Study of the Mnemonic Functions of Dopamine Using a Novel Molecular Imaging

Rajendra Badgaiyan, M.D.

Massachusetts General Hospital

Funded in December, 2005: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Can Molecular PET Imaging Show the Neurochemistry of Human Memory?

The investigators will use PET with a molecular tracer to see if this approach can reveal the neurochemistry of dopamine transmission that is involved in human memory.

The effects of impaired dopamine transmission on cognition in a number of neurological and psychiatric conditions is unclear, because scientists lack reliable methods for studying the neurochemical changes that are associated with cognition.  Conventional imaging has not been able to detect the relatively small and transient neurochemical changes in dopamine transmission that scientists suspect are involved in cognition.  To address this problem, the researchers have modified PET imaging by combining it with a molecular imaging technique.  This technique involves radioactively labeling a molecule that binds to the same receptor on brain cells to which dopamine usually binds.  According to the researchers' prior studies, however, when dopamine is activated, it displaces this molecule.  

The researchers, therefore, will use PET with this labeled molecular tracer in healthy volunteers to determine whether this technique can measure the extent to which dopamine displaces the labeled molecule on brain cell receptors during volunteers’ performance of nonprocedural memory tasks.  If so, the researchers would be able to identify aspects of human memory that are dopamine-dependent.  Success in using this technique in healthy volunteers would pave the way for using it in patients with conditions such as Parkinson’s disease and schizophrenia, to see how dopamine is altered in patients as they perform memory tasks. 

Significance: The findings may provide a better understanding of the role of the neurotransmitter dopamine in human cognition and memory and may lead to the development of new therapies for diseases in which dopamine transmission is impaired, such as Parkinson’s disease, Huntington’s disease, Tourette syndrome, schizophrenia, bipolar disorder, and depression.

ABSTRACT

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Study of the Mnemonic Functions of Dopamine Using a Novel Molecular Imaging

Because of the lack of a reliable technique to study neurochemistry of human cognition, the brain regulation of cognitive functions has not been well understood. We have recently demonstrated that the neurotransmitter released during a cognitive task performance can be detected using the molecular imaging technique if the technique is appropriately modified to allow detection of transient and relatively small changes in receptor kinetics (expected during cognitive activations). In our experiments, we modified the technique and exploited the competition between endogenously released striatal dopamine and its ligand for receptor occupancy to show that dopamine released during performance of a motor planning and a procedural memory task displaces the ligand from receptor sites. The displacement suggested that endogenous dopamine is released during performance of the studied tasks.

In the proposed study we plan to use the modified method to test our hypotheses that molecular imaging can be used to explore the neurochemistry of human memory and to resolve controversies in cognitive concepts. Proposed experiments will probe dopaminergic involvement in the processing of nonprocedural memory tasks that are impaired following the striatal lesions. These tasks include associative, non-associative, and semantic memory tasks. Since nonprocedural memory tasks do not consistently activate the basal ganglia in neuroimaging experiments, despite being impaired in the patients with striatal lesions, the role of striatum in the processing of human nonprocedural memory is unclear. It is not known whether the inconsistency between the neuroimaging and lesion studies is due to subthreshold hemodynamic response or disruption of neural tracts in the brain-damaged patients.

Proposed experiments may help explain the inconsistency by probing involvement of striatal dopamine in the processing of nonprocedural memory. The results will provide better insight into dopaminergic control of human memory and will help in formulation of novel therapeutic strategies for the treatment of neurological and psychiatric conditions that are associated with impaired dopamine neurotransmission. These conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, schizophrenia, bipolar disorder, and depression. More significantly, the proposed study will provide preliminary data to help us develop the molecular imaging technique so that it can be used to study the neurochemistry and pathophysiology of cognitive disorders that are dependent on dopamine neurotransmission.

HYPOTHESIS

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Hypothesis:
Our knowledge of the neurochemistry of human cognition is limited because of the lack of a reliable technique to study neurochemical changes associated with cognitive processing. We have recently shown that a modified molecular imaging technique offers a promising possibility. Using this technique we propose to study the aspects of human memory that are processed by dopaminergic system.

Goals:
The goals of the study are to examine:

1. Whether the molecular imaging technique can be used to identify aspects of human memory that are processed by the striatal dopamine. We propose to study three forms of nonprocedural memory: associative, non-associative, and semantic. All of these forms of memory are impaired following striatal lesions.

2. Whether the controversy concerning striatal processing of nonprocedural memory can be resolved using molecular imaging technique. Since the technique will use a novel approach, it will provide information (concerning neurochemistry) that cannot be obtained by conventional imaging methods. Additional data acquired in this study will provide better insight into the role of the striatum and the dopamine system in human mnemonic processing.

Methods:
Using a modified molecular imaging technique, striatal dopamine release during the performance of mnemonic tasks will be examined. In all of the experiments, after administration of a radiolabeled dopamine ligand (11C-raclopride), volunteers will be asked to perform one of the memory tasks. Concentration of the ligand during the task performance will be monitored dynamically using a PET camera, to estimate the release of dopamine in different striatal areas. The study will include following mnemonic tasks:

1. Associative memory: Using a paired associate paradigm, volunteers will be asked to retrieve the word that was previously associated with a cued word.

2. Non-associative memory: This will use a stem completion task in which volunteers will be asked to complete 3 letter word stems using a studied word.

3. Semantic memory: In this experiment, processing of semantically related words will be examined using a lexical decision task.

SELECTED PUBLICATIONS

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Badgaiyan R. D., Fischman A. J., and Alpert N. M.  Striatal dopamine release in sequential learning.  Neuroimage. 2007 Nov 15;38(3):549-56.

Fischman A.J. and Badgaiyan R.D.  Cortical activations, psychiatric symptoms, and climacteric women.  Menopause. 2006 Nov-Dec;13(6):856-8.

Badgaiyan R.D.  Cortical activation elicited by unrecognized stimuli.  Behav Brain Funct. 2006 May 16;2:17.

Badgaiyan R.D. Conscious awareness of retrieval: An exploration of the cortical connectivity. Int J Psychophysiol. 2005 Feb;55(2):257-62.

Badgaiyan R. D., Fischman A. J., and Alpert N. M. Striatal dopamine release during unrewarded motor task in human volunteers. Neuroreport. 2003 Aug 6;14(11):1421-4.

Alpert N. M., Badgaiyan R. D., Livini E. and Fischman A. J.  A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems.  Neuroimage. 2003 Jul;19(3):1049-60.