(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

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