Liggan DY, Kay J: Pract Res 1999; 8(2):____ ____psychotherapy: a
review. J PsychotherNeurobiology; Affect;aspects of
Psychotherapy andSome neurobiological Attachment; Memory
Some Neurobiological Aspects of
Psychotherapy
A Review
Deborah Y. Liggan, M.D.
Jerald Kay, M.D.
he role of learning in the conduct of psychotherapy
Ever since the idea was accepted that memory is
Tdates back to mid-century. The neuroanatomist
associated with alterations in synaptic strength, studies
Ramón y Cajal1 had earlier discovered that information
on the cellular and molecular mechanisms responsible
could be stored by modifying the connections between
for the plastic changes in neurons have attracted wide
communicating nerve cells in order to form associations.
interest in the scientific community. This article
In 1949 this idea was formalized by Hebb,2 who sug-
explores the process of memory consolidation leading to
gested that such modifications should take place between
persistent modifications in synaptic plasticity as a
the connected cells if and only if both neurons were
mechanism by which psychotherapy facilitates changes
simultaneously active. From this idea emerged the well-
in the permanent storage of information acquired
known Hebb s rule: When an axon of cell A is near
throughout the individual s life. The psychobiological
enough to excite a cell B and repeatedly and persistently
interrelationships of affect, attachment, and memory
takes part in firing it, some growth process or metabolic
offer a perspective regarding the etiology and treatment
change takes place in one or both cells such that A s
of clinical disturbances of affect. Analogies between efficacy, as one of the cells firing B, is increased. Infor-
mation is therefore encoded by strengthening the con-
brain physiology and modes of psychotherapy provide
nections between neurons that are simultaneously
the foundation for a review of psychiatric disorders
activated. The discovery of Hebb-like synaptic plasticity
involving the inability to control fear, obsessions,
in a putative memory structure was one of the most im-
compulsions, and delusions, all of which respond to
portant neurophysiological finds of the 1950s. Hebb s
psychotherapeutic interventions.
main interest was considering how complex neural net-
(The Journal of Psychotherapy Practice and
works could account for phenomena such as perception
Research 1999; 8:103 114)
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
Neurobiology and Psychotherapy
tion of neural networks. Studies of various forms of forms of synaptic plasticity at CNS synapses: 1) LTP me-
synaptic plasticity in the central nervous system provided diated by N-methyl-D-aspartate (NMDA) receptor acti-
insights into the cellular and molecular mechanisms for vation; 2) LTP mediated by voltage-dependent calcium
certain types of learning and memory.3 5 Synaptic plas- channel activation; and 3) LTD mediated by the NMDA
ticity became the target of much neurobiological re- receptor. A detailed review of the status of research into
search as its role in memory formation was elucidated. the mechanisms underlying LTP has been presented by
Evidence indicated that activity-dependent short-term Bliss and Collingridge.22 Suffice it to say that the neural
and long-term changes in strength of synaptic transmis- mechanism underlying cortical representational remod-
sion are important for memory processes. eling is that it is a result of synaptic plasticity, primarily
Cortical maps are dynamic constructs that are re- LTP of excitatory synapses following a Hebbian learning
modeled in detail by behaviorally important experiences rule. Post and Weiss23 posit that mechanisms involved in
through life. Over the past decade, the number of ex- neuronal learning and memory, such as LTP and LTD,
perimental papers reporting physiological plasticity in are used and reused in the molding of personality and
primary neocortical regions, following certain types of behavior based on experience. They postulate that for
controlled sensory experience, has increased greatly.6 9 higher order processes such as emotional memory, such
These reports have been characterized by specific changes neuroplasticity is occurring at increasingly larger num-
in receptive fields of individual neurons and/or the dis- bers of synapses and cell assemblies with increasing
tributions of receptive fields across cortical maps. In par- mechanistic complexity and self-organization. Experi-
allel with developments in the field of cortical map plas- ments conducted by Bear24 reveal that many synapses
ticity, studies of synaptic plasticity characterized specific in the hippocampus and neocortex are bidirectionally
elementary forms of plasticity, including associative modifiable, that the modifications persist long enough to
long-term potentiation (LTP) and long-term depression contribute to long-term memory storage, and that key
(LTD) of excitatory postsynaptic potentials.10,11 A great variables governing the sign of synaptic plasticity are the
deal of the experimental work linking modifiable syn-
apses to macroscopic brain behavior has been carried
FIGURE 1. The hippocampus may store long-term memory
for weeks and gradually transfer it to specific
out in the hippocampal formation, a part of the limbic
regions of the cerebral cortex. The diagram
system that has long been implicated in memory forma-
illustrates this process for visual memory.
tion.12 15 There is now a multitude of experimental evi-
Neural input travels to the visual cortex and
then to the hippocampus, where it is stored for
dence linking hippocampal long-term potentiation to
several weeks before it is transferred back to
memory formation.16 21
the cortex for long-term memory. The hippo-
In this article, we examine a memory model of psy-
campus has three major synaptic pathways, each
chotherapy based on brain plasticity as a prerequisite for capable of long-term potentiation, which is
thought to play a role in the storage process.
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
104 J Psychother Pract Res, 8:2, Spring 1999
Liggan and Kay
amount of NMDA receptor activation and the recent new habit-based manner is engrained in the implicit
history of cortical activity (Figure 1). The principle com- memory system. Within this proposition, psychothera-
mon to representation formation in nearly all neural net- peutic change may be attributed to a process of insight
works is that of associability, which is the idea that or to the provision of abstract explanations regarding
streams of information are combined by forming, underlying relationship patterns.
strengthening, or pruning connections between them to Animal research examining habituation, sensiti-
form new representations that can later be retrieved.25,26 zation, and classical conditioning has offered some in-
Most accounts of perceptual learning are concerned triguing insights into how learning affects the brain. The
with changes in neuronal sensitivity or changes in the simplest neural chain investigated was the monosynaptic
way a stimulus is represented across two distinct memory reflex arc, which is used to describe the mechanism of
systems, depicted in Figure 2 as explicit and implicit primary learning in the gill withdrawal reflex of the ma-
memory. These two types of memory are fundamentally rine snail Aplysia californica.41 43 In habituation, an animal
separate brain functions that rely on different sets of learns to suppress its response to a stimulus that is neither
neural structures and physiologic properties, and they rewarding nor harmful. In contrast, sensitization occurs
result in distinct patterns of neural activity as detected when the animal encounters a harmful stimulus and
by positron emission tomography (PET)27 and electro- learns to respond more vigorously to a variety of other
encephalography.28 The explicit memory system records stimuli. Classical conditioning describes learning by as-
experience for later recall by utilizing temporal lobe sociating one type of stimulus with another. The animal
structures, especially the hippocampus.29,30 In contrast, is exposed to an initially weak or ineffective stimulus that
implicit memory is an enduring neural structure that becomes highly effective in producing a response after
depends on the basal ganglia and whose existence is in- it has been associated with a strong unconditioned stimu-
ferred from observable influence on emotional behav- lus.44 Because gill withdrawal in the Aplysia is a change
iors related to early attachment experiences. Information that occurs within the reflex arc, it is sometimes referred
from this system is not available for conscious recall.31 36 to as an intrinsic change.45 Bernibeu et al.46 reported that
Comprehensive reviews of implicit memory have been there is a direct link between learning and learned be-
provided by Reber,37 Schacter,38 Schacter et al.,39 and havior and neurotransmitters. At the synaptic level in the
Squire et al.30 Aplysia, serotonin may be one of the mediators in behav-
The distinction between the two memory systems is iorally learned changes in stimulus response.47 Many
significant both in the course of development over the
life cycle and in the context of memory modulation
FIGURE 2. Explicit memory refers to conscious recollection of
through psychotherapy. Amini et al.40 emphasize that
facts and events and depends on the integrity of
evidence exists to support the hypothesis that human
limbic/diencephalic structures. Implicit memory
refers to a heterogeneous collection of abilities.
infants are equipped with a functional memory system
In the case of implicit memory, experience
at birth and that memory is more capable of implicit
alters behavior nonconsciously without
learning than explicit learning at this neurodevelopmen-
providing access to any memory content.
Reprinted with permission from L.R. Squire and
tal stage. Information regarding affect undergoes proc-
M. Zola-Morgan,  The medial temporal lobe
essing in the implicit system. The implicit system is
memory system. Science 1991; 253:1380 1386.
capable of extracting and storing prototypes and rules
Copyright 1991 American Association for the
from exposure to large amounts of complex information. Advancement of Science.
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
J Psychother Pract Res, 8:2, Spring 1999 105
Neurobiology and Psychotherapy
simple neural circuits receive input from superordinate Because early attachment memories may be implic-
circuits, and learning-induced plasticity may occur at the itly unconscious�ł rather than repressed, as stated in clas-
superordinate level. In eyelid conditioning in mammals, sic analytic literature�ł the memory model of psycho-
it appears that the site of plasticity necessary for the con- therapy offers an interesting psychobiologic perspective.
ditioning is in a higher order circuit in the cerebel- Amini et al.40 posit that psychotherapy is not merely a
lum.48,49 Considered in relation to the reflex arc, this is conversation or an intellectual exchange of words and
sometimes called an extrinsic change. ideas. Instead, it is an attachment relationship, which is
Extrapolating from this animal research, it is be- a physiologic process capable of regulating neurophysi-
lieved that implicit memory provides an empirical basis ology and altering underlying neural structure.
for postulating the mechanisms by which people might The psychobiologic conceptualization of psycho-
come to have memories of which they are unaware, that therapy offered by Amini and colleagues is that psycho-
are based on early emotional experiences and that act in therapy may function as an attachment relationship
an unconscious way to guide behavior, expectations, and whose purpose is to regulate affective homeostasis and
impressions relating to relationships.40,50 In order for restructure attachment-related implicit memory. There-
these interactions to exert long-lasting influences on be- fore, when patients participate in psychotherapy, they
havior, they must be encoded in the type of memory that first of all activate the implicit memory system and then
is believed to be implicit in nature.51 The existence of engage the mechanism whereby implicitly stored mate-
implicit memory represents an important part of the the- rial can be modified.
ory of maladaptive affective learning characteristic of
psychiatric disorders. HOW PSYCHOTHERAPY STIMULATES
The assertion that affective attunement can result in BRAIN CELLS AND SYNAPSES
changes in neural structure and is critical to the long-term
stability of the emotional life of the individual clearly Whether learning-induced anatomical changes in the
implies that early affective interactions are permanently nervous system are necessary for storage of long-term
encoded in memory.40 Central to the memory model of memory has been discussed by several authors, includ-
psychotherapy is attachment research demonstrating ing Morris,5 Greenough et al.,54 and Martinez and Der-
that early patterns of responsiveness exhibited by attach- rick.55 The search for a model of the neural mechanisms
ment figures can have far-reaching consequences during of memory is based on discoveries that training or dif-
neural development. ferential experience leads to significant changes in brain
The capacity for affective self-regulation is postu- neurochemistry, anatomy, and electrophysiology. Con-
lated to be minimal at birth and is thought to be enhanced sequently, it is generally accepted that psychotherapy is
by exposure to experiences of appropriate attachment a powerful intervention that directly affects and changes
relationships. Notable deficits in the adequacy of the at- the brain.
tachment relationship result in disorganized neurobe-
havioral repertoires and impaired capacity for internal 1. Psychotherapy affects cerebral metabolic rates. Landmark
self-regulation.40 The inability to self-regulate is clinically investigations by Baxter et al.56 and Schwartz et al.57
manifested by an inability to self-soothe or to modulate demonstrated that psychotherapy and fluoxetine pro-
anger. duced decreased cerebral metabolic rates in the right
Rosenblum et al.52 demonstrated this model of at- caudate nucleus. The two interventions appeared to
tachment with respect to the rhesus monkey. Exposure have similar physiological effects. Additionally, van der
of monkeys in early life to an inadequate attachment fig- Kolk58 conducted clinical trials of patients diagnosed
ure engendered permanent vulnerability to anxious and with posttraumatic stress syndrome. After treatment
depressed states and to poor social functioning. Addi- with eye movement desensitization and reprocessing
tionally, there are intriguing similarities between the be- (EMDR), they reported increased prefrontal metabo-
haviors of animals that exhibit the isolation syndrome lism and decreased limbic system activation in single-
and the behaviors of character-disordered patients.53 In photon emission computed tomography (SPECT) scans
these personality disorders, a particular consequence of of the patients. The imaging data provide additional
early attachment failure is an exaggerated and prolonged support for the findings of controlled clinical studies that
reliance on external sources of regulation. have shown that EMDR may be effective. In EMDR,
106 J Psychother Pract Res, 8:2, Spring 1999
Liggan and Kay
patients focus on their memories of a traumatic event underlie the experience-dependent changes in discrete
while moving their eyes rapidly back and forth. When brain areas consequent to psychotherapy.
used several times, this exercise somehow appears to Although there is no evidence that psychotherapy
change the patient s cognition of the traumatic incident. directly stimulates brain plasticity, there are many rea-
sons to assume this mechanism of action. It is postulated
2. Psychotherapy affects serotonin metabolism. Viinamaki that in psychotherapy, learning through exploration
et al.59 used SPECT imaging before and after 1 year of gives increased synaptic field potentials in the perforant
dynamic psychotherapy in a patient with bipolar person- path synapses. This increase has been demonstrated in
ality disorder and depression. Her imaging studies were animal models in which a group of spatially trained adult
compared at the same timepoints to those of a control rats showed faster spatial learning and higher basal
bipolar patient who received no therapy and to those of dendritic spine density compared with two control
10 healthy control subjects. Both patients initially had groups. On the basis of the unchanged dendritic length
decreased serotonin uptake in prefrontal cortex and and branching pattern, the results suggest the formation
thalamus compared with the healthy control subjects. of new synapses.65
After 1 year, the psychotherapy patient had normal Greenough et al.54 note several observations that re-
serotonin uptake. These findings suggest that dynamic late number of synapses and degree of dendritic branch-
psychotherapy can affect serotonin metabolism. ing to the amount and sites of learning or experience in
Viinamaki s clinical work was preceded by evidence the rat. Environmental stimulation has been found to
from animal studies establishing a relationship between increase brain weight (especially forebrain), cortical
serotonin and learning. Injecting serotonin into the an- thickness, the number of glial cells, the glia-to-neuron
terior limbic cortex of dogs with low serotonin blood ratio, and neuronal cell body and nucleus size, and to
levels has been shown to reduce the effects of classical alter synaptic profiles by increasing dendritic branching,
conditioning.60 A high level of conditioned and uncon- dendritic spine density, and the number of discontinu-
ditioned reflexes in dogs was accompanied by low sero- ous synapses.66 Note that the changes occur in brain
tonin blood levels.61 Although Viinamaki s study has a regions involved in the learned tasks; if learning is
number of methodological problems (such as a relatively confined to one side of the brain, the synaptic and
small N ) and has not yet been replicated, the clinical dendritic changes are also confined to that side. These
significance of these findings is that most exposure treat- findings were replicated by Kolb and Whishaw,67 who
ments for anxiety disorder are based on the principles found that experience produces multiple, dissociable
of classical conditioning.62 The underlying concept is changes in the brain, including increases in dendritic
that successful exposure therapy reduces patient anxiety length, increases (or decreases) in spine density, synapse
through extinction of a classically conditioned reflex. formation, increased glial activity, and altered metabolic
activity.
3. Psychotherapy affects the thyroid axis. Joffe et al.63 re- For more comprehensive reviews of synaptic and
ported that in treating patients with depression, those activity-dependent plasticity in cortex as well as in other
who responded to cognitive-behavioral therapy had sig- areas and systems, see Byrne,68 Brown et al.,69 Tyler et
nificant decreases in measures of thyroxine (T4), whereas al.,70 Madison et al.,71 Tsumoto,72 Bear and Kirkwood,73
those who did not respond to the therapy had increases Bliss and Collingridge,22 Linden and Connor,74 Bear and
in T4. Therefore, cognitive-behavioral therapy had an Abraham,75 and Katz and Shatz.76
effect similar to that of antidepressant medication on the
thyroid axis.
PARALLELS BETWEEN BRAIN PHYSIOLOGY AND
SCHOOLS OF PSYCHOTHERAPY
4. Psychotherapy stimulates processes akin to brain plasticity.
Brain plasticity refers to the brain s ability to change In psychotherapy, some kinds of affective dysfunction
structure and function. Brain plasticity is regarded as can be successfully managed by the re-establishment of
prerequisite for any long-lasting change in behavior, homeostatic regulation through an improved and func-
cognition, and emotion, and thus for all measurable tioning attachment relationship. The major forms of psy-
psychotherapeutic effects.64 Of particular interest to the chotherapy (behavioral, cognitive, and psychodynamic)
current review is Hebbian synaptic plasticity thought to can be conceptualized as reflecting interventions at
J Psychother Pract Res, 8:2, Spring 1999 107
Neurobiology and Psychotherapy
different levels of psychological organization.77 Depend- right-handed individuals) and that the right cerebral
ing on where in the brain one measures and on the kind hemisphere specializes in intuitive, spatial, and holistic
of therapy or differential experience the individual has activities. Tucker also reported that negative emotions
undergone, one may expect to find an increase in num- are more often lateralized to the left hemisphere.
ber of synapses and an increase in their size. Whether Gottschalk et al.95 endorsed the significance of correla-
the brain shows plastic changes in response to a particular tion between the left temporal lobe and social aliena-
kind of experience depends on the brain region, the kind tion/personal disorganization scores derived from analy-
of experience, and special circumstances or treatments sis of cerebral glucose metabolic rates in wakeful subjects.
that enhance or impair plasticity.78 For example, behav- Although it may be premature to conclude that the left
ioral psychotherapy focuses on dysfunction in simple forms temporal lobe is a cerebral focus for certain types of psy-
of learning and memory (operant and associative condi- chopathological processes that can be ameliorated by
tioning) and related motor behavior.79 This paradigm in- psychodynamic psychotherapy, these findings encour-
volves brain structures such as the amygdala, basal gan- age further exploration of the mechanism of psycho-
glia, and hippocampus.80 82 therapeutic action.
Cognitive psychotherapy focuses on specific patterns of
information processing. These symptoms are used as
TRAUMATIC STRESS AND PLASTICITY
clues by which to define specific verbal thoughts and
assumptions or schemata that account for both the symp- Many psychiatric disorders involve the inability to
tomatic state and the psychological vulnerability to that control fear: anxiety disorders, phobias, and posttrau-
state.83 Cognitive theory predicts the kinds of thinking matic stress disorder. Neurons in a number of brain re-
patterns encountered with each disorder. For example, gions undergo physiological changes during aversive
anxious patients perceive danger in situations that are classical conditioning.96 Studies of the physiology of
not dangerous; depressed patients see evidence of per- learning have suggested that many brain regions show
sonal defect in situations that offer no objective reasons physiological changes during learning. Thus, it is not sur-
for self-deprecation. Paranoid patients may misconstrue prising that plasticity has been found throughout the fear
situations in terms of being deceived or attacked.84,85 Ac- conditioning circuitry: in the auditory thalamic areas that
cording to cognitive theory, negative cognitions play a project to the amygdala;97 100 in the auditory cortex;101,102
pivotal role in the development and maintenance of the in the lateral, basolateral, and central nuclei of the
psychopathological state. Thus, the initial objectives of amygdala;103,104 and in the lateral hypothalamus.105
treatment are to teach the patient to recognize these cog- The amygdala is involved in both the acquisition
nitions. Thereafter, the patient learns to evaluate and and the expression of fear conditioning.106 112 Numerous
modify such thinking patterns. Therapy then focuses on studies in both rats and humans indicate the importance
the identification and modification of dysfunctional atti- of the amygdala in the acquisition and expression of
tudes that are inferred from the patient s stereotyped learned fear. The identification of the amygdala as an
thinking and behavioral patterns. These schemata are essential neural substrate for fear conditioning has per-
values derived from early life experiences and support mitted neurophysiological examinations of synaptic pro-
moment-to-moment thinking patterns.86 Putative brain cesses in the amygdala that may mediate this condition-
areas include the neocortex, specifically the frontal ing. Recent studies of synaptic transmission and plasticity
cortex. in the amygdala shed light on the relationships of these
Psychodynamic psychotherapy has as its central focus in- processes to aversive learning and memory.113 For exam-
terpersonal representation: a set of expectations about ple, Adamec114 reports that lasting changes in anxiety-
self, others, and their relationship that organizes related like behavior may be produced in several ways. These
affect, thought, and behavior.87 92 The neuropsychologi- include partial limbic kindling, injection of a beta-car-
cal underpinnings of interpersonal representations prob- boline, and brief, noninjurious exposure of rodents to
ably involve complex neurocircuitry incorporating lat- cats (predator stress).
eralized cerebral hemispheres and subcortical areas.93 Emerging data support the idea that behavioral
The concept of lateralization was documented by changes following induced anxiety-like behavior may
Tucker s94 observations that the left cerebral hemisphere model anxiety associated with posttraumatic stress dis-
specializes in verbal, linear, and analytic functions (in order. These mechanisms likely involve initiation of
108 J Psychother Pract Res, 8:2, Spring 1999
Liggan and Kay
long-term potentiation by NMDA receptors and prolon- ditioning in rats suggest that neocortex, although not nec-
gation of LTP by creatinine kinase (CCK) receptors. To essary for the acquisition of conditioned fear, is necessary
the extent that response to the stressors mimics the symp- for extinction once fear conditioning has been ac-
toms of PTSD, the data implicate NMDA-mediated pro- quired.118 In this way, psychotherapy deals with the
cesses in the creation of what van der Kolk115 has called deliberate act of recollecting explicit memories.43 Theo-
permanent emotional memories in PTSD. Because the retically, working with emotional memories in psycho-
blocking of CCK receptors before and after the stressor therapy by asking patients to recall and associate acti-
prevents lasting increases in anxiety-like behavior, inter- vates the amygdala. The patient participates in an active
ventions to block CCK receptors shortly after a traumatic process of new learning, resulting in extinction of sensory
stressor might be efficacious in mitigating the perma- and cognitive associations to the original trauma. Thus,
nence of these emotional memories. Transmitter systems undoing traumatic memories is not passive forgetting. It
involved in neural plasticity underlie increased anxiety is an active process involving new learning, probably as
and defense. This high level of physiological arousal and the orbitofrontal cortex becomes more activated.
inability to regulate autonomic responses to both internal
and external stimuli markedly diminish the individual s
OBSESSIVE-COMPULSIVE DISORDER
ability to make use of feelings as important signals.58 To
compensate for the hyperarousal, the victim attempts to Obsessive-compulsive disorder (OCD) is a neurobi-
avoid feelings and situations reminiscent of the trauma ological disorder caused by an imbalance in the brain
by shutting down psychologically and becoming numb neurotransmitter serotonin. Jenike et al.119 presented re-
to stimuli. sults from a magnetic resonance imaging (MRI)-based
Correlates of gross neuronal activity can be assessed brain segmentation study demonstrating that patients
by observing which territories are relatively more or less with OCD had significantly less total white matter,
active. This is accomplished by imaging studies that re- greater total neocortex, and greater opercular volumes.
flect cerebral metabolism or blood flow, since both are Functional neuroimaging studies of OCD have primarily
tightly coupled to neuronal activity. Functional brain im- implicated orbitofrontal and anterior cingulate cortex,
aging techniques help characterize how multiple mental as well as striatum, showing hyperactivity during neutral
operations and the spatially distributed processes that states that is accentuated during symptom provoca-
subserve them work in concert to produce normal hu- tion.120 PET scans have shown that patients with OCD
man emotions and how their dysfunction produces dis- have significantly elevated glucose metabolic rates in
orders of fear.97 The explicit memory system is impli- both cerebral hemispheres, the heads of the caudate nu-
cated in the encoding of facts related to the trauma. clei, the orbital gyri, and the orbital gyri relative to the
Activity of the amygdala associated with long-term stor- ipsilateral hemisphere.121 Glucose metabolic rate is
age of memories of emotionally arousing versus neutral closely tied to neuronal functioning. Therefore, it is clear
events viewed on film has been measured by PET imag- that at some level, obsessive-compulsive disorder is me-
ing.116 In that study, emotional films enhanced glucose diated through serotonin-based neurochemical process-
metabolism in the right amygdala. es of the brain.
The amygdala is probably responsible for extinction Behavioral therapy for OCD consists of exposure
of sensory and cognitive associations to original trauma and response prevention interventions. Exposure con-
and activation of traumatic memories. This would ex- sists of asking the patient to interact with stimuli that
plain increased activity of the amygdala in PTSD. Ex- result in the obsession or ritualistic behavior. Response
tinction is the process through which the strength of a prevention consists of delaying, diminishing, or discon-
conditioned response is weakened by repeated exposure tinuing anxiety-reducing rituals. The response preven-
to the conditioned stimulus in the absence of the uncon- tion principle is based on the idea that anxiety slowly
ditioned stimulus. Considerable evidence suggests that decreases when the performance of the ritual is blocked.
extinction of conditioned fear does not occur passively; When anxiety reduction no longer depends on the ritu-
that is, the memory persists in the absence of explicit als, the ritual compulsion will be extinguished. Current
extinction training, and when extinction occurs it is not research in animals and humans has demonstrated that
passive forgetting but instead is an active process involv- neurochemical changes due to behavioral interventions
ing new learning.117 Data from studies of emotional con- are similar to the effects of pharmacologic therapies.122
J Psychother Pract Res, 8:2, Spring 1999 109
Neurobiology and Psychotherapy
Especially in the treatment of OCD, there is over- hallucinations develop.132
whelming evidence that behavior therapy is capable of It has been hypothesized that delusions and related
producing changes in brain chemistry that may be similar phenomena arise from some disturbance of the cognitive
to the effects of serotonergic medications.123 Investiga- machinery of belief, memory, and their associated neural
tors found that 3 weeks of intensive behavior therapy representations.18,133 Delusions are characterized by an
had an effect on serotonin activity as measured by imip- aberrant belief plus a gradual spreading of the belief sys-
ramine binding and changes in platelet serotonin level.124 tem to incorporate new information as the disease prog-
owever, the major neurobiological evidence comes from resses. It is as if the associations between ideas that form
two recent studies using PET conducted by Baxter et the framework of a normal belief system had become so
al.56 and replicated by Schwartz et al.57 The findings of immutable that the usual processes of assimilation and
Baxter et al.56 provided evidence that glucose metabolic incorporation of new information can no longer operate.
rates in the right head of the caudate nucleus change This observation leads to the hypothesis that mecha-
when OCD is treated successfully with either fluoxetine nisms of synaptic plasticity may be abnormal in these
or behavior therapy. Schwartz et al.57 found that after patients.
successful behavior modification, there is significant bi- The increasing empirical support for a limbic sub-
lateral decrease in glucose metabolism in the caudate strate of schizophrenic symptomatology is based on three
nucleus. These studies are significant because they con- factors:
firm that behavior therapy can cause neurochemical
changes in the brain. 1. Anatomical, physiological, pharmacological, and
behavioral findings are most consistent with the view
that neuropathological changes within the limbic
SCHIZOPHRENIA AS A LIFETIME DISORDER OF
system, specifically within the hippocampal forma-
BRAIN PLASTICITY
tion, may represent a biological substrate of schizo-
phrenia.132
Chronic schizophrenia is characterized by change in the
normal cortical structure of the brain, asymmetric reduc- 2. The biological mechanism underlying transient psy-
chosis may be long-term potentiation of synaptic
tion, and often ventricular enlargement.125 129 The de-
bate continues as to whether these anomalies occur early transmission within the hippocampal formation.132
in development or represent an active, progressive pro- 3. The effects of dopamine manipulation on these be-
haviors may be mediated by direct actions on the
cess continuing after the onset of psychosis. DeLisi130
proposes that the underlying basis for the neuropa- compromised limbic system of the psychotic pa-
tient.133
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 Defect or negative symptoms, which apparently do not
maldevelopment prenatally and through early child- respond well to neuroleptic treatment134 but do respond to
hood, is activated again during adolescent pruning of atypical antipsychotics, have been proposed to reflect fron-
neurons, and again during the gradual aging process in tal lobe dysfunction.135 These symptoms may be attribut-
the brain throughout adulthood. able to changes in prefrontal cortex metabolism that are
Structural change in the hippocampal formation has secondary to limbic pathology.136 Conceivably, then, hip-
become popular as a proposed neurobiological substrate pocampal dysfunction could be directly responsible for
for schizophrenic disorders. Hippocampal function is positive symptoms and indirectly involved, via frontal pro-
particularly sensitive to neurochemical modulation, and jections, in the negative symptoms.132
the expression of monoamine receptors in the temporal The implications of this theoretical framework sup-
lobe is altered in schizophrenic patients.131 An attractive port psychotherapeutic interventions in the treatment of
proposal is that behavioral plasticity, in the form of long- schizophrenia. There is a growing body of literature pro-
term potentiation of hippocampal synaptic transmission, moting cognitive-behavioral therapies aimed at the
may mediate transient psychosis.132 Moreover, the dis- modification of delusions. Psychological approaches to
turbed hippocampal neuroarchitecture found in schizo- treatment-resistant symptoms of psychosis all emphasize
phrenic patients may be susceptible to potentiation and the importance of normalization of even the most bizarre
may be dysfunctional to the degree that delusions and personal experiences. Although antipsychotic drugs are
110 J Psychother Pract Res, 8:2, Spring 1999
Liggan and Kay
generally successful at attenuating behavioral dysfunc- alter the structure and function of nerve cells and their
tion in schizophrenic patients, prevention of further ac- connections. Further studies revealed changes in cortical
crual of hippocampal damage would also be beneficial. thickness, size of synaptic contacts, number of dendritic
Given the prominent role of stress and related hormones spines, and dendritic branching, constituting a mecha-
in the degeneration of hippocampal pyramidal neurons, nism by which psychotherapy facilitates changes in the
it may be advantageous for at-risk persons to minimize permanent storage of memory. Psychotherapy alters the
the level of environmental stress and maximize their ca- neurochemistry and physiology of the brain by provid-
pacity to cope adaptively with stressors. Hogarty et al.137 ing a stimulus that leaves a memory trace. Neural net-
devised a disorder-relevant and disorder-specific therapy work research and memory research have proceeded in
for schizophrenia. Four key fundamentals of this personal parallel to elucidate the theoretical properties of ideal
therapy are 1) theoretical grounding in the stress-vulner- neural networks and the actual properties of information
ability model; 2) consideration of stress-related dysregu- storage in the brain. Long-term potentiation serves as a
lation as proximate to symptom exacerbation; 3) sequen- model of activity-dependent synaptic plasticity proposed
tial use of interventions of graded complexity based on to underlie memory.
the patient s stage of recovery; and 4) flexible use of a The study of learning and memory not only brings
range of therapeutic techniques to accommodate the in- us closer to understanding how psychotherapy pro-
dividual needs, deficits, and preferences of patients with duces emotional and behavioral changes in patients,
this heterogeneous disorder. Goals include developing but also gives us new perspectives on psychiatric dis-
self-recognition of the links between stresses, maladap- orders involving the inability to control fear, obses-
tive responses, the reactions of others, and symptoms. sions, compulsions, and delusions. We anticipate that
more direct evidence of links between neurobiology
SUMMARY
and the psychotherapeutic processes will be available
as neurobiologists and psychotherapists collaborate on
Supporting Hebb s 1949 hypothesis of use-induced plas-
future studies.
ticity of the nervous system, learning has been found to
REFERENCES
1. Ramón y Cajal SR: Histologie du systŁme nerveux de l homme et projections from thalamocortical neurons to the SI cortex of the
des vertŁbres, vol 2 (1911), translated by Azoulay L. Madrid, In- cat demonstrated by the use of intracortical microstimulation. So-
stituto Ramón y Cajal, 1952 matosensory Research 1988; 5:349 372
2. Hebb DO: The Organization of Behavior. New York, Wiley, 1949 10. Buonomano DV, Merzenich MM: Cortical plasticity: from syn-
3. Andersen P, Sundberg SH, Sveen O, et al: Specific long-lasting apses to maps. Annu Rev Neurosci 1998; 21:149 186
potentiation of synaptic transmission in hippocampal slices. Nature 11. Cansino S, Williamson SJ: Neuromagnetic fields reveal cortical
1977; 266:736 737 plasticity when learning an auditory discrimination task. Brain Res
4. Bliss TVP, Lomo T: Long-lasting potentiation of synaptic transmis- 1997; 764(1 2):53 66
sion in the dentate area of the anaesthetized rabbit following stimu- 12. Davis M: The role of the amygdala in fear and anxiety. Annu Rev
lation of the perforant path. J Physiol (Lond) 1973; 232:331 356 Neurosci 1992; 15:353 375
5. Morris RGM: Does synaptic plasticity play a role in learning in the 13. Kesner RP, Walser R, Winzenfried G: Central but not basolateral
vertebrate brain? In Parallel Distributed Processing: Implications amygdala mediates memory for positive affective experiences. Be-
for Psychology and Neurobiology, edited by Morris RGM. Oxford, hav Brain Res 1989; 33:189 195
Clarendon, 1989, pp 248 285 14. LeDoux JE: Brain mechanisms of emotion and emotional learning.
6. Clark SA, Allard R, Jenkins WM, et al: Receptive fields in the body Current Opinions in Neurobiology 1992; 2:191 198
surface map in adult cortex defined by temporally correlated in- 15. LeDoux JE: Emotion: clues from the brain. Annu Rev Psychol
puts. Nature 1988; 332:444 445 1995; 46:209 235
7. Kaas JH, Nelson RJ, Sur M, et al: Multiple representations of the 16. Barnes CA: Memory deficits associated with senescence: a neuro-
body within the primary somatosensory cortex of primates. Science physiological and behavioral study in the rat. Journal of Compara-
1979; 204:521 523 tive Physiology and Psychology 1979; 93:74 104
8. Merzenich MM: Sources of intraspecies and interspecies cortical 17. Deupree D, Turner D, Watters C: Spatial performance correlates
map variability in mammals: conclusions and hypotheses, in Com- with in vitro potentiation in young and aged Fischer 344 rats. Brain
parative Neurobiology: Modes of Communication in the Nervous Res 1991; 544:1 9
System, edited by Cohen MJ, Strumwasser F. New York, Wiley, 18. Jeffery KJ, Morris RGM: Cumulative long-term potentiation in the
1985, pp 105 116 rat dentate gyrus correlates with but does not modify performance
9. Snow PJ, Nudo RJ, Rivers W, et al: Somatotopically inappropriate in the water maze. Hippocampus 1993; 3:133 140
J Psychother Pract Res, 8:2, Spring 1999 111
Neurobiology and Psychotherapy
19. Laroche S, Doyere V, Bloch V: Linear relation between the mag- Press, 1987
nitude of long-term potentiation in the dentate gyrus and associative 43. Kupfermann I, Kandel ER: Neuronal controls of a behavioral re-
learning in the rat: a demonstration using commissural inhibition sponse mediated by the abdominal ganglion of Aplysia. Science
and local infusion of an N-methyl-D-aspartate receptor antagonist. 1969; 164:847 850
Neuroscience 1989; 28:375 386 44. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science,
20. Marren S, Patel K, Thompson RF, et al: Individual differences in 3rd edition. New York, Elsevier, 1995
emergence neophobia predict magnitude of perforant-path long- 45. Krasne FB, Glanzman DL: What we can learn from invertebrate
term potentiation (LTP) and plasma corticosterone levels in rats. learning. Annu Rev Psychol 1995; 46:585 624
Psychobiology 1993; 21:2 10 46. Bernibeu R, Stein ML, Fin C, et al: Role of hippocampal NO in
21. Morris RGM, Andersen E, Lynch G, et al: Selective impairment the acquisition and consolidation of inhibitory avoidance learning.
of learning and blockade of long-term potentiation by an N-methyl- Learning and Memory 1995; 6:1498 1500
D-aspartate receptor antagonist, AP5. Nature 1986; 319:774 776 47. Alkon DL, Sakakibara M, Naito S, et al: The role of neurochemical
22. Bliss TVP, Collingridge GL: A synaptic model of memory: long- modulation in learning. Neurosci Res 1986; 3:487 498
term potentiation in the hippocampus. Nature 1993; 361:31 39 48. Lavond D, Kim JJ, Thompson RF: Mammalian brain substrates of
23. Post RM, Weiss SR: Emergent properties of neural systems: how aversive conditioning. Annu Rev Psychol 1993; 44:317 342
focal molecular neurobiological alterations can affect behavior. 49. Wang JH, Ko GY, Kelly PT: Cellular and molecular bases of mem-
Dev Psychopathol 1997; 9:907 929 ory: synaptic and neuronal plasticity. J Clin Neurophysiol 1997;
24. Bear MF: A synaptic basis for memory storage in the cerebral cor- 14:264 293
tex. Proc Natl Acad Sci USA 1996; 93:13453 13459 50. White SA, Fernald RD: Changing through doing: behavioral in-
25. Jeffery KJ, Reid IC: Modifiable neuronal connections: an overview fluences on the brain. Recent Prog Horm Res 1997; 52:455 473
for psychiatrists. Am J Psychiatry 1997; 154:156 164 51. Schacter DL: Implicit memory: history and current status. J Exp
26. Goda Y, Stevens CF: Synaptic plasticity: the basis of particular Psychol 1987; 13:501 518
types of learning. Curr Biol 1996; 6:375 378 52. Rosenblum LA, Coplan JD, Friedman S, et al: Adverse early ex-
27. Squire LR, Ojemann JG, Miezin FM, et al: Activation of the hip- periences affect noradrenergic and serotonergic functioning in
pocampus in normal humans: a functional anatomical study of adult primates. Biol Psychiatry 1994; 35:221 227
memory. Proc Natl Acad Sci USA 1992; 89:1837 1841 53. Reite M, Capitanio JP: On the nature of social separation and social
28. Paller KA: Recall and stem-completion priming have different elec- attachment, in The Psychobiology of Attachment and Separation,
trophysiological correlates and are modified differently by directed edited by Reite M, Field T. New York, Academic Press, 1985
forgetting. J Exp Psychol Learn Mem Cogn 1990; 16:1021 1032 54. Greenough WT, Withers GS, Wallace CS: Morphological changes
29. Bondi MW, Kaszniak AW: Implicit and explicit memory in Alz- in the nervous system arising from behavioral experience: what is
heimer s disease and Parkinson s disease. J Clin Exp Neuropsychol the evidence they are involved in learning and memory? In The
1991; 13:339 358 Biology of Memory, edited by Squire LR, Lindenlaub E. Stuttgart,
30. Squire LR, Knowlton B, Musen G: The structure and organization Schattauer, 1990, pp 159 185
of memory. Annu Rev Psychol 1993; 44:453 495 55. Martinez JL, Derrick BE: Long-term potentiation and learning.
31. Bruner JS, Postman L: Emotional selectivity in perception and re- Annu Rev Psychol 1996; 47:173 203
action. J Pers 1947; 16:69 77 56. Baxter LR, Schwartz JM, Bergman KS, et al: Caudate glucose me-
32. Eslinger PJ, Damasio AR: Preserved motor learning in Alzheimer s tabolism rate changes with both drug and behavior therapy for
disease: implications for anatomy and behavior. J Neurosci 1986; obsessive-compulsive disorder. Arch Gen Psychiatry 1992;
6:3006 3009 49:681 689
33. Grosse DA, Wilson RS, Fo JH: Maze learning in Alzheimer s dis- 57. Schwartz J, Stoessel P, Baxter L, et al: Systematic changes in cere-
ease. Brain Cogn 1991; 15:1 9 bral glucose metabolic rate after successful behavior modification
34. Knopman D, Nissen MJ: Procedural learning is impaired in Hunt- treatment of obsessive compulsive behavior. Arch Gen Psychiatry
ington s disease: evidence from the serial reaction time task. 1996; 53:109 113
Neuropsychologia 1991; 29:245 254 58. van der Kolk BA: The psychobiology of posttraumatic stress dis-
35. Kunst-Wilson WR, Zajonc RB: Affective discrimination of stimuli order. J Clin Psychiatry 1997; 58(suppl 9):16 24
that cannot be recognized. Science 1980; 207:557 558 59. Viinamaki H, Kuikka J, Tiihonnen J, et al: Changes in monoamine
36. Levin HS: Memory deficit after closed head injury. J Clin Exp transport density related to clinical treatment: a case controlled
Neuropsychol 1989; 12:129 153 study. Nordic Journal of Psychiatry 1998; 55:39 44
37. Reber AS: Implicit learning and tacit knowledge. J Exp Psychol 60. Pastukhov VA, Bolondinskii VK: Participation of serotonergic
Gen 1989; 118:219 235 mechanisms in the regulation of visceral functions during condi-
38. Schacter DL: Implicit knowledge: new perspectives on uncon- tioned reflex activity. Fiziol Zh 1985; 71:688 693
scious processes. Proc Natl Acad Sci USA 1992; 89:11113 11117 61. Bolondinskii V: Relation between the level of conditioned reflex
39. Schacter DL, Chiu CY, Ochsner KN: Implicit memory: a selective activity and concentration of serotonin in the blood of normal and
review. Annu Rev Neurosci 1993; 16:159 182 neurotic dogs. Zh Vyssh Nerv Deiat Im I P Pavlova 1984; 34:339
40. Amini F, Lewis T, Lannon R, et al: Affect, attachment, memory: 344
contributions toward psychobiologic integration. Psychiatry 1996; 62. Baer L: Behavior therapy: endogenous serotonin therapy? J Clin
59:213 239 Psychiatry 1996; 57(suppl 6):33 35
41. Castellucci VF, Carew TJ, Kandel ER: Cellular analysis of long- 63. Joffe R, Segal Z, Singer W: Change in thyroid hormone levels fol-
term habituation of the gill-withdrawal reflex of Aplysia californica. lowing response to cognitive therapy for major depression. Am J
Science 1978; 202:1306 1308 Psychiatry 1996; 153:411 413
42. Kandel ER, Schacher S, Castelluci VF, et al: The long and short 64. Bogerts B: Plasticity of brain structure and function as the neuro-
of memory in Aplysia: a molecular perspective, in Fidia Research biological principle of psychotherapy. Zeitschrift f�r Klinische Psy-
Foundation Neuroscience Award Lectures. Padua, Italy, Liviana chologie, Psychiatrie und Psychotherapie 1996; 44:243 252
112 J Psychother Pract Res, 8:2, Spring 1999
Liggan and Kay
65. Andersen P, Moser E, Moser MB, et al: Cellular correlates to spatial 92. Kohut H: The psychoanalytic treatment of narcissistic personality
learning in the rat hippocampus. J Physiol Paris 1996; 90(5 6):349 disorders: outline of a systematic approach. Psychoanal Study
66. Schrott LM: Effect of training and environment on brain morphol- Child 1968; 23:86 113
ogy and behavior. Acta Paediatr 1997; 422(suppl):45 47 93. Watt DF: Higher cortical functions and the ego: explorations of
67. Kolb B, Whishaw IQ: Brain plasticity and behavior. Annu Rev the boundary between behavioral neurology, neuropsychology,
Psychol 1998; 49:43 64 and psychoanalysis. Psychoanalytic Psychology 1990; 7:487 527
68. Byrne JH: Cellular analysis of associative learning. Physiology Re- 94. Tucker DM: Lateral brain function, emotion, and conceptualiza-
view 1987; 67:329 439 tion. Psychol Bull 1981; 89:19 46
69. Brown TH, Kairiss EW, Keenan CL: Hebbian synapses: biophysi- 95. Gottschalk LA, Fronczek J, Buchsbaum MS: The cerebral neuro-
cal mechanisms and algorithms. Annu Rev Neurosci 1990; 13:475 biology of hope and hopelessness. Psychiatry 1993; 56:270 281
511 96. Thompson RF, Berger TW, Madden J: Cellular processes of learn-
70. Tyler T, Aronadou V, Berry RL, et al: LTP in neocortex. Seminars ing and memory in the mammalian CNS. Annu Rev Neurosci 1983;
in Neuroscience 1990; 2:365 379 6:447 491
71. Madison DV, Malenka RC, Nicoll RA: Mechanisms underlying 97. Reiman EM, Lane RD, Ahern GL, et al: Neuroanatomical corre-
long-term potentiation of synaptic transmission. Annu Rev Neuro- lates of externally and internally generated human emotion. Am J
sci 1991; 14:379 397 Psychiatry 1997; 154:918 925
72. Tsumoto T: Long-term potentiation and long-term depression in 98. Gabriel M, Slatwick SE, Miller JD: Multiple unit activity of the
the neocortex. Prog Neurobiol 1992; 39:209 228 rabbit medial geniculate nucleus in conditioning, extinction, and
73. Bear MF, Kirkwood A: Neocortical long-term potentiation. Curr reversal. Physiological Psychology 1976; 4:124 134
Opin Neurobiol 1993; 3:197 202 99. Ryugo DK, Weinberger NM: Differential plasticity of morphologi-
74. Linden DJ, Connor JA: Long-term synaptic depression. Annu Rev cally distinct neuron populations in the medial geniculate body of
Neurosci 1995; 18:319 357 the cat during classical conditioning. Behavioral Biology 1978;
75. Bear MF, Abraham WC: Long-term depression in the hippocam- 22:275 301
pus. Annu Rev Neurosci 1996; 19:437 462 100. Edeline JM, Weinberger NM: Associative retuning in the thalamic
76. Katz LC, Shatz CJ: Synaptic activity and the construction of cortical source of input to the amygdala and auditory cortex: receptive field
circuits. Science 1996; 274:1133 1138 plasticity in the medial division of the medial geniculate body. Be-
77. Cohen LJ, Stein D, Galynker I, et al: Towards an integration of hav Neurosci 1992; 106:81 105
psychological and biological models of obsessive compulsive dis- 101. Weinberger NM, Diamond DM: Physiological plasticity in audi-
order: phylogenetic considerations. CNS Spectrums 1997; tory cortex: rapid induction by learning. Progressive Neurobiology
2(10):26 44 1987; 29:1 55
78. Rosenzweig MR: Aspects of the search for neural mechanisms of 102. Edeline JM, Weinberger NM: Receptive field plasticity in the audi-
memory. Annu Rev Psychol 1996; 47:1 32 tory cortex during frequency discrimination training: selective re-
79. Foa EB, Steketee G, Ozarow BJ: Behavior therapy with obsessive tuning independent of task difficulty. Behavioral Neuroscience
compulsives, in Obsessive-Compulsive Disorder, edited by Mav- 1993; 107:82 103
issakalian M, Turner SM, Michelson L. New York, Plenum, 1985, 103. LeGal LaSalle G, Ben-Ari Y: Unit activity in the amygdaloid com-
pp 49 129 plex: a review, in The Amygdaloid Complex, edited by Ben-Ari
80. Soubrie P: Reconciling the role of central serotonin neurones in Y. New York, Elsevier/North-Holland, 1981, pp 227 237
human and animal behavior. Behav Brain Sci 1986; 9:319 364 104. Pascoe JP, Kapp BS: Electrophysiological characteristics of
81. Gray JA: The Psychology of Fear and Stress. New York, Cambridge amygdaloid central nucleus neurons during Pavlovian fear condi-
University Press, 1987 tioning in the rabbit. Behav Brain Res 1985; 16:117 133
82. Stein DJ, Shoulberg N, Helton K, et al: The neuroethological ap- 105. Ono T, Nakamura K, Nishijo H, et al: Lateral hypothalamus and
proach to obsessive-compulsive disorder. Compr Psychiatry 1992; amygdala involvement in rat learning behavior. Advances in Bios-
33:274 281 cience 1988; 70:123 126
83. Beck AT, Friedman A: Cognitive Therapy of Personality Disorders. 106. LeDoux JE: Emotion, in Handbook of Physiology, edited by
New York, Guilford, 1990 Mountcastle NB, Plum F, Geiger SR. Bethesda, MD, American
84. Beck AT: Cognitive Therapy and the Emotional Disorders. New Physiological Society, 1987, pp 419 459
York, International Universities Press, 1976 107. LeDoux JE: Information flow from sensation to emotion: plasticity
85. Rush AJ (ed): Short-term Psychotherapies for Depression. New in the neural computation of stimulus value, in Learning and Com-
York, Guilford, 1982 putational Neuroscience: Foundations of Adaptive Networks, ed-
86. Karasu TB (ed): Psychosocial Therapies: Section II of The Psychi- ited by Garriel M, Moore J. Cambridge, MA, MIT Press, 1990, pp
atric Therapies. Washington, DC, American Psychiatric Associa- 3 52
tion, 1984 108. Davis M, Hitchcock JM, Rosen JB: Anxiety and the amygdala:
87. Greenspan S: The Development of the Ego: Implications for Per- pharmacological and anatomical analysis of the fear-potentiated
sonality Theory, Psychopathology, and the Psychotherapeutic Pro- startle paradigm, in The Psychology of Learning and Motivation,
cess. Madison, CT, International Universities Press, 1989 edited by Bower GH. San Diego, CA, Academic Press, 1987, pp
88. Mahler M, Pine F, Bergman A: The Psychological Birth of the 21:263 305
Human Infant. New York, Basic Books, 1975 109. Kapp BS, Pascoe JP, Bixler MA: The amygdala: a neuroanatomical
89. Stern D: The Interpersonal World of the Infant. New York, Basic systems approach to its contributions to aversive conditioning, in
Books, 1986 Neuropsychology of Memory, edited by Buttlers N, Squire LR.
90. Fast I, Marsden G, Cohen L, et al: The self as subject: a formulation New York, Guilford, 1984, pp 473 488
and assessment strategy. Psychiatry 1996; 59:34 47 110. Kapp BS, Wilson A, Pascoe J, et al: A neuroanatomical systems
91. Mitchell SA: Relational Concepts in Psychoanalysis: An Integra- analysis of conditioned bradycardia in the rabbit, in Learning and
tion. Cambridge, MA, Harvard University Press, 1988 Computational Neuroscience: Foundations of Adaptive Networks,
J Psychother Pract Res, 8:2, Spring 1999 113
Neurobiology and Psychotherapy
edited by Gabriel M, Moore J. Cambridge, MA, MIT Press, 1990, 122. Neziroglu F, Hsia C: Reconceptualization of behavior therapy for
pp 53 90 obsessive-compulsive disorder from a learning and neurochemical
111. Kapp BS, Whalen PJ, Supple WF, et al: Amygdaloid contributions perspective. CNS Spectrums 1998; 3:47 53
to conditioned arousal and sensory information processing, in The 123. Baer L: Behavior therapy: Endogenous serotonin therapy? J Clin
Amygdala: Neurobiological Aspects of Emotion, Memory, and Psychiatry 1996; 57(suppl 6):33 35
Mental Dysfunction, edited by Aggleton JP. New York, Wiley-Liss, 124. Neziroglu F, Yaryura-Tobias JA: Over and Over Again: Under-
1992, pp 229 254 standing Obsessive-Compulsive Disorder, revised edition. New
112. Gentile CG, Jarrell TW, Teich A, et al: The role of amygdaloid York, Lexington Books, 1995
central nucleus in the retention of differential Pavlovian condition- 125. Benes FM, Sorenson I, Bird ED: Reduced neuronal size in posterior
ing of bradycardia in rabbits. Behav Brain Res 1986; 20:263 273 hippocampus of schizophrenic patients. Schizophr Bull 1991;
113. Maren S: Synaptic transmission and plasticity in the amygdala: an 17:597 608
emerging physiology of fear conditioning circuits. Mol Neurobiol 126. Conrad AJ, Scheibel AB: Schizophrenia and the hippocampus: the
1996; 13:1 22 embryological hypothesis extended. Schizophr Bull 1987; 13:577
114. Adamec R: Transmitter systems involved in neural plasticity un- 587
derlying increased anxiety and defense: implications for under- 127. Jeste DV, Lohr JB: Hippocampal pathologic findings in schizo-
standing anxiety following traumatic stress. Neurosci Biobehav Rev phrenia. Arch Gen Psychiatry 1989; 46:1019 1024
1997; 21:755 765 128. Kovelman JA, Scheibel AB: A neurohistological correlate of schizo-
115. van der Kolk BA: Psychological Trauma. Washington, DC, Ameri- phrenia. Biol Psychiatry 1984; 19:1601 1621
can Psychiatric Press, 1987 129. Roberts GW, Bruton CJ: Notes from the graveyard: Neuropa-
116. Cahill L, Haier RJ, Fallon J, et al: Amygdala activity at encoding thology and schizophrenia. Neuropathol Appl Neurobiol 1990;
correlated with long-term, free recall of emotional information. 16:3 16
Proc Natl Acad Sci USA 1996; 93:8016 8021 130. DeLisi LE: Is schizophrenia a lifetime disorder of brain plasticity,
117. Bouton ME, Swartzentruber D: Sources of relapse after extinction growth and aging? Schizophr Res 1997; 23:119 129
in Pavlovian and instrumental learning. Clin Psychol Rev 1991; 131. Joyce JN: The dopamine hypothesis of schizophrenia: limbic in-
11:123 140 teractions with serotonin and norepinephrine. Psychopharmacol-
118. LeDoux JE, Romanski L, Xagoraris A: Indelibility of subcortical ogy 1993; 112:S16 S34
emotional memories. Journal of Cognitive Neuroscience 1989; 132. Port RL, Seybold KS: Hippocampal synaptic plasticity as a bio-
1:238 243 logical substrate underlying episodic psychosis. Biol Psychiatry
119. Jenike MA, Breiter HC, Baer L, et al: Cerebral structural abnor- 1995; 37:318 324
malities in obsessive compulsive disorder: a quantitative mor- 133. Spitzer M: A cognitive neuroscience view of schizophrenic thought
phometric magnetic resonance imaging study. Arch Gen disorder. Schizophr Bull 1997; 23:29 50
Psychiatry 1996; 53:625 632 134. Goldberg SC: Negative and deficit symptoms in schizophrenia do
120. Hoehn-Saric R, Benkelfat C: Structural and functional brain imag- not respond to neuroleptics. Schizophr Bull 1985; 11:453 456
ing in obsessive compulsive disorder, in Current Insights in Ob- 135. Fuster JM: The Prefrontal Cortex. New York, Raven, 1980
sessive Compulsive Disorder, edited by Hollander E, Zohar J, 136. Weinberger NM: Dynamic regulation of receptive fields and maps
Marazziti D. New York, Wiley, 1994, pp 183 214 in the adult sensory cortex. Annu Rev Neurosci 1995; 18:129 158
121. Baxter J, Schwartz J, Mazziotta J, et al: Cerebral glucose metabolic 137. Hogarty GE, Kornblith SJ, Greenwald D, et al: Personal therapy:
rates in nondepressed patients with obsessive compulsive disorder. a disorder-relevant psychotherapy for schizophrenia. Schizophr
Am J Psychiatry 1988; 145:1560 1563 Bull 1995; 21:379 393
114 J Psychother Pract Res, 8:2, Spring 1999