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Verbal and Non-Verbal Learning in Humans. Fig. 4. Success in novel word learning in subjects receiving placebo or L-dopa (mean values with standards errors of the means for two daily sessions with 200 trials each). In addition, also shown are results in the subgroup (n = 10) receiving relatively higher doses of L-dopa because their body weights were below the group median. Scores for the reassessments and transfer sessions also are displayed. (From Knecht et al. 2004.)

improved in chronic stroke patients with non-fluent aphasia, However, in another study bromocriptine was not superior to placebo in stroke patients with non-fluent aphasia.

Some preliminary evidence coming from an open-label study with four patients indicated that ► amantadine might be effective in non-fluent speech.

Noradrenergic Substances

Healthy Subjects Several studies have demonstrated that d-amphetamine facilitates verbal memory performance, improves information processing and enhances new word learning. These effects were independent of drug-induced increases of blood pressure and heart rate. It seems that there is an individual optimal d-amphema-tine dose, since an inverted U-shaped relationship was observed between amount of d-amphetamine and working-memory processing efficiency. This suggests that high doses of d-amphetamine can even impair memory processing. Another factor that influences the results of d-amphetamine application is the cognitive performance at baseline. The drug was effective in individuals with a low working-memory capacity, but deteriorated performance in subjects with high working-memory capacity at baseline.

Patient Groups Two studies performed in stroke patients with aphasia suggested a beneficial effect of d-amphetamine. However, when patients were re-evaluated 6 months later, the effect was gone.

Cholinergic Substances

Healthy Subjects There are no studies that explicitly investigate the effect of cholinergic transmission on verbal learning.

Patient Groups In one study with 26 stroke patients, donepezil reduced the severity of aphasia and improved picture naming to stronger degree than placebo.

Piracetam

The mode of action is unknown, but there is some evidence that ► piracetam enhances glucose utilization and cellular metabolism in the brain.

Healthy Subjects There are no studies available that investigated piracetam effects on verbal learning.

Patient Groups Placebo-controlled trials in subacute stroke patients (n = 203) indicated that application of 4.8 mg piracetam daily reduced aphasic symptoms as evaluated by the Aachener Aphasie Test (Greener et al. 2001). Treatment duration was at least 6 weeks. A positron emission tomography (► PET) study demonstrated increased activity in speech-relevant brain areas as the left transverse temporal gyrus, Wernicke's area and Broca's area in the piracetam group, but not in the placebo group.

Conclusions

Currently, evidence is limited regarding a positive effect of psychoactive drugs that enhance neurotransmission or support cell metabolism. In healthy subjects, the most convincing and most consistent studies were found for the improvement of cognitive function and verbal learning by D-amphetamine and levodopa. Results obtained in elderly healthy subjects might suggest that ageing per se is associated with a subclinical reduction of neurotransmission and that substitution of dopaminergic, cholinergic (and potentially also serotonergic) neurotransmission can be more beneficial than in young subjects.

In patients, acquisition of new abilities or re-acquisition of old abilities is more difficult. We do not know enough about the consequences of brain lesions, e.g., stroke or traumatic brain injury, on neurotransmission. Therefore, it is still unpredictable who might benefit from which type of enhancement of neurotransmission. Hopefully, brain imaging techniques will help to develop hypothesis-driven concepts of specific neuropharmacological interventions. Until then, one can recommend piracetam for treatment of post-stroke aphasia and levodopa for recovery of motor functions.

Floel A, et al. (2005b) Dopaminergic effects on encoding of a motor memory in chronic stroke. Neurology 65(3):472-474 Greener J, Enderby P, Whurr R (2001) Pharmacological treatment for aphasia following stroke. Cochrane Database Syst Rev CD000424 Knecht S, Breitenstein C, Bushuven S, Wailke S, Kamping S, Floel A, Zwitserlood P, Ringelstein EB (2004) Levodopa: faster and better word learning in normal humans. Ann Neurol 56(1):20-26 Liepert J (2008) Pharmacotherapy in restorative neurology. Curr Opin

Neurol 21(6):639-643 Martinsson L, Hardemark H, Eksborg S (2007) Amphetamines for improving recovery after stroke. Cochrane Database Syst Rev CD002090.

Plewnia C, Hoppe J, Cohen LG, Gerloff C (2004) Improved motor skill acquisition after selective stimulation of central norepinephrine. Neurology 62:2124-2126 Scheidtmann K, Fries W, Muller F, Koenig E (2001) Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomized, double-blind study. Lancet 358:787-790

Zittel S, Weiller C, Liepert J (2008) Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair 22(3):311-314

Verum Definition

Literally, "the truth'' - a drug with a known and established effect on psychomotor function - which when included as one of the treatment conditions in a study of the effects of an unknown drug serves to demonstrate the sensitivity of the selected psychometric tests to drug-induced changes.

Cross-References

► Acetylcholinesterase and Cognitive Enhancement

► Cognitive Enhancers: Neuroscience and Society

► Cognitive Enhancers: Novel Approaches

► Cognitive Enhancers: Role of the Glutamate System

► Declarative and Nondeclarative Memory

► Long-Term Potentiation and Memory

► Psychomotor Performance (human)

► Psychomotor Stimulants

► Short-Term and Working Memory in Humans

► Spatial Learning in Humans

► Synaptic Plasticity

References

Floel A, Breitenstein C, Hummel F, Celnik P, Gingert C, Sawaki L, Knecht S, Cohen LG (2005a) Dopaminergic influences on formation of a motor memory. Ann Neurol 58(1):121-130

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