Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease

https://doi.org/10.1016/S0022-510X(01)00641-4Get rights and content

Abstract

The changes of regional cerebral blood flow (rCBF) in Parkinson's disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn–Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinson's disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to l-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by motor dysfunctions such as tremor, rigidity, bradykinesia and impaired postural reflex. In PD, the major pathological changes occur in the nigrostriatal dopaminergic neurons, part of which are innervated to the supplementary motor area (SMA) or primary motor cortex via the putamen, globus pallidus, and thalamus, although numerous non-dopaminergic neurons in other parts of the brain are also impaired [1]. The SMA interacts with the primary motor cortex [2] and modulates volitional motor function. Several lines of evidence suggest impaired SMA function in PD. For example, movement-related potentials derived from the SMA have been found to be decreased in PD [3], [4]. After pallidotomy followed by improved motor performance, movement-related changes of the regional cerebral blood flow (rCBF) have been demonstrated to increase in both the SMA and premotor cortex but not in the primary motor cortex [5]. Thus, for the comprehensive understanding of pathophysiological changes in PD, it is important to elucidate the cortical functions, which are closely related to the nigrostriatal pathways. In some studies, in comparison with controls, regional cerebral metabolism (rCMR) or rCBF in PD patients has been reported to be decreased in the frontal [6], [7], [8], [9], [10], parietal [7], [10], [11], [12], [13], [14], [15], [16], [17], [18], temporal [6], [7], [10], and occipital [7], [10], [16], [18], [19] lobes, as well as in the cerebellum [6], while in others, it has been observed to be unchanged in the occipital lobe [6] and cerebellum [10]. In addition, abnormalities in basal ganglia have been reported [6], [8], [10], [13], [18], [20], [21], although the results were not consistent among these studies. This inconsistency may be due to several causes. First, in most studies, rCBF or rCMR values might be affected not only by motor impairments, but also by aging, cognitive dysfunction, the effects of drugs and so on. Second, selected regions of interest (ROIs), dependent on the observer's a priori choice and hypothesis, were not always consistent with the real distribution of abnormalities and might have been influenced by brain volume and the extent of brain atrophy. The anatomical normalization technique enables us to compare individual brain images on a voxel by voxel basis, even if the size and shape of each image are different [22], [23]. In fact, using statistical parametric mapping (SPM), which is one method of anatomical normalization, increases in rCBF in the putamen, globus pallidus, insula, and inferior temporal gyrus, and so on have been demonstrated in PD [24]. However, rCBF data in the basal ganglia and the each cortical area may be easily affected by artifacts due to cortical or subcortical atrophy not uncommon in PD cases [25]. Because the variations in cortical or subcortical atrophy cannot be compensated for by the anatomical normalization technique alone, in this study, the extent of brain atrophy was evaluated using X-ray CT, and then PD cases without obvious brain atrophy were subjected to the SPM analysis of single-photon emission computed tomographic (SPECT) imaging.

Section snippets

Subjects

All PD cases were diagnosed by a neurologist following the United Kingdom Parkinson's Disease Brain Bank criteria for idiopathic PD [26]. First, the extent of brain atrophy was evaluated in all subjects using X-ray CT. Then, to minimize artifacts, PD cases showing minor ischemic lesions or a brain atrophy score (BAS, see later) less than the mean minus 2SD of controls were excluded from the present analyses. The 18 patients who fulfilled the above criteria were subjected to SPECT analysis, the

Results

The controls minus PD comparison demonstrated a rCBF decrement in the left SMA and the right dorsolateral prefrontal cortex (DLPFC) (uncorrected p<0.001, Fig. 1A and Table 2), and additionally, in the right SMA and the left DLPFC (uncorrected p<0.005, Fig. 1B and Table 2). Compared with the controls, the rCBF decrements in the SMA were evident both in the I/II (uncorrected p<0.05, data not shown) and III/IV (uncorrected p<0.001, Fig. 2A and Table 3) subgroups, but there were no significant

Discussion

In PD, activation studies using positron emission tomography [5], [33], [34] and SPECT [35] imaging have clearly revealed a decreased activation in the SMA, insular cortex, anterior cingulate area, etc. However, previous studies which did not include motor tasks failed to show rCBF decreases in these areas. In this study, first we excluded patients showing brain atrophy and then SPECT images of the study patients were compared with age-matched controls using the SPM technique without motor

Acknowledgments

We are greatly indebted to the staff of the Institute of Development, Aging and Cancer, Tohoku University and, in particular, to Mr. Tachio Sato and Mr. Kazuya Kumekawa for excellent technical assistance.

References (57)

  • H. Shibasaki et al.

    Clinical studies of the movement-related cortical potential (MP) and the relationship between the dentatorubrothalamic pathway and readiness potential (RP)

    J. Neurol.

    (1978)
  • J.P. Dick et al.

    The Bereitschaftspotential is abnormal in Parkinson's disease

    Brain

    (1989)
  • S.T. Grafton et al.

    Pallidotomy increases activity of motor association cortex in Parkinson's disease: a positron emission tomographic study

    Ann. Neurol.

    (1995)
  • L.I. Wolfson et al.

    Alterations of regional cerebral blood flow and oxygen metabolism in Parkinson's disease

    Neurology

    (1985)
  • M. Globus et al.

    Cerebral blood flow and cognitive impairment in Parkinson's disease

    Neurology

    (1985)
  • J.S. Perlmutter et al.

    Regional blood flow in hemiparkinsonism

    Neurology

    (1985)
  • L. Defebvre et al.

    Tomographic measurements of regional cerebral blood flow in progressive supranuclear palsy and Parkinson's disease

    Acta Neurol. Scand.

    (1995)
  • G.L. Lenzi et al.

    Regional impairment of cerebral oxidative metabolism in Parkinson's disease

    J. Neurol. Neurosurg. Psychiatry

    (1979)
  • D.E. Kuhl et al.

    Patterns of local cerebral glucose utilization determined in Parkinson's disease by the [18F]fluorodeoxyglucose method

    Ann. Neurol.

    (1984)
  • G. Pizzolato et al.

    [99mTc]-HM-PAO SPECT in Parkinson's disease

    J. Cereb. Blood Flow Metab.

    (1988)
  • M. Sasaki et al.

    Regional cerebral glucose metabolism in patients with Parkinson's disease with or without dementia

    Ann. Nucl. Med.

    (1992)
  • R.F. Peppard et al.

    Cerebral glucose metabolism in Parkinson's disease with and without dementia

    Arch. Neurol.

    (1992)
  • H. Tachibana et al.

    Twelve-month follow-up study of regional cerebral blood flow in Parkinson's disease

    Dementia

    (1995)
  • N.I. Bohnen et al.

    Motor correlates of occipital glucose hypometabolism in Parkinson's disease without dementia

    Neurology

    (1999)
  • R.S. Miletich et al.

    Regional cerebral blood flow imaging with 99mTc-bicisate SPECT in asymmetric Parkinson's disease: studies with and without chronic drug therapy

    J. Cereb. Blood Flow Metab.

    (1994)
  • K.J. Friston et al.

    Statistical parametric maps in functional imaging: a general linear approach

    Hum. Brain Mapp.

    (1995)
  • S. Minoshima et al.

    Anatomic standardization: linear scaling and nonlinear warping of functional brain images

    J. Nucl. Med.

    (1994)
  • Y. Imon et al.

    SPECT image analysis using statistical parametric mapping in patients with Parkinson's disease

    J. Nucl. Med.

    (1999)
  • Cited by (80)

    • Alexithymia

      2021, Handbook of Clinical Neurology
      Citation Excerpt :

      Given the high prevalence of alexithymia in PD, it is tempting to infer that the substantia nigra is necessary for emotional awareness in humans. However, there is ample evidence that PD is also associated with downstream effects at cortical sites including the prefrontal cortex and insula (Kikuchi et al., 2001; Cools et al., 2002). Therefore it is likely that alexithymia in PD represents a secondary consequence of the loss of dopaminergic input to fronto-opercular structures, rather than a primary consequence of disrupted emotional awareness encoding in nigrostriatal circuits.

    • The effect of subthalamic nucleus - Deep brain stimulation and different stimulation frequencies on cerebral hemodynamics in Parkinson's disease: A transcranial doppler study

      2020, Clinical Neurology and Neurosurgery
      Citation Excerpt :

      In addition to motor symptoms, several previous studies have demonstrated that some autonomic symptoms including psychiatric symptoms, sleep disorders, autonomic dysfunction, and fatigue may improve following STN-DBS [5–7]. Clinical studies have shown reduced regional cerebral blood flow in PD patients [8,9]. In advanced PD, regional cerebral blood flow has been found to decline especially in the supplementary motor area and prefrontal cortex [9].

    View all citing articles on Scopus
    View full text