Design of Experiments

Fundamentals of a Memory Experiment and Two Manipulations

THE skeleton of the memory experiment should have three phases: a study or acquisition phase, a retention interval, and a test or retrieval phase. Testing acquisition versus retrieval  is a common experimental manipulation. For example, subjects might be required to learn one or more lists of words before drug administration and then asked to recall the material during the period of drug action (table 6). For most drugs, recall would not be impaired, even if the subjects seem to be very drowsy and sedated. In contrast, recall of word lists learned after drug administration would be greatly reduced.

Table 6. Experimental Design to Test for Acquisition versus  Retrieval Deficit

Table 6. Experimental Design to Test for Acquisition versus  Retrieval Deficit
Table 6. Experimental Design to Test for Acquisition versus  Retrieval Deficit

Another manipulation is to test for state-dependent memory  or to control its effects. The most common design has been the 2 × 2 (table 7), in which subjects learn material in either a drug or a placebo state and later try to recall the information in either the same or the opposite state.82There would thus be four groups of subjects assigned to the following treatment conditions during acquisition and recall: drug–drug, drug–placebo, placebo–drug, and placebo–placebo. Symmetrical state-dependent memory would be demonstrated if the drug–drug and placebo–placebo groups recalled better than the drug–placebo and placebo–drug groups. Asymmetrical state-dependent memory would be demonstrated if the drug–placebo group recalled less than the drug–drug group. The subject is further complicated by the sensitivity of state-dependent effects to the type of memory tasks used. 117,118 

Table 7. Experimental Design for State-dependent Memory

Table 7. Experimental Design for State-dependent Memory
Table 7. Experimental Design for State-dependent Memory

The Definitive Standard

For drug studies, the definitive standard design is the randomized, prospective, concurrent assignment of subjects to the drug and placebo groups, under double-blind conditions, in which neither the subjects nor the researchers can determine which treatment is being used. Unfortunately, there are circumstances in which this strategy may not be feasible. It may not be possible to “blind” patients to some treatments that have recognizable effects, e.g. , treatment with general anesthetics. It may not be ethical to use a placebo group, e.g. , in surgical and invasive procedures that require a sham procedure, or if there is a risk of exacerbation of illness.

Comparison Groups

Investigation of drug effects has one significant design advantage over many studies of cognitive impairments: the possible use of pretreatment and posttreatment comparisons . Premorbid assessment is usually not available when impairment is caused by trauma or disease. In studying the effects of drugs, however, it is possible to compare the behavior of the subject, both before and after administration of the drug, allowing unambiguous attribution of behavioral changes to the influence of the drug. A second fundamental design component is the use of a nondrug (placebo) control  sample in which subjects receive identical treatment except for administration of the drug. Both design elements are essential. Pretreatment–posttreatment comparisons alone are inadequate because practice on experimental tasks, environmental influences, fatigue, and a host of other factors can change behavior over time and affect the comparison of performance before and after drug administration. Comparison of treatment and control groups alone is also inadequate unless it can be established that the groups are equivalent before treatment. Otherwise, an observed difference could have existed regardless of treatment or a true difference could have been masked by different baseline measurements between groups.

Inclusion of a placebo control group is particularly important in assessing the influence of a drug on learning and performance. In several of our studies, we have noted little or no difference in performance between pretreatment and posttreatment with an active drug.95These failures to find significant differences might be incorrectly attributed to a lack of a treatment effect except that the control group performance showed marked improvement in the same task from pretreatment to posttreatment. For example, figure 10shows performance in learning sequences of 15 digits. Placebo subjects demonstrated an immediate improvement from their first test to their second, with no further improvement. For diazepam-treated subjects, the improvement was delayed, with greater delays for higher doses. In other words, the drug suppressed the usual performance improvement that occurs with repeated practice, thereby showing a reduction in new learning caused by the drug. Thus, a placebo-controlled design is essential to assess practice effects. Otherwise, drug effects may be confounded with practice effects.

Fig. 10. Mean number of digits recalled at intervals before and after diazepam and placebo treatments. Zero was the time of drug administration. A different random 15-digit number was presented each time. The score represents the mean of three trials. From Ghoneim et al.  95; used with permission.

Fig. 10. Mean number of digits recalled at intervals before and after diazepam and placebo treatments. Zero was the time of drug administration. A different random 15-digit number was presented each time. The score represents the mean of three trials. From Ghoneim et al.  95; used with permission.

An “active” control  group, e.g. , a group treated with a benzodiazepine when investigating a new potential amnesic agent, may also be included in the design. This would be advantageous when the sensitivity of the tests used has not been established, as a safeguard against false-negative results, and as a standard for comparison with the new drug–induced effects.

Issues Related to Studies of the Long-term Effects of Drug Abuse

Methodologic flaws are common in studies of the effects of drug abuse on cognition. The majority of the studies have not included measures of premorbid cognitive function, raising the possibility that differences between drug users and controls existed before the onset of drug use, rather than being caused by drug use. Some studies have not included a control group of nonusers. To convincingly demonstrate cognitive deficits in drug users, comparison with an appropriately matched control group is essential. Many studies have involved sample sizes too small to provide valid conclusions. These methodologic flaws can be avoided by measuring pre-morbid cognitive function, including a control group, and using a large sample size. To control for the possibility that drug abusers were poorer mentally and intellectually before starting their abuse, Block et al.  40pioneered matching drug users and nonusers on their previous scores during the fourth grade on the Iowa Test of Basic Skills achievement tests. 119Another methodologic constraint in studies of recreational drug users is the fact that most subjects use more than one drug. It is therefore important when investigating one specific drug to take a careful drug history and set strict maximal limits on the frequency and quantity of use of other drugs when recruiting subjects.

Pharmacologic Factors

Dose–Response Effects

One of the most elementary considerations in pharmacology is the relation between the size of the dose administered and the size of the measured behavioral response. However, the simple assumption that larger doses result in greater effects than smaller doses may not be true. For example, midrange doses of physostigmine exert positive effects on memory performance, whereas higher and lower doses impair it. 120,121Other “memory-enhancing” drugs, such as epinephrine and other endogenous stress hormones, may also show similar “inverted-U” dose–effect curves. 122–125This shape of the curve has been variously explained as being due to the high doses inducing hyperstimulation effects, producing state dependency, or facilitating learning of other interfering material. 126Other drugs may show a biphasic action on behavior, with small doses improving and larger doses impairing behavior. 127 

Effects of Repeated Administration


Tolerance  has been defined as a shortened duration and decreased intensity of drug effects after repeated administration. Short-term tolerance to psychoactive drugs may develop within the time course of a single dose. Behavioral impairment may recover toward baseline levels while the plasma concentrations of the drug remain relatively high. This has been demonstrated for many drugs, including barbiturates, benzodiazepines, caffeine, and cocaine. 128–130The rapid distribution of a drug in and out of the brain may produce the same effects as short-term tolerance. Experiments with steady state blood concentrations may be needed to distinguish between distribution effects and short-term tolerance.

With repeated administration, long-term tolerance to the behavioral effects of psychoactive drugs can develop. 131,132The opposite effect to tolerance has occasionally been reported. Repeated administration of cocaine may produce sensitization  or heightened responses. 133,134 

Pharmacokinetic–Pharmacodynamic Relations

The relative ease of measuring a psychotropic drug concentration in blood (or other body fluids) compared with objective dynamic measurements of memory or other central nervous system (CNS) effects has led many to assume that blood concentrations are synonymous or linearly related to drug effects, which may not be true. If a continuous or repeatable discrete measure of a drug effect can be obtained with concurrent measurement of drug blood concentrations, it is possible to develop pharmacokinetic–pharmacodynamic (PK-PD) modeling concepts to characterize relevant parameters that quantify drug effects. 135There are several advantages for studying PK-PD relations 136,137: (1) It allows more complete understanding of the determinants of drug action, including phenomena such as distributional delay of effect, formation of active metabolites, and short-term tolerance. (2) It quantitates the effects of the drug on the brain by calculating values for parameters such as Cp50AMNand Cp50SED, which represent the plasma drug concentrations required to produce one half of maximal amnesia and sedation. 138As valid measures of intrinsic drug potency and brain sensitivity within an individual, those parameters allow exploration of the psychotropic differences between drugs and explanations of effects of factors such as aging and drug–drug and drug–disease interactions on the drugs’ actions. (3) The information would make it possible to design optimal infusion schemes for drugs during conscious sedation and anesthesia or during investigations of their behavioral effects. (4) It provides a rationale for monitoring drug plasma concentrations as indicators of clinical efficacy or toxicity and use for medicolegal purposes.

Several steps are involved in studying the PK-PD relation and evaluating drug action: (1) Pharmacokinetics  describe and predict the time course of concentrations in body fluids, usually blood (fig. 11). Arterial blood sampling allows for the calculation of accurate data during drug distribution and the rate of blood–brain equilibration. 139It is the preferred site because most of the studies in the literature evaluate the effects of single bolus doses or relatively short infusions and are performed during the distribution/redistribution phase. The issue of plasma protein binding is also of importance 140,141because the unbound (free) drug in plasma is presumed to represent the drug fraction that is available for transport across the blood–brain barrier. (2) Pharmacodynamics  describes the time course and intensity of drug effects (fig. 11). This is the difficult step and is the reason for the deficiency of adequate studies of the pharmacokinetic–amnesic relation for drugs. The behavioral tests must be short, amenable to frequent repetitions, and sensitive to low drug doses and concentrations. The brevity of the tests reduces subjects’ fatigue, and the test sensitivity allows determination of memory function over a wide range of drug concentrations. We developed in our laboratory the use of a 15-digit number serial learning task, repeated over three trials for such studies.95The task is sensitive, short (approximately 3.5 min), and can be administered as frequently as desired to correspond to changing drug concentrations. The task may also be administered several times before the actual study to reduce improvement in performance over time. There is virtually no limit to the numbers that can be generated by a computer, unlike words or pictorial lists. To compensate for any residual practice effects, one may use a placebo correction. Changes over baseline scores after administration of active medication are corrected by subtraction of scores at corresponding times after placebo administration. (3) PK-PD modeling  describes the relation between the dose (concentration) and its effects. Data should be obtained from repeated and simultaneous sampling over a wide range of drug concentrations. A mathematical model is developed that fits the data and allows inference of the effect site concentrations based on plasma concentrations. Various PK-PD models may be used. 135–137,142The most appealing is the sigmoid Emaxmodel, because of its similarity to the receptor binding model. Interpretation of the concentration–effect relation can be complicated by the lack of a temporal relation between the two variables, so-called hysteresis. Two types of cognition–blood drug concentration curves may be found (fig. 11). The drug effect may decrease with time for the same drug concentration, described as clockwise hysteresis as shown by the arrows in figure 11. This may be caused by tolerance (short-or long-term), progressive learning of the task, and the presence of active antagonistic metabolites. 143,144It is not possible to separate tolerance from learning without a placebo control. The formation of active antagonistic metabolites is rare, but there are a few examples of metabo-lites that alter the dynamics of the parent drug by modifying its kinetics, e.g. , 5-hydroxy-pentobarbital. 144The presence of clockwise hysteresis has some important practical applications. Medicolegally, blood concentrations may not adequately predict impairments from these drugs.

Fig. 11. Definitions of pharmacokinetics and pharmacodynamics and types of hysteresis.

Fig. 11. Definitions of pharmacokinetics and pharmacodynamics and types of hysteresis.

Another type of drug concentration–effect curve can demonstrate anticlockwise hysteresis. The effect of the drug increases with time for a given drug concentration, which, when taken sequentially, produces a direction that is counterclockwise. A common cause is the delay for a drug to be transported from the systemic circulation (sampling site) to its site of action and then to elicit a measurable response. This type of hysteresis may be missed because of infrequent early sampling and assay of the drug in venous rather than arterial blood. 139,142Another cause is the production of active metabolites from the parent drug. These would have maximum concentrations and a combined peak activity at some later time compared with the parent drug concentration. 145Other uncommon causes are delayed drug action, drugs working through a cascade reaction, and short-term sensitization or up-regulation of receptors.

The applicability of mathematical models to describe the pharmacodynamic response becomes questionable when hysteresis occurs. The hysteresis must be collapsed or removed. One frequently used approach assumes an effect compartment 146to correlate memory changes with changes in the blood concentrations of drug. It can be thought of as the kinetically defined biophase of the CNS actions of the drug. The drug effect is directly related to its concentration at the receptor site. A link model 142describes the transfer between the plasma and effect compartments. The equilibration delay between the compartments is characterized by the rate constant ke0with units of reciprocal time, which governs the transfer of drug.

Specificity of Memory Effects

All of the drugs currently available for human use that are capable of producing amnesia also cause sedation. There is no drug that only affects memory. For theoretical and clinical reasons, it is important to separate the effects on memory systems from impairments in attention, arousal, or mood. It is also important when investigating potential memory-enhancing drugs to separate effects on alertness, attention, and fatigue from genuine effects on learning and memory. The general consensus is that drug-induced amnesia is independent of sedation. Table 8summarizes the approaches that have been used to dissociate the effects on memory and sedation. One method is to study two or more drugs that produce the same effects on sedation but different effects on memory. For example, Green et al.  147compared chlorpromazine with lorazepam in doses that produced equal degrees of sedation but found that memory was impaired only by lorazepam. Curran et al.  148compared the effects of diphenhydramine with those of scopolamine and lorazepam. In the doses used, the three drugs produced similar levels of sedation, but the antihistamine did not impair memory. It should be noted, however, that because tests of sedation and memory may vary in difficulty, dissociations of this kind do not provide compelling evidence for independence between the two behaviors.

Table 8. Methods for Dissociating the Effects on Memory and Sedation

Table 8. Methods for Dissociating the Effects on Memory and Sedation
Table 8. Methods for Dissociating the Effects on Memory and Sedation

Another method of demonstrating the specificity of the memory effects of drugs is to study the rates of development of tolerance to the actions of the drug. Overall, the evidence is that tolerance develops to sedative effects much faster than it develops to memory effects. For example, tolerance develops to the sedative effects of diazepam after its 3-week administration to healthy volunteers but not to its amnesic effects. 149Tolerance develops to the memory effects of alprazolam after 8 weeks of treatment in patients 150and at least 6 months after treatment with other benzodiazepines. 151,152An alternative way of dissociating the two effects would be to show differential reversal of amnesic and sedative effects by an antagonist. Use of small doses of flumazenil 153or pretreatment with flumazenil before administration of a benzodiazepine 154results in reduction of sedative effects without relief of memory impairment. A fourth method of dissociation is through demonstration of different dose–response curves for sedation and amnesia. 155–157Using the auditory event-related potential with different groups of drugs that produced equivalent sedative but differing amnesic effects, Curran et al.  148and Veselis et al.  158(also more recently, Veselis RA, Reinsel RA, Feshchenko AV, Johnson R: Thiopental and propofol effects on memory are dissociable by event related potentials. Poster presented at the 50th Annual Meeting of the Association of University Anesthesiologists, Milwaukee, Wisconsin, May 1–3, 2003) reported that early components of the event-related potential were affected similarly by sedatives, whereas later components were affected more by amnesics. Statistical methods are also important for showing this dissociation. Analysis of covariance can be used to separate effects attributable to sedation. However, covariance assumes a linear relation between variate and covariate, and the relation between memory and sedation maybe more complex than that. 159,160More recently, Veselis et al.  138used several statistical scaling procedures, normalization of drug concentration levels, and arbitrary standards of memory and sedation to compare memory performance after equisedative doses of four drugs (midazolam, propofol, thiopental, and fentanyl). These drugs exhibited very different sedation and amnesia relations for the same criteria of felt sedation and objective memory impairment. For example, propofol at low serum concentrations showed a high likelihood of exceeding the criterion of memory impairment well before it met the criterion of sedation. In contrast, fentanyl exceeded the sedation criteria and showed low probability of amnesia for the same concentration range (fig. 12). Finally, Eger’s group has demonstrated chemical compounds that suppress learning without causing sedation in animals 161–163and shown that the two functions need not be inseparable.

Fig. 12. Probability of amnesia being present as a function of normalized serum concentration using a logistic regression (LR) model. Amnesia  is defined as recognition of fewer than half of the words presented. Confidence intervals for Cp50AMNare given as horizontal bold lines  for each drug. The vertical line  at x = 5 represents the Cp50SED.From Veselis et al.  138; modified with permission.

Fig. 12. Probability of amnesia being present as a function of normalized serum concentration using a logistic regression (LR) model. Amnesia  is defined as recognition of fewer than half of the words presented. Confidence intervals for Cp50AMNare given as horizontal bold lines  for each drug. The vertical line  at x = 5 represents the Cp50SED.From Veselis et al.  138; modified with permission.

Brain Imaging


Functional neuroimaging opens a window to view the brain at work. It provides a unique in vivo  opportunity to study the neurobiology of human memory and its functional and neural architecture. It is also a rapidly developing, highly interdisciplinary and complex technical field, requiring multidisciplinary teams of scientists (in physics, radiologic science, mathematics, statistics, computer programming, engineering, cognitive neuroscience, and medicine). 164Brain imaging has been used relatively recently to investigate several areas of memory, including the nature and function of components of the memory systems and regional cerebral blood flow changes associated with performance of memory tasks under the influence of drugs. 165–169Many new insights have been gained, and these in turn promise a deeper understanding of the foundations of memory.


The two major techniques are positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Both measure neuronal activity by assessing changes in local cerebral blood flow. For the PET method, a radioactive tracer is injected immediately before the start of a cognitive task. The radiotracer accumulates in the brain in direct proportion to the local blood flow. For the most widely used fMRI method, called BOLD (blood oxygen level dependent), images are generated through changes in blood oxygenation that accompany neuronal activity without the need for a radioactive tracer. When neural activity increases, local blood flow and oxygen consumption increase, but the former increases more than the latter, resulting in a local increase in the amount of oxygenated blood and a net decrease in deoxyhemoglobin. Deoxyhemoglobin is paramagnetic, resulting in local magnetic field changes that provide the imaging contrast. 170 

Research Design

At least two issues need to be considered when planning neuroimaging studies, as discussed here.

Control of Other Mental Activities during the Scanning Period.

If the researcher wants to construct, for example, an episodic memory retrieval task in which the subject recalls orally during scanning the words of a list learned earlier, changes in blood flow should be the result of memory retrieval and not due to other mental activities. A common strategy is to use a paired image subtraction design. In addition to the scan during the word list recall, another scan is taken during a control condition that shares the same mental operations except for those of explicit retrieval. For example, we asked the subjects in our laboratory 171to repeatedly count “1, 2, 3, . . .” aloud at a rate of approximately 1 number/s, which is expected to match the rate of verbal output during the memory test. This repetitious rehearsal in short-term memory of a vastly over-learned and automatized sequence should minimize episodic memory retrieval. Subtracting the blood flow maps during the control state, which accounts for speech activity, from those during the activation state would identify the regions that are involved in the desired memory task. This subtraction method has been criticized. There is no guarantee that the performance in the experimental task will differ from the control state in only one way. Also, the addition of the extra processing component per se  in the experimental task may affect processes common to the experimental and control tasks. If so, it would not be possible to subtract them out. 172Nonetheless, the majority of results from studies of memory have been generated by this method, and robust and reliable patterns of activation have been demonstrated. 173 

Some researchers also use a resting state as a baseline. Subjects lie quietly without specific instructions regarding mental activities. Critics argue that the variability in the mental state during such a condition is such that it may not serve a useful purpose. 164In our laboratory, we ask the subjects immediately after the period to describe what they had been thinking to discern differences in mental states between subjects in the experimental and control groups. 174 

Control of Stimulus Presentations Relative to the Scanning Sequence.

The characteristics of the stimulus, its mode of delivery, its timing, and its timing and duration in relation to the scanning periods must be precisely controlled. 175 

Image Acquisition

A widely used PET radiotracer is oxygen-15–labeled water (H215O), which has a half-life of approximately 2 min, allowing a series of injections to be performed every 12–15 min. For each injection, the cognitive task and scanning are performed during the time that the labeled blood perfuses the brain. It provides a 40-s window on brain activity, with a spatial resolution of approximately 6–10 mm. The advantages of PET include relatively silent scanning, accessibility of the patient for monitoring, and the ability to provide quantitative as well as relative measures of blood flow. The latter is important in studies with drugs that may affect global cerebral blood flow, either directly or indirectly, e.g. , via  changes in arterial carbon dioxide tension (Pa CO2). The advantages of fMRI compared with PET include the avoidance of exposure of subjects to ionizing radiation and improved spatial and temporal resolution. Its limitations are confining the subject inside the scanner, with its risks of limited monitoring and claustrophobia in some individuals, acoustic noise, and signal artifact at the base of the brain. 164 

Methods with High Temporal Resolution

Both PET and fMRI have high spatial but poor temporal resolution. Conversely, electroencephalography, event-related potentials, and magnetoencephalography rapidly measure the current flows induced by synaptic activity. Electroencephalography  and event-related potentials  quantify electric potentials with electrodes at the scalp. Magnetoencephalography  is a newer technique in which the magnetic fields associated with current flow within neurons induce a current in a detection coil on the scalp. To pick up these small signals, the detection coils are coupled to a superconductive device within a magnetically shielded room. 164However, the accurate localization of neuronal current flows based on data generated by these methods alone is problematic. Recently, techniques have been developed that use both hemodynamic and electromagnetic measures to arrive at estimates of brain activation with high spatial and temporal resolutions. These methods range from simple juxtaposition to simultaneous integrated techniques. 176 

Image Processing and Analysis

Images are reconstructed before statistical analysis. They are corrected for sources of noise in the signal due to scanner drift or artifacts, are realigned to correct for slight head movement, and may undergo spatial smoothing. 164Usually the subject’s functional results are displayed on his/her own structural magnetic resonance imaging scan; otherwise, images are transformed to a stereotactic coordinate space, based on a common template. 177This is done to counteract individual differences in brain size and gyral anatomy and facilitates group analyses, as well as the communication of results across laboratories. Typically, the comparison of blood flow maps associated with the cognitive task and its control is performed using a t  test, regression, or multivariate statistical approaches. 178,179 

Brief Summary of the Neural Basis of Memory

Tulving et al.  180proposed the hemispheric encoding/ retrieval asymmetry model. According to this model, the prefrontal regions in the left hemisphere tend to be differentially activated during episodic encoding and semantic retrieval, whereas the right prefrontal regions tend to be differentially involved during episodic memory retrieval (fig. 13). Considerable evidence supports this model, 181although some critics have argued that this hemispheric asymmetry seems to depend to some extent on the type of stimuli used. 182,183The latest version of the model acknowledges that the right pre-frontal lateralization of episodic retrieval seems less complete than originally proposed. 184A second general observation of the neuroimaging literature is that prefrontal regions seem to interact with posterior brain regions during memory encoding and retrieval. 173,Episodic encoding  usually involves activation of the left prefrontal, left temporal, and anterior cingulate regions. The left hippocampus is usually involved with verbal material, and the right hippocampus is involved with nonverbal materials. 185–187There are two functional neuroimaging studies that demonstrate that activation of the amygdala at encoding is correlated with later recall of emotional material. 188,189,Episodic retrieval  usually activates the right prefrontal region, the anterior cingulate region, the cerebellum, and the hippocampus. 190,191,Semantic retrieval  is usually associated with activation of the left prefrontal, left temporal, and anterior cingulate regions. 190,192For working memory , the central executive is typically associated with activation of prefrontal regions, the phonologic loop is associated with the parietal regions (for storage) and the Broca area (for rehearsal), and the visuospatial sketch pad is associated with the occipitotemporal, occipitoparietal, inferior prefrontal, and superior prefrontal regions. Object maintenance tends to be left lateralized, and spatial maintenance tends to be to be right lateralized. 193,194,Priming  is accompanied by reductions in the amount of neural activation relative to naive or baseline task performance (fig. 14). Decreased activation bilaterally in occipitotemporal cortical areas is usually associated with perceptual priming, and the left inferior frontal cortex is usually associated with conceptual priming. 191,195,196Last, aversive conditioning  is associated with activation of the amygdala. 197,198,Table 9summarizes these results. It should be emphasized, however, that there are discrepancies and uncertainties about precise anatomic localization of various memory processes. For example, in a review of verbal working memory by Ivry and Fiez, 199Broca area activation was found in only 9 of 12 data sets by different groups of investigators. Neuroimaging is a “noisy” technique, and results obtained in one study may not be replicated in a second. Assumptions that the cognitive tasks used in different studies evaluate the same memory processes may not be certain, and teasing apart the different operations involved in complex mental functions is far from easy.

Table 9. Brain Regions Activated during Learning and Memory

Table 9. Brain Regions Activated during Learning and Memory
Table 9. Brain Regions Activated during Learning and Memory

Fig. 13. Hemispheric asymmetrical involvement of left and right prefrontal cortex during episodic encoding and episodic retrieval. From Nyberg and Cabeza 173; used with permission.

Fig. 13. Hemispheric asymmetrical involvement of left and right prefrontal cortex during episodic encoding and episodic retrieval. From Nyberg and Cabeza 173; used with permission.

Fig. 14. Positron emission tomography scans of three vertical slices through the brain revealed the areas of activation (whitened ) during administration of lists of words. In the unpracticed or naive subject (left column ), the anterior cingulate (top row ), temporal and frontal lobes (middle row ), and right cerebellum (bottom row ) are active, but the practiced subject performs the task with no activation of these areas (middle column ). Introduction of a new list of words reverses these practice-induced changes (right column ). (The reader should refer to the original reference for reviewing the colored pictures). From Posner and Raichle 196; used with permission.

Fig. 14. Positron emission tomography scans of three vertical slices through the brain revealed the areas of activation (whitened ) during administration of lists of words. In the unpracticed or naive subject (left column ), the anterior cingulate (top row ), temporal and frontal lobes (middle row ), and right cerebellum (bottom row ) are active, but the practiced subject performs the task with no activation of these areas (middle column ). Introduction of a new list of words reverses these practice-induced changes (right column ). (The reader should refer to the original reference for reviewing the colored pictures). From Posner and Raichle 196; used with permission.

Network Analyses

The standard subtraction approach to analyzing functional neuroimaging data can be used to identify the brain regions active in certain tasks. However, it does not indicate the functional interrelations between such regions and regions that do not show differential activity but may still be part of the specific functional network. The network approach complements the subtraction approach in characterizing the functionally specialized brain regions and their interactions. 200–202Several procedures have been used to identify the different brain regions and how they interact in a given network model. A commonly used procedure is structural equation modeling  or path analysis. 203Briefly, the following steps are involved: (1) Brain regions differentially activated through subtraction analysis are identified. (2) The regions are linked to each other on the basis of neuroanatomy to create an anatomic network model. (3) Regional cerebral blood flow correlations among the regions are calculated. (4) Structural equation modeling is applied to the regional cerebral blood flow correlations among the regions. The values or weights for the different connections are calculated.


Functional neuroimaging has been used to investigate the normal operations of memory with considerable success. The scope of this work has not been matched by studies in subjects with drug-induced memory changes. Future investigations will no doubt define the neural substrates associated with memory impairment (or enhancement), differentiate between the substrates of sedative–hypnotic effects and amnesic effects, and determine the neuroanatomic signatures of each drug. Potential or currently accepted therapeutic interventions in pathologic states might also be closely examined using neuroimaging.

Overview of Memory-impairing Drugs

A wide variety of drugs impair memory. These include the benzodiazepines, anticholinergic agents, alcohol, anesthetics, barbiturates, cannabis derivatives, β-adrenergic blockers, and others. The benzodiazepines and the anticholinergics have been investigated more than the others. These drugs have a wide diversity of chemical structures, which vary from the monoatomic xenon and the biatomic nitrous oxide to the more complex structure of a benzodiazepine, a barbiturate, or a halogenated volatile anesthetic. Benzodiazepines, barbiturates, and volatile anesthetics act at the γ-aminobutyric acid type A (GABAA) receptors potentiating chloride currents. Xenon, nitrous oxide, and ketamine seem to have their major effects at the N -methyl-d-aspartate receptors. Cholinergic antagonists act at muscarinic receptors. βBlockers act at β-adrenergic receptors. Marijuana acts on cannabinoid receptors. Drugs such as ethanol act on receptors for serotonin, acetylcholine, GABA, glutamate, glycine, and dopamine. Differentiating which receptor is mediating amnesia, subjective experience (sedation, hypnosis, anxiolysis), or other behavioral effects is difficult to assess. However, despite the disparity in molecular structure, selective targets, chemical transmitters, and specific binding areas in the brain, these diverse agents seem to produce similar profiles of memory impairment. It seems that there are multiple pathways to the final effects on memory. This kind of commonality agrees with the current view that memory is a distributed property of cortical systems rather than exclusive to specific areas. 204,205Thus, one brain region may be part of more than one neural network subserving different memory abilities. The general characteristics of drug impairments are displayed in table 10.

Table 10. General Characteristics of Amnesic Drugs

Table 10. General Characteristics of Amnesic Drugs
Table 10. General Characteristics of Amnesic Drugs

Effects on STM versus LTM and Components of Working Memory

Drugs, with the exception of general anesthetics,35,206spare short-term memory (STM) but impair long-term memory (LTM).49,159Therefore, sensitive memory tasks are those that minimize the contribution of STM and maximize the contribution of LTM, e.g. , a test that examines the delayed retention of a relatively long list of items. If immediate recall is tested, the position of the items in the list should be analyzed to exclude those whose performance relies more on STM.

A gradual increase in a general anesthetic dose produces a progressive impairment of STM or working memory until events occurring only 1–2 s before cannot be remembered. 206Learning ceases before loss of consciousness and STM function. A small further increase in anesthetic dose is associated with loss of consciousness. 207Few studies have examined the effects of drugs on components of working memory. Rusted and Warburton 208used dual-task paradigms to investigate the effects of scopolamine. The drug produced impairments of the central executive component, which confirmed earlier observations with the drug.33Gorissen and Ehling 209also used dual-task experiments to test the effects of benzodiazepines. Although dividing attention reduced memory performance, this manipulation was no more disruptive in those given diazepam versus  those given placebo. Both groups of investigators agree that reduced attentional resources due to impairments of the central executive are not sufficient to explain the effects of the drugs on memory. 210 

Effects on Explicit versus Implicit Memory

Drugs act prominently on explicit memory. The effects on implicit memory have not been studied as extensively as with explicit memory, and their results have been conflicting. Most of the studies have investigated the effects of priming. Some studies showed preservation of implicit memory through performance on perceptual tasks such as the word-generation test,67,153,211–215whereas others found impairment. 216–220There are some studies on the effects of drugs on procedural learning as exemplified by motor skill acquisition tasks. The majority suggest preservation, 159but others do not.61It should be remembered that areas of the brain involved in attention and explicit memory may be needed early in skill learning and that these areas become less important as learning proceeds. 221,222Also, a drug effect may be caused by a general slowing of performance related to the sedative effect of the drug.67,153,159In general, it is possible to conclude that impairment of explicit memory usually is more pronounced than that of implicit memory, effortful cognitive processes are much more impaired than automatic ones, there is usually diminished contamination of indirect test performance by explicit memory, and impairments are usually milder in forced-choice recognition than in yes–no recognition. 223(Subjects in a forced-choice recognition, unlike yes–no recognition, where they may not respond if they are not sure, may be guided by the sensation of familiarity and guessing, which may fall within the domain of implicit memory.)

Effects on Explicit Memory

Pharmacologic agents act on episodic memory by impeding the acquisition of new information (this is described by some authors as impairment of encoding or the related components of storage or consolidation of the material to be learned or its transfer from STM to LTM).49,159,224,225How drugs impair acquisition remains to be elucidated. The effects on learning can be easily demonstrated when looking at the shape of the serial position curves of the items being learned. 226One of the most stable characteristics of human learning is the skewed serial position function observed in serial list learning (e.g. , learning a 15-digit sequence over three trials). Under the influence of drugs, the curve becomes perfectly symmetrical (fig. 15). Drugged subjects are forced to rely more on STM (which is not usually impaired) to aid performance, producing an increase in recall of the last few items of the list with the reduced recall from the primary region of the curve, which is obtained from LTM. 226Sometimes the drug effect may not be manifested by a decrease in number of items learned, but a failure to benefit from previous practice.95Therefore, such a performance decrement would be missed if subjects were not repeatedly tested (fig. 12). A performance decrement could also be missed if the subjects are required to attain a specific criterion of learning, thus equating learning between drugged and un-drugged subjects. Then, a later recall would be similar for the two groups.

Fig. 15. Relative proportion of errors across serial position in volunteers treated with placebo or diazepam before and after treatment. From Hinrichs et al.  226; used with permission.

Fig. 15. Relative proportion of errors across serial position in volunteers treated with placebo or diazepam before and after treatment. From Hinrichs et al.  226; used with permission.

Drugs reduce learning and memory of information presented after their administration (anterograde amnesia) but do not alter retrieval of previously stored material. 159Indeed, some drugs produce retrograde enhancement of recall of material acquired before the drug intake. The most probable cause for the latter is that drugged subjects learn so little while under the influence of the drug that there is less interference and therefore less forgetting of the material learned before drug administration. 227Retrieval processes remain intact except with subanesthetic concentrations of general anesthetics.35,36,117,228 

Semantic Memory

Retrieval of semantic information is generally intact as to be expected from testing preexperimental memory.3,159In the common task that assesses semantic fluency, e.g. , “list as many animals as you can in 1 min or as many words beginning with the letter T in 1 min,” drugged subjects often provide lower correct responses compared with a placebo group. However, impairment of semantic memory can only be inferred with confidence if it can be demonstrated that slowing of performance on the task is not due to drowsiness or psychomotor impairment. Better evidence for impairment of semantic memory is a drug-induced increase in the number of incorrect responses. For example, Curran and Morgan 229recently reported that habitual abusers of ketamine made semantic errors while performing a category-generation task (e.g. , for the category fruit : oranges, juice , vitamins , . . .). Such effects are very uncommon. Remembering and knowing are two subjective states of awareness associated with memory. Tulving12proposed that the two states reflect autonoetic and noetic consciousness that respectively characterize episodic and semantic memory systems. 230When subjects are asked to make remember/know judgments indicating whether they have a specific recollection of the presentation of a word during the study phase (remember ; recollection-based recognition) or the word seems familiar (know ; familiarity-based recognition), remember responses are more reduced by drugs as compared with familiarity.49,231,232 

Dose–Effect Functions

Drugs produce dose- and time-related decrements  in episodic memory.95The impairments are also additive, e.g. , taking a benzodiazepine with alcohol 233or with a subanesthetic concentration of an inhalation anesthetic. 217,The elderly are more sensitive  to the behavioral effects of drugs, including memory. The cause may be pharmacokinetic (e.g. , altered rates of distribution or elimination) or pharmacodynamic (e.g. , changes at the receptor or transmitter sites). A third cause is a lower baseline performance of the elderly. Table 11summarizes the memory changes in healthy older adults. 234–237These changes may make equal cognitive decrements in the young and the old more noticeable and more serious in the latter. A modest decline in the cognitive abilities of a young person may have little or no effect on that person’s activities. The same loss in an older individual who is already performing at a lower level or exerting more effort to maintain comparable behavior may have serious objective and clinical consequences. 238As with other CNS-active drugs, tolerance and cross-tolerance  to the effects of the drugs may occur. However, although marked tolerance to the sedative and attentional effects of the benzodiazepines occurs with continued administration, only minor tolerance to the memory effects occurs. 149–152The same pattern has been produced in animals. 239,240There was also no cross-tolerance for memory impairment between ethanol and benzodiazepines. 233,State-dependent drug effects  in humans are controversial. Some studies show state dependency,79,80,228,241but the majority show asymmetrical state-dependent memory effects or equivocal results at best. 117,242 

Table 11. Memory Changes Associated with Aging

Table 11. Memory Changes Associated with Aging
Table 11. Memory Changes Associated with Aging

Subjective Assessment of Memory Function, Real-life Memory, and Memory for Emotional Events

It is not uncommon for subjects’ performance on memory tasks to vary sharply from their own subjective evaluations of their behavior. Patients may not notice or be appropriately concerned about even fairly large impairments in learning and cognitive abilities. 226In the few studies in which tasks involving “everyday memory” demands were used, impairment was found. 243It is expected that amnesia for emotionally significant and stressful events, such as those related to surgery, accidents, or crimes, would be less than those for standard presentations of neutral verbal and visual stimuli. Real-life events maybe subject to a greater encoding elaboration because they are likely to be represented in several sensory modalities and/or evoke release of stress hormones during and after emotionally arousing events, which interact with the amygdala complex to modulate the storage of these events. 244Affective reactions could also take place in the absence of conscious awareness of stimuli. 245Some drugs may produce selective impairments of cognitive functions. For example, in a series of studies by Cahill et al. , 246propranolol impaired subjects’ recall of emotionally arousing but not neutral elements of a story. Using the same task with two patients who had bilateral damage to the amygdala, they found a similar pattern of memory, suggesting that adrenergic function in the amygdala mediates memory for emotional material.

Distortions of Memory

Daniel Schacter 247recently wrote a fascinating book about the errors and imperfections of normal memory, what he called “the seven sins of memory”: transience, absentmindedness, blocking, misattribution, suggestibility, bias, and persistence. The effects of drugs on these normal memory malfunctions have yet to be systematically explored. A recent study by Mintzer and Griffiths 232found that triazolam, in addition to reducing rates of true recognition of studied words, reduced rates of false recognition to nonstudied words. This was consistent with reports of reduced false-recognition rates in patients with organic amnesic syndromes. 248It is possible to conclude that false recognition relies on normal memory mechanisms that are impaired in drug-induced and organic amnesias. Some drugs, such as methamphetamine, benzodiazepines, and marijuana, also produce an increase in intrusions, i.e. , false recall of words that were not on the presented lists. 249–251The drugs may impair formation of new associations between distinct items or between an item and its context, 251may cause irrelevant associations from semantic memory, 250or, as in the case of stimulant drugs, may lead the subjects to adopt a strategy of little inhibition in their recall, “recalling” every word that occurs to them. Nondrugged subjects typically filter their responses, and some correct responses may be inhibited because of a much stricter confidence criterion. 249 

Disease, Drugs, and Memory

Most studies of the behavioral effects of drugs have been conducted using healthy volunteers, but there may be some differences in drug actions related to the pathology in patients. Several diseases are associated with cognitive deficits that may affect the patients’ independence and quality of life. Factors that may influence the level of impairment include the severity of the disease, age at onset, duration, interaction with the effects of aging, and adequate therapeutic interventions preventing and/or controlling further cognitive impairments. Major depression  is associated with memory impairments. Noradrenergic tricyclic antidepressants and serotonergic drugs may be equally effective in treating the depression, but the improvement of memory performance is significantly greater with the latter type of drugs. 252,253This is consistent with the literature on serotonergic neurotransmission and memory. 254In epilepsy,  declarative memory functions show characteristic patterns of impairment when mediotemporal and associated neocortical structures are affected by lesions, ongoing epileptic activity, or the undesired side effects of drugs or operative treatment. The “new” antiepileptic drugs (e.g. , oxcarbazepine, vigabatrim) seem to have no or minor cognitive effects as compared with “older” drugs (e.g. , phenytoin, phenobarbital). 255,256 

Cognitive dysfunction, particularly memory loss, is common in schizophrenia . 257,258Optimal pharmacologic treatment may lead to more effective treatment of the cognitive deficits. 258,259Newer antipsychotic drugs (e.g. , risperidone, olanzapine) ameliorate the cognitive deficits better than conventional agents (e.g. , haloperidol, clozapine). 260,Parkinson disease  is associated with subtle but widespread cognitive impairment. Dopaminergic agents may enhance cognitive functions in some patients and impair them in others, according to the level of dopamine depletion in different parts of the brain. The cognitive changes may also be task specific. 261–263Patients with diabetes mellitus  may have cognitive deficits including those of memory. Although the peripheral neuropathy is widely known, involvement of the CNS is much less recognized in diabetes. 264–267Bent et al.  268recently compared three groups of subjects, insulin-dependent diabetics, non–insulin-dependent diabetics, and a control group, using a battery of cognitive tasks including memory tests. The diabetic patients (combined together) scored at a lower level than the control group, but most of the impairment occurred in the non–insulin-dependent diabetics (particularly those controlled by oral hypoglycemic drugs), perhaps emphasizing the need for effective management of the disease or a deleterious effect of the latter drugs.

Two other endocrine dysfunctions and therapies are associated with cognitive disturbances. In Cushing syndrome, hypersecretion of cortisol  is associated with a high incidence of impairment of memory, hippocampal atrophy, and depression. Pharmacologic use of glucocorticoids is similarly productive of mood change and memory deficit. Reduction of glucocorticoid concentrations, either through discontinuation of steroid treatment or through use of agents that block glucocorticoid synthesis, ameliorates the adverse behavioral effects. 269,Estrogens  have been used to treat some menopausal symptoms such as hot flashes as well as osteoporosis. Studies suggest some beneficial effects on learning and memory in postmenopausal women, although clinical trials in dementias have not been successful. 270–272On the other hand, the use of luteinizing hormone-releasing hormone analogs to treat patients with carcinoma of the prostate has been associated with impaired memory. 273 

Patients with anxiety disorders  may show reductions in cognitive and psychomotor functions. Adequate therapeutic interventions may cause improvements in performance, 274,275contrary to the effects observed in healthy subjects given same drugs. 276However, other investigators found the same effects of drugs in patients and healthy volunteers, with two exceptions. First, the anxiolytic effects of drugs were easily perceived by the patients but have rarely been reported in healthy volunteers. This dimension of feeling is probably too stable in healthy subjects to be affected by these drugs. The second difference was the slower rate of learning to perform the various behavioral tasks by the patients. This necessitates longer practice sessions than those used for healthy volunteers to achieve a stable performance before drug administration. 277,278The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers an additional avenue for development of a new generation of anxiolytics free from cognitive side effects. 279Also, the discovery that α2-GABAAreceptors mediate anxiolysis, whereas α1-GABAAreceptors mediate sedation and amnesia, may fulfill the same promise. 280 

Sleep difficulties  affect approximately one third of adults. Untreated sleep disturbances are associated with increased risk for the development of psychiatric disorders (specifically major depression), memory impairment, reduced work performance, increased rate of accidents, and a compromised quality of life. 281,282Treatment with benzodiazepines may also lead to memory impairment and residual sleepiness affecting daytime performance. 283Zaleplon, a novel nonbenzodiazepine drug, is rapidly eliminated from the body and does not produce cognitive impairment or residual sedation the next day. 284,285In addition, it does not produce rebound effects. 286It is almost unique in these respects. 281 

Memory Function in the Perianesthetic and Perisurgical Periods

The gradual loss of STM and LTM memory  with an increase in anesthetic dose until loss of consciousness is achieved has been described above. 206However, 0.1–0.2% of patients in general surgical cases (with potentially higher numbers during cardiac, obstetric, and trauma surgical procedures) may recall intraoperative memories or experience what is referred to in the anesthesia literature as awareness . 287It is mostly caused by too-light anesthesia, particularly when muscle relaxants are used. Its most feared sequela is posttraumatic stress disorder. 288,Implicit memory  for events during general anesthesia may occur in a few patients, only some of the time and particularly after light levels of anesthesia. Learning may be more perceptual than engaging in elaborate processing of information, and it may be more evident if patients are tested soon after the end of surgery. 289 

Memory Impairment during Postoperative Recovery.

Memory impairment in the early recovery phase  after general anesthesia is common. In a recent study by Rundshagen et al. , 29053% of the patients did not recall this period when they were asked 24 h later. Hence, giving written instructions and information to escorts of patients returning home on the same day of surgery is important. The results of memory and cognitive tests usually return to the preoperative values approximately 1–4 days after surgery. 291–293In addition to the variable sensitivities of the tests, it is possible that some patients, even while experiencing severe fatigue or aftereffects of sedation, may muster sufficient resources to perform satisfactorily for short periods. 294Also, individual variation in recovery is often masked when results are expressed in terms of group means. 295There are anecdotal reports of patients reporting forgetfulness or inability to concentrate for several days after general anesthesia. These residual impairments  may be due to the residual effects of the anesthetics or increased metabolic demands induced by the endocrine responses to surgery. 296,297Patients who are admitted to an intensive care unit  may experience memory problems while there. They frequently have little or no recall of their stay in the unit and may remember only nightmares, hallucinations, or paranoid delusions. Some of the contributing factors are the illness and treatment with sedative–hypnotics that may impair memory as well as the physical constraints, the social isolation, and the life-threatening nature of the illness, which may lead to the hallucinations and delusions. 298 

Transient global amnesia  (TGA) has been reported in few cases after general anesthesia. 299,300Patients with TGA have sudden onset of severe memory impairment, including both anterograde and retrograde amnesia, which lasts 2–12 h. Clinical examination during TGA shows a relatively isolated amnesic syndrome with an otherwise normal neurologic examination. TGA generally occurs in persons aged older than 50 yr and resolves spontaneously after several hours. After the attacks, patients remain unable to recall the period of TGA, and they occasionally exhibit a period of permanent retrograde amnesia before the onset of TGA. Kritchevsky et al.  301studied 11 patients with TGA. During the episode, the patients had severe anterograde amnesia for verbal and nonverbal material and retrograde amnesia that typically covered at least two decades.

Prolonged Postoperative Problems.

Psychological distress may become apparent 2–3 months after surgery as a result of factors such as slower-than-anticipated recovery and progression of disease. 302Patients may report more memory problems during this period, which may reflect general psychological distress more than actual deficits in memory performance. 302,303It is not uncommon for subjective evaluations and objective measures of memory to show poor association. 304CNS complications of cardiac surgery  have been the subject of considerable research. 305Cognitive impairment is common, affecting as many as 80% of patients a few days after surgery and persisting in one third. Millar et al.  306stress the importance of a patient’s preexisting cognitive and emotional states, in addition to age and other factors, for increasing the risk of an adverse outcome. Pharmacologic neuroprotection may, in the future, offer an improved outcome. 307 

Electroconvulsive therapy  is effective in the treatment of patients with depression, bipolar disorders, schizophrenia, and catatonia. 308Adverse effects on memory are the most common side effects and are the most distressing to many patients. 309Owing to a combination of anterograde and retrograde effects, many patients may manifest persistent loss of memory for some events that transpired in the interval starting several months before and extending to several weeks after the electroconvulsive course. Some patients experience persistent amnesia extending several years before electroconvulsive treatments. Profound and persistent retrograde amnesia may be more likely in patients with preexisting neurologic impairment and patients who receive large numbers of treatments, using methods that accentuate short-term cognitive side effects (e.g. , sine wave stimulation, bilateral electrode placement, high electrical stimulus intensity). 310The deficits in memory are largely restricted to episodic declarative memory and involve consolidation and retrieval processes. 311 

Drugs of Abuse

There is evidence that compulsion to repetitive drug intake and its persistence are based on a pathologic usurpation of molecular mechanisms that are normally involved in learning and memory. 312–314Progress in understanding these mechanisms may lead to more effective therapies for addiction than are currently present. The drugs have detrimental effects on memory and cognition. Although the short-term effects are similar to those of other drugs, 225,229,315,316studies of their long-term effects have yielded inconsistent findings.40Some studies have found deficits in memory, attention, abstraction, decision making, and visuospatial abilities. 317–325Others failed to find deficits in some of the same functions, and a few studies of stimulant abusers (cocaine and amphetamine) even suggested improved performance. 326–328Methodologic flaws account for many of these inconsistencies, as explained in the section on design of experiments. However, the evidence is persuasive that long-term regular recreational use of some drugs may be associated with persistent impairment of memory and cognition and may not be reversed by prolonged abstinence, which is an important and worrisome concern. Also, the concomitant use of more than one drug may have additive negative effects.40,229,318,329–332 

Developmental Memory Deficits

Some drugs administered to fetuses and infants may induce apoptotic neurodegeneration in the developing brain and persistent learning and memory deficits. The period of peak brain growth occurs in humans between the last month of gestation and first 6 months after birth. 333,334Ethanol; marijuana; phenobarbital; phenytoin; nitrous oxide; a combination of midazolam, nitrous oxide, and isoflurane; and other drugs that block N -methyl-d-aspartate receptors or hyperactivate GABAAreceptors may be neurotoxic in young animals. 335–338Other than the effects of alcohol, 339the neurobehavioral disturbances produced by other drugs must be evaluated in humans. Perhaps the technology of brain imaging can be adapted to infants to study human development. Subtle changes in learning and memory in the absence of dysmorphogenic effects may be easily overlooked. 334Significant brain development also occurs during adolescence. 340Changes in cerebral blood flow and metabolic rate are associated with increases in myelinization and decreases in gray matter, which reflect maturation and remodeling of the brain. 341,342Effects of drugs during this period may be due to direct neurotoxicity or indirect hormonal changes. Wilson et al.  343found significant effects correlating the age of first use of marijuana to brain morphology. Subjects who started using marijuana early (before the age of 17 yr) had a smaller percent of cortical gray matter and increased white matter compared with subjects who started later. Animal data also showed greater histologic changes in peripubertal animals versus  young adults exposed to cannabinoids. 344 

Effects of Drugs in a Hyperbaric Environment

Nitrogen narcosis (euphoria and cognitive and motor dysfunctions) may be precipitated when compressed air is breathed by a scuba diver. Narcosis may occur at depths of 66 ft of water (3 atm) or greater and significantly increase the risks of the underwater environment. 345Depth results in a significant impairment of memory, which contributes to the dangers of diving. 346Drugs taken by some divers to combat nausea and vomiting, e.g. , scopolamine and dimenhydrinate, may add to the cognitive impairments of diving. 347It is sound advice that people avoid all drugs, particularly psychoactive drugs, before diving.

Drugs and Neuroanatomy of Memory

Two main areas of the brain that play important roles in pathologic dysfunctions of memory, the medial temporal lobes and frontal lobes, have been recognized. Damage to each one of these areas produces its characteristic profile of memory deficits. The medial temporal lobe memory system refers to the hippocampal formation together with the adjacent perirhinal and parahippocampal cortices. 348It is necessary for establishing long-term explicit or declarative memory, which can be assessed by tests of recall and recognition. The frontal lobes are essential for STM or working memory and when accurate memory depends on organization, search, selection, and verification in the retrieval of stored information. Damage to the frontal cortex does not typically involve recollection per se  unless some organizational component is needed to facilitate performance. 349Frontal lobe–sensitive tests include the Wisconsin Card Sorting Test, the Stroop test, tests for confabulation, 350word fluency tests, and tests for source memory. 351Generally, the effects of drugs on memory result from functional disruption of the medial temporal lobe system. Frontal lobe involvement may be restricted to a few drugs, such as ketamine.63

Memory-enhancing Drugs

As the world population ages, the incidence and prevalence of various dementias (Alzheimer disease, multi-infarct dementia, senile dementia, and others) will increase in the absence of effective treatments for alleviating symptoms and preventing progression of these ailments. Successful drugs should have a great impact on individuals, their families, and society. A cure for established symptomatic disease may not be feasible because of the apparent irreversibility of cerebral lesions, but prevention and slowing or arresting the progress of the disease are reasonable goals. This highlights the importance of current attempts to define the criteria for assessment of memory associated with mild cognitive impairment, 352a stage of cognitive dysfunction beyond normal aging (people who are more forgetful than they ought to be for their age and education) but of insufficient magnitude to qualify for the diagnosis of clinically probable Alzheimer disease. Several studies have shown that subjects diagnosed as having mild cognitive impairment progress to Alzheimer disease at a much higher rate than age-matched controls. 353This stage of cognitive impairment is becoming an important target for potential therapeutic intervention and has recently been approved by the U.S. Food and Drug Administration for clinical treatments.

Cholinesterase inhibitors (e.g. , donepezil, rivastigmine, galantamine) are the first line of treatment of Alzheimer disease and the only drugs of proven benefit. 354,355The rationale for their use is based on evidence in patients with Alzheimer disease of deficits in the enzymes responsible for synthesis of acetylcholine in postmortem studies, 356loss of cholinergic projection neurons in other autopsies, 357and declines of cerebral acetylcholinesterase activity in imaging studies in vivo . 358Unfortunately, the effects of cholinesterase inhibitors are modest, and the disease eventually progresses despite treatment. There is some preliminary evidence that antioxidant therapy, specifically with vitamin E or selegiline, may delay the time to clinical worsening of the disease. The strategy is based on evidence for increased oxidative stress and free radical injury in the Alzheimer diseased brain. 354,355Despite the publications of some epidemiologic studies that suggest associations between the use of antiinflammatory drugs (nonsteroidal antiinflammatory agents and prednisone) or estrogen with a lower incidence of Alzheimer disease, clinical trials have not shown any beneficial effects. 270,271,359,360 

The amyloid hypothesis of Alzheimer disease holds that cerebral deposition of insoluble β-amyloid peptide is critical for the pathogenesis of the disease. 361Agents that interfere with β-amyloid production or aggregation are therefore being developed. Such drugs theoretically could reduce β-amyloid burden and may confer protection against the development of the disease. 355,360The fate of the β-amyloid protein is determined by the actions of secretases that cleave it into different fragments. Several researchers demonstrated that immunization with amyloid peptide in transgenic mice prevented cognitive dysfunction. 362–364These significant advances in knowledge about the disease at the molecular level remain to be translated into effective therapies in humans. Other new strategies include the use of glutamatergic agonists and serotonergic antagonists based on the hypothesis that synaptic transmission at cortical neurons represents a balance between cholinergic, glutamatergic, and serotonergic influences. New findings indicate that treatment with lipid-lowering drugs may also be associated with a reduced risk for the disease. 365–368 

Novel drugs are also being developed based on the molecular changes that occur at memory-related synapses. Encoding involves activation of α-amino-3-hyroxy-5-methyl-4 isoxazole propionic acid (AMPA)–type glutamate receptors, which then depolarize the postsynaptic region and unblock N -methyl-d-aspartate–type glutamate receptors. 369Consolidation involves new protein synthesis. The CREB (cAMP–response element binding proteins, which switch on and off the genes needed to form LTM) family of transcription factors are important for the gene signaling. 370Biotechnology companies are introducing compounds that modulate the AMPA compounds, with preliminary encouraging results. 353If these new pharmacologic agents and others prove to be devoid of serious adverse effects, they may also be used for treatment of the normal decline of memory produced by aging. Pardridge 371recently drew attention to the fact that the majority of newly developed drugs do not cross the blood–brain barrier. If progress with development of new drugs for the brain is to keep pace with progress in the molecular neurosciences, drug-delivery strategies based on endogenous blood–brain barrier transport systems must be explored.


Memory is a critical mental function. The history of drug effects on memory is as old as the history of its systematic study. There are three aims for studying the psychopharmacology of memory: evaluating drugs, modeling memory deficits in pathologic disorders, and contributing to a comprehensive account of memory.

Memory tests should be theoretically driven rather than components of a fixed battery of neuropsychologic tests. A memory experiment usually has three stages: a study phase, a retention interval, and a test phase. We propose a battery of tests that may include tests for working memory, episodic LTM, semantic LTM, and implicit memory. We favor free recall and recognition tests for episodic memory and a priming task for implicit memory. The contents of the battery can be changed to fit the aims of a specific investigation. It is important when investigating memory-impairing drugs to separate the effects on memory from impairments in attention, arousal, or mood. It is also important to separate the effects on memory from enhancement of alertness and attention, and decreased fatigue when investigating memory-enhancing drugs. The accepted standard for the design of an experiment is the randomized, prospective, concurrent assignments of subjects to the drug and placebo groups under double-blind conditions. Two comparison groups are usually necessary: pretreatment and posttreatment, and experimental and control groups. In the study of drug abusers, measurement of premorbid cognitive function, inclusion of a control group, and use of a large sample size are necessary.

Two major techniques, PET and fMRI, are used for functional neuroimaging. However, an explosion of new methods that promise to improve temporal and spatial resolutions and allow studies of the brain from infancy to old age are on the horizon. It is possible to identify the neural networks serving each memory function by combining the anatomic model and interregional correlations. A fundamental change from localizing memories in specific areas to viewing memory as distributed cortical networks that support specific mnemonic processes is rapidly evolving.

A wide variety of drugs impair memory. The amnesia is independent of sedation. In general, drugs produce a similar profile of memory impairment. They impair acquisition. With the exception of general anesthetics, they do not impair STM. They produce anterograde but not retrograde amnesia. Retrieval processes remain intact except with subanesthetic concentrations of general anesthetics. Drugs usually do not impair semantic memory, automatic processes, or learning of skills and procedures. Impairment of implicit memory is less than that of explicit memory. Amnesia for emotionally significant and stressful events is also less than that for neutral stimuli. Amnesia is dose and time related. Impairments are additive with those produced by other drugs, and the elderly are more impaired. Tolerance and cross-tolerance may be less for memory than for the other behavioral effects. Much remains to be investigated. For example, the specific encoding operations that are involved in drug impairments must be elucidated. Dose–response curves for drugs acting at different receptors and through different neurotransmitters or on different forms of memory may provide valuable insight into this vital behavior. Factors that contribute to altered sensitivity to drug effects are largely unknown. The question of possible irreversibility of memory and cognitive problems associated with long-term abuse of some drugs must be answered.

Development of memory-enhancing drugs is of great concern to a progressively aging population. Attempts to diagnose mild cognitive impairment before progression to an established disease are also equally important. Several new strategies for drug development seem to be promising. These include the use of glutamatergic agonists, serotonergic antagonists, and new pharmacologic agents of exquisite selectivity involved in the molecular changes that occur at the memory-related synapses. Development of strategies for breaching the blood–brain barrier will ensure the delivery of these drugs to their desired sites. All of these developments promise rapid advances in the therapeutics of memory and are important contributions to its understanding.

This review would not have been possible without the contributions of the author’s past and present collaborators. The author is deeply grateful for their thoughts, efforts, and intellectual companionship.


References 1–116 appear in part 1 of this article in the April issue of the Journal (Anesthesiology 2004; 100:987–1002); some of those references are re-cited in part 2.

Mewaldt SP, Ghoneim MM, Choi WW, Korttila K, Peterson RC: Nitrous oxide and human state-dependent memory. Pharmacol Biochem Behav 1988; 30:83–7
Eich JE, Birnbaum IM: Repetition, cuing and state-dependent memory. Mem Cogn 1982; 10:103–14
Hieronymus AN, Lindquist EF, Hoover HD: Manual for school administrators, Iowa Tests of Basic Skills. Chicago, Riverside, 1982
Davis KL, Hollister LE, Overall J, Johnson A, Train K: Physostigmine: Effects on cognition and affect in normal subjects. Psychopharmacology 1976; 51:23–7
Davis KL, Mohs RC, Tinklenberg JR, Pfefferbaum A, Hollister LE, Kopell BS: Physostigmine: Improvement of long-term memory processes in normal humans. Science 1978; 201:272–4
Izquierdo I: Nimodipine and the recovery of memory. Trends Pharmacol Sci 1990; 11:309–10
Kaplan GB, Tai NT, Greenblatt DJ, Shader RI: Caffeine-induced behavioural stimulation is dose- and concentration-dependent. Br J Pharmacol 1990; 100:435–9
Bruce M, Scott N, Lader M, Marks V: The psychopharmacological and electrophysiological effects of single doses of caffeine in healthy human subjects. Br J Clin Pharmacol 1986; 22:81–7
McGaugh JL: Involvement of hormonal and neuromodulatory systems in the regulation of memory storage. Annu Rev Neurosci 1989; 12:255–64
Izquierdo I: Different forms of post-training memory processing. Behav Neural Biol 1989; 51:171–202
Ashton H, Marsh VR, Millman JE, Rawlins MD, Telford R, Thompson JW: Biphasic dose-related responses of the CNV (contingent negative variation) to intravenous nicotine in man. Br J Clin Pharmacol 1980; 10:579–89
Ghoneim MM, Hinrichs JV, Chiang CK, Loke WH: Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam. J Clin Psycho-pharmacol 1986; 6:75–80
Ellinwood EH Jr, Linnoila M, Easler ME, Molter DW: Profile of acute tolerance to three sedative anxiolytics. Psychopharmacology 1983; 79:137–41
Ambre JJ, Belknap SM, Nelson J, Ruo TI, Shin SG, Atkinson AJ: Acute tolerance to cocaine in humans. Clin Pharmacol Ther 1988; 44:1–8
Zwyghuizen-Doorenbos A, Roehrs TA, Lipschutz L, Timms V, Roth T: Effects of caffeine on alertness. Psychopharmacology 1990; 100:36–9
Griffiths RR, Woodson PP: Caffeine dependence: A review of human and laboratory animal studies. Psychopharmacology 1988; 94:437–51
Tatum AL, Seevers MH: Experimental cocaine addiction. J Pharmacol Exp Ther 1929; 36:401–10
Shuster L, Yu G, Bates A: Sensitization to cocaine stimulation in mice. Psychopharmacology 1977; 52:185–90
Holford NH, Sheiner LB: Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981; 6:429–53
Laurijssens BE, Greenblatt DJ: Pharmacokinetic-pharmacodynamic relationships for benzodiazepines. Clin Pharmacokinet 1996; 30:52–76
Campbell DB: The use of kinetic-dynamic interactions in the evaluation of drugs. Psychopharmacology 1990; 100:433–50
Veselis RA, Reinsel RA, Feshchenko VA, Wronski M: The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations. Anesthesiology 1997; 87:749–64
Stanski DR, Hudson RJ, Homer TD, Saidman LJ, Meathe E: Pharmacometrics: Pharmacodynamic modeling of thiopental anesthesia. J Pharmacokinet Bio-pharm 1984; 12:223–40
Koch-Weser J, Sellers EM: Binding of drugs to serum albumin: I. N Engl J Med 1976; 294:311–6
Ghoneim MM, Pandya HB, Kelly SE, Fischer LJ, Cory RJ: Binding of thiopental to plasma proteins: Effects of distribution in the brain and heart. Anesthesiology 1976; 45:635–9
Bührer M, Maitre PO, Crevoisier C, Stanski DR: Electroencephalographic effects of benzodiazepines: II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol Ther 1990; 48:555–67
Schulz R, Reimann IW: Practice effect of volunteers in repeated psychometric testing: How to handle this intervening variable in clinical pharmacology studies? Methods Find Exp Clin Pharmacol 1988; 10:657–61
Yamamoto I, Ho IK, Loh HH: The antagonistic effects of 5-ethyl-5-(3-hydroxy-1-methylbutyl)-barbituric acid on pentobarbital narcosis in both naive and tolerant mice. Life Sci 1978; 22:1103–12
Dingemanse J, Thomassen D, Mentink BH, Danhof M: Strategy to assess the role of (inter)active metabolites in pharmacodynamic studies in-vivo: A model study with heptabarbital. J Pharm Pharmacol 1988; 40:552–7
Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J: Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin Pharmacol Ther 1979; 25:358–71
Green JF, McElholm A, King DJ: A comparison of the sedative and amnestic effects of chlorpromazine and lorazepam. Psychopharmacology (Berl) 1996; 128:67–73
Curran HV, Poovibunsuk P, Dalton J, Lader MH: Differentiating the effects of centrally acting drugs on arousal and memory: An event-related potential study of scopolamine, lorazepam and diphenhydramine. Psychopharmacology (Berl) 1998; 135:27–36
Ghoneim MM, Mewaldt SP, Berie JL, Hinrichs JV: Memory and performance effects of single and 3-week administration of diazepam. Psychopharmacology (Berl) 1981; 73:147–51
Curran HV, Bond A, O’Sullivan G, Bruce M, Marks I, Lelliot P, Shine P, Lader M: Memory functions, alprazolam and exposure therapy: A controlled longitudinal study of agoraphobia with panic disorder. Psychol Med 1994; 24: 969–76
Lucki I, Rickels K, Geller AM: Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology (Berl) 1986; 88:426–33
Tata PR, Rollings J, Collins M, Pickering A, Jacobson RR: Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med 1994; 24:203–13
Curran HV, Birch B: Differentiating the sedative, psychomotor and amnesic effects of benzodiazepines: A study with midazolam and the benzodiazepine antagonist, flumazenil. Psychopharmacology (Berl) 1991; 103:519–23
Hommer D, Weingartner H, Breier A: Dissociation of benzodiazepine-induced amnesia from sedation by flumazenil pretreatment. Psychopharmacology (Berl) 1993; 112:455–60
Roache JD, Griffiths RR: Comparison of triazolam and pentobarbital: Performance impairment, subjective effects and abuse liability. J Pharmacol Exp Ther 1985; 234:120–33
Rich JB, Brown GG: Selective dissociations of sedation and amnesia following ingestion of diazepam. Psychopharmacology (Berl) 1992; 106:346–50
Weingartner HJ, Sirocco K, Rawlings R, Joyce E, Hommer D: Dissociations in the expression of the sedative effects of triazolam. Psychopharmacology (Berl) 1995; 119:27–33
Veselis RA, Reinsel RA, Feshchenko VA: Drug-induced amnesia is a separate phenomenon from sedation: Electrophysiologic evidence. Anesthesiology 2001; 95:896–907
Ghoneim MM, Mewaldt SP: Benzodiazepines and human memory: A review. Anesthesiology 1990; 72:926–38
Curran HV: Benzodiazepines, memory and mood: A review. Psychopharmacology (Berl) 1991; 105:1–8
Kandel L, Chortkoff BS, Sonner J, Laster MJ, Eger EI II: Nonanesthetics can suppress learning. Anesth Analg 1996; 82:321–6
Sonner JM, Li J, Eger EI II: Desflurane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane suppress learning by a mechanism independent of the level of unconditioned stimulation. Anesth Analg 1998; 87:200–5
Dutton RC, Rampil IJ, Eger EI II: Inhaled nonimmobilizers do not alter the middle latency auditory-evoked response of rats. Anesth Analg 2000; 90:213–7
Stern E, Silbersweig DA: Advances in functional neuroimaging methodology for the study of brain systems underlying human neuropsychological function and dysfunction. J Clin Exp Neuropsychol 2001; 23:3–18
Schacter DL, Wagner AD, Buckner RL: Memory systems of 1999, The Oxford Handbook of Memory. Edited by Tulving E, Craik FIM. New York, Oxford University Press, 2000, pp 627–43
Coull JT, Frith CD, Dolan RJ, Frackowiak RS, Graspy PM: The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur J Neurosci 1997; 9:589–98
O’Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, Andreasen NC, Boles Ponto L, Watkins GL, Hurtig RR, Hichwa RD: Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology 2002; 26:802–16
Alkire MT, Pomfrett CJD, Haler RJ, Gianzero MV, Chan CM, Jacobsen BP, Fallon JH: Functional brain imaging during anesthesia in humans: Effects of halothane on global and regional cerebral glucose metabolism. Anesthesiology 1999; 90:701–9
Veselis RA, Reinsel RA, Feshchenko VA, Dnistrian AM: A neuroanatomical construct for the amnesic effects of propofol. Anesthesiology 2002; 97:329–37
Posner MI, Raichle ME: Images of Mind. New York, Scientific American Library, 1994, pp 53–81, 228–31
Block RI, O’Leary DS, Hichwa RD, Augustinack JC, Boles Ponto LL, Ghoneim MM, Arndt S, Hurtig RR, Watkins GL, Hall JA, Nathan PE, Anedreasen NC: Effects of frequent marijuana use on memory-related regional cerebral blood flow. Pharmacol Biochem Behav 2002; 72:237–50
Price CJ, Friston KJ: Cognitive conjunction: A new approach to brain activation experiments. Neuroimage 1997; 5:261–70
Nyberg L, Cabeza R: Brain imaging of memory, The Oxford Handbook of Memory. Edited by Tulving E, Craik FIM. New York, Oxford University Press, 2000, pp 501–19
Block RI, O’Leary DS, Enrhardt JC, Augistinack JC, Ghoneim MM, Arndt S, Hall JA: Effects of frequent marijuana use on brain tissue volume and composition. Neuroreport 2000; 11:491–6
Hurtig RR, Hichwa RD, O’Leary DS, Ponto LLB, Narayana S, Watkins GL, Andreasen NC: Effects of timing and duration of cognitive activation in [15O] water PET studies. J Cereb Blood Flow Metab 1994; 14:423–30
Dale AM, Halgren E: Spatiotemporal mapping of brain activity by integration of multiple imaging modalities. Curr Opin Neurobiol 2001; 11:202–8
Mazziotta JC, Toga AW, Evans A, Fox P Lancaster J: A probabilistic atlas of the human brain: Theory and rationale for its development. The International Consortium for Brain Mapping (ICBM). Neuroimage 1995; 2:89–101
Arndt ST, Cizadlo NC, Andreasen G, Zeien G, Harris G, O’Leary DS, Watkins GL, Boles Ponto LL, Hichwa RD: A comparison of approaches to the 15O PET Cognitive activation studies. J Neuropsychiatry statistical analysis of H21995; 7:155–68
Friston KJ, Homes AP, Worsley KJ, Poline J-P, Frith CD, Frackowiak RSJ: Statistical parametric maps in functional imaging: A general linear approach. Hum Brain Mapp 1995; 2:189–210
Tulving E, Kapur S, Craik FIM, Moscovitch M, Houle S: Hemispheric encoding/retrieval asymmetry in episodic memory: Positron emission tomography findings. Proc Natl Acad Sci U S A 1994; 91:2016–20
Nyberg L, Cabeza R, Tulving E: PET studies of encoding and retrieval: The HERA model. Psychon Bull Rev 1996; 3:135–48
Miller MB, Kingstone A, Gazzaniga MS: Hemispheric encoding asymmetry is more apparent than real. J Cogn Neurosci 2002; 14:702–8
Desgranges B, Baron JC, Eustache F: The functional neuroanatomy of episodic memory: The role of the frontal lobes, the hippocampal formation, and other areas. Neuroimage 1998; 8:198–213
Lepage M, Ghaffar O, Nyberg L, Tulving E: Prefrontal cortex and episodic memory retrieval mode. Proc Natl Acad Sci U S A 2000; 97:506–11
Yancy SW, Phelps EA: Functional neuroimaging and episodic memory: A perspective. J Clin Exp Neuropsychol 2001; 23:32–48
Haxby JV, Ungerleider LG, Horwitz B, Maisog JM, Rapoport SL, Grady CL: Face encoding and recognition in the human brain. Proc Natl Acad Sci U S A 1996; 93:922–7
Kapur S, Tulving E, Cabeza R, McIntosh AR, Houle S, Craik FIM: The neural correlates of intentional learning of verbal materials: A PET study in humans. Cogn Brain Res 1996; 4:243–9
Cahill L, Haier RJ, Fallon J, Alkire MT, Tang C, Keator D, Wu J, McGaugh JL: Amygdala activity at encoding correlated with long-term free recall of emotional information. Proc Natl Acad Sci U S A 1996; 93:8016–21
Hamann SB, Ely TD, Grafton ST, Kilts CD: Amygdala activity related to enhanced memory for pleasant and aversive stimuli. Nat Neurosci 1999; 2:289–93
Cabeza R, Nyberg L: Imaging cognition: An empirical review of PET studies with normal subjects. J Cogn Neurosci 1997; 9:1–26
Schacter DL, Buckner RL, Koutstaal W: On the relations among priming, conscious recollection, and intentional retrieval: Evidence from neuroimaging research. Neurobiol Learn Mem 1998; 70:284–303
Buckner RL, Tulving E: Neuroimaging studies of memory: Theory and recent PET results, Handbook of Neuropsychology, vol 10. Edited by Boller F, Grafman J. Amsterdam, Elsevier, 1995, pp 439–66
Smith EE, Jonides J: Neuroimaging analyses of human working memory. Proc Natl Acad Sci U S A 1998; 95:12061–8
Fiez JA: Bridging the gap between neuro imaging and neuropsychology: Using working memory as a case-study. J Clin Exp Neuropsychol 2001; 23:19–31
Gabrieli JDE: Cognitive neuroscience of human memory. Annu Rev Psychol 1998; 49:87–115
Posner MI, Raichle ME: Images of Mind. New York, Scientific American Library, 1994, p 127
Buchel C, Morris J, Dolan RJ, Friston KJ: Brain systems mediating aversive conditioning: An event-related fMRI study. Neuron 1998; 20:947–57
LaBar KS, Gatenby C, Gore JC, LeDoux JE, Phelps EA: Amygdalocortical activation during conditioned fear acquisition and extinction: A mixed trial fMRI study. Neuron 1998; 20:937–45
Ivry RB, Fiez JA: Cerebellar contribution to thought and imagery, The New Cognitive Neurosciences. Edited by Gazzaniga MS. Cambridge, MIT Press, 1998, pp 999–1018
Horwitz B, McIntosh AR, Haxby JV, Grady CL: Network analysis of brain cognitive function using metabolic and blood flow data. Behav Brain Res 1995; 66:187–93
Cabeza R, McIntosh AR, Tulving E, Nyberg L, Grady CL: Age-related differences in effective neural connectivity during encoding and recall. Neuroreport 1997; 8:3479–83
Petersson KM, Reis A, Ingvar M: Cognitive processing in literate and illiterate subjects: A review of some recent behavioral and functional neuroimaging data. Scand J Psychol 2001; 42:251–67
McIntosh AR, Gonzalez-Lima F: Structural equation modeling and its application to network analysis in functional brain imaging. Hum Brain Mapp 1994; 2:2–22
Fuster JM: Network memory. Trends Neurosci 1997; 20:451–9
McIntosh AR: Mapping cognition to the brain through neural interactions. Memory 1999; 7:523–48
Jones JG, Aggarwal S: Monitoring the depth of anesthesia, Awareness during Anesthesia. Edited by Ghoneim MM. Oxford, Butterworth-Heineman, 2001, pp 69–91
Andrade J: Learning during sedation, anesthesia and surgery, Awareness during Anesthesia. Edited by Ghoneim MM. Oxford, Butterworth-Heinemann, 2001, pp 93–102
Rusted JM, Warburton DM: The effects of scopolamine on working memory in healthy volunteers. Psychopharmacology 1988; 96:145–52
Gorissen MEE, Eling PATM: Dual task performance after diazepam intake: Can resource depletion explain the benzodiazepine-induced amnesia? Psychopharmacology 1998; 138:354–61
Rusted JM: Cholinergic blockade: Are we asking the right questions? J Psychopharmacol 1994; 8:54–9
Fang JC, Hinrichs JV, Ghoneim MM: Diazepam and memory: Evidence for spared memory function. Pharmacol Biochem Behav 1987; 28:347–52
Hirshman E, Passannante A, Arndt J: Midazolam amnesia and conceptual processing in implicit memory. J Exp Psychol (Gen) 2001; 130:453–65
Danion JM, Zimmermann M-A, Willard-Schroeder D, Grange D, Singer L: Diazepam induces a dissociation between explicit and implicit memory. Psychopharmacology 1989; 99:238–43
Block RI, Ghoneim MM, Pathak D, Kumar V, Hinricks JV: Effects of a subanesthetic concentration of nitrous oxide on overt and covert assessments of memory and associative processes. Psychopharmacology 1988; 96:324–31
Block RI, Ghoneim MM, Sum-Ping ST, Ali MA: Human learning during general anaesthesia and surgery. Br J Anaesth 1991; 66:170–8
Ghoneim MM, Block RI, Sum-Ping ST, El-Zahaby HM, Hinricks JV: The interactions of midazolam and flumazenil on human memory and cognition. Anesthesiology 1993; 79:1183–92
Ghoneim MM, Block RI, Dhanaraj VJ: Interaction of a subanaesthetic concentration of isoflurane with midazolam: Effects on responsiveness, learning and memory. Br J Anaesth 1998; 80:581–7
Danion JM, Zimmermann MA, Willard-Schoeder D, Grange D, Welsch M, Imbs JL, Singer L: Effects of scopolamine, trimipramine and diazepam on explicit memory and repetition priming in healthy volunteers. Psychopharmacology 1990; 102:422–4
Brown MW, Brown J, Bowes J: Absence of priming coupled with substantially preserved recognition in lorazepam induced amnesia. Q J Exp Psychol 1989; 41A:599–617
Stewart SH, Rioux GF, Connolly JF, Dunphy SC, Teehan MD: Effects of oxazepam and lorazepam on implicit and explicit memory: Evidence for possible influences of time course. Psychopharmacology 1996; 128:139–49
Squire LR, Kandel ER: Memory, From Mind to Molecules. New York, Scientific American Library, 2000, pp 176–8
Petersen S, Van Mier H, Fiez JA, Raichle ME: The effects of practice on the functional anatomy of task performance. Proc Natl Acad Sci U S A 1998; 95: 853–60
Block RI, Ghoneim MM, Hinrichs JV, Kumar V, Pathak D: Effects of a subanaesthetic concentration of nitrous oxide on memory and subjective experience: Influence of assessment procedures and types of stimuli. Hum Psychopharmacol 1988; 3:257–65
Block RI, Farinpour R, Braverman K: Effects of marijuana smoking on cognition and their relationship to smoking technique. Pharmacol Biochem Behav 1992; 43:907–17
Birnbaum IM, Parker ES: Acute effects of alcohol on storage and retrieval, Alcohol and Human Memory. Edited by Birnbaum IM, Parker ES. Hillsdale, New Jersey, Lawrence Erlbaum, 1977, pp 99–108
Hinrichs JV, Mewaldt SP, Ghoneim MM, Berie JL: Diazepam and learning: Assessment of acquisition deficits. Pharmacol Biochem Behav 1982; 17:165–70
Hinrichs JV, Ghoneim MM, Mewaldt SP: Diazepam and memory: Retrograde facilitation produced by interference reduction. Psychopharmacology 1984; 84:158–62
Adam N, Castro AD, Clark DL: State-dependent learning with a general anesthetic (isoflurane) in man. TIT J Life Sci 1974; 4:125–34
Curran VH, Morgan C: Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction 2000; 95:575–90
Gardiner JM, Richardson-Klavehn A: Remembering and knowing, The Oxford Handbook of Memory. Edited by Tulving E, Craik FIM. New York, Oxford University Press, 2000, pp 229–44
Curran HV, Gardiner JM, Java R, Allen DJ: Effects of lorazepam on recollective experience in cognition memory. Psychopharmacology 1993; 110: 374–8
Mintzer MZ, Griffiths RR: Acute effects of triazolam on false recognition. Mem Cogn 2000; 28:1357–65
Nichols JM, Martin F, Kirkby KC: A comparison of the effect of lorazepam on memory in heavy and low social drinkers. Psychopharmacology 1993; 112: 475–82
Balota DA, Dolan PO, Duchek JM: Memory changes in healthy older adults, The Oxford Handbook of Memory. Edited by Tulving E, Craik FIM. New York, Oxford University Press, 2000, pp 395–409
Craik FIM, Jennings JM: Human Memory, The Handbook of Aging and Cognition. Edited by Craik FIM, Salthouse TA. Hillsdale, New Jersey, Erlbaum, 1992, pp 51–110
Craik FIM, McDowd JM: Age differences in recall and recognition. J Exp Psychol (Learn Mem Cogn) 1987; 13:474–9
LaVoie D, Light LL: Adult age differences in repetition priming: A meta-analysis. Psychol Aging 1994; 9:539–53
Hinrichs JV, Ghoneim MM: Diazepam, behavior, and aging: Increased sensitivity or lower baseline performance? Psychopharmacology 1987; 92:100–5
Hughes LM, Wasserman EA, Hinrichs JV: Chronic diazepam administration and appetitive discrimination learning: Acquisition versus steady-state performance in pigeons. Psychopharmacology 1984; 84:318–22
Moon Y, Ghoneim MM, Gormezano I: Nitrous oxide: Sensory, motor, associative and behavioral tolerance effects in classical conditioning of the rabbit nictitating membrane response. Pharmacol Biochem Behav 1994; 47:523–9
Weingartner H: Human state-dependent learning, Drug Discrimination and State-Dependent Learning. Edited by Ho BT, Richards D III, Chute D. New York, Academic Press, 1977, pp 361–82
Petersen RC, Ghoneim MM: Diazepam and human memory: Influence on acquisition, retrieval, and state-dependent learning. Prog Neuropsychopharmacol 1980; 4:81–9
Buffett-Jerrott SE, Stewart SH, Teehan MD: A further examination of the time-dependent effects of oxazepam and lorazepam on implicit and explicit memory. Psychopharmacology 1998; 138:344–53
Cahill L: Neurobiology of memory for emotional events: Converging evidence from infrahuman and human studies. Cold Spring Harb Symp Quant Biol 1996; LXI:259–64
Murphy ST, Monahan JL, Zajonc RB: Additivity of nonconscious affect: Combined effects of priming and exposure. J Pers Soc Psychol 1995; 69:589–602
Cahill L, Babinsky R, Markowitsch HJ, McGaugh JL: The amygdala and emotional memory. Nature 1995; 377:295–6
Schacter DL: The Seven Sins of Memory. New York, Houghton Mifflin Co., 2001
Schacter DL, Verfaellie M, Anes MD: Illusory memories in amnesic patients: Conceptual and perceptual false recognition. Neuropsychology 1997; 11:331–42
Mewaldt SP, Ghoneim MM: The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory. Pharmacol Biochem Behav 1979; 10:205–10
Block RI, Wittenborn JR: Marijuana effects on semantic memory: Verification of common and uncommon category members. Psychol Rep 1984; 55: 503–12
Gorissen MEE, Curran HV, Eling PATM: Proactive interference and temporal context encoding after diazepam intake. Psychopharmacology 1998; 138: 334–43
Levkovitz Y, Caftori R, Avital A, Richter-Levin G: The SSRIs drug Fluoxetine, but not the noradrenergic tricyclic drug Desipramine, improves memory performance during acute major depression. Brain Res Bull 2002; 58:345–50
Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM: Acute administration of citalopram facilitates memory consolidation in healthy volunteers. Psychopharmacologia 2002; 163:106–10
Meneses A: Could the 5-HT1B receptor inverse agonism affect learning consolidation? Neurosci Behav Rev 2001; 25:193–201
Helmstaedter C, Kurthen M: Memory and epilepsy: Characteristics, course, and influence of drugs and surgery. Curr Opin Neurol 2001; 14:211–6
Brunbech L, Sabers A: Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: A comparative review of newer versus older agents. Drugs 2002; 62:593–604
Kuperberg G, Heckers S: Schizophrenia and cognitive function. Curr Opin Neurobiol 2000; 10:205–10
Galletly CA, Clark CR, MacFarlane AC: Treating cognitive dysfunction in patients with schizophrenia. J Psychiatry Neurosci 2000; 25:117–24
Rollnik JD, Borsutzky M, Huber TJ, Mogk H, Seifert J, Emrich HM, Schneider U: Short-term cognitive improvement in schizophrenics treated with typical and atypical neuroleptics. Neuropsychobiology 2002; 45:74–80
Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA: Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159:1018–28
Kulisevsky J: Role of dopamine in learning and memory: Implications for the treatment of cognitive dysfunction in patients with Parkinson’s disease. Drugs Aging 2000; 16:365–79
Kimberg DY, Aguirre GK, Lease J, D’Esposito M: Cortical effects of bromocriptine, a D-2 dopamine receptor agonist, in human subjects, revealed by fMRI. Hum Brain Mapp 2001; 12:246–57
Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW: Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers. Psychopharmacologia 2001; 159:10–20
Perlmuter LC, Hakami MK, Hodgson Harrington C, Ginsberg J, Katz J, Singer DE, Nathan DM: Decreased cognitive function in ageing non insulin-dependent diabetic patients. Am J Med 1984; 77:1043–8
Perlmuter LC, Tun PA, Sizer N, McGlinchey RE, Nathan DM: Age and diabetes related changes in verbal fluency. Exp Aging Res 1987; 13:9–14
Tun PA, Perlmuter LC, Russo P, Nathan DM: Memory self-assessment and performance in aged diabetics and non-diabetics. Exp Aging Res 1987; 13:151–7
Mooradian AD, Perryman K, Fitten J, Kavonian GD, Morley JE: Cortical function in elderly non-insulin dependent diabetic patients: Behavioural and electrophysiologic studies. Arch Intern Med 1988; 148:1369–72
Bent N, Rabbitt P, Metcalfe D: Diabetes mellitus and the rate of cognitive ageing. Br J Clin Psychol 2000; 39:349–62
Reus VI, Wolkowitz OM: Antiglucocorticoid drugs in the treatment of depression. Expert Opin Investig Drugs 2001; 10:1789–96
Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P: Toward selective Erbeta agonists for central nervous system disorders: Synthesis and characterization of aryl benzthiophenes. J Med Chem 2002; 45: 1399–401
Anthony M, Williams JK, Dunn BK: What would be the properties of an ideal SERM? Ann N Y Acad Sci 2001; 949:261–78
Shaywitz SE, Shaywitz BA, Pugh KR, Fulbright RK, Skudlarski P, Mencl WE, Constable RT, Naftolin F, Palter SF, Marchione KE, Katz L, Shankweiler DP, Fletcher JM, Lacadie C, Keltz M, Gore JC: Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999; 281:1197–202
Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, Swanson C, Watson RB, Gardiner RA: Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: A randomized controlled trial. Br J Urol 2002; 90:427–32
Parrot AC, Hindmarsch I: Clobazam: A benzodiazepine derivative: Effects upon human psychomotor performance under different levels of task reinforcement. Arch Int Pharmacodyn Ther 1978; 232:261–8
Nakano S, Ogawa N, Kawazu Y, Osato E: Effects of antianxiety drug and personality on stress-inducing psychomotor performance test. J Clin Pharmacol 1978; 18:125–30
Ghoneim MM, Mewaldt SP, Hinrichs JV: Dose-response analysis of the behavioral effects of diazepam: II. Psychomotor performance, cognition and mood. Psychopharmacology 1984; 82:296–300
Linnoila M, Erwin CW, Brendle A, Simpson D: Psychomotor effects of diazepam in anxious patients and healthy volunteers. J Clin Psychopharmacol 1983; 3:88–96
Ghoneim MM, Hinrichs JV, Noyes R Jr, Anderson DJ: Behavioral effects of diazepam and propranolol in patients with panic disorder and agoraphobia. Neuropsychobiology 1984; 11:229–35
Chojnacka-Wojcik E, Koodzinska A, Pilc A: Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2001; 2:1112–9
Möhler H, Fritschy JM, Rudolph M: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2–8
Roth T: The relationship between psychiatric diseases and insomnia. Int Clin Pract 2001; 116(suppl):3–8
Howard SK, Gaba DM, Smith BE, Weinger MB, Herndon C, Keshavacharya S, Rosekind MR: Simulation study of rested versus  sleep-deprived anesthesiologists. Anesthesiology 2003; 98:1345–55
Roth T, Roehrs TA: Issues in the use of benzodiazepine therapy. J Clin Psychiatry 1992; 53(suppl):14–8
Vermeeren A, Danjou PE, O’Hanlon JF: Residual effects of evening and middle-of-the-night administration of zaleplon 10 and 20 mg on memory and actual driving performance. Hum Psychopharmacol Clin Exp 1998; 13:S98–S107
Danjou P, Paty I, Fruncillo R, Worthington Munnuh P, Cevallous W, Martin P: A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. Br J Clin Pharmacol 1999; 48:367–74
Fry J, Scharf M, Mangano R, Fujimori M, Zaleplon Clinical Study Group: Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Int Clin Psychopharmacol 2000; 15:141–52
Sandin RH, Enlund G, Samuelsson P, Lennmarken C: Awareness during anesthesia: A prospective case study. Lancet 2000; 355:707–11
Ghoneim MM: Awareness during anesthesia, Awareness during Anesthesia. Edited by Ghoneim MM. Oxford, Butterworth-Heineman, 2001, pp 1–22
Ghoneim MM: Implicit memory for events during anesthesia, Awareness during Anesthesia. Edited by Ghoneim MM. Oxford, Butterworth-Heineman, 2001, pp 23–68
Rundshagen I, Schnabel K, Schulte am Esch J: Recovery of memory after general anaesthesia: Clinical findings and somatosensory evoked responses. Br J Anaesth 2002; 88:362–8
Ghoneim MM, Hinrichs JV, O’Hara MW, Mehta MP, Pathak D, Kumar V, Clark CR: Comparison of psychologic and cognitive functions after general or regional anesthesia. Anesthesiology 1988; 69:507–15
Riis J, Lomholt B, Haxholdt O, Kehlet H, Valentin N, Danielsen U, Dyrberg V: Immediate and long-term mental recovery from general versus epidural anesthesia in elderly patients. Acta Anaesthesiol Scand 1983; 27:44–9
Tzabar Y, Asbury AJ, Millar K: Cognitive failures after general anesthesia for day-case surgery. Br J Anaesth 1996; 76:194–7
Millar K: The effects of anaesthetic and analgesic drugs, Handbook of Human Performance. Vol 2. Edited by Smith AP, Jones DM. London, Academic Press, 1992, 337–85
Hickey S, Asbury AJ, Millar K: Psychomotor recovery after outpatient anaesthesia: Individual impairment may be masked by group analysis. Br J Anaesth 1991; 66:345–52
Davison LA, Steinhelber JC, Eger EI, Stevens WC: Psychological effects of halothane and enflurane anesthesia. Anesthesiology 1975; 43:313–24
Kehlet H: Stress-free surgery and anaesthesia. Acta Anaesthesiol Scand 1979; 23:503–4
Jones C, Griffiths RD, Humphris G: Disturbed memory and amnesia related to intensive care. Memory 2000; 8:79–94
Wood T, Donegan J: Transient global amnesia following general anesthesia. Anesthesiology 1985; 62:807–09
Ghoneim MM: Transient global amnesia: A cause for postanesthetic memory disorder (letter). Anesth Analg 1998; 87:977–82
Kritchevsky M, Zouzounis J, Squire LR: Transient global amnesia and functional retrograde amnesia: Contrasting examples of episodic memory loss. Philos Trans R Soc Lond B Biol Sci 1997; 352:1747–54
O’Hara MW, Ghoneim MM, Hinrichs JV, Mehta MP, Wright EJ: Psychological consequences of surgery. Psychosom Med 1989; 51:356–70
Popiela T, Kulig J, Hanisch J, Bock PR: Influence of a complementary treatment with oral enzymes on patients with colorectal cancers: An epidemiological retrolective cohort study. Cancer Chemother Pharmacol 2001; 47(suppl): S55–63
Sackeim HA, Stern Y: The neuropsychiatry of memory and amnesia, The American Psychiatric Press Textbook of Neuropsychiatry, 3rd edition. Edited by Yudofsky SC, Hales RE. Washington, DC, American Psychiatric Press, 1997, pp 501–18
Arrowsmith JE, Grocott HP, Reves JG, Newman MF: Central nervous system complications of cardiac surgery. Br J Anaesth 2000; 84:378–93
Millar K, Asbury AJ, Murray GD: Pre-existing cognitive impairment as a factor influencing outcome after cardiac surgery. Br J Anaesth 2001; 86:63–7
Roach GW: Pro: Prevention of neurologic dysfunction associated with cardiac surgery requires pharmacologic brain protection. J Cardiothorac Vasc Anesth 1997; 11:793–5
Fink M: Convulsive therapy: A review of the first 55 years. J Affect Disord 2001; 63:1–15
Donahue AB: Electroconvulsive therapy and memory loss: A personal journey. J ECT 2000; 16:133–43
Sackeim HA: Memory and ECT: From polarization to reconciliation (editorial). J ECT 2000; 16:87–96
Squire LR, Alvarez P: Retrograde amnesia and memory consolidation: A neurobiological perspective. Curr Opin Neurobiol 1995; 5:169–77
Hyman SE, Malenka RC: Addiction and the brain: The neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001; 2:695–703
Everitt BJ, Dickinson A, Robbins TW: The neuropsychological basis of addictive behaviour. Brain Res (Brain Res Rev) 2001; 36:129–38
Miyata H, Yanagita T: Neurobiological mechanisms of nicotine craving. Alcohol 2001; 24:87–93
Block RI, Wittenborn JR: Marijuana effects on associative processes. Psychopharmacology 1985; 85:426–30
O’Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, Andreasen NC, Boles Ponto L, Watkins GL, Hurtig RR, Hichwa RD: Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology 2002; 26:802–16
Block RI, Ghoneim MM: Effects of chronic marijuana use on human cognition. Psychopharmacology 1993; 110:219–28
Block RI, O’Leary DS, Hichwa RD, Augustinack JC, Boles Ponto LL, Ghoneim MM, Arndt S, Hurtig RR, Watkins GL, Hall JA, Nathan PE, Andreasen NC: Effects of frequent marijuana use on memory-related regional cerebral blood flow. Pharmacol Biochem Behav 2002; 72:237–50
Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R, Wynne K, Baker NB, Hunter J, Carthy T, Booker E, London M, Deakin JF, Sahakian BJ, Robbins TW: Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: Evidence for monoaminergic mechanisms. Neuropsychopharmacology 1999; 20:322–39
Rosselli M, Ardila A: Cognitive effects of cocaine and polydrug abuse. J Clin Exp Neuropsychol 1996; 18:122–35
Beatty WW, Katzung VM, Moreland VJ, Nixon SJ: Neuropsychological performance of recently abstinent alcoholics and cocaine abusers. Drug Alcohol Depend 1995; 37:247–53
Beatty WW, Blanco CR, Hames KA, Nixon SJ: Spatial cognition in alcoholics: Influence of concurrent abuse of other drugs. Drug Alcohol Depend 1997; 44:167–74
Mittenberg W, Motta S: Effects of chronic cocaine abuse on memory and learning. Arch Clin Neuropsychol 1993; 8:477–83
Parsons OA, Prigatano GP: Memory functioning in alcoholics, Alcohol and Human Memory. Edited by Birnbaum IM, Parker ES. Hillsdale, New Jersey, Lawrence Erlbaum, 1977, pp 185–94
Cermak LS: The contribution of a “processing” deficit to alcoholic Korsakoff patients’ memory disorder, Alcohol and Human Memory. Edited by Birnbaum IM, Parker ES. Hillsdale, New Jersey, Lawrence Erlbaum, 1977, pp 195–208
Bolla KI, Rothman R, Cadet JL: Dose-related neurobehavioral effects of chronic cocaine use. J Neuropsychiatry Clin Neurosci 1999; 11:361–9
Hoff AL, Riordan H, Morris L, Cestaro V, Wieneke M, Alpert R, Wang GJ, Volkow N: Effects of crack cocaine on neurocognitive function. Psychiatry Res 1996; 60:167–76
Robinson JE, Heaton RK, O’Malley SS: Neuropsychological functioning in cocaine abusers with and without alcohol dependence. J Int Neuropsychol Soc 1999; 5:10–9
Bolla KI, Funderburk FR, Cadet JL: Differential effects of cocaine and cocaine alcohol on neurocognitive performance. Neurology 2000; 54:2285–92
Rosenberg NL, Grigsby J, Dreisbach J, Busenbark D, Grigsby P: Neuropsychologic impairment and MRI abnormalities with chronic solvent abuse. J Toxicol 2002; 40:21–34
Parrott AC: Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 2002; 71:837–44
Morgan MJ, McFie L, Fleetwood H, Robinson JA: Ecstasy (MDMA): Are the psychological problems associated with its use reversed by prolonged abstinence? Psychopharmacologia 2002; 159:294–303
Dobbing J, Sands J: The brain growth spurt in various mammalian species. Early Hum Dev 1979; 3:79–84
Jevtovic-Todorovic V, Hartma RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–82
Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Horster F, Tenkova T, Dikranian K, Olney JW: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287:1056–60
Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW: Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant, and neurotoxin. Nat Med 1998; 4:460–3
Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L: Prenatal alcohol and marijuana exposure: Effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol 2002; 24:309–20
Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Koppe JG, van De Poll NE, Boer K: Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr 2000; 89: 533–41
Streissguth AP, O’Malley K: Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders. Semin Clin Neuropsychiatry 2000; 5:177–90
Jernigan TL, Trauner DA, Hasselink JR, Tallal PA: Maturation of human cerebrum observed in vivo during adolescence. Brain 1991; 114:2037–49
Reiss AL, Abrams MT, Singer HS, Ross JL, Denckla MB: Brain development, sex and IQ in children: A volumetric imaging study. Brain 1996; 119: 1763–74
Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW: Mapping cortical change across the human life span. Nat Neurosci 2003; 6:309–15
Wilson W, Mathew R, Turkington T, Hawk T, Coleman RE, Provenzale J: Brain morphological changes and early marijuana use: A magnetic resonance and positron emission tomography study. J Addict Disord 2000; 19:1–22
Landfield PW, Cadwallader LB, Vincent S: Quantitative changes in hippocampal structure following long-term exposure to delta-9-tetra hydrocannabinol: Possible mediation by glucocorticoid systems. Brain Res 1988; 443:47–62
Abraini JH: Inert gas and raised pressure: Evidence that motor decrements are due to pressure per se and cognitive decrements due to narcotic action. Eur J Physiol 1997; 433:788–91
Fowler B, Hendricks P, Porlier G: Effects of inert gas narcosis on rehearsal strategy in a learning task. Undersea Biomed Res 1987; 14:469–76
Taylor DM, O’Toole KS, Auble TE, Ryan CM, Sherman DR: The psychometric and cardiac effects of dimenhydrinate in the hyperbaric environment. Pharmacotherapy 2000; 20:1051–4
Zola SM, Squire LR: The medial temporal lobe and the hippocampus, The Oxford Handbook of Memory. Edited by Tulving E, Craik FIM. New York, Oxford University Press, 2000, pp 485–500
Moscovitch M, Winocur G: The frontal cortex and working with memory, Principles of Frontal Lobe Function. Edited by Stuss DT, Knight RT. London, Oxford University Press, 2000, pp 188–208
Moscovitch M: Confabulation and the frontal systems: Strategic versus associative retrieval in neuropsychological theories of memory, Varieties of Memory and Consciousness: Essays in Honour of Endel Tulving. Edited by Roedriger HL, Craik FIM. Hillsdale, NJ, Erlbaum 1989, pp 133–56
Glisky EL, Polster MR, Routhieaux BC: Double dissociation between item and source memory. Neuropsychology 1995; 9:229–35
Blennow K; Vanmechelen E; Hampel H: CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001; 24:87–97
Lynch G: Memory enhancement: The search for mechanism-based drugs. Nat Neurosci 2002; 5(suppl):1035–8
Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL: Practice parameter: Management of dementia (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2001; 56:1154–66
Knopman DS, Morris JC: An update on primary drug therapies for Alzheimer disease. Arch Neurol 1997; 54:1406–9
Davies P, Maloney AJ: Selective loss of central cholinergic neurons in Alzheimer’s disease (letter). Lancet 1976; 2:1403
Rasool CG, Svendsen CN, Selkoe DJ: Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer’s disease. Ann Neurol 1986; 20:482–8
Kuhl DE, Koeppe RA, Minoshima S, Synder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR: In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease. Neurology 1999; 52:691–9
Wilkinson D: Drugs for treatment of Alzheimer’s disease. Intl J Clin Pract 2001; 55:129–4
Hoozemans JJ, Rozemuller AJ, Veerhuis R, Eikelenboom P: The immunological aspects of Alzheimer’s disease: Therapeutic implications. Biodrugs 2001; 15:325–37
Selkoe D: Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 1996; 271:18295–8
Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG: A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 2000; 408:975–9
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D: A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000; 408:979–82
Morgan D, Diamond D, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW: A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000; 408:982–5
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G: Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl co-enzyme A reductase inhibitors. Arch Neurol 2000; 57:1439–43
Bruno V, Battaglia G, Copani A, D’Onofrio M, Di Iorio P, De Blasi A, Melchiorri D, Flor PJ, Nicoletti F: Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab 2001; 21:1013–33
Buccafusco JJ, Terry AV Jr: Multiple central nervous system targets for eliciting beneficial effects on memory and cognition. J Pharmacol Exp Ther 2000; 295:438–46
Branchek TA, Blackburn TP: 5-HT6 receptors as emerging targets for drug discovery. Annu Rev Pharmacol Toxicol 2000; 40:319–34
Staubli U, Rogers G, Lynch G: Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci U S A 1994; 91:777–81
Barco A, Alarcon JM, Kandel ER: Expression of Constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 2002; 108:689–703
Pardridge WM: Blood-brain barrier drug targeting: The future of brain drug development. Mol Interventions 2003; 3:90–105