1. All India Institute of Medical Sciences, New Delhi – 110 029, INDIA
EFFECT OF LEVADOPA ON THE WORKING MEMORY
IN PARKINSON’S DISEASE : AN fMRI STUDY
M. SAXENA1, S. SENTHIL KUMARAN2, VINAY GOYAL1, S. SINGH1, and M. BEHARI1 Department of Neurology1, Department of N.M.R.2
All India Institute of Medical Sciences, New Delhi – , INDIA
INTRODUCTION
BACKGROUND
Parkinson's disease (PD) is a chronic and progressive neuro-degenerative disorder of the central nervous system, often associated with dementia and grey matter loss in frontal cortex1. Dopaminergic loss in the striatonigral and mesocortical pathway is responsible for heterogenic cognitive impairment in PD. We are exploring whether short term memory lossis present in PD patients.
The effect of dopaminergic administration on memory function has been attempted in a number of studies using psychological and verbal battery tests (Mohr et al. 1989, Singh et al. 2006, Kulisevsky et al 2004, Sawamoto et al. 2008). All these studies evaluated cognitive function on the response of the patient rather than functional state of the brain. The present study uses functional MRI to understand the functional aspect of the cognitive behavior of PD subjects.
METHODOLOGY
Patients fulfilling UK PD Brain Bank clinical diagnostic criteria were recruited from the movement disorder clinic of a tertiary care center in India from January 2009 to October Age and gender matched healthy individuals served as controls. The study was approved by the IEC/ IRB and all subjects signed informed consent form before participation. Nineteen subjects of 55.3 ± 15 yrs, (13 M, 6 F) suffering from PD for 4.9 ± 3.8 years were recruited from the neurology clinic of our institute and eleven healthy volunteers (5 M, 6 F) in the age range 45 to 50 years. The patients were investigated using standard Unified Parkinson’s disease rating scale (UPDRS) and functional MRI both in the ‘off’ (no dopaminergic drugs or any other medication for at least 12 hrs before the fMRI scan) and ‘on’ (2 hours after dopaminergic agent was administered). The studies were carried out on 1.5 T MR Scanner (Avanto, Siemens, Germany). The design matrix was block paradigms having active phase of known objects and unknown images and a baseline phase (figure 1). The patients observed carefully 24 pictures presented for 2 s each. During the recollection phase (15 minutes later), 96 images {28 from household items (HH), 28 from fruits and vegetables (FV), 20 from landscapes (LS) and 20 from water bodies (WB)} were presented and the subjects were instructed to give a response by pressing the assigned key on the Lumina LP400 response pad as to whether they had seen that image earlier or not. Post-processing was done using SPM2. One way ANOVA (with p<0.001, cluster threshold 5) was used for group analysis while paired t-test was applied between the on and off state.
Figure 1. Design matrix used for the memory task
Controls
Controls
Figure 3: The working memory response in the subjects during recollection of objects (using Lumina Response pad)
Table 1. Cluster count of brain activation for Known images
Area
No. of Clusters
(1 Cluster=2x2x2mm3)
controls
PD-off
PD-on
Precuneus (BA 7) 59 10 46
Occipital Gyrus (BA 17,18,19)
147
419
355
Superiror temporal gyrus (BA 21,22) 24
Inferior Frontal Gyrus (BA 43,44) - 21
Insula (BA 13) 11
Cerebellar Tonsil
Middle & Medial Frontal Gyrus 23 68
Thalamus
137
Fusiform gyrus (BA 37)
165
359
Superior Frontal Gyrus (BA 8) 30
Anterior Prefrontal gyrus (BA 10)
Table 2. Cluster count of brain activation for Unknown images
Area
No. of Clusters
(1Cluster=2x2x2mm3)
controls
PD-off
PD-on
Precuneus (BA 7)
188 56 88
Occipital Gyrus (BA 17,18,19)
5228
1830
367
Superiror temporal gyrus (BA 21,22) 37 -
Inferior Frontal Gyrus (BA 43,44) 10 21
Insula (BA 13)
311 14
Cerebellar Tonsil
151
Middle & Medial Frontal Gyrus
156 55
Thalamus 11 46
Fusiform gyrus (BA 37)
3529
184
Superior Frontal Gyrus (BA 8) 38
Anterior Prefrontal gyrus (BA 10) 42 45
“Off”
“Off”
“On”
“On”
Figure 2: The BOLD activation pattern for known images in controls, “off-state” patients, and “on-state patients”
Figure 4: The BOLD activation pattern for unknown images in controls, “off-state” patients, and “on-state patients”
DISCUSSION
RESULTS
The patients exhibited MMSE 23 ± 10.44; Hoehn & Yahr Stage 1.64 ± 0.98; having dopa equivalence of 110 ± 13 mg per day. Anterior pre-frontal cortex (aPFC) BA 10 is responsible for identifying target and non target stimuli was active in controls for both “known” and “unknown” images, but not in patients.. BA 7 shown to act as a memory buffer2 was active for the “unknown” objects but was inactivate for “known” objects in patients.
The precuneus (BA 7), regarded as a memory buffer was equally active in controls for both “known” and “unknown” objects but lesser in PD patients.
More activation was observed in the occipital gyrus (BA 18, 19) in case of patients for known images as compared to controls. But for the unknown images the patients showed lesser activaton.It appears that patients recruit more of the occipital gyrus in observing the images as compared to controls.
The superior temporal gyrus (STG) (BA 21, 22) was found to be activated in controls only and probably may be responsible for registering new facts.
Cerbellar tonsil and fusiform gyrus was activated only for the unknown images and its activation was less active in the patients(tables 1 and 2).
PD is characterized with increase in progressive brain volume loss in the medial temporal lobe and reduced activation of the fronto-niagral striatum co-related with cognitive decline3,4. In comparison to age and sex matched controls, PD subjects exhibit impairment of short term memory, which shows marginal recovery on dopa administration (Figure 3). It seems the aPFC undergoes degeneration in PD patients1. Precuneus(BA 7) , considered to be a memory buffer may be impaired in PD. Patients recruit more occipital gyrus to observe images.
CONCLUSION
Memory is affected in PD subjects as compared to controls.
L-dopa therapy helps in marginal restoration of working memory.
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