Pharmacological modulation of prefrontal cortical activity during a working memory task in young and older humans: a PET study with physostigmine.
OBJECTIVE
Age-associated cholinergic dysfunction may contribute to the cognitive decline observed during aging, including a decline in working memory. The current study was designed to determine how healthy aging influences the neural response to working memory before and during pharmacological potentiation of the cholinergic system.


METHODS
In 13 young and 13 older healthy volunteers, regional cerebral blood flow (rCBF) was measured by using [15O]H2O and positron emission tomography across 10 scans that alternated between a working-memory-for-faces task and rest. In all subjects, the first two scans were obtained during intravenous saline infusion. Seven young and eight older subjects then received intravenous infusion of physostigmine, a cholinesterase inhibitor, and the remaining six young and five older subjects continued to receive saline.


RESULTS
In the placebo condition, task-specific rCBF increases in prefrontal regions were observed in the right middle and inferior frontal cortices in young subjects and in more anterior and ventral prefrontal regions in older individuals. Physostigmine during the working memory task significantly improved performance in both age groups. The right prefrontal regions that were selectively recruited in each age group during the placebo condition showed significantly lower rCBF during physostigmine administration.


CONCLUSIONS
Cholinergic enhancement does not affect structurally defined cortical regions but rather modulates neural activity in functionally defined regions, that is, in task-related prefrontal cortical areas that are selectively and distinctively recruited in young and older subjects.
Freo
Ulderico
U
Laboratory of Clinical Biochemistry, Medical School, University of Pisa, Via Roma, 55, I-56126 Pisa, Italy.
Ricciardi
Emiliano
E
Pietrini
Pietro
P
Schapiro
Mark B
MB
Rapoport
Stanley I
SI
Furey
Maura L
ML
D000328:Adult; D000367:Age Factors; D000368:Aged; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging; D001931:Brain Mapping; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D010104:Oxygen Radioisotopes; D010830:Physostigmine / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014867:Water
D002800:Cholinesterase Inhibitors; D010104:Oxygen Radioisotopes; D014867:Water; D010830:Physostigmine