(Editor’s Note: given the growing media attention to three apparently separate worlds -cognitive enhancement via drugs, brain fitness training software, computerized neurocognitive assessments-, I found it refreshing to see our co-founder Elkhonon Goldberg introduce the topic of cognotropic drugs with an integrative perspective in the much updated new edition of his classic book, now titled The New Executive Brain: Frontal Lobes In A Complex World. Below goes an excerpt).

For many neuropsychologists, like myself, science is a labor of love, but seeing patients is bread and butter. Traditionally, the clinical contribution of neuropsychology has been mostly diagnostic, with precious little to offer patients by way of treatment. Neuropsychology is not the only clinical discipline for years consigned to helpless voyeurism. Every discipline concerned with cognition shares this humbling predicament. A psychiatrist treating a schizophrenic patient or a depressed patient finds him- or herself in a similar position. There are ample pharmacological tools to treat the patient’s psychosis or mood, but very few to treat the patient’s cognition. Even though psychiatrists increasingly recognize that cognitive impairment is often more debilitating in their patients than psychosis or mood disorder, traditionally, very little direct effort has been aimed at improving cognition.

A neurologist treating a patient recovering from the effects of head injury does not fare much better. There are adequate means to control the patient’s seizures but not his or her cognitive changes, despite the fact that cognitive impairment is usually far more debilitating than an occasional seizure. Society has been so preoccupied with saving lives, treating hallucinations, controlling seizures, and lifting depression that cognition (memory, attention, planning, problem solving) has been largely ignored. Granted, various neuroleptics, anticonvulsants, antidepressants, sedatives, and stimulants do have an effect on cognition, but it is an ancillary effect of a drug designed to treat something else.

Alzheimer’s disease and other dementias have been society’s wake-up call. Here, in the most affluent country in the most affluent of times, human minds were succumbing to decay before human bodies, a sharp challenge to the tacit popular belief that the “body is frail but soul is forever.” This provided an impetus for the development of an entirely new class of drugs, which can be termed familially as “cognotropic.” Their primary and explicit purpose is to improve cognition.

Since medical and public preoccupation with dementia focuses on memory, most of the pharmacological efforts have been directed at improving memory. At the time of this writing, a handful of drugs known as “Alzheimer’s drugs” or “memory enhancers” have been approved by the U.S. Food and Drug Administration (FDA). In reality, both designations are somewhat misleading. The drugs in question are anticholinesterases. They are designed to inhibit an enzyme necessary for the breakdown of the neurotransmitter acetylcholine in the synapse, and thus to prolong its action after its release into the synapse. Acetylcholine is a neurotransmitter that plays an important role in memory as well as in other cognitive functions. Biochemical processes involving acetylcholine (“cholinergic transmission”) are impaired in Alzheimer’s dementia, but they are also impaired in many other disorders.

My first encounter with this class of drugs took place in the late 1970s and involved physostigmine (Antilirium), a first-generation anticholinesterase, now out of use as a cognitive enhancer. We gave it to a patient recovering from severe head injury. The problem with physostigmine was that its length of action (halflife) was so miserably short that no sustained therapeutic effect could be reasonably expected. At best, a very fleeting, short-term improvement could be hoped for. To capture this improvement, my colleagues and I designed a brief battery of neuropsychological tests, which my research assistants Bob Bilder and Carl Sirio rushed to administer with clockwork timing during carefully calculated, and very narrow, windows of opportunity. Fleeting though it was (and at times overshadowed by vicious diarrhea), subtle memory improvement was reproducibly present. This was a cause for hope that with some improvements this class of medications could someday have real clinical value.

A number of years later, tacrine (Cognex) appeared on the market, followed by donepezil (Aricept). These drugs are also anticholinesterases, but with a much longer action and a more meaningful therapeutic effect. They should not be thought of as exclusively “Alzheimer’s drugs” since their utility is not limited to Alzheimer’s disease. I have observed a significant, albeit transient, therapeutic effect of these drugs on cognition in patients with Parkinson’s disease and brain damage due to hypoxia.

Although their effect is still transient and inconsistent, the advent of these second- and third-generation anticholinesterase drugs opened a new chapter in pharmacology, ushering in cognotropic medications.

More recently, a new drug, Namenda (memantine), was approved by the FDA. It targets several receptors in the brain: glutaminergic, serotonergic, and cholinergic. Its most pronounced effect is presumed to be one of a glutamate antagonist. Targeting glutamate, a ubiquitous neurotransmitter mediating mostly excitatory processes in the neocortex and elsewhere in the brain, has opened a “second front” in the pharmacological assault on dementia. Interestingly, stimulating GABA, a mostly inhibitory neurotransmitter working in tandem with glutamate, was shown to slow the progression of a dementia-like condition in the monkey.

In the next few years we will undoubtedly witness a boom in the cognotropic pharmacology acting on various biochemical systems. Much further research is needed for it to become established and some controversy is inevitable, but the concept of cognotropic drugs is provocative and timely.

Interesting work on cognotropic pharmacology is being done in Europe as well. An audacious program to investigate neuroanatomically precise effects of various drugs has been under way in Russia for some time. Scientists at the Bourdenko Institute of Neurosurgery in Moscow, where I trained in Luria’s lab 40 years ago, have reported an array of specific drug effects. According to them, levodopa (L-dopa), a precursor of the neurotransmitter dopamine, improves the functions we typically associate with the posterior aspect of left frontal lobe: motor sequencing, speech initiation, and expressive language. To put it in technical terms, the Russians claim that L-dopa reduces the symptoms of dynamic aphasia, transcortical motor aphasia, and Broca’s aphasia. By the same token, L-dopa seems to retard the functions commonly associated with the parietal lobes (spatial orientation and spatial construction). According to the Russians, L-glutamic acid, an analogue of the neurotransmitter glutamate, improves other functions associated with the frontal lobes. It improves insight into one’s condition (reduces symptoms of anosognosia) and improves the sense of humor, time estimation, and time sequencing. L-Glutamic acid also improves the functions commonly associated with the parietal lobes. L-Tryptophan, a precursor of the neurotransmitter serotonin, improves the functions of the parietal lobe but retards the functions of the frontal lobes. At the same time, L-tryptophan interferes with the functions of the frontal lobes, particularly the left frontal lobe. Ameridin, an anticholinesterase not commonly known in the United States, seems to improve the functions of the parietal lobes, particularly the left parietal lobe. It improves comprehension of grammar and reduces the symptoms of “semantic aphasia.” These claims made by the Russian scientists associating various neuroactive drugs with particular cortical functions are more specific and in a way more ambitious than most Western claims to this effect. They require careful review and replication, but they are extremely provocative.

But where do the prefrontal cortex and the executive functions fit in? Executive deficit is easily as common and debilitating as memory impairment, and so there should be as much societal pressure for the development of cognotropic frontallobe pharmacology. Here, too, developments are at an embryonic stage, but some forward movement is evident. We have discussed the role of dopamine in frontal lobe function, so it should come as no surprise that dopamine-enhancing pharmacology has shown some promise.

The dopamine system is complex, with a number of different receptors. To be truly effective, dopamine pharmacology must be receptor-specific. As we learn more about the variety of dopamine receptors, we are learning about the receptor-specific action of dopamine-enhancing drugs. Bromocriptine (Ergoset or Parlodel), a dopamine D2 receptor agonist, has been shown to improve working memory, a function closely linked to the frontal lobes, in normal adults. The efficacy of two more recently developed D2 receptor agonists, ropinirole (Requip) and pramipexole (Mirapex), has yet to be established.

Currently, a great deal of interest exists in identifying specific dopamine receptors and developing receptor-specific pharmacology. But the thrust of this research is driven by the treatment of schizophrenia, which requires dopamine receptor–specific antagonists. To boost the function of the frontal lobes, dopamine agonists may be required with an affinity to various dopamine receptors, including D1 and D4. This poses a new challenge to pharmaceutical industry and research.

Cognotropic pharmacology of the frontal lobes holds out particular promise in those disorders where frontal lobe dysfunction is present without massive structural damage to the frontal lobes. In such conditions neurotransmitter receptor sites are largely intact, which makes pharmacological intervention more promising. Mild traumatic brain injury (TBI) is such a condition. This is a particularly poignant disease, since it afflicts young people, often in good physical shape and with undiminished life expectancy. Following traumatic brain injury, problems with working memory, decision making, attention, motivation, and impulse control are common. Bromocriptine tends to improve these functions in patients with head injury. So does amantadine (Symmetrel), a drug presumed to facilitate dopamine release and delay dopamine reuptake following its release into the synapse. Mirtazapine (Remeron), typically used to treat depression, has been shown to enhance dopaminergic transmission in the frontal lobes.

The advent of these drugs signals the beginning of frontal-lobe cognotropic pharmacology. Here, too, a second front was recently opened. A new “schizophrenia” drug is in clinical trials at the time of this writing. Developed at Lilly by pharmacologist Darryle Schoepp, this as of yet unnamed agent is supposed to impact in particular the frontal lobes, but by acting on the glutamate system instead of the dopaminergic one. As is the case with the anticholinesterases, even though the motivation behind the development of the drug was triggered by a particular disorder, its biochemical target may have an impact on a wide range of other disorders; these patients may also benefit from the drug.

I hope there is much more to follow. But the true excitement will come when the cutting-edge pharmacology is combined with cutting-edge neuropsychology, when fine cognitive measures are used to guide cognotropic pharmacology in precise, individualized ways. The actor-centered cognitive tasks shown to be so exquisitely sensitive to distinct variants of frontal lobe dysfunction may prove to be particularly useful in guiding custom-tailored cognotropic pharmacology of the frontal lobes.

– Reprinted with permission from The New Executive Brain: Frontal Lobes In A Complex World by Elkhonon Goldberg, published by Oxford University Press, Inc. © 2009, Oxford University Press. Available via Amazon.com Here.

Our previous interview with Dr. Goldberg:

- On Cognitive Training and Brain Fitness Computer Programs