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The Neurobiology of Psychotherapy

October 22, 2015
Randon Welton, MD
Jerald Kay, MD
Publication Article

Psychiatric Times
Vol 32 No 10
Volume 32 Issue 10

An update on what happens in the brain when the mind is engaged in

psychotherapy.

Table 1. Main brain system involved in mediating attachment

TABLE 2. Main brain system involved in mediating empathy

A recent Institute of Medicine report acknowledges the efficacy

of a broad range of psychosocial interventions.1 It challenges
us to “identify key elements that drive an intervention’s effect.”
The report describes key clinical tasks such as the therapist’s
ability to engage with a patient, understand the patient’s
worldview, and help the patient manage his or her emotional
 TABLE 3. Main brain system involved in mediating learning

TABLE 4. Main brain system involved in mediating emotion

regulation

TABLE 5. Main brain system involved in mediating fear

extinction

responses. The psychiatric community should also look into the

neurobiological changes that accompany and may be
responsible for an intervention’s effect. Although early
psychoanalysts made little effort to connect functions of the
mind to definable portions of the brain, from the beginning
there was a belief that such a relationship may exist. Freud
confidently predicted that one day there would be a
neurological understanding of the work he initiated.

The deficiencies in our description would probably vanish if we

were already in a position to replace psychological terms by
physiological or chemical ones. Biology is truly a land of
unlimited possibilities. We may expect it to give us the most
surprising information and we cannot guess what answers it
will return in a few dozen years to the questions we have put to
it.2

Almost 100 years have passed since Freud wrote those words,
and many of his questions remain unanswered. Steady
progress, however, has been made in the development of a
neurobiological understanding of what happens in the brain
when the mind is engaged in psychotherapy. Advances in
cognitive neuroscience and neuroimaging have facilitated a
greater appreciation of the neuroanatomy and
neurophysiology of the CNS. The technology to study the real-
time functioning of the brain through measurement of blood
flow or glucose uptake, for example, has been widely used for
a quarter of a century. Numerous challenges endure, such as
subtle individual variations of neural circuitry, uncertainty as to
the proper area to study, and the possibility that differing
forms of therapy affect the brain differently. Within the
boundaries created by these limitations, however, there is an
emerging understanding of the neurobiological correlates of
some common psychotherapy elements.

Although different approaches utilize various terms and

concepts, there are some components that are found in most
forms of efficacious psychotherapy. There must be some
emotional engagement (attachment) between the patient and
therapist. The therapist will struggle to understand and express
the patient’s experience (empathy). By learning about
themselves and their environment, patients will decide to make
changes. As therapy continues, they will develop new abilities
to regulate their emotions. Many patients will be forced to face
and overcome feared relationships or situations (fear
extinction). There is a neurobiological literature developing on
each of these common components of psychotherapy.

Attachment

Forming nurturing attachments with others remains a

challenge throughout life especially for those with early
trauma. The neurochemistry of attachment involves the
neuropeptides oxytocin and arginine vasopressin. Both of
these messengers are released from the hypothalamus by
sexual stimulation and stress. In combination with estrogen,
oxytocin helps induce maternal behavior, while the absence of
oxytocin makes it more difficult for animals to adapt to social
settings and leads to abnormal displays of aggression. Infusing
or blocking oxytocin also causes dramatic changes in mating
behaviors. Arginine vasopressin has myriad effects on normal
mammals including altering displays of aggression and the
animal’s tendency to affiliate with or protect others.

In humans, oxytocin is associated with a number of factors that

affect attachment including trust, empathy, eye contact, and
generosity. Oxytocin infusions in healthy individuals tend to
decrease anxiety and the stress associated with social
situations while shifting attention from negative to positive
information. The reduction in distress appears related to a
reduction in activity in the amygdala. In a study of women with
borderline personality disorder, oxytocin infusion decreased
their amygdala activation when exposed to angry faces.3
Although the effect is mediated by past experiences, intra-
nasal infusion of oxytocin may increase an individual’s ability to
infer the mental state and intention of others based on their
facial expression. Oxytocin specifically aids in parent-child
bonding. Administering oxytocin to parents increases the social
engagement of the parent and child and leads to an increase in
oxytocin in the child.

The mu-opioid receptor also appears to be involved in

attachment. Activation of the mu-opioid receptor leads to a
general sense of pleasure as well as analgesia. In animal
models, removing the mother from the child leads to distress
that is at least partially mediated through mu-opioid activity.
Animals with an increased activation of the opioid system had
more attachment behaviors and louder and more prolonged
protests when separated. Their separation distress could be
partially reversed by non-sedating opioid agonists.4 Patients
with borderline personality disorder have differences in
baseline mu-opioid receptor concentrations and in the
endogenous opioid system response to negative emotional
challenges. These differences might be related to their difficulty
with emotion regulation.

Attachment therefore correlates with neurochemical changes

within the brain. This might be most evidenced in parent-child
interactions but may play a significant role in psychotherapy as
well. A study of mothers with postpartum depression
undergoing psychodynamic psychotherapy found that daily
infusions of oxytocin over 12 weeks were associated with a
decrease in narcissistic traits but not in depressive personality
traits or depressive symptoms.5 Depressed men who received
oxytocin infusions while in psychotherapy performed better on
tests of inferring the mental state of others but were more
likely to experience anxiety during the session.6 These findings
hint of a complex interaction between oxytocin and the
therapist-patient relationship (Table 1).

Empathy

Empathy entails the ability to consider the world from

another’s point of view and in some way to share his or her
emotional experiences. Neurobiological correlates of empathy
were first described in the early 1990s with the discovery of
mirror neurons. Researchers who were studying the neuronal
activity involved in organizing and monitoring movements
noted that some of the same premotor cortex neurons were
activated while observing others make corresponding
movements.7,8 Neurons that were activated when a monkey
grabbed food were activated when the researcher grabbed
food but not when the researcher pushed or struck the food.
These neurons were referred to as mirror neurons.
Mirror neurons in humans are not limited to simple
movements. Watching dance leads to activation in the brains
of other dancers. Greater activation occurs when dancers watch
movements they already know. Mirror neurons activate while
watching facial expressions and seem to be partially impaired
in individuals with autistic disorders. Human mirroring
networks also exist for pain and emotional distress.
Researchers created pain by sticking subjects with a needle and
monitored which areas of the brain were activated.9 Similar
pathways were activated when the researchers brought the
needle close to the subject but did not make contact and when
subjects watched researchers pricking their own fingers.
Witnessing others display disgust activates many of the same
areas that are activated when one smells an unpleasant odor.

Mirroring neurons also fire when observing others being

rejected or embarrassed. The areas most involved in mirroring
physical pain, emotional distress, and social discomfort are the
anterior cingulate cortex and insula. These areas help
individuals automatically imagine themselves experiencing
what they witness others experiencing. It should be noted that
the studies of mirror neurons in humans are preliminary and
not without controversy.

The posterior portions of the superior temporal sulcus have

similar activities. This region activates when witnessing social
behavior and predicting future actions. When a figure is
walking toward you, activation of the superior temporal sulcus
is greater when the figure is looking at you, which indicates the
prospect of an upcoming interaction. Activation also increases
when the other person’s behavior is different than expected.

In a study by Wyk and colleagues,10 an actor displayed

pleasure or disgust to one of two identical objects and then
randomly picked up one of the objects. When there was
incongruent action (picking the object after showing disgust or
not picking the object after a display of pleasure), there was
increased activity in the observer’s posterior superior temporal
sulcus region.

Experiencing empathy appears to require proper activation of

portions of the insula and anterior cingulate cortex as we seek
to understand the emotional experience of others. A properly
functioning posterior superior temporal sulcus allows us to
determine and predict the social actions of others, and will
tend to activate when someone violates societal expectations.

Oxytocin and arginine vasopressin are also implicated in

empathy. A study of polymorphisms in the genes of 367 young
adults found that variations in the emotional aspect of
empathy were associated with the oxytocin receptor gene,
while the cognitive aspect of empathy was associated with the
gene for the arginine vasopressin 1a receptor.11 A highly
complex interaction of neurotransmitters and brain activation
allows the therapist to understand the patient’s experience
(Table 2).

Learning

Early in the 20th century Cajal proposed that the brain stored
information by modifying neuronal connections. Learning
involved changing individual neurons and their connections
with each other. In the mid-20th century Hebb proposed his
rule stating that when one neuron’s repeated excitation is
involved in the excitation of a neighboring neuron, the
connection between the two of them grows more efficient. Put
colloquially, “Neurons that fire together wire together.” This
implies that synapses change over time.

The first demonstration of this in the hippocampus occurred in

1973. After exposing neurons to strong, high-frequency
stimulation, their connection to other neurons in the
hippocampus became stronger.12 The discovery of
hippocampal neurogenesis established the process of neuronal
plasticity and upended the long-held belief that CNS cells were
neurophysiologically and neuroanatomically incapable of
growth.

Using the California sea slug (Aplysia californica), Kandel13

demonstrated that habituation-a decrease in response to a
stimulus-could be attained with a single training session of 10
stimulations. These effects lasted minutes to hours and
appeared to be a result of changes in the amount of
neurotransmitter released with the stimulation. Training
sessions on 4 consecutive days resulted in an effect that lasted
weeks. This long-term learning was associated with changes in
interneuronal connections.

Preliminary studies in humans have found measurable changes

in the brain based on learning stemming from juggling and
playing video games.14,15 Experimental data demonstrate that
the neurons in the brain are capable of learning-induced
change. Psychotherapy includes components of experiential
and didactic learning that is expected to create change in the
patient’s brain. Many psychotherapies focus on thoughts or
patterns that are initially outside the awareness of the patient.
Therapy creates new memories to modify older, dysfunctional
ones and in some cases creates new psychic structures. This
learning must involve changes in interneuronal connections
(Table 3).

Emotion regulation

Patients in psychotherapy are taught to understand, accept, or

manage their emotional responses in new ways. Researchers
are looking into how emotion regulation modifies brain
activity. One common strategy for altering emotions is
reappraisal, when the individual deliberately tries to alter the
meaning or relevance of an event. Reappraisal strategies link
cognitive control with emotional experience. Attempts to
deliberately decrease aversive emotions, sadness, and sexual
arousal through cognitive reappraisal have found that
reappraisal strategies most commonly activate multiple areas
within the prefrontal cortex and posterior parietal cortex.
Activation of these areas during reappraisal leads to decreased
activity in portions of the amygdala. These studies have
demonstrated specific neuronal circuitry, for example, between
the hippocampus, prefrontal cortex, and amygdala, which are
strengthened by psychotherapeutic treatment.16,17

Suppression, an intentional attempt to minimize the display of

emotions, may also decrease the intensity of emotions.
Subjects were asked to suppress their emotions while
observing sad pictures. When suppressing their emotions,
there was an increase in activity in the right orbitofrontal and
dorsolateral prefrontal cortices.18 Other studies have found
activation of the dorsal anterior cingulate cortex, dorsomedial
prefrontal cortex, and lateral prefrontal cortex with
suppression.19

Cognitive reappraisal and suppression seem to have distinctly

different neurophysiological mechanisms. In a head-to-head
study both strategies were successful at decreasing subjective
emotional experience, but there were differences in brain
activation.20 Reappraisal led to increased activity in the
prefrontal cortex and decreased activity in the right amygdala
and left insula. Suppression increased activity in the right
ventral-lateral prefrontal cortex but did not decrease activity in
the amygdala or insula (Table 4).

Fear extinction

Learning to be afraid, or fear conditioning, involves pairing a

previously innocuous stimulus (conditioned stimulus) with an
aversive stimulus (unconditioned stimulus). The mind begins to
associate the previously benign stimulus with the unpleasant
one, and the individual experiences heightened anxiety
whenever presented with the new conditioned stimulus. The
process of fear conditioning involves interactions of the
amygdala, insula, anterior cingulate cortex, and medial
prefrontal cortex.

The process of unlearning fear is known as fear extinction. Fear

extinction does not consist of erasing old memories; rather it is
the creation of new, benign associations. The underlying fear is
still present, but successful fear extinction leads to a reduction
in the amplitude and likelihood of a fearful response. This
occurs when the once feared stimulus or situation no longer
brings about any adverse consequences. Fear extinction is a
principal therapeutic component of exposure therapies for
specific phobias and for PTSD, but learning to confront feared
memories, situations, and people can be found in a broad
range of psychotherapies.

Fear extinction requires a functional ventral-medial prefrontal

cortex, rostral anterior cingulate cortex, and hippocampus.
Activation of these regions leads to decreased amygdala
activity. Clinical studies have demonstrated that the addition of
D-cycloserine, a partial N-methyl-D-aspartate (NMDA)
glutamate agonist, may improve outcomes in exposure-based
therapies for acrophobia and social phobias.21 Conversely,
NMDA antagonists, by decreasing NMDA activity, can inhibit
the formation of long-term fear extinction.

While decreasing the activity in the amygdala leads to an acute

reduction in perceived fear, the long-term persistence of fear
extinction requires the activity of the ventral-medial prefrontal
cortex and rostral anterior cingulate cortex. These appear to be
vital in connecting the cognitive and emotional experiences
and solidifying the learning.

The hippocampus aids in fear extinction by placing events into

a context. This context helps determine how generally the brain
applies the new learning. Because the previous fear is not
erased, when the individual encounters the once feared stimuli
there is activation of both the fearful and fear extinguished
pathways. The context, provided by interactions between the
hippocampus and ventromedial prefrontal cortex, determines
which set of behaviors is predominately activated (Table 5).
The work of the psychotherapist is to help solidify the most
healthy and adaptive responses.

Prediction of response to psychotherapy

Studies have begun to examine the ability to predict a patient’s

response to psychotherapy based on neurobiological factors.
One of the many changes that occur with depression is the
elevation of metabolism in the posterior insula. Studies have
found that changes in connectivity and activation of the insula
predicted a positive response to psychotherapy in patients with
depression.22-24 Another study found that increased
metabolism in the subcollasal cingulate cortex and superior
temporal sulcus was associated with no response to
escitalopram or cognitive-behavior therapy treatment for
depression.25

Conclusion

Although a precise description of the neurophysiological

changes that occur during psychotherapy is currently
impossible, it is likely that future imaging and neurobiological
investigation will elucidate this process. The neurobiological
correlates to many of the common elements of psychotherapy
such as attachment, empathy, memory, learning, emotional
regulation, and fear extinction are emerging. While we still
cannot answer all of Freud’s questions, or our own questions,
the artificial dichotomy between the functioning of the mind
and brain during psychotherapy seems less imposing.

Disclosures:

Dr Welton is Associate Professor of Psychiatry and Director of

Residency Training and Dr Kay is Emeritus Professor of
Psychiatry, Boonshoft School of Medicine, Wright State
University, Dayton, OH. The authors report no conflicts of
interest concerning the subject matter of this article.

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