Liggan DY, Kay J: Some neurobiological aspects of psychotherapy: a

review. J Psychother Pract Res 1999; 8(2):____–____

Psychotherapy and Neurobiology; Affect; Attachment; Memory

Some Neurobiological Aspects of
Psychotherapy

A Review

Deborah Y. Liggan, M.D.

Jerald Kay, M.D.

Ever since the idea was accepted that memory is
associated with alterations in synaptic strength, studies
on the cellular and molecular mechanisms responsible
for the plastic changes in neurons have attracted wide
interest in the scientific community. This article
explores the process of memory consolidation leading to
persistent modifications in synaptic plasticity as a
mechanism by which psychotherapy facilitates changes
in the permanent storage of information acquired
throughout the individual’s life. The psychobiological
interrelationships of affect, attachment, and memory
offer a perspective regarding the etiology and treatment
of clinical disturbances of affect. Analogies between
brain physiology and modes of psychotherapy provide
the foundation for a review of psychiatric disorders
involving the inability to control fear, obsessions,
compulsions, and delusions, all of which respond to
psychotherapeutic interventions.

(The Journal of Psychotherapy Practice and

Research 1999; 8:103–114)

T

he role of learning in the conduct of psychotherapy
dates back to mid-century. The neuroanatomist

Ramón y Cajal

1

had earlier discovered that information

could be stored by modifying the connections between
communicating nerve cells in order to form associations.
In 1949 this idea was formalized by Hebb,

2

who sug-

gested that such modifications should take place between
the connected cells if and only if both neurons were
simultaneously active. From this idea emerged the well-
known Hebb’s rule: When an axon of cell A is near
enough to excite a cell B and repeatedly and persistently
takes part in firing it, some growth process or metabolic
change takes place in one or both cells such that A’s
efficacy, as one of the cells firing B, is increased. Infor-
mation is therefore encoded by strengthening the con-
nections between neurons that are simultaneously
activated. The discovery of Hebb-like synaptic plasticity
in a putative memory structure was one of the most im-
portant neurophysiological finds of the 1950s. Hebb’s
main interest was considering how complex neural net-
works could account for phenomena such as perception
and memory. His postulate of synaptic changes offered
a theory of how such changes could support the forma-

Received October 19, 1998; revised December 7, 1998; accepted
December 14, 1998. From the Department of Psychiatry, Wright State
University School of Medicine, Dayton, Ohio. Address correspon-
dence to Dr. Liggan, Department of Psychiatry, Wright State Univer-
sity School of Medicine, Dayton, OH 45401-0927.

Copyright © 1999 American Psychiatric Association

J Psychother Pract Res, 8:2, Spring 1999

103

tion of neural networks. Studies of various forms of
synaptic plasticity in the central nervous system provided
insights into the cellular and molecular mechanisms for
certain types of learning and memory.

3–5

Synaptic plas-

ticity became the target of much neurobiological re-
search as its role in memory formation was elucidated.
Evidence indicated that activity-dependent short-term
and long-term changes in strength of synaptic transmis-
sion are important for memory processes.

Cortical maps are dynamic constructs that are re-

modeled in detail by behaviorally important experiences
through life. Over the past decade, the number of ex-
perimental papers reporting physiological plasticity in
primary neocortical regions, following certain types of
controlled sensory experience, has increased greatly.

6–9

These reports have been characterized by specific changes
in receptive fields of individual neurons and/or the dis-
tributions of receptive fields across cortical maps. In par-
allel with developments in the field of cortical map plas-
ticity, studies of synaptic plasticity characterized specific
elementary forms of plasticity, including associative
long-term potentiation (LTP) and long-term depression
(LTD) of excitatory postsynaptic potentials.

10,11

A great

deal of the experimental work linking modifiable syn-
apses to macroscopic brain behavior has been carried
out in the hippocampal formation, a part of the limbic
system that has long been implicated in memory forma-
tion.

12–15

There is now a multitude of experimental evi-

dence linking hippocampal long-term potentiation to
memory formation.

16–21

In this article, we examine a memory model of psy-

chotherapy based on brain plasticity as a prerequisite for
any long-lasting change in behavior, cognition, and emo-
tions, and therefore for all psychotherapeutic effects. Af-
ter considering learning-induced anatomical changes
demonstrated by psychotherapy trials, we present analo-
gies between brain physiology and psychotherapy
schools. Finally, we discuss brain plasticity from the per-
spective of psychiatric disorders involving the inability
to control fear, obsessions, compulsions, and delusions,
all of which respond to psychotherapeutic interventions.

THE NEUROBIOLOGY OF MEMORY:

IMPLICATIONS FOR PSYCHOTHERAPY

What happens to information once it has been
transduced by the sensory receptors and passed into the
brain? Long-term potentiation is currently regarded as
the best existing memory model. There are three known

forms of synaptic plasticity at CNS synapses: 1) LTP me-
diated by N-methyl-

D

-aspartate (NMDA) receptor acti-

vation; 2) LTP mediated by voltage-dependent calcium
channel activation; and 3) LTD mediated by the NMDA
receptor. A detailed review of the status of research into
the mechanisms underlying LTP has been presented by
Bliss and Collingridge.

22

Suffice it to say that the neural

mechanism underlying cortical representational remod-
eling is that it is a result of synaptic plasticity, primarily
LTP of excitatory synapses following a Hebbian learning
rule. Post and Weiss

23

posit that mechanisms involved in

neuronal learning and memory, such as LTP and LTD,
are used and reused in the molding of personality and
behavior based on experience. They postulate that for
higher order processes such as emotional memory, such
neuroplasticity is occurring at increasingly larger num-
bers of synapses and cell assemblies with increasing
mechanistic complexity and self-organization. Experi-
ments conducted by Bear

24

reveal that many synapses

in the hippocampus and neocortex are bidirectionally
modifiable, that the modifications persist long enough to
contribute to long-term memory storage, and that key
variables governing the sign of synaptic plasticity are the

FIGURE 1. The hippocampus may store long-term memory

for weeks and gradually transfer it to specific
regions of the cerebral cortex. The diagram
illustrates this process for visual memory.
Neural input travels to the visual cortex and
then to the hippocampus, where it is stored for
several weeks before it is transferred back to
the cortex for long-term memory. The hippo-
campus has three major synaptic pathways, each
capable of long-term potentiation, which is
thought to play a role in the storage process.

Neurobiology and Psychotherapy

104

J Psychother Pract Res, 8:2, Spring 1999

amount of NMDA receptor activation and the recent
history of cortical activity (Figure 1). The principle com-
mon to representation formation in nearly all neural net-
works is that of associability, which is the idea that
streams of information are combined by forming,
strengthening, or pruning connections between them to
form new representations that can later be retrieved.

25,26

Most accounts of perceptual learning are concerned

with changes in neuronal sensitivity or changes in the
way a stimulus is represented across two distinct memory
systems, depicted in Figure 2 as explicit and implicit
memory. These two types of memory are fundamentally
separate brain functions that rely on different sets of
neural structures and physiologic properties, and they
result in distinct patterns of neural activity as detected
by positron emission tomography (PET)

27

and electro-

encephalography.

28

The explicit memory system records

experience for later recall by utilizing temporal lobe
structures, especially the hippocampus.

29,30

In contrast,

implicit memory is an enduring neural structure that
depends on the basal ganglia and whose existence is in-
ferred from observable influence on emotional behav-
iors related to early attachment experiences. Information
from this system is not available for conscious recall.

31–36

Comprehensive reviews of implicit memory have been
provided by Reber,

37

Schacter,

38

Schacter et al.,

39

and

Squire et al.

30

The distinction between the two memory systems is

significant both in the course of development over the
life cycle and in the context of memory modulation
through psychotherapy. Amini et al.

40

emphasize that

evidence exists to support the hypothesis that human
infants are equipped with a functional memory system
at birth and that memory is more capable of implicit
learning than explicit learning at this neurodevelopmen-
tal stage. Information regarding affect undergoes proc-
essing in the implicit system. The implicit system is
capable of extracting and storing prototypes and rules
from exposure to large amounts of complex information.
Once learned implicitly, rules may exert a self-perpetu-
ating bias for interpreting later experience in a manner
consistent with past experience, regardless of the appro-
priateness of such an interpretation. Therefore, the infor-
mation learned in this way is not available for conscious
processing and reflection, but rather guides behavior
without impinging on consciousness.

In psychotherapy, these patterns of implicit rules are

revealed and reflected upon, and change occurs through
the learning of new patterns explicitly repeated until the

new habit-based manner is engrained in the implicit
memory system. Within this proposition, psychothera-
peutic change may be attributed to a process of insight
or to the provision of abstract explanations regarding
underlying relationship patterns.

Animal research examining habituation, sensiti-

zation, and classical conditioning has offered some in-
triguing insights into how learning affects the brain. The
simplest neural chain investigated was the monosynaptic
reflex arc, which is used to describe the mechanism of
primary learning in the gill withdrawal reflex of the ma-
rine snail Aplysia californica.

41–43

In habituation, an animal

learns to suppress its response to a stimulus that is neither
rewarding nor harmful. In contrast, sensitization occurs
when the animal encounters a harmful stimulus and
learns to respond more vigorously to a variety of other
stimuli. Classical conditioning describes learning by as-
sociating one type of stimulus with another. The animal
is exposed to an initially weak or ineffective stimulus that
becomes highly effective in producing a response after
it has been associated with a strong unconditioned stimu-
lus.

44

Because gill withdrawal in the Aplysia is a change

that occurs within the reflex arc, it is sometimes referred
to as an intrinsic change.

45

Bernibeu et al.

46

reported that

there is a direct link between learning and learned be-
havior and neurotransmitters. At the synaptic level in the
Aplysia, serotonin may be one of the mediators in behav-
iorally learned changes in stimulus response.

47

Many

FIGURE 2. Explicit memory refers to conscious recollection of

facts and events and depends on the integrity of
limbic/diencephalic structures. Implicit memory
refers to a heterogeneous collection of abilities.
In the case of implicit memory, experience
alters behavior nonconsciously without
providing access to any memory content.
Reprinted with permission from L.R. Squire and
M. Zola-Morgan, “The medial temporal lobe
memory system.” Science 1991; 253:1380–1386.
Copyright 1991 American Association for the
Advancement of Science.

Liggan and Kay

J Psychother Pract Res, 8:2, Spring 1999

105

simple neural circuits receive input from superordinate
circuits, and learning-induced plasticity may occur at the
superordinate level. In eyelid conditioning in mammals,
it appears that the site of plasticity necessary for the con-
ditioning is in a higher order circuit in the cerebel-
lum.

48,49

Considered in relation to the reflex arc, this is

sometimes called an extrinsic change.

Extrapolating from this animal research, it is be-

lieved that implicit memory provides an empirical basis
for postulating the mechanisms by which people might
come to have memories of which they are unaware, that
are based on early emotional experiences and that act in
an unconscious way to guide behavior, expectations, and
impressions relating to relationships.

40,50

In order for

these interactions to exert long-lasting influences on be-
havior, they must be encoded in the type of memory that
is believed to be implicit in nature.

51

The existence of

implicit memory represents an important part of the the-
ory of maladaptive affective learning characteristic of
psychiatric disorders.

The assertion that affective attunement can result in

changes in neural structure and is critical to the long-term
stability of the emotional life of the individual clearly
implies that early affective interactions are permanently
encoded in memory.

40

Central to the memory model of

psychotherapy is attachment research demonstrating
that early patterns of responsiveness exhibited by attach-
ment figures can have far-reaching consequences during
neural development.

The capacity for affective self-regulation is postu-

lated to be minimal at birth and is thought to be enhanced
by exposure to experiences of appropriate attachment
relationships. Notable deficits in the adequacy of the at-
tachment relationship result in disorganized neurobe-
havioral repertoires and impaired capacity for internal
self-regulation.

40

The inability to self-regulate is clinically

manifested by an inability to self-soothe or to modulate
anger.

Rosenblum et al.

52

demonstrated this model of at-

tachment with respect to the rhesus monkey. Exposure
of monkeys in early life to an inadequate attachment fig-
ure engendered permanent vulnerability to anxious and
depressed states and to poor social functioning. Addi-
tionally, there are intriguing similarities between the be-
haviors of animals that exhibit the isolation syndrome
and the behaviors of character-disordered patients.

53

In

these personality disorders, a particular consequence of
early attachment failure is an exaggerated and prolonged
reliance on external sources of regulation.

Because early attachment memories may be implic-

itly unconscious



rather than repressed, as stated in clas-

sic analytic literature



the memory model of psycho-

therapy offers an interesting psychobiologic perspective.
Amini et al.

40

posit that psychotherapy is not merely a

conversation or an intellectual exchange of words and
ideas. Instead, it is an attachment relationship, which is
a physiologic process capable of regulating neurophysi-
ology and altering underlying neural structure.

The psychobiologic conceptualization of psycho-

therapy offered by Amini and colleagues is that psycho-
therapy may function as an attachment relationship
whose purpose is to regulate affective homeostasis and
restructure attachment-related implicit memory. There-
fore, when patients participate in psychotherapy, they
first of all activate the implicit memory system and then
engage the mechanism whereby implicitly stored mate-
rial can be modified.

HOW PSYCHOTHERAPY STIMULATES

BRAIN CELLS AND SYNAPSES

Whether learning-induced anatomical changes in the
nervous system are necessary for storage of long-term
memory has been discussed by several authors, includ-
ing Morris,

5

Greenough et al.,

54

and Martinez and Der-

rick.

55

The search for a model of the neural mechanisms

of memory is based on discoveries that training or dif-
ferential experience leads to significant changes in brain
neurochemistry, anatomy, and electrophysiology. Con-
sequently, it is generally accepted that psychotherapy is
a powerful intervention that directly affects and changes
the brain.

1. Psychotherapy affects cerebral metabolic rates. Landmark
investigations by Baxter et al.

56

and Schwartz et al.

57

demonstrated that psychotherapy and fluoxetine pro-
duced decreased cerebral metabolic rates in the right
caudate nucleus. The two interventions appeared to
have similar physiological effects. Additionally, van der
Kolk

58

conducted clinical trials of patients diagnosed

with posttraumatic stress syndrome. After treatment
with eye movement desensitization and reprocessing
(EMDR), they reported increased prefrontal metabo-
lism and decreased limbic system activation in single-
photon emission computed tomography (SPECT) scans
of the patients. The imaging data provide additional
support for the findings of controlled clinical studies that
have shown that EMDR may be effective. In EMDR,

Neurobiology and Psychotherapy

106

J Psychother Pract Res, 8:2, Spring 1999

patients focus on their memories of a traumatic event
while moving their eyes rapidly back and forth. When
used several times, this exercise somehow appears to
change the patient’s cognition of the traumatic incident.

2. Psychotherapy

affects

serotonin

metabolism. Viinamaki

et al.

59

used SPECT imaging before and after 1 year of

dynamic psychotherapy in a patient with bipolar person-
ality disorder and depression. Her imaging studies were
compared at the same timepoints to those of a control
bipolar patient who received no therapy and to those of
10 healthy control subjects. Both patients initially had
decreased serotonin uptake in prefrontal cortex and
thalamus compared with the healthy control subjects.
After 1 year, the psychotherapy patient had normal
serotonin uptake. These findings suggest that dynamic
psychotherapy can affect serotonin metabolism.

Viinamaki’s clinical work was preceded by evidence

from animal studies establishing a relationship between
serotonin and learning. Injecting serotonin into the an-
terior limbic cortex of dogs with low serotonin blood
levels has been shown to reduce the effects of classical
conditioning.

60

A high level of conditioned and uncon-

ditioned reflexes in dogs was accompanied by low sero-
tonin blood levels.

61

Although Viinamaki’s study has a

number of methodological problems (such as a relatively
small N ) and has not yet been replicated, the clinical
significance of these findings is that most exposure treat-
ments for anxiety disorder are based on the principles
of classical conditioning.

62

The underlying concept is

that successful exposure therapy reduces patient anxiety
through extinction of a classically conditioned reflex.

3. Psychotherapy affects the thyroid axis. Joffe et al.

63

re-

ported that in treating patients with depression, those
who responded to cognitive-behavioral therapy had sig-
nificant decreases in measures of thyroxine (T

4

), whereas

those who did not respond to the therapy had increases
in T

4

. Therefore, cognitive-behavioral therapy had an

effect similar to that of antidepressant medication on the
thyroid axis.

4. Psychotherapy stimulates processes akin to brain plasticity.
Brain plasticity refers to the brain’s ability to change
structure and function. Brain plasticity is regarded as
prerequisite for any long-lasting change in behavior,
cognition, and emotion, and thus for all measurable
psychotherapeutic effects.

64

Of particular interest to the

current review is Hebbian synaptic plasticity thought to

underlie the experience-dependent changes in discrete
brain areas consequent to psychotherapy.
Although there is no evidence that psychotherapy
directly stimulates brain plasticity, there are many rea-
sons to assume this mechanism of action. It is postulated
that in psychotherapy, learning through exploration
gives increased synaptic field potentials in the perforant
path synapses. This increase has been demonstrated in
animal models in which a group of spatially trained adult
rats showed faster spatial learning and higher basal
dendritic spine density compared with two control
groups. On the basis of the unchanged dendritic length
and branching pattern, the results suggest the formation
of new synapses.

65

Greenough et al.

54

note several observations that re-

late number of synapses and degree of dendritic branch-
ing to the amount and sites of learning or experience in
the rat. Environmental stimulation has been found to
increase brain weight (especially forebrain), cortical
thickness, the number of glial cells, the glia-to-neuron
ratio, and neuronal cell body and nucleus size, and to
alter synaptic profiles by increasing dendritic branching,
dendritic spine density, and the number of discontinu-
ous synapses.

66

Note that the changes occur in brain

regions involved in the learned tasks; if learning is
confined to one side of the brain, the synaptic and
dendritic changes are also confined to that side. These
findings were replicated by Kolb and Whishaw,

67

who

found that experience produces multiple, dissociable
changes in the brain, including increases in dendritic
length, increases (or decreases) in spine density, synapse
formation, increased glial activity, and altered metabolic
activity.
For more comprehensive reviews of synaptic and
activity-dependent plasticity in cortex as well as in other
areas and systems, see Byrne,

68

Brown et al.,

69

Tyler et

al.,

70

Madison et al.,

71

Tsumoto,

72

Bear and Kirkwood,

73

Bliss and Collingridge,

22

Linden and Connor,

74

Bear and

Abraham,

75

and Katz and Shatz.

76

PARALLELS BETWEEN BRAIN PHYSIOLOGY AND

SCHOOLS OF PSYCHOTHERAPY

In psychotherapy, some kinds of affective dysfunction
can be successfully managed by the re-establishment of
homeostatic regulation through an improved and func-
tioning attachment relationship. The major forms of psy-
chotherapy (behavioral, cognitive, and psychodynamic)
can be conceptualized as reflecting interventions at

Liggan and Kay

J Psychother Pract Res, 8:2, Spring 1999

107

different levels of psychological organization.

77

Depend-

ing on where in the brain one measures and on the kind
of therapy or differential experience the individual has
undergone, one may expect to find an increase in num-
ber of synapses and an increase in their size. Whether
the brain shows plastic changes in response to a particular
kind of experience depends on the brain region, the kind
of experience, and special circumstances or treatments
that enhance or impair plasticity.

78

For example, behav-

ioral psychotherapy focuses on dysfunction in simple forms
of learning and memory (operant and associative condi-
tioning) and related motor behavior.

79

This paradigm in-

volves brain structures such as the amygdala, basal gan-
glia, and hippocampus.

80–82

Cognitive psychotherapy focuses on specific patterns of

information processing. These symptoms are used as
clues by which to define specific verbal thoughts and
assumptions or schemata that account for both the symp-
tomatic state and the psychological vulnerability to that
state.

83

Cognitive theory predicts the kinds of thinking

patterns encountered with each disorder. For example,
anxious patients perceive danger in situations that are
not dangerous; depressed patients see evidence of per-
sonal defect in situations that offer no objective reasons
for self-deprecation. Paranoid patients may misconstrue
situations in terms of being deceived or attacked.

84,85

Ac-

cording to cognitive theory, negative cognitions play a
pivotal role in the development and maintenance of the
psychopathological state. Thus, the initial objectives of
treatment are to teach the patient to recognize these cog-
nitions. Thereafter, the patient learns to evaluate and
modify such thinking patterns. Therapy then focuses on
the identification and modification of dysfunctional atti-
tudes that are inferred from the patient’s stereotyped
thinking and behavioral patterns. These schemata are
values derived from early life experiences and support
moment-to-moment thinking patterns.

86

Putative brain

areas include the neocortex, specifically the frontal
cortex.

Psychodynamic psychotherapy has as its central focus in-

terpersonal representation: a set of expectations about
self, others, and their relationship that organizes related
affect, thought, and behavior.

87–92

The neuropsychologi-

cal underpinnings of interpersonal representations prob-
ably involve complex neurocircuitry incorporating lat-
eralized cerebral hemispheres and subcortical areas.

93

The concept of lateralization was documented by

Tucker’s

94

observations that the left cerebral hemisphere

specializes in verbal, linear, and analytic functions (in

right-handed individuals) and that the right cerebral
hemisphere specializes in intuitive, spatial, and holistic
activities. Tucker also reported that negative emotions
are more often lateralized to the left hemisphere.
Gottschalk et al.

95

endorsed the significance of correla-

tion between the left temporal lobe and social aliena-
tion/personal disorganization scores derived from analy-
sis of cerebral glucose metabolic rates in wakeful subjects.
Although it may be premature to conclude that the left
temporal lobe is a cerebral focus for certain types of psy-
chopathological processes that can be ameliorated by
psychodynamic psychotherapy, these findings encour-
age further exploration of the mechanism of psycho-
therapeutic action.

TRAUMATIC STRESS AND PLASTICITY

Many psychiatric disorders involve the inability to
control fear: anxiety disorders, phobias, and posttrau-
matic stress disorder. Neurons in a number of brain re-
gions undergo physiological changes during aversive
classical conditioning.

96

Studies of the physiology of

learning have suggested that many brain regions show
physiological changes during learning. Thus, it is not sur-
prising that plasticity has been found throughout the fear
conditioning circuitry: in the auditory thalamic areas that
project to the amygdala;

97–100

in the auditory cortex;

101,102

in the lateral, basolateral, and central nuclei of the
amygdala;

103,104

and in the lateral hypothalamus.

105

The amygdala is involved in both the acquisition

and the expression of fear conditioning.

106–112

Numerous

studies in both rats and humans indicate the importance
of the amygdala in the acquisition and expression of
learned fear. The identification of the amygdala as an
essential neural substrate for fear conditioning has per-
mitted neurophysiological examinations of synaptic pro-
cesses in the amygdala that may mediate this condition-
ing. Recent studies of synaptic transmission and plasticity
in the amygdala shed light on the relationships of these
processes to aversive learning and memory.

113

For exam-

ple, Adamec

114

reports that lasting changes in anxiety-

like behavior may be produced in several ways. These
include partial limbic kindling, injection of a beta-car-
boline, and brief, noninjurious exposure of rodents to
cats (predator stress).

Emerging data support the idea that behavioral

changes following induced anxiety-like behavior may
model anxiety associated with posttraumatic stress dis-
order. These mechanisms likely involve initiation of

Neurobiology and Psychotherapy

108

J Psychother Pract Res, 8:2, Spring 1999

long-term potentiation by NMDA receptors and prolon-
gation of LTP by creatinine kinase (CCK) receptors. To
the extent that response to the stressors mimics the symp-
toms of PTSD, the data implicate NMDA-mediated pro-
cesses in the creation of what van der Kolk

115

has called

permanent emotional memories in PTSD. Because the
blocking of CCK receptors before and after the stressor
prevents lasting increases in anxiety-like behavior, inter-
ventions to block CCK receptors shortly after a traumatic
stressor might be efficacious in mitigating the perma-
nence of these emotional memories. Transmitter systems
involved in neural plasticity underlie increased anxiety
and defense. This high level of physiological arousal and
inability to regulate autonomic responses to both internal
and external stimuli markedly diminish the individual’s
ability to make use of feelings as important signals.

58

To

compensate for the hyperarousal, the victim attempts to
avoid feelings and situations reminiscent of the trauma
by shutting down psychologically and becoming numb
to stimuli.

Correlates of gross neuronal activity can be assessed

by observing which territories are relatively more or less
active. This is accomplished by imaging studies that re-
flect cerebral metabolism or blood flow, since both are
tightly coupled to neuronal activity. Functional brain im-
aging techniques help characterize how multiple mental
operations and the spatially distributed processes that
subserve them work in concert to produce normal hu-
man emotions and how their dysfunction produces dis-
orders of fear.

97

The explicit memory system is impli-

cated in the encoding of facts related to the trauma.
Activity of the amygdala associated with long-term stor-
age of memories of emotionally arousing versus neutral
events viewed on film has been measured by PET imag-
ing.

116

In that study, emotional films enhanced glucose

metabolism in the right amygdala.

The amygdala is probably responsible for extinction

of sensory and cognitive associations to original trauma
and activation of traumatic memories. This would ex-
plain increased activity of the amygdala in PTSD. Ex-
tinction is the process through which the strength of a
conditioned response is weakened by repeated exposure
to the conditioned stimulus in the absence of the uncon-
ditioned stimulus. Considerable evidence suggests that
extinction of conditioned fear does not occur passively;
that is, the memory persists in the absence of explicit
extinction training, and when extinction occurs it is not
passive forgetting but instead is an active process involv-
ing new learning.

117

Data from studies of emotional con-

ditioning in rats suggest that neocortex, although not nec-
essary for the acquisition of conditioned fear, is necessary
for extinction once fear conditioning has been ac-
quired.

118

In this way, psychotherapy deals with the

deliberate act of recollecting explicit memories.

43

Theo-

retically, working with emotional memories in psycho-
therapy by asking patients to recall and associate acti-
vates the amygdala. The patient participates in an active
process of new learning, resulting in extinction of sensory
and cognitive associations to the original trauma. Thus,
undoing traumatic memories is not passive forgetting. It
is an active process involving new learning, probably as
the orbitofrontal cortex becomes more activated.

OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder (OCD) is a neurobi-
ological disorder caused by an imbalance in the brain
neurotransmitter serotonin. Jenike et al.

119

presented re-

sults from a magnetic resonance imaging (MRI)-based
brain segmentation study demonstrating that patients
with OCD had significantly less total white matter,
greater total neocortex, and greater opercular volumes.
Functional neuroimaging studies of OCD have primarily
implicated orbitofrontal and anterior cingulate cortex,
as well as striatum, showing hyperactivity during neutral
states that is accentuated during symptom provoca-
tion.

120

PET scans have shown that patients with OCD

have significantly elevated glucose metabolic rates in
both cerebral hemispheres, the heads of the caudate nu-
clei, the orbital gyri, and the orbital gyri relative to the
ipsilateral hemisphere.

121

Glucose metabolic rate is

closely tied to neuronal functioning. Therefore, it is clear
that at some level, obsessive-compulsive disorder is me-
diated through serotonin-based neurochemical process-
es of the brain.

Behavioral therapy for OCD consists of exposure

and response prevention interventions. Exposure con-
sists of asking the patient to interact with stimuli that
result in the obsession or ritualistic behavior. Response
prevention consists of delaying, diminishing, or discon-
tinuing anxiety-reducing rituals. The response preven-
tion principle is based on the idea that anxiety slowly
decreases when the performance of the ritual is blocked.
When anxiety reduction no longer depends on the ritu-
als, the ritual compulsion will be extinguished. Current
research in animals and humans has demonstrated that
neurochemical changes due to behavioral interventions
are similar to the effects of pharmacologic therapies.

122

Liggan and Kay

J Psychother Pract Res, 8:2, Spring 1999

109

Especially in the treatment of OCD, there is over-

whelming evidence that behavior therapy is capable of
producing changes in brain chemistry that may be similar
to the effects of serotonergic medications.

123

Investiga-

tors found that 3 weeks of intensive behavior therapy
had an effect on serotonin activity as measured by imip-
ramine binding and changes in platelet serotonin level.

124

owever, the major neurobiological evidence comes from
two recent studies using PET conducted by Baxter et
al.

56

and replicated by Schwartz et al.

57

The findings of

Baxter et al.

56

provided evidence that glucose metabolic

rates in the right head of the caudate nucleus change
when OCD is treated successfully with either fluoxetine
or behavior therapy. Schwartz et al.

57

found that after

successful behavior modification, there is significant bi-
lateral decrease in glucose metabolism in the caudate
nucleus. These studies are significant because they con-
firm that behavior therapy can cause neurochemical
changes in the brain.

SCHIZOPHRENIA AS A LIFETIME DISORDER OF

BRAIN PLASTICITY

Chronic schizophrenia is characterized by change in the
normal cortical structure of the brain, asymmetric reduc-
tion, and often ventricular enlargement.

125–129

The de-

bate continues as to whether these anomalies occur early
in development or represent an active, progressive pro-
cess continuing after the onset of psychosis. DeLisi

130

proposes that the underlying basis for the neuropa-
thology of schizophrenia resides in the periodic activa-
tion of a defective gene or genes that determine the rate
of cerebral growth. This process causes subtle cortical
maldevelopment prenatally and through early child-
hood, is activated again during adolescent pruning of
neurons, and again during the gradual aging process in
the brain throughout adulthood.

Structural change in the hippocampal formation has

become popular as a proposed neurobiological substrate
for schizophrenic disorders. Hippocampal function is
particularly sensitive to neurochemical modulation, and
the expression of monoamine receptors in the temporal
lobe is altered in schizophrenic patients.

131

An attractive

proposal is that behavioral plasticity, in the form of long-
term potentiation of hippocampal synaptic transmission,
may mediate transient psychosis.

132

Moreover, the dis-

turbed hippocampal neuroarchitecture found in schizo-
phrenic patients may be susceptible to potentiation and
may be dysfunctional to the degree that delusions and

hallucinations develop.

132

It has been hypothesized that delusions and related

phenomena arise from some disturbance of the cognitive
machinery of belief, memory, and their associated neural
representations.

18,133

Delusions are characterized by an

aberrant belief plus a gradual spreading of the belief sys-
tem to incorporate new information as the disease prog-
resses. It is as if the associations between ideas that form
the framework of a normal belief system had become so
immutable that the usual processes of assimilation and
incorporation of new information can no longer operate.
This observation leads to the hypothesis that mecha-
nisms of synaptic plasticity may be abnormal in these
patients.

The increasing empirical support for a limbic sub-

strate of schizophrenic symptomatology is based on three
factors:

1.

Anatomical, physiological, pharmacological, and
behavioral findings are most consistent with the view
that neuropathological changes within the limbic
system, specifically within the hippocampal forma-
tion, may represent a biological substrate of schizo-
phrenia.

132

2.

The biological mechanism underlying transient psy-
chosis may be long-term potentiation of synaptic
transmission within the hippocampal formation.

132

3.

The effects of dopamine manipulation on these be-
haviors may be mediated by direct actions on the
compromised limbic system of the psychotic pa-
tient.

133

Defect or negative symptoms, which apparently do not

respond well to neuroleptic treatment

134

but do respond to

atypical antipsychotics, have been proposed to reflect fron-
tal lobe dysfunction.

135

These symptoms may be attribut-

able to changes in prefrontal cortex metabolism that are
secondary to limbic pathology.

136

Conceivably, then, hip-

pocampal dysfunction could be directly responsible for
positive symptoms and indirectly involved, via frontal pro-
jections, in the negative symptoms.

132

The implications of this theoretical framework sup-

port psychotherapeutic interventions in the treatment of
schizophrenia. There is a growing body of literature pro-
moting cognitive-behavioral therapies aimed at the
modification of delusions. Psychological approaches to
treatment-resistant symptoms of psychosis all emphasize
the importance of normalization of even the most bizarre
personal experiences. Although antipsychotic drugs are

Neurobiology and Psychotherapy

110

J Psychother Pract Res, 8:2, Spring 1999

generally successful at attenuating behavioral dysfunc-
tion in schizophrenic patients, prevention of further ac-
crual of hippocampal damage would also be beneficial.
Given the prominent role of stress and related hormones
in the degeneration of hippocampal pyramidal neurons,
it may be advantageous for at-risk persons to minimize
the level of environmental stress and maximize their ca-
pacity to cope adaptively with stressors. Hogarty et al.

137

devised a disorder-relevant and disorder-specific therapy
for schizophrenia. Four key fundamentals of this personal
therapy are 1) theoretical grounding in the stress-vulner-
ability model; 2) consideration of stress-related dysregu-
lation as proximate to symptom exacerbation; 3) sequen-
tial use of interventions of graded complexity based on
the patient’s stage of recovery; and 4) flexible use of a
range of therapeutic techniques to accommodate the in-
dividual needs, deficits, and preferences of patients with
this heterogeneous disorder. Goals include developing
self-recognition of the links between stresses, maladap-
tive responses, the reactions of others, and symptoms.

SUMMARY

Supporting Hebb’s 1949 hypothesis of use-induced plas-
ticity of the nervous system, learning has been found to

alter the structure and function of nerve cells and their
connections. Further studies revealed changes in cortical
thickness, size of synaptic contacts, number of dendritic
spines, and dendritic branching, constituting a mecha-
nism by which psychotherapy facilitates changes in the
permanent storage of memory. Psychotherapy alters the
neurochemistry and physiology of the brain by provid-
ing a stimulus that leaves a memory trace. Neural net-
work research and memory research have proceeded in
parallel to elucidate the theoretical properties of ideal
neural networks and the actual properties of information
storage in the brain. Long-term potentiation serves as a
model of activity-dependent synaptic plasticity proposed
to underlie memory.

The study of learning and memory not only brings

us closer to understanding how psychotherapy pro-
duces emotional and behavioral changes in patients,
but also gives us new perspectives on psychiatric dis-
orders involving the inability to control fear, obses-
sions, compulsions, and delusions. We anticipate that
more direct evidence of links between neurobiology
and the psychotherapeutic processes will be available
as neurobiologists and psychotherapists collaborate on
future studies.

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