Effects of methylphenidate on working memory in pigeons

To assess the effects of methylphenidate on working memory, pigeons were trained in a delayed matching-to-sample task. Delay interval duration (0.2, 1, 3, 6, or 12 sec) was varied within sessions in order to separate delay-dependent from delay-independent effects of the drug on performance. A reduction in the sample response requirement from five responses to one response effectively reduced attention to the stimulus and impaired overall accuracy. Methylphenidate was administered in doses of 0.0 (saline control), 0.25, 2.5, and 10 mg/kg. Relative to performance with saline, accuracy was significantly reduced with 10 mg/kg methylphenidate to the same extent in both fixed ratio (FR) 1 and FR 5 conditions. The smaller doses had no effect, and there was no evidence that accuracy improved with drug administration. Intercepts and slopes of exponential functions fitted to measures of discriminability plotted as a function of delay showed that methylphenidate affected delay-independent aspects of performance (initial discriminability), but not delay-dependent aspects (rate of forgetting).     

Methylphenidate reduces abnormalities of stimulus classification in adolescents with attention deficit disorder.

Forty-eight adolescents with attention deficit disorder (ADD) received placebo and methylphenidate (M = 35.21 mg/day) for 3 consecutive weeks each. ADD patients who received placebo in the first phase of treatment were compared with unmedicated normal adolescents. ADD and normal adolescents did not differ in slope of reaction time as a function of memory load in a Sternberg (1969) memory task. These results may be interpreted as reflecting normal rates of memory search in ADD. However, in comparison with normal subjects, ADD subjects made disproportionately more errors to targets and lacked faster latencies of the P3b component of event-related potentials for targets than nontargets. These findings suggest abnormalities in stimulus classification. Methylphenidate did not affect ADD patients' rates of memory search, but it did reduce misclassifications of targets at high memory loads. The drug also evoked the normal pattern of slower P3b latencies for nontargets by shortening latencies for targets. Thus the stimulant reduced ADD adolescents' abnormalities in stimulus classification.     

An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD)

Twenty-four adults (24 to 53 years old) with Attention-Deficit/Hyperactivity Disorder (ADHD), Combined Type, were studied in a double-blind, placebo-controlled, crossover study of Pycnogenol and methylphenidate. Pycnogenol is an antioxidant derived from the bark of the French maritime pine tree. Methylphenidate is a standard pharmaceutical intervention for ADHD. Anecdotal reports suggest that Pycnogenol improves concentration in adults with ADHD without adverse side effects. Participants received Pycnogenol, methylphenidate, and placebo, each for three weeks, in a randomized and counterbalanced order. Although ADHD symptoms improved during treatment, neither methylphenidate nor Pycnogenol outperformed the placebo control, as measured by self-report rating scales, rating scales completed by the individual's significant other, and a computerized continuous performance test. The conservative dosage levels and relatively brief length of treatment may have contributed to the absence of significant differences among treatment conditions. Implications for future research are noted.     

Is an epigenetic switch the key to persistent extinction?

Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories.     

Relative efficacy of methylphenidate and behavior modification in hyperkinetic children: An interim report

Children reported to be hyperactive in school and with behavior difficulties at home were randomly assigned to methylphenidate, behavior therapy and placebo, or behavior therapy with methylphenidate for an 8-week period. Rating scales were obtained from teachers and parents. Independent blind observers rated childrens' classroom behavior on a weekly basis. A behavior therapy program was implemented in the home and at school. Methylphenidate dosage was individualized. Ratings of behavior deviance were significantly reduced by all treatments. However, a significant advantage for the groups receiving methylphenidate was found over the group receiving behavior therapy and placebo. No significant differences between methylphenidate alone and methylphenidate combined with behavior therapy were obtained. Global ratings of improvement done by teachers favored the combined treatment of behavior therapy and methylphenidate over behavior therapy and placebo. No differences among treatments were found in the mothers' global ratings of improvement. The results indicate that though all three treatments were effective, methylphenidate was significantly superior to behavior therapy alone.This study was supported in part by grant MH 18579, and by grant No. 3-621 from the Long Island Jewish-Hillside Medical Center. The authors wish to thank the behavior therapists, Drs. Jeffrey Felixbrod and Marion Pheterson, as well as Ms. Patricia Ramsey, who was responsible for data analysis.     

Context Memory in Korsakoff’s Syndrome

Memory for contextual information and target-context integration are crucial for successful episodic memory formation and are impaired in patients with Korsakoff's syndrome. In this paper we review the evidence for the notion that a context memory deficit makes an important contribution to the amnesia in these patients. First, we focus on anterograde memory for contextual (spatial and temporal) information. Next, the use of contextual cues in memory retrieval is examined and their role in retrograde amnesia and confabulation. Evidence on the role of contextual cues and associations in working memory is discussed in relation to the underlying neurocognitive mechanisms and their dissociation from long-term encoding. Finally, we focus on implicit learning of contextual information in Korsakoff patients. It can be concluded that Korsakoff patients are impaired in the explicit processing of contextual information and in target-context binding, both in long-term (retrograde and anterograde) memory and in working memory. These results extend the context memory deficit hypothesis. In contrast, implicit contextual learning is relatively preserved in these patients. These findings are discussed in relation to evidence of dysfunction of the extended diencephalic-hippocampal memory circuit in Korsakoff's syndrome.     

Prepotent response inhibition predicts treatment outcome in attention deficit/hyperactivity disorder

Objective: Inhibition deficits, including deficits in prepotent response inhibition and interference control, are core deficits in ADHD. The predictive value of prepotent response inhibition and interference control was assessed for outcome in a 10-week treatment trial with methylphenidate. Methods: Thirty-four children with ADHD (ages 8–12) received 10 weeks of methylphenidate treatment. At pretest prepotent response inhibition was assessed using the Stop-Signal Task; interference control was assessed using the Stroop Color-Word task. Methylphenidate was individually titrated to an optimal dose. Treatment outcome was assessed by parent- and teacher-rated ADHD behavior. Results: Only stop-signal reaction time of the Stop-Signal Task was a significant predictor of parent-rated levels of inattention and hyperactivity/impulsivity at outcome. Children with lower levels of inhibition showed worse outcome after 10 weeks of treatment, independent of medication dose. Conclusions: Low levels of prepotent response inhibition are associated with worse response to treatment with methylphenidate. Prepotent response inhibition may be an intermediate phenotypical predictor of treatment outcome.     

Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats

Recent pre-clinical research has indicated that chronic treatment with methylphenidate (Ritalin^®) in young animals can result in lasting and potentially detrimental alterations in brain function that can persist into adulthood. Chronic methylphenidate-induced neuronal alterations may result in behavior and cognitive deficits that include increases in behavioral responses and impairment in recognition memory. This study compared the cognitive consequences following chronic treatment with two doses (5 and 10 mg/kg) of methylphenidate on recognition and spatial memory in adult male Long-Evans rats using an established oral dosing procedure. The animals were then tested in the Object Recognition test at 14 days post treatment and the Object Placement test at 21 days post treatment. The results indicate that repeated exposure to oral methylphenidate impaired the performance of rats in these tests. The current findings add to recent research demonstrating negative consequences in rats pre-treated with methylphenidate, and extend previous findings to include deficits in spatial recognition memory.     

Latent memory for sensitization in Aplysia

In the analysis of memory it is commonly observed that, even after a memory is apparently forgotten, its latent presence can still be revealed in a subsequent learning task. Although well established on a behavioral level, the mechanisms underlying latent memory are not well understood. To begin to explore these mechanisms, we have used Aplysia, a model system that permits the simultaneous study of memory at the behavioral, cellular, and molecular levels. We first demonstrate that robust latent memory is induced by long-term sensitization training of the tail-elicited siphon withdrawal reflex. It is revealed by its ability to facilitate the subsequent induction of three mechanistically distinct temporal domains of sensitization memory: short-term, intermediate-term, and long-term memory. Under our training conditions, the latent memory persists for at least 2 d following the decay of original memory expression but appears to be gone by 4 d. Interestingly, we also find that latent memory is induced even in the absence of overt memory for the original training. These findings now permit the analysis of the cellular and molecular architecture of a common feature of learning and memory.     

Methylphenidate and stimulus control of avoidance behavior

The introduction of a warning signal that preceded a scheduled shock modified the temporal distribution of free-operant avoidance responses. With response-shock and shock-shock intervals held constant, response rates increased only slightly when the response-signal interval was reduced. The result is consistent with Sidman's (1955) findings under different conditions, but at variance with Ulrich, Holz, and Azrin's (1964) findings under similar conditions. Methylphenidate in graded doses increased response rates, modifying frequency distributions of interresponse times. Drug treatment may have disrupted a "temporal discrimination" formed within the signal-shock interval. More simply, methylphenidate influenced response rates by increasing short response latencies after signal onset; this effect was more prominent than the drug's tendency to increase the frequency of pre-signal responses. When signal-onset preceded shock by 2 sec, individual differences in performance were marked; methylphenidate suppressed responding in one rat as a function of increasing dose levels to a greater degree than in a second animal, but both subjects received more shocks than under control conditions.     

PKA and PKC are required for long-term but not short-term in vivo operant memory in Aplysia

We investigated the involvement of PKA and PKC signaling in a negatively reinforced operant learning paradigm in Aplysia, learning that food is inedible (LFI). In vivo injection of PKA or PKC inhibitors blocked long-term LFI memory formation. Moreover, a persistent phase of PKA activity, although not PKC activity, was necessary for long-term memory. Surprisingly, neither PKA nor PKC activity was required for associative short-term LFI memory. Additionally, PKA and PKC were not required for the retrieval of short- or long-term memory (STM and LTM, respectively). These studies have identified key differences between the mechanisms underlying nonassociative sensitization, operant reward learning, and LFI memory in Aplysia.     

Learning in a simple motor system

Motor learning is a very basic, essential form of learning that appears to share common mechanisms across different motor systems. We evaluate and compare a few conceptual models for learning in a relatively simple neural system, the vestibulo-ocular reflex (VOR) of vertebrates. We also compare the different animal models that have been used to study the VOR. In the VOR, a sensory signal from the semicircular canals is transformed into a motor signal that moves the eyes. The VOR can modify the transformation under the guidance of vision. The changes are persistent and share some characteristics with other types of associative learning. The cerebellar cortex is directly linked to the VOR reflex circuitry in a partnership that is present in all vertebrates, and which is necessary for motor learning. Early theories of Marr, Albus, and Ito, in which motor memories are stored solely in the cerebellar cortex, have not explained the bulk of the experimental data. Many studies appear to indicate a site of learning in the vestibular nuclei, and the most successful models have incorporated long-term memory storage in both the cerebellar cortex and the brainstem. Plausible cellular mechanisms for learning have been identified in both structures. We propose that short-term motor memory is initially stored in the cerebellar cortex, and that during consolidation of the motor memory the locus of storage shifts to include a brainstem site. We present experimental results that support our hypothesis.     

Self-control in hyperactive boys in anger-inducing situations: Effects of cognitive-behavioral training and of methylphenidate

The effects of cognitive-behavioral intervention and methylphenidate on anger control in hyperactive boys were investigated in two studies. The anger-inducing stimuli in both studies involved verbal provocation from peers. Study 1 assessed a brief intervention using self-control strategies, while Study 2 employed a longer training period and a control intervention that focused on enhancement of empathy. Both studies included methylphenidate versus placebo comparisons. Methylphenidate reduced the intensity of the hyperactive boys' behavior but did not significantly increase either global or specific measures of self-control. Cognitive-behavioral treatment, when compared to control training, was more successful in enhancing both general self-control and the use of specific coping strategies. There was no advantage for the combination of methylphenidate plus cognitive-behavioral intervention. Implications for intervention to ameliorate the social and interpersonal difficulties of hyperactive children are discussed.Major support for this study was provided by NIDA grant 01070. This research was also facilitated by a grant from the Spencer Foundation. The many training staff and raters, too numerous to mention individually here, are deserving of our special thanks. We also appreciate the cooperation of Marion Jacobs and the staff of the UCLA Psychology Clinic, where the first study was held, and of Howard Adelman and the staff of Fernald School, where the second study was housed; the clinical and administrative skills of Stephen Alkus, who organized the intervention program for the first study; the talents and diligence of David Neswald, who coordinated much of the videotape scoring; and the ever-present contributions of Doris Finck, who also edited and dubbed the video segments. Medication and placebos were supplied by CIBA-Geigy.     

Effects of methylphenidate (Ritalin) on information processing in hyperactive children

The effect of methylphenidate on information-processing efficiency was studied in 12 hyperactive, nonretarded children. Performance on six efficiency tasks (Posner Letter Matching, Reaction Time, Memory Search, Category Verification, Item Identification, and Word-Span) and a general measure of on-task behavior were compared for children receiving methylphenidate or a placebo. The median drug dosage was .38 mg/kg, and it was ingested 1 1/2 hours prior to testing. Children blind to the drug-placebo condition were tested on 4 days. In general, methylphenidate-related improvements in attention to on-task behaviors were found. An overall analysis of processing speed suggested that methylphenidate improved efficiency. Methylphenidate significantly decreased reaction times to simple and complex stimulus arrays; differences due to the drug remained even when on-task attentive behaviors were statistically removed. Significantly fewer identification errors occurred on the Posner task in the methylphenidate condition. Results indicated that methylphenidate improved general attentional behaviors and positively influenced processes that define perceptual efficiency.The first author was supported by NIH Training Grant No. HD 07184. We appreciate the assistance of Dr. Robert Sweeney in carrying out this research and the useful comments of Ellen B. Ryan and Jeanne D. Day.     

Analyses of habituation in Caenorhabditis elegans

Although the nonassociative form of learning, habituation, is often described as the simplest form of learning, remarkably little is known about the cellular processes underlying its behavioral expression. Here, we review research on habituation in the nematode Caenorhabditis elegans that addresses habituation at behavioral, neural circuit, and genetic levels. This work highlights the need to understand the dynamics of a behavior before attempting to determine its underlying mechanism. In many cases knowing the characteristics of a behavior can direct or guide a search for underlying cellular mechanisms. We have highlighted the importance of interstimulus interval (ISI) in both short- and long-term habituation and suggested that different cellular mechanisms might underlie habituation at different ISIs. Like other organisms, C. elegans shows both accumulation of habituation with repeated training blocks and long-term retention of spaced or distributed training, but not for massed training. Exposure to heat shock during the interblock intervals eliminates the long-term memory for habituation but not the accumulation of short-term habituation over blocks of training. Analyses using laser ablation of identified neurons, and of identified mutants have shown that there are multiple sites of plasticity for the response and that glutamate plays a role in long-term retention of habituation training.     

Impairment of single-trial memory formation by oral methylphenidate in the rat

High synaptic concentrations of dopamine and/or norepinephrine can impair the working memory function of the prefrontal cortex and impede attention and learning. Methylphenidate, a dopamine and norepinephrine transporter blocker known to facilitate these cognitive processes at low doses, was hypothesized to interfere with memory storage at doses that may raise concentrations of these neurotransmitters to systemically disruptive levels. In the present experiments, a dose of 10.0mg/kg of this drug was administered to female and male Long-Evans rats using a novel oral administration procedure designed to model the normal mode of delivery to humans. It was found to interfere with single-trial memory acquisition in a delayed object recognition test, a spontaneous learning task that involves no appetitive or aversive motivator. The time that the rats spent in overt exploration of the to-be-remembered objects during the acquisition trial was not affected, suggesting that the drug may have impaired processes of memory formation independently of interference with attention.     

The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.     

Methylphenidate in treatment of adults with Attention-Deficit/Hyperactivity Disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) can persist into adulthood with a continuation of the pattern of childhood psychopathology, cognition and functioning. Adult comorbidities include substance use disorders, antisocial personality disorder, anxiety, and depression. Studies have shown that as in children, methylphenidate treatment for adults can lead to a robust, dose-dependent improvement in ADHD symptoms. Future research is needed to evaluate the safety and efficacy of long-term treatment with methylphenidate (MPH).     

Competition between two memory traces for long-term recognition memory

Previous studies investigating the processes which underlie memory consolidation focused almost exclusively on isolated learning events. Here I studied the competition of two similar memory traces for consolidation non-conditioned recognition memory in adult male C57BL/6JOlaHsd mice using the olfactory cues based social discrimination procedure. My results show that the interference phenomena that cause forgetting are time-dependent, and that retroactive interference can be discriminated from proactive interference. Furthermore, both types of interference can be suppressed by subcutaneous anisomycin treatment immediately after presentation of the interference stimulus. These findings imply that interference phenomena, which result from the competition of two similar memory traces for long-term recognition memory, are related to the progress of memory consolidation and linked to protein synthesis.