3
DE VELOPMENT AND N EUR OBI OLOG Y Assistant Editor: Paul j. Lombroso, M.D. Development of the Cerebral Cortex: XI\( Stress Impairs Prefrontal Cortical Function AMY F.T. ARN STEN, PH.D. A ltl-year-old boy has been referred to you at the school's insistence. For the past 6 months, he has had behavioral problems in class. He has difficulty paying attent ion, has been easily agitated, and fails to inh ibit inappropri ate and aggres- sive impul ses. His parents rep ort that he has always been active but he was never like this before. Does he suddenly A. have atte nt ion-deficit/hyperactivity disorder (AD H D) ? A little probing reveals that the parents' marriage is in trouble and that their child's probl ems in school coincide with prob- lems at home . Recent advances in neurobiological research may help us unde rstand reactive behavioral problems in chil- dren. Neurochemical changes in the prefrontal cortex (PFC) D. >- a: i w :I Cl :I: l- +l- + Iii W III Iii III till! III z III Z III Z 0 ::::i w Z 0 w 0 :c < 0 I-' 01-' I-' w III I-' 1-'< > < <!Z 15 < 15< < ... ... ... c c c Increasing levels of 01 receptor stimulation 80% 40% 220 Fig. 1 Dopa mine acring at D I receprors in rhe prefrontal cortex (PFe) produces an inverted U dose response whereby either roo lin le or roo much D I recepror stimularion impairs neuro nal or cognitive func rion. A-C: Highly schematic representation of the work of Yang and Seamans (19%) of the e1ecrrophysiological effects of dopamin e or D I agonisrs on PFC pyram idal cell functio n. Intracellular record ings from PFe slices showed that D I recepror stimulation diminishes the calcium currents rhar convey signals from rhe distal dendrites to the cell body. A: Wirh insufficient D I receptor stirnulation , all signals are conveyed to the soma, resulting in diffuse , unfo cused infor mal ion. T his is represent ed in A by the large arro w of incomi ng signals. T he behavioral cor relate is poor worki ng memor y and poo r attention regulation. B: Wirh optimal levels of DI recepro r stimulation. signal transfer is focused such tha t on ly the largest. coordinated signals are conveyed ro rhe cell. T his is represented in B by the normal-sized arrow. T he behavioral correlate is oprima l wo rking memory an d attent ion regularion. C: Al very high levels of DI receplor stimulation such as duri ng stress, calciu m currents are blocked and signal transfe r is abolished. T his is represented by the small arrow. T he behavioral correlate is once again poor working memory and atte ntion regularion. D: T hese elecrroph ysiological results fir very well with cognit ive studies, whereby an inverted lJ is observed wirh changing levels of D I recepror stimulation. In rhis figure. working memory performance in rats was impaired by either insufficiem or excessive D I receplor stim ulatio n in the PFe. Adapt ed from Zah n et al, (1997), Supr ano rmal srimularion of DI dopamine receprors in the rodent cortex impairs spatial wor king memory performance .] Neurosci 17:8 528- 8535. I. AM. ACAD. CHILD ADO LE SC. PSYC HI ATRY. 3 8: 2 , FEBRU ARY 1999

( Stress Impairs Prefrontal Cortical Function · Lombroso, M.D. Development ofthe Cerebral Cortex: XI\(Stress Impairs Prefrontal Cortical Function AMY F.T.ARNSTEN, PH.D. A ltl-year-oldboy

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Page 1: ( Stress Impairs Prefrontal Cortical Function · Lombroso, M.D. Development ofthe Cerebral Cortex: XI\(Stress Impairs Prefrontal Cortical Function AMY F.T.ARNSTEN, PH.D. A ltl-year-oldboy

DE VELOPMENT AND N EUR OBI OLOG Y Assistant Editor: Paul j. Lombroso, M.D.

Development of the Cerebral Cortex: XI\(Stress Impairs Prefrontal Cortical Function

AMY F.T. ARNSTEN, PH.D.

A ltl-year-old boy has been referred to you at the schoo l'sinsistence. For th e past 6 months, he has had behavior alproblems in class. He has difficulty paying attent ion , has beeneasily agitated , and fails to inh ibit inapp ropri ate and aggres­sive impulses. H is parents report tha t he has always beenactive but he was never like thi s before. Does he suddenly

A.

have atte nt ion-de fic it/ hy perac tivity d isorder (AD H D) ? Alittl e probing reveals that the parents' marriage is in troubleand th at the ir ch ild's probl ems in school coincide with prob­lems at home . Recent advances in neurobiological researchmay help us understand reactive beh avioral problems in chil­dren. Neurochemical changes in the prefrontal cortex (PFC)

D.>-a:iw:ICl

~l§:I:

l- +l- + Iii ~ W III IiiIII till! III z IIIZ III Z 0 ::::i w Z0 z~ w 0 :c < ~

0I-' 01-'

~I-' w III I-'

~ 1-'<~

> <<!Z 15< 15< <... ... ...c c c

Increasing levels of 01 receptor stimulation

80%

40%

220

Fig. 1 Dopamine acring at D I receprors in rhe prefrontal cortex (PFe) produces an inverted U dose responsewhere by eit her roo lin le or roo mu ch D I recepro r stimularion impairs neuro nal or cognitive func rion. A-C:

Highly schematic represen tation of the work of Yang and Seamans (19%) of the e1ecrrophysiological effects of

dopamin e or D I agonisrs on PFC pyram idal cell functio n. Intracellular record ings from PFe slices showedthat D I recepror stimulation diminishes the calcium currents rhar convey signals from rhe distal dendrites tothe cell body. A: Wirh insufficient D I receptor stirn ulat ion , all signals are conveyed to the soma, resulting indiffuse , unfocused infor mal ion. T his is represent ed in A by the large arrow of incomi ng signals. T he behavioral

cor relate is poor worki ng memory and poo r attent ion regulation. B: W irh optimal levels of DI recepro rstimulation. signal transfer is focused such tha t on ly the largest. coord inated signals are conveyed ro rhe cell.

T his is represented in B by the normal-sized arrow. T he behavioral correlate is oprima l wo rking memory andattent ion regular ion . C : Al very high levels of DI receplor stimulation such as duri ng stress, calciu m currents

are blocked and signal transfe r is abolished. T his is represented by th e small arrow. T he behavioral correlate is

once again poor working memory and atte ntion regularion. D: T hese elecrroph ysiological results fir very wellwith cognit ive studies, whereby an inverted lJ is observed wirh changing levels of D I recepror stimulation. Inrhis figure. working memory performance in rats was impaired by either insufficiem or excessive D I receplorstim ulation in the PFe. Adapt ed from Zah n et al, (1997), Supranormal srim ularion of DI dopamine receprors

in the rodent cortex imp airs spatial wor king me mo ry perfo rma nce.] Neurosci 17:8528-8535.

I . AM. AC A D . C H I LD ADO LESC. PSYC H IATRY. 3 8: 2 , FEBRUA RY 19 9 9

Page 2: ( Stress Impairs Prefrontal Cortical Function · Lombroso, M.D. Development ofthe Cerebral Cortex: XI\(Stress Impairs Prefrontal Cortical Function AMY F.T.ARNSTEN, PH.D. A ltl-year-oldboy

during periods of stress may take this brain region "off-line,"making the child less able [Q govern his behavior.

The PFC is situated anterior to the motor cortices in thefrontal lobe. It is much larger in primates than in other mam­mals. It continues to develop throughout adolescence. Thisregion of our brains is critical for using "working memory," aform of memory that is required to appropriately guidebehavior. Working memory has been called "scratch-pad"memory, because thi s type of memory must be constantlyupdated. Memories can be called up from long-term storageor from more recent buffers. The PFC uses these representa­tions [Q effectively guide behavior, freeing us from respondingonly to our immediate environment, inhibiting inappropriateresponses or distractions, and allowing us to plan and orga­nize. Animals or humans with lesions [Q the PFC exhibit poorattention regulation, disorganized and impulsive behavior,and hyperactivity.

Recent research in animals indicates that exposure to stresscan produce a functional "lesion" of the PFC During stressexposure, carecholamines are released in both the peripheraland central nervous systems. In the periphery, the carechola­mines norepinephrine and epinephrine are released from thesympathetic nervous system and adrenal gland, respectively.These catecholamine actions serve to "turn on" our heart andmuscles and "turn off" the stomach to prepare for fight-or­flight responses during stress.

In the brain, high levels of the carecholarnines dopamineand norepinephrine are released in the PFC during stressexposure, even during relatively mild psychological stress. Asbasal levels of dopamine and norepinephrine have essentialbeneficial influences on PFC function , it was originallypresumed that high levels of catecholamine release duringstress might facilitate PFC function. However, research inmonkeys and rats demonstrated the contrary: exposure tostress impairs the working memory functions of the PFCThese findings in animals are consistent with older literaturedemonstrating that humans exposed to loud noise stress areless able to sustain attention or to inhibit inappropriate re­sponses, functions now known to be carried out by the PFCAs in animal studies, these changes are most evident underconditions in which the subject feels no control over the stress.

A number of studies indicate that stress-induced workingmemory deficits result from high levels of catecholaminereceptor stimulation on neurons in the PFC (Fig. 1). Work­ing memory deficits during stress can be ameliorated byagents that prevent catecholamine release or block catechola­mine receptors. For example, stress-induced cognitive deficitscan be ameliorated by pretreatment with aradrenergic recep­tor agonists such as clonidine or guanfacine, which decreasestress-induced catecholamine release and enhance PFC func­tion through actions at postsynaptic arreceptors in the PFC

J. AM. ACAD. CHILD A DOLESC. PSYCHIATRY. .i8:2. FE II R U A RY 1999

DEVELOPMENT AND NEUROBIOLOGY

Stress-induced cognitive deficits can also be prevented by

treating with compounds that block either dopamine 01 ornoradrenergic aI-receptors, suggesting that dopamine andnorepinephrine have their detrimental effects in the PFCthrough actions at Oland aI-receptors, respectively. Consis­tent with this interpretation, intra-PFC infusions of either01 or at-agonists impair working memory.

Electrophysiological recordings similarly indicate that highlevels of 01 receptor stimulation can interfere with PFCneuronal function. Studies of aI-receptors have not beendone. For example, large amounts of 01 agonist abolish thecalcium currents that convey signals along dendrites, effec­tively "strangling" information transfer from dendrite to soma(Fig. 1). Conversely, low levels of 01 receptor antagonistscan enhance memory-related neuronal responses in monkeysperforming working memory tasks. Thus, high levels of 01receptor stimulation erode the working memory responsesthat the PFC uses to effectively guide behavior.

Active neurochemical mechanisms to take the PFC "off­line" during stress may have had survival value in evolution,allowing faster, instinctual mechanisms regulated by subcor­tical and posterior cortical areas to regulate behavior duringstress. However, these brain actions may often be maladaptivein human society when we are in need of PFC regulation toact appropriately, e.g., in the classroom when behavior mustbe highly controlled.

The reversal of stress-induced cognitive deficits with phar­macological treatments in animals suggests that medicationmay also be helpful in children with stress-related behavioralproblems. The animal research showed that stress-inducedPFC deficits could be prevented by pretreatment with verylow doses of neuroleptics or with an aradrenergic agonist.However, drawing parallels between children and animalsshould be made with caution for several reasons. The labora­tory studies were performed with acute stress exposure inadult animals; the effects of pharmacological interventionshave not been tested under chronic stress conditions or injuvenile animals. Furthermore, even in animal studies theresults with neuroleptics were problematic: there was a verynarrow therapeutic dose window, and even low clinical doseswere usually too high to restore PFC function. The danger oftardive dyskinesia and other neuroleptic-related disorders alsocautions against the use of these compounds in children.

The usefulness of aradrenergic agonists in preventingstress-induced cognitive deficits in animals may have moreclinical relevance, as clonidine and guanfacine arc already inuse for the treatment of AOHO. Animal studies indicate thatguanfacine is more effective than clonidine in preventingstress-induced working memory deficits. It is important to

note that aradrenergic agonists improve working memoryperformance in animals under conditions of either insuf-

221

Page 3: ( Stress Impairs Prefrontal Cortical Function · Lombroso, M.D. Development ofthe Cerebral Cortex: XI\(Stress Impairs Prefrontal Cortical Function AMY F.T.ARNSTEN, PH.D. A ltl-year-oldboy

ARNSTEN

fieient (e.g., catecholamine depletion) or excessive (e.g., stress)catecholamine receptor stimulation in the PFC. This qualitymay enhance the clinical utility of these compounds, but itdoes not help us distinguish between hypo- versus hyper­catecholaminergic states when considering potential etiologiesof PFC disorders in children. The animal data indicate thatbehavioral problems could arise from both states, as eithertoo little or too much catecholamine receptor stimulation

results in PFC dysfunction.Our new neurobiological perspective suggests that behav­

ioral problems in children can arise from PFC dysfunctiondue to either external factors, such as exposure to a stressfulenvironment, or from inherent changes in PFC circuits, suchas genetic changes in dopamine or norepinephrine trans­porters. It is possible that we assign the ADHD diagnosis tochildren with inherent changes, while those with visiblecauses for their behavioral problems are less likely to be giventhis diagnosis.

Current research suggests that common neurochemicalchanges in the PFC may underlie these problems irrespectiveof the cause. The similarity between ADHD symptoms andstress-induced PFC deficits may help to explain why ADHDis often not taken seriously as a true biological disorder. Ournew understanding of stress effects on PFC function may alsohelp to clarify why highly structured, low-stress environmentscan be especially helpful in treating children with ADHDand related problems. By understanding that behavioralproblems may have a neurobiological basis, we may be able todeal with them more compassionately and intelligently.

WEB SITES OF INTEREST

WWW.stfcss.org

www.aaets.org

ADDITIONAL READINGS

Arnsrcn AFT (1997), Catecholamine regulation of prefrontal cortex. J Psy­chopharmacol 11:151-162

Arnsten AF1~ Goldman-Rakic PS (1998). Noise stress impairs prefrontalcortical cognitive funcrion in monkeys: evidence for a hyperdopam­inergic mechanism. Arch Gen Psychiatry 55:362-369

Arnsten AFT. Steere JC Hunt RD (1996). The contribution of alpha-2notadrenergic mechanisms to prefrontal cortical cognitive function:potential significance to attention deficit hyperactivity disorder. Arch GenPsychiatry 53:448-455

Barkley RA (1997), ADHD and the Nature ofSelf-Control. New York: GuilfordBroadbent D (1971). Decision and Stress. London: Academic PressGoldman-Rakic PS (1992), Working memory and the mind. Sci Am 267:

110-117Yang CR. Seamans JK (1996). Dopamine D1 receptor actions in layers V-VI

rat prefronral cortex in vitro: modulation of dendritic-somatic signalintegration. J Neurosci 16:1922-1935

Zahrt J. Taylor JR. Mathew RG. Arnsten AFT (1997), Supranormal stimula­tion of D 1 dopamine receptors in the rodent cortex impairs spatial work­ing memory performance. J Neurosci 17:8528-8535

Accepted Augmt 13, 1')98.

Dr. Arnstm is Research Scientist. Section of Neurobiology. Yale Unioersity

School of Medicine. Nell' Hallen. CT

Correspondence to Dr. Arnsten, Section of Neurobiology. Yale University

SdJOo! of Medicine, 330 Cedar Strut, Nell' Hauen, CT 06520; e-mail:

amy.amstmG.iJyale.edu.

Dr. Lombrosos e-mail address is [email protected].

0890-8567!99/3802-0220/$03.00/0©1999 by the American Academyof Child and Adolescent Psychiatry.

Erratum

In analyses of data that were published in the article "Validity of DSM-IV Attention-Deficit/HyperactivityDisorder for Younger Children" by Benjamin B. Lahey et al. (Vol. 37, pp. 695-702), one symptom of inattentionreported by teachers was incorrectly labeled in the SAS program. As a result, the number of inattention symptomsreported by teachers was underestimated for some children. After the error was corrected, one additional child metDSM-IV criteria for ADHD and some children's assignment to the subtypes of ADHD changed (2 more childrenmet criteria for the combined type, 2 fewer children met criteria for the predominantly hyperactive-impulsive type,and 1 more child met criteria for the predominantly inattentive type). When all statistical analyses were repeatedusing the corrected variable, there were few changes in findings. Unlike in the published findings, however, childrenwho met criteria for the combined type were significantly more likely to have had an unintentional injury than thecomparison children, children who met criteria for the combined type were not rated by teachers as exhibiting moreshy/withdrawn behavior than comparison children, children who met criteria for the combined type were not ratedby teachers as ignored by more classmates than comparison children, and children who met criteria for the pre­dominantly inattentive type were not given significantly lower ratings of adaptive functioning by interviewers thancomparison children. When children who met criteria for oppositional defiant disorder or conduct disorder weredropped from the sample in follow-up analyses, children who met criteria for the predominantly hyperactive­impulsive type exhibited significantly greater underachievement in mathematics relative to intelligence than com­parison children. Overall, the findings still strongly support the validity of all subtypes of the diagnosis of DSM-IVADHD in terms of concurrent impairment. A corrected copy of the article may be obtained from Benjamin B.Lahey, Ph.D., Department of Psychiatry (MC 3077), University of Chicago, 5841 South Maryland Avenue,Chicago, IL 60637, or via e-mail at [email protected]. The author regrets the errors.

222 J. AM. ACAD. CIIILD ADOLESC. PSYCHIATRY, 38:2. FEIlRUARY 1999