do psychotherapies produce neurobiological effects?

REVIEW ARTICLE

Do psychotherapies produce neurobiologicaleffects?

Kumari V. Do psychotherapies produce neurobiological effects?Acta Neuropsychiatrica 2006: 18:61–70. # Blackwell Munksgaard 2006

Background: An area of recent interest in psychiatric research is theapplication of neuroimaging techniques to investigate neural eventsassociated with the development and the treatment of symptoms in anumber of psychiatric disorders.Objective: To examine whether psychological therapies modulatebrain activity and, if so, to examine whether these changes similar tothose found with relevant pharmacotherapy in various mental disorders.Methods: Relevant data were identified from Pubmed and PsycInfosearches up to July 2005 using combinations of keywords including‘psychological therapy’, ‘behaviour therapy’, ‘depression’, ‘panic dis-order’, ‘phobia’, ‘obsessive compulsive disorder’, ‘schizophrenia’, ‘psy-chosis’, ‘brain activity’, ‘brain metabolism’, ‘PET’, ‘SPECT’ and ‘fMRI’.Results: There was ample evidence to demonstrate that psychologicaltherapies produce changes at the neural level. The data, for example indepression, panic disorder, phobia and obsessive compulsive disorder(OCD), clearly suggested that a change in patients’ symptoms andmaladaptive behaviour at the mind level with psychological techniques isaccompanied with functional brain changes in relevant brain circuits. Inmany studies, cognitive therapies and drug therapies achieved therapeu-tic gains through the same neural pathways although the two forms oftreatment may still have different mechanisms of action.Conclusions: Empirical research indicates a close association betweenthe ‘mind’ and the ‘brain’ in showing that changes made at the mind levelin a psychotherapeutic context produce changes at the brain level. Theinvestigation of changes in neural activity with psychological therapies isa novel area which is likely to enhance our understanding of themechanisms for therapeutic changes across a range of disorders.

Veena Kumari

Department of Psychology, Institute of Psychiatry, King’s College

London, London, UK

Keywords: behaviour therapy; brain; functional neuroimaging;

neural networks; psychiatric disorders

Correspondence: Veena Kumari, PhD, PO 78, Institute of

Psychiatry, De Crespigny Park, London SE5 8AF, UK,

Tel: þ44 207 848 0233; Fax: þ44 207 848 0646;

E-mail: [email protected]

Introduction

Recent advances in neuroimaging techniqueshave helped to enhance the understanding ofneural correlates of mental phenomena in psy-chiatric disorders (1). An area of continuinginterest in psychiatric research has been the appli-cation of imaging techniques, such as positronemission tomography (PET) and functional mag-netic resonance imaging (FMRI), to elucidate thebrain changes associated with symptoms of thedisorder and their treatment with pharmacother-apy (2–5). In several psychiatric disorders, psy-chological therapies are also known to be

effective in reducing symptoms, for example indepression (6,7), phobia (8–10) and panic disorder(11–13). Therefore, a topical question, central tothe approach of elucidating the brain basis ofmental disorders, is: do psychological therapieshave neurobiological effects?

Empirical research has begun to answer thisquestion, with relevant data now emerging fromstudies in patients with depression, panic disorder,phobia, obsessive compulsive disorder (OCD)and schizophrenia. Brain changes seen withnon-pharmacological means in healthy popula-tions, such as increased dopamine tone during

Blackwell Munksgaard 2006: 18: 61–70 # 2006 The AuthorPrinted in Singapore. All rights reserved Journal compilation # 2006 Blackwell Munksgaard

ACTA NEUROPSYCHIATRICA

# Blackwell Munksgaard, Acta Neuropsychiatrica, 18, 61–70 61

meditation-induced changes of consciousness (14)and increased left-frontal lobe activity, which isgenerally associated with positive emotions(15,16), during rest as well as emotional challengein trained meditators relative to (non-trained) con-trols (17), have also indicated that changes at themind level are accompanied by changes at thebrain level. As pointed out by Baxter et al. (18),this is perhaps not surprising given that even inlower animals such as the sea plug, Aplysia, learn-ing of stimulus-response behaviour, which is ger-mane to many behaviour therapy techniques (19),is mediated by changes at the synaptic level (20,21).

The aims of this article are to describe theknown or potential neural effects of psychologi-cal therapies in a therapeutic context, to discussthem in terms of possible underlying mechanismswhich lead to therapeutic changes, and to com-pare them with those found to accompany ther-apeutic changes with relevant pharmacologicaltreatments. To achieve these aims, relevant datawere identified from Pubmed and PsycInfosearches up to July 2005 using combinations ofkeywords including ‘psychological therapy’, ‘cog-nitive behaviour therapy’, ‘depression’, ‘panicdisorder’, ‘phobia’, ‘obsessive compulsive disor-der’, ‘schizophrenia’, ‘psychosis’, ‘brain activity’,‘brain metabolism’, ‘PET’, ‘SPECT’ and ‘fMRI’.

Neurobiological effects of psychotherapies

The specific details of all relevant studies arepresented in Table I and discussed in the follow-ing sections classified by the disorder.

Depression

A well-known neural model of depression impli-cates limbic-cortical dysregulation (3,22). Thereis empirical evidence for functional abnormalitiesof the temporal, limbic, frontal and basal gangliaregions in this disorder (23,24). Increased activityin the ventral structures and decreased activity inthe dorsal structures have been particularly asso-ciated with a symptomatic depressive state(22,25–27). Neural changes in the prefrontalregions have been most consistently associatedwith anti-depressant response, although thedirection of such changes varies (increases ordecreases are seen) across studies and treatments(25,27–29). Hypo-responding of the rostral cin-gulate has been associated with resistance topharmacotherapy in depression (30,31).

Randomized clinical trials have shown thatpatients suffering from both mild and major

depression respond equally well to cognitive ther-apy and antidepressant drug therapy (6,7). Thefirst study (32) to examine the neural effects of apsychological intervention, interpersonal therapy(IPT), reported changes primarily in the frontaland temporal regions with IPT (Table I), whichwere considered to be associated with clinicalimprovements. This study also examined theneural effects of paroxetine treatment in a para-llel group and reported similar changes as seen inthe group treated with IPT. In addition, the par-oxetine-treated group showed decreased metabo-lism in the ventrolateral prefrontal cortex as alsoreported previously with paroxetine treatment(28). It is difficult to determine from this studywhether the effect of paroxetine in the ventrolat-eral prefrontal cortex was specific to this treatmentor was present because of a greater improvementin this group relative to the IPT group (Table I).Another study (33) which examined the neuralchanges with IPT or venlafaxine hydrochloridereported increased blood flow in the right basalganglia in both treatment groups but increasedlimbic blood flow only in the IPT group.However, the symptom reduction was againmore prominent in the drug-treated group, andallocation to IPT or drug treatment was based onpatient preference as was the case in the firststudy (32). Although the interpretations of theresults of these two studies were complicated bysuch confounding issues, they opened an import-ant avenue of scientific enquiry in showing theeffects of IPT at the brain level in depression

In a more recent study (34) which examined theneural effects of cognitive behaviour therapy(CBT) vs. those of paroxetine, the main neuralchanges associated with CBT were found to bedifferent to those seen with pharmacotherapy andinvolved increased activity (post-treatment > pre-treatment) in the cingulate, frontal and hippocam-pus regions. Interestingly, patients treated withCBT in this study responded as well as thosetreated with pharmacotherapy, and both groupsshowed decreased metabolism in the ventrolat-eral prefrontal cortex, an effect that was pre-viously seen with pharmacotherapy but not withIPT (32). This particular finding strengthens theargument for change in the ventrolateral prefron-tal cortex to be associated with an improvedclinical state. The neural effects unique to CBTare suggested to reflect a cortical ‘top–down’mechanism of action for CBT (35). However,further data would be required to firmly establishthis position since this study also allocatedpatients to CBT based on their preference, andthus the possibility that different pre-treatment

Kumari

62

Tabl

e1.

Revie

wed

stud

ies

ofth

eef

fect

sof

psyc

holo

gica

lthe

rapi

eson

brai

nac

tivity

Auth

or/s

Diso

rder

Imag

ing

mod

ality

Subj

ects

and

desig

nPs

ycho

ther

apy

deta

ilsCo

mpa

rison

with

drug

ther

apy

Expe

rimen

tCl

inica

lfin

ding

sNe

ural

effe

cts.

Brod

yet

al.(

32)

Depr

essio

nPE

T24

patie

nts

and

16he

alth

yco

ntro

lssc

anne

dtw

icew

ith12

wee

ksof

inte

rval.

All

subj

ects

drug

-free

atth

etim

eof

initi

alsc

an.

Betw

een

scan

s,10

patie

nts

(5M

,5F)

rece

ived

paro

xetin

ean

d14

patie

nts

(8M

,6F)

rece

ived

IPT.

Allo

catio

nto

treat

men

tty

peba

sed

onpa

tient

pref

eren

ce.

Wee

klyIP

Tse

ssio

nsfo

r12

wee

ksw

itha

train

edth

erap

ist.

The

IPT

sess

ions

focu

sed

onim

prov

emen

tof

patie

nts’

socia

lne

twor

ksan

dre

duct

ion

ofde

pres

sive

sym

ptom

s.Th

epr

imar

ypr

oble

mfo

ciof

ther

apy

wer

ero

letra

nsiti

onfo

rsix

patie

nts,

inte

rper

sona

ldisp

ute

fort

hree

patie

nts,

socia

ldef

icitf

oron

ean

dgr

ief

foro

nepa

tient

.

Yes

Rest

ing

stat

eBo

thtre

atm

ents

prod

uced

clini

cali

mpr

ove-

men

tbu

tth

isw

asgr

eate

rin

the

drug

-tre

ated

grou

p.

Decr

ease

sin

pref

ront

alco

rtex

and

left

ante

rior

cingu

late

and

incr

ease

sin

left

tem

pora

llo

bem

etab

olism

inbo

thpa

roxe

tine-

and

IPT-

treat

edpa

tient

grou

ps.

Thes

ech

ange

sw

ere

not

seen

inth

ehe

alth

yco

ntro

lgro

upex

cept

fora

nin

crea

sein

the

right

infe

riort

empo

ralm

etab

olism

.

Mar

tinet

al.(

33)

Depr

essio

nSP

ECT

28pa

tient

ssc

anne

dtw

ice(a

tbas

eline

and

then

post

-trea

tmen

t).Al

lpat

ients

drug

-free

atth

etim

eof

initi

alsc

an.

Wee

kly1

hIP

Tse

ssio

nsw

ithth

esa

meth

erap

istfo

r6w

eeks

.Ye

sRe

stin

gst

ate

Both

treat

men

tspr

oduc

edsig

nific

ant

clinic

alim

prov

emen

twith

som

ewha

tgre

ater

impr

ovem

enti

nth

edr

ug-tr

eate

dgr

oup.

Both

treat

men

tspr

oduc

edin

crea

sed

bloo

dflo

win

the

right

basa

lgan

glia.

Limbi

cbl

ood

flow

incr

ease

dw

ithIP

Ton

ly.Be

twee

nsc

ans,

13pa

tient

s(4

M,9

F)al

loca

ted

tore

ceive

IPT

and

15pa

tient

s(4

M,

11F)

tore

ceive

venl

afax

ine

hydr

ochl

orid

efo

r6w

eeks

23pa

tient

sran

dom

ized

tore

ceive

drug

treat

men

tor

IPT.

Thre

epa

tient

sal

low

edno

n-ra

ndom

ized

venl

afax

inean

don

epa

tient

non-

rand

omize

dIP

Tw

hoex

pres

sed

stro

ngpr

efer

ence

.

Gold

appl

eet

al.(

34)

Depr

essio

nPE

T14

drug

-free

patie

nts

(initi

ally

17bu

t3

did

not

com

plet

e)sc

anne

dbe

fore

and

afte

rtre

atm

ent

with

CBT.

Com

paris

onto

anin

depe

nden

tgr

oup

of13

6-w

eek

paro

xetin

e-tre

atm

ent

resp

onde

rsca

rried

out

toex

amin

esp

ecifi

city

ofid

entif

ied

CBT

effe

cts.

15–2

0in

divid

ualiz

edse

ssio

nof

CBT

bya

train

edth

erap

istac

cord

ingto

the

treat

men

tm

anua

lde

scrib

edby

Beck

etal

.(93

).

Yes

Rest

ing

stat

eNi

nepa

tient

smet

the

crite

ria(a

tlea

st50

%re

ducti

onin

depr

essio

nra

tings

)fo

ra

full

resp

onse

.Rem

ainin

gfiv

esh

owed

nole

ssth

an35

%re

ducti

onin

depr

essio

nra

tings

.Al

lpat

ient

swer

ein

clude

din

the

analy

sisof

treat

men

teffe

cts.

Incr

ease

dm

etab

olism

inth

ehi

ppoc

ampu

san

dde

creas

edm

etab

olism

inth

efro

ntal

and

parie

tal

corti

ces

with

CBT.

The

reve

rse

patte

rnse

enw

ithpa

roxe

tine-

treat

men

t(i.e

.dec

reas

ein

the

hipp

o-ca

mpu

san

din

crea

ses

inth

efro

ntal

and

parie

tal

regi

ons).

Addit

iona

luni

que

chan

ges

seen

with

each

.CB

Tgr

oup:

incr

ease

dm

etab

olism

inth

ean

terio

rcin

gula

tean

dde

crea

sed

met

abol

ismin

the

med

-ia

lfro

ntal

,orb

italf

ront

alan

dpo

sterio

rcin

gula

tePe

roxe

tine

grou

p:In

crea

sed

met

aboli

smin

brai

nin

stem

and

cere

bellu

man

dde

crea

sed

met

ab-

olism

vent

ral

subg

enua

lcin

gula

tew

ithpa

roxe

-tin

e-tre

atm

ent.

Com

mon

tobo

thgr

oups

:dec

reas

edm

etab

olism

inth

eve

ntra

llat

eral

pref

ront

alco

rtex.

Pras

koet

al.(

38)

Pani

cdi

sord

erPE

T12

patie

nts

scan

ned

twice

,bef

ore

and

afte

rCBT

.Al

lpat

ient

sdr

ug-fr

eeat

the

time

ofin

itial

scan

.Af

tert

heba

selin

esc

ans,

sixpa

tient

s(3

M,3

F)ra

ndom

lyas

signe

dto

rece

iveCB

Tan

dsix

patie

nts

(3M

,3F

)to

rece

ivean

ti-de

pres

sant

med

icatio

n(2c

italop

ram,

2ser

tralin

e,2v

enlaf

axine

)fo

r3

mon

ths.

6-w

eek

CBT

grou

ptre

atm

ent

prog

ram

me(th

ree

grou

pse

ssion

s/w

eek)

cons

istin

gof

educ

atio

nan

dco

rrecti

vein

form

atio

n,co

gniti

vere

stru

cturin

g,tra

ining

india

phra

gmat

icbr

eath

ingan

dre

laxat

ion,

intro

cept

ivean

din

vivo

expo

sure

and

prob

lemso

lving

.Tw

oind

ividu

albo

oste

rse

ssion

sin

the

8th

and

12th

wee

ks.

Yes

Rest

ing

stat

eBo

thgr

oups

show

edcli

nica

lim

prov

emen

t.CB

T-tre

ated

grou

pap

pear

edto

show

am

ore

rapi

dch

ange

.

Both

treat

men

tsin

crea

sed

upta

kein

the

left

hemi

sphe

rein

the

pref

ront

al,

tem

poro

parie

tal

and

occip

ital

regi

ons

and,

inth

erig

hthe

mi-

sphe

re,p

oste

riorc

ingu

lum

and

decr

ease

dup

take

inth

ein

the

left

hem

isphe

rein

the

front

al,

tem

pora

land

parie

talr

egio

ns.

Do psychotherapies produce neurobiological effects?

63

Ta

ble

1:(c

onti

nued

)

Auth

or/s

Diso

rder

Imag

ing

mod

ality

Subj

ects

and

desig

nPs

ycho

ther

apy

deta

ilsCo

mpa

rison

with

drug

ther

apy

Expe

rimen

tCl

inica

lfin

ding

sNe

ural

effe

cts.

Paqe

tteet

al.(4

3)Ph

obia

fMRI

12dr

ug-fr

eew

omen

with

spid

erph

obia

scan

ned

befo

rean

daf

ter

effe

ctive

CBT

and

13he

alth

yw

omen

scan

ned

once

.

Phob

icsu

bject

sm

eton

cea

wee

kw

ithth

eir

ther

apist

sfo

ra

3-h

inte

nsive

grou

p(n¼

4/gr

oup)

sess

ion.

The

ther

apy

cons

isted

ofgr

adua

l-exp

osur

e-ba

sed

treat

men

tto

spide

rs(9

)us

inggu

ided

mas

tery

(94).

NoAc

tivat

ion

para

digm

.W

ithin

asin

gle

expe

rimen

t,su

bjec

tsw

ere

expo

sed

tofiv

e30

-sbl

ocks

offil

mex

cerp

tsof

liv-

ing

spid

ers

inca

ptivi

ty(a

cti-

vatio

nco

nditi

on),

alte

rnat

ing

with

five

30-s

bloc

ksof

emo-

tiona

llyne

utra

lfilm

exce

rpts

disp

layin

gbu

tterfl

ies

inna

t-ur

e(co

ntro

lco

nditi

on).

Activ

atio

nan

dco

ntro

lblo

cks

sepa

rate

dby

15-s

blan

kbl

uesc

reen

.

Allp

hobic

subj

ects

resp

onde

dw

ellt

oCB

T.Th

epr

e-se

lect

edcr

iteria

for

are

spon

sew

asde

fined

asbe

ingab

leto

touc

hth

een

tire

serie

sof

pict

ures

show

ing

spid

ers,

the

tele

visio

nsc

reen

show

ingth

esp

iders

and

the

real

spide

rsw

ithou

trep

ortin

gfe

arre

actio

ns.

Befo

reCB

T,fM

RIac

tivity

inth

edo

rsola

tera

lpr

efro

ntal

corte

xan

dth

epa

ra-h

ippo

cam

pal

gyru

sco

rrela

ted

with

trans

ient

fear

durin

gth

evie

win

gof

phob

ogen

icth

est

imuli

inph

obic

sub-

ject

s.Th

ese

brai

nre

spon

ses

wer

eab

sent

inhe

alth

yco

ntro

lsan

din

phob

icsu

bjec

tsaf

ter

they

impr

oved

clini

cally

with

CBT.

Baxt

eret

al.(1

8)OC

DPE

T18

OCD

patie

nts

scan

ned

twice

.Al

lpa

tient

sdr

ug-fr

eeat

the

time

ofin

itial

scan

.Be

twee

nth

esc

ans,

nine

patie

nts

(3M

,6

F)re

ceive

dtre

atm

entw

ithflu

exet

ine

hydr

ochl

orid

ean

dni

nepa

tient

s(4

M,5

F)re

ceive

dCB

Tov

er8–

12w

eeks

.

Once

ortw

icea

wee

kmet

with

thei

rthe

rapi

stfo

rap

prox

imat

ely

1h

forr

evie

wof

assig

nmen

tsfo

rin

divid

ualiz

edex

posu

rean

dre

spon

sepr

even

tion

exer

cises

whi

chsu

bject

sdi

das

hom

ewor

kan

dse

lf-m

onito

red

with

grap

hs/d

iarie

s.M

any

patie

nts

also

atte

nded

CBT

grou

pfo

rpat

ients

.

Yes

Rest

ing

stat

eSi

xpat

ients

met

the

pre-

esta

blish

edcri

terio

n(at

least

30%

redu

ction

insy

mpt

omsc

ores

)fo

racli

nical

resp

onse

.

Righ

tca

udat

enu

cleus

met

abol

ism,

divid

edby

ipsil

ater

alhe

misp

here

met

abol

ism(C

d/he

m)

dece

ased

afte

rtre

atm

enti

nbo

thCB

Tan

ddr

ug-

treat

edgr

oups

.The

sech

ange

swer

eno

tdet

ecte

din

the

heal

thy

cont

rolg

roup

atre

-sca

nnin

g.

Allo

catio

nto

treat

men

tty

peba

sed

onpa

tient

pref

eren

ce.

Four

heal

thy

cont

rols

(2M

,2F)

scan

ned

twice

with

8–12

wee

ksin

terv

al.

Rema

inin

gth

ree

wer

epo

oror

non-

resp

onde

rs.

Schw

artz

etal

.(50

)OC

DPE

TNi

nedr

ug-fr

eepa

tient

s(2

M,7

F)sc

anne

dtw

ice:

befo

rean

daf

ter

8–12

wee

ksof

CBT.

Furth

er,

nine

drug

-free

patie

nts

from

apr

eviou

sst

udy

(18)

inclu

ded

inan

alys

is.

Sim

ilarp

roce

dure

sas

desc

ribed

forB

axte

reta

l.(1

8).No

Rest

ing

stat

eNe

wsa

mpl

e:six

patie

nts

met

the

pre-

esta

blish

edcr

iterio

nfo

racli

nica

lres

pons

e.Re

maini

ngth

reew

erep

ooro

rnon

-resp

onde

rs.To

tals

ample

:12

(outo

f18)

patie

nts

mett

hecri

terio

nfo

racli

nical

resp

onse

.

Bila

tera

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64

characteristics may be a reason for differentialpost-treatment effects of CBT and pharma-cotherapy cannot be discounted.

A recent meta-analysis (36) has shown thatpatients who respond well to CBT have differentbiological deficits to those who respond well topharmacotherapy. Specifically, limbic–corticalconnections have been demonstrated to differentiateresponders from non-responders to pharma-cotherapy, with additional limbic abnormalities inthe non-responder group, while a more limitedlimbic–cortical connection and additional cortical–cortical connections are found to differentiateresponders to CBT from responders to pharma-cotherapy. Further studies are required toexamine modulation of brain activity withpsychological and pharmacological therapieswhile taking (pre-treatment) patient characteris-tics, their past treatment history and currentpreferences into account.

Panic disorder

The neuroanatomical model proposed byGorman et al. (37) links the clinical phenomenaof unexpected panic attacks to discharge of brainstem nuclei, anticipatory anxiety to limbic activ-ation and kindling, and avoidance to medialprefrontal cortical activation. Both pharma-cotherapy and CBT are known to amelioratethe symptoms of this disorder (11–13). In themodel by Gorman et al. (37), pharmacotherapyis hypothesized to achieve its effect throughstabilization of brain stem nuclei and CBTthrough modification of cognitive processing atthe level of the prefrontal cortex and the hippo-campus. The predictions relevant to the hypothe-sized neural effects of CBT seem to have receivedindirect support from the earlier noted neuraleffects of CBT in depression.

To date only one study (38) has examined themodulation of neural activity with CBT in panicdisorder. This study also examined the neuraleffects of treatment with an anti-depressant in aparallel-group design and random allocation ofpatients to receive CBT or anti-depressant treat-ment. It reported similar neural changes in thefrontal and temporal regions (and no change insubcortical regions) and improvements of similarmagnitude, with a more rapid decrease in psy-chopathology with CBT, in both treatmentgroups. The neural regions affected by bothtreatments, as suggested themselves by theauthors (38), are part of an alarm system thatsignals danger. Post-treatment neural effects in

this study thus seem associated with clinicalimprovements, regardless of the treatment type.The two forms of treatments may still have dif-ferent mechanisms of action. This study had onlysix subjects in each treatment arm and thus mayhave lacked power to detect additional, perhapsmore subtle, neural effects unique to CBT andpharmacotherapy which, if found, may informabout particular mechanisms leading to clinicalimprovements via CBT or anti-depressant treat-ment in this disorder.

Phobia

Increased cerebral blood flow in the visual asso-ciation cortex and decreased blood flow in thehippocampus, posterior cingulate, orbitofrontal,prefrontal and temporal cortices have beenreported in association with fear and anxietygenerated by phobogenic stimulation (e.g. videoof spiders to arachnophobes) in patients withspecific phobias (39,40). Of these, increased activ-ity in the visual cortex to phobogenic stimulationhas been linked to enhanced visual attention tonoted significance (potential threat) of the phobicstimulus and reduced activity in the hippocam-pus, posterior cingulate, orbitofrontal, prefrontaland temporal cortices to reduced conscious pro-cessing of this stimulus and a defence reaction toit (39,40). Hyperactivity in the limbic and para-limbic regions during imagery of the specificphobogenic stimulus has also been seen andinterpreted as reflecting autonomic hyperactivityand exaggerated anxiety responses to this stimu-lus (41). The neural response in the right frontalcortex has been suggested to be directly related tothe use of cognitive strategies for coping with thephobogenic stimulus, based on the observationsof reduced activation in this region in fearful (butnot panic) patients but increased activation inthose who showed severe panic (42).

An effective therapeutic approach for reducingthe symptoms of specific phobias is CBT consist-ing of exposure-based treatment to phobogenicstimuli together with education for changingnegative cognitive misattributions related tothese stimuli (8–10). There is only one publishedstudy so far on the neurobiological effects ofCBT in this disorder (43). The observations ofthis study suggest that successful CBT modifiesneural activity in the dorsolateral prefrontal cor-tex (suggested to reflect the use of pro-activemeta-cognitive strategies aimed at self-regulationof fear and anxiety) and the para-hippocampalgyrus (suggested to be related to automatic


65

re-activation of the fear memory) in response tothe phobogenic stimulus. These authors (43)posit that their observations lend strong supportto the view (44) that ‘CBT reduces phobic avoid-ance by de-conditioning contextual fear learnedat the level of hippocampal/parahippocampalregion, and by decreasing cognitive misattribu-tions and catastrophic thinking at the level of theprefrontal cortex’.

OCD

Several neuroimaging studies (45–48) indicatethat a cortico-striato-thalamic brain circuit isheavily involved in production of OCD symp-toms, that is recurrent unwanted thoughts(obsessions) and conscious, ritualized acts (com-pulsions). There is evidence that both pharma-cotherapy using strong selective serotoninreuptake blockers and specific behaviour therapyconsisting of exposure and response preventioneffectively reduce the symptoms of OCD in mostpatients (49).

The neural changes associated with behaviourtherapy vs. those associated with pharmacother-apy (fluxetine hydrocholoride) in OCD wereinvestigated using PET by Baxter et al. (18)more than a decade ago. These researchersreported similar changes in the right caudatemetabolic rate with both forms of treatments.In a later study, the same research group (50)observed changes in caudate function in patientswho improved with behaviour therapy but not inthose whose symptoms failed to respond to it.These findings have been interpreted as reflectinga normalizing effect of successful treatments onthe functions of the caudate nucleus which areimplicated in the development of habit patternsand also in determining whether a given stimulusimpinges upon the cortico-striato-thalamic cir-cuit involved in OCD and therefore affects theindividual’s behaviour (18,50).

Schizophrenia

The main candidate brain regions for abnormal-ities in schizophrenia have been the frontal cortex,temporal cortex, striatum, amygdala, hippocam-pus and thalamus (51). Typical antipsychotics,which mainly act on the dopamine-D2 receptors,exert their therapeutic effects via their actions inthe striatum, though other areas such as the fron-tal cortex, thalamus and hippocampus are alsoimplicated (2). Newer atypical antipsychotics,

which affect dopamine receptors to a lesser extentand, in addition, affect serotonergic, muscarinic,histaminergic and a-1 adrenergic receptors (52),seem to induce more widespread changes in manybrain regions, including the frontal cortex, thala-mus and basal ganglia regions (4,53,54). In recentyears, attention has focused on the benefits ofCBT as an adjunct treatment to drug therapy,especially for medication-resistant patients(55–59). CBT addresses positive, behaviouraland emotional symptoms while taking intoaccount the stage of the disorder and the person’sspecific needs and has been shown to reliablydiminish positive symptoms of schizophreniaand the related distress (58,60–63). In some stud-ies, CBT has also been shown to have strongeffects on negative symptoms and/or depression,with suggestions that they might be secondary toits effects on positive symptoms (64–67). It isfurther associated with a reduced relapse rate(66,68) and improved social adjustment (69) com-pared with routine care. The clinical effects ofCBT can be medium to large (57,70) and gainmay continue over time (57).

One fMRI study (71) has reported increasedfrontal activity during a working memory taskin a group of six schizophrenia patients withsevere cognitive difficulties after 12 weeks of cog-nitive remediation therapy, but there is no pub-lished study of the neural correlates of the effectsof CBT on symptoms of the illness in schizophre-nia. It is plausible that CBT, as in depression(34), also acts via cortical ‘top–down’ mechan-isms in schizophrenia, especially in patients whohave not responded well to medication (so far theeffects of CBT are most reliably shown in thisparticular group). On theoretical and empiricalgrounds, the neural region (within a neuralnetwork) likely to be particularly implicated inthe effectiveness of CBT in schizophrenia, interms of its effects on symptoms, depression andsubjective mood (65), is the anterior cingulate. Ithas connections with both cortical and subcorti-cal structures and thus has the capacity to amal-gamate emotional and cognitive experiences. Thesymptoms of thought insertion and alien controlin schizophrenia have been attributed to deficitsin self-monitoring of thoughts and intentions(72). There is empiric evidence that positivesymptoms, such as hallucinations and delusions,reflect impaired awareness of self-generatedverbal material and misattribution of speech(73–76). Anterior cingualte has also been impli-cated in self-monitoring and implementation ofselected action in healthy subjects (73,77).Importantly, activation deficit in AC in patients

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with schizophrenia, revealed with fMRI, isassociated with impaired self-monitoring ofperformance (78). In an exploratory study (79),cognitive flexibility has emerged as a predictor ofresponsiveness to CBT; this function may alsoinvolve the anterior cingulate given its role inonline monitoring, error detection and conflict.On the basis of the evidence in other disorders,the dorsolateral prefrontal cortex and the hippo-campus should also be considered of great interestin the investigations of neural mechanisms under-lying CBT effects in schizophrenia. It would alsobe important to establish whether schizophreniapatients who show a meaningful clinical responseto CBT have differential brain/cognitive profilesto those who fail to respond or from those whorespond well to pharmacotherapy.

Other

Some data very relevant to the aim of this articlehave very recently emerged from a study ofpatients with irritable bowel syndrome (IBS)(80). IBS is considered to manifest disturbancein the brain-gut axis (81). IBS patients also showhigh rates of psychiatric comorbidity (82), tem-poral patterns of symptoms during sleep-wakecycle (disappearance of symptoms during sleep)(83), and the lack of correspondence betweenpain intensity and measured gut motility (84).Imaging evidence reveals differences betweenIBS patients and healthy controls in neuralresponses to actual or anticipated rectal stimuli(85). Cognitive factors such as the beliefs andthoughts of IBS patients about their symptomsalso affect the symptoms of IBS (86,87).Cognitive therapy has been shown to be effectivein IBS (88).

A very recent study (80) has shown that cogni-tive therapy, consisting of self-monitoring, cogni-tive reappraisal, worry control and problemsolving training, reduces limbic activity duringrectal balloon distension in patients with IBS.These data suggest that cognitive therapy in IBSproduces changes in the network of brain circuitsinvolving limbic regions that are commonly asso-ciated with attention to fear-related stimuli andvigilance (89). As noted earlier for OCD, similarneural changes were previously reported by pla-cebo-controlled drug studies of IBS patients(90,91). It is possible that the cognitive therapyand pharmacotherapy of IBS achieved therapeu-tic gains through a common (presumably symp-tom related) pathway, though the two forms of

treatments may have different mechanisms ofaction.

Conclusions

The reviewed studies clearly demonstrate thatpsychological interventions, such as CBT, areable to modify activity in dysfunctional neuralcircuitries linked to development of various psy-chopathological conditions. The data availableso far, for example in depression, panic disorder,phobia and OCD, clearly suggest that a change inpatients’ symptoms and maladaptive behaviourat the mind level with psychological techniquescould potentially change (normalize) the brain atthe functional level in the same way as faultybrain signals resulting from dysfunctional neuralcircuitries lead to psychopathological behaviour.

Investigation of changes in neural activity withpsychological therapies is clearly a novel area inwhich well-conducted research is likely to haveimportant implications for our understanding ofthe mechanisms of formation and maintenance ofsymptoms as well as of therapeutic change. Forexample, if it is shown that the treatmentachieves its effect on a specific symptom by tar-geting a particular process, it would suggest theinvolvement of this specific process in mainte-nance of that symptom (92). The study ofchanges in brain activity with an effective psy-chological treatment allows us to establishchanges associated with a therapeutic responseas it has (if any) minimal side-effects and lacksdirect pharmaceutical actions to obscure brainchanges directly related to behavioural change,whereas brain changes induced by pharmacolo-gical compounds may reflect (i) the therapeuticchange, (ii) other side-effects or (iii) merely indi-cate the primary route of action of the drugirrespective of its therapeutic effects, for example,anti-dopaminergic actions in the case of typicalantipsychotics in schizophrenia. Such anapproach may also inform about the mainte-nance of particular symptoms. Although relevantresearch has begun in some disorders, themechanism for therapeutic change with drugand/or psychological therapies is yet to be firmlyestablished in most psychiatric conditions. Amajor limitation has been that not all patientsrespond to the same kind of therapy, suggestingthat variables before the initiation of a particulartherapy need to be taken into account. It wouldbe very valuable for future research to investigatepredictors of responsiveness to psychological aswell as drug therapies in relevant disorders to


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devise the most beneficial treatment plan for anindividual patient.

Acknowledgements

The author expresses profound gratitude to Professor David M.Clark (Institute of Psychiatry, King’s College London, London)for his insightful comments on many ideas presented in thisarticle and thanks the Wellcome Trust for financial support(067427/z/02/z).

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do psychotherapies produce neurobiological effects?

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