Thomas R,
      3. Lio P,
      4. et al
      . Activation and habituation in olfaction—an fMRI study. Neuroimage 2001;13:547–60.
      OpenUrlPubMedWeb of Science
    17. ↵
      1. Gibb WRG,
      2. Lees AJ
      . The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:745–52.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Hoehn MM,
      2. Yahr MD
      . Parkinsonism—onset progression and mortality. Neurology 1967;17:427–42.
      OpenUrlFREE Full Text
    19. ↵
      1. Fahn S,
      2. Marsden CD,
      3. Calne D,
      4. Goldstein M
      1. Fahn S,
      2. Elton RL
      . Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent Developments in Parkinson’s Disease. Florham Park, NJ: Macmillan Health Care Information, 1987:153–64.
    20. ↵
      1. Folstein MF,
      2. Folstein SE,
      3. Mchugh PR
      . Mini-mental state—practical method for grading cognitive state of patients for clinician. J Psychiatr Res 1975;12:189–98.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Beck AT,
      2. Erbaugh J,
      3. Ward CH,
      4. et al
      . An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Kobal G,
      2. Klimek L,
      3. Wolfensberger M,
      4. et al
      . Multicenter investigation of 1,036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identification, odor discrimination, and olfactory thresholds. Eur Arch Otorhinolaryngol 2000;257:205–11.
      OpenUrlCrossRefPubMed
    23. ↵
      1. Doty RL,
      2. Stern MB,
      3. Pfeiffer C,
      4. et al
      . Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992;55:138–42.
      OpenUrlAbstract/FREE Full Text
    24. ↵
      1. Radil T,
      2. Roth J,
      3. Ruzicka E,
      4. et al
      . Olfactory dysfunction: A symptom of Parkinson’s disease? Ceska A Slovenska Neurologie A Neurochirurgie 1995;58:286–9.
      OpenUrl
    25. ↵
      1. Levy LM,
      2. Henkin RI,
      3. Lin CS,
      4. et al
      . Odor memory induces brain activation as measured by functional MRI. J Comput Assist Tomogr 1999;23:487–98.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      1. Friston KJ,
      2. Holmes AP,
      3. Worsley KJ,
      4. et al
      . Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995;2:189–210.
      OpenUrlPubMed
    27. ↵
      1. Sobel N,
      2. Prabhakaran V,
      3. Zhao Z,
      4. et al
      . Time course of odorant-induced activation in the human primary olfactory cortex. J Neurophysiol 2000;83:537–51.
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Worsley KJ,
      2. Marrett S,
      3. Neelin P,
      4. et al
      . A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996;4:58–73.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      1. Winston JS,
      2. Gottfried JA,
      3. Kilner JM,
      4. et al
      . Integrated neural representations of odor intensity and affective valence in human amygdala. J Neurosci 2005;25:8903–7.
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Calvert GA,
      2. Hansen PC,
      3. Iversen SD,
      4. et al
      . Detection of audio-visual integration sites in humans by application of electrophysiological criteria to the BOLD effect. Neuroimage 2001;14:427–38.
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Elliott R,
      2. Frith CD,
      3. Dolan RJ
      . Differential neural response to positive and negative feedback in planning and guessing tasks. Neuropsychologia 1997;35:1395–404.
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Rolls ET
      . Precis of the brain and emotion. Behav Brain Sci 2000;23:177–91.
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      1. Cools R,
      2. Barker RA,
      3. Sahakian BJ,
      4. et al
      . Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex 2001;11:1136–43.
      OpenUrlAbstract/FREE Full Text
    34. ↵
      1. Kish SJ,
      2. Shannak K,
      3. Hornykiewicz O
      . Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease—pathophysiologic and clinical implications. N Engl J Med 1988;318:876–80.
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. Ferdon S,
      2. Murphy C
      . The cerebellum and olfaction in the aging brain: a functional magnetic resonance imaging study. Neuroimage 2003;20:12–21.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Kobal G,
      2. Hummel T,
      3. Vantoller S
      . Differences in human chemosensory evoked-potentials to olfactory and somatosensory chemical stimuli presented to left and right nostrils. Chem Senses 1992;17:233–44.
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Samuel M,
      2. Ceballos-Baumann AO,
      3. Blin J,
      4. et al
      . Evidence for lateral premotor and parietal overactivity in Parkinson’s disease during sequential and bimanual movements—A PET study. Brain 1997;120:963–76.
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Monchi O,
      2. Petrides M,
      3. Doyon J,
      4. et al
      . Neural bases of set-shifting deficits in Parkinson’s disease. J Neurosci 2004;24:702–10.
      OpenUrlAbstract/FREE Full Text
    39. ↵
      1. Grossman M,
      2. Cooke A,
      3. DeVita C,
      4. et al
      . Grammatical and resource components of sentence processing in Parkinson’s disease—An fMRI study. Neurology 2003;60:775–81.
      OpenUrlAbstract/FREE Full Text
    40. ↵
      1. Bruck A,
      2. Aalto S,
      3. Nurmi E,
      4. et al
      . Striatal subregional 6-[F-18]fluoro-L-dopa uptake in early Parkinson’s disease: A two-year follow-up study. Mov Disord 2006;21:958–6.
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Funding: This study was supported by grants from the Swiss National Science Foundation (Grant No. 3100-068282 and 3100A0-100633).

    • Competing interests: None declared.

    • Ethics approval: The study was approved by the Ethics Committee of the University Hospital of Basel, Switzerland.