Drugs and Human Memory (Part 2)

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.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. 117,118For 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.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.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 would be when the sensitivity of the has not been a and a standard for comparison with the new are common in studies of the effects of drug on The of the studies have not included of cognitive the that differences between drug and existed before the of drug than being caused by drug studies have not included a control group of cognitive in drug comparison with an control group is essential. studies have sample to can be by cognitive a control group, and a sample control for the that drug and before their drug and on their during the on the of in studies of drug is the that most subjects use more than one drug. It is important when investigating one drug to a drug and on the and of use of other when of the most in is the between the of the and the of the behavioral the that in greater effects than may not be For example, of effects on memory higher and drugs, and other may also of the has been being to the effects, state or learning of other may a action on with and has been a and of drug effects after repeated administration. to may the time of a impairment may baseline the of the drug has been demonstrated for many drugs, and of a drug in and of the may the same effects with state may be to between effects and repeated to the behavioral effects of can opposite effect to has been administration of may or of a drug in other with measurements of memory or other effects has many to that are or to drug effects, which may not be a or of a drug effect can be with concurrent of drug it is possible to to that drug effects. are several for studying It more of the of drug of of active and It the effects of the drug on the by for which the drug required to one of and of drug and sensitivity an of the differences between and of effects of factors and drug–drug and on the The information would it possible to design for during and or during of their behavioral effects. It a for drug of or and use for are in studying the and drug and the time of in usually for the of during drug and the of is the because most of the studies in the the effects of or and are during the phase. The of is also of the drug in is to the drug that is available for the the time and of drug effects is the and is the for the of studies of the for The behavioral be to and to drug and The of the fatigue, and the test sensitivity of memory over a of drug in our the use of a learning repeated over three for task is and can be to to drug The task may also be several before the study to improvement in performance over is no to the that can be by a words or for practice effects, one may use a placebo over baseline after administration of active are by of after placebo administration. the between the and its effects. should be from repeated and over a of drug A is that the and of the effect on may be used. most is the because of its to the of the can be complicated by the lack of a between the of drug may be The drug effect may with time for the same drug by the in figure may be caused by learning of the and the of active is not possible to from learning a placebo The of active is there are a of that the of the drug by its e.g. , of has some important may not from type of drug can The effect of the drug with time for a drug when a that is A common is the for a drug to be from the to its of action and then to a type of may be because of and of the drug in than is the of active from the drug. would have and a some later time with the drug are drug a and or of of to the when The be or an effect memory changes with changes in the of drug. It can be of the of the of the drug. The drug effect is to its the A the between the and effect The between the is by the of which the of of the available for use that are of also is no drug that For and it is important to the effects on memory from in or It is also important when investigating potential to effects on and from effects on learning and The general is that is of the that have been to the effects on memory and is to study or more that the same effects on different effects on For example, with in that of that memory was by the effects of with of and In the the three of the not It should be however, that because of and memory may in of this not for between the of the of the memory effects of is to study the of of to the of the drug. the is that to effects than it to memory effects. For example, to the effects of after its administration to not to its amnesic effects. to the memory effects of after of treatment in patients after treatment with other of the effects would be to of amnesic and effects by an of of pretreatment with before administration of a benzodiazepine in reduction of effects of memory A of is of different for and the potential with different groups of that equivalent amnesic effects, more and effects on memory are by the of the of that of the potential by later more by are also important for showing this of can be to effects to a between and and the between memory and more than several of drug and of memory and to compare memory performance after of four and very different and for the same of and memory For example, showed a of the of memory impairment before it the of In contrast, the and showed of for the same group has demonstrated that learning in that the not be a to the It a in to study the of memory and its and It is also a and of cognitive and has been to several of the and of of the memory and changes with performance of memory tasks under the influence of new have been and in a of the of are and Both by assessing changes in For the a is before the of a cognitive The in the in to the For the most are changes in that the for a and the more than the in a in the of and a in is in changes that the to be when studies, the to for example, an memory retrieval task in which the subject during the words of a learned changes in should be the of memory retrieval and not to other A common strategy is to use a In to the during the word is during a control that the same except for of For example, we asked the subjects in our . . a of which is to the of during the memory in memory of a and should memory the during the control which for from during the state would the that are in the memory has been is no that the performance in the experimental task from the control state in one the of the component in the experimental task may affect common to the experimental and control it would not be possible to the of from studies of memory have been by this and and of have been researchers also use a state a that the in the state during a is that it may not a our we the subjects after the period to been to differences in between subjects in the experimental and control groups. of the its of its and its and in to the be is which has a of 2 allowing a of to be For the cognitive task and are during the time that the the It a on with a of The of of the for and the to of The is important in studies with that may affect either or e.g. , changes in The of with the of of subjects to and and are the subject the with its of and in some and the of the and have and the by and with the is a in which the with a in a on the the are to a a the of on by alone is have been that use both and to of with and from to are before are for of in the to or are to for and may the are on are to a on a common is to differences in and and group the of the comparison of with the cognitive task and its control is a or the retrieval to this the in the to be during and the to be during memory retrieval this some have that this to to some on the type of used. of the that the of retrieval less than second general of the is that seem to with during memory and usually of the and The is usually with and the is with are studies that that of the is with later recall of retrieval usually the the the and the retrieval is usually with of the and memory , the is with of the is with the and the and the is with the and to be and to be to be is by in the of to or baseline task performance in is usually with and the is usually with is with of the It should be however, that there are and of memory For example, in a of memory by and was in of by different groups of is a and in one study may not be in a that the cognitive tasks in different studies the same memory may not be and the different in is from standard to can be to the active in it not the between and that not may be of the The the in the and their procedures have been to the different and in a A is or the following are are The are to other on the of to an the are is to the the The or for the different are has been to the of memory with The of this has not been by studies in subjects with memory no the with memory impairment between the of effects and amnesic effects, and determine the of drug. or in might also be of the and The and the have been more than the have a of which from the and the to the more of a a or a and the type A and seem to have their effects the on on for and which is or other behavioral effects is to the in and in the seem to of memory It that there are to the effects on of with the that memory is a of than to one may be of more than one different memory The general of drug are in with the of general memory memory memory tasks are that the of and the of e.g. , a test that the retention of a of immediate recall is the of the in the should be to performance more on in a general a impairment of or memory before be before of and A further in is with of studies have the effects of on of and to the effects of The drug of the which with the and to test the effects of memory this manipulation was no more in versus Both groups of that to of the are not to the effects of the on on The effects on memory have not been with and their have been of the studies have the effects of studies showed of memory performance on tasks the are some studies on the effects of on learning by acquisition The should be that of the in and memory may be in learning and that less important learning a drug effect may be caused by a general of performance to the effect of the it is possible to that impairment of memory usually is more than that of cognitive are more than there is usually of test performance by and are usually in than in in a may not if are not may be by the of and which may the of on memory by the acquisition of new information is by some impairment of or the of or of the material to be learned or its from to acquisition to be The effects on learning can be demonstrated when the of the of the being of the most of learning is the observed in learning , learning a over three the influence of drugs, the subjects are to more on is not usually to an in recall of the of the with the recall from the of the which is from the drug effect may not be by a in of a to from a performance would be if subjects not A performance could also be if the subjects are required to a of thus learning between and a later recall would be for the learning and memory of information after their administration not retrieval of some of recall of material before the drug The most for the is that subjects learn little under the influence of the drug that there is less and less of the material learned before drug administration. except with of general of information is to be from the common task that e.g. , many can in or many words with the in subjects with a placebo group. impairment of memory can be with if it can be demonstrated that of performance on the task is not to or for impairment of memory is a in the of For example, and that of a task , for the , , . . effects are very and are of with that the and that and memory subjects are asked to have a of the of a word during the study or the word are more by with and in are also e.g. , a benzodiazepine with with a of an are more to the behavioral effects of drugs, The may be , of or or , changes the or A is a baseline performance of the the memory changes in changes may cognitive in the and the more and more in the A in the cognitive of a may have little or no effect on that The same in an is a or more to behavior may have and with other drugs, and to the effects of the may marked to the and effects of the occurs with to the memory effects same has been in was also no for memory impairment between and drug effects in are studies state the state-dependent memory effects or is not for performance on memory tasks to from their of their may not or be even in learning and cognitive the studies in which tasks impairment was is that for significant and to or would be less than for standard of and subject to a greater because are to be in several of during and after which with the to the of could also in the of of may of cognitive For example, in a of studies by , recall of not elements of a the same task with patients to the a of that in the memory for a the and of of and The effects of on memory have to be A study by and that in to of true of words, of to was with of in patients with amnesic is possible to that on memory that are in and drugs, and also an in , recall of words that not on the may of new between or between an and its from in the of drugs, may the subjects to a strategy of little in their word that occurs to subjects their and some may be because of a studies of the behavioral effects of have been there may be some differences in drug to the in are with cognitive that may affect the and of that may influence the of impairment the of the with the effects of and further cognitive is with memory and may be in the the improvement of memory performance is greater with the type of is with the on and memory of impairment when and are by or the effects of or treatment. The , seem to have no or cognitive effects with , particularly memory is common in . treatment may to more treatment of the cognitive , the cognitive better than , is with cognitive may cognitive in some patients and in to the of in different of the The cognitive changes may also be task with may have cognitive of the is of the is less in three groups of subjects, and a control group, a of cognitive tasks memory The patients a than the control group, most of the impairment in the by the for of the or a effect of the other and are with cognitive In of is with a of impairment of and use of is of change and memory of either of treatment or use of that the behavioral effects. have been to some some effects on learning and memory in in have not been the other the use of to patients with of the has been with with may in cognitive and may in to the effects observed in subjects same other the same effects of in patients and with the effects of by the patients have been in of is in subjects to be by The second difference was the of learning to the behavioral tasks by the practice than for to a performance before drug administration. of which the of the an for of a new of from cognitive effects. the that and may the same affect one of are with risk for the of memory of and a of with may also to memory impairment and performance. a drug, is from the and not cognitive impairment or the it not effects. is in of and memory with an in of is has been of patients in general surgical higher during and trauma surgical may recall or is to in the . is caused by particularly when are used. most is memory for during general may in a some of the time and particularly after of may be more than in of and it may be more if patients are after the of impairment in the after general is In a study by , of the patients not recall this period when asked and information to of patients on the same of is The of memory and cognitive usually to the after to the of the it is possible that some even or of may to for in is masked when are in of group are of patients or to for several after general may be to the effects of the or by the to are to an may memory have little or no recall of their in the and may or of the factors are the and treatment with that may memory the the and the of the which may to the and has been in after general with have of memory both and which during a amnesic with an occurs in than and after several the patients to recall the period of and a period of before the of patients with the the patients for and material and that may after a of factors and of disease. may more memory during this which may general more than in memory performance. is not for and of memory to of have been the subject of impairment is many of patients a after and in one the of a cognitive and in to and other for the risk of an in the an is in the treatment of patients with and effects on memory are the most common effects and are the most to many to a of and effects, many patients may of memory for some that in the several before and to several after the patients several before and may be more in patients with impairment and patients receive of that cognitive effects , in memory are to memory and and retrieval is that to drug and its are on a of that are in learning and in may to more for than are The have effects on memory and the effects are to of other drugs, of their effects have studies have in and to find in some of the same and a studies of and even performance. for many of in the on design of the is that use of some may be with impairment of memory and and may not be by which is an important and the use of more than one drug may have to and may in the and learning and memory The period of occurs in between the of and first after a of and and other that or may be in than the effects of by other be in the of can be to to study changes in learning and memory in the of effects may be also occurs during in and are with in and in which and of the of during this period may be to or significant effects the of first use of to the of a of and with subjects also showed greater changes in versus to and cognitive and may be when is by a may of of or greater and the of the in a significant impairment of which to the of by some to and e.g. , and may to the cognitive of is that drugs, particularly drugs, before of the that important in of the and have been to one of its of memory The memory to the with the and is for or which can be by of recall and The are essential for or memory and when memory on and in the retrieval of to the not unless some component is to performance. the the for and for the effects of on memory from of the may be to a drugs, the the and of and in the of treatments for and of should have a on their and A for established may not be because of the of and or the of the are the of to the for assessment of memory with cognitive of cognitive are more than to be for their and of to for the of disease. studies have that subjects cognitive impairment to a higher than of cognitive impairment is an important for potential and has been by the and for , are the first of treatment of and the of for their use is on in patients with of in the for of in studies, of in other of in studies in . the effects of are and the treatment. is some that with or may the time to of the disease. The strategy is on for and in the the of some studies that between the use of and or with a of have not effects. of that of is for the of the disease. that with or are being could and may the of the disease. of the is by the of that it different researchers demonstrated that with in cognitive significant in the the to be in new the use of and on the that a between and that treatment with may also be with a risk for the disease. are also being on the changes that of which then the and new The which on and the to of factors are important for the are that the with new and to be of effects, may also be for treatment of the of memory by to the that the of not the with of new for the is to with in the on be is a The of drug effects on memory is the of its are three for studying the of drugs, memory in and to a of should be than of a of A memory experiment usually has three a study phase, a retention interval,