Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration.
Erythropoietin (Epo) has neuroprotective and neurotrophic effects and improves cognitive function in animal models of neurodegenerative and neuropsychiatric illness. In humans, weekly Epo administration over 3 months improves cognitive function in schizophrenia. The neural underpinnings and time-course of this effect of Epo are currently unknown. It is also unclear whether the cognitive improvement reflects direct neurobiological actions or is secondary to hematological effects. We therefore assessed the actions of single administration of Epo (40,000 IU) vs. saline to healthy volunteers on cognitive and neural measures of executive function using a verbal fluency task and N-back working memory (WM) paradigm during functional magnetic resonance imaging (fMRI) on day 3 and 7 after administration in two separate cohorts of subjects. Epo modulated neuronal response in a fronto-parietal network during WM performance at both time points; on day 3 after administration, activation was increased in left-hemisphere frontal and cingulate cortex and reduced in the right parietal cortex; in contrast, neural response was enhanced in a right-lateralized fronto-parietal network and reduced in left-side regions 1 week post-administration. In addition, Epo-treated volunteers displayed improved verbal fluency performance 1 week post-administration. These effects occurred in the absence of changes in hematological measures suggesting that they reflect direct neurobiological actions of Epo. The findings are consistent with enduring effects of Epo on neurotrophic signaling and induction of neurochemical changes over time in neural networks typically affected in neuropsychiatric illness. The present study supports the notion that Epo may have clinical applications in the treatment of psychiatric disorder characterized by cognitive dysfunction.
Miskowiak
Kamilla
K
Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. kamilla.miskowiak@psych.ox.ac.uk
Inkster
Becky
B
O'Sullivan
Ursula
U
Selvaraj
Sudhakar
S
Goodwin
Guy M
GM
Harmer
Catherine J
CJ
D000328:Adult; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D015331:Cohort Studies; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000627:therapeutic use; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D010296:Parietal Lobe / Q000187:drug effects / Q000502:physiology; D013850:Thinking / Q000187:drug effects* / Q000502:physiology; D013995:Time; D013997:Time Factors; D016896:Treatment Outcome; D014705:Verbal Behavior / Q000187:drug effects / Q000502:physiology