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Learning, the foundation of adaptive and intelligent behavior, is based on plastic changes in neural assemblies, reflected by the modulation of electric brain responses. In infancy, auditory learning implicates the formation and strengthening of neural long-term memory traces, improving discrimination skills, in particular those forming the prerequisites for speech perception and understanding. Although previous behavioral observations show that newborns react differentially to unfamiliar sounds vs. familiar sound material that they were exposed to as fetuses, the neural basis of fetal learning has not thus far been investigated. Here we demonstrate direct neural correlates of human fetal learning of speech-like auditory stimuli. We presented variants of words to fetuses; unlike infants with no exposure to these stimuli, the exposed fetuses showed enhanced brain activity (mismatch responses) in response to pitch changes for the trained variants after birth. Furthermore, a significant correlation existed between the amount of prenatal exposure and brain activity, with greater activity being associated with a higher amount of prenatal speech exposure. Moreover, the learning effect was generalized to other types of similar speech sounds not included in the training material. Consequently, our results indicate neural commitment specifically tuned to the speech features heard before birth and their memory representations. mismatch negativity | event-related potentials D uring the fetal period the brain undergoes extensive developmental changes as new synapses are formed (1) and axonal connections between neurons are myelinated (2), facilitating efficient recognition and analysis of complex information. In audition, the functional maturation of the developing nervous system is driven by external input, which is evidenced by, for instance, the rapid reorganization of the auditory cortex by external stimuli soon after the onset of hearing in rats (3). This was suggested to occur in humans usually by the gestational age of 27 wk (4). Such plastic changes in neural assemblies during early development indicate that humans have some learning capability even before birth (5, 6). However, this learning capability may be based predominantly on the discrimination of low-pitched sounds that can penetrate the intrauterine walls (7-9). This lowpitch information may play an important role in early speech discrimination of newborns (10) by facilitating learning to segment incoming speech into meaningful units.Consistent with this, previous behavioral studies have shown that fetuses become attuned to a variety of features of the surrounding auditory environment. For example, fetuses habituate to the native language of the environment or of the mother (11, 12), familiar melodies (13) or fragments of stories heard during pregnancy (14), and even the mother's voice (15). In addition to learning-based habituation involving the laterobasal amygdala only (16), fetuses, for example, react differently to native and nonnative vowels (17) or f...

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Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

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Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

RationaleExperienced cannabis users demonstrate tolerance to some of the impairing acute effects of cannabis.ObjectivesThe present study investigates whether event-related potentials (ERPs) differ between occasional and heavy cannabis users after acute Δ9-tetrahydrocannabinol (THC) administration, as a result of tolerance.MethodsTwelve occasional and 12 heavy cannabis users participated in a double-blind, placebo-controlled, crossover study. On two separate days, they smoked a joint containing 0 or 500 μg/kg body weight THC. ERPs were measured while subjects performed a divided attention task (DAT) and stop signal task (SST).ResultsIn the DAT, THC significantly decreased P100 amplitude in occasional but not in heavy cannabis users. P300 amplitude in the DAT was significantly decreased by THC in both groups. The N200 peak in the SST was not affected by treatment in neither of the groups. Performance in the SST was impaired in both groups after THC treatment, whereas performance in the DAT was impaired by THC only in the occasional users group.ConclusionsThe present study confirms that heavy cannabis users develop tolerance to some of the impairing behavioral effects of cannabis. This tolerance was also evident in the underlying ERPs, suggesting that tolerance demonstrated on performance level is not (completely) due to behavioral compensation.

RationaleMethylphenidate inhibits the reuptake of dopamine and noradrenaline and is used to treat children with attention deficit hyperactivity disorder (ADHD). Besides reducing behavioral symptoms, it improves their cognitive function. There are also observations of methylphenidate-induced cognition enhancement in healthy adults, although studies in this area are relatively sparse. We assessed the possible memory-enhancing properties of methylphenidate.ObjectiveIn the current study, the possible enhancing effects of three doses of methylphenidate on declarative and working memory, attention, response inhibition and planning were investigated in healthy volunteers.MethodsIn a double blind placebo-controlled crossover study, 19 healthy young male volunteers were tested after a single dose of placebo or 10, 20 or 40 mg of methylphenidate. Cognitive performance testing included a word learning test as a measure of declarative memory, a spatial working memory test, a set-shifting test, a stop signal test and a computerized version of the Tower of London planning test.ResultsDeclarative memory consolidation was significantly improved relative to placebo after 20 and 40 mg of methylphenidate. Methylphenidate also improved set shifting and stopped signal task performance but did not affect spatial working memory or planning.ConclusionsTo the best of our knowledge, this is the first study reporting enhanced declarative memory consolidation after methylphenidate in a dose-related fashion over a dose range that is presumed to reflect a wide range of dopamine reuptake inhibition.